Patent Application
20210121426
The present invention relates to blood purification by an alkalinizing agent.
The number of patients with end-stage kidney disease (ESKD) who require dialysis and transplantation is increasing worldwide. The number has tended to increase also in Japan, and the number of dialysis patients at the end of 2014 was 320,000.
Chronic kidney disease (CKD) is recognized to be likely to get ESKD. CKD is a concept encompassing kidney disease that chronically progresses regardless of the underlying disease, and is a concept encompassing all clinical conditions in which kidney function indicated by glomerular filtration rate (GFR) deteriorates, or findings that suggest damage in kidneys is maintained chronically (3 months or longer). Because CKD has not only a risk of progression to ESKD, but also a strong risk of developing into cardiovascular disease (CVD) etc., it is very important to detect CKD in early stages and perform appropriate treatment. Many CKD treatment methods have been established so far, but they are still insufficient, and further development of nephroprotective agents is required.
In CKD, various uremic substances accumulate in the body as renal clearance decreases. Among them, a concentration of indoxyl sulfate, which is a metabolic end-product of tryptophan, in blood increases with progression of CKD, and a high concentration (100 μM to 1 mM) of indoxyl sulfate accumulates in the blood. Indoxyl sulfate is known to be deeply involved in progression of kidney damage due to kidney fibrosis, and CKD complications such as CVD due to vascular calcification. It is reported that a concentration of indoxyl sulfate in serum correlates with a mortality rate and incidence of cardiovascular events in dialysis patients (Non-Patent Literature 1). In addition, it is considered that, by reducing a concentration of indoxyl sulfate in blood in CKD patients, progression to ESKD can be suppressed, and onset of CVD related to kidney failure can be suppressed. In fact, a spherical carbonaceous adsorbent (KREMEZIN (registered trademark)) which adsorbs indole, which is a precursor of indoxyl sulfate, in the intestinal tract to decrease a concentration of indoxyl sulfate in blood, delays introduction of dialysis in CKD patients, thereby ameliorating arteriosclerosis (Non-Patent Literature 2).
Meanwhile, because a concentration of bicarbonate ions (HCO3−) in blood decreases and metabolic acidosis develops in patients with advanced CKD, an alkalinizing agent such as sodium bicarbonate or a citric acid preparation is administered. In addition, it is reported that progression of CKD is suppressed by administration of sodium bicarbonate that is an alkalinizing agent (Non-Patent Literature 3). Furthermore, it is reported that oral administration of sodium bicarbonate suppresses kidney tubular cell damage due to acidic urine in an animal model with nephrosis caused by protein overload (Non-Patent Literature 4).
However, there is no report regarding suppression of progression of kidney damage by administering an alkalinizing agent to early-stage CKD patients, and there is also no report regarding a decrease in concentration of uremic substance in blood.
An object of the present invention is to provide a medicine useful for blood purification in a patient with kidney disease. Another object of the present invention is to provide a medicine useful for suppressing progression of chronic kidney disease (advancing in severity of chronic kidney disease), treating and preventing uremic symptoms, and delaying introduction of dialysis. Still another object of the present invention is to provide a medicine useful for suppressing progression from acute kidney failure to chronic kidney disease. Still another object of the present invention is to provide a food for promoting excretion of uremic substance outside the body. Still another object of the present invention is to provide a food for maintenance of kidney function (for example, for suppression of kidney tubular damage, for protection of kidney tubular cells, or for maintenance of kidney tubular function). Still another object of the present invention is to provide a method for determining suppression of progression of chronic kidney disease, or a method for determining a decrease in concentration of uremic substance in blood, and/or a promotion of excretion of uremic substance into urine.
The inventors of the present invention have performed extensive studies to achieve the above-mentioned objects. As a result, they have found that an agent that alkalinizes a body fluid is useful for promoting excretion of uremic substance from the body of a patient with kidney disease (for example, promoting excretion of uremic substance into urine), and therefore have completed the present invention.
In one aspect, the present invention provides a pharmaceutical composition for promoting excretion of uremic substance outside the body, comprising an alkalinizing agent.
In one aspect, the present invention provides a pharmaceutical composition for decreasing a concentration of uremic substance in blood, comprising an alkalinizing agent.
In one aspect, the present invention provides a pharmaceutical composition for promoting excretion into urine in chronic kidney disease, comprising an alkalinizing agent.
In one aspect, the present invention provides a pharmaceutical composition for ameliorating uremic symptoms in chronic kidney disease, comprising an alkalinizing agent.
In one aspect, the present invention provides a pharmaceutical composition for delaying introduction of dialysis in chronic kidney disease, comprising an alkalinizing agent.
In one aspect, the present invention provides a pharmaceutical composition for treating or preventing cardiovascular disease associated with chronic kidney disease, comprising an alkalinizing agent.
In one aspect, the present invention provides a pharmaceutical composition for suppressing progression from acute kidney failure to chronic kidney disease, comprising an alkalinizing agent.
In one aspect, the present invention provides a food composition for promoting excretion of uremic substance outside the body, comprising an alkalinizing agent.
In one aspect, the present invention provides a method for determining suppression of progression of chronic kidney disease.
In one aspect, the present invention provides a method for determining a decrease in concentration of uremic toxins in blood of a human, and/or a promotion of excretion of uremic toxins into urine.
That is, the present invention has the following aspects.
(2) A pharmaceutical composition for promoting excretion of uremic substance into urine, comprising an alkalinizing agent.
(3) A pharmaceutical composition for promoting excretion of uremic substance outside the body, comprising an alkalinizing agent.
(4) The pharmaceutical composition according to (2) or (3), wherein the excretion into urine or the excretion outside the body depends on a concentration of uremic substance in blood.
(5) The pharmaceutical composition according to any one of (1) to (4), which is administered to a patient with chronic kidney disease or acute kidney failure.
(6) The pharmaceutical composition according to any one of (1) to (5), wherein the uremic substance is at least one selected from the group consisting of indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid.
(7) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance are indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid.
(8) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance are indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine.
(9) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is indoxyl sulfate and phenylacetyl-L-glutamine.
(10) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is indoxyl sulfate and hippuric acid.
(11) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is phenylacetyl-L-glutamine and p-cresyl sulfate.
(12) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is indoxyl sulfate.
(13) A pharmaceutical composition for ameliorating uremic symptoms in chronic kidney disease, comprising an alkalinizing agent.
(14) A pharmaceutical composition for delaying introduction of dialysis in chronic kidney disease, comprising an alkalinizing agent.
(15) A pharmaceutical composition for treating or preventing cardiovascular disease associated with chronic kidney disease, comprising an alkalinizing agent.
(16) The pharmaceutical composition according to (15), which ameliorates arteriosclerosis.
(17) A pharmaceutical composition for suppressing progression of chronic kidney disease, comprising an alkalinizing agent.
(18) A pharmaceutical composition for treating or preventing kidney tubular damage, comprising an alkalinizing agent.
(19) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient with early-stage chronic kidney disease.
(20) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient with stage G3b or lower chronic kidney disease.
(21) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient with stage G2 to stage G3b chronic kidney disease.
(22) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient with stage G2 and stage G3a chronic kidney disease.
(23) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient with stage G2 chronic kidney disease.
(24) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient in which a urinary β2-microglobulin concentration is 290 μg/L or less.
(25) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient in which a urinary β2-microglobulin concentration is 50 to 150 μg/L.
(26) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient in which a blood cystatin C concentration is 0.5 to 2.2 mg/L.
(27) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient in which a blood cystatin C concentration is 1.0 to 1.3 mg/L.
(28) A pharmaceutical composition for suppressing progression from acute kidney failure to chronic kidney disease, comprising an alkalinizing agent.
(29) The pharmaceutical composition according to any one of (1) to (28), wherein the alkalinizing agent is a pharmaceutically acceptable salt of citric acid or a hydrate thereof, or a mixture thereof.
(30) The pharmaceutical composition according to any one of (1) to (29), wherein the alkalinizing agent is a sodium citrate, potassium citrate, or a hydrate thereof, or a mixture thereof.
(31) The pharmaceutical composition according to any one of (1) to (30), wherein the alkalinizing agent comprises a mixture of sodium citrate or a hydrate thereof, and potassium citrate or a hydrate thereof.
(32) The pharmaceutical composition according to any one of (1) to (31), wherein the alkalinizing agent is sodium citrate or a hydrate thereof.
(33) The pharmaceutical composition according to any one of (1) to (32), which is a tablet.
(34) The pharmaceutical composition according to any one of (1) to (33), wherein a decrease in concentration of the uremic substance in blood compared to before the start of administration of the alkalinizing agent is detected 12 weeks after the administration of the alkalinizing agent.
(35) The pharmaceutical composition according to any one of (1) to (34), wherein an increase in concentration of the uremic substance in urine compared to before the start of administration of the alkalinizing agent is detected 12 weeks after the administration of the alkalinizing agent.
(36) The pharmaceutical composition according to any one of (1) to (35), wherein an increase in amount of the uremic substance excreted outside the body compared to before the start of administration of the alkalinizing agent is detected 12 weeks after the administration of the alkalinizing agent.
(37) The pharmaceutical composition according to any one of (1) to (36), wherein administration of the alkalinizing agent suppresses an increase of a urinary β2-microglobulin concentration.
(38) The pharmaceutical composition according to any one of (1) to (37), wherein, by administration of the alkalinizing agent, after 12 weeks from the administration, an increase of a urinary β2-microglobulin concentration is suppressed.
(39) The pharmaceutical composition according to any one of (1) to (38), wherein, by administration of the alkalinizing agent, a urinary β2-microglobulin concentration is not substantially decreased compared to before the start of the administration.
(40) The pharmaceutical composition according to any one of (1) to (39), wherein, by administration of the alkalinizing agent, after 12 weeks from the administration, a urinary β2-microglobulin concentration is not substantially decreased compared to before the start of the administration.
(41) The pharmaceutical composition according to any one of (1) to (40), wherein administration of the alkalinizing agent does not substantially increase blood cystatin C compared to before the start of the administration.
(42) The pharmaceutical composition according to any one of (1) to (41), wherein, by administration of the alkalinizing agent, after 12 weeks from the administration, blood cystatin C is not substantially increased compared to before the start of the administration.
(43) The pharmaceutical composition according to any one of (1) to (42), wherein, by administration of the alkalinizing agent, amelioration of kidney proximal tubular damage and/or amelioration of glomerular damage is not recognized compared to before the start of the administration; and a decrease in a concentration of the uremic substance in blood, a promotion of excretion of the uremic substance into urine, and/or a promotion of excretion of the uremic substance outside the body is recognized compared to before the start of the administration.
(44) The pharmaceutical composition according to any one of (1) to (43), wherein, by administration of the alkalinizing agent, after 12 weeks from the administration of the alkalinizing agent, amelioration of kidney proximal tubular damage and/or amelioration of glomerular damage is not recognized compared to before the start of the administration; and a decrease in a concentration of the uremic substance in blood, a promotion of excretion of the uremic substance into urine, and/or a promotion of excretion of the uremic substance outside the body is recognized, compared to before the start of the administration.
(45) The pharmaceutical composition according to any one of (1) to (44), wherein the alkalinizing agent is administered at 1 to 3 g/day.
(46) The pharmaceutical composition according to any one of (1) to (45), wherein the alkalinizing agent is administered at 1 to 1.5 g/day.
(47) The pharmaceutical composition according to any one of (1) to (46), wherein the alkalinizing agent is administered such that a pH of early morning urine becomes pH 5.2 to pH 6.8.
(48) The pharmaceutical composition according to any one of (1) to (47), wherein the alkalinizing agent is administered such that a pH of early morning urine becomes pH 6.0 or more and less than pH 6.2.
(49) The pharmaceutical composition according to any one of (1) to (48), wherein the alkalinizing agent is administered for 12 weeks or longer.
(50) The pharmaceutical composition according to any one of (1) to (49), wherein the alkalinizing agent is administered for 12 weeks.
(50-1) The pharmaceutical composition according to any one of (1) to (50), wherein administration of the alkalinizing agent increases an amount of uremic substance in urine.
(50-2) The pharmaceutical composition according to any one of (1) to (50) and (50-1), wherein administration of the alkalinizing agent increases a concentration of uremic substance in urine.
(50-3) The pharmaceutical composition according to any one of (1) to (50), (50-1), and (50-2), wherein administration of the alkalinizing agent exerts an effect of decreasing a concentration of uremic substance in blood, an effect of promoting excretion of uremic substance into urine, and/or an effect of promoting excretion of uremic substance outside the body, and the effects are recognized with respect to placebo administration.
(50-4) The pharmaceutical composition according to any one of (1) to (50) and (50-1) to (50-3), wherein administration of the alkalinizing agent exerts an effect of decreasing a concentration of uremic substance in blood, an effect of promoting excretion of uremic substance into urine, and/or an effect of promoting excretion of uremic substance outside the body, and the effects are recognized with respect to before administration of the alkalinizing agent.
(50-5) The pharmaceutical composition according to any one of (1) to (50) and (50-1) to (50-4), which is a tablet.
(50-6) The pharmaceutical composition according to any one of (1) to (50) and (50-1) to (50-5), wherein the urine is early morning urine.
(51) A food composition for decreasing a concentration of uremic substance in blood, promoting excretion of uremic substance into urine, and/or promoting excretion of uremic substance outside the body, wherein the food composition comprises an alkalinizing agent.
(52) The food composition according to (51), wherein the alkalinizing agent is an alkali metal salt of citric acid or a hydrate thereof, or a mixture thereof.
(52-1) The food composition according to (51) or (52), which maintains kidney function (suppresses kidney tubular damage, protects kidney tubular cells, or maintains kidney tubular function).
(52-2) The food composition according to any one of (51), (52), and (52-1), wherein the alkalinizing agent is ingested at 1 to 3 g/day.
(52-3) The food composition according to any one of (51), (52), (52-1), and (52-2), wherein the alkalinizing agent is ingested at 1 to 1.5 g/day.
(52-4) The food composition according to any one of (51), (52), and (52-1) to (52-3), wherein a concentration of uremic substance in blood is decreased compared to before the start of ingesting the alkalinizing agent, or compared to placebo ingestion.
(52-5) The food composition according to any one of (51), (52), and (52-1) to (52-4), wherein a concentration of uremic substance in urine increases compared to before the start of ingesting the alkalinizing agent, or compared to placebo ingestion.
(52-6) The food composition according to any one of (51), (52), and (52-1) to (52-5), wherein an amount of uremic substance in urine increases compared to before the start of ingesting the alkalinizing agent, or compared to placebo ingestion.
(52-7) The food composition according to any one of (51), (52), and (52-1) to (52-6), wherein an amount of uremic substance excreted outside the body increases compared to before the start of ingesting the alkalinizing agent, or compared to placebo ingestion.
(52-8) The food composition according to any one of (51), (52), and (52-1) to (52-7), wherein ingestion of the alkalinizing agent suppresses an increase of a urinary β2-microglobulin concentration.
(52-9) The food composition according to any one of (51), (52), and (52-1) to (52-8), wherein, by ingestion of the alkalinizing agent, a urinary β2-microglobulin concentration is not substantially decreased compared to before the ingestion of the alkalinizing agent or ingestion of placebo.
(52-10) The food composition according to any one of (51), (52), and (52-1) to (52-9), wherein ingestion of the alkalinizing agent does not substantially increase blood cystatin C.
(52-11) The food composition according to any one of (51), (52), and (52-1) to (52-10), wherein the alkalinizing agent is ingested for 12 weeks or longer.
(52-12) The food composition according to any one of (51), (52), and (52-1) to (52-11), wherein the alkalinizing agent is ingested for 12 weeks.
(53) A method for determining suppression of progression of chronic kidney disease, comprising measuring a pH of urine.
(54) A method for determining a decrease in concentration of uremic substance in blood of a patient with chronic kidney disease, comprising measuring a pH of urine.
(55) A method for determining promotion of excretion of uremic substance into urine of a patient with chronic kidney disease, comprising measuring a pH of urine.
Furthermore, the present invention has the following aspects.
(56) A pharmaceutical composition for decreasing a concentration of uremic substance in blood, wherein the pharmaceutical composition comprises an alkalinizing agent, and the pharmaceutical composition is a tablet.
(57) A pharmaceutical composition for promoting excretion of uremic substance into urine, wherein the pharmaceutical composition comprises an alkalinizing agent, and the pharmaceutical composition is a tablet.
(58) The pharmaceutical composition according to (56) or (57), which is administered to a patient with chronic kidney disease or acute kidney failure.
(59) The pharmaceutical composition according to any one of (56) to (58), wherein the uremic substance is at least one selected from the group consisting of indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid.
(60) The pharmaceutical composition according to any one of (56) to (59), wherein the uremic substance is indoxyl sulfate.
(61) A pharmaceutical composition for suppressing progression of chronic kidney disease, wherein the pharmaceutical composition comprises an alkalinizing agent, and the pharmaceutical composition is a tablet.
(62) A pharmaceutical composition for treating or preventing kidney tubular damage, wherein the pharmaceutical composition comprises an alkalinizing agent, and the pharmaceutical composition is a tablet.
(63) The pharmaceutical composition according to any one of (56) to (62), wherein the alkalinizing agent is a pharmaceutically acceptable salt of citric acid or a hydrate thereof, or a mixture thereof.
(64) The pharmaceutical composition according to any one of (56) to (63), wherein the alkalinizing agent comprises a mixture of sodium citrate or a hydrate thereof, and potassium citrate or a hydrate thereof.
Furthermore, the present invention has the following aspects.
(65) A food composition which is for maintenance of kidney function, comprising an alkalinizing agent.
(66) The food composition according to (65), wherein the maintenance of kidney function is suppression of kidney tubular damage, protection of kidney tubular cells, or maintenance of kidney tubular function.
(67) The food composition according to (66), wherein the kidney tubule is a kidney proximal tubule.
(68) The food composition according to any one of (65) to (67), wherein the alkalinizing agent is an acceptable salt of citric acid as food or a hydrate thereof, or a mixture thereof.
(69) The food composition according to any one of (65) to (68), wherein the alkalinizing agent comprises a mixture of sodium citrate or a hydrate thereof, and potassium citrate or a hydrate thereof.
(70) The food composition according to any one of (65) to (69), wherein the alkalinizing agent is sodium citrate or a hydrate thereof.
(71) The food composition according to any one of (65) to (70), which is a tablet.
(72) The food composition according to any one of (65) to (71), wherein an effect of the maintenance of kidney function is indicated on packaging, a container, or an instruction leaflet for the food composition.
(73) The food composition according to any one of (65) to (71), wherein an effect of suppression of kidney tubular damage, protection of kidney tubular cells, or maintenance of kidney tubular function is indicated on packaging, a container, or an instruction leaflet for the food composition.
(74) The food composition according to any one of (65) to (72), which is ingested by a healthy subject concerned about kidney health.
(75) The food composition according to any one of (65) to (71) and (73), which is ingested by a healthy subject concerned about kidney tubular health.
(76) The food composition according to any one of (65) to (75), which is ingested by a subject in which a urinary β2-microglobulin concentration is 290 μg/L or less.
(77) The food composition according to any one of (65) to (76), which is ingested by a subject in which a urinary β2-microglobulin concentration is 50 to 150 μg/L.
(78) The food composition according to any one of (65) to (77), which is ingested by a subject in which a blood cystatin C concentration is 0.5 to 2.2 mg/L.
(79) The food composition according to any one of (65) to (78), which is ingested by a subject in which a blood cystatin C concentration is 1.0 to 1.3 mg/L.
(80) The food composition according to any one of (65) to (79), wherein ingestion of the food composition suppresses an increase of a urinary β2-microglobulin concentration.
(81) The food composition according to any one of (65) to (80), wherein, by ingestion of the food composition, after 12 weeks from the ingestion, an increase of a urinary β2-microglobulin concentration is suppressed.
(82) The food composition according to any one of (65) to (81), wherein, by ingestion of the food composition, a urinary β2-microglobulin concentration is not substantially decreased compared to before the start of the ingestion or placebo.
(83) The food composition according to any one of (65) to (82), wherein, by ingestion of the food composition, after 12 weeks from the ingestion, a urinary β2-microglobulin concentration is not substantially decreased compared to before the start of administration or placebo.
(84) The food composition according to any one of (65) to (83), wherein ingestion of the food composition does not substantially increase blood cystatin C compared to before the start of the ingestion.
(85) The food composition according to any one of (65) to (84), wherein ingestion of the food composition does not substantially increase blood cystatin C compared to placebo.
(86) The food composition according to any one of (65) to (85), wherein ingestion of the food composition suppresses, in early morning urine, an increase of a β2-microglobulin amount which is associated with progression of a stage of chronic kidney disease.
(87) The food composition according to any one of (65) to (86), wherein ingestion of the food composition does not affect glomerular function in a patient with chronic kidney disease, and suppresses kidney proximal tubular cell damage associated with progression of a stage of chronic kidney disease to protect kidney proximal tubular cells.
By the pharmaceutical composition and the like provided by the present invention, uremic substance is excreted outside the body in mammals. By the method provided by the present invention, it is possible to preliminarily determine as to whether or not uremic substance is excreted outside the body and/or whether or not a progression of chronic kidney disease can be suppressed. By the food composition and the like provided by the present invention, it is possible to maintain kidney function in mammals, more specifically, to suppress kidney tubular damage, protect kidney tubular cells, or maintain kidney tubular function.
A pharmaceutical composition provided by the present invention can comprise an alkalinizing agent as an active ingredient.
The alkalinizing agent is an agent having the ability to increase the HCO3− concentration and pH of body fluids of mammals (particularly a human), such as blood or urine. Examples of alkalinizing agents include a pharmaceutically acceptable salt of citric acid or a hydrate thereof, or a mixture thereof, and sodium bicarbonate (baking soda). Examples of a pharmaceutically acceptable salt of citric acid include an alkali metal salt of citric acid. Examples of an alkali metal salt of citric acid include potassium citrate and sodium citrate. Potassium citrate may be a hydrate such as a stable potassium citrate monohydrate (C6H5K3O7.H2O), and sodium citrate may be a hydrate such as sodium citrate dihydrate (C6H5Na3O7.2H2O).
Examples of preferable alkalinizing agents include sodium citrate, potassium citrate, or a hydrate thereof, or a mixture thereof. For example, an alkalinizing agent may be a mixture of a potassium citrate monohydrate (C6H5K3O7.H2O) and sodium citrate dihydrate (C6H5Na3O7.2H2O). A mixing ratio of a potassium citrate monohydrate (C6H5K3O7.H2O) and a sodium citrate dihydrate (C6H5Na3O7.2H2O) can be appropriately set by those skilled in the art. For example, a molar ratio of a potassium citrate monohydrate to a sodium citrate dihydrate can be set to 1 (for a potassium citrate monohydrate) to 0.01 to 100 (for a sodium citrate dihydrate). The mixing ratio may be about 1:1 as a molar ratio.
In addition, additional examples of preferable alkalinizing agents include sodium citrate or a hydrate thereof, for example, a sodium citrate dihydrate (C6H5Na3O7.2H2O).
Furthermore, additional examples of preferable alkalinizing agents include potassium citrate or a hydrate thereof, for example, a potassium citrate monohydrate (C6H5K3O7.2H2O).
In one embodiment, the alkalinizing agent contained in the pharmaceutical composition of the present invention may comprise a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof.
In another embodiment, the alkalinizing agent contained in the pharmaceutical composition of the present invention may be composed of only a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof.
In the present specification, when referring to the weight of an alkalinizing agent (for example, a potassium citrate monohydrate (C6H5K3O7.H2O) and a sodium citrate dihydrate (C6H5Na3O7.2H2O)), this weight may be a dry weight.
In the present specification, a uremic substance is a substance (waste products, toxins, and the like) excreted by normal kidneys, and it means a substance that increases (accumulates) in the blood and causes uremic symptoms or diseases when the excretory function deteriorates due to some cause such as deteriorated kidney function. Examples of uremic substance include indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid.
Among them, indoxyl sulfate is produced by oxidation and sulfate conjugation of indole produced by enteric bacteria from tryptophan derived from dietary protein. Most of the indoxyl sulfate is present by being bound to albumin in the blood and is not metabolized. In healthy subjects, it is excreted from the kidneys into the urine, but in a case of a patient with kidney disease, it remains accumulated at high concentrations in the blood.
Indoxyl sulfate, which is a uremic substance, not only causes uremia in a patient with kidney disease, but also causes a patient with chronic kidney disease to be subjected to introduction of dialysis.
Accordingly, by reducing a concentration of indoxyl sulfate in blood, the uremic symptoms of a patient with kidney disease are ameliorated, and thereby treatment and/or prevention of uremia becomes possible. In addition, it is possible to delay the introduction of dialysis in a patient with chronic kidney disease by decreasing a concentration of indoxyl sulfate in blood. In one embodiment, a patient with chronic kidney disease has progressive chronic kidney disease.
In the present specification, the expression [A, B, and/or C] represents “at least one selected from the group consisting of A, B, and C.” Accordingly, for example, “indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and/or argininosuccinic acid” means at least one selected from the group consisting of “indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid.”
In addition, indoxyl sulfate, which is a uremic substance, causes myocardial fibrosis, arteriosclerosis, vascular smooth muscle cell proliferation, vascular endothelial cell injury, thickening of the arterial wall, calcification of the aorta, and the like, and allows cardiovascular disease (for example, heart failure, myocardial infarction), which is one of the complications in a patient with chronic kidney disease, and/or a stroke, which is a cerebrovascular disease, to develop.
Accordingly, decreasing a concentration of indoxyl sulfate in blood suppresses myocardial fibrosis, arteriosclerosis, vascular smooth muscle cell proliferation, vascular endothelial cell injury, thickening of the arterial wall, calcification of the aorta, and the like, and thereby it becomes possible to treat and/or prevent cardiovascular disease, which is one of the complications in a patient with chronic kidney disease, and/or cerebrovascular disease.
In one aspect, in the pharmaceutical composition provided by the present invention, it is possible to decrease a concentration of uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and a combination thereof) in the blood. Examples of indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and a combination thereof include indoxyl sulfate, p-cresyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine; indoxyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; indoxyl sulfate and hippuric acid; indoxyl sulfate and phenylacetyl-L-glutamine; p-cresyl sulfate and phenylacetyl-L-glutamine; hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate; p-cresyl sulfate; hippuric acid; and phenylacetyl-L-glutamine.
In the present specification, “decreasing a concentration of uremic substance in the blood” means that the concentration of uremic substance in the blood after administration of the pharmaceutical composition provided by the present invention decreases compared to the concentration of uremic substance in the blood before the administration, or means that the concentration of uremic substance in the blood is decreased by administration of the pharmaceutical composition provided by the present invention, compared to placebo administration.
In one embodiment, administration of the pharmaceutical composition provided by the present invention decreases a concentration of uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and a combination thereof (for example, indoxyl sulfate, p-cresyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine; indoxyl sulfate, hippuric acid, and phenyl acetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; indoxyl sulfate and hippuric acid; indoxyl sulfate and phenylacetyl-L-glutamine; p-cresyl sulfate and phenylacetyl-L-glutamine; hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate; p-cresyl sulfate; hippuric acid; or phenylacetyl-L-glutamine)) in the blood compared to before administration, but an amount of decrease thereof is 1% to 5%, 3% to 5%, 1% to 10%, 3% to 10%, 5% to 10%, 1% to 15%, 3% to 15%, 5% to 15%, 1% to 30%, 1% to 40%, 3% to 40%, 5% to 40%, 1% to 50%, 3% to 50%, 5% to 50%, 30% to 50%, 1% to 60%, 5% or more, 10% or more, or 30% or more of a concentration of uremic substance in the blood before administration.
In one embodiment, an amount of decrease in concentration of uremic substance in the blood is calculated by Calculation Equation (1).
Amount of decrease in concentration of uremic substance in blood (%)=[(concentration (ng/mL) of uremic substance in blood before administration of pharmaceutical composition−concentration (ng/mL) of uremic substance in blood after administration of pharmaceutical composition)/concentration (ng/mL) of uremic substance in blood before administration of pharmaceutical composition]×100 (1)
In one embodiment, continuous administration of the pharmaceutical composition provided by the present invention for 6, 12, or 24 weeks decreases a concentration of uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and a combination thereof (for example, indoxyl sulfate, p-cresyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine; indoxyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; indoxyl sulfate and hippuric acid; indoxyl sulfate and phenylacetyl-L-glutamine; p-cresyl sulfate and phenylacetyl-L-glutamine; hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate; p-cresyl sulfate; hippuric acid; or phenylacetyl-L-glutamine)) in the blood compared to before administration, but an amount of decrease thereof is 1% to 5%, 3% to 5%, 1% to 10%, 3% to 10%, 5% to 10%, 1% to 15%, 3% to 15%, 5% to 15%, 1% to 30%, 1% to 40%, 3% to 40%, 5% to 40%, 1% to 50%, 3% to 50%, 5% to 50%, 30% to 50%, 1% to 60%, 5% or more, 10% or more, or 30% or more of a concentration of uremic substance in the blood before administration.
In one aspect, in the pharmaceutical composition provided by the present invention, it is possible to promote excretion of uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and a combination thereof) into urine. Examples of indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and a combination thereof include indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine; indoxyl sulfate, phenylacetyl-L-glutamine, and argininosuccinic acid; indoxyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate and hippuric acid; indoxyl sulfate and phenylacetyl-L-glutamine; hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl-L-glutamine; p-cresyl sulfate and hippuric acid; indoxyl sulfate and argininosuccinic acid; p-cresyl sulfate and argininosuccinic acid; hippuric acid and argininosuccinic acid; phenylacetyl-L-glutamine and argininosuccinic acid; indoxyl sulfate; p-cresyl sulfate; hippuric acid; argininosuccinic acid; and phenylacetyl-L-glutamine.
In the present specification, “promoting excretion of uremic substance into the urine” means that a concentration of uremic substance in the urine after administration increases compared to the concentration of uremic substance in the urine before administration of the pharmaceutical composition provided by the present invention; means that a concentration of uremic substance in the urine increases by administration of the pharmaceutical composition provided by the present invention compared to placebo administration; means that an amount of uremic substance in the urine after administration increases compared to the amount of uremic substance in urine before administration of the pharmaceutical composition provided by the present invention; or means that the amount of uremic substance in the urine increases by administration of the pharmaceutical composition provided by the present invention compared to placebo administration.
In the present specification, “in urine” means, for example, “in early morning urine.”
In one embodiment, by administration of the pharmaceutical composition provided by the present invention, a concentration of uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and a combination thereof (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine; indoxyl sulfate, phenylacetyl-L-glutamine, and argininosuccinic acid; indoxyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate and hippuric acid; indoxyl sulfate and phenylacetyl-L-glutamine; hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl-L-glutamine; p-cresyl sulfate and hippuric acid; indoxyl sulfate and argininosuccinic acid; p-cresyl sulfate and argininosuccinic acid; hippuric acid and argininosuccinic acid; phenylacetyl-L-glutamine and argininosuccinic acid; indoxyl sulfate; p-cresyl sulfate; hippuric acid; argininosuccinic acid; or phenylacetyl-L-glutamine)) in urine increases by 1% to 100%, 1% to 50%, 3% to 50%, 5% to 50%, 10% to 50%, 15% to 50%, 1% to 40%, 5% to 40%, 10% to 40%, 1% to 30%, 5% to 30%, 10% to 30%, 15% to 30%, 10% or more, 20% or more, 30% or more, or 40% or more, compared to before administration.
In one embodiment, the amount of increase in concentration of uremic substance in urine is calculated by Calculation Equation (2).
Amount of increase in concentration of uremic substance in urine (%)=[(concentration (ng/mL) of uremic substance in urine after administration of pharmaceutical composition−concentration (ng/mL) of uremic substance in urine before administration of pharmaceutical composition)/concentration (ng/mL) of uremic substance in urine before administration of pharmaceutical composition]×100 (2)
In one embodiment, by continuous administration of the pharmaceutical composition provided by the present invention for 6, 12, or 24 weeks, a concentration of uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and a combination thereof (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine; indoxyl sulfate, phenylacetyl-L-glutamine, and argininosuccinic acid; indoxyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate and hippuric acid; indoxyl sulfate and phenylacetyl-L-glutamine; hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl-L-glutamine; p-cresyl sulfate and hippuric acid; indoxyl sulfate and argininosuccinic acid; p-cresyl sulfate and argininosuccinic acid; hippuric acid and argininosuccinic acid; phenylacetyl-L-glutamine and argininosuccinic acid; indoxyl sulfate; p-cresyl sulfate; hippuric acid; argininosuccinic acid; or phenylacetyl-L-glutamine)) in urine increases by 1% to 100%, 1% to 50%, 3% to 50%, 5% to 50%, 10% to 50%, 15% to 50%, 1% to 40%, 5% to 40%, 10% to 40%, 1% to 30%, 5% to 30%, 10% to 30%, 15% to 30%, 10% or more, 20% or more, 30% or more, or 40% or more, compared to before administration.
In one aspect, in the pharmaceutical composition provided by the present invention, it is possible to promote excretion of uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and a combination thereof) from blood into urine, thereby promoting excretion of the uremic substance outside the body. Examples of indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and a combination thereof include indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine; indoxyl sulfate, phenylacetyl-L-glutamine, and argininosuccinic acid; indoxyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate and hippuric acid; indoxyl sulfate and phenylacetyl-L-glutamine; hippuric acid and phenyl acetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl-L-glutamine; p-cresyl sulfate and hippuric acid; indoxyl sulfate and argininosuccinic acid; p-cresyl sulfate and argininosuccinic acid; hippuric acid and argininosuccinic acid; phenylacetyl-L-glutamine and argininosuccinic acid; indoxyl sulfate; p-cresyl sulfate; hippuric acid; argininosuccinic acid; and phenylacetyl-L-glutamine.
In one embodiment, by administration of the pharmaceutical composition provided by the present invention, a ratio of a concentration of uremic substance in urine to a concentration of uremic substance in blood after administration increases compared to a ratio of a concentration of uremic substance in urine to a concentration of uremic substance in blood before administration of the pharmaceutical composition provided by the present invention. In one embodiment, administration of the pharmaceutical composition provided by the present invention increases the ratio of a concentration of uremic substance in urine to a concentration of uremic substance in blood, compared to placebo administration.
In one embodiment, by administration of the pharmaceutical composition provided by the present invention, a ratio of a concentration of uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and a combination thereof (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine; indoxyl sulfate, phenylacetyl-L-glutamine, and argininosuccinic acid; indoxyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate and hippuric acid; indoxyl sulfate and phenylacetyl-L-glutamine; hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl-L-glutamine; p-cresyl sulfate and hippuric acid; indoxyl sulfate and argininosuccinic acid; p-cresyl sulfate and argininosuccinic acid; hippuric acid and argininosuccinic acid; phenylacetyl-L-glutamine and argininosuccinic acid; indoxyl sulfate; p-cresyl sulfate; hippuric acid; argininosuccinic acid; or phenylacetyl-L-glutamine)) in urine with respect to a concentration of uremic substance in blood (a concentration (ng/mL) in urine/a concentration (ng/mL) in blood) increases by 1% to 100%, 1% to 50%, 3% to 50%, 5% to 50%, 10% to 50%, 15% to 50%, 1% to 40%, 5% to 40%, 10% to 40%, 1% to 30%, 5% to 30%, 10% to 30%, 15% to 30%, 10% or more, 20% or more, 30% or more, or 40% or more, compared to before administration.
In one embodiment, an increase in ratio of a concentration of uremic substance in urine to a concentration of uremic substance in blood (a concentration (ng/mL) in urine/a concentration (ng/mL) in blood) is calculated by Calculation Equation (3).
Amount of increase in ratio of a concentration of uremic substance in urine to a concentration of uremic substance in blood (%)=[(ratio of concentration of uremic substance in urine to concentration of uremic substance in blood after administration of pharmaceutical composition−ratio of concentration of uremic substance in urine to concentration of uremic substance in blood before administration of pharmaceutical composition)/ratio of concentration of uremic substance in urine to concentration of uremic substance in blood before administration of pharmaceutical composition]×100 (3)
In one embodiment, by continuous administration of the pharmaceutical composition provided by the present invention for 6, 12, or 24 weeks, a ratio of a concentration of uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and a combination thereof (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine; indoxyl sulfate, phenylacetyl-L-glutamine, and argininosuccinic acid; indoxyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate and hippuric acid; indoxyl sulfate and phenylacetyl-L-glutamine; hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl-L-glutamine; p-cresyl sulfate and hippuric acid; indoxyl sulfate and argininosuccinic acid; p-cresyl sulfate and argininosuccinic acid; hippuric acid and argininosuccinic acid; phenylacetyl-L-glutamine and argininosuccinic acid; indoxyl sulfate; p-cresyl sulfate; hippuric acid; argininosuccinic acid; or phenylacetyl-L-glutamine)) in urine with respect to a concentration of uremic substance in blood (a concentration (ng/mL) in urine/a concentration (ng/mL) in blood) increases by 1% to 100%, 1% to 50%, 3% to 50%, 5% to 50%, 10% to 50%, 15% to 50%, 1% to 40%, 5% to 40%, 10% to 40%, 1% to 30%, 5% to 30%, 10% to 30%, 15% to 30%, 10% or more, 20% or more, 30% or more, or 40% or more, compared to before administration.
In one embodiment, the administration of the pharmaceutical composition provided by the present invention promotes excretion of the uremic substance outside the body depending on a concentration of uremic substance in blood.
In one embodiment, the administration of the pharmaceutical composition provided by the present invention promotes excretion of uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and a combination thereof) into urine depending on a concentration of uremic substance in blood. For example, in a case where a concentration of uremic substance in blood is high, the amount of uremic substance excreted into the urine becomes a high value in accordance with the high concentration of uremic substance in blood. In a case where the concentration of uremic substance in blood is low, the amount of uremic substance excreted into the urine becomes a low value. Such excretion of uremic substance into urine depending on a concentration of uremic substance in blood suggests that the pharmaceutical composition provided by the present invention has a low risk of side effects and excellent safety. Examples of indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and a combination thereof include indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine; indoxyl sulfate and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl-L-glutamine; indoxyl sulfate; p-cresyl sulfate; and phenylacetyl-L-glutamine.
In one embodiment, the administration of the pharmaceutical composition provided by the present invention promotes excretion of uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and a combination thereof) into urine depending on a concentration of uremic substance in blood, and thereby a concentration of uremic substance in blood is decreased. Examples of indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and a combination thereof include indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine; indoxyl sulfate and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl-L-glutamine; indoxyl sulfate; p-cresyl sulfate; and phenylacetyl-L-glutamine.
In one embodiment, administration of the pharmaceutical composition provided by the present invention excretes indoxyl sulfate into the urine depending on a concentration of indoxyl sulfate in blood, and as a result, a ratio of a concentration of indoxyl sulfate in urine to a concentration of indoxyl sulfate in blood (a concentration in urine/a concentration in blood) can become 1 to 1000, preferably 1 to 200, more preferably 1 to 100, and even more preferably 10 to 100. In this embodiment, the pharmaceutical composition provided by the present invention may be administered to a human (for example, a patient with chronic kidney disease) in which a concentration of indoxyl sulfate in blood is 0.01 to 100n/mL (for example, 0.1 to 30 μg/mL). Furthermore, as a result of the administration, the concentration of indoxyl sulfate in blood may become 0.01 to 10 μg/mL (for example, 0.03 to 10 μg/mL).
In one embodiment, administration of the pharmaceutical composition provided by the present invention excretes p-cresyl sulfate into the urine depending on a concentration of p-cresyl sulfate in blood, and as a result, a ratio of a concentration of p-cresyl sulfate in urine to a concentration of p-cresyl sulfate in blood (a concentration in urine/a concentration in blood) can become 0.1 to 1000, preferably 1 to 300, more preferably 1 to 150, and even more preferably 1 to 100. In this embodiment, the pharmaceutical composition provided by the present invention may be administered to a human (for example, a patient with chronic kidney disease) in which a concentration of p-cresyl sulfate in blood is 0.003 to 300 μg/mL (for example, 0.01 to 30 μg/mL). Furthermore, as a result of the administration, the concentration of p-cresyl sulfate in blood may become 0.001 to 100 μg/mL (for example, 0.001 to 30 μg/mL).
In one embodiment, administration of the pharmaceutical composition provided by the present invention excretes phenylacetyl-L-glutamine into the urine depending on a concentration of phenylacetyl-L-glutamine in blood, and as a result, a ratio of a concentration of phenylacetyl-L-glutamine in urine to a concentration of phenylacetyl-L-glutamine in blood (a concentration in urine/a concentration in blood) can become 1 to 1500, preferably 1 to 1000, more preferably 1 to 800, and even more preferably 10 to 600. In this embodiment, the pharmaceutical composition provided by the present invention may be administered to a human (for example, a patient with chronic kidney disease) in which a concentration of phenylacetyl-L-glutamine in blood is 0.03 to 30 μg/mL (for example, 0.1 to 10 μg/mL). Furthermore, as a result of the administration, the concentration of phenylacetyl-L-glutamine in blood may become 0.01 to 10 μg/mL (for example, 0.03 to 10 μg/mL).
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a plurality of humans (for example, patients with chronic kidney disease), and a ratio of a concentration of indoxyl sulfate in urine to a concentration of indoxyl sulfate in blood in each individual (a concentration in urine/a concentration in blood) shows high correlation. In this embodiment, high correlation may be indicated by a Pearson test in which an r value is 0.4 to 1, 0.5 to 1, 0.6 to 1, or 0.7 to 1 (preferably 0.7 to 1). In addition, the pharmaceutical composition provided by the present invention may be administered to a human (for example, a patient with chronic kidney disease) in which a concentration of indoxyl sulfate in blood is 0.01 to 10 μg/mL (for example, 0.1 to 10 μg/mL), and as a result of the administration, a concentration of indoxyl sulfate in blood may become 0.01 to 10 μg/mL (for example, 0.1 to 10 μg/mL).
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a plurality of humans (for example, patients with chronic kidney disease), and a ratio of a concentration of p-cresyl sulfate in urine to a concentration of p-cresyl sulfate in blood in each individual (a concentration in urine/a concentration in blood) shows high correlation. In this embodiment, high correlation may be indicated by a Pearson test in which an r value is 0.4 to 1, 0.5 to 1, 0.6 to 1, or 0.7 to 1 (preferably 0.7 to 1). In addition, the pharmaceutical composition provided by the present invention may be administered to a human (for example, a patient with chronic kidney disease) in which a concentration of p-cresyl sulfate in blood is 0.001 to 100 μg/mL (for example, 0.01 to 50 μg/mL), and as a result of the administration, a concentration of p-cresyl sulfate in blood may become 0.001 to 100 μg/mL (for example, 0.01 to 50 μg/mL).
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a plurality of humans (for example, patients with chronic kidney disease), and a ratio of a concentration of phenylacetyl-L-glutamine in urine to a concentration of phenylacetyl-L-glutamine in blood in each individual (a concentration in urine/a concentration in blood) shows high correlation. In this embodiment, high correlation may be indicated by a Pearson test in which an r value is 0.4 to 1, 0.5 to 1, 0.6 to 1, or 0.7 to 1 (preferably 0.7 to 1). In addition, the pharmaceutical composition provided by the present invention may be administered to a human (for example, a patient with chronic kidney disease) in which a concentration of phenylacetyl-L-glutamine in blood is 0.01 to 10 μg/mL (for example, 0.05 to 10 μg/mL), and as a result of the administration, a concentration of phenylacetyl-L-glutamine in blood may become 0.01 to 10 μg/mL (for example, 0.05 to 10 μg/mL).
Because of the characteristics of the pharmaceutical composition provided by the present invention, the pharmaceutical composition provided by the present invention, in one aspect, not only can be used as a pharmaceutical composition for decreasing a concentration of uremic substance in blood and/or a pharmaceutical composition for promoting excretion of uremic substance into urine, but also can be used as any of a pharmaceutical composition for ameliorating uremic symptoms in a patient with kidney disease, a pharmaceutical composition for treating and/or preventing uremic symptoms in a patient with kidney disease, a pharmaceutical composition for suppressing progression of chronic kidney disease, and a pharmaceutical composition for delaying introduction of dialysis in a patient with chronic kidney disease.
In the present specification, the term “amelioration” is a concept encompassing bringing “pathological” or “abnormal” symptoms, conditions, or diseases closer to “healthy” or “normal” conditions, or action therefor; and making “pathological” or “abnormal” symptoms, conditions, or diseases “healthy” or “normal” conditions, or action therefor. Accordingly, in one embodiment, the term “amelioration” encompasses a concept in which a numerical value indicative of “pathological” or “abnormal” symptoms or conditions decreases or increases in accordance with the “amelioration,” and becomes closer to a normal value or becomes a normal value. In another embodiment, the term “amelioration” encompasses a concept in which, in accordance with the “amelioration,” a concentration of uremic substance in blood is decreased, a concentration of uremic substance in urine increases, and a concentration of uremic substance in urine may turn to a decrease when a concentration of uremic substance in blood becomes sufficiently small.
In the present specification, the term “healthy” represents a state in which there is no acute or chronic disease or disorder, and the term “normal” represents in a state that a healthy subject usually expresses.
In the present specification, the term “treatment” encompasses a concept in which “pathological” or “abnormal” symptoms, conditions, or diseases are eliminated, completely cured, healed, or in remission, and action therefor; a deterioration in “pathological” or “abnormal” symptoms, conditions, or diseases is suppressed, and action therefor; and the “amelioration.” The term suppression has the meaning to be described later. In one embodiment, the term “treatment” means that “pathological” or “abnormal” symptoms, conditions, or diseases are eliminated, completely cured, healed, or in remission, and means action therefor. In another embodiment, the term “treatment” means that “pathological” or “abnormal” symptoms, conditions, or diseases are eliminated, completely cured, healed, or in remission.
In the present specification, the term “prevention” encompasses a concept in which onset of “pathological” or “abnormal” symptoms, conditions, or diseases is prevented before they occur, and action therefor.
In the present specification, the term “delay” encompasses a concept in which a time for an object phenomenon to occur is extended, and action therefor; and a time is extended so that the object phenomenon does not occur.
In the present specification, the term “suppression” encompasses a concept in which a deterioration or progression of symptoms, conditions, or diseases is stopped or slowed down, or action therefor; and the symptoms, conditions, or the diseases are ameliorated, or action therefor. The term amelioration has the meaning as described above. The above-mentioned “deterioration or progression of symptoms, conditions, or diseases” includes a deterioration or progression of “pathological” or “abnormal” symptoms, conditions, or diseases; and a deterioration or progression of “pathological” or “abnormal” symptoms, conditions, or diseases from “healthy” or “normal” conditions. In one embodiment, the term “suppression” means that a deterioration or progression of symptoms, conditions, or diseases is stopped or slowed down, or means action therefor. In another embodiment, the term “suppression” means that a deterioration or progression of symptoms, conditions, or diseases is stopped or slowed down.
The symptoms, conditions, or diseases are compared before and after administration of the pharmaceutical composition provided by the present invention.
In addition, because of the characteristics of the pharmaceutical composition provided by the present invention as described above, in one aspect, the pharmaceutical composition provided by the present invention can be used as any of a pharmaceutical composition for suppressing myocardial fibrosis in a patient with kidney disease, a pharmaceutical composition for suppressing arteriosclerosis in a patient with kidney disease, a pharmaceutical composition for suppressing vascular smooth muscle cell proliferation in a patient with kidney disease, a pharmaceutical composition for suppressing vascular endothelial cell injury in a patient with kidney disease, a pharmaceutical composition for suppressing thickening of the arterial wall of a patient with kidney disease, a pharmaceutical composition for suppressing calcification of the aorta of a patient with kidney disease, and a pharmaceutical composition for treating and/or preventing cardiovascular disease associated with chronic kidney disease.
In addition, it has been reported that, when a drug that decreases a concentration of indoxyl sulfate in blood was administered to a patient with non-diabetic chronic kidney disease, the pulse wave velocity and carotid intima-media complex thickness, which are indicators of arteriosclerosis, were significantly improved compared to those before administration (Nakamura T., et al.: Oral ADSORBENT AST-120 decreases carotid intima-media thickness and arterial stiffness in patients with chronic renal failure. Kidney Blood Press Res, 27:121-6, 2004). Accordingly, in one aspect, the pharmaceutical composition provided by the present invention which decreases the concentration of indoxyl sulfate in blood can be used as a pharmaceutical composition for ameliorating arteriosclerosis or a pharmaceutical composition for ameliorating thickening of the arterial wall (for example, carotid artery) of a patient with kidney disease (preferably a patient with chronic kidney disease, more preferably a patient with non-diabetic chronic kidney disease).
In addition, drugs that decrease the concentration of indoxyl sulfate in blood have been reported to suppress cisplatin-induced acute kidney injury (Morisaki T., et. Al., Regulation of renal organic ion transporters in cisplatin-induced acute kidney injury and uremia in rats. Pharm. Res., 25 (11): 2526-33, 2008). Accordingly, in one aspect, the pharmaceutical composition provided by the present invention which decreases the concentration of indoxyl sulfate in blood can be used as a pharmaceutical composition for treating acute kidney failure, or a pharmaceutical composition for suppressing progression from acute kidney failure to chronic kidney disease.
In addition, p-cresyl sulfate, which is a uremic substance, has been reported to be a causative substance of vascular endothelial damage (Meijers B. K., et. Al., The uremic retention solute p-cresyl sulfate and markers of endothelial damage., Am. J. Kidney Dis., 54: 891-901, 2009).
In one aspect, the pharmaceutical composition provided by the present invention which promotes excretion of p-cresyl sulfate into urine can be used as a pharmaceutical composition for suppressing vascular endothelial damage in a patient with kidney disease (preferably a patient with chronic kidney disease).
In addition, phenylacetyl-L-glutamine, which is a uremic substance, has been reported to increase the risk of developing cardiovascular disease in a patient with chronic kidney disease.
In one aspect, the pharmaceutical composition provided by the present invention which promotes excretion of phenylacetyl-L-glutamine into urine can be used as a pharmaceutical composition for treating and/or preventing cardiovascular disease in a patient with chronic kidney disease.
In one embodiment, since the pharmaceutical composition provided by the present invention promotes excretion of uremic substance into urine, such as indoxyl sulfate, p-cresyl sulfate, hippuric acid, argininosuccinic acid, and phenylacetyl-L-glutamine, the pharmaceutical composition provided by the present invention can be used as a pharmaceutical composition for promoting excretion of indoxyl sulfate, p-cresyl sulfate, hippuric acid, argininosuccinic acid, and/or phenylacetyl-L-glutamine into urine of a patient with kidney disease (preferably a patient with chronic kidney disease).
In one embodiment, in order to decrease indoxyl sulfate concentration in the blood, p-cresyl sulfate concentration in blood, hippuric acid concentration in blood, and/or phenylacetyl-L-glutamine concentration in blood, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof (for example, a mixture of potassium citrate monohydrate and sodium citrate dihydrate) is administered to a patient with kidney disease (preferably a patient with chronic kidney disease).
In one embodiment, in order to increase indoxyl sulfate concentration in urine, p-cresyl sulfate concentration in urine, urinary hippuric acid concentration, urinary argininosuccinic acid concentration, and/or urinary phenylacetyl-L-glutamine concentration (preferably to increase indoxyl sulfate concentration in urine, p-cresyl sulfate concentration in urine, and phenylacetyl-L-glutamine concentration in urine), a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof (for example, a mixture of potassium citrate monohydrate and sodium citrate dihydrate) is administered to a patient with kidney disease (preferably a patient with chronic kidney disease).
In one embodiment, sodium bicarbonate is administered to a patient with kidney disease (preferably a patient with chronic kidney diseases) to decrease blood p-cresyl sulfate concentration and/or blood phenylacetyl-L-glutamine concentration.
In one embodiment, sodium bicarbonate is administered to a patient with kidney disease (preferably a patient with chronic kidney disease) to increase the urinary argininosuccinic acid concentration.
In one aspect, the pharmaceutical composition provided by the present invention can be used as a pharmaceutical composition for treating kidney tubular damage, a pharmaceutical composition for preventing kidney tubular damage, or a pharmaceutical composition for suppressing kidney tubular damage. A kidney tubule may be, for example, a kidney proximal tubule.
In another aspect, the pharmaceutical composition provided by the present invention can be used as a pharmaceutical composition for maintaining kidney function.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for suppressing kidney tubular cell damage, a pharmaceutical composition for protecting kidney tubular cells, or a pharmaceutical composition for maintaining kidney tubular cell function (for example, reabsorption of water, sodium ion, potassium ion, calcium ion, phosphate ion, bicarbonate ion, chloride ion, glucose, amino acid, vitamin, and the like).
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for suppressing kidney proximal tubular cell damage, a pharmaceutical composition for protecting kidney proximal tubular cells, or a pharmaceutical composition for maintaining kidney proximal tubular cell function (for example, reabsorption of glucose, amino acid, vitamin, and the like).
In one embodiment, the pharmaceutical composition provided by the present invention suppresses an increase in the amount (concentration) of β2-microglobulin in urine (for example, early morning urine) associated with progression of a stage of chronic kidney disease.
In one embodiment, the pharmaceutical composition provided by the present invention does not affect the glomerular function of a patient with chronic kidney disease, whereas it suppresses kidney proximal tubular cell damage associated with progression of a stage of chronic kidney disease to protect kidney proximal tubular cells.
In the present specification, “maintenance of kidney function” means, for example, suppression of kidney tubular damage, protection of kidney tubular cells, or maintenance of kidney tubular function. A kidney tubule may be, for example, a kidney proximal tubule, and one aspect of maintenance of kidney tubular function or kidney proximal tubular function is to maintain kidney tubular cell function or to maintain kidney proximal tubular cell function.
In the present specification, “protection of cells” means maintenance or preservation of cell states or suppression of cell damage. The term suppression has the above-mentioned meaning.
In the present specification, “maintenance of cell function” means preservation of cell function or suppression of deterioration of cell function. The term suppression has the above-mentioned meaning.
The state or function of cells is compared before and after administration of the pharmaceutical composition provided by the present invention.
In the present specification, “early morning urine” represents the first urine after getting up.
In one embodiment, the pharmaceutical composition provided by the present invention suppresses an increase in the amount (concentration) of β2-microglobulin in urine (for example, early morning urine) 6 weeks, 12 weeks, and/or 24 weeks after administration, as compared with that before the start of administration.
In one embodiment, the pharmaceutical composition provided by the present invention suppresses an increase in the amount (concentration) of β2-microglobulin in urine (for example, early morning urine) associated with progression of a stage of chronic kidney disease, but an amount (concentration) of β2-microglobulin in urine (for example, early morning urine) is not substantially decreased compared to that before the start of administration of the pharmaceutical composition provided by the present invention. In this embodiment, for example, in a case where the amount (concentration) of β2-microglobulin in urine (for example, early morning urine) before the start of administration of the pharmaceutical composition provided by the present invention is 1, the amount (concentration) of β2-microglobulin in urine (for example, early morning urine) after administration may be 0.7 to 1.0 or 1.0 or more, 0.8 to 1.0 or 1.0 or more, 0.85 to 1.0 or 1.0 or more, 0.9 to 1.0 or 1.0 or more 0.7 to 2.0, 0.8 to 2.0, 0.85 to 2.0, 0.9 to 2.0, 0.7 to 1.6, 0.8 to 1.6, 0.85 to 1.6, or 0.9 to 1.6.
In one embodiment, the pharmaceutical composition provided by the present invention suppresses an increase in the amount (concentration) of β2-microglobulin in urine (for example, early morning urine) associated with progression of a stage of chronic kidney disease, but an amount (concentration) of β2-microglobulin in urine (for example, early morning urine) is not substantially decreased 6 weeks after administration, 12 weeks after administration, and/or 24 weeks after administration, compared to that before the start of administration of the pharmaceutical composition provided by the present invention. In this embodiment, for example, in a case where the amount (concentration) of β2-microglobulin in urine (for example, early morning urine) before the start of administration of the pharmaceutical composition provided by the present invention is 1, the amount (concentration) of β2-microglobulin in urine (for example, early morning urine) 6 weeks after administration, 12 weeks after administration, or 24 weeks after administration may be 0.7 to 1.0 or 1.0 or more, 0.8 to 1.0 or 1.0 or more, 0.85 to 1.0 or 1.0 or more, 0.9 to 1.0 or 1.0 or more 0.7 to 2.0, 0.8 to 2.0, 0.85 to 2.0, 0.9 to 2.0, 0.7 to 1.6, 0.8 to 1.6, 0.85 to 1.6, or 0.9 to 1.6.
In one embodiment, the pharmaceutical composition provided by the present invention does not substantially increase the amount (concentration) of cystatin C in the blood (for example, plasma) compared to before the start of administration. In this embodiment, for example, in a case where the amount (concentration) of cystatin C in blood (for example, in plasma) before the start of administration of the pharmaceutical composition provided by the present invention is 1, the amount (concentration) of cystatin C in blood (for example, in plasma) after administration may be 1.0 or less or 1.0 to 1.2, 1.0 or less or 1.0 to 1.15, 1.0 or less or 1.0 to 1.1, 1.0 or less or 1.0 to 1.05, 0.9 to 1.2, 0.9 to 1.15, 0.9 to 1.1, 0.9 to 1.05, 0.95 to 1.2, 0.95 to 1.15, 0.95 to 1.1, or 0.95 to 1.05.
In one embodiment, the pharmaceutical composition provided by the present invention does not substantially increase the amount (concentration) of cystatin C in the blood (for example, plasma) 6 weeks after administration, 12 weeks after administration, and/or 24 weeks after administration, compared to before the start of administration. In this embodiment, for example, in a case where the amount (concentration) of cystatin C in blood (for example, in plasma) before the start of administration of the pharmaceutical composition provided by the present invention is 1, the amount (concentration) of cystatin C in blood (for example, in plasma) 6 weeks after administration, 12 weeks after administration, or 24 weeks after administration may be 1.0 or less or 1.0 to 1.2, 1.0 or less or 1.0 to 1.15, 1.0 or less or 1.0 to 1.1, 1.0 or less or 1.0 to 1.05, 0.9 to 1.2, 0.9 to 1.15, 0.9 to 1.1, 0.9 to 1.05, 0.95 to 1.2, 0.95 to 1.15, 0.95 to 1.1, or 0.95 to 1.05.
In one embodiment, by administration of the pharmaceutical composition provided by the present invention, despite no amelioration in kidney proximal tubular damage and/or glomerular damage is recognized 6 weeks after administration, 12 weeks after administration, and/or 24 weeks after administration as compared to before the start of administration, a decrease in the blood concentration of the uremic substance, promotion of urinary excretion of the uremic substance, and/or promotion of excretion of the uremic substance outside of the body is observed 6 weeks after administration, 12 weeks after administration, and/or 24 weeks after administration, as compared to before the start of administration.
In one embodiment, by administration of the pharmaceutical composition provided by the present invention, despite no amelioration in kidney proximal tubular damage and/or glomerular damage is recognized 6 weeks after administration, 12 weeks after administration, and/or 24 weeks after administration as compared to before the start of administration, a decrease in the blood concentration of the uremic substance, promotion of urinary excretion of the uremic substance, and/or promotion of excretion of the uremic substance outside the body is observed 6 weeks after administration, 12 weeks after administration, and/or 24 weeks after administration, as compared to before the start of administration.
The pharmaceutical composition provided by the present invention is orally or parenterally administered to a human or other mammals. Examples of parenteral administration include intravenous administration, subcutaneous administration, intramuscular administration, intra-articular administration, transmucosal administration, transdermal administration, nasal administration, rectal administration, intrathecal administration, intraperitoneal administration, and local administration
The pharmaceutical composition provided by the present invention may be prepared as an alkalinizing agent as it is or may be prepared by mixing an alkalinizing agent with a pharmaceutically acceptable carrier such as excipients (for example, lactose, D-mannitol, crystalline cellulose, and glucose), binders (for example, hydroxypropylcellulose (HPC), gelatin, and polyvinylpyrrolidone (PVP)), lubricants (for example, magnesium stearate, and talc), disintegrants (for example, starch and carboxymethylcellulose calcium (CMC-Ca)), diluents (for example, water for injection and saline), and other additives if necessary (for example, pH adjusters, surfactants, solubilizers, preservatives, emulsifiers, tonicity agents, and stabilizers), or may be preparation such as a tablet, capsule, suspension, injection, or suppository. For example, in the case of a tablet, the alkalinizing agent may be mixed with excipients (for example, lactose, D-mannitol, crystalline cellulose, and glucose), disintegrants (for example, starch and carboxymethylcellulose calcium (CMC-Ca)), binders (for example, hydroxypropylcellulose (HPC), gelatin, and polyvinylpyrrolidone (PVP)), lubricants (for example, magnesium stearate and talc), and the like to be formulated.
The tablet according to the present invention will be described in more detail below.
In one embodiment, the pharmaceutical composition provided by the present invention is a tablet. The tablet provided by the present invention may comprise pharmaceutically acceptable additives customary in the pharmaceutical field, in addition to an alkalinizing agent (for example, potassium citrate or a hydrate thereof; sodium citrate or a hydrate thereof; a mixture of potassium citrate monohydrate and sodium citrate dihydrate; or sodium bicarbonate). Examples of such additives include excipients, binders, disintegrants, fluidizers, flavoring agents, lubricants, pH adjusters, surfactants, stabilizers, and fragrances.
The content of the alkalinizing agent in the tablet provided by the present invention may be 10% to 95% by weight, preferably 30% to 90% by weight, and more preferably 60% to 85% by weight with respect of the tablet.
Examples of excipients that can be used in the tablets provided by the present invention include lactose (for example, lactose hydrate, and anhydrous lactose), sugars such as glucose, sucrose, fructose, and maltose, sugar alcohols such as erythritol, sorbitol, maltitol, xylitol, and D-mannitol, starch (for example, corn starch, potato starch, rice starch, and wheat starch), crystalline cellulose, magnesium aluminate metasilicate, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium lactate, and ethylcellulose, among which crystalline cellulose is particularly preferable.
The content of the excipient in the tablet provided by the present invention may be 1% to 95% by weight, preferably 1% to 80% by weight, more preferably 3% to 80% by weight, and even more preferably 3% to 20% by weight with respect to the tablet.
Examples of binders that can be used in the tablets provided by the present invention include hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, dextrin, methylcellulose, polyvinyl alcohol, sodium alginate, aminoalkyl methacrylate copolymer, polyethylene glycol, pregelatinized starch (for example, partially pregelatinized starch), agar, and gelatin, among which hydroxypropylcellulose is particularly preferable.
The content of the binder in the tablet provided by the present invention may be 0.1% to 30% by weight, preferably 0.1% to 10% by weight, and more preferably 0.3% to 3% by weight with respect to the tablet.
Examples of disintegrants that may be used in tablets provided by the present invention include croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, low substituted hydroxypropylcellulose, crospovidone, starch (for example, wheat starch, corn starch, and partially pregelatinized starch), and carmellose, among which partially pregelatinized starch is particularly preferable.
The content of the disintegrant in the tablet provided by the present invention may be 0.3% to 20% by weight, preferably 1% to 10% by weight, and more preferably 3% to 10% by weight with respect to the tablet.
Examples of fluidizers that can be used in the tablets provided by the present invention include light anhydrous silicic acid, talc, and magnesium aluminate metasilicate.
The content of the fluidizers in the tablet provided by the present invention may be 0.03% to 3% by weight, preferably 0.1% to 3% by weight, and more preferably 0.3% to 3% by weight with respect to the tablet.
Examples of flavoring agents that can be used in the tablets provided by the present invention include citric acid (for example, anhydrous citric acid), acidulants such as malic acid, acetic acid, tartaric acid, fumaric acid, and ascorbic acid (where, the said flavoring agent does not comprise the alkalinizing agent according to the present invention), saccharin sodium, dipotassium glycyrrhizinate, aspartame (registered trademark), and sweeteners such as stevia, thaumatin, and sucralose.
The content of the flavoring agent in the tablet provided by the present invention may be 0.03% to 3% by weight, preferably 0.1% to 3% by weight, and more preferably 0.3% to 3% by weight with respect to the tablet.
Examples of lubricants that can be used in the tablets provided by the present invention include magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, sucrose fatty acid esters, carnauba wax, macrogol, and sodium stearyl fumarate, among which magnesium stearate is particularly preferable.
The lubricant content in the tablet provided by the present invention may be 0.1% to 30% by weight, preferably 0.3% to 10% by weight, and more preferably 1% to 3% by weight with respect to the tablet.
Examples of pH adjusters that can be used in the tablets provided by the present invention include citric acid, phosphates (for example, sodium dihydrogen phosphate and potassium dihydrogen phosphate), carbonates (for example, magnesium carbonate and sodium carbonate), tartrate, fumarate, acetate, and amino acid salts (where, the pH adjuster does not include the alkalinizing agent according to the present invention).
The content of the pH adjuster in the tablet provided by the present invention may be 0.1% to 30% by weight, preferably 0.3% to 10% by weight, and more preferably 1% to 5% by weight with respect to the tablet.
Examples of surfactants that can be used in the tablets provided by the present invention include sodium lauryl sulfate, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, macrogol, and poloxamer. The content of the surfactant in the tablet provided by the present invention may be 0.01% to 3% by weight, preferably 0.03% to 1% by weight, and more preferably 0.03% to 0.5% by weight with respect to the tablet.
Examples of stabilizers that can be used in tablets provided by the present invention include citric acid (for example, anhydrous citric acid), malic acid, acetic acid, tartaric acid, maleic acid, ascorbic acid, edetate sodium, and tocopherol (where, the stabilizer does not include the alkalinizing agent according to the present invention), among which anhydrous citric acid is particularly preferable.
The content of the stabilizer in the tablet provided by the present invention may be 0.01% to 30% by weight, preferably 0.1% to 30% by weight, and more preferably 1% to 20% by weight with respect to the tablet.
Examples of fragrances that can be used in the tablets provided by the present invention include citrus flavors such as lemon, orange, and grapefruit, peppermint, spearmint, and menthol. An appropriate amount thereof can be contained in the tablet (for example, 0.01% to 1% by weight, and more preferably 0.01% to 0.1% by weight with respect to the tablet).
The total content of the alkalinizing agent and the pharmaceutically acceptable additives in the tablet provided by the present invention does not exceed 100% by weight with respect to the tablet.
The tablet provided by the present invention can be an uncoated tablet comprising the above components and not having a coating layer, or a film-coated tablet having a coating layer. The content of the coating layer can be appropriately set by those skilled in the art. For example, it may be 0.1% to 10% by weight with respect to the uncoated tablet. In the coating layer, in addition to the coating base, a plasticizer, a coloring agent, a brightening agent, and the like can be appropriately incorporated. Examples of coating bases that can be used for tablets provided by the present invention include hydroxypropylcellulose, hydroxypropyl methylcellulose, ethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer, and polyvinylpyrrolidone, among which hydroxypropyl methylcellulose is particularly preferable. The content of the coating base in the tablet provided by the present invention may be 0.01% to 10% by weight, and preferably 0.3% to 3% by weight with respect to the tablet.
Examples of coating plasticizers that can be used in tablets provided by the present invention include triethyl citrate, medium chain fatty acid triglyceride, triacetin, glycerin, and propylene glycol and polyethylene glycol (for example, Macrogol 6000), among which Macrogol 6000 is particularly preferable. The content of the coating plasticizer in the tablet provided by the present invention may be 0.01% to 1% by weight, and preferably 0.03% to 3% by weight with respect to the tablet.
Examples of coating colorants that can be used in the tablets provided by the present invention include titanium oxide, yellow iron sesquioxide, iron sesquioxide, black iron oxide, food blue No. 2, and food blue No. 2 aluminum lake. The content of the coating colorant in the tablet provided by the present invention may be 0.01% to 1% by weight, and preferably 0.03% to 3% by weight with respect to the tablet.
Examples of coating brighteners that can be used in tablets provided by the present invention include carnauba wax. The content of the coating brightener in the tablet provided by the present invention may be 0.0001% to 0.1% by weight, and preferably 0.001% to 0.01% by weight with respect to the tablet.
The pharmaceutical composition provided by the present invention can be produced by a method known in the pharmaceutical field. For example, in the case of tablets, the production method may comprise a mixing step of mixing an additive with an alkalinizing agent (for example, potassium citrate or a hydrate thereof; sodium citrate or a hydrate thereof; a mixture of potassium citrate monohydrate and sodium citrate dihydrate; or sodium bicarbonate), a granulation step, a tableting step, and/or a coating step.
The mixing step may comprise a step of mixing an alkalinizing agent and an additive such as an excipient, a stabilizer, a disintegrant and/or a binder. In addition, before the tableting step, a step in which a mixture comprising the alkalinizing agent and an additive is mixed with a lubricant, flavoring agent, and/or fragrance may further be provided. Mixing can be performed using a V-type mixer, a W-type mixer, a container mixer, a tumbler mixer, a stirring mixer, or the like.
The granulation step can be performed by a known granulation method in the pharmaceutical field. Examples of granulation methods include a dry granulation method, a wet granulation method, and a fluidized bed granulation method.
As one embodiment, the mixture obtained in the mixing step and the granulated product obtained in the granulation step are appropriately pulverized and/or sieved to obtain a mixture or granulated product having a desired particle size. The pulverization can be performed by a pulverizer known in the pharmaceutical field, such as a ball mill, a jet mill, or a hammer mill. The sieving can be performed using a 16 mesh sieve (aperture of 1000 μm) to 32 mesh sieve (aperture of 500 μm), and the like.
The tableting step can be performed by a tableting method known in the pharmaceutical field. Examples of tableting methods include a direct tableting method, a dry tableting method, a wet tableting method, and an external lubricant tableting method. For example, the mixture or granulated product obtained in the above steps can be tableted using a tableting machine known in the pharmaceutical field, such as a single-shot tableting machine or a rotary tableting machine. When using a single tableting machine, a rotary tableting machine, and the like, a tableting pressure of 1 kN to 30 kN can be employed.
The coating step can be performed by a method known in the pharmaceutical field. For example, the coating can be performed by spray coating the outside of the uncoated tablet with a coating liquid appropriately comprising a coating base, and a plasticizer, colorant, brightener, or the like.
In one embodiment, the tablet provided by the present invention can be produced by mixing an alkalinizing agent with excipients (for example, lactose, D-mannitol, crystalline cellulose, and/or glucose), binders (for example, hydroxypropylcellulose (HPC), gelatin, and/or polyvinylpyrrolidone (PVP)), stabilizers (for example, anhydrous citric acid), disintegrants (for example, starch (for example, partially pregelatinized starch) and/or carboxymethylcellulose calcium (CMC-Ca)), and lubricants (for example, magnesium stearate) to obtain uncoated tablets by tableting; and forming, on the outside of the uncoated tablet, a coating layer comprising a coating base (for example, hydroxypropylcellulose, hydroxypropyl methylcellulose, and/or PVP), plasticizers (for example, triethyl citrate and/or Macrogol 6000), colorants (for example, iron sesquioxide and/or titanium oxide), and brighteners (for example, carnauba wax).
In one embodiment, the tablets obtained can have a hardness of 10 to 200 N, preferably 30 to 150 N.
The amount of the alkalinizing agent in the pharmaceutical composition provided by the present invention can be appropriately set.
In one embodiment, the amount of the alkalinizing agent in the pharmaceutical composition provided by the present invention may be set to an amount that enables amelioration in acid urine in gout or hyperuricemia by administering the alkalinizing agent to a human, or an amount smaller that the above amount. For example, an amount may be set to be 1% to 50% or 10% to 20% of the daily dose approved in Japan for amelioration in acid urine in gout or hyperuricemia (for example, in a case where the alkalinizing agent is a citric acid preparation: a tablet in which one tablet comprises 231.5 mg of potassium citrate (C6H5K3O7.H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7.2H2O) is orally administered 3 times a day, 2 tablets at one time; and in a case where the alkalinizing agent is sodium bicarbonate: oral administration of 3 to 5 g a day).
In one embodiment, the pharmaceutical composition provided by the present invention is a tablet, and it may comprise 10 mg to 1 g, preferably, 100 mg to 500 mg, and more preferably 400 mg to 500 mg of potassium citrate monohydrate or sodium citrate dihydrate as an alkalinizing agent in one tablet.
In one embodiment, the pharmaceutical composition provided by the present invention is a tablet, and it may comprise, in one tablet, 10 mg to 300 mg for each, a total of 20 mg to 600 mg, preferably, 150 to 250 mg for each, a total of 400 to 500 mg, and more preferably 190 to 240 mg for each, a total of 400 to 450 mg of potassium citrate monohydrate and sodium citrate dihydrate.
In one embodiment, the pharmaceutical composition provided by the present invention is a tablet, and may comprise, in one tablet, 10 mg to 1 g, preferably 100 mg to 500 mg of sodium bicarbonate as an alkalinizing agent.
In one embodiment, the pharmaceutical composition provided by the present invention is a tablet, and it comprises, as an alkalinizing agent, potassium citrate monohydrate 231.5 mg and sodium citrate dihydrate 195.0 mg; and may comprise, as an additive, anhydrous citric acid, crystalline cellulose, partially pregelatinized starch, hydroxypropylcellulose, magnesium stearate, hypromellose, macrogol 6000, titanium oxide, and carnauba wax.
As one embodiment, a tablet comprising potassium citrate monohydrate 231.5 mg and sodium citrate dihydrate 195.0 mg may be a single dosage unit.
In the present specification, “dosage unit” represents a unit of the preparation, and “one dosage unit” represents the minimum unit of the preparation. Accordingly, for example, in the case of tablets, the dosage unit is each tablet, and one dosage unit represents one tablet. In the case of an injection, the dosage unit is an injection contained in a sealed container such as an ampoule or vial, and one dosage unit represents an injection contained in a sealed container such as one ampoule or vial.
In a case where the pharmaceutical composition provided by the present invention is administered to a human or other mammals, one or more of the above dosage units may be administered at one time, or the one dosage unit may be divided and administered.
The dose of the alkalinizing agent is appropriately determined according to the type of the alkalinizing agent, the method of administration, the age, weight, sex, symptom, sensitivity to the drug, and the like of a subject of administration, but it may be adjusted depending on the condition of symptom amelioration.
In one embodiment, in a case of an oral administration of a mixture of potassium citrate monohydrate and sodium citrate dihydrate or sodium bicarbonate as an alkalinizing agent to a human, half of the daily dose approved in Japan for amelioration in acid urine in gout or hyperuricemia (for example, in a case where the alkalinizing agent is a citric acid preparation: a tablet in which one tablet comprises 231.5 mg of potassium citrate (C6H5K3O7.H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7.2H2O) is orally administered 3 times a day, 2 tablets at one time; and in a case where the alkalinizing agent is sodium bicarbonate: oral administration of 3 to 5 g a day) may be set to a daily dose.
In one embodiment, in a case of an oral administration of a mixture of potassium citrate monohydrate and sodium citrate dihydrate or sodium bicarbonate as an alkalinizing agent to a human, the daily dose approved in Japan for amelioration in acid urine in gout or hyperuricemia (for example, in a case where the alkalinizing agent is a citric acid preparation: a tablet in which one tablet comprises 231.5 mg of potassium citrate (C6H5K3O7.H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7.2H2O) is orally administered 3 times a day, 2 tablets at one time; and in a case where the alkalinizing agent is sodium bicarbonate: oral administration of 3 to 5 g a day) may be set to a daily dose.
In one embodiment, in a case of an oral administration of a mixture of potassium citrate monohydrate and sodium citrate dihydrate or sodium bicarbonate as an alkalinizing agent to a human, half of the daily dose approved in Japan for amelioration in acid urine in gout or hyperuricemia (for example, in a case where the alkalinizing agent is a citric acid preparation: a tablet in which one tablet comprises 231.5 mg of potassium citrate (C6H5K3O7.H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7.2H2O) is orally administered 3 times a day, 2 tablets at one time; and in a case where the alkalinizing agent is sodium bicarbonate: oral administration of 3 to 5 g a day) may be set to a daily dose to start administration, and thereafter, the dosage may be increased to a daily dosage approved in Japan for the amelioration of acidic urine in gout and hyperuricemia.
In one embodiment, the dosage amount of the alkalinizing agent may be a dosage amount such that, when the alkalinizing agent is orally administered, the pH of human urine (for example, early morning urine) becomes pH 5.2 to pH 6.8, pH 5.5 to pH 6.8, pH 5.8 to pH 6.8, pH 5.8 to pH 6.5, pH 5.8 to pH 6.2, pH 5.8 or more and less than pH 6.2, pH 6.0 to pH 6.5, pH 6.0 to pH 6.4, pH 6.0 to pH 6.3, pH 6.0 to pH 6.2, pH 6.0 or more and less than pH 6.2, pH 6.1 to pH 6.3, pH 6.2 to 6.8, pH 6.2 to pH 6.5, or pH 6.5 to 6.8.
In one embodiment, the dosage amount of the alkalinizing agent may be a dosage amount such that, when the alkalinizing agent is orally administered, the pH of human urine (for example, early morning urine) becomes pH 5.2 to pH 6.8, pH 5.5 to pH 6.8, pH 5.8 to pH 6.8, pH 5.8 to pH 6.5, pH 5.8 to pH 6.2, pH 5.8 or more and less than pH 6.2, pH 6.0 to pH 6.5, pH 6.0 to pH 6.4, pH 6.0 to pH 6.3, pH 6.0 to pH 6.2, pH 6.0 or more and less than pH 6.2, pH 6.1 to pH 6.3, pH 6.2 to 6.8, pH 6.2 to pH 6.5, or pH 6.5 to 6.8, 6 weeks, 12 weeks, or 24 weeks after the oral administration of the alkalinizing agent.
In one embodiment, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate as an alkalinizing agent is orally administered to a human, potassium citrate monohydrate and sodium citrate dihydrate may be administered at 0.1 to 5 g/day for each, a total of 0.2 to 10 g/day, 0.1 to 3 g/day for each, a total of 0.2 to 6 g/day, 0.5 to 3 g/day for each, a total of 1 to 6 g/day, preferably, 0.5 to 1.5 g/day for each, a total of 1 to 3 g/day, 1 to 1.5 g/day for each, a total of 2 to 3 g/day, or 0.5 to 1 g/day for each, a total of 1 to 2 g/day; or may be divided and administered 1 to 5 times a day, preferably 3 times a day.
In one embodiment, when potassium citrate monohydrate or sodium citrate dihydrate is orally administered to a human as an alkalinizing agent, it may be administered at 1 to 10 g/day, 1 to 6 g/day, 2 to 5.5 g/day, 1 to 3 g/day, 2 to 3 g/day, or 1 to 1.5 g/day; or may be divided and administered 1 to 5 times a day, preferably 3 times a day.
In one embodiment, when sodium bicarbonate is orally administered to a human as an alkalinizing agent, it may be administered at 1 to 6 g/day, preferably 1 to 3 g/day, or 3 to 5 g/day; or may be divided and administered 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the alkalinizing agent may be administered for a long period of time, for example, for 1 week, 2 weeks, 3 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 40 weeks, 60 weeks, 80 weeks, 100 weeks, 120 weeks, 1 week or more, 2 weeks or more, 3 weeks or more, 6 weeks or more, 8 weeks or more, 10 weeks or more, 12 weeks or more, 24 weeks or more, 40 weeks or more, 60 weeks or more, 80 weeks or more, 100 weeks or more, 120 weeks or more, 6 to 24 weeks, 12 to 24 weeks, 6 to 30 weeks, 12 to 30 weeks, 6 to 40 weeks, 12 to 40 weeks, 6 to 60 weeks, 12 to 60 weeks, 6 to 80 weeks, 12 to 80 weeks, 6 to 100 weeks, 12 to 100 weeks, 6 to 120 weeks, or 12 to 120 weeks.
In one embodiment, by continuous administration for 6 weeks, continuous administration for 12 weeks, and/or continuous administration for 24 weeks of the pharmaceutical composition provided by the present invention, beneficial effects for a patient with kidney disease (for example, chronic kidney disease) (for example, an effect of decreasing a concentration of uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and/or argininosuccinic acid) in blood, an effect of increasing a concentration of uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and/or argininosuccinic acid) in urine (an effect of promoting excretion into urine), and/or an effect of increasing a urinary β2-microglobulin concentration) can be detected.
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a human suffering from kidney disease. Kidney disease includes acute kidney failure and chronic kidney disease unless otherwise specified.
Examples of acute kidney failure include acute kidney failure due to drugs (for example, platinum preparations such as non-steroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, aminoglycoside antibiotics, new quinolone antibacterials, iodinated contrast agents, platinum preparations such as cisplatin, and the like), and acute kidney failure caused by kidney ischemia.
Chronic kidney disease (CKD) is a concept encompassing kidney disease that chronically progresses regardless of the underlying disease, and is a concept encompassing all clinical conditions in which kidney function expressed by glomerular filtration rate (GFR) deteriorates, or findings that suggest damage in kidneys is maintained chronically (3 months or longer).
According to the CKD Medical Guide 2012 (Nichijinkaishi 2012), the severity of chronic kidney disease is evaluated by classification according to cause (Cause: C), kidney function (GFR: G), and proteinuria (albuminuria: A).
The classification of GFR is as follows.
The classification by proteinuria (albuminuria: A) is classified as follows using the urine albumin/creatinine (Cr) ratio when the primary disease is diabetes.
In addition, in a case where the primary disease is hypertension other than diabetes, nephritis, polycystic kidneys, transplanted kidneys, and the like, proteinuria (albuminuria: A) is classified using the urine protein/creatinine (Cr) ratio as follows.
According to CKD medical care guide 2012 (Nichijinkaishi 2012), the severity classification of chronic kidney disease (CKD) is expressed as, for example, diabetes G2A3, chronic nephritis G3bA1, and the like using the above C, G, and A.
However, it is considered that the severity of chronic kidney disease has conventionally been described only in the stages classified by GFR, and as in the related art, the severity of chronic kidney disease can be expressed in stages of G1, G2, G3a, G3b, G4, and G5.
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with low-severity, early-stage chronic kidney diseases.
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease of stage G3b or lower, preferably stage G2 or lower.
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease in stage G2 or more and stage G3b or less (for example, stage G2 and stage G3a; or stage G2, stage G3a and stage G3b).
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease in stage G3b or less and microalbuminuria, preferably administered to a patient with kidney disease in stage G2 and chronic albuminuria.
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease in stage G2 or more and stage G3b or less (for example, stage G2 and stage G3a; or stage G2, stage G3a and stage G3b) and which is microalbuminuria.
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease in stage G3b or lower and whose urinary protein excretion is less than 3.5 g/gCr, and is preferably administered to a patient with chronic kidney disease in stage G2 and whose urinary protein excretion is less than 3.5 g/gCr.
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease in stage G2 or more and stage G3b or less (for example, stage G2 and stage G3a; or stage G2, stage G3a and stage G3b) and whose urinary protein excretion is less than 3.5 g/gCr.
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with progressive chronic kidney disease.
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease whose concentration of β2-microglobulin in urine (for example, early morning urine) is 2000 μg/L or less, 1000 μg/L or less, 800 μg/L or less, 290 μg/L or less, 200 μg/L or less, 1 to 2000 μg/L, 1 to 1000 μg/L, 1 to 800 μg/L, 1 to 290 μg/L, 1 to 200 μg/L, 10 to 2000 μg/L, 10 to 1000 μg/L, 10 to 800 μg/L, 10 to 290 μg/L, 10 to 200 μg/L, or 80 to 200 μg/L.
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease whose cystatin C in blood (for example, in plasma or in serum) is 0.1 to 3.0 mg/L, 0.1 to 2.0 mg/L, 0.1 to 1.6 mg/L, 0.1 to 1.3 mg/L, 0.5 to 3.0 mg/L, 0.5 to 2.0 mg/L, 0.5 to 1.6 mg/L, 0.5 to 1.3 mg/L, or 0.9 to 1.3 mg/mL.
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease whose indoxyl sulfate concentration in blood is 0.001 to 100 μg/mL (for example, 0.1 to 30 μg/mL) In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease whose concentration of p-cresyl sulfate in blood is 0.003 to 300 μg/mL (for example, 0.01 to 30 μg/mL).
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease whose hippuric acid concentration in blood is 0.01 to 100 μg/mL (for example, 0.01 to 10 μg/mL).
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease whose argininosuccinic acid concentration in blood is 0.01 to 100 μg/mL (for example, 0.1 to 10 μg/mL).
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease whose concentration of phenylacetyl-L-glutamine in blood is 0.03 to 30 μg/mL (for example, 0.1 to 10 μg/mL).
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient receiving treatment according to a CKD medical guide. For example, it is administered to a patient subjected to, according to CKD medical guide, blood pressure management (administration of RA inhibitors such as ARB and ACE inhibitors, diuretics, Ca antagonists), anti-proteinuria measures (administration of RA inhibitors, and the like), blood glucose level control (administration of a-glucosidase inhibitor, and the like), lipid management (administration of statins, fibrates, and the like), anemia management (for example, erythropoietin administration), and/or bone/mineral measures (bisphosphonate administration and the like).
In one embodiment, the pharmaceutical composition provided by the present invention is used in combination with an antihypertensive agent (for example, ARB, ACE inhibitor, diuretic, Ca antagonist).
In one embodiment, the pharmaceutical composition provided by the present invention is used in combination with a spherical carbonaceous adsorbent (sold in Japan as KREMEZIN (registered trademark)) obtained by oxidation and reduction treatment of spherical fine porous carbon derived from petroleum hydrocarbons at high temperature.
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with low-severity, early-stage chronic kidney disease (for example, a patient with chronic kidney disease in stage G3b or lower, preferably stage G2 to stage G3b, more preferably stage G2 and stage G3a, and even more preferably stage G2), and thereby a concentration of uremic substance (for example, indoxyl sulfate, hippuric acid, and/or phenylacetyl-L-glutamine) in blood of a patient is decreased, and excretion of uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, hippuric acid, argininosuccinic acid, and/or phenylacetyl-L-glutamine) outside the body (for example, into urine) is promoted. In this embodiment, the pharmaceutical composition provided by the present invention may be a pharmaceutical composition for ameliorating uremic symptoms, a pharmaceutical composition for treating or preventing uremia, a pharmaceutical composition for suppressing progression of chronic kidney disease, a pharmaceutical composition for delaying introduction of dialysis, a pharmaceutical composition for suppressing myocardial fibrosis, a pharmaceutical composition for suppressing arteriosclerosis, a pharmaceutical composition for ameliorating arteriosclerosis, a pharmaceutical composition for suppressing vascular smooth muscle cell proliferation, a pharmaceutical composition for suppressing vascular endothelial cell injury, a pharmaceutical composition for suppressing arterial wall thickening, a pharmaceutical composition for ameliorating arterial wall thickening, a pharmaceutical composition for suppressing calcification of the aorta, or a pharmaceutical composition for treating or preventing cardiovascular disease, which is a complication (for example, heart failure, myocardial infarction, stroke, and the like).
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with low-severity, early-stage chronic kidney disease (for example, a patient with chronic kidney disease in stage G3b or lower, preferably stage G2 to stage G3b, more preferably stage G2 and stage G3a, and even more preferably stage G2), and thereby an increase in urinary β2-microglobulin in the patient is suppressed. In this embodiment, the pharmaceutical composition provided by the present invention may be a composition for suppressing damage of kidney tubule (for example, kidney proximal tubule), a composition for suppressing damage of kidney tubular cells (for example, kidney proximal tubular cells), a composition for protecting kidney tubular cells (for example, kidney proximal tubular cells), or a pharmaceutical composition for maintaining kidney tubular cell function (for example, reabsorption of glucose, amino acids, and the like) (for example, kidney proximal tubular cell function).
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease having a moderate severity or higher (for example, a patient with chronic kidney disease in stage G3b or higher), and thereby a concentration of uremic substance (for example, indoxyl sulfate, hippuric acid, and/or phenylacetyl-L-glutamine) in blood of the patient is decreased, and excretion of uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, hippuric acid, argininosuccinic acid, and/or phenylacetyl-L-glutamine) outside the body (for example, into urine) is promoted. In this embodiment, the pharmaceutical composition provided by the present invention may be a pharmaceutical composition for ameliorating uremic symptoms, a pharmaceutical composition for treating or preventing uremia, a pharmaceutical composition for suppressing progression of chronic kidney disease, a pharmaceutical composition for delaying introduction of dialysis, a pharmaceutical composition for suppressing myocardial fibrosis, a pharmaceutical composition for suppressing arteriosclerosis, a pharmaceutical composition for ameliorating arteriosclerosis, a pharmaceutical composition for suppressing vascular smooth muscle cell proliferation, a pharmaceutical composition for suppressing vascular endothelial cell injury, a pharmaceutical composition for suppressing arterial wall thickening, a pharmaceutical composition for ameliorating arterial wall thickening, a pharmaceutical composition for suppressing calcification of the aorta, a pharmaceutical composition for suppressing a decrease in energy production in muscle cells, a pharmaceutical composition for suppressing a decrease in muscle mass and/or muscle strength, or a pharmaceutical composition for treating or preventing cardiovascular disease, which is a complication (for example, heart failure, myocardial infarction, stroke, and the like).
In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease having a moderate severity or higher (for example, a patient with chronic kidney disease in stage G3b or higher), and thereby an increase in urinary β2-microglobulin in the patient is suppressed. In this embodiment, the pharmaceutical composition provided by the present invention may be a composition for suppressing damage of kidney tubule (for example, kidney proximal tubule), a composition for suppressing damage of kidney tubular cells (for example, kidney proximal tubular cells), a composition for protecting kidney tubular cells (for example, kidney proximal tubular cells), or a pharmaceutical composition for maintaining kidney tubular cell function (for example, reabsorption of glucose, amino acids, and the like) (for example, kidney proximal tubular cell function).
Examples of other embodiments of the present invention include the following:
2. Food Composition
In one embodiment, the food composition provided by the present invention comprises an alkalinizing agent and exhibits an effect of promoting excretion, outside the body, of uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and/or argininosuccinic acid, preferably indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine, more preferably indoxyl sulfate and phenylacetyl-L-glutamine, and even more preferably indoxyl sulfate).
In one embodiment, the food composition provided by the present invention comprises an alkalinizing agent and exhibits an effect of decreasing the concentration of uremic substance in blood.
In one embodiment, the food composition provided by the present invention comprises an alkalinizing agent and exhibits an effect of promoting excretion of uremic substance into urine.
In one embodiment, the food composition provided by the present invention comprises an alkalinizing agent and exhibits a kidney function maintenance effect.
In one embodiment, the food composition provided by the present invention comprises an alkalinizing agent and exhibits an effect of suppressing kidney tubular damage. Examples of kidney tubules include a kidney proximal tubule.
In one embodiment, the food composition provided by the present invention comprises an alkalinizing agent and exhibits an effect of suppressing kidney proximal tubular cell damage.
In one embodiment, the food composition provided by the present invention comprises an alkalinizing agent and exhibits an effect of protecting kidney proximal tubular cells.
In one embodiment, the food composition provided by the present invention comprises an alkalinizing agent, and exhibits an effect of maintaining kidney tubular function (for example, reabsorption of water, sodium ion, potassium ion, calcium ion, phosphate ion, bicarbonate ion, chloride ion, glucose, amino acid, vitamin, and the like). Examples of kidney tubules include a kidney proximal tubule, and examples of kidney proximal tubular function include reabsorption of glucose, amino acids, vitamins, and the like.
In the above-described embodiment, the food composition provided by the present invention exhibits an effect of suppressing an increase in the amount (concentration) of β2-microglobulin in urine (for example, early morning urine) associated with progression of a stage of chronic kidney disease.
In the above-described embodiment, the food composition provided by the present invention does not affect the glomerular function of a patient with chronic kidney disease, whereas it exhibits an effect of suppressing kidney proximal tubular cell damage associated with progression of a stage of chronic kidney disease to protect kidney proximal tubular cells.
For the alkalinizing agent, the alkalinizing agent described in “1. Pharmaceutical composition” above can be applied. Examples of alkalinizing agents include a pharmaceutically acceptable salt of citric acid as acceptable salts of citric acid as food (for example, an alkali metal salt of citric acid or a hydrate thereof, or a mixture thereof), and sodium bicarbonate. A mixture of a potassium citrate monohydrate (C6H5K3O7.H2O) and a sodium citrate dihydrate (C6H5Na3O7.2H2O), or sodium citrate dihydrate is preferable.
Uremic substance is also as described in “1. Pharmaceutical composition” above. Examples of uremic substances include indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid.
The content of the alkalinizing agent in the food composition provided by the present invention can be appropriately determined depending on the type of food. Examples of food compositions include foods for specified health use, dietary supplements, functional foods, hospital patient foods, and supplements. The form of these food compositions is not particularly limited as long as it comprises an effective amount of an alkalinizing agent for exerting the above-mentioned effects and can be taken orally. The form may be a form of a normal food or drink, or the food composition may be provided as a preparation suitable for oral administration, for example, a preparation such as a tablet, a capsule, or a suspension, among preparations that can be applied to the pharmaceutical composition. Regarding the constitution and production method of these preparations, in the present specification, the constitution and production method of the pharmaceutical preparation described in the above “1. Pharmaceutical composition” can be applied as it is, and known formulation techniques in the field of pharmaceutical preparation technology itself can be also be applied.
For example, in the case of foods for specified health use, dietary supplements, functional foods, or foods for hospital patients, per serving of food, an amount of ⅓ of a total of 1 to 3 g of a potassium citrate monohydrate and a sodium citrate dihydrate may be contained as an alkalinizing agent, or an amount of ⅓ of 1 to 6 g of a sodium hydrogen carbonate may be contained as an alkalinizing agent. When specified health foods, dietary supplements, functional foods, hospital patient foods, or supplements are provided as tablets, for example, per tablet, 70% to 80% by weight of the alkalinizing agent may be contained in 300 mg to 600 mg of a tablet.
When the food composition provided by the present invention is not formulated and is provided in the form of a normal food or drink, it can be appropriately produced by those skilled in the art depending on the type of the food. For example, it can be produced by blending an alkalinizing agent (for example, potassium citrate and/or sodium citrate) with the food material.
The form of the food and drink is a liquid or milky or pasty food such as a beverage, soy sauce, milk, yogurt, or miso; a semi-solid food such as jelly or gummy; solid foods such as rice cakes, gums, tofu, and supplements; powdered foods; and the like.
Examples of beverages include fruit juice, fruit drinks, coffee drinks, oolong tea drinks, green tea drinks, tea drinks, barley tea drinks, vegetable drinks, carbonated soft drinks, fruit extract drinks, vegetable extract juices, near water, sports drinks, diet drinks, and the like.
In beverages, additives such as antioxidants, fragrances, various esters, organic acids, organic acid salts, inorganic acids, inorganic acid salts, inorganic salts, pigments, emulsifiers, preservatives, seasonings, sweeteners, acidulants, fruit juice extracts, vegetable extracts, nectar extract, pH adjusters, and quality stabilizers can be blended in individually or in combination.
The food composition provided by the present invention can be used in the same manner as the method of using the pharmaceutical composition described in the above “1. Pharmaceutical composition,” and can also be used within a range not intended to treat or prevent diseases. That is, when the alkalinizing agent contained in the food composition according to the present invention is used as a reference, it can be applied to an application target of the pharmaceutical composition such that the amount of the alkalinizing agent used in the food composition becomes the same as the alkalinizing agent contained in the pharmaceutical composition. In addition, in one embodiment, the “food composition” according to the present invention can be applied to a subject (for example, a human or other mammals) who does not have “morbid” or “abnormal” symptoms, conditions, or diseases, that is, a subject (for example, a human or other mammals) in a “healthy” or “normal” state in order to maintain or enhance a “healthy” or “normal” state. Furthermore, it can be applied to a “healthy subject concerned about kidney health” or “healthy subject concerned about kidney tubule health” in order to maintain or improve a “healthy” or “normal” state. In this case, even if the alkalinizing agent is a component of the pharmaceutical composition or a component of the food composition, the pharmacological effect of the alkalinizing agent itself is basically the same. Accordingly, the application amount and application method of the food composition can be appropriately adjusted based on the alkalinizing agent according to an expected effect.
A food composition applied to a subject (for example, a human or other mammals) who does not have “morbid” or “abnormal” symptoms, conditions, or diseases, that is, a subject (for example, a human or other mammals) in a “healthy” or “normal” state in order to maintain or enhance a “healthy” or “normal” state, may be particularly referred to as “functional food” in some cases.
The term “administration” described in the above “1. Pharmaceutical composition” can also be applied to the “food composition” according to the present invention. Furthermore, regarding the “food composition” according to the present invention, the term “administration” can be read as “ingestion.” Accordingly, for example, the terms “administer,” “administered,” and the like can be read as “is ingested,” “ingest,” “ingesting,” and the like, with different word forms depending on the context.
Accordingly, the embodiments of the food composition according to the present invention include the following: <1> A food composition for decreasing a concentration of uremic substance in blood, wherein the food composition comprises an alkalinizing agent;
In one embodiment, the “food composition” according to the present invention is ingested by a subject (for example, a human or other mammals) in which a urinary β2-microglobulin concentration is 290 μg/L or less, preferably 50 to 150 μg/L.
In one embodiment, the “food composition” according to the present invention is ingested by a subject (for example, a human or other mammals) in which a blood cystatin C concentration is 0.5 to 2.2 mg/L, preferably 1.0 to 1.3 mg/L.
In one embodiment, the ingestion of the “food composition” according to the present invention suppresses an increase in urinary β2-microglobulin concentration.
In one embodiment, the ingestion of the “food composition” according to the present invention suppresses an increase in urinary β2-microglobulin concentration 12 weeks after the administration.
In one embodiment, the ingestion of the “food composition” according to the present invention does not substantially decrease a urinary β2-microglobulin concentration compared to before the start of administration.
In one embodiment, the ingestion of the “food composition” according to the present invention does not substantially decrease a urinary β2-microglobulin concentration 12 weeks after administration, compared to before the start of administration.
In one embodiment, the ingestion of the “food composition” according to the present invention does not substantially increase blood cystatin C compared to before the start of administration.
In one embodiment, the ingestion of the “food composition” according to the present invention does not substantially increase blood cystatin C compared to before the start of administration.
In one embodiment, the ingestion of the “food composition” according to the present invention suppresses, in early morning urine, an increase of a β2-microglobulin amount which is associated with progression of a stage of chronic kidney disease.
In one embodiment, the ingestion of the “food composition” according to the present invention does not affect the glomerular function of a patient with chronic kidney disease, whereas it suppresses kidney proximal tubular cell damage associated with progression of a stage of chronic kidney disease progression to protect kidney proximal tubular cells.
3. Method for Determining Decrease in Concentration of Uremic Substance in Blood
In one embodiment, the present invention provides a method for determining a decrease in concentration of uremic substance (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and/or argininosuccinic acid, preferably indoxyl sulfate, hippuric acid, and phenylacetyl-L-glutamine, more preferably indoxyl sulfate and phenylacetyl-L-glutamine, and even more preferably indoxyl sulfate) in blood of a patient with chronic kidney disease, comprising measuring a pH of urine.
In addition, in one embodiment, the present invention provides a method for determining a promotion of excretion of uremic substance (indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and/or argininosuccinic acid, preferably indoxyl sulfate, p-cresyl sulfate, hippuric acid, and phenylacetyl-L-glutamine, more preferably indoxyl sulfate and phenylacetyl-L-glutamine, and even more preferably indoxyl sulfate) into urine of a patient with chronic kidney disease, comprising measuring a pH of urine.
Measurement of the content of uremic substance (for example, indoxyl sulfate) in body fluid can be performed by a HPLC method or enzyme method. However, these measurement methods require specialized and expensive reagents.
As described in the present specification, a concentration of uremic substance in blood (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and/or argininosuccinic acid) is decreased by administering the alkalinizing agent, and thereby excretion of these uremic substance into the urine is promoted. Accordingly, by measuring a pH of urine of a patient with chronic kidney disease, very simply and inexpensively, it is possible to determine a decrease in concentration of uremic substance in blood (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and/or argininosuccinic acid), and/or a promotion of excretion of uremic substance into urine (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and/or argininosuccinic acid). For the measurement of pH, a well-known technique may be used. For example, a pH test paper, a pH test solution, or a simple pH measuring device can be used.
In one embodiment, a patient with chronic kidney disease measures a pH of early morning urine (wake up first urine) over time from the start of taking an alkalinizing agent (for example, a mixture of a potassium citrate monohydrate and a sodium citrate dihydrate, or sodium citrate dihydrate), and if the urine pH is high, it can be easily determined that a decrease in concentration of uremic substance in blood (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and/or argininosuccinic acid, preferably indoxyl sulfate, hippuric acid, and/or phenylacetyl-L-glutamine, more preferably indoxyl sulfate and phen ylacetyl-L-glutamine, and even more preferably indoxyl sulfate), and/or a promotion of excretion of uremic substance into urine (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and/or argininosuccinic acid, preferably indoxyl sulfate, p-cresyl sulfate, hippuric acid, and/or phenylacetyl-L-glutamine, more preferably indoxyl sulfate and phenylacetyl-L-glutamine, and even more preferably indoxyl sulfate) is achieved.
In addition, in one embodiment, a patient with chronic kidney disease measures a pH of early morning urine (wake up first urine) over time after taking an alkalinizing agent (for example, a mixture of a potassium citrate monohydrate and a sodium citrate dihydrate, or sodium citrate dihydrate). If the urine pH is within a range of 5.2 to 6.8 (for example, the pH of urine is within a range of pH 5.5 to pH 6.8, pH 5.8 to pH 6.8, pH 5.8 to pH 6.5, pH 5.8 to pH 6.2, pH 5.8 or more and less than pH 6.2, pH 6.0 to pH 6.5, pH 6.0 to pH 6.4, pH 6.0 to pH 6.3, pH 6.0 to pH 6.2, pH 6.0 or more and less than pH 6.2, pH 6.1 to pH 6.3, pH 6.2 to 6.8, pH 6.2 to pH 6.5, or pH 6.5 to 6.8), it can be easily determined that a decrease in concentration of uremic substance in blood (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and/or argininosuccinic acid, preferably indoxyl sulfate, hippuric acid, and/or phenylacetyl-L-glutamine, more preferably indoxyl sulfate and phenylacetyl-L-glutamine, and even more preferably indoxyl sulfate), and/or a promotion of excretion of uremic substance into urine (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and/or argininosuccinic acid, preferably indoxyl sulfate, p-cresyl sulfate, hippuric acid, and/or phenylacetyl-L-glutamine, more preferably indoxyl sulfate and phenylacetyl-L-glutamine, and even more preferably indoxyl sulfate) is achieved.
The determination, which is thus obtained as above, as to whether or not a decrease in concentration of uremic substance in blood (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and/or argininosuccinic acid), and/or a promotion of excretion of uremic substance into urine (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and/or argininosuccinic acid) is achieved can aid the diagnosis of whether or not progression of chronic kidney disease is suppressed.
Accordingly, in one embodiment, the present invention provides a method for determining suppression of progression of chronic kidney disease, comprising measuring the pH of urine (for example, early morning urine) of a patient to which an alkalinizing agent (for example, a mixture of a potassium citrate monohydrate and a sodium citrate dihydrate, or sodium citrate dihydrate) has been administered. If it is recognized that the urine pH increases over time or the urine pH is within the range of 5.8 to 6.8 (for example, the urine pH is within the range of 6.0 to 6.2), this can then aid the diagnosis that progression of a stage of chronic kidney disease progression are suppressed.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in decreasing a concentration of uremic substance in blood, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in decreasing a concentration of uremic substance in blood, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in promoting excretion of uremic substance into urine, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in promoting excretion of uremic substance into urine, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in ameliorating uremic symptoms in a patient with kidney disease, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in ameliorating uremic symptoms in a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in treating or preventing uremia in a patient with kidney disease, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in treating or preventing uremia in a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing progression of chronic kidney disease, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing progression of chronic kidney disease, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in delaying introduction of dialysis to a patient with chronic kidney disease, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in delaying introduction of dialysis to a patient with chronic kidney disease, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing myocardial fibrosis in a patient with kidney disease, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing myocardial fibrosis in a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing arteriosclerosis in a patient with kidney disease, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing arteriosclerosis in a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing vascular smooth muscle cell proliferation in a patient with kidney disease, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing vascular smooth muscle cell proliferation in a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing vascular endothelial cell injury in a patient with kidney disease, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing vascular endothelial cell injury in a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing thickening of the arterial wall of a patient with kidney disease, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing thickening of the arterial wall of a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing calcification of the aorta of a patient with kidney disease, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing calcification of the aorta of a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in treating or preventing cardiovascular disease in a patient with kidney disease, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in treating or preventing cardiovascular disease in a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in ameliorating arteriosclerosis in a patient with kidney disease, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in ameliorating arteriosclerosis in a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in ameliorating thickening of the arterial wall of a patient with kidney disease, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in ameliorating thickening of the arterial wall of a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in treating of acute kidney failure, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in treating of acute kidney failure, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing progression from acute kidney failure to chronic kidney disease, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing progression from acute kidney failure to chronic kidney disease, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in treating or preventing kidney tubular damage, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in treating or preventing kidney tubular damage, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing kidney tubular damage, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing kidney tubular damage, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing kidney proximal tubular cell damage, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing kidney proximal tubular cell damage, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in protecting kidney proximal tubular cells, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in protecting kidney proximal tubular cells, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in maintaining kidney proximal tubular cell function, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in maintaining kidney proximal tubular cell function, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in promoting excretion of uremic substance outside the body, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in promoting excretion of uremic substance outside the body, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in excreting uremic substance into urine depending on a concentration of uremic substance in blood, in which 0.5 to 1.5 g/day of each of a potassium citrate monohydrate and a sodium citrate dihydrate as the alkalinizing agent are orally administered at a total of 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in excreting uremic substance into urine depending on a concentration of uremic substance in blood, in which one dosage unit (preferably one tablet) contains 231.5 mg potassium citrate monohydrate and 195.0 mg sodium citrate dihydrate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in decreasing a concentration of uremic substance in blood, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in decreasing a concentration of uremic substance in blood, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in promoting excretion of uremic substance into urine, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in promoting excretion of uremic substance into urine, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in ameliorating uremic symptoms in a patient with kidney disease, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in ameliorating uremic symptoms in a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in treating or preventing uremia in a patient with kidney disease, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in treating or preventing uremia in a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing progression of chronic kidney disease, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing progression of chronic kidney disease, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in delaying introduction of dialysis to a patient with chronic kidney disease, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in delaying introduction of dialysis to a patient with chronic kidney disease, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing myocardial fibrosis in a patient with kidney disease, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing myocardial fibrosis in a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing arteriosclerosis in a patient with kidney disease, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing arteriosclerosis in a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing vascular smooth muscle cell proliferation in a patient with kidney disease, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing vascular smooth muscle cell proliferation in a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing vascular endothelial cell injury in a patient with kidney disease, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing vascular endothelial cell injury in a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing thickening of the arterial wall of a patient with kidney disease, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing thickening of the arterial wall of a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing calcification of the aorta of a patient with kidney disease, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing calcification of the aorta of a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in treating or preventing cardiovascular disease in a patient with kidney disease, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in treating or preventing cardiovascular disease in a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use ameliorating arteriosclerosis in a patient with kidney disease, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in ameliorating arteriosclerosis in a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use ameliorating thickening of the arterial wall of a patient with kidney disease, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in ameliorating thickening of the arterial wall of a patient with kidney disease, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in treating acute kidney failure, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in treating acute kidney failure, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing progression from acute kidney failure to chronic kidney disease, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing progression from acute kidney failure to chronic kidney disease, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in treating or preventing kidney tubular damage, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in treating or preventing kidney tubular damage, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing kidney tubular damage, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing kidney tubular damage, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing kidney proximal tubular cell damage, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in suppressing kidney proximal tubular cell damage, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in protecting kidney proximal tubular cells, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in protecting kidney proximal tubular cells, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in maintaining kidney proximal tubular cell function, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in maintaining kidney proximal tubular cell function, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in promoting excretion of uremic substance outside the body, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in promoting excretion of uremic substance outside the body, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in excreting uremic substance into urine depending on a concentration of uremic substance in blood, in which sodium bicarbonate as the alkalinizing agent is orally administered at 1 to 3 g/day, 1 to 5 times a day, preferably 3 times a day.
In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalinizing agent for use in excreting uremic substance into urine depending on a concentration of uremic substance in blood, in which one dosage unit (preferably one tablet) contains 500 mg sodium bicarbonate, and 3 to 6 dosage units per day are orally administered in three divided doses per day.
Hereinafter, the present invention will be further described by examples, but the present invention is not limited thereto.
A human clinical trial was conducted to examine whether oral administration of a combination preparation of hydrates of potassium citrate and sodium citrate, and a sodium bicarbonate preparation, which are oral alkalinizing agents, promotes excretion of uremic substance into urine.
1. Method 47 patients with chronic kidney diseases in stage G2 to G3b (eGFR: 30 to 89 ml/min/1.73 m2) were randomly divided into a group to which a combination preparation of hydrates of potassium citrate and sodium citrate had been administered (a group A: 16 patients), a group to which a sodium bicarbonate preparation (sodium hydrogen carbonate) had been administered (a group B: 16 patients), and a control group (a group C: 15 patients). Patients were assigned to each group so that age, sex, presence of diabetes, and eGFR were not biased. Each group was treated according to the “CKD medical care guide-summary of treatment” (hereinafter referred to as standard treatment).
An alkalinizing agent was not administered to the control group. To the group A, 3 tablets a day in which each tablet contained potassium citrate (C6H5K3O7.H2O) 231.5 mg and a sodium citrate hydrate (C6H5Na3O7. 2H2O) 195.0 mg were orally administered 3 times a day (morning, noon, evening) for 24 weeks. A pH of early morning urine was controlled over time so that the dosage could be increased up to 6 tablets, 3 times a day (morning, noon, evening) as needed according to the discretion of the physician in cases where a pH of early morning urine was less than pH 6.5. To the group B, 3 tablets a day in which each tablet contained 500 mg of sodium bicarbonate were orally administered 3 times a day (morning, noon, evening) for 24 weeks. A pH of early morning urine was controlled over time so that the dosage could be increased up to 6 tablets, 3 times a day (morning, noon, evening) as needed according to the discretion of the physician in cases where a pH of early morning urine was less than pH 6.5.
Early morning urine and blood were collected before the start of administration, and 6 weeks, 12 weeks, and 24 weeks after the start of administration, and each specimen was stored at −80° C. Methods used in the present field for indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid in urine and blood (Sato, E., et. al., Metabolic alteration by indoxyl sulfate in skeletal muscle induce uremic sarcopenia in chronic kidney disease., Sci Rep. 2016 Nov. 10; 6:36618. doi: 10.1038/srep36618, and the like) were referred to, and quantitative analysis was performed using the following liquid chromatography triple quadrupole mass spectrometer (LC-MS/MS).
For LC, NANOSPACE SI-2 (manufactured by Shiseido) was used, and CAPCELLPAK MGM was selected as the analytical column.
For MS, TSQ Quantiva (manufactured by Thermo Fisher Scientific Co., Ltd.) was used, and five compounds were ionized in the negative mode and detected using the Selected Reaction Monitoring method. The quantitative value was calculated using a calibration curve prepared with a standard solution of each compound.
In addition, the amount of urinary β2-microglobulin was measured by latex agglutination method using the LZ test “Eiken” β2-M and LZ-β2-M standard U “Eiken” (Eiken Chemical Co., Tokyo, Japan). Furthermore, the amount of cystatin C in the serum was measured by a colloidal gold agglutination method using Nescoat GC Cystatin C (Nm) (Alfresa Pharma, Osaka, Japan).
For statistical analysis, the Mann-Whitney test was used for comparison between groups, and the Wilcoxon test was used for comparison of changes over time. The Pearson test was used for correlation.
2. Result
Based on the measurement results using LC-MS/MS, for respective patients in the group A (the group to which the combination preparation of hydrates of potassium citrate and sodium citrate was administered), the group B (the group to which the sodium bicarbonate preparation was administered), and the group C (the control group), the following was calculated:
Then, the average value and SD of each group were calculated for (i) to (ix) above. For each of (iv) to (ix) above, the average value and SD of each group were calculated for all data of 6 weeks, 12 weeks, and 24 weeks after the start of administration in each group.
The results are shown in tables below. In the tables and drawings, the group A: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered was described as “Citrate,” and the group B: the group to which the sodium bicarbonate preparation had been administered was described as “Bicarbonate.” In addition, the numerical value in the parenthesis in the tables indicates the number of cases.
In the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), an indoxyl sulfate concentration in plasma 6, 12, and 24 weeks after the administration was a lower value, compared to those of the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered) and the group C (Control: the control group) (refer to Table 1-1-1). In addition, in the group A, an indoxyl sulfate (IS) concentration in early morning urine 12 and 24 weeks after administration was a higher value than that in the group C (refer to Table 1-2-1). The indoxyl sulfate concentration in plasma at 6 to 24 weeks was a significantly lower value in the group A than those in the groups B and C (refer to Table 1-1-1), and the indoxyl sulfate concentration in early morning urine at 6 to 24 weeks was significantly greater in the group A than those in the groups B and C (refer to Table 1-2-2).
In addition, by administering the combination preparation of hydrates of potassium citrate and sodium citrate to patients with chronic kidney disease, the concentration of indoxyl sulfate, which is a uremic substance, in urine increased compared to before administration, and the concentration of indoxyl sulfate in blood decreased compared to before administration. Even with the same alkalinizing agent, such an effect was not recognized in the case of the sodium bicarbonate preparation. Compared with the sodium bicarbonate preparation, the combination preparation of hydrates of potassium citrate and sodium citrate exhibited an excellent effect of decreasing an indoxyl sulfate concentration in blood, and an excellent effect of increasing an indoxyl sulfate concentration in urine. The effect of decreasing the indoxyl sulfate concentration in blood and the effect of increasing the indoxyl sulfate concentration in urine by the combination preparation of hydrates of potassium citrate and sodium citrate were recognized from 12 weeks after the administration.
Based on the value of the ratio of indoxyl sulfate concentration in urine to indoxyl sulfate concentration in plasma, it was shown that administration of the combination preparation of hydrates of potassium citrate and sodium citrate led to the excretion of indoxyl sulfate from blood into urine, and thereby excretion thereof outside the body was promoted. The effect of excretion of indoxyl sulfate from blood into urine was recognized by administration of the combination preparation of hydrates of potassium citrate and sodium citrate, but not by administration of the sodium bicarbonate preparation (refer to Table 1-3-1 and Table 1-3-2).
ap = 0.0288, bp = 0.0451 vs Control and cp = 0.0350 vs Bicarbonate (Mann-Whitney)
actual measurement value from week 0)
159
dp = 0.0073 vs Control and p = 0.0385 vs Bicarbonate (Mann-Whitney)
p = 0.0103 vs 0 week (W
)
indicates data missing or illegible when filed
actual measurement value from week 0)
a p = 0.0141 vs Control and
cp = 0.0233,
dp = 0.0438 vs Bicarbonate (Mann-Whitney)
p = 0.0482,
p = 0.0322 and dp = 0.0141 vs Control (Mann-Whitney)
p = 0.0479, fp = 0.0413 and
p = 0.0151 vs 0 week (Wilcoxon)
indicates data missing or illegible when filed
14.91 ± 56.11 b
b p = 0.0239,
c p = 0.0006 vs Control and
dp = 0.0457,
ep = 0.0292 vs Bicarbonate (Mann-Whitney)
Regarding p-cresyl sulfate (PCS), in the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), the concentration of p-cresyl sulfate in the early morning urine 12 and 24 weeks after administration was a higher value than that of the group C (Control: the control group). In the group A (the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), even when compared to the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered), the p-cresyl sulfate concentration in the early morning urine at 6, 12, and 24 weeks after administration was a higher value (refer to Table 2-2-1). An increase in p-cresyl sulfate concentration in early morning urine at 6 to 24 weeks was recognized only in the group A (refer to Table 2-2-2).
In addition, administration of the combination preparation of hydrates of potassium citrate and sodium citrate to patients with chronic kidney diseases increased the concentration of p-cresyl sulfate, which is a uremic substance, in urine compared to before administration (refer to Table 2-2-1 and Table 2-2-2). Even with the same alkalinizing agent, such an effect was not recognized in the case of the sodium bicarbonate preparation, and the combination preparation of hydrates of potassium citrate and sodium citrate exhibited a stronger effect of increasing a concentration of p-cresyl sulfate in urine as compared to the sodium bicarbonate preparation. The effect of increasing the p-cresyl sulfate concentration in urine by the combination preparation of hydrates of potassium citrate and sodium citrate was recognized from 12 weeks after administration.
On the other hand, administration of the sodium bicarbonate preparation decreased the concentration of p-cresyl sulfate, which is a uremic substance, in plasma as compared to before administration (refer to Table 2-1-2). Such an effect of decreasing a concentration of p-cresyl sulfate in plasma was more strongly recognized in the group B as compared to the group A and group C (refer to Table 2-1-2).
Based on the value of the ratio of p-cresyl sulfate concentration in urine to p-cresyl sulfate concentration in plasma, it was shown that administration of the combination preparation of hydrates of potassium citrate and sodium citrate led to the excretion of p-cresyl sulfate from blood into urine, and thereby excretion thereof outside the body was promoted. It was shown that the effect of excretion of p-cresyl sulfate from blood into urine was more strongly recognized by administration of the combination preparation of hydrates of potassium citrate and sodium citrate than by administration of the sodium bicarbonate preparation (refer to Table 2-3-1 and Table 2-3-2).
actual measurement value from week 0)
14.3 ± 3291
−6.8 ± 2982
c p = 0.0377 vs Bicarbonate (Mann-Whitney)
actual measurement value from week 0)
ap = 0.0170,
bp = 0.0109 vs Control and
cp = 0.0242 vs Bicarbonate (Mann-Whitney)
a p = 0.0221, b p = 0.0094, c p = 0.0364 and d p = 0.0055 vs Control (Mann-Whitney)
Regarding hippuric acid (HA), in the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), a hippuric acid concentration in plasma 24 weeks after the administration was a lower value, compared to those of the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered) and the group C (Control: the control group) (refer to Table 3-1-1). Such an effect was not seen in the administration of the sodium bicarbonate preparation. In addition, in the group A, the hippuric acid concentration in the early morning urine 12 and 24 weeks after administration was a higher value than that in the group C (refer to Table 3-2-1).
In addition, by administering the combination preparation of hydrates of potassium citrate and sodium citrate to patients with chronic kidney diseases, the concentration of hippuric acid, which is a uremic substance, in plasma 24 weeks after administration was decreased as compared to that before administration (refer to Tables 3-1-1 and 3-2-2), and the concentration of hippuric acid in urine increased compared to that before administration (refer to Tables 3-2-1 and 3-2-2). An increase in hippuric acid concentration in the early morning urine at 6 to 24 weeks was recognized only in the group A (refer to Table 2-2-2). Even with the same alkalinizing agent, compared with the sodium bicarbonate preparation, the combination preparation of hydrates of potassium citrate and sodium citrate exhibited an excellent effect of increasing a hippuric acid concentration in urine. The effect of increasing the hippuric acid concentration in urine by the combination preparation of hydrates of potassium citrate and sodium citrate was recognized from 6 weeks after administration.
Based on the value of the ratio of hippuric acid concentration in urine to hippuric acid concentration in plasma, it was shown that administration of the combination preparation of hydrates of potassium citrate and sodium citrate led to the excretion of hippuric acid from blood into urine, and thereby excretion thereof outside the body was promoted. In addition, it was shown that the effect of excretion of hippuric acid from blood into urine at 6 to 24 weeks was more strongly recognized by administration of the combination preparation of hydrates of potassium citrate and sodium citrate than by administration of the sodium bicarbonate preparation (refer to Table 3-3-1 and Table 3-3-2).
bp = 0.0181 and cp = 0.0215 vs 0 week (Wilcoxon)
actual measurement value from week 0)
722.3 ± 1023 c
a p = 0.0430,
c p = 0.0164,
e p = 0.0008 vs Control and
dp = 0.0093 vs Bicarbonate (Mann-Whitney)
actual measurement value from week 0)
a p = 0.0431 vs Control (Mann-Whitney)
bp = 0.0239 vs Control and p = 0.0355,
p = 0.0478 vs Bicarbonate (Mann-Whitney)
fp = 0.0479 vs 0 Week (Wilcoxon)
indicates data missing or illegible when filed
7.2 ± 73.2
−50.2 ± 688.3b
ap = 0.0451,
bp = 0.0170 vs Control (Mann-Whitney)
Regarding argininosuccinic acid (ASA), in the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), a concentration of argininosuccinic acid in the early morning urine was a higher value than that of the group C (Control: the control group), whereas the value was lower than that of the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered) (refer to Table 4-2-1).
In addition, administration of the combination preparation of hydrates of potassium citrate and sodium citrate to patients with chronic kidney diseases increased the concentration of argininosuccinic acid, which is a uremic substance, in urine compared to before administration (refer to Table 4-2-1 and Table 4-2-2). The effect of increasing the argininosuccinic acid concentration in urine by the combination preparation of hydrates of potassium citrate and sodium citrate was recognized from 12 weeks after administration. The increase in argininosuccinic acid concentration in early morning urine at 6 to 24 weeks was more increased in the group B than in the group A (refer to Table 4-2-2).
Based on the value of the ratio of an argininosuccinic acid concentration in urine to an argininosuccinic acid concentration in plasma, it was shown that administration of the combination preparation of hydrates of potassium citrate and sodium citrate led to the excretion of argininosuccinic acid from blood into urine, and thereby excretion thereof outside the body was promoted. In addition, it was shown that the effect of excretion of argininosuccinic acid from blood into urine at 6 to 24 weeks was more strongly recognized by administration of the sodium bicarbonate preparation than that by administration of the combination preparation of hydrates of potassium citrate and sodium citrate (refer to Table 4-3-1 and Table 4-3-2).
actual measurement value from week 0)
66.9 ± 690.0
bp = 0.0215 vs 0 week (Wilcoxon)
a p = 0.0105 and
b p = 0.0175 vs Control (Mann-Whitney)
2.54 ± 10.20a
ap = 0.0403 vs Control (Mann-Whitney)
Regarding phenylacetyl-L-glutamine (PAG), in the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), a phenylacetyl-L-glutamine concentration in plasma was a lower value compared to that of the group C (Control: the control group) (refer to Table 5-1-1). In the group A, a phenylacetyl-L-glutamine concentration in early morning urine 12 and 24 weeks after administration was a higher value than that in the group C (refer to Table 5-2-1).
In addition, administration of the combination preparation of hydrates of potassium citrate and sodium citrate to patients with chronic kidney diseases increased the concentration of phenylacetyl-L-glutamine, which is a uremic substance, in urine 12 and 24 weeks after administration, compared to before administration (refer to Table 5-2-1 and Table 5-2-2). Even with the same alkalinizing agent, such an effect was not recognized in the case of the sodium bicarbonate preparation. The effect of increasing the phenylacetyl-L-glutamine concentration in urine by the combination preparation of hydrates of potassium citrate and sodium citrate was recognized from 12 weeks after administration. Administration of the combination preparation of hydrates of potassium citrate and sodium citrate to patients with chronic kidney diseases decreased the concentration of phenylacetyl-L-glutamine, which is a uremic substance, in plasma compared to before administration (refer to Table 5-1-1 and Table 5-2-2). The effect of decreasing a phenylacetyl-L-glutamine concentration in plasma was strongly recognized by the sodium bicarbonate preparation than that by the combination preparation of hydrates of potassium citrate and sodium citrate (refer to Table 5-1-2).
Based on the value of the ratio of phenylacetyl-L-glutamine concentration in urine to phenylacetyl-L-glutamine concentration in plasma, it was shown that administration of the combination preparation of hydrates of potassium citrate and sodium citrate led to the excretion of phenylacetyl-L-glutamine from blood into urine, and thereby excretion thereof outside the body was promoted. In addition, it was shown that the effect of excretion of phenylacetyl-L-glutamine from blood into urine was more strongly recognized by administration of the combination preparation of hydrates of potassium citrate and sodium citrate than that by administration of the sodium bicarbonate preparation (refer to Table 5-3-1 and Table 5-3-2).
ap = 0.0326 and cp = 0.0065 vs Control (Mann-Whitney)
actual measurement value from week 0)
ap = 0.0151, bp = 0.0335 vs 0 week (Wilcoxon)
actual measurement value from week 0)
18263 ± 60893 b
b p = 0.0105,
c p = 0.0062 vs Control and
a p = 0.0287,
dp = 0.0282 vs Bicarbonate (Mann-Whitney)
ap = 0.0358 and bp = 0.0107 vs Control (Mann-Whitney)
cp = 0.0103 vs 0 week (Wilcoxon)
b p = 0.0194 vs Control (Mann-Whitney)
Effects of potassium citrate/sodium citrate hydrate (Citrate) and sodium bicarbonate (Bicarbonate) on a concentration of each uremic substance in plasma, a concentration of each uremic substance in early morning urine, and a ratio of a concentration of uremic substance in early morning urine to a concentration of uremic substance in plasma are summarized in the following tables. In the tables below, the sodium bicarbonate preparation (Bicarbonate) is a reference drug for the case of the combination preparation of hydrates of potassium citrate and sodium citrate (Citrate), and the combination preparation of hydrates of potassium citrate and sodium citrate (Citrate) is a reference drug for the case of the sodium bicarbonate preparation (Bicarbonate). When the effect is significantly superior to the control group or the reference drug group, O is described, when the effect is significantly inferior to the control group or the reference drug group, X is described, and when there is no significant difference, —is described. The effect of the group to which the sodium bicarbonate preparation (Bicarbonate) had been administered with respect to the control group for the indoxyl sulfate concentration in the early morning urine is indicated as (0) in the tables below. This is because in the group to which the sodium bicarbonate preparation (Bicarbonate) had been administered, the indoxyl sulfate concentration in the early morning urine significantly increased compared to that of the control group, but the indoxyl sulfate concentration in the early morning urine after administration of the sodium bicarbonate preparation (Bicarbonate) decreased compared to before the start of the administration, and thus whether or not there is an effect of promoting excretion of indoxyl sulfate into the urine cannot be determined.
Based on the tables below, the effect of decreasing the concentration of uremic substance in blood (plasma) by the alkalinizing agent was clearly recognized in the cases of indoxyl sulfate (IS) and phenylacetyl-L-glutamine (PAG). Among them, for the case of indoxyl sulfate (IS), administration of the combination preparation of hydrates of potassium citrate and sodium citrate (Citrate) significantly decreased the concentration of uremic substance in blood (plasma) compared to administration of the sodium bicarbonate preparation (Bicarbonate).
In addition, an effect of increasing a uremic substance concentration in urine by the alkalinizing agent (an effect of excreting uremic toxin substances into urine) is clearly recognized by indoxyl sulfate (IS), p-cresyl sulfate (PCS), hippuric acid (HA), argininosuccinic acid (ASA), and phenylacetyl-L-glutamine (PAG). Among them, in the cases of indoxyl sulfate (IS), p-cresyl sulfate (PCS), and phenylacetyl-L-glutamine (PAG), administration of the combination preparation of hydrates of potassium citrate and sodium citrate (Citrate) significantly increased the concentration of uremic substance in urine (excretion into urine) than that by administration of the sodium bicarbonate preparation (Bicarbonate).
The excretion of uremic substance from the blood into the urine by the alkalinizing agent (an effect of excretion outside of the body) is clearly recognized in the cases of indoxyl sulfate (IS), p-cresyl sulfate (PCS), and phenylacetyl-L-glutamine (PAG). Among them, for the case of indoxyl sulfate (IS), administration of the combination preparation of hydrates of potassium citrate and sodium citrate (Citrate) significantly increased excretion of uremic substance from the blood into the urine (excretion outside of the body) compared to administration of the sodium bicarbonate preparation (Bicarbonate).
Based on the above table, it can be generally understood that the combination preparation of hydrates of potassium citrate and sodium citrate exhibits a greater effect of excreting the uremic substance outside the body compared to the sodium bicarbonate preparation. In addition, administration of the alkalinizing agent to patients with stage G2 chronic kidney disease as well as stage G3b can suppress progression of chronic kidney disease, and it was suggested that the combination preparation of hydrates of potassium citrate and sodium citrate further suppresses the progression of chronic kidney disease than the sodium bicarbonate preparation.
The results of measuring the amount of urinary β2-microglobulin and the amount of cystatin C in serum are shown below.
ap = 0.0338, cp = 0.0220 vs Control and bp = 0.0077, dp = 0.0156 vs Bicarbonate (Mann-Whitney)
ep = 0.0110 and fp = 0.0068 vs 0 week (Wilcoxon)
ug/L from week 0)
59.1 ± 161.7
162.0 ± 281.8 c
a p = 0.0095,
d p = 0.0415,
e p = 0.0295 vs Bicarbonate and
b p = 0.0002,
c p = 0.0437 vs Control (Mann-Whitney)
p = 0.0303 vs 0 week (Wilcoxon)
indicates data missing or illegible when filed
The concentration of cystatin C in the plasma was not different between the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered), and the group C (Control: the control group), and there was no influence on the function of glomeruli by the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered, and the group to which the sodium bicarbonate preparation had been administered (Table 8).
On the other hand, regarding a urinary β2-microglobulin concentration, in the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), a urinary β2-microglobulin concentration was a lower value compared to that of the group C (Control: the control group), and even in comparison with the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered), a urinary β2-microglobulin concentration of the group A (the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered) was a lower value. The group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered) had a higher urinary β2-microglobulin concentration than that of the group C (Control: the control group). Administration of the combination preparation of hydrates of potassium citrate and sodium citrate suppresses an increase in urinary 32-microglobulin concentration associated with progression of the stage, and it was recognized that there is no change in the urinary β2-microglobulin concentration compared to before administration.
Based on these results, it was shown that administration of the combination preparation of hydrates of potassium citrate and sodium citrate suppresses kidney tubular damage (kidney proximal tubular damage) associated with progression of the stage. In addition, it was shown that administration of the sodium bicarbonate preparation did not suppress kidney tubular damage (kidney proximal tubular damage) associated with progression of the stage, and it rather worsened the progression. These effects were recognized from 6 weeks after administration.
In addition, an effect of increasing a concentration of uremic substance in urine and an effect of decreasing a concentration of uremic substance in blood by administration of the combination preparation of hydrates of potassium citrate and sodium citrate was not recognized to have a correlation with an effect of suppressing an increase in urinary β2-microglobulin concentration by administration of the combination preparation of hydrates of potassium citrate and sodium citrate. It was suggested that an effect of promoting excretion of uremic substance into urine by administration of the combination preparation of hydrates of potassium citrate and sodium citrate was not caused only by suppression of glomerular and kidney proximal tubular damage.
Relevance of each of a concentrations of indoxyl sulfate (IS) in early morning urine and a concentration of indoxyl sulfate (IS) in plasma at 6, 12, and 24 weeks after the start of the test (6 W, 12 W, and 24 W) was analyzed using a Pearson test for each of the group C (Control: the control group), the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered), and all the patients (all the patients in the groups A, B, and C). The results are shown in
For indoxyl sulfate, a higher correlation between plasma concentration and urine concentration was recognized in the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered as compared to the control group, and a high correlation was recognized even when compared to the group to which the sodium bicarbonate preparation had been administered (refer to r values in
Relevance of each of a concentrations of p-cresyl sulfate (PCS) in early morning urine and a concentration of p-cresyl sulfate (PCS) in plasma at 6, 12, and 24 weeks after the start of the test (6 W, 12 W, and 24 W) was analyzed using a Pearson test for each of the group C (Control: the control group), the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered), and all the patients (all the patients in the groups A, B, and C). The results are shown in
Regarding p-cresyl sulfate, a correlation between plasma concentration and urine concentration was recognized between the control group, the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered, and the group to which the sodium bicarbonate preparation had been administered, and a higher correlation was recognized in the group to which the sodium bicarbonate preparation had been administered as compared to the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered (refer to r values in
Relevance of each of a concentrations of hippuric acid (HA) in early morning urine and a concentration of hippuric acid (HA) in plasma at 6, 12, and 24 weeks after the start of the test (6 W, 12 W, and 24 W) was analyzed using a Pearson test for each of the group C (Control: the control group), the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered), and all the patients (all the patients in the groups A, B, and C). The results are shown in
Regarding hippuric acid, no high correlation between plasma concentration and urinary concentration in the control group, the group to which the sodium bicarbonate preparation had been administered, and the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered was recognized.
Relevance of each of a concentrations of argininosuccinic acid (ASA) in early morning urine and a concentration of argininosuccinic acid (ASA) in plasma at 6, 12, and 24 weeks after the start of the test (6 W, 12 W, and 24 W) was analyzed using a Pearson test for each of the group C (Control: the control group), the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered), and all the patients (all the patients in the groups A, B, and C). The results are shown in
Regarding argininosuccinic acid, no high correlation between plasma concentration and urine concentration in the control group, the group to which the sodium bicarbonate preparation had been administered, and the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered was recognized.
Relevance of each of a concentrations of phenylacetyl-L-glutamine (PAG) in early morning urine and a concentration of phenylacetyl-L-glutamine (PAG) in plasma at 6, 12, and 24 weeks after the start of the test (6 W, 12 W, and 24 W) was analyzed using a Pearson test for each of the group C (Control: the control group), the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered), and all the patients (all the patients in the groups A, B, and C). The results are shown in
Regarding phenylacetyl-L-glutamine, a correlation between plasma concentration and urine concentration was recognized between the control group, the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered, and the group to which the sodium bicarbonate preparation had been administered, and a higher correlation was recognized in the group to which the sodium bicarbonate preparation had been administered as compared to the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered (refer to r values in
Relevance of respective concentrations of indoxyl sulfate (IS), p-cresyl sulfate (PCS), hippuric acid (HA), argininosuccinic acid (ASA), and phenylacetyl-L-glutamine (PAG) in early morning urine at 6, 12, and 24 weeks after the start of the test (6 W, 12 W, and 24 W) was analyzed using a Pearson test for each of the group C (Control: the control group), the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), and the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered). The results are shown in Table 9. In the table, “Contro” indicates the control group, “Citrate” indicates the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered, and “Bicarb” indicates the group to which the sodium bicarbonate preparation had been administered.
As a result, in the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered high correlation was observed between indoxyl sulfate and phenylacetyl-L-glutamine, p-cresyl sulfate and phenylacetyl-L-glutamine, and argininosuccinic acid and phenylacetyl-L-glutamine. In the group to which the sodium bicarbonate preparation had been administered, high correlation was observed between indoxyl sulfate and argininosuccinic acid, indoxyl sulfate and phenylacetyl-L-glutamine, p-cresyl sulfate and argininosuccinic acid, p-cresyl sulfate and phenylacetyl-L-glutamine, and argininosuccinic acid and phenylacetyl-L-glutamine. It was suggested that the combination preparation of hydrates of potassium citrate and sodium citrate may increase concentrations of indoxyl sulfate, phenylacetyl-L-glutamine, p-cresyl sulfate, and argininosuccinic acid in urine by the same mechanism. In addition, it was suggested that the sodium bicarbonate preparation may increase concentrations of indoxyl sulfate, phenylacetyl-L-glutamine, p-cresyl sulfate, and argininosuccinic acid in urine by the same mechanism.
Relevance of respective concentrations of indoxyl sulfate (IS), p-cresyl sulfate (PCS), hippuric acid (HA), argininosuccinic acid (ASA), and phenylacetyl-L-glutamine (PAG) in plasma at 6, 12, and 24 weeks after the start of the test (6 W, 12 W, and 24 W) was analyzed using a Pearson test for each of the group C (Control: the control group), the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), and the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered). The results are shown in Table 10. In the table, “Contro” indicates the control group, “Citrate” indicates the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered, and “Bicarb” indicates the group to which the sodium bicarbonate preparation had been administered.
As a result, in the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered high correlation was observed between indoxyl sulfate and p-cresyl sulfate, indoxyl sulfate and phenylacetyl-L-glutamine, and p-cresyl sulfate and phenylacetyl-L-glutamine. In the group to which the sodium bicarbonate preparation had been administered, a high correlation was recognized between indoxyl sulfate and p-cresyl sulfate. It was suggested that the combination preparation of hydrates of potassium citrate and sodium citrate may reduce concentrations of indoxyl sulfate, phenylacetyl-L-glutamine, and p-cresyl sulfate in blood by the same mechanism. In addition, it was suggested that the sodium bicarbonate preparation may reduce concentrations of p-cresyl sulfate and phenylacetyl-L-glutamine in blood by the same mechanism. It was suggested that the combination preparation of hydrates of potassium citrate and sodium citrate and the sodium bicarbonate preparation have different mechanisms for reducing the concentration of uremic substance in blood.
A urinary specific gravity of early morning urine before the start of the test (0 W) and at 6, 12, and 24 weeks after the start of the test (6 W, 12 W, and 24 W) was analyzed for each of the group C (Control: the control group), the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), and the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered). The results are shown in Table 11-0-1. In addition, amounts of change in each urinary specific gravity after 6, 12, and 24 weeks after the start of the test are respectively shown as a % relative value with respect to each urinary specific gravity before the start of the test, and a difference from urinary specific gravity before the start of the teste in Tables 11-0-2 and 11-0-3. The urinary specific gravity was measured using a urine hydrometer (PAL-09S, Atago Co., Ltd., Tokyo, Japan).
p = 0.0464 vs 0 week (Wilcoxon)
indicates data missing or illegible when filed
99.80 ± 0.51c
ap = 0.0023,
bp = 0.0577,
cp = 0.0734,
dp = 0.0289 and
ep = 0.0715 vs Citrate (Mann-Whitney)
ap = 0.0100,
bp = 0.0652 (Kruskal-Wallis) and
cp = 0.0084,
dp = 0.0941 vs Citrate (Dunn)
Actual measurement value vs week 0)
−0.0023 ± 0.0041d,d
0.0002 ± 0.0058b
ap = 0.0023,
bp = 0.0592,
cp = 0.0704,
dp = 0.0289 and
ep = 0.0746 vs Citrate (Mann-Whitney)
ap = 0.0102,
bp = 0.0668 (Kruskal-Wallis) and
cp = 0.0085,
dp = 0.0956 vs Citrate (Dunn)
As a result of the above measurement, compared with the group C (Control: the control group), in the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered) and the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered), the urinary specific gravity value was maintained or increased over 6, 12, and 24 weeks after the start of the test. In addition, compared to the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered), in the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), the urinary specific gravity showed tendency to be more favorably maintained or to increase.
It could be understood that maintaining or increasing the urinary specific gravity is based on maintenance or improvement of kidney function. Accordingly, based on the above results, administration of the alkalinizing agent to patients with stage G2 chronic kidney disease as well as stage G3b can suppress progression of chronic kidney disease, and it was suggested that the combination preparation of hydrates of potassium citrate and sodium citrate further suppresses the progression of chronic kidney disease than the sodium bicarbonate preparation.
Values obtained by correcting respective concentrations of uremic substance in early morning urine, that is, indoxyl sulfate (IS), p-cresyl sulfate (PCS), phenylacetyl-L-glutamine (PAG), hippuric acid (HA), and argininosuccinic acid (ASA) before the start of the test (0 W), and 6, 12, and 24 weeks after the start of the test (6 W, 12 W, and 24 W) by the following equation using the urinary specific gravity before the start of the test (0 W), and at 6, 12, and 24 weeks after the start of the test (6 W, 12 W, and 24 W) were analyzed for each of the group C (Control: the control group), the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), and the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered). Medical Examination, Vol. 44, No. 1, 1995, pages 79-83 by Tetsuo Aoki et al. was referred to. A urinary specific gravity 1.022 was converted into a reference value.
Specific gravity correction value (unit/1.022·UG)=actual measurement value×(1.022−1.000)/(specific gravity value−1.000)
The results are shown in Table 11-1-1, Table 11-2-1, Table 11-3-1, Table 11-4-1, and Table 11-5-1. In addition, amounts of change in the values obtained by correcting, with the urinary specific gravity, the concentration of the uremic substance in the early morning urine 6, 12, and 24 weeks after the start of the test are respectively shown as a % relative value with respect to the correction value before the start of the test, and a difference from the correction value before the start of the test in Table 11-1-2, Table 11-1-3, Table 11-2-2, Table 11-2-3, Table 11-3-2, Table 11-3-3, Table 11-4-2, Table 11-4-3,
(45-48)
p = 0.0849,
p = 0.0559,
p = 0.0065,
p = 0.0729,
p = 0.0266 and
p = 0.0849 vs Bicarbonate (Mann-Whitney)
p = 0.0052 and
p = 0.0730 vs 0 week (Wilcoxon)
p = 0.0844,
p = 0.0301 (Kruskal-Wallis) and
p = 0.0909,
p = 0.0385 vs Citrate (Dunn)
indicates data missing or illegible when filed
(45-48)
indicates data missing or illegible when filed
Actual measurement value vs week 0)
ap = 0.0251,
bp = 0.0135 and
cp = 0.0651 vs Bicarbonate (Mann-Whitney)
ap = 0.0648,
bp = 0.0368 (Kruskal-Wallis) and
cp = 0.0581,
dp = 0.0429 vs Citrate (Dunn)
p = 0.0507 vs 0 week (Wilcoxon)
indicates data missing or illegible when filed
(45-48)
85 ± 97c,f
ap = 0.0095,
bp = 0.0125,
cp = 0.0149,
dp = 0.0240 vs Citrate (Mann-Whitney)
ap = 0.0129,
bp = 0.0449,
cp = 0.0869 (Kruskal-Wallis) and
dp = 0.0250,
ep = 0.0439,
fp = 0.0398,
gp = 0.0849 vs Citrate (Dunn)
indicates data missing or illegible when filed
Actual measurement value vs week 0)
(45-48)
7.6 ± 53.3
−29.8 ± 66.1b,d
ap = 0.0226,
bp = 0.0007,
cp = 0.0214,
dp = 0.0287 and
ep = 0.0465 vs Citrate (Mann-Whitney)
ap = 0.0025,
bp = 0.0661,
cp = 0.0795 (Kruskal-Wallis) and
dp = 0.0020,
ep = 0.0736,
fp = 0.0863,
gp = 0.0849 vs Citrate (Dunn)
indicates data missing or illegible when filed
p = 0.0302 and
p = 0.0110 vs 0 week (Wilcoxon)
indicates data missing or illegible when filed
76 ± 60
ap = 0.0828 and
bp = 0.0799 vs Bicarbonate (Mann-Whitney)
Actual measurement value vs week 0)
ap = 0.0078,
cp = 0.0385,
dp = 0.0491 vs Bicarbonate and
bp = 0.0712 vs Control (Mann-Whitney)
ap = 0.0248,
bp = 0.0613 (Kruskal-Wallis) and
cp = 0.0197 vs Bicarbonate (Dunn)
Actual measurement value vs week 0)
indicates data missing or illegible when filed
p = 0.0413 vs 0 week (Wilcoxon)
indicates data missing or illegible when filed
Actual measurement value vs week 0)
As a result, in the cases of indoxyl sulfate (IS), p-cresyl sulfate (PCS), and phenylacetyl-L-glutamine (PAG), the concentration of uremic substance in urine (excretion into urine) significantly increased in the group to which the combination preparation of hydrates of potassium citrate and sodium citrate (Citrate) had been administered than that group to which the sodium bicarbonate preparation (Bicarbonate) had been administered and the control group. Also regarding the cases of hippuric acid (HA) and argininosuccinic acid (ASA), the concentration of uremic substance in urine (excretion into urine) increased in the group to which the combination preparation of hydrates of potassium citrate and sodium citrate (Citrate) had been administered than that group to which the sodium bicarbonate preparation (Bicarbonate) had been administered and the control group. In addition, administration of the combination preparation of hydrates of potassium citrate and sodium citrate (Citrate) increased concentrations of indoxyl sulfate (IS), p-cresyl sulfate (PCS), and phenylacetyl-L-glutamine (PAG) in the urine (excretion into urine) compared to before the start of the test (0 W).
The osmotic pressure of early morning urine before the start of the test (0 W) and at 6, 12, and 24 weeks after the start of the test (6 W, 12 W, and 24 W) was analyzed for each of the group C (Control: the control group), the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), and the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered). The results are shown in Table 12-0-1. In addition, amounts of change in the osmotic pressure of each early morning urine after 6, 12, and 24 weeks after the start of the test are respectively shown as a % relative value with respect to the osmotic pressure of the early morning urine before the start of the test, and a difference from osmotic pressure of early morning urine before the start of the teste in Tables 12-0-2 and 12-0-3. The osmotic pressure was measured using the freezing point depression method.
p = 0.0616 vs 0 week (Wilcoxon)
indicates data missing or illegible when filed
89 ± 26c
ap = 0.0123,
bp = 0.0997 and
cp = 0.0436 vs Citrate (Mann-Whitney)
ap = 0.0382 (Kruskal-Wallis) and
bp = 0.0358 vs Citrate (Dunn)
mOsm/kg vs week 0)
59 ± 184
ap = 0.0179 and
bp = 0.0375 vs Citrate (Mann-Whitney)
ap = 0.0597 (Kruskal-Wallis) and
bp = 0.0618 vs Citrate (Dunn)
As a result of the above measurement, compared with the group C (Control: the control group), in the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered) and the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered), the osmotic pressure value of early morning urine was maintained or increased over 6, 12, and 24 weeks after the start of the test. In addition, compared to the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered), in the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), an osmotic pressure in the early morning urine showed tendency to be more favorably maintained or to increase.
It could be understood that maintaining or increasing the osmotic pressure of early morning urine is based on maintenance or improvement of kidney function.
Accordingly, based on the above results, administration of the alkalinizing agent to patients with stage G2 chronic kidney disease as well as stage G3b can suppress progression of chronic kidney disease, and it was suggested that the combination preparation of hydrates of potassium citrate and sodium citrate further suppresses the progression of chronic kidney disease than the sodium bicarbonate preparation.
Values obtained by correcting respective concentrations of uremic substance in early morning urine, that is, indoxyl sulfate (IS), p-cresyl sulfate (PCS), phenylacetyl-L-glutamine (PAG), hippuric acid (HA), and argininosuccinic acid (ASA) before the start of the test (0 W), and 6, 12, and 24 weeks after the start of the test (6 W, 12 W, and 24 W) by the following equation using the osmotic pressure of early morning urine before the start of the test (0 W), and at 6, 12, and 24 weeks after the start of the test (6 W, 12 W, and 24 W) were analyzed for each of the group C (Control: the control group), the group A (Citrate: the group to which the combination preparation of hydrates of potassium citrate and sodium citrate had been administered), and the group B (Bicarbonate: the group to which the sodium bicarbonate preparation had been administered). Medical Examination, Vol. 44, No. 1, 1995, pages 79-83 by Tetsuo Aoki et al. was referred to. In addition, a urine osmotic pressure 770 mOsm/kg was converted into a reference value.
Osmotic pressure correction value (unit/500 mOsm·P)=actual measurement value×500/osmotic pressure value
The results are shown in Table 12-1-1, Table 12-2-1, Table 12-3-1, Table 12-4-1, and Table 12-5-1. In addition, amounts of change in the values obtained by correcting, with the osmotic pressure of the early morning urine, the concentration of the uremic substance in the early morning urine 6, 12, and 24 weeks after the start of the test are respectively shown as a % relative value with respect to the correction value before the start of the test, and a difference from the correction value before the start of the test in Table 12-1-2, Table 12-1-3, Table 12-2-2, Table 12-2-3, Table 12-3-2, Table 12-3-3, Table 12-4-2, Table 12-4-3, Table 12-5-2, and Table 12-5-3.
(45-48)
p = 0.0424,
p = 0.0060,
p = 0.0939,
p = 0.0214, and
p = 0.0650 vs Bicarbonate (Mann-Whitney)
p = 0.0092 and
p = 0.0413 vs 0 week (Wilcoxon)
p = 0.0830,
p = 0.0266 (Kruskal-Wallis) and
p = 0.0880,
p = 0.0416, vs Bicarbonate (Dunn)
indicates data missing or illegible when filed
Actual measurement value vs week 0)
ap = 0.0169 vs Bicarbonate (Mann-Whitney)
ap = 0.0492 (Kruskal-Wallis) and
bp = 0.0445 vs Bicarbonate (Dunn)
p = 0.0637 and
p = 0.0507 vs 0 week (Wilcoxon)
indicates data missing or illegible when filed
86 ± 35d
161 ± 352b,d
ap = 0.0054,
bp = 0.0127,
cp = 0.0085,
dp = 0.0259 vs Citrate and
ep = 0.0704 vs Control (Mann-Whitney)
ap = 0.0085,
bp = 0.0266 (Kruskal-Wallis) and
cp = 0.0120,
dp = 0.0524,
ep = 0.0241 vs Citrate (Dunn)
Actual measurement value vs week 0)
−29.5 ± 69.8b,d
ap = 0.0117,
bp = 0.0047,
cp = 0.0093,
dp = 0.0465 vs Citrate (Mann-Whitney)
ap = 0.0080,
bp = 0.0436 (Kruskal-Wallis) and
cp = 0.0407,
dp = 0.0130,
ep = 0.0370 vs Citrate (Dunn)
p = 0.0256 and
p = 0.0092 vs 0 week (Wilcoxon)
indicates data missing or illegible when filed
75 ± 55
ap = 0.0764 and
bp = 0.0912 vs Bicarbonate (Mann-Whitney)
indicates data missing or illegible when filed
Actual measurement value vs week 0)
4.6 ± 65.8
ap = 0.0912,
bp = 0.0386,
cp = 0.0712,
dp = 0.0510 vs Bicarbonate and
ep = 0.0491 vs Control (Mann-Whitney)
ap = 0.0794,
bp = 0.0727 (Kruskal-Wallis) and
cp = 0.0903 vs Bicarbonate (Dunn)
Actual measurement value vs week 0)
p = 0.0302 vs 0 week (Wilcoxon)
indicates data missing or illegible when filed
94 ± 42
ap = 0.0716 vs Control (Mann-Whitney)
Actual measurement value vs week 0)
ap = 0.0364 vs Control (Mann-Whitney)
ap = 0.0935 (Kruskal-Wallis) and
bp = 0.0962 vs Control (Dunn)
As a result, in the cases of p-cresyl sulfate (PCS) and phenylacetyl-L-glutamine (PAG), the concentration of uremic substance in urine (excretion into urine) significantly increased in the group to which the combination preparation of hydrates of potassium citrate and sodium citrate (Citrate) had been administered than that group to which the sodium bicarbonate preparation (Bicarbonate) had been administered and the control group. Also regarding the cases of indoxyl sulfate (IS), hippuric acid (HA), and argininosuccinic acid (ASA), the concentration of uremic substance in urine (excretion into urine) increased in the group to which the combination preparation of hydrates of potassium citrate and sodium citrate (Citrate) had been administered than that group to which the sodium bicarbonate preparation (Bicarbonate) had been administered and the control group. In addition, administration of the combination preparation of hydrates of potassium citrate and sodium citrate (Citrate) increased concentrations of indoxyl sulfate (IS), p-cresyl sulfate (PCS), and phenylacetyl-L-glutamine (PAG) in the urine (excretion into urine) compared to before the start of the test (0 W).
By the pharmaceutical composition and the like provided by the present invention, uremic substance are excreted outside the body in mammals. By the method provided by the present invention, it is possible to preliminarily determine as to whether or not uremic substances are excreted outside the body and/or whether or not progression of chronic kidney disease can be suppressed.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2017-082423 | Apr 2017 | JP | national |
| 2017-085741 | Apr 2017 | JP | national |
| 2017-103935 | May 2017 | JP | national |
| PCT/JP2017/032931 | Sep 2017 | JP | national |
Priority is claimed on Japanese Patent Application No. 2017-82423, filed on Apr. 18, 2017; Japanese Patent Application No. 2017-85741, filed on Apr. 24, 2017; Japanese Patent Application No. 2017-103935, filed on May 25, 2017; and International Application No. PCT/JP2017/032931, filed on Sep. 12, 2017, the contents of which are incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/JP2018/009679 | 3/13/2018 | WO | 00 |
