Patent Application
20190192456
This application claims the benefit of European Patent Application No. 17306889.1 filed December 21, 2017, the entire content of which is incorporated herein by reference.
The present disclosure relates to the prevention of cardiovascular, gastrointestinal and obstetrical events during pregnancy, delivery, and peripartum period in women suffering from an orphan disease, namely vascular Ehlers-Danlos syndrome (vEDS). More specifically, the disclosure pertains to the use of celiprolol for treating vEDS in women during pregnancy and during the peripartum period.
Vascular Ehlers-Danlos syndrome (OMIM#13050; EDS vascular type) is a rare genetic disease caused by mutations in the COL3A1 gene encoding type III procollagen. Its evolution is characterized by recurrent, unpredictable and potentially life-threatening arterial, gastrointestinal and obstetrical accidents or events in young adults [1, 2]. In women, pregnancy and more particularly delivery and the peripartum period are associated with increased risk of uterine and/or arterial rupture, which have been associated with maternal death [3-5]. Case-series and small patient cohorts initially proposed maternal mortality rates ranging from 25 to 38.5% [6, 7], which were updated in the year 2000's to 11.5% in a large patient cohort [1]. More recently, these estimates have been further revised to a lower mortality rate of 5.3% [8].
Other complications, such as premature rupture of membranes, preterm labour and prematurity can also occur in this patient population, but have been extensively documented in patients without taking into account the specific subtypes of Ehlers-Danlos syndromes (EDS). These data also often relied on patient surveys without medical interview [9, 10]. Finally, it is not known whether maternal morbidity and mortality of vascular EDS may be improved by specific care strategies. Programmed caesarean section (c-section) has been suggested to improve vEDS patient outcome, but without formal proof of efficacy nor any evaluation of neonatal outcome [7]. Consequently, contraindication of pregnancy in vascular EDS has been discussed recurrently and has been subject of a formal recommendation [7, 11].
In 2010, Ong et al. reported the results of a clinical trial study for assessing the effects of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome (BBEST study). However, pregnant women and women likely to become pregnant were considered as ineligible for enrollment in this study because of the potential risks of celiprolol treatment for the fetus. The adverse effects on the fetus that were anticipated and thus led to the exclusion of pregnant women in the BBEST study were intrauterine growth retardation, hypotonicity and neonatal hypoglycaemia.
Thus there remains an unmet medical need for novel, appropriate and effective treatment of women with vEDS during pregnancy, delivery and the peripartum (or perinatal) period.
The present disclosure provides, inter glia, methods of treating vEDS in women during pregnancy, delivery and the peripartum period by administering to such women celiprolol or a pharmaceutically acceptable salt thereof. The present disclosure discloses that such treatment efficiently and effectively protected these women from cardiovascular, gastrointestinal and obstetrical accidents and events, and surprisingly, that such treatment did not have any of the expected adverse effects on the fetus.
The present disclosure further provides for the use of celiprolol or a pharmaceutically acceptable salt thereof for preventing cardiovascular, obstetrical and gastrointestinal events in vEDS women during pregnancy, delivery and the perinatal or peripartum period.
In one embodiment, the present disclosure provides a method for treating vEDS in a woman during pregnancy, during delivery, or during the peripartum period, the method comprising administering to the woman celiprolol or a pharmaceutically acceptable salt thereof, thereby treating vEDS in the woman. In some embodiments, celiprolol, or a pharmaceutically acceptable salt thereof, is administered to the woman at a dosage of at least 100 mg per day. In some embodiments, celiprolol, or a pharmaceutically acceptable salt thereof, is administered to the woman at a dosage ranging from about 200 mg to about 600 mg per day; from about 200 mg to about 500 mg per day; or from about 200 mg to about 600 mg per day. In some embodiments, the daily dosage of celiprolol, or a pharmaceutically acceptable salt thereof, is obtained by administering celiprolol, or a pharmaceutically acceptable salt thereof, to the women once daily, twice daily, or thrice daily.
In some embodiments, the present disclosure provides a method for treating a woman having vEDS during pregnancy, during delivery, or during the peripartum period by administering or providing celiprolol, or a pharmaceutically acceptable salt, to the woman, wherein the method prevents or reduces cardiovascular, gastrointestinal, or obstetrical events. In some embodiments, the present disclosure provides a method for treating a woman having vEDS during pregnancy, during delivery, or during the peripartum period with celiprolol, or a pharmaceutically acceptable salt, wherein the method prevents or reduces the risk of arterial dissection or arterial rupture; prevents or reduces the risk of obstetrical accidents; prevents or reduces the risk of uterine rupture; or prevents or reduces the risk of pregnancy-related or pregnancy-associated death. In some embodiments, the present disclosure provides a method for treating a woman having vEDS, wherein the treatment is during pregnancy, during delivery, or during the peripartum period, wherein the method comprises administering to the woman celiprolol, or a pharmaceutically acceptable salt thereof, wherein the method prevents or reduces the risk of death following termination of pregnancy, or prevents or reduces the risk of preterm birth.
The present disclosure provides a method of treating vascular Ehlers-Danlos syndrome in a woman during pregnancy, during delivery and during the peripartum period, the method comprising administering celiprolol, or a pharmaceutically acceptable salt thereof, to the woman.
In one embodiment of the present disclosure, a method is provided for treating vEDS in a woman during pregnancy, during delivery, or during the peripartum period, the method comprising administering to the woman celiprolol, or a pharmaceutically acceptable salt thereof, thereby treating vEDS in the woman during pregnancy, during delivery, or during the peripartum period. In some embodiments, celiprolol, or a pharmaceutically acceptable salt thereof, is administered to the woman at a dosage of at least 100 mg per day. In some embodiments, celiprolol, or a pharmaceutically acceptable salt thereof, is administered to the woman at a dosage ranging from about 200 mg to about 600 mg per day; from about 200 mg to about 500 mg per day; from about 200 mg to about 400 mg per day. In some embodiments, celiprolol, or a pharmaceutically acceptable salt thereof, is administered to the woman at a dosage of about 100 mg per day, at a dosage of about 200 mg per day, at a dosage of about 300 mg per day, at a dosage of about 400 mg per day, at a dosage of about 500 mg per day, or at a dosage of about 600 mg per day. In some embodiments, the daily dosage of celiprolol, or a pharmaceutically acceptable salt thereof, is obtained by administering celiprolol, or a pharmaceutically acceptable salt thereof, to the women once daily, twice daily, or thrice daily.
In some embodiments, treatment of a woman having vEDS during pregnancy, during delivery, or during the peripartum period with celiprolol, or a pharmaceutically acceptable salt thereof, according to the methods of the present disclosure, prevents or reduces cardiovascular, gastrointestinal, or obstetrical events. In some embodiments, treatment of a woman having vEDS during pregnancy, during delivery, or during the peripartum period with celiprolol, or a pharmaceutically acceptable salt thereof, according to the methods of the present disclosure, prevents or reduces the risk of arterial dissection or arterial rupture; prevents or reduces the risk of obstetrical accidents; prevents or reduces the risk of uterine rupture; or prevents or reduces the risk of pregnancy-related or pregnancy-associated death. In some embodiments, treatment of a woman having vEDS during pregnancy, during delivery, or during the peripartum period with celiprolol, or a pharmaceutically acceptable salt thereof, does not result in neonatal hypoglycaemia or intrauterine growth retardation. In some embodiments, treatment of a woman having vEDS during pregnancy, during delivery, or during the peripartum period with celiprolol, or a pharmaceutically acceptable salt thereof, according to the methods of the present disclosure, prevents or reduces the risk of death following termination of pregnancy, or prevents or reduces the risk of preterm birth.
As used herein, the terms “treat”, “treatment” and “treating” refer to any reduction of one or more symptom(s) associated with vascular Ehlers-Danlos syndrome; for example, reduction of the occurrence and/or severity of cardiovascular and/or obstetrical accidents, and/or a decrease of the risk of maternal death during pregnancy and post-partum period that results from the administration of celiprolol alone or combined with one or more other therapies or care of these patients.
As used herein, the term “comprise” or “include” is intended to mean that the compositions and methods include the recited elements, but not excluding others. “Consist essentially of” when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination. For example, a composition consisting essentially of the elements as defined herein would not exclude other elements that do not materially affect the basic and novel characteristic(s) of the claimed invention. “Consist of” shall mean excluding more than trace amount of other ingredients and substantial method steps recited. Embodiments defined by each of these transition terms are within the scope of this disclosure.
The term “about” when used before a numerical value indicates that the value may vary within reasonable range, such as ±10%, ±5%, and ±1%. The expression “about x” includes the value “x.”
The singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the mutation” includes a plurality of mutations.
Celiprolol (brand names Cardem®, Selectol®, Celipres®, Celipro®, Celol® Cordiax®, Dilanorm®, Edsivo™) is a medication in the class of beta blockers. Its chemical formula is N′-(3-Acetyl-4-(3-((1,1-dimethylethyl)amino)-2-hydroxypropoxy)phenyl)-N,N-diethylurea, its CAS number is 56980-93-9 and Drug Bank number is DB04846.
In the present text, the peripartum period is defined as the last month of pregnancy to five months postpartum.
According to one embodiment, the present disclosure provides a method of treating vascular Ehlers-Danlos syndrome in a woman during pregnancy, during delivery, or during the peripartum period, the method comprising administering celiprolol, or a pharmaceutically acceptable salt thereof, to a woman in need thereof, wherein treatment begins with a titration period wherein celiprolol, or a pharmaceutically acceptable salt thereof, is administered at a dosage of about 100 mg daily during one month and increased by steps of about 100 mg/day every month over a about 3-month period to reach a dosage of about 400 mg per day (or at least 400 mg per day).
In other embodiments, a dose escalation regimen is used for such treatment. In the dose escalation regimen provided herein, the first daily dosage is about 100 mg during the initial month, the initial 30 days, or the initial 28 days; the second daily dosage is about 200 mg (e.g., about 200 mg once daily, about 100 mg twice-daily) during the second month, the second 30 days, or the second 28 days; the third daily dosage is about 300 mg (e.g., about 300 mg once daily, about 150 mg twice daily, about 100 mg thrice daily) during the third month; and the fourth daily dosage is about 400 mg daily (e.g., about 400 mg once daily, about 200 mg twice daily). Methods of the present disclosure can further comprise additional steps after the three-month dose escalation/up-titration period, to further increase the daily dose of celiprolol, or a pharmaceutically acceptable salt thereof, administered to the woman. According to a particular embodiment, one or two additional dosage increases are performed after the three-month dose escalation/up-titration period, to reach a daily dosage of greater than 400 mg, such as for example, about 500 mg or about 600 mg of celiprolol, or a pharmaceutically acceptable salt thereof.
In some embodiments, provided is celiprolol or a pharmaceutically acceptable salt thereof for use in treating vascular Ehlers-Danlos syndrome in a woman during pregnancy, during delivery, or during the peripartum period, wherein treatment begins with 80 to 110 mg (e.g., about 91.25 mg) daily celiprolol or an equivalent amount of a pharmaceutically acceptable salt of celiprolol and increases to 300 to 440 mg (e.g., about 365 mg) daily celiprolol or an equivalent amount of a pharmaceutically acceptable salt of celiprolol within six months. In some embodiments, provided is a method for treating vascular Ehlers-Danlos syndrome in a woman in need thereof during pregnancy, during delivery, or during the peripartum period, comprising administering to the woman a 80 to 110 mg (e.g., about 91.25 mg) daily dose of celiprolol or an equivalent amount of a pharmaceutically acceptable salt of celiprolol and increasing the daily dose to 300 to 440 mg (e.g., about 365 mg) within six months. In some embodiments, at least a 80 to 110 mg daily (e.g., 91.25 mg) dose increase is made within two months. In some embodiments, at least a 170 to 210 mg (e.g., about 182.5 mg) daily dose increase is made within four months. In some embodiments, at least a 260 to 310 mg (e.g., about 273.75 mg) daily dose increase is made within six months. In some embodiments, at least a 260 to 310 mg (e.g. about 273.75 mg) daily dose increase is made within four months. An equivalent amount of a pharmaceutically acceptable salt of celiprolol is the weight amount of the salt that provides the stated amount of celiprolol. For example, 200 mg of the HCl salt of celiprolol (celiprolol hydrochloride) provides and is equivalent to 182.5 mg of celiprolol.
In some embodiments, celiprolol, or a pharmaceutically acceptable salt thereof, is administered to the woman at a daily dosage of about 91.25 mg celiprolol for a first period of time; followed by administering celiprolol, or a pharmaceutically acceptable salt thereof, to the woman at a daily dosage of about 182.5 mg celiprolol for a second period of time; followed by administering celiprolol, or a pharmaceutically acceptable salt thereof, to the woman at a daily dosage of about 273.75 mg celiprolol for a third period of time; and following by administering celiprolol, or a pharmaceutically acceptable salt thereof, to the woman at a dosage of about 365 mg celiprolol.
In some embodiments, at least 365 mg per day (e.g., 182.5 mg twice per day) celiprolol, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered to the woman within 120 days (e.g., within 90 days) of the initial dosage of celiprolol, or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the initial dosage of celiprolol is 91.25 mg per day, or an equivalent amount of a pharmaceutically acceptable salt thereof.
In some embodiments, the present disclosure provides a method for treating vEDS in a woman in need thereof during pregnancy, during delivery and/or during the peripartum period, the method comprising administering celiprolol, or a pharmaceutically acceptable salt thereof, to the woman at a first daily dosage of about 91.25 mg celiprolol for one month; followed by administering celiprolol, or a pharmaceutically acceptable salt thereof, to the woman a second daily dosage of about 182.5 mg celiprolol for one month; followed by administering celiprolol, or a pharmaceutically acceptable salt, to the woman a third daily dosage of about 273.75 mg celiprolol for one month; and followed by providing or administering celiprolol, or a pharmaceutically acceptable salt thereof, to the woman a fourth daily dosage of about 365 mg celiprolol, thereby treating vEDS.
In some embodiments, the present disclosure provides for the use of celiprolol, or a pharmaceutically acceptable salt thereof, for treatment of vEDS in a woman in need thereof during pregnancy, during delivery and during the peripartum period, wherein celiprolol, or a pharmaceutically acceptable salt thereof, is administered to the woman at a first daily dosage of about 91.25 mg celiprolol for about 1 month, followed by a second daily dose of about 182.5 mg celiprolol for about 1 month, followed by a third daily dose of about 273.75 mg celiprolol for about 1 month, and followed by a fourth daily dose of about 365 mg celiprolol.
In some embodiments, the dosage of celiprolol,or a pharmaceutically acceptable salt thereof, is reduced (e.g., reduced by about 91.25 mg celiprolol per day) if any signs of intolerance to the drug (e.g., swelling, fatigue, or flu-like symptoms) are experienced by the woman during up-titration or follow-up.
In some embodiments, the method further includes administering a dosage of at least 456 mg per day (e.g., at least 547.5 mg per day) celiprolol. In some embodiments, the dosage is increased to at least 456 mg per day celiprolol after the three-month up-titration or dose escalation period.
In some embodiments, the celiprolol or pharmaceutically acceptable salt thereof is celiprolol hydrochloride.
In some embodiments, provided is celiprolol hydrochloride for use in treating vascular Ehlers-Danlos syndrome in a woman during pregnancy, during delivery, or during the peripartum period, wherein treatment with celiprolol hydrochloride begins with 90 to 110 mg (e.g., about 100 mg) daily and increases to 360 to 440 mg (e.g., about 400 mg) daily within six months. In some embodiments, provided is a method for treating vascular Ehlers-Danlos syndrome in a woman in need thereof during pregnancy, during delivery, or during the peripartum period, comprising administering to the woman a 90 to 110 mg (e.g., about 100 mg) daily dose of celiprolol hydrochloride and increasing the daily dose to 360 to 440 mg (e.g., about 400 mg) within six months. In some embodiments, at least a 90 to 110 mg (e.g., about 100 mg) daily dose increase is made within two months. In some embodiments, at least a 180 to 220 mg (e.g., about 200 mg) daily dose increase is made within four months. In some embodiments, at least a 270 to 330 mg (e.g., about 300 mg) daily dose increase is made within six months. In some embodiments, at least a 270 to 330 mg (e.g., about 300 mg) daily dose increase is made within four months.
In some embodiments, the initial daily dosage is about 100 mg celiprolol hydrochloride. In some embodiments, the second daily dosage is about 200 mg celiprolol hydrochloride. In some embodiments, the third daily dosage is about 300 mg celiprolol hydrochloride. In some embodiments, the fourth daily dosage is about 400 mg celiprolol hydrochloride. In other embodiments, the fifth daily dosage is greater than 400 mg (e.g., about 500 mg or about 600 mg) celiprolol hydrochloride.
In some embodiments, the disclosure provides a method of treating vascular Ehlers-Danlos syndrome in a woman in need thereof during pregnancy, during delivery and during the peripartum period. This method includes administering at least 400 mg per day (e.g., 200 mg twice per day) celiprolol hydrochloride to the woman within 120 days (e.g., within about 90 days) of the initial dosage of celiprolol hydrochloride. In some embodiments, the initial dosage of celiprolol hydrochloride is about 100 mg per day.
In one embodiment, the present disclosure provides a method for treating vEDS in a woman in need thereof during pregnancy, during delivery and during the peripartum period, the method comprising administering celiprolol hydrochloride to the woman at a first daily dosage of about 100 mg for about one month; followed by administering celiprolol hydrochloride to the woman a second daily dosage of about 200 mg for about one month; followed by administering celiprolol hydrochloride to the woman a third daily dosage of about 300 mg for about one month; and followed by administering celiprolol hydrochloride to the woman a fourth daily dosage of about 400 mg, thereby treating vEDS.
In some embodiments, the dosage of celiprolol hydrochloride is reduced (e.g., reduced by about 100 mg per day) if any signs of intolerance to the drug (e.g., swelling, fatigue, or flu-like symptoms) are experienced by the patient during up-titration or follow-up.
In some embodiments, the method further includes administering a dosage of at least 500 mg per day (e.g., at least 600 mg per day) celiprolol hydrochloride. In some embodiments, the dosage is increased to at least 500 mg per day after the three-month up-titration or dose escalation period.
In some embodiments, the first period of time is about one month, about 30 days, or about 28 days. In some embodiments, the second period of time is about one month, about 30 days, or about 28 days. In some embodiments, the third period of time is about one month, about 30 days, or about 28 days.
In some embodiments, celiprolol is administered in a pharmaceutical composition comprising celiprolol or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition is a tablet formulation, such as a film coated tablet. In some embodiments, the pharmaceutical composition is an immediate release formulation, such as an immediate release tablet formulation. In some embodiments, each tablet comprises about 182.5 mg celiprolol or about 200 mg of celiprolol hydrochloride.
In some embodiments, celiprolol is not administered within one hour of a meal. In some embodiments, celiprolol is not administered 1 hour before, or 2 hours after a meal.
In some embodiments, celiprolol is not co-administered with itraconazole, grapefruit juice, orange juice, chlorthalidone, hydrochlorothiazide, theophylline, or rifampicin. In some embodiments, celiprolol is not co-administered with a substrate of MATE1, MATE2-K, BCRP, or P-gp transporter. In some embodiments, celiprolol is not co-administered with calcium channel blockers, such as phenylalkylamine and benzothiazepine, hypotensive agents, or oral antidiabetic (hypoglycemics) drugs. In some embodiments, when co-administered with one or more of the agents, such as itraconazole, the dosage of celiprolol is reduced.
In some embodiments, celiprolol is not co-administered with general anesthesia. In some embodiments, anesthesia is not administered within about 24 hours of the last celiprolol dose. In some embodiments, anesthesia is not administered within about 48 hours of the last celiprolol dose.
In some embodiments, celiprolol is not administered to a woman having one or more of the following conditions: cardiogenic shock, decompensated cardiac failure, sick-sinus syndrome, heart block greater than first degree, severe bradycardia, severe renal impairment with creatinine clearance less than about 15 mL/minute, hypotension, or hypersensitivity to celiprolol.
In some embodiments, when treatment with celiprolol is discontinued, it is discontinued after gradually reducing the dosage over a period of at least one week, such as one to two weeks.
In some embodiments, provided is celiprolol or a pharmaceutically acceptable salt of celiprolol for use in treating vascular Ehlers-Danlos syndrome in a woman during pregnancy, during delivery and during the peripartum period that is receiving a 300 to 440 mg daily dose of celiprolol or an equivalent amount of a pharmaceutically acceptable salt of celiprolol, and having a need to cease the treatment, wherein the daily dose is reduced for no more than about 100 mg of celiprolol or an equivalent amount of a pharmaceutically acceptable salt of celiprolol per day. In some embodiments, provided is method for ceasing the treatment of celiprolol or a pharmaceutically acceptable salt of celiprolol in a woman during pregnancy, during delivery and during the peripartum period that is receiving a 300 to 440 mg daily dose of celiprolol or an equivalent amount of a pharmaceutically acceptable salt of celiprolol and having a need to cease the treatment, comprising reducing the daily dose for no more than about 100 mg of celiprolol or an equivalent amount of a pharmaceutically acceptable salt of celiprolol per day. In some embodiments, the reduction continues for at least 5 days. In some embodiments, the reduction continues for at least 7 days. In some embodiments, the reduction continues for at least 10 days.
In some embodiments, provided is celiprolol hydrochloride for use in treating vascular Ehlers-Danlos syndrome in a woman during pregnancy, during delivery and during the peripartum period that is receiving a 360 to 440 mg daily dose of celiprolol hydrochloride and having a need to cease the treatment, wherein the daily dose of celiprolol hydrochloride is reduced for no more than about 100 mg a day. In some embodiments, provided is method for ceasing the treatment of celiprolol hydrochloride in a patient that is receiving a 360 to 440 mg daily dose of celiprolol hydrochloride and having a need to cease the treatment, comprising reducing the daily dose of celiprolol hydrochloride for no more than about 100 mg a day. In some embodiments, the reduction continues for at least 5 days. In some embodiments, the reduction continues for at least 7 days. In some embodiments, the reduction continues for at least 10 days.
In some embodiments, the method is initiated as soon as pregnancy is confirmed, or soon thereafter. In other embodiments, the method is initiated soon after the woman gives birth. In some embodiments, treating woman according to one of the methods provided herein occurs during pregnancy and continues into the peripartum period.
In some embodiments, the woman with vEDS has been treated with celiprolol or a pharmaceutically acceptable salt, and the dosage is not adjusted or reduced in anticipation of becoming pregnant or after confirmation of pregnancy. In some embodiments, the dosage is not adjusted or reduced during pregnancy, during delivery and/or during the peripartum period.
In some embodiments, the method comprises continuing administration of celiprolol or a pharmaceutically acceptable salt without dose adjustment to a woman who has been treated with celiprolol or a pharmaceutically acceptable salt, and who may become pregnant or is confirmed of being pregnant.
In some embodiments, the woman is diagnosed with vEDS based on a phenotype of vEDS, or based on a molecular test vEDS (e.g., the woman is determined to have vEDS based on one or more genetic tests such as a test that determines that the woman has a glycine substitution within the triple helix or a splice-site variant within COL3A1 gene).
In some embodiments, the woman has a glycine substitution within the triple helix or a splice-site variant within COL3A1 gene. In some embodiments, the woman has previously had an acute vEDS-related event (e.g., an arterial event such as a rupture or dissection) prior to the initial dose of celiprolol, or a pharmaceutically acceptable salt thereof.
In certain embodiments, provided is
1. Celiprolol or a pharmaceutically acceptable salt thereof, for use in treating vascular Ehlers-Danlos syndrome in a woman during pregnancy, during delivery, or during the peripartum period.
2. Celiprolol or a pharmaceutically acceptable salt thereof, for the use of 1 above, wherein celiprolol or a pharmaceutically acceptable salt thereof is administered to the woman a dosage of at least 100 mg per day.
3. Celiprolol or a pharmaceutically acceptable salt thereof, for the use of 1 or 2 above, wherein celiprolol or a pharmaceutically acceptable salt thereof is administered to the woman at a dosage ranging from 200 mg to 600 mg per day.
4. Celiprolol or a pharmaceutically acceptable salt thereof, for the use of any of 1 to 3 above, wherein celiprolol or a pharmaceutically acceptable salt thereof is administered to the woman at a daily dosage of 200 mg to 400 mg.
5. Celiprolol or a pharmaceutically acceptable salt thereof, for the use of any of 1 to 4 above, wherein celiprolol or a pharmaceutically acceptable salt thereof is administered twice daily.
6. Celiprolol or a pharmaceutically acceptable salt thereof, for the use of any of 1 to 5 above, wherein administration of celiprolol or a pharmaceutically acceptable salt thereof to the woman prevents or reduces the risk of cardiovascular and/or digestive and/or obstetrical events.
7. Celiprolol or a pharmaceutically acceptable salt thereof, for the use of any of 1 to 6 above, wherein administration of celiprolol or a pharmaceutically acceptable salt thereof to the woman prevents or reduces the risk of arterial dissection and rupture.
8. Celiprolol or a pharmaceutically acceptable salt thereof, for the use of any of 1 to 7 above, wherein administration of celiprolol or a pharmaceutically acceptable salt thereof to the woman prevents or reduces the risk of obstetrical accidents.
9. Celiprolol or a pharmaceutically acceptable salt thereof, for the use of any of 1 to 8 above, wherein administration of celiprolol or a pharmaceutically acceptable salt thereof to the woman prevents or reduces the risk of uterine rupture.
10. Celiprolol or a pharmaceutically acceptable salt thereof, for the use of any of 1 to 9 above, wherein administration of celiprolol or a pharmaceutically acceptable salt thereof to the woman reduces the risk of pregnancy-related death.
11. Celiprolol or a pharmaceutically acceptable salt thereof, for the use of any of 1 to 10 above, wherein administration of celiprolol or a pharmaceutically acceptable salt thereof to the woman reduces the risk of death of the woman during the first year following termination of pregnancy.
12. Celiprolol or a pharmaceutically acceptable salt thereof, for the use of any of 1 to 11 above, wherein administration of celiprolol or a pharmaceutically acceptable salt thereof to the woman reduces the risk of preterm birth.
13. A method for treating vascular Ehlers-Danlos syndrome in a woman during pregnancy, during delivery, or during the peripartum period, the method comprising administering celiprolol, or a pharmaceutically acceptable salt thereof, to the woman during pregnancy, during delivery, or during the peripartum period, thereby treating vascular Ehlers-Danlos syndrome in the woman.
14. The method of 13 above, wherein celiprolol, or a pharmaceutically acceptable salt thereof, is administered to the woman a dosage of at least 100 mg per day.
15. The method of 13 above, wherein celiprolol, or a pharmaceutically acceptable salt thereof, is administered to the woman at a dosage ranging from about 200 mg to about 600 mg per day.
16. The method of 13 above, wherein celiprolol, or a pharmaceutically acceptable salt thereof, is administered to the woman at a daily dosage of about 200 mg to about 400 mg.
17. The method of any one of 13-16 above, wherein celiprolol, or the pharmaceutically acceptable salt thereof, is administered twice daily.
18. The method of any one of 13-17 above, wherein the method prevents or reduces the risk of cardiovascular and/or digestive and/or obstetrical events.
19. The method of any one of 13-18 above, wherein the method prevents or reduces the risk of arterial dissection and rupture.
20. The method of any one of 13-19 above, wherein the method prevents or reduces the risk of obstetrical accidents.
21. The method of any one of 13-20 above, wherein the method prevents or reduces the risk of uterine rupture.
22. The method of any one of 13-21 above, wherein the method reduces the risk of pregnancy-related death.
23. The method of any one of 13-22 above, wherein the method reduces the risk of death of the woman during the first year following termination of pregnancy.
24. The method of any one of 13-24 above, wherein the method reduces the risk of preterm birth.
Other characteristics of the disclosure will also become apparent in the course of the description which follows of the biological assays which have been performed in the framework of the disclosure and which provide it with the required experimental support, without limiting its scope.
The inventors herein report the analysis of a French cohort of vascular EDS patients. They specifically analyzed the issues and complications of pregnancies in women with molecularly proven vascular EDS or retrospectively obligate carriers of COL3A1 genetic variants. This analysis provides recent and precise estimates of maternal mortality and morbidity in this condition. The authors also describe the successful use of celiprolol for preventing cardiovascular and/or digestive and/or obstetrical events in women or during pregnancy, delivery and during the peripartum period.
For the mortality analysis, the medical charts and pedigrees of all patients known to the French referral center for rare vascular diseases (AP-HP, Centre de Référence des Maladies Vasculaires Rares, Hôpital Européen Georges Pompidou, Paris, France) for having a molecularly confirmed vascular EDS, were screened for past or ongoing pregnancies, and for maternal deaths in probands and pedigrees. All families known to our center with at least one proband diagnosed with vascular EDS (nationwide patient cohort) were considered for participation to the maternal mortality analysis after exclusion of ascendants of patients with neomutations (see below). Patients with a personal history of pregnancy were considered for participation to the obstetrical interview study.
To be eligible to the mortality analysis, families with one affected proband were to have a complete medical record for at least the index case, and a complete pedigree made by a genetic counsellor over two generations showing numbers of siblings, ascendants (aunts and uncles, grand-fathers and grand-mothers), number of life- and still-born children for each child-bearing woman, their age and cause of death when applicable.
In order to identify affected women within each family, all pedigrees were screened for transmitters (patients with an identified pathogenic mutation within the COL3A1 gene), likely transmitters (ascendants within one family branch with clinical features evocative of vascular EDS and/or characteristic arterial/digestive or obstetrical events, or a first degree ascendant without clinical features of vascular EDS, with one second degree ascendant with clinical features evocative of vascular EDS and/or characteristic arterial/digestive or obstetrical events) and unlikely transmitters (ascendants without clinical events evocative of vascular EDS, or without evocative arterial/digestive/obstetrical events, or having died of natural or identifiable non-vascular EDS related causes). In case of pedigrees with proven neomutations (both parents tested negative), only probands were considered for analysis.
Maternal deaths were determined according to definitions of the 10th revision of the International Classification of Diseases of the World Health Organization (Geneva 2004). Pregnancy-related deaths defined as the death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the cause of death, were determined for probands, first and second degree ascendants. Late maternal deaths, defined by the death of a woman from direct or indirect obstetrical causes more than 42 days but less than one year after termination of pregnancy, were also considered, in order to increase the accuracy of the analysis. A global maternal mortality ratio was then determined, which encompassed pregnancy-related and late maternal mortality ratios. All mortality ratio calculations excluded accidental or incidental causes.
For purpose of clarity and according to common use, all mortality ratios are reported as mortality rates and are expressed per 100 live-births, with their respective 95% confidence interval (95% CI).
Patients eligible for the maternal morbidity study had a first interview with a senior physician of our centre, during which relevant obstetrical data were collected. For each pregnancy, date and time of delivery were recorded, as well as term of pregnancy at birth, expressed in weeks of amenorrhea (WA). In case of preterm labour or premature rupture of membranes (PROM), gestational age of occurrence was noted. Ongoing treatments during pregnancy were recorded, especially betablockers (celiprolol). In case of anaesthesia, type of (epineural, general) and complications were collected (haematoma, leakage of spinal fluid, pneumothorax for general anaesthesia). Delivery was described as follows: type (vaginal, c-section), duration of labour for vaginal delivery and the use of forceps or episiotomy. Vascular complications were defined by the occurrence of arterial dissections and ruptures during pregnancy, delivery and during the post-partum period defined as 42 days after delivery. Haemorrhagic complications were defined by, either significant bleeding when reported as such by patients and/or medical records, either by bleeding requiring blood transfusion or post-partum haemorrhage. Bleeding events >1000 ml with hemodynamic collapse are reported as haemorrhagic shock. Perineal damage was defined by the occurrence of a perineal tear related or not with episiotomy. Perineal injury was graded according to Sultan et al. [12], from grade I (limited defect of perineal skin), to grade IV (injury of the perineum involving the anal sphincter complex and epithelium) perineal tears.
After the first interview, all relevant obstetrical data, especially term of pregnancies and obstetrical complications (preterm labour, PROM, uterine rupture, haemorrhage) were independently checked for accuracy of diagnosis and staging by a senior obstetrician during a second interview, and hospital records of deliveries were checked, when available.
The study protocol was approved by the ethics committee of the French Society of Cardiology and all participants gave written informed consent.
For each newborn, weight and height at birth were recorded and presented as a function of term of pregnancy, as previously described [13]. Health status at birth was assessed by the APGAR score [14] noted in the children's health record, and any significant event that occurred at birth was collected (respiratory failure, pneumothorax, significant verifiable birth defects).
Descriptive statistics used numbers and percentages for qualitative variables, means and standard deviations for Gaussian quantitative variables, and medians and inter-quartile intervals for non Gaussian ones. Group comparisons were performed using Fisher exact tests for qualitative variables and two sample Wilcoxon tests for quantitative ones. Comparisons of observed distributions and theoretical ones were performed using exact tests and confidence intervals for proportions were computed using the Clopper-Pearson method. All tests were two-sided, with a p-value <0.05 considered as significant. Computations were performed using the SAS v9 (SAS Institute Inc., Cary, N.C., USA) statistical package.
Reference charts for birth weight and size were constructed according to Battaglia et al. [13] with normal values based on approximately 57 000 newborn of the Paris (France) area as reported by Salomon et al.[15].
A total of n=158 families were screened for participation to the maternal mortality analysis (screening period from 2000 to 2014). After exclusion of incomplete pedigrees and of ascendants of patients with proven neomutations (
Amongst these n=60 families were n=98 parturients, being either probands (n=43), either first or second degree relatives (n=55), of which n=15 (27%) were genetically proven carriers of the mutation and n=40 (73%) were likely transmitters. These women totaled n=172 pregnancies (term pregnancies with live-born children: n=156; miscarriages: n=9; stillbirths: n=4; abortions n=3).
Distribution of live-born children, maternal deaths and surviving mothers by generation is shown in
Maternal mortality rates for probands and ascendants are shown in Table 2. Despite marked differences, maternal mortality rates of 1st and 2nd degree ascendants did not differ significantly from probands (p=ns). Overall maternal mortality for all 3 generations was 6.4% 95% CI [3.1-11.5]. Interestingly, maternal death represented almost half (45.4%) of all causes of death in female patients aged 15 to 49 years in this cohort. As expected, maternal death occurred during delivery and the post-partum period, rather than during the course of pregnancy or within one year after delivery. Pregnancy-related mortality was significantly lower in probands when compared to ascendants, but most probands were still of child-bearing age at the time of the study, and thus have had fewer pregnancies. Amongst the n=43 probands, n=6 patients were delivered with specific protective measures and all survived the post-partum period.
†patient highly suspect of vascular EDS (characteristic facial appearance, acrogeria, death at delivery consecutive to uterine rupture), in which genetic testing was not possible. She was not removed from analysis because of the rarity of maternal deaths and the risk of significantly underestimating maternal mortality calculations.
Between November 2008 and July 2012, n=39 consecutive female patients with molecularly confirmed vascular EDS totalizing n=82 pregnancies were included in the obstetrical morbidity interview study (Table 3). These pregnancies divided into n=59 live-born children (term pregnancies), spontaneous abortions (n=12), voluntary terminations (n=7), medical abortion (n=1), still-births (n=2) and ectopic pregnancy (n=1).
One patient (3.2%) died seven months after delivery of spontaneous renal and hepatic artery rupture, despite a programmed and uneventful preterm c-section and normal arterial assessment before and after the post-partum period. Prevalence of arterial events (dissection, rupture) was low (5% of pregnancies) due to an obvious recruitment bias inherent to the study design (inclusion of surviving patients), and because a majority of patients (76%) was not diagnosed with vascular EDS at the time of their respective deliveries.
Prevalence of maternal non-lethal disease-related events including arterial accidents and uterine ruptures was 13%. Uterine rupture occurred repeatedly (n=2) in n=1 (2.5%) parturient, the first at 16 weeks of amenorrhea of a second pregnancy resulting in foetal death and the second at 38 weeks of amenorrhea of a third pregnancy, prompting urgent c-section. Other vEDS-related complications were n=1 colonic rupture during the post-partum period, n=1 bladder perforation during c-section and n=1 papillary muscle rupture causing acute mitral insufficiency requiring surgical repair (reported previously) [16].
One fifth of patients (n=9) had already presented a first major arterial (n=6) or digestive (n=3) event prior to their first pregnancy. Arterial accidents (n=12) were predominantly dissections (n=9) of the carotid, vertebral and iliac arteries. Spontaneous carotido-cavernous fistula occurred in two (5%) patients and one (2.5%) patient was diagnosed with an aneurysm of the splenic artery, which remained unremarkable throughout pregnancy and after the post-partum period. Digestive events were exclusively spontaneous colon perforations (n=3 patients). None of these patients experienced complications related to these events during their respective pregnancies, deliveries and post-partum periods.
Almost half of patients (49%) had two and only one (2.5%) patient had 3 pregnancies with live-born children.
For most women, pregnancy remained unremarkable. One pregnancy was interrupted by medical decision at 10 weeks of amenorrhea because of the occurrence of a carotid-cavernous fistula requiring treatment. A second pregnancy was interrupted by a spontaneous uterine rupture at 16 weeks of amenorrhea of a second pregnancy (see above). A second foetal death occurred at 24 weeks of amenorrhea related to eclampsia in a first pregnancy.
As a consequence of preterm labour and PROM (Table 3), n=19 (31) of births were preterm, with a median term of 38 [35-39] weeks of amenorrhea, Deliveries were predominantly vaginal n=35 (57%) vs. n=19 (31%) by c-section. Conversion to c-section in the course of labour was necessary in n=3 (5%) deliveries.
Vaginal delivery was marked by the occurrence of perineal tears in n=19 cases (49%), half of which were third degree or more (Table 3). These tears occurred despite a widespread use of episiotomy and required repeat surgical repair in two patients. Despite important perineal morbidity, significant incontinence (urinary and faecal) occurred in only n=3 (8%) patients, persisting over 6 months after delivery in n=1 (3%) patient only.
Haemorrhagic complications in relation with uterine atony occurred predominantly during c-section (6/19, 32%), requiring blood transfusion in 5 deliveries out of 6, and haemostatic hysterectomy in one patient. Bleeding accidents were significantly associated with c-section when compared with vaginal delivery (Table 4). Bleeding during vaginal delivery was mainly related to direct tissular injury (tears), rather than uterine bleeding. Other indirect obstetrical complications were pulmonary embolism (n=1), deep (n=2) and superficial (n=1) vein thrombosis. Overall indirect obstetric event rate (haemorrhage and perineal complications) was 28/59 (47%).
No acute non-lethal arterial event (dissection or rupture) was diagnosed during any delivery. However, asymptomatic bilateral iliac artery dissection was evidenced during a systematic post-delivery vascular assessment in a 28 year old patient after vaginal delivery of a first pregnancy. Since a majority of patients gave birth without being diagnosed with vascular EDS, other undetected arterial events may have occurred. Conversely, in the n=12 (19%) deliveries (in n=11 parturients) in which specific protective measures were applied (see below), no silent arterial defect was identified after a systematic vascular assessment made between the and 3rd months after delivery.
More than two thirds of patients (72%) had anaesthesia during delivery, dividing into epineural analgesia in n=27 (61%) and primary general anaesthesia in n=12 (27%) deliveries. Secondary conversion to general anaesthesia was necessary in n=5 (11%) cases. These conversions were mainly related to haemorrhagic and perineal complications requiring either haemostatic, either reparative surgery. No arterial, digestive, neurologic or respiratory complication formally related to anaesthesia was identified in any delivery.
In n=12 (20%) pregnancies of this cohort, diagnosis of maternal vascular EDS (n=11, 28%) was suspected (n=2) or genetically confirmed (n=9) at the time of delivery, with consequent obstetrical management (prescription of celiprolol 200 mg BID in n=7 patients covering 7/12 pregnancies; preterm c-section in n=11/12 deliveries, of which 9 were scheduled). Notably, celiprolol was well tolerated, as no dose adjustment was necessary in any patient throughout pregnancy and the post-partum period, in comparison to the dosage prescribed prior to the beginning of each respective pregnancy. No arterial event (dissection, rupture), nor uterine rupture occurred in any patient treated with celiprolol, and all patients treated with celiprolol survived respective pregnancies and post-partum periods.
Two foetal deaths occurred during pregnancy, the first after a spontaneous uterine rupture, and the second in a context of eclampsia (see above). Amongst the n=59 live-born, prematurity-related acute respiratory failure occurred in n=4 (7%) newborn, of which two required prolonged respiratory assistance. Other reported events were a bilateral pneumothorax occurring during respiratory assistance (n=1), pulmonary valve stenosis (n=1), renal atrophy (n=1), amniotic band complicated with toe constriction (n=1), epispadias (n=1) and umbilical cord rupture (n=1) at clamping.
Despite significant prematurity, newborns did not show significant intrauterine growth retardation as illustrated in
Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the disclosure. The disclosure of all patent and scientific literature cited herein are expressly incorporated in their entirety by reference.
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| Number | Date | Country | Kind |
|---|---|---|---|
| 17306889.1 | Dec 2017 | EP | regional |
