Title: Treatment of renal disorders
United States Patent: 6,521,647
Issued: February 18, 2003
Inventors: Foster; Adrian Paul (Kent, GB)
Assignee: Pfizer Inc. (New York, NY)
Appl. No.: 818403
Filed: March 27, 2001
The invention described herein relates to the use of calcium channel
blockers such as amlodipine in the treatment of renal disease in
normotensive animals. Also described are new unit doses of amlodipine
suitable for the treatment of renal disease in normotensive cats.
Description of the Invention
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;
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
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
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.TM.,
which for cats is administered at about 0.5 to about 1 mg/kg per day for
cats as a 2.5 mg or 5 mg dose.
The calcium channel blockers (and/or other active agents) can be
administered alone but will generally be administered in admixture with a
suitable pharmaceutical excipient, diluent or carrier selected with regard
to the intended route of administration and standard pharmaceutical or
veterinary practice. Suitable pharmaceutical carriers, excipents, diluents,
etc. can be found in Remington's Pharmaceutical Science, A. Osol, a standard
reference text in the field.
For example, the calcium channel blocker (and/or other active agents) can be
administered orally, buccally or sublingually in the form of tablets,
capsules, ovules, elixirs, syrups, boluses, powders, pastes, drenches,
medicated food or drinking water or other liquid, solutions or suspensions,
which may contain flavouring or colouring agents, for immediate-, delayed-,
modified-, sustained-, pulsed- or controlled-release applications.
Such tablets may contain excipients such as microcrystalline cellulose,
silicified microcrystalline cellulose, lactose, sodium citrate, calcium
carbonate, dibasic calcium phosphate and glycine, disintegrants such as
starch (optionally pre-gelatinised, preferably corn, potato or tapioca
starch), sodium starch glycollate, croscarmellose sodium and certain complex
silicates, and granulation binders such as polyvinylpyrrolidone,
hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose,
gelatin and acacia. Additionally, lubricating agents such as magnesium
stearate, stearic acid, glyceryl behenate and talc may be included.
Additionally cyclodextrin solublity modifiers may be included. Additionally
antioxidants may be included. Agents to improve palatability, such as
flavouring agents (e.g. yeast, yeast extract, pork liver) may also be
included. The agents apart from the calcium channel blocker may be present
in intimate mixture with the calcium channel blocker, or they may be
separated, e.g. in a bilayer, trilayer or other multlayer tablet or coated
tablet, or a microparticulate capsule.
Solid compositions of a similar type may also be employed as fillers in
gelatin capsules. Preferred excipients in this regard include lactose,
starch, a cellulose, milk sugar or high molecular weight polyethylene
glycols. For aqueous suspensions and/or elixirs, the calcium channel
blockers (and/or other active agents) may be combined with various
sweetening or flavouring agents, colouring matter or dyes, with emulsifying
and/or suspending agents and with diluents such as water, ethanol, propylene
glycol and glycerin, and combinations thereof.
The calcium channel blockers (and/or other active agents) can also be
administered parenterally, for example, intravenously, intra-arterially,
intraperitoneally, intrathecally, intraventricularly, intraurethrally,
intrasternally, intracranially, intramuscularly or subcutaneously, or they
may be administered by infusion techniques. For such parenteral
administration they are best used in the form of a sterile aqueous solution,
or sterile aqueous or oil suspension, which may contain other substances,
for example, enough salts or glucose to make the solution isotonic with
blood. The aqueous solutions should be suitably buffered (preferably to a pH
of from 3 to 9), if necessary. The preparation of suitable parenteral
formulations under sterile conditions is readily accomplished by standard
pharmaceutical techniques well-known to those skilled in the art.
The calcium channel blockers (and/or other active agents) can also be
administered intranasally or by inhalation and are conveniently delivered in
the form of a dry powder inhaler or an aerosol spray presentation from a
pressurised container, pump, spray or nebuliser with the use of a suitable
propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, a hydrofluoroalkane such as
1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or
1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or
other suitable gas. In the case of a pressurised aerosol, the dosage unit
may be determined by providing a valve to deliver a metered amount. The
pressurised container, pump, spray or nebuliser may contain a solution or
suspension of the active compound, e.g. using a mixture of ethanol and the
propellant as the solvent, which may additionally contain a lubricant, e.g.
sorbitan trioleate. Capsules and cartridges (made, for example, from
gelatin) for use in an inhaler or insufflator may be formulated to contain a
powder mix of the compound and a suitable powder base such as lactose or
Alternatively, the calcium channel blocker (and/or other active agents) can
be administered in the form of a suppository or pessary, or may be applied
topically in the form of a gel, a pour-on, spot-on, dip, spray, mousse,
shampoo, collar or powder formulation, ear tag, hydrogel, lotion, solution,
cream, gel, paste, patch, ointment or dusting powder. The calcium channel
blockers (and/or other active agents) may also be dermally or transdermally
administered, for example, by the use of a skin patch. They may also be
administered by the pulmonary or rectal routes.
For application topically to the skin, the calcium channel blocker (and/or
other active agents) can be formulated as a suitable ointment containing the
active compound suspended or dissolved in, for example, a mixture with one
or more of the following: mineral oil, liquid petrolatum, white petrolatum,
propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax
and water. Alternatively, they can be formulated as a suitable lotion or
cream, suspended or dissolved in, for example, a mixture of one or more of
the following: mineral oil, sorbitan monostearate, a polyethylene glycol,
liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol,
2-octyldodecanol, benzyl alcohol and water.
As an alternative for treating animals, the compounds may be administered
with the animal feedstuff and for this purpose a concentrated feed additive
or premix may be prepared for mixing with the normal animal feed.
For treatment of companion animals, further delivery devices are envisioned
within the scope of this invention, such as the "chew" or masticable
formulations mentioned in GB Patent application nos. 0007112.6 and
0010846.4, and the references therein. These formulations include:
an oral formulation for a medicament comprising:
a solid masticable portion and one or more reservoir portions encompassed by
said solid masticable portion;
the solid masticable portion consisting of a fully edible material, having a
Young's modulus of 0.01-5 MPa, and compressive strength in the range
the reservoir portion or portions comprising a releasable dose of the
medicament in a fluid (preferably a liquid) form, with a viscosity below 800
mPa.s at body temperature (ca. 36-ca.40oC.),
such that on mastication, the masticable portion is ruptured and the unit
dose of the medicament is released in a short space of time from the
reservoir portion into the oral cavity.
The calcium channel blockers (and/or other active agents mentioned above)
can also be administered together with yet further active agents should the
medical need arise.
The physician or veterinarian in any event will determine the actual dosage
which will be most suitable for any individual patient and it will vary with
the age, weight and response of the particular patient. The dosages
mentioned herein are exemplary of the average case. There can, of course, be
individual instances where higher or lower dosage ranges are merited and
such are within the scope of this invention. The skilled person will
appreciate that, in the treatment of certain conditions the compounds may be
taken as a single or multiple dose as needed or desired.
The route of administration will depend on a number of factors, and in
accordance with standard medical and veterinary practice, including the
species of animal to be treated, size of the animal, ease of administration,
Based on the results disclosed herein, the envisioned dosage regime for
amlodipine in the treatment of renal disease, such as chronic renal failure,
in normotensive animals, is 0.125-0.25 mg/kg/day.
For the treatment of renal disease in normotensive (and hypertensive)
domestic cats the envisioned amlodipine dosage regime is 0.125-0.25
mg/kg/day, which translates to 0.4 mg/cat/day for cats weighing from 1.6 kg
up to about 3 kg, 0.8 mg/cat/day for cats weighing between 3-6.5 kg, and 1.2
mg/cat/day for cats weighing about 6.5-9.5 kg. Cats falling outside these
weight ranges will of course be treatable in proportion to their weight.
Oral administration is preferred, preferably of a tablet.
Benazepril may be co-administered at 0.5 to 1 mg/kg per day, e.g. as a 2.5
mg or 5 mg dose for domestic cats (as in Fortekor.TM. mentioned above).
Other ACE inhibitors and/or endothelin-reducing agents may be
co-administered with the calcium channel blocker such as amlodipine
according to the medical need, efficacy, etc.
The efficacy of calcium channel blockers such as amlodipine in the treatment
of chronic renal failure, in the dosages mentioned and with the populations
mentioned can be demonstrated by measurement of renal function (e.g. by GFR
measurements or any other measurements known in the art such as renal plasma
flow using appropriate markers such as creatinine, inulin, iohexol,
radioisotopes and other validated markers of dynamic renal function, urine
concentrations of analytes such as protein and/or protein indexed to urine
creatinine concentration, etc.). Measurements can be made before treatment,
during treatment and after treatment by methods well-known in the art. For
control purposes, a similar population can be treated with a placebo instead
of a calcium channel blocker. Efficacy studies should be appropriately
controlled for concurrent disease conditions, drug treatments, diet etc.
that may confound the interpretation of data used to assess treatment of
renal failure, and appropriate statistical analyses applied to variables.
For measurement of blood pressure, e.g. to define the normotensive
subpopulation, there are numerous methods mentioned in the art, such as that
disclosed by P S Snyder, in J. Vet.Intern. Med.(1998): 12:157. Henik (supra)
defines hypertension in cats as a blood pressure of 170 mm Hg or more. Some
other workers in the field define the level at 175 mm Hg or more.
Claim 1 of 5 Claims
What is claimed is:
1. A method of treating renal disease in normotensive animals comprising
administration of an effective amount of a calcium channel blocker,
optionally in the presence of an antihypertensive agent that reduces the
effect of endothelin and/or angiotensin.
If you want to learn more
about this patent, please go directly to the U.S.
Patent and Trademark Office Web site to access the full