Methods and compositions for treating diseases associated with excesses in ACE

• US 20030040509A1
• Filed: 08/06/2002
• Published: 02/27/2003
• Est. Priority Date: 08/06/2001
• Status: Abandoned Application

• Current Assignee: Genomed LLC de
• Original Assignee: Genomed LLC de
• Inventors: Moskowitz, David W.
• Application Number:
  US10/213,330
• Publication Number:
  US 20030040509A1
• Time in Patent Office: Days
• US Class Current: 514/171
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 : Antipsoriatics
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• CPC Class Codes: A61P 19/08 : for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 : for osteoporosis
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• CPC Class Codes: A61P 25/08 : Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 : Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 : for treating abuse or dependence
• CPC Class Codes: A61P 25/34 : Tobacco-abuse
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 27/12 : for cataracts
• CPC Class Codes: A61P 27/16 : Otologicals
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/20 : for DNA viruses
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• CPC Class Codes: A61P 5/18 : of the parathyroid hormones
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• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Over 40 common diseases, in addition to congestive heart failure (CHF) due to hypertension (HTN) or non-insulin dependent diabetes mellitus (type II diabetes mellitus) (NIDDM), atherosclerotic peripheral vascular disease (ASPVD) due to HTN or NIDDM, and chronic obstructive pulmonary disease; emphysema (COPD), are associated with the ACE D/D genotype and should also respond to an adequate tissue-inhibitory dose of ACE inhibitors such as quinapril. Several of these diseases have now been successfully treated using higher than normal dosages of ACE inhibitors, especially hydrophobic ACE inhibitors, with good outcomes. ACE inhibitors have also been found to be useful in inhibiting apoptosis and aging in general. Dosages that have been utilized are typically greater than quinapril at a dose of 40 to 80 mg/day, i.e. up to 1 mg/kg per day for a “typical” 80 kg patient. New formulations of ACE inhibitors have been developed for these higher dosages, including 80 mg tablets, controlled and/or sustained release formulations, and formulations containing a second active agent such as a diuretic, or a compound such as furosemide 20 mg/day (for creatinine <2.5 mg/dl) or furosemide 40 mg/day (for creatinine >2.5 mg/dl), to prevent fluid retention and congestive heart failure in patients with renal failure. The ACE inhibitors can also be combined with an angiotensin receptor blocker.

Claims

1. A method for treating diseases associated with a excess of angiotensin enzyme activity comprising administering an effective dosage of an ACE inhibitor to inhibit tissue ACE.

2. The method of claim 1 wherein greater than 95% of the tissue ACE is inhibited.

3. The method of claim 1 wherein a dosage of a hydrophobic ACE inhibitor equivalent to 80 mg/day or greater quinapril is administered to a patient.

4. The method of claim 3 further comprising administering aldosterone with the ACE inhibitor.

5. The method of claim 3 wherein a hydrophobic ACE inhibitor is administered in a dosage equivalent to quinapril, from 20 mg once a day once daily, to 20 mg twice a day after one to two months, to 40 mg twice a day after an additional one to two months, to 80 mg twice a day after an additional one ot two months.

6. The method of claim 1 wherein the disease is selected from the group consisting of end-stage renal disease with hypertension, end-stage renal disease with non-insulin dependent diabetes mellitus (type II diabetes mellitus), end-stage renal disease due to focal segmental glomerulosclerosis (FSGS), membranous glomerulonephritis (GN), membranoproliferalive GN (MPGN), kidney stones, IgA GN, obstructive uropathy, and acquired renal cystic disease of end-stage renal disease.

7. The method of claim 6 to delay progression of renal failure due to hypertension or type II NIDDM, administer hydrophobic ACE inhibitor before adding any additional anti-hypertensive agent.

8. The method of claim 1 wherein the ACE inhibitor is administered in a dosage equivalent to ramipril dose of 0.5 mg/kg/day or quinapril 2 mg/kg/day.

9. The method of claim 1 wherein the disease to be treated is selected from the group consisting of cigarette abuse, asthma, pulmonary hypertension, pulmonary embolism, left ventricular hypertrophy, atherosclerotic peripheral vascular disease, deep vein thrombosis, and chronic obstructive pulmonary disease or emphysema.

10. The method of claim 1 wherein the disease to be treated is selected from the group consisting of Obesity (BMI>

30), Cholesterol>

200, hypertriglyceridemia, hypercholesterolemia, and mixed hyperlipidemia, NIDDM/retinopathy, and NIDDM/neuropathy.

11. The method of claim 1 wherein the disease to be treated is selected from the group consisting of scleroderma, lupus (SLE), gout, hypothyroidism, tertiary hyperparathyroidism in end-stage renal disease (ESRD), the need for frequent de-clotting of vascular access in ESRD patients, Paget'"'"'s disease of bone, osteoporosis, allergy to penicillin or sulfa, allergic sinusitis or rhinitis, pelvic inflammatory disease, prevention of hip fractures, eczema, psoriasis, basal cell skin cancer, Osteoarthritis (DJD), degenerative disc disease, and Rheumatoid arthritis.

12. The method of claim 1 wherein the disease to be treated is selected from the group consisting of GERD, gallstones, peptic ulcer disease, hiatal hernia, diverticulosis, gastritis, pancreatitis, ascites, alcoholic hepatitis, cirrhosis, cholecystitis, diverticulitis, irritable bowl syndrome, inflammatory bowel disease, and inguinal hernia.

13. The method of claim 1 wherein the disease to be treated is solid tumors, leukemias, and lymphomas.

14. The method of claim 1 wherein the disease to be treated is selected from the group consisting of stroke (CVA), TIA/s/p CEA, seizures, Alzheimer'"'"'s disease, dementia (non-specific), headaches, migraine headache, parkinsonism, and multi-infarct dementia.

15. The method of claim 1 wherein the disease to be treated is Bipolar affective disorder, schizophrenia, depression, anxiety, and drug abuse.

16. The method of claim 1 wherein the disease to be treated is selected from the group consisting of glaucoma and cataracts.

17. The method of claim 1 wherein the disease to be treated is presbycusis.

18. The method of claim 1 wherein the disease to be treated is viral hepatitis A, viral hepatitis B, tuberculosis, HIV infection or complications of HIV infection such as HIV-associated nephropathy and AIDS.

19. The method of claim 1 wherein the ACE inhibitor is administered in combination with a compound such as fludrocortisone acetate to a patient who has a serum K+ concentration above 4.5 mEq/l before initial dosing.

20. The method of claim 1 wherein the ACE inhibitor is administered with an angiotensin II receptor antagonist.

21. The method of claim 1 wherein the ACE inhibitor is administered with a diuretic.

22. The method of claim 1 wherein the ACE inhibitior is a hydrophilic ACE inhibitors selected from the group consisting of captopril, enalapril, and lisinopril.

23. The method of claim 1 wherein the ACE inhibitor is a hydrophobic ACE inhibitors selected from the group consisting of ramipril, benazepril, and quinapril.

24. The method of claim 1 comprising treating a non-human animal.

25. A method of determining if a disease can be treated with ACE inhibitors comprising calculating the odds ratio of association between a disease and the ACE D/D genotype and determining if the odds ratio is greater than 1.0

26. The method of claim 25 wherein the odds ratio is 2.0 or greater.

27. The method of claim 25 wherein the odds ratio is between 1.0 and less than 2.0.

28. A dosage formulation for treating disorders associated with the ACE D/D genotype comprising an amount of an ACE inhibitor effective to inhibit greater than 95% tissue ACE or a dosage delivering greater than 80 mg/day of an ACE inhibitor such as quinapril.

29. The dosage formulation of claim 28 in the form of tablets providing a dosage selected from the group consisting of 80, 100 and 200 mg quinapril.

30. The dosage formulation of claim 28 equivalent to a ramipril dose of 0.5 mg/kg/day or quinapril 2 mg/kg/day.

31. The dosage formulation of claim 28 in a sustained or controlled release carrier.

32. The dosage formulation of claim 31 comprising a dosage equivalent to 200 mg quinapril in a carrier providing sustained release over a period of up to one day.

33. The dosage formulation of claim 31 comprising a dosage equivalent to 100 mg SR quinapril in a carrier providing sustained release over a period of up to one day.

34. The dosage formulation of claim 28 in the form of tablets providing a dosage selected from the group consisting of 20 mg, 50 mg, 100 mg and 200 mg ramipril.

35. The dosage formulation of claim 28 comprising an ACE inhibitor in an amount effective to inhibit tissue ACE and a diuretic.

36. The dosage formulation of claim 28 comprising an ACE inhibitor in combination with an angiotensin receptor blocker.

37. The dosage formulation of claim 28 comprising an ACE inhibitor in combination with a compound increasing aldosterone levels or the effects thereof.

38. The dosage formulation of claim 37 comprising Quinapril 40 mg with 0.05 mg Florinef, or Quinapril 80 mg with 0.05 mg Florinef.

39. A formulation of an ACE inhibitor for administration to an animal comprising a carrier selected from the group consisting of animal feed and chewable tablets.