WO2006121853A1 - Combination therapy with sulodexide and a blood pressure reducing agent in the treatment of diabetic nephropathy - Google Patents
Combination therapy with sulodexide and a blood pressure reducing agent in the treatment of diabetic nephropathy Download PDFInfo
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- WO2006121853A1 WO2006121853A1 PCT/US2006/017403 US2006017403W WO2006121853A1 WO 2006121853 A1 WO2006121853 A1 WO 2006121853A1 US 2006017403 W US2006017403 W US 2006017403W WO 2006121853 A1 WO2006121853 A1 WO 2006121853A1
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- Prior art keywords
- sulodexide
- blood pressure
- patients
- reducing agent
- day
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention is directed to a method of treating patients suffering from nephropathy of diabetic origin by administration of sulodexide in combination with an inhibitor of an angiotensin converting enzyme (ACE) and/or with an angiotensin II receptor blocker (ARB).
- ACE angiotensin converting enzyme
- ARB angiotensin II receptor blocker
- ESRD end-stage renal disease
- ACE angiotensin converting enzyme
- A2 angiotensin II receptor blocker
- ACE inihibitors and ARBs are known to reduce blood pressure, but exhibit differential clinical effects.
- the final active messenger of the rennin- angiotensin pathway is angiotensin II which binds to ATI receptors to cause vasoconstriction and fluid retention, both of which lead to an increase in blood pressure.
- ACE inhibitors are known to reduce blood pressure and act as vasodilators in hypertension and congestive heart failure by inhibiting in the renin-angiotensin pathway angiotensin II which binds to the ATI receptors to cause vasoconstriction and fluid retention. ARB also reduces blood pressure by blocking the ATI receptors.
- ACE inhibitors e.g., captopril, enalapril, fosinopril, lisinopril, and ramipril
- ARB's are also currently available of the market (e.g., losartan, valsartan, irbesartan and candesartan).
- Sulodexide which belongs to a class of drags known as glycosaminoglycans (GAGs) has been approved for "vascular indications" and has been marketed in multiple countries for such indications.
- GAGs glycosaminoglycans
- US Patent No. 5,496,807 reports on the evaluation of sulodexide in the treatment of diabetic nephropathy, and when administered intramuscularly or orally in doses of approximately 50 to 100 mg/day, produces reductions in albumin excretion rate (AER) of 35 to 62% in macroalbuminuric patients and 20 to 50% in microalbuminuric patients.
- AER albumin excretion rate
- Sulodexide has also been evaluated at a dose of at least 200 mg/day (US Patent Publication No. 2002/0065233) and normoalbuminuria was achieved in 42% of patients.
- the mechanism by which sulodexide decreases albumin excretion in patients with diabetic nephropathy is believed to include the following: (1) the restoration of the physiologic glomerular membrane anionic charge barrier via enhanced synthesis and sulfation of heparan sulfate in renal vascular membranes, and direct replenishment of renal heparan sulfate, (2) the inhibition of TGF beta-1 mediated mesangial matrix overproduction, (3) the inhibition of endothelin mediated tubulo-interstitial fibrosis, and (4) the inhibition of mesangial cell hyperplasia.
- Invest., 81, 69, (1988) showed in animals the potential protective effect of heparin and its derivatives in models of experimental nephropathy not related to diabetic nephropathy, like chronic nephrosis from aminoglycosides and renal pathologies resulting from the subtotal renal ablation in the rat.
- Sulodexide therapy was administered to patients receiving ongoing ACE inhibitor therapy. Results demonstrate that reductions in AER were equivalent in patients treated concomitantly with ACE inhibitors and those not treated with ACE inhibitors.
- the present invention is directed to a pharmaceutical composition
- a pharmaceutical composition comprising (a) sulodexide in an amount sufficient to significantly decrease the amount of urinary albumin; (b) a blood pressure reducing agent; and (c) a pharmaceutically acceptable carrier.
- the blood pressure reducing agent is an angiotensin converting enzyme (ACE) inhibitor.
- the blood pressure reducing agent is an angiotensin II (A2) receptor blocker (ARB).
- the amount of the blood pressure reducing agent in the composition is the maximal approved dosage for that particular agent.
- the present invention is directed to a method for treating a patient suffering from type I or type II diabetic nephropathy comprising administering a pharmaceutical composition comprising sulodexide to a patient concurrently with a blood pressure reducing agent, hi certain embodiments, concurrently administering includes administering the ACE inhibitor and/or ARB simultaneously with sulodexide, or within 30 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours or within 24 hours of each other.
- the blood pressure reducing agent is an ACE inhibitor and/or an ARB.
- the dosage of the blood pressure reducing agent administered to the patient is the maximum approved dose of such agent.
- the sulodexide and the blood pressure reducing agent can be administered together in a single dose or can be administered separately.
- patients were already being treated with a blood pressure reducing agent prior to the start of sulodexide administration.
- the patient is a mammal, preferably a human.
- sulodexide is administered in an amount of 10-1000 mg/day, preferably 50-500 mg/day, more preferably 100-400 mg/day.
- the patient is administered 200 mg/day.
- the patient is administered 400 mg/day.
- the sulodexide is administered orally.
- the present invention is directed to pharmaceutical compositions and methods for the treatment of a patient suffering from diabetic nephropathy with persistent microalbuminuria in type 1 and type 2 diabetes which encompasses co-administering an effective amount of sulodexide, preferably in orally administrable form, which effective amount is sufficient to significantly decrease the amount of albumin excreted in the urine of the patient, and a blood pressure reducing agent.
- a blood pressure reducing agent is an angiotensin converting enzyme (ACE) inhibitor.
- ACE an angiotensin II
- ARB angiotensin II
- the blood pressure reducing agent is a combination of one or more ACE inhibitors and/or one or more ARBs.
- the amount of the blood pressure reducing agent is a maximum approved dose for such agent.
- the amount of sulodexide can be administered one or more times per day, and said amount being sufficient to reduce albumin excretion but insufficient to cause adverse side effects.
- the present invention encompasses unit dosage forms of sulodexide in a range from about 100 mg to about 1000 mg, and includes any value encompassed within the range. In a specific embodiment, a 200 mg dose of sulodexide is administered. In another embodiment, a 400 mg dose of sulodexide is administered.
- the method of administration, according to the present invention may be oral, mucosal, parenteral, intramuscular or transdermal, and is preferably oral.
- ACE inhibitors are well known in the art.
- Exemplary ACE inhibitors and their approved maximum dose include, but are not limited to, Lotensin® (benazepril) 40 mg/day, Capoten® (captopril) 450 mg/day, Vasotec® (enalapril) 40 mg/day, Monopril® (fosinopril) 40 mg/day, Univasc® (moexipril) 30 mg/day, Aceon® (perindopril) 16 mg/day, Accupril® (quinapril) 80 mg/day, Altace® (ramipril) 20 mg/day, Mavik® (trandolapril) 8 mg/day, and Zestril® or Prinivil® (lisinopril) 80 mg/day.
- ARBs are also well known in the art. Exemplary ARBs and their approved maximum dose incldue, but are not limited to, Atacand® (candesartan) 32 mg/day, Teveten® (eprosartan) 800 mg/day, Avapro® (irbesartan) 300 mg/day, Cozaar® (losartan) 100 mg/day, Diovan® (valsartan) 320 mg/day, Micardis® (telmisartan) 80 mg/day, and Benicar® (olmesartan) 40 mg/day.
- the following parameters can be measured: (A) observed urinary albumin creatinine ratio (ACR) level, (B) percentage of patients achieving therapeutic "success," a binary composite endpoint defined as conversion to normoalbuminuria (ACR ⁇ 20 mg/g) and a 25% reduction in ACR level relative to baseline or a 50% reduction in ACR level relative to baseline, (C) percentage of patients achieving normoalbuminuria, (D) percent change from baseline on various additional endpoints, including plasma fibrinogen, serum creatinine, reciprocal of the serum creatinine, and serum albumin.
- the safety assessments included adverse events monitoring, concomitant medication use, physical examinations, sequential blood chemistries, hematology, coagulation profiles, urinalysis, and serum creatinine.
- a blood pressure reducing agent e.g., an inhibitor of an angiotensin converting enzyme (ACE) and/or an angiotensin II (A2) receptor blocker as background therapy has been evaluated in the following study.
- ACE angiotensin converting enzyme
- A2 angiotensin II
- DM microalbuminuric diabetes mellitus
- DM-2 patients who were currently receiving a maximum approved dose of either an ACE inhibitor or A2 receptor blocker (stable for 2 months). All patients gave informed consent and the study was conducted in compliance with U.S. Food and Drug Administration regulations.
- Exemplary ACE inhibitors and their approved maximum dose that were being taken by the patients in this study include Lotensin® (benazepril) 40 mg/day, Capoten® (captopril) 450 mg/day, Vasotec® (enalapril) 40 mg/day, Monopril® (fosinopril) 40 mg/day, Univasc® (moexipril) 30 mg/day, Aceon® (perindopril) 16 mg/day, Accupril® (quinapril) 80 mg/day, Altace® (ramipril) 20 mg/day, Mavik® (trandolapril) 8 mg/day, and Zestril® or Prinivil® (lisinopril) 80 mg/day.
- Exemplary A2 receptor blockers and their approved maximum dose that were being taken by the patients in this study include Atacand® (candesartan) 32 mg/day, Teveten® (eprosartan) 800 mg/day, Avapro® (irbesartan) 300 mg/day, Cozaar® (losartan) 100 mg/day, Diovan® (valsartan) 320 mg/day, Micardis® (telmisartan) 80 mg/day, and Benicar® (olmesartan) 40 mg/day.
- Group I was administered 200 mg of sulodexide orally for 6 months
- Group II was administered 400 mg of sulodexide orally for 6 months
- Group III was not administered any dosage of sulodexide but instead was administered a placebo.
- Patients on a maximum approved dose of a blood pressure reducing agent are treated with sulodexide or placebo for six (6) months and are post-treated for an additional two (2) months.
- ACR urinary albumin creatinine ratio
- B percentage of patients achieving "therapeutic success", which is a binary composite end point defined as conversion from microalbuminuria to normalbunimuria (with a least a 25% reduction in microalbumnuria) as measured by albumin/creatinine ratio (ACR), or at least a 50% reduction in ACR level relative to baseline
- C percentage of patients achieving normoalbuminuria
- D percent change from baseline on various additional endpoints, including plasma fibrinogen, serum creatinine, reciprocal of the serum creatinine, and serum albumin.
- the safety assessments in this study included adverse events monitoring, concomitant medication use, physical examinations, sequential blood chemistries, hematology, coagulation profiles, urinalysis, and serum creatinine.
- Table 1 summarizes therapeutic success for Group I and Group II patients combined as compared to Group III patients.
- Table 2 summarizes therapeutic success for Group I patients as compared to Group III patients.
- KRX-101 two doses of sulodexide (200 mg and 400 mg) were compared to placebo in patients with diabetic microalbuminuria on maximal therapy with an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).
- ACEi angiotensin converting enzyme inhibitor
- ARB angiotensin receptor blocker
- Patients were treated with sulodexide or placebo for six months and followed for an additional two months post-treatment.
- Patients were randomized 1:1:1, placebo, 200 mg and 400 mg of sulodexide, respectively.
- the primary endpoint for the study was the percentage of patients achieving "Therapeutic Success" at six months.
- a patient is considered a "Therapeutic Success” if they achieve one of the following outcomes following 6 months on study:
- ACR 50% reduction in albumin to creatinine ratio
- the data is being presented in two ways. First, the 200 mg arm is compared to placebo. Next, the data is presented as Active (200 mg and 400 mg) vs. Placebo; this was the primary endpoint defined by the protocol. Information on the effects of the 400 mg arm alone can be found in the footnotes to the tables. The dose response relationship of sulodexide previously demonstrated up to 200 mg was not observed from 200 mg to 400 mg in this study.
- the Therapeutic Success was 20% on intent to treat basis and 18% on a per protocol basis.
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- Urology & Nephrology (AREA)
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Abstract
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2008510255A JP2008540448A (en) | 2005-05-05 | 2006-05-05 | Combination therapy with sulodexide and antihypertensive agent in the treatment of diabetic nephropathy |
CA002606880A CA2606880A1 (en) | 2005-05-05 | 2006-05-05 | Combination therapy with sulodexide and a blood pressure reducing agent in the treatment of diabetic nephropathy |
EP06759150A EP1883412A4 (en) | 2005-05-05 | 2006-05-05 | Combination therapy with sulodexide and a blood pressure reducing agent in the treatment of diabetic nephropathy |
AU2006244446A AU2006244446A1 (en) | 2005-05-05 | 2006-05-05 | Combination therapy with sulodexide and a blood pressure reducing agent in the treatment of diabetic nephropathy |
IL187142A IL187142A0 (en) | 2005-05-05 | 2007-11-04 | Combination therapy with sulodexide and a blood pressure reducing agent in the treatment of diabetic nephropathy |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US67909605P | 2005-05-05 | 2005-05-05 | |
US60/679,096 | 2005-05-05 | ||
US73697305P | 2005-11-14 | 2005-11-14 | |
US60/736,973 | 2005-11-14 |
Publications (1)
Publication Number | Publication Date |
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WO2006121853A1 true WO2006121853A1 (en) | 2006-11-16 |
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ID=37396874
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US2006/017403 WO2006121853A1 (en) | 2005-05-05 | 2006-05-05 | Combination therapy with sulodexide and a blood pressure reducing agent in the treatment of diabetic nephropathy |
Country Status (6)
Country | Link |
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EP (1) | EP1883412A4 (en) |
JP (1) | JP2008540448A (en) |
AU (1) | AU2006244446A1 (en) |
CA (1) | CA2606880A1 (en) |
IL (1) | IL187142A0 (en) |
WO (1) | WO2006121853A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009121959A1 (en) * | 2008-04-04 | 2009-10-08 | Universiteit Maastricht | Use of glycosaminoglycan for restoring glycocalyx |
US8372886B2 (en) | 2005-12-22 | 2013-02-12 | Kiacta Sarl | Treatment of renal disorders, diabetic nephropathy and dyslipidemias |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104017102B (en) * | 2014-06-19 | 2016-02-24 | 深圳市海普瑞药业股份有限公司 | Ethanol precipitation prepares the method for Sulodexide raw material from heparin byproduct |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5496807A (en) * | 1993-05-10 | 1996-03-05 | Alfa Wassermann S.P.A. | Method of treatment of diabetic nephropathy by means of sulodexide of medicines containing it |
US6218417B1 (en) * | 1997-06-27 | 2001-04-17 | Nicox, S.A. | Ace-inhibitor nitric salts |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7259152B2 (en) * | 2000-06-07 | 2007-08-21 | Alfa Wasserman, Inc. | Methods and compositions using sulodexide for the treatment of diabetic nephropathy |
-
2006
- 2006-05-05 CA CA002606880A patent/CA2606880A1/en not_active Abandoned
- 2006-05-05 WO PCT/US2006/017403 patent/WO2006121853A1/en active Application Filing
- 2006-05-05 EP EP06759150A patent/EP1883412A4/en not_active Withdrawn
- 2006-05-05 JP JP2008510255A patent/JP2008540448A/en active Pending
- 2006-05-05 AU AU2006244446A patent/AU2006244446A1/en not_active Abandoned
-
2007
- 2007-11-04 IL IL187142A patent/IL187142A0/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5496807A (en) * | 1993-05-10 | 1996-03-05 | Alfa Wassermann S.P.A. | Method of treatment of diabetic nephropathy by means of sulodexide of medicines containing it |
US6218417B1 (en) * | 1997-06-27 | 2001-04-17 | Nicox, S.A. | Ace-inhibitor nitric salts |
Non-Patent Citations (1)
Title |
---|
See also references of EP1883412A4 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8372886B2 (en) | 2005-12-22 | 2013-02-12 | Kiacta Sarl | Treatment of renal disorders, diabetic nephropathy and dyslipidemias |
WO2009121959A1 (en) * | 2008-04-04 | 2009-10-08 | Universiteit Maastricht | Use of glycosaminoglycan for restoring glycocalyx |
Also Published As
Publication number | Publication date |
---|---|
EP1883412A1 (en) | 2008-02-06 |
EP1883412A4 (en) | 2008-09-03 |
CA2606880A1 (en) | 2006-11-16 |
IL187142A0 (en) | 2008-06-05 |
AU2006244446A1 (en) | 2006-11-16 |
JP2008540448A (en) | 2008-11-20 |
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