Patent Grant
10894072
Embodiments of the invention generally relate to supplements for treating fibromyalgia and related fibromyalgia symptoms.
hGH: The primary biological function of hGH includes stimulating growth, cell repair and regeneration. Once the primary growth period of adolescence concludes, the primary function of hGH in adulthood becomes that of cell regeneration and repair, helping regenerate skin, bones, heart, lungs, liver and kidneys to their optimal, youthful cell levels. As is the case with many of our other hormones or their precurors, such as testosterone, oestrogen, progesterone, DHEA and melatonin, hGH levels decline with age. Therapeutically, many of these hormones can be replaced to offset some of the effects of aging such as menopausal symptoms in women or erectile dysfunction in men. The human body, like every other living entity, works on daily, or circadian, as well as monthly and annual rhythms. Daily growth hormone secretion diminishes with age with roughly half the levels at age forty that we had when we were twenty, and about one-third of those youthful levels at age sixty. In some sixty-year olds, the levels are as low as 25% of the hGH levels in a twenty-year old. Symptoms of aging include loss of muscle, increase of fat, decreased physical mobility, decreased energy levels and as a result, diminished socialization, diminished healing ability and an increased risk of cardiovascular disease and decreased life expectancy. Low hGH levels are associated with the aging process and early disease. For example, Rosen and Bengtsson noted an increased death rate from cardiovascular disease in hGH deficient patients (Rosen, T., Bengtsson, B. A., Lancet 336 (1990): 285-2880).
Until recently human growth hormone (hereinafter alternatively referred to as hGH) was available only in expensive injectable forms, and benefits from the restoration of hGH levels available only to those with the ability to pay. Most recently substances that can trigger the release of human growth hormone from an individual's own anterior pituitary gland have become available. These are generically referred to as secretagogues. Secretagogues have the ability to restore hGH levels, potentially to the levels found in youth. See for reference the book entitled “Grow Young With hGH” by Dr. Ronald Klatz, President of the American Academy of Anti-Aging, published in 1997 by Harper Collins.
HGH-deficient adults have marked reductions in lean body mass, and within months of hGH treatment, gains in lean body mass, skin thickness and muscle mass are observed. (Cuneo R C et al. J Appl Physiol 1991; 70:695-700; Cuneo R C et al. J Appl Physiol 1991; 70:688-694; Rudman D et al. N Engl J Med 1969; 280:1434-1438).
It is well-established that intravenous (IV) administration of some amino acids results in significant hGH secretion. Intravenous infusion of 183 mg of arginine/kg body weight in females increased hGH levels >20-fold and 30 g of arginine elevated serum hGH levels 8.6 fold in males (Merimee T J et al. N Engl J Med 1969; 280:1434-1438; Alba-Roth J et al. J Clin Endocrinol Metab 1988; 67:1186-1189). Other amino acids, such as methionine, phenylalanine, lysine, histidine, and ornithine have also led to marked increases in hGH (Alba-Roth, Muller, Schopohl, & von Werder, 1988; Chromiak & Antonio, 2002; Gourmelen, M., M. Donnadieu, et al. (1972) Ann Endocrinol (Paris) 33(5): 526-528).
Given the difficulties in IV administration of amino acids for widespread use, interest in elucidating the hGH response to oral amino acid supplements prompted testing of such supplements containing mainly arginine, lysine and ornithine at varying amounts. Yet the pronounced variability in results among these studies, which differed in aspects including subject population, supplement composition, and dosage methodologies, make clear the complexities involved in the design of an effective supplement for supporting hGH levels in the general public. (Suminski R R et al. Int J Sport Nutr 1997; 7:48-60; Lambert M I et al. Int J Sport Nutr 1993; 3:298-305; Corpas E et al. J Gerontol 1993; 48:M128-M133; Isidori A et al. Curr Med Res Opin 1981; 7:475-481; Fogelholm G M et al. Int J Sport Nutr 1993; 3:290-297; Chromiak J A, Antonio J. Nutrition 2002 Jul. 18 (7-8):657-61).
Thus determination of an effective and safe oral functional blend that stimulates hGH secretion in the general population is important to determine since athletes, entertainers and now the general public seek effective hGH support supplements and understand hGH to have rejuvenating properties.
Indeed, once partial to athletes and entertainers, the desire for effective supplements to provoke growth hormone (hGH) increases now extends to the general public. Despite proceeding literature on oral amino acids for use in stimulating hGH, evidence for an optimized oral amino acid-containing blend able to stimulate hGH in the general public including both men and women of a wide age range is not clear.
Fibromyalgia: Scientists estimate that fibromyalgia affects 5 million Americans age 18 or older. For unknown reasons, between 80 and 90 percent of those diagnosed with fibromyalgia are women; however, men and children also can be affected. Most people are diagnosed during middle age, although the symptoms often become present earlier in life.
Fibromyalgia is a common syndrome characterized by fatigue, chronic pain, and other symptoms that are exacerbated by obesity and psychosocial factors such as stress. Furthermore, many patients with fibromyalgia exhibit diminished hGH release, as indicated by reduced insulin-like growth factor 1 (IGF-1), a mediator of hGH action and a long-term indicator of hGH levels. Fibromyalgia typically makes people feel tired and causes muscle pain and “tender points.” Tender points are places on the neck, shoulders, back, hips, arms or legs that hurt when touched. People with fibromyalgia may have other symptoms, such as trouble sleeping, morning stiffness, headaches, and problems with thinking and memory, sometimes called “fibro fog.” No one knows what causes fibromyalgia. Although fibromyalgia is often considered an arthritis-related condition, it is not truly a form of arthritis (a disease of the joints) because it does not cause inflammation or damage to the joints, muscles, or other tissues. It is this characteristic that distinguishes fibromyalgia from a disease entity, instead being a syndrome, classified by a heterogeneous symptomology profile. Indeed, fibromyalgia can cause significant pain and fatigue, and it can interfere with a person's ability to carry on daily activities.
The causes of fibromyalgia are unknown, but there are probably a number of factors involved. Many people associate the development of fibromyalgia with a physically or emotionally stressful or traumatic event, such as an automobile accident. Some connect it to repetitive injuries. Others link it to an illness. For others, fibromyalgia seems to occur spontaneously. People with rheumatoid arthritis and other autoimmune diseases are particularly likely to develop fibromyalgia. There is no cure for fibromyalgia, but some medicines (e.g., analgesics and nonsteroidal anti-inflammatory drugs), can help manage the symptoms.
In various studies, it has been found that some of the clinical features of fibromyalgia resemble the ones described in the adult growth hormone deficiency (GHD) syndrome. Furthermore, insulin-like growth factor 1 (IGF-1) levels have been observed to be frequently reduced in patients with fibromyalgia. To that end, one study assessed 24 hour spontaneous hGH secretion, hGH responses to growth hormone-releasing hormone (GHRH), and IGF-1 and IGF binding protein 3 (IGF-BP3) levels before and after 4 days treatment with human (h)GH. It was found that, in comparison with controls, patients with fibromyalgia exhibited a marked decrease in spontaneous hGH secretion. In contrast, hGH responses to GHRH were similar in controls and in patients with fibromyalgia. Finally, treatment with hGH led to an increase in plasma IGF-1 and IGF-BP3 levels in patients with fibromyalgia. Thus, patients with fibromyalgia exhibited a marked decrease in spontaneous hGH secretion, but normal pituitary responsiveness to exogenously administered GHRH, thus suggesting the existence of an alteration at the hypothalamic level in the neuroendocrine control of hGH in patients with fibromyalgia. (Leal-Cerro et al., J Clin Endocrinol Metab 1999; 84:3378-3381).
Functional deficits in hGH secretion and use of hGH administration as a complementary treatment have been suggested for fibromyalgia. One study involving 120 patients in a placebo-controlled study investigated the efficacy and safety of low-dose hGH as an add-on therapy in patients with both severe fibromyalgia and low insulin-like growth factor 1 levels. Standard treatment for fibromyalgia (selective serotonin re-uptake inhibitors, opioids, and amitriptyline) was maintained throughout the study. Number and intensity of tender points, Fibromyalgia Impact Questionnaire (FIQ) with its subscales, and EuroQol 5 dimensions test (EQ5D) with visual analogue scale (VAS) were assessed at different time points. Patients receiving hGH treatment showed significantly improved FIQ scores compared with placebo group. In this study, addition of hGH to the standard treatment was shown to be effective in reducing pain, showing sustained action over time. (Cuatrecasa et. al., PAIN 2012; 153:1382-1389).
In view of evidence of diminished growth hormone secretion, expressed by means of low insulin-like growth factor 1 (IGF-1) serum levels, in a subset of fibromyalgia patients, the efficacy and safety of low dose hGH as an adjunct to standard therapy in the treatment of severe, prolonged and well-treated fibromyalgia patients with low IGF-1 levels was investigated in another study. Twenty-four patients were enrolled in a randomized, open-label, controlled study, where patients were randomly assigned to receive either hGH subcutaneously (titrated depending on IGF-1) added to standard therapy or standard therapy alone during one year. The number of tender points, FIQ and the EQ-5D, including a Quality of Life visual analogic scale (EQ-VAS) were assessed at different time-points. At the end of the study, the hGH group showed a 60% reduction in the mean number of tender points (pairs) compared to the control group. Similar improvements were observed in FIQ score and EQ-VAS scale. The concomitant administration of hGH and standard therapy was well tolerated, and no patients discontinued the study due to adverse events. (Cuatrecasas et. al., BMC Musculoskeletal Disorders 2007; 8:119-127).
To determine whether suboptimal growth hormone production could be relevant to the symptomatology of fibromyalgia, another study assessed the clinical effects of treatment with growth hormone. Fifty women with fibromyalgia and low IGF-1 levels were enrolled in a randomized, placebo-controlled, double-blind study of 9 months' duration, where they received daily subcutaneous injections of hGH or placebo. Two outcome measures, the Fibromyalgia Impact Questionnaire and the number of fibromyalgia tender points, were evaluated at 3-monthly intervals by a blinded investigator. An unblinded investigator reviewed the IGF-1 results monthly and adjusted the hGH dose to achieve an IGF-1 level of about 250 ng/mL. Daily hGH injections resulted in a prompt and sustained increase in IGF-1 levels. The treatment group showed a significant improvement over the placebo group at nine months in both the FIQ score and the tender point score. After discontinuing growth hormone, patients experienced a worsening of symptoms. This suggests that a diminished endogenous growth hormone secretion may be responsible for some of the symptoms of fibromyalgia. (Bennett et. al., Am J Med 1998; 104:227-231).
It would be desirable to provide a nutritional supplement for elevating hGH release, in particular an amino acid-containing composition that is well tolerated having the result of increasing or elevating hGH release in individuals that have fibromyalgia or in individuals suffering from fibromyalgia symptoms, including in individuals having reduced hGH secretion. Although some existing nutritional supplements claim to impact the production of natural human growth hormone, there is a need for an improved nutritional supplement that efficiently enhances the production and effect of natural human growth hormone in patients having fibromyalgia.
The present invention is a nutritional supplement. It is a novel amino acid-containing secretagogue composition, which, taken orally, stimulates the pituitary gland to increase serum levels of hGH in order to treat fibromyalgia and fibromyalgia-associated symptoms.
A particular embodiment of the present disclosure relates to administration of an oral nutritional supplement that includes the amino acids l-lysine, l-arginine, oxo-proline, and one of either cysteine or glutamine. The amino acids may be delivered as non-toxic salts thereof, effective complexes thereof, stable chelates thereof, active esters thereof, functional derivatives thereof, and mixtures thereof which are effective to increase hGH levels in the general population.
Another particular embodiment relates to administration of an oral nutritional supplement that consists essentially of l-lysine HCl, l-arginine HCl, oxo-proline, N-acetyl-l-cysteine, l-glutamine, and schizonepeta (aerial parts) powder.
The present invention relates to a nutritional supplement for use by a human being. The nutritional supplement is an amino acid-containing secretagogue composition, which, taken orally, stimulates the pituitary gland to increase serum levels of hGH. Increased levels of hGH may result in inhibition of insulin depression, inhibition of hyperglycaemia and increase in insulin effectiveness, enhancement of fat conversion, lowering of cholesterol, and normalization of lipid balance. The supplement of the present invention works as a dietary supplement by assisting the body's own ability to secrete hGH naturally in a manner that is safe and effective, as well as being affordable.
A particular embodiment of the present disclosure relates to an oral nutritional supplement that includes l-lysine, l-arginine, oxo-proline, and one of either cysteine or glutamine. The supplement may additionally include both cysteine and glutamine and/or schizonepeta powder. In particular embodiments, a functional dosage includes the l-arginine at a level between 0.1-6 mmol and the oxo-proline between 0.1-8 mmol, and/or the l-lysine in an amount between 0.1-12 mmol. The cysteine and/or glutamine may be contained at a level between 0.001-6 mmol. In another particular embodiment, a functional dosage includes the l-arginine HCl at a level between 2.5-4.5 mmol and the oxo-proline between 4-6 mmol, and/or the l-lysine HCl in an amount between 7-9 mmol. The cysteine and/or glutamine may be contained at a level between 0.001-0.5 mmol. The cysteine can be n-acetyl L-cysteine and the glutamine may be l-glutamine. The amino acids may be delivered as non-toxic salts thereof, effective complexes thereof, stable chelates thereof, active esters thereof, functional derivatives thereof, and mixtures thereof which are effective to increase hGH levels in the general population. The nutritional supplement may be present in an amount of 2.9 grams. The nutritional supplement may be in any acceptable and known oral formulation, such as powder, tablet, capsule, liquid, or wafer form.
Another particular embodiment relates to an oral nutritional supplement that consists essentially of l-lysine HCl, l-arginine HCl, oxo-proline, N-acetyl-l-cysteine, l-glutamine, and schizonepeta (aerial parts) powder. In particular embodiments, a functional dosage includes the l-arginine HCl at a level between 0.1-6 mmol and the oxo-proline between 0.1-8 mmol, and/or the l-lysine HCl in an amount between 0.1-12 mmol. The n-acetyl L-cysteine and/or l-glutamine may be contained at a level between 0.001-6 mmol. In another particular embodiment, a functional dosage includes the l-arginine HCl at a level between 2.5-4.5 mmol and the oxo-proline between 4-6 mmol, and/or the l-lysine HCl in an amount between 7-9 mmol. The n-acetyl L-cysteine and/or l-glutamine may be contained at a level between 0.001-0.5 mmol. The nutritional supplement may be in any acceptable and known oral formulation, such as powder, tablet, capsule, liquid, or wafer form.
Other embodiments are drawn to methods of increasing human growth hormone in humans that include orally administering the disclosed nutritional supplement to a human being suffering from fibromyalgia. Particular embodiments of the invention relate to oral administration of the disclosed nutritional supplement to a human that is at least 30 years old. The nutritional supplement may be administered from one to three times daily or, alternatively, may be administered every other day, or may be administered once a week. In particular embodiments, the nutritional supplement may be administered on an empty stomach.
In accordance with the “consist essentially of” language, the nutritional supplement of the third embodiments is essentially limited to the aforementioned ingredients and does not include any additional active ingredients intended to add nutritional content (e.g., vitamins, minerals, etc.), but may include additional ingredients not intended to add nutritional content such as ingredients intended to fulfill a non-nutritional purpose (e.g., coloring, fillers, flavoring, an ingredient for maintaining the structural form, etc.).
Each ingredient of the nutritional supplement of the present invention may be prepared in accordance with any method known to one of ordinary skill in the art. Alternatively, each ingredient may be obtained in a fully prepared from a commercially available source.
The nutritional supplement of the present invention may be in any suitable oral administration form, including but not limited to: a chewable form, a liquid form, a spray form, a capsule form, a suppository form, dissolvable wafer, and a powder form.
Irrespective of the structural form of the nutritional supplement, the ingredients of the nutritional supplement may be distributed homogeneously or non-homogeneously within the nutritional supplement.
The nutritional supplement of the present invention may be ingested on a regular basis, such as a daily or weekly intake at a dosage tailored to an individual's needs; i.e., the nutritional supplement is to be taken regularly as multiples (1×, 2×, etc.) of the structural units (pills, tablets, capsules, liquid dose, etc.) in accordance with the needs of the individual. For example, a senior citizen leading a sedentary life may need higher daily doses than does a young person engaged in regular strenuous exercise (e.g., a weight lifter). Alternatively, the nutritional supplement of the present invention may be ingested on an as-needed basis at a dosage tailored to the individual's needs. Medical or nutritional counseling may be beneficial for arriving at a desirable or optimal dosage tailored to the individual's needs.
The combination of types of amino acids, mass ranges, and specific formulations have been selected to be synergistically balanced and of adequate quantity to achieve the desired physiological effect, namely, growth hormone release. Improper combinations of the amino acids may be ineffective. The component amino acids are synergistic in the sense that several of them when combined together, synergistically stimulate the release of human growth hormone. The combination was also chosen to reduce or inhibit chemical combination or reaction between the amino acids.
A cross-over, placebo controlled, double-blind study involved 16 healthy subjects [12 males, 4 females; 9 Caucasian, 6 African American, 1 other; mean age=32±14 years; body mass index=26.4±5.0 ranging from 19.1 to 36.8 kg/m2]. Each subject reported to the Inpatient Unit on two occasions one week apart. After an overnight fast, subjects had an IV line placed and baseline bloods samples were drawn at −30, −15, and 0 minutes. Subjects were then asked to swallow the capsules of the test supplement or an identical looking placebo.
The administered supplement is a novel 2.9 g/dose blend of l-lysine HCl, l-arginine HCl, oxo-proline, N-acetyl-l-cysteine, l-glutamine, and schizonepeta (aerial parts) powder.
Blood was drawn at 15, 30, 60 and 90 and 120 minutes for assay. Human growth hormone (hGH) was measured at each time point using the Siemens Immulite 2000 (intra-assay CV was 3.72%, inter-assay CV was 5.70%, and the detection limit for hGH was 0.05 ng/ml.
Mean growth hormone increased eight-fold over baseline (equivalent to 682%) after the supplement from 0.17 at baseline to 1.33 ng/ml at 120 minutes compared to a mean decrease of 52% after placebo from 0.93 to 0.45 ng/ml (
Mean levels of hGH reached after the subcutaneous injection of 0.06 IU of hGH in the treatment of hGH deficient subjects was 0.4 ng/ml, a value that was clearly in the range of values seen in our study with oral amino acids (Janssen Y J et al. Br J Clin Pharmacol 1999; 47:273-278).
The present study involved a broad range of ages and BMI's and included both genders. An additional advantage of this study of the amino-acid containing blend over previous hGH evaluations is that it contained a placebo control group and was randomized and double-blinded.
Three patients received open-label, daily, oral amino-acid blend of the present disclosure for 18 weeks. At each visit (baseline, week 6, 12, and 18), patients also received dietary and exercise counseling (28 kcal/kg diet and 45 min/day walk). Measurements included body weight, serum IGF-1, IGF-BP3, HbA1c, fasting lipids, fibromyalgia symptoms (measured with a standardized Fibromyalgia Questionnaire), and stress symptoms (measured by the Perceived Stress Scale [PSS]).
At week 18, the individual changes from baseline in body weight were −5.8, −7.4, and −11.8 pounds, respectively, as detailed below. IGF-1 increased in all patients; individual changes were 19, 94, and 49 ng/mL, respectively. Patients reported improvements in fatigue, muscle ache, joint pain, and other fibromyalgia symptoms. Stress, measured by PSS, was substantially reduced from baseline in all patients. All patients had reductions in LDL cholesterol, triglycerides, and HbA1c. There were no adverse events or other safety findings associated with the treatment.
Patient 1
The patient is a 78 year old male with past medical history of fibromyalgia for 10 years, with recent left leg DVT, acute occlusive thrombus in the femoral, popliteal, gastrocnemius, geniculate, posterior tibial, peroneal and soleal veins, pulmonary embolism, HTN. He has been in a relatively stable condition in terms of his comorbidities, and his complaints consisted mainly of items listed in a standardized Fibromyalgia Questionnaire (FQ). His physical exam was unremarkable except diffuse myofascial tenderness with multiple trigger point sensitivity affecting his extremities and the paraspinal area. His work-up revealed no other specific etiology, suggesting possible fibromyalgia relapse. He was placed on a complex medical management including Guaifenesine, anti-inflammatory and muscle relaxant medications, and physical therapy, but no significant improvement was achieved. Lifestyle recommendations include assigned diet of 28 kcal/kg/day, no salycilate restriction, and 45 min walk daily minimum. The amino-acid blend was added to the management, and he was monitored for progression.
Daily use of the human growth hormone (hGH) secretagouge amino-acid blend over the 18 week treatment course demonstrated significant increases in IGF-1 by 13.3% (143 to 162 ng/ml. Weight loss was 5.8 lbs over the 18 week treatment with progressive improvements across categories of the FQ, notably in muscle mass, bowel movements, libido, memory, parameters of pain and stiffness, fatigue, and social interest.
Patient 2
The patient is a 59-year-old white female with past medical history of fibromyalgia for eight years, asthma and multiple respiratory infections in the past, diabetes mellitus type 2, hypertension, Crohn's Disease, depression, postmenopausal syndrome, hyperlipidemia, hypothyroidism, and uveitis. The patient had no known drug allergies. Social history was noncontributory.
Her general condition has been in a relatively stable condition in terms of her comorbidities, and her complaints consisted mainly of items listed in the standardized Fibromyalgia Questionnaire (FQ). Her physical exam was unremarkable except diffuse myofascial tenderness with multiple trigger point sensitivity affecting her extremities and the paraspinal area. Her work-up revealed no other specific etiology, suggesting possible fibromyalgia relapse. She was placed on a complex medical management including Guaifenesine, anti-inflammatory and muscle relaxant medications with physical therapy, but no significant benefit was reported. Lifestyle recommendations include assigned diet of 28 kcal/kg/day, no salycilate restriction, and 45 min walk daily minimum. The amino-acid blend was added to the management and she was monitored for progression.
Daily use of the human growth hormone (hGH) secretagouge amino-acid blend over the 18 week treatment course demonstrated significant increases in IGF-1 by 56.3% (167 to 261 ng/ml). Weight loss was 7.4 lbs over the 18 week treatment with progressive improvements across categories of the FQ, notably in muscle mass, bowel movements, libido, memory, parameters of pain and stiffness, fatigue, and social interest.
Patient 3
The patient is a 63-year-old white male with past medical history of fibromyalgia for 12 years, pacemaker implantation, (Guidant twelve years prior) secondary to sick sinus syndrome; bradycardia; coronary artery disease; hypertension; hyperlipidemia; syncope; vestibulopathy; claudication in connection to diabetic vasculopathy; hypersensitivity; carotid sinus syndrome, status post carotid artery stenting on the left; Parkinson disease; asthma; type 2 diabetes mellitus with mild retinopathy and neuropathy; benign prostatic hypertrophy; depression; COPD (ex-smoker); status post carotid endarterectomy; hypothyroidism; and allergic rhinitis. The patient had no known drug allergies.
The patient has been in his usual state of health, except his complaints consisted mainly of items listed in the standardized Fibromyalgia Questionnaire (FQ). His physical exam was unremarkable except diffuse myofascial tenderness with multiple trigger point sensitivity affecting his extremities and the paraspinal area. His work-up revealed no other specific etiology, suggesting possible fibromyalgia relapse. He was placed on a complex medical management including Guaifenesine, anti-inflammatory and muscle relaxant medications, and physical therapy, but no significant improvement was achieved. Lifestyle recommendations include assigned diet of 28 kcal/kg/day, no salycilate restriction, and 45 min walk daily minimum. The amino-acid blend was added to the management and he was monitored for progression.
Daily use of the human growth hormone (hGH) secretagouge amino-acid blend over the 18 week treatment course demonstrated significant increases in IGF-1 by 44.5% (110 to 159 ng/ml. Weight loss was 11.8 lbs over the 18 week treatment with progressive improvements across categories of the FQ, notably in muscle mass, bowel movements, libido, memory, parameters of pain and stiffness, fatigue, and social interest.
In all 3 patients, 18 weeks of daily amino-acid blend supplementation along with diet and exercise resulted in weight loss and increased IGF-1, as well as improved lipids and HbA1c. There were also notable improvements in fibromyalgia symptoms and the ability to cope with stress. Increases in IGF-1 reflect increased endogenous hGH release. In patients with fibromyalgia and reduced hGH release, the amino-acid blend represents a potential low-risk treatment to ameliorate fibromyalgia symptoms by amplifying endogenous hGH.
While embodiments of the present invention have been described herein for purposes of illustration, many modifications and changes will become apparent to those skilled in the art. Accordingly, the appended claims are intended to encompass all such modifications and changes as fall within the true spirit and scope of this invention.
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| Number | Date | Country | |
|---|---|---|---|
| 20180228859 A1 | Aug 2018 | US |
