Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-27
2003-02-18
Henley, Ray (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06521647
ABSTRACT:
This invention relates to the treatment of renal disease in animals, especially chronic renal failure.
Renal disease, including renal failure (acute and chronic) is a common clinical problem which tends to increase with the age of animals (including humans). Conditions are described in “The Merck Manual”, 16th edition, ch.149, pp.1661,1665 (Merck Research Laboratories (1992), and are commonly, but not always, associated with abnormally high blood pressure (hypertension). Renal disease often results in long suffering periods where the patient endures uncomfortable and painful symptoms, often involving injury to eyes, heart and brain. Dialysis and kidney transplantation can be used as treatments if circumstances allow, but these procedures can have serious complications, including, for transplantation, organ rejection.
In animals the underlying aetiology of the disease can be uncertain, even when histopathological examination has taken place (see e.g. J. Elliott and P J Barber,
J.Small Animal Practice
(February 1998) vol.39, 78; A R Michell,
Vet.Annual
(1995) 35:159).
There are many commonly used measurements of renal function such as those mentioned by D R Finco et al, in
J Vet Intern Med
(1999) 13:516-528—glomerular filtration rate (GFR), plasma creatinine concentration, morphologic examination of kidney tissue, blood urea nitrogen, incidental biological events such as hypertension and proteinurea. Michell (supra) defines chronic renal failure as a “failure of clearance”. Finco (supra) suggests that declining GFR measurements are the most reliable indicator of the disease.
Treatment of renal disease associated with hypertension with antihypertensive agents has been propounded, for example with angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, etc. (see e.g. J M Bright, Proc.17th ACVIM, Chicago (1999), pp 134-135). Other treatments are mentioned by Brown, Scott A: Evaluation of chronic renal disease: A staged approach. Compendium on Continuing Education for the Practicing Veterinarian Vol 21: 752-763, 1999.
With regard to chronic renal failure associated with hypertension, treatment with amlodipine has been propounded, e.g. by:
Henik et al in
J.Am.Animal Hosp. Assoc.,
May/June 1997, vol.33);
P S Snyder, in
J. Vet.Intern. Med.
(1998): 12:157;
K L Cooke et al, in
J Vet. Intern. Med.
(1998); 12:123;
G P Reams et al, Am.J.Kidney Diseases (Dec 1987), vol X no.6, 446;
www.ccweb.net/marvistavet/html/body/chronic_renal_failure.html; and
C J Pearce et al, New Horizons (1996) vol.4 no. 1) 123.
Amlodipine, disclosed in EP 0 089 167, etc., is a dihydropyridine calcium channel blocker which is licensed for use as an antihypertensive and antianginal agent. It is sold as the besylate salt (disclosed in EP 0 244 944, etc.) in 2.5 mg, 5 mg and 10 mg dosages under the trade names Norvasc, Norvas, Istin, Amlor, etc. by Pfizer Inc. and related companies. Both of these publications are herein incorporated by reference.
We have now surprisingly found that calcium channel blockers such as amlodipine (e.g. as the besylate salt) can be used to treat renal disease in animals which are not hypertensive, i.e. animals which are “normotensive”. “Normotensive” means having systemic arterial blood pressure values within normal or reference ranges established for the animal species of interest, using acceptable methods for measuring such blood pressure under appropriate circumstances, and below generally accepted “hypertensive” ranges for such animals. Within an animal species, reference range values may be established for representative subclasses, races, breeds, etc. (e.g. humans, lab. animals, specific subpopulations, etc.).
The prior art does not disclose or suggest that renal disease in normotensive patients, especially normotensive companion animals such as cats, can be treated with a calcium channel blocker such as amlodipine.
An aspect of the current invention is the treatment of renal disease in normotensive animals with a calcium channel blocker.
Preferably the animal is a mammal.
A preferred mammal is a human.
Another preferred group of mammals are companion animals such as horses, and domestic cats and dogs.
The most preferred companion animal is a domestic cat.
Preferably the renal disease is chronic renal failure.
Preferably the calcium channel blocker is a dihydropyridine calcium channel blocker such as amlodipine, nifedipine, nitrendipine, nimodipine, nicardipine, felodipine, etc.
The calcium channel blocker can be present as a pharmaceutically acceptable salt or solvate thereof. Pharmaceutically acceptable salts and solvates are non-toxic to the species being treated.
Suitable pharmaceutically acceptable salts for dihydropyridine calcium channel blockers include acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, bisulphate, acid citrate, bitartrate, ethansulphonate, sulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzenesulphonate (besylate), p-toluenesulphonate (tosylate), methanesulphonate (mesylate), succinate, salicylate, nitrate, etc.
More preferably the calcium channel blocker is amlodipine and the pharmaceutically acceptable salts thereof, including acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, bisulphate, acid citrate, bitartrate, ethansulphonate, sulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzenesulphonate (besylate), p-toluenesulphonate (tosylate), methanesulphonate (mesylate), succinate, salicylate, nitrate, etc.
Most preferred is the amlodipine besylate salt.
“Pharmaceutically acceptable” and related phrases mentioned herein include the corresponding veterinary equivalents.
“Treatment” refers to prevention, alleviation and/or cure of the condition.
Another aspect of the invention is the administration, to a normotensive animal, of an efficacious amount of a calcium channel blocker, such as between 0.01 to 3 mg/kg, preferably between 0.1 mg/kg and 0.3 mg/kg, more preferably between 0.12 and 0.25 mg/kg, amlodipine (preferably administered as the besylate salt) of the animal to treat renal disease such as chronic renal failure.
Another aspect of the invention is a unit dosage form of amlodipine which comprises about 0.1-1.5 mg, preferably about 0.2-0.6, or about 0.8 to 1.5 mg, most preferably about 0.1, 0.2, 0.4, 0.6, 0.8, 1.0, 1.2 or 1.5 mg amlodipine per unit, where amlodipine is preferably present as its besylate salt, suitable for, or adapted for, the treatment of normotensive cats with renal disease, such as chronic renal failure. Such unit doses can also be used to treat renal disease in animals with hypertension.
Optionally the calcium channel blocker can be administered/formulated with an antihypertensive agent of a different class (i.e. not another calcium channel blocker) such as an agent which reduces the effect of angiotensin and/or endothelin (defined herein as “other active agents”).
Suitable agents include angiotensin converting enzyme (ACE) inhibitors such as those licensed for use in treating hypertension, such as benazepril, benazeprilat, captopril, enalapril, enalaprilat, fosinopril sodium, lisinopril, pentopril, perindopril, quinapril hydrochloride, quinaprilat, ramipril, ramiprilat, trandolapril, zofenopril calcium, and the like.
Certain combinations of calcium channel blockers and ACE inhibitors are disclosed in International Patent Application publication no. WO 96/28185, which is herein incorporated by reference.
For such combination therapies, co-administration may take place in a number of different ways, including:
the active agents may be present in the same dosage form for single administration;
the active agents may be administered in separate dosage forms, by the same or different administration routes, and at the same, substantially the same or at different times.
A suitable ACE inhibitor for co-administration in the treatment of renal disease is thought to be benazepril, currently marketed as Fortekor™, which for cats is administered at about 0.5 t
Ginsburg Paul H.
Henley Ray
Kohn & Associates PLLC
Ling Lorraine B.
Pfizer Inc.
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