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WO2004098587A1 - Mycophenolate mofetil en nephropathie diabetique - Google Patents

Mycophenolate mofetil en nephropathie diabetique Download PDF

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Publication number
WO2004098587A1
WO2004098587A1 PCT/IN2004/000123 IN2004000123W WO2004098587A1 WO 2004098587 A1 WO2004098587 A1 WO 2004098587A1 IN 2004000123 W IN2004000123 W IN 2004000123W WO 2004098587 A1 WO2004098587 A1 WO 2004098587A1
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WO
WIPO (PCT)
Prior art keywords
treatment
patients
mmf
lisinopril
diabetic nephropathy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2004/000123
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English (en)
Inventor
Sachidananda Moorthy
Atignal Shankara Rao Arvind
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Clinigene International Pvt Ltd
Original Assignee
Clinigene International Pvt Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Clinigene International Pvt Ltd filed Critical Clinigene International Pvt Ltd
Priority to US10/983,465 priority Critical patent/US7728033B2/en
Priority to AU2004229026A priority patent/AU2004229026B2/en
Publication of WO2004098587A1 publication Critical patent/WO2004098587A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis

Definitions

  • the invention relates to use of mycophenolate mofetil alone or in combination with Lisinopril in diabetic nephropathy patients for . improvement in proteinuria in patients with diabetic nephropathy.
  • Diabetes mellitus is one of the common systemic diseases affecting the kidneys.
  • diabetic nephropathy would have developed.
  • the incidence of nephropathy in type 2 diabetes is uncertain.
  • the involvement of diabetes is essentially glomerular.
  • the primary pathogenic role of hyperglycemia in diabetic renal disease is so well established that diabetic nephropathy is today considered as Hyperglycemic Glomerulopathy. Mortality and morbidity in them is, due to cardiovascular disease, probably accelerated by hypertension and hyperlipidemia.
  • Biochemical, hormonal, immunological and rheological factors have been shown to be etiologically important in the pathogenesis of diabetic nephropathy.
  • biochemical factors implicated include hyperglycemia and glycosylated proteins in blood and basement membrane of the kidneys. Also, there is experimental and clinical evidence to suggesting that recruitment of monocytes into glomeruli may play a role in the pathogenesis of this diabetic complication.
  • ACE inhibitors Angiotensin Converting Enzyme inhibitors
  • ACE inhibitors also may decrease retinopathy progression in type 1 diabetics (Chaturvedi et al. 1998).
  • MMF Mycophenolate mofetil
  • MPA mycophenolic acid
  • IMPDH inosine monophosphate dehydrogenase
  • MMF ameliorates the renal lesions in several models of experimental glomerular disease.
  • the ability of MMF to suppress not only the immune response, but also smooth cell proliferation makes the drug a candidate for preventing renal fibrosis, as myofibrobalsts share many features with vascular smooth muscle cells.
  • Preliminary results suggest that MMF is effective in several types of glomerulonephritis after conventional therapy had failed (Badid et al. 2001).
  • Prednisone in 62 patients The age of these patients ranged from 9- 54 years. Each of the patients had protein excretion rates >2g per day. The dose of the MMF given to the patients varied from 1-1.5g per day whereas a control group received 30-40 mg of Prednisone per day. Fifteen patients in each of the groups had been followed for seventy two weeks. Whereas both groups of patients showed reduction of proteinuria after 3 and 6 months, the decrease in the MMF patients was greater after 6 months. This decrease in proteinuria continued in the MMF group through 72 weeks. Chen et al concluded in this preliminary report that MMF was superior to Prednisone in decreasing proteinuria, protecting renal function and also decreasing blood lipid levels.
  • MMF may be an exception to this generalization because the MMF-treated patients were able to achieve a greater degree of immunosuppression yet suffered little increase in the incidence of infection or bone marrow suppression.
  • Dooley et al. 1999 Dooley and his coworkers concluded in their study that MMF is well tolerated and has possible efficacy in controlling major renal manifestation of systemic lupus erythomatosis. In lupus nephritis, these authors found that 0.5 to 1.5 g/d dose of MMF were sufficient. Miller et. al.
  • MMF mycophenolate mofetil
  • ESRD end stage renal disease
  • ACE inhibitors have been shown to lower the intraglomerular hypertension and thus reduce hyperfiltration of diabetic nephropathy. It is therefore, recommended that in diabetics with even normal blood pressure, ACE inhibitors be given to lower intraglomerular pressure.
  • Mycophenolate mofetil prevents the development of glomerular injury in experimental diabetes (Utimura et al. 2003). Diabetic rats exhibited marked glomerular hyperfiltration and hypertension. They developed progressive albuminuria and exhibited widespread glomerulosclerotic lesions associated with macrophage infiltration at 8 months. Treatment with MMF had no effect on blood pressure, glomerular dynamics or blood glucose levels, but did prevent albuminuria, glomerular macrophage infiltration and glomerulosclerosis.
  • MMF may help prevent the progression of diabetic nephropathy.
  • the present invention discloses the effect of MMF alone or in combination with Lisinopril in comparison to Lisinopril alone on the progression of diabetic nephropathy.
  • the invention relates to use of MMF alone or MMF in combination with Lisinopril for the treatment of diabetic nephropathy.
  • the method of treatment of diabetic nephropathy of the instant invention is more effective than method of treatment of diabetic nephropathy using lisinopril alone.
  • DETAILED DESCRIPTION OF THE INVENTION The instant invention relates to a method of treatment of diabetic nephropathy using mycophenolate mofetil alone or combination of mycophenolate mofetil with lisinopril. Definitions
  • Effectiveness End points in the present invention is the parameters, which represent the measure of the drugs ability to improve the signs and /or symptoms of the disease.
  • Safety Endpoints in the present invention is the parameters, which represent any incidence of adverse events and in particular the serious adverse events that may be associated with the use of the drug treatment for diabetic nephropathy.
  • MMF mycophenolate mofetil.
  • ACE in the present invention means any drug or molecule that are ACE inhibitors selected from one among and not limited to lisinopril, aptopril, enalapril.
  • the term "Micral test” is a measure of albumin excretion rate in urine.
  • VI represents the visit no. 1 of the patient during which the subject is screened for eligibility to participate in the drug trial for treatment of diabetic nephropathy.
  • V2 represents the visit no. 2 of the patients during which the said patients are subjected to treatment with either MMF or Lisinopril alone or in combination of both.
  • V3 represents the visit no. 3 of the patients, one month after initialization of the treatment [V2]; during which the said patients are reveiwed and if deemed fit is subjected to further treatment with either MMF or Lisinopril alone or in combination of both.
  • V4 represents the visit no. 4 of the patients, three months after initialization of the treatment [V2]; during which the said patients are reviewed and if deemed fit is subjected to further treatment with either MMF or Lisinopril alone or in combination of both.
  • V5" represents the visit no. 5 of the patients, six months after initialization of the treatment [V2]; during which the said patients are reviewed and if deemed fit is subjected to further treatment with either MMF or Lisinopril alone or in combination of both.
  • Phase 1 Screening Phase (Duration 1 to 4 weeks): 294 patients were screened on their first visit (VI), based on the given inclusion and exclusion criteria to determine if they were eligible for the study and to assess likelihood of compliance with study protocol.
  • a patient is based on the following criteria Male diabetic patients; age 18-65 years; micral test positive (albumin excretion rate 20-200 ⁇ gm/min); patient must be able to swallow the oral medications to be used in the study; patient must sign an informed consent prior to the study.
  • the exclusion of a subject from the study is based on the following criteria: Female patients of any age; clinical evidence of SLE; well- documented history of Henoch-Schonlein Purpura; clinical evidence of cirrhosis or chronic active liver disease; abnormal laboratory values at the time of study entry; absolute neutrophil count (ANC) ⁇ 2000/nm 3 , or hematocrit (HCT) ⁇ 28%; AER > 200 ⁇ gm/min; known contraindication or allergy to the administration of MMF or Lisinopril; history of significant gastrointestinal disorder, e.g.
  • Phase 2 Treatment Phase (6 months):
  • Every patient who qualifies the screening phase is assigned one of the treatment arms. During this phase patients are monitored closely and efficacy and safety parameters are assessed every month.
  • MMF The dose of MMF was given during the study would be 500 mg twice a day throughout the study.
  • Lisinopril The starting dose of Lisinopril was given in the study was 5 mg twice a day. In case of hypertensive patients, dose can be titrated upwards based on investigator's discretion, which in turn is based on the patient's "safety end point".
  • MMF + Lisinopril In the patients who received both the drugs, the dose of MMF was 500 mg twice a day and Lisinopril was 5 mg twice a day. In case of hypertensive patients, dose of Lisinopril can be titrated upwards based on investigator's discretion, which in turn is based on the patient's "safety end point".
  • the Primary Efficacy Endpoints includes the 24 h Urine protein which is measured using the Calorimetric method Pyrogallol Red / SDS liquid stable single reagent.
  • the Urine protein/creatinine ratio is also compared.
  • Serum creatinine level (in ⁇ mol/L)
  • Example 1 The values of base line lab parameters like 24 h Urine protein and estimated GFR are obtained from the patients in visit no. 2 [V2] prior to treatment with MMF. The values of the parameters in V2 are compared against the values obtained at Visit 3 [V3], which is scheduled 1 month from V2. MMF at the end of 1 month of treatment reduced proteinuria in 67% of the patients. The effect of the treatment on proteinuria is disclosed in the table below.
  • the values of base line lab parameters like 24 h Urine protein and estimated GFR are obtained from the patients at V2 prior to treatment with MMF.
  • the values of the parameters in V2 are compared against the values obtained at V3, which is scheduled 3 months from V2 during which patients receive 500 mg of MMF twice daily.
  • MMF treatment at the end of 3 months reduced proteinuria in 67% of the patients.
  • the effect of the treatment on proteinuria is disclosed in the table below.
  • Example 3 The values of base line lab parameters like 24 h Urine and estimated GFR are obtained from the patients at V2 prior to treatment with Lisinopril. The values of the parameters at V2 are compared against the values obtained at V3, which is scheduled 1 month from V2, during which patients received 5mg of Lisinopril twice daily. Lisinopril treatment at the end of 1 month reduced proteinuria in 42% of the patients. The effect of the treatment on proteinuria is disclosed in the table below.
  • Urine protein and estimated GFR are obtained from the patients at V2 prior to treatment with Lisinopril.
  • the values of the parameters at V2 are compared against the values obtained at V4, which is scheduled 3 month from V2, during which patients received 5mg of Lisinopril twice daily.
  • Lisinopril treatment at the end of 3 month reduced proteinuria in 40% of the patients.
  • the effect of the treatment on proteinuria is disclosed in the table below.
  • the values of base line lab parameters like 24 h Urine and estimated GFR are obtained from the patients at V2 prior to treatment with Lisinopril.
  • the values of the parameters at V2 are compared against the values obtained at V5, which is scheduled 6 month from V2, during which patients received 5mg of Lisinopril twice daily.
  • Lisinopril treatment at the end of 6 month reduced proteinuria in 50% of the patients.
  • the effect of the treatment on proteinuria is disclosed in the table below.
  • Urine protein and estimated GFR are obtained from the patients at V2 prior to treatment with the combination of MMF and Lisinopril.
  • the patients were treated with 500 mg of MMF twice daily along with Lisinopril 5 mg twice daily.
  • the values of the parameters in V2 are compared against the values obtained at V3, which is scheduled 1 month from V2.
  • MMF and Lisinopril combination treatment at the end of 1 month of treatment reduced proteinuria in 75% of the patients.
  • the effect of the treatment on proteinuria is disclosed in the table below.
  • Urine protein, urine protein/creatinine ratio and estimated GFR are obtained from the patients at V2 prior to treatment with the combination of MMF and Lisinopril.
  • the patients were treated with 500 mg of MMF twice daily along with Lisinopril 5 mg twice daily.
  • the values of the parameters in V2 are compared against the values obtained at V4, which is scheduled 3 month from V2.
  • MMF and Lisinopril combination treatment at the end of 3 month of treatment reduced proteinuria in 100% of the patients.
  • the effect of the treatment on proteinurea is disclosed in the table below.
  • Urine protein, urine protein/creatinine ratio and estimated GFR are obtained from the patients at V2 prior to treatment with the combination of MMF and Lisinopril.
  • the patients were treated with 500 mg of MMF twice daily along with Lisinopril 5 mg twice daily.
  • the values of the parameters in V2 are compared against the values obtained at V5, which is scheduled 6 month from V2.
  • MMF and Lisinopril combination treatment at the end of 6 month of treatment reduced proteinuria in 100% of the patients.
  • the effect of the treatment on proteinuria is disclosed in the table below.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention a trait à un procédé de traitement de la néphropathie diabétique mettant en oeuvre du mycophénolate mofétil seul ou en combinaison avec du lisinoprile.
PCT/IN2004/000123 2003-05-05 2004-05-05 Mycophenolate mofetil en nephropathie diabetique Ceased WO2004098587A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/983,465 US7728033B2 (en) 2003-05-05 2004-11-08 Mycophenolate mofetil in diabetic nephropathy
AU2004229026A AU2004229026B2 (en) 2003-05-05 2004-11-09 Mycophenolate mofetil in diabetic nephropathy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN377/MAS/2003 2003-05-05
IN377CH2003 2003-05-05

Related Child Applications (2)

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US10/983,465 Continuation-In-Part US7728033B2 (en) 2003-05-05 2004-11-08 Mycophenolate mofetil in diabetic nephropathy
AU2004229026A Division AU2004229026B2 (en) 2003-05-05 2004-11-09 Mycophenolate mofetil in diabetic nephropathy

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WO2004098587A1 true WO2004098587A1 (fr) 2004-11-18

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1656941A1 (fr) * 2004-11-09 2006-05-17 Clinigene International Private Limited Préparations pharmaceutiques pour le traitement de la nephropathie diabétique
WO2006086498A3 (fr) * 2005-02-08 2006-11-02 Aspreva Pharmaceuticals Sa Traitement de maladies vasculaires, auto-immunes et inflammatoires, a l'aide de faibles doses d'inhibiteurs de l'impdh
US7728033B2 (en) 2003-05-05 2010-06-01 Clinigene International Private Limited Mycophenolate mofetil in diabetic nephropathy

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HAO, L. ET AL.: "Mycophenolate Mofetil Can Prevent the Development of Diabetes in BB Rats", ANN.NY ACAD.SCI., vol. 696, 1993, pages 328 - 332 *
REMUZZI, G. ET AL.: "Combining an Antiproteinuric Approach with Mycophenolate Mofetil Fully Suppresses Progessive Nephropathy of Experimental Animals", J.AM.SOC.NEPHROL., vol. 10, 1999, pages 1542 - 1549 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7728033B2 (en) 2003-05-05 2010-06-01 Clinigene International Private Limited Mycophenolate mofetil in diabetic nephropathy
EP1656941A1 (fr) * 2004-11-09 2006-05-17 Clinigene International Private Limited Préparations pharmaceutiques pour le traitement de la nephropathie diabétique
WO2006086498A3 (fr) * 2005-02-08 2006-11-02 Aspreva Pharmaceuticals Sa Traitement de maladies vasculaires, auto-immunes et inflammatoires, a l'aide de faibles doses d'inhibiteurs de l'impdh
US8957071B2 (en) 2005-02-08 2015-02-17 Aspreva Pharmaceuticals S.A. Treatment of vascular, autoimmune and inflammatory diseases using low dosages of IMPDH inhibitors

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