Angiotensin II receptor antagonists for the prevention or treatment of systemic diseases in cats
阅读说明：本技术 用于预防或治疗猫的全身性疾病的血管收缩素ii受体拮抗剂 (Angiotensin II receptor antagonists for the prevention or treatment of systemic diseases in cats ) 是由 B·阿尔布雷希特 S·安克 S·克利 S·J·莱纳 M·施塔克 A·M·特拉斯 T·M· 于 2018-07-05 设计创作，主要内容包括：本发明描述一种用于预防或治疗需要此治疗的猫的高血压的方法。该方法包括向该猫施用治疗有效量的血管收缩素II受体1(AT-1)拮抗剂(沙坦(sartan)),其中该沙坦的治疗有效量以在治疗期内改变的每日剂量施用,在该治疗期期间第一时间段该沙坦的每日剂量为1.0至5.0mg/kg体重,且在该治疗期期间第一时间段之后的第二时间段该沙坦的每日剂量减少。(The present invention describes a method for preventing or treating hypertension in a cat in need of such treatment. The method comprises administering to the cat a therapeutically effective amount of an angiotensin II receptor 1(AT-1) antagonist (sartan), wherein the therapeutically effective amount of the sartan is administered AT a daily dose that varies over a treatment period during which the daily dose of the sartan is between 1.0 and 5.0mg/kg body weight for a first period of time and during which the daily dose of the sartan is reduced for a second period of time after the first period of time.)
1. An angiotensin II receptor 1(AT-1) antagonist (sartan) for use in a method of preventing or treating hypertension in a cat in need of such prevention or treatment, wherein the method comprises administering to the cat a therapeutically effective amount of an angiotensin II receptor 1(AT-1) antagonist (sartan), wherein the therapeutically effective amount of the sartan is administered AT a daily dose that varies over a treatment period during which a daily dose of sartan for a first period of time is from 1.0 to 5.0mg/kg body weight and during which the daily dose of sartan is reduced for a second period of time after the first period of time.
2. The angiotensin II receptor 1(AT-1) antagonist (sartan) according to claim 1 for use in a method for the prevention or treatment of hypertension in cats, wherein the hypertension is associated with chronic kidney disease or hyperthyroidism.
3. The angiotensin il receptor 1(AT-1) antagonist (sartan) according to claim 1 for use in a method for the prevention or treatment of hypertension in cats, wherein the hypertension is idiopathic hypertension.
4. The angiotensin il receptor 1(AT-1) antagonist (sartan) according to any of claims 1 to 3 for use in a method for the prevention or treatment of hypertension in a cat, wherein the daily dose is varied based on a Systolic Blood Pressure (SBP) measurement of the cat.
5. The angiotensin il receptor 1(AT-1) antagonist (sartan) according to any of claims 1 to 4 for use in a method of prevention or treatment of hypertension in cats wherein the second period of time reduces the daily dose of the sartan in increments ranging from 0.10 to 0.50mg/kg body weight.
6. The angiotensin il receptor 1(AT-1) antagonist (sartan) according to any one of claims 1 to 5 for use in a method for the prevention or treatment of hypertension in a cat, wherein the daily dose of the sartan is reduced when the Systolic Blood Pressure (SBP) measurement of the cat is reduced by AT least 10mmHg or AT least 20mmHg, or 10 to 150mmHg, 10 to 100mmHg, 10 to 80mmHg, 10 to 50mmHg, 10 to 30mmHg, 10 to 20mmHg, 20 to 150mmHg, 20 to 100mmHg, 20 to 80mmHg, 20 to 50mmHg, or 20 to 30mmHg relative to the baseline SBP measurement of the cat prior to the first time period.
7. The angiotensin il receptor 1(AT-1) antagonist (sartan) according to any one of claims 1 to 6 for use in a method for the prevention or treatment of hypertension in a cat, wherein the daily dose of the sartan is reduced when the cat's Systolic Blood Pressure (SBP) measurement falls from the cat's baseline SBP measurement before the first period of time to (AT or below) a threshold value.
8. The angiotensin II receptor 1(AT-1) antagonist (sartan) according to claim 7 for use in a method for the prevention or treatment of hypertension in cats wherein the threshold value is 160 or 170 mmHg.
9. The angiotensin il receptor 1(AT-1) antagonist (sartan) according to any of claims 1 to 8 for use in a method for the prevention or treatment of hypertension in a cat, wherein the daily dose of the sartan in the second period of time is increased or decreased for a third period of time after the second period of time and based on a change in the SBP of the cat measured AT the end of the second period of time.
10. The angiotensin il receptor 1(AT-1) antagonist (sartan) according to any of claims 1 to 9 for use in a method for the prevention or treatment of hypertension in cats wherein the daily dose of the sartan during the first time period is between 2.0 and 3.0mg/kg body weight and the daily dose of the sartan during the second time period is between 0.125 and 2.0mg/kg body weight during the treatment period.
11. The angiotensin il receptor 1(AT-1) antagonist (sartan) according to any of claims 1 to 10 for use in a method for the prevention or treatment of hypertension in a cat, wherein the first period of time is AT least 14 days, or AT least 28 days, or AT least 120 days.
12. The angiotensin il receptor 1(AT-1) antagonist (sartan) according to any of claims 1 to 11 for use in a method for the prevention or treatment of hypertension in cats wherein the daily administration is oral administration.
13. The angiotensin il receptor 1(AT-1) antagonist (sartan) according to any of claims 1 to 12 for use in a method of prevention or treatment of hypertension in a cat, wherein the daily administration of a therapeutically effective amount of AT least a part of the treatment period is provided in a single dose.
14. The angiotensin il receptor 1(AT-1) antagonist (sartan) according to any of claims 1 to 12 for use in a method of prevention or treatment of hypertension in a cat, wherein the daily administration of a therapeutically effective amount of AT least a part of the treatment period is provided in multiple doses.
15. The angiotensin II receptor 1(AT-1) antagonist (sartan) according to any of claims 1 to 14 for use in a method of preventing or treating hypertension in a cat, wherein the method excludes administration of a therapeutically effective amount of an angiotensin II receptor 1(AT-1) antagonist (sartan) to cats with an age of less than 9 months, or wherein the angiotensin II receptor 1(AT-1) antagonist (sartan) is administered to cats with an age of AT least 9 months, or wherein the angiotensin II receptor 1(AT-1) antagonist (sartan) is administered to cats with an age of 9 months and older.
16. A kit of parts comprising:
a container containing a liquid formulation of a pharmaceutical composition comprising a vasopressin II receptor 1(AT-1) antagonist (sartan) and one or more pharmaceutically acceptable diluents and/or carriers, in an amount therapeutically effective to prevent or treat hypertension in a cat in need of such treatment; and
a syringe comprising a barrel and optionally having volume scale markings, optionally imprinted thereon in 0.25mL increments or less than 0.25mL increments or in 0.10mL increments or less than 0.10mL increments.
17. The kit of parts of claim 16 further comprising an adapter connected to the open end of the container, the adapter including an opening extending through the adapter, wherein the adapter opening is smaller in size than the container open end, and optionally the syringe barrel includes an open end having a geometry corresponding to the geometry of the adapter opening to facilitate a friction fit between the barrel open end and the adapter when the barrel open end is inserted into the adapter opening.
Technical Field
The present invention relates to the field of veterinary medicine, and in particular to the prevention or treatment of systemic diseases in cats. In particular, the present invention relates to a method for the prevention or treatment of systemic diseases in cats, wherein the method comprises administering to a cat in need of such treatment a therapeutically effective amount of the angiotensin II receptor 1(AT-1) antagonist (sartan).
Background
The incidence of renal disease is high in senior cats, and chronic renal failure is considered the most important one. The incidence of Chronic Kidney Disease (CKD) in cats has been reported to be up to 20%, with 53% of cats being older than 7 years of age (Lefebre, Toutain 2004, j.vet.pharm.thermap.27, 265-281; Wolf AM north.am.vet.convergence 2006). Survival rates for cats with mild to moderate azotemia and extra-renal clinical symptoms (IRIS stages 2 and 3) ranged from 1 to 3 years. Early management and therapy was considered successful in influencing CKD prognosis (Wolf AM North AM.
Chronic Renal Failure (CRF), at least in its final stage, regardless of the underlying cause, is characterized by irreversible structural damage to the kidney. Thus, progressive irreversible damage that is first localized to a portion of the nephron (e.g., glomeruli, peritubular capillaries, tubules, or interstitial tissue) is ultimately responsible for the creation of damage in the remaining (but initially unaffected) portion of the nephron due to its functional interdependence. New nephrons cannot be formed to replace other nephrons irreversibly damaged by the disease. In a biopsy finding study of cats with primary renal azotemia, tubulointerstitial nephritis was observed in 70%, glomerulonephropathy occurred in 15%, lymphoma was 11% and amyloidosis was observed in 2% of the samples. CRF is recognized by reduced renal function or the presence of renal injury (Polzin, Osborne, Ross 2005 in Ettinger SJ, Feldman CE (eds.) Textbook of Veterinery Internal Medicine, 6 th edition, Vol.2 Chapter 260, 1756-.
Vasopressin II plays an important role in pathophysiology, especially as the most potent agent for increasing blood pressure in the human body. In addition to its blood pressure-increasing effect, it is known that vasopressin II also has a growth-promoting effect, which causes left ventricular hypertrophy, vascular thickening, atherosclerosis, renal failure and stroke. In small animals, inhibition of angiotensin II by ACE inhibitors has been shown to exhibit a renoprotective effect through its ability to simultaneously lower blood pressure and control proteinuria.
The aim of the current treatment is to delay disease progression in cats by improving kidney function, in particular glomerular function, by maintaining glomerular perfusion. This includes dietary protein restriction, altering dietary lipid intake, limiting phosphate and treatment with Angiotensin Converting Enzyme (ACE) inhibitors (p.j. barber (2004) The Kidney in chandlerea, Gaskell CJ, Gaskell RM (eds.) Feline Medicine and Therapeutics, 3 rd edition, Blackwell Publishing, Oxford, UK).
ACE inhibitors, in particular enalapril (enalapril), benazepril (benazepril), imidapril (imidapril) and ramipril (ramipril), were initially developed in small animal medicine to control Chronic Heart Failure (CHF). Based on the pathophysiological role of the renin-vasoconstrictor-aldosterone system (RAAS) in the progression of chronic heart failure and in the progression of renal injury, these agents have been shown to be useful in the treatment of Chronic Kidney Disease (CKD) in order to delay disease progression and reduce morbidity and distress in small animals, including cats. Strong evidence in this regard is the recent potential approval of benazepril for the treatment of feline CRF in europe (Lefebre Toutain,2004J Vet Pharm thermal 27, 265-281). However, renal function protection by ACE inhibitors may be mediated by proteinuria rather than by blood pressure reduction. This phenomenon was shown because ramipril's effect on blood pressure decreased proteinuria comparable to placebo (Remuzzi et al, 2006, J Clininvest 116, (2) 288-.
From a clinical perspective, ACE inhibitors are not preferred targets for blocking RAAS due to their lack of specificity for the phenomenon of vasopressin I and "vasopressin escape", where alternative enzymatic pathways (such as cathepsin, trypsin or cardiac chymosin) may also convert vasopressin I. In addition, ACE activity is up-regulated during long-term treatment with ACE inhibitors and angiotensin I levels are higher due to stimulation of renin secretion (Burnier and Brunner,2000, The Lancet,355, 637-645).
It is therefore an object of the present invention to provide a new therapeutic approach for the treatment or prevention of chronic kidney disease in cats.
Another more general aspect of the invention is to provide a novel therapeutic approach for treating or preventing systemic diseases in cats; preferably, the systemic diseases are those related to vasopressin II or to the renin-vasopressin-aldosterone system (RAAS).
Yet another aspect of the present invention is to provide a novel therapeutic approach for treating or preventing hypertension in cats.
Disclosure of Invention
Before the embodiments of the invention are explained, it is to be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a formulation" includes a plurality of such formulations, reference to "a carrier" includes reference to one or more carriers known to those skilled in the art and equivalents thereof, and so forth. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All ranges and values given may vary by 1 to 5% unless otherwise indicated or otherwise known to those skilled in the art, and thus the term "about" is omitted from the embodiments. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the materials, excipients, carriers, and methods reported in the publications that might be used in connection with the invention. Nothing herein is to be construed as an admission that the disclosure is not entitled to antedate such disclosure by virtue of prior invention.
The solution to the above technical problem is achieved by the embodiments characterized in the present invention and claims.
According to the present invention, the methods described herein are for the prevention or treatment of hypertension (also known as hypertension) in a cat in need of such treatment, wherein the methods comprise administering to the cat a therapeutically effective amount of a vasopressin II receptor 1(AT-1) antagonist (sartan), the therapeutically effective amount of the sartan being administered AT a daily dose that varies over the treatment period. For example, the daily dose of sartan during a first period of time during the treatment period may be 1.0 to 5.0mg/kg body weight, wherein the daily dose of sartan during a second period of time after the first period of time during the treatment period is reduced.
Specifically, the following items are disclosed herein:
1. an angiotensin II receptor 1(AT-1) antagonist (sartan) for use in a method of preventing or treating hypertension in a cat in need of such prevention or treatment, wherein the method comprises administering to the cat a therapeutically effective amount of an angiotensin II receptor 1(AT-1) antagonist (sartan), wherein the therapeutically effective amount of the sartan is administered AT a daily dose that varies over a treatment period during which a daily dose of sartan for a first period of time is 1.0 to 5.0mg/kg body weight and during which the daily dose of sartan for a second period of time after the first period of time is reduced.
2. An angiotensin II receptor 1(AT-1) antagonist (sartan) according to
3. An angiotensin II receptor 1(AT-1) antagonist (sartan) according to
4. An angiotensin II receptor 1(AT-1) antagonist (sartan) according to
5. The angiotensin II receptor 1(AT-1) antagonist (sartan) according to
6. An angiotensin II receptor 1(AT-1) antagonist (sartan) according to
7. An angiotensin II receptor 1(AT-1) antagonist (sartan) according to
8. The angiotensin II receptor 1(AT-1) antagonist (sartan) according to
9. The angiotensin II receptor 1(AT-1) antagonist (sartan) according to
10. The angiotensin II receptor 1(AT-1) antagonist (sartan) according to
11. An angiotensin II receptor 1(AT-1) antagonist (sartan) according to
12. An angiotensin II receptor 1(AT-1) antagonist (sartan) according to
13. The angiotensin II receptor 1(AT-1) antagonist (sartan) according to
14. The angiotensin II receptor 1(AT-1) antagonist (sartan) according to
15. The angiotensin II receptor 1(AT-1) antagonist (sartan) according to
16. The angiotensin II receptor 1(AT-1) antagonist (sartan) according to
17. The angiotensin II receptor 1(AT-1) antagonist (sartan) according to
18. The angiotensin II receptor 1(AT-1) antagonist (sartan) according to
19. The angiotensin II receptor 1(AT-1) antagonist (sartan) according to
20. The angiotensin II receptor 1(AT-1) antagonist (sartan) according to
21. A method for the prevention or treatment of hypertension in a cat in need of such treatment, wherein the method comprises administering to the cat a therapeutically effective amount of an angiotensin II receptor 1(AT-1) antagonist (sartan), wherein the therapeutically effective amount of sartan is administered AT a daily dose which varies over a treatment period during which the daily dose of sartan is between 1.0 and 5.0mg/kg body weight for a first period of time and during which the daily dose of sartan is reduced for a second period of time after the first period of time.
22. The method of clause 21, wherein the hypertension is associated with chronic kidney disease or hyperthyroidism.
23. The method of clause 21, wherein the hypertension is idiopathic hypertension.
24. The method of any one of clauses 21 to 23, wherein the daily dose is varied based on a Systolic Blood Pressure (SBP) measurement of the cat.
25. The method of any of clauses 21 to 24, wherein the daily dose of sartan for the second period of time is reduced in increments ranging from 0.10 to 0.50mg/kg body weight.
26. The method of any of clauses 21 to 25, wherein the daily dose of sartan is reduced when the Systolic Blood Pressure (SBP) measurement of the cat is reduced by at least 10mmHg relative to the baseline SBP measurement of the cat prior to the first time period.
27. The method of clause 26, wherein the daily dose of sartan is reduced when the SBP measurement of the cat is reduced by at least 20mmHg relative to the baseline SBP measurement of the cat determined prior to the first time period.
28. The method of any of clauses 21 to 25, wherein the daily dose of sartan is reduced when the cat's Systolic Blood Pressure (SBP) measurement decreases from the baseline SBP measurement of the cat before the first time period to a value that does not exceed a threshold value.
29. The method of clause 28, wherein the threshold does not exceed 160 or 170 mmHg.
30. The method of any of clauses 21 to 29, wherein the daily dose of sartan for the second period of time increases or decreases for a third period of time after the second period of time and is based on the change in SBP of the cat measured at the end of the second period of time.
31. The method of any of clauses 31 to 30, wherein the daily dose of sartan during the treatment period for the first time period is 2.0 to 3.0mg/kg body weight and the daily dose of sartan during the second time period is 0.125 to 2.0mg/kg body weight.
32. The method of any one of clauses 21 to 31, wherein the first period of time is at least 14 days, or at least 28 days, or at least 120 days.
33. The method of any one of clauses 21 to 32, wherein daily administration is oral administration.
34. The method of any of clauses 21 to 33, wherein the daily administration of the therapeutically effective amount for at least a portion of the treatment period is provided as a single dose.
35. The method of any of clauses 21 to 33, wherein the daily administration of a therapeutically effective amount of at least a portion of the treatment period is provided in multiple doses.
36. The method of any of clauses 21 to 35, wherein the method excludes administration of a therapeutically effective amount of the angiotensin II receptor 1(AT-1) antagonist (sartan) to cats that are less than 9 months old.
37. A kit of parts comprising:
a container containing a liquid formulation of a pharmaceutical composition comprising a vasopressin II receptor 1(AT-1) antagonist (sartan) and one or more pharmaceutically acceptable diluents and/or carriers in an amount therapeutically effective to prevent or treat hypertension in a cat in need thereof; and
a syringe comprising an optional barrel having volume scale markings, optionally imprinted thereon in 0.25mL increments or less than 0.25mL increments or in 0.10mL increments or less than 0.10mL increments.
38. The kit of parts of item 37, further comprising an adapter connected to the open end of the container, the adapter comprising an opening extending through the adapter, wherein the adapter opening is smaller in size than the open end of the container.
39. The kit of claim 37 or item 38, wherein the syringe barrel comprises an open end having a geometry that corresponds to a geometry of the adapter opening to facilitate a friction fit between the syringe open end and the adapter when the syringe open end is inserted into the adapter opening.
40. The method of any one of items 21 to 35 or the kit of parts of any one of items 37 to 39, wherein the cat is at least 9 months old or a 9 month old and older cat.
The use of the
In the study, it was found that cats tolerate a pharmacodynamically effective dose of sartan. For example, the effect of renal outcome of lower (80mg once daily) and higher dose (80mg twice daily) telmisartan were compared in an open-label study of non-diabetic hypertensive human patients with proteinuria nephropathy. The results enhance the concept of achieving more effective RAAS inhibition by higher doses of 160mg per day. This dose corresponds to a plasma level of about 2800 ± 2400ng/ml (cmax ± SD) which exceeds the non-effective dose in toxicity studies in animals such as dogs and rats. (Investigator crochure 1994, archival data) the resulting dose and days at about 2 to 3mg/kg body weight would therefore be expected to be toxic in cats. Experimental toxicity studies have surprisingly shown that such doses (up to 3mg/kg) are well tolerated in cats. As used herein, the term "mg/kg" refers to the dosage in mg/kg cat body weight.
In addition, it has been found that sartan is also effective in blocking the vasopressin II
Table 1: abbreviations
Abbreviations
Pharmacokinetic parameters
AUC
Area under plasma concentration curve
Cmax
Maximum measured plasma concentration
V/f
Volume of distribution (V), and f is absolute bioavailability
MRT
Average residence time
t1/2
Half-life of elimination
tmax of
To reach C
Maximum ofTime of
Thus, in one embodiment, the invention relates to a method for the prevention or treatment of systemic diseases in cats, wherein the method comprises administering to the cat in need of such treatment a therapeutically effective amount of the angiotensin II receptor 1(AT-1) antagonist (sartan).
As used herein, the term "systemic disease" means, but is not limited to, cardiovascular, such as Dilated Cardiomyopathy (DCM), Mitral Insufficiency (MI), Hypertrophic Cardiomyopathy (HCM); and other acquired or inherited heart diseases, such as cardiopulmonary diseases, systemic hypertension, such as hypertension associated with renal disease, chronic renal failure, and other vascular diseases or metabolic disorders, such as diabetes. Thus, according to another aspect, the present invention relates to a method for preventing or treating a systemic disease in a cat by administering to the cat a therapeutically effective amount of the angiotensin II receptor 1(AT-1) antagonist (sartan), wherein the systemic disease is selected from the group of: cardiovascular diseases such as Dilated Cardiomyopathy (DCM), Mitral Insufficiency (MI), Hypertrophic Cardiomyopathy (HCM); and other acquired or inherited heart diseases, hypertension (including systemic hypertension), metabolic disorders such as diabetes.
As used herein, the term "systemic hypertension" means, but is not limited to, forms of hypertension associated with kidney disease, chronic renal failure, and other vascular diseases. For example, systemic hypertension can include hypertension of unknown etiology, hypertension associated with chronic kidney disease, hypertension associated with hyperthyroidism, controlled hypertension, and idiopathic hypertension. Specifically, systemic hypertension (also referred to herein as hypertension) is defined as a sustained increase in systemic blood pressure (e.g., systolic blood pressure or SBP with 160mmHg or greater than 160 mmHg). There are two subfractions of hypertension: primary (or idiopathic) hypertension, where no underlying disease can be identified, and secondary hypertension that appears as a complication of systemic disease. In recent years, idiopathic hypertension has been gradually recognized in small animal medicine. The most common disease of secondary hypertension in cats is Chronic Kidney Disease (CKD) and hyperthyroidism. Other diseases such as hyperaldosteronism or pheochromocytoma are a very rare cause of secondary hypertension in cats and often lead to severe and often therapy-resistant hypertension.
The pathogenesis of idiopathic hypertension in feline patients is not fully understood. However, activation of the renin-vasoconstrictor-aldosterone system (RAAS) is thought to occur in infected cats. However, chronic kidney disease-associated HT is induced by RAAS activation and ultimately aldosterone production. The effects are mediated primarily via the angiotensin-II receptor type 1 (AT-1). Chronic RAAS activation leads to persistent hypertension via systemic vasoconstriction, intravascular fluid expansion, and sympathetic nerve activation. The underlying mechanism of hypertension secondary to feline hyperthyroidism has not been determined, but is suspected to be RAAS dysfunction. In some cats, hypertension is present when hyperthyroidism is diagnosed, while in other cats, hypertension develops after the thyroid status has recovered.
Regardless of the cause, hypertension can lead to local or systemic diseases through destructive effects of the vascular beds of various organs. Clinically, hypertension-related injuries are often identified in the eye, brain, kidneys, heart and vessels. According to the common aspects of ACVIM of hypertension in dogs and cats (identification, assessment, and management Guidelines for systemic hypertension in dogs and cats in Brown et al. assessment, and management of systemic hypertension. ACVIM Consensus State J Vet Intern Med 2007; 21: 542-. Hypertension in cats has a significant risk of further organ damage. Activation and/or dysfunction of RAAS appears to play a key role in the development of feline hypertension of various etiologies. Thus, RAAS inhibition appears to be a reasonable therapeutic target for hypertensive cats with idiopathic hypertension or secondary hypertension due to CKD or hyperthyroidism.
Thus, in another embodiment, the invention relates to a method for preventing or treating systemic hypertension (also referred to herein as hypertension) in a cat, wherein the method comprises administering to a cat in need of such treatment a therapeutically effective amount of a angiotensin II receptor 1(AT-1) antagonist (sartan), wherein the hypertension is associated with one or more other systemic diseases including, but not limited to, CKD, hyperthyroidism, controlled hypertension and idiopathic hypertension. In another embodiment, a therapeutically effective amount of sartan is administered to the cat at a daily dose that varies over the treatment period. The variation of the treatment period may be that the daily dose of sartan is 1.0 to 5.0mg/kg body weight during a first period of time during the treatment period and the daily dose of sartan is reduced during a second period of time after the first period of time during the treatment period. The daily dose of sartan for the second period of time may be reduced in increments ranging from 0.10 to 0.50mg/kg body weight. In one embodiment the daily dose of sartan for the second period of time may be reduced in increments ranging from 0.10 to 0.50mg/kg cat body weight. The daily dose of sartan may be reduced based on certain criteria of the cat, such as the measured Systolic Blood Pressure (SBP) of the cat. For example, the daily dose of sartan may be reduced when the SBP measurement of the cat is reduced by at least 10mmHg relative to the baseline SBP measurement of the cat prior to the first time period. In another embodiment, the daily dose of sartan may be reduced when the SBP measurement of the cat does not exceed a predetermined value or threshold (e.g. 120 mmHg). As described herein, the daily dose of sartan may be further reduced by any suitable amount for any number of consecutive dosage periods and based on a positive cat response to such reduced dose.
In humans, vasopressin II receptor 1(AT1 receptor antagonist (sartan) is known to significantly reduce proteinuria in diabetic and non-diabetic patients, even those with mild to moderate Chronic Renal Failure (CRF). in addition, there is published evidence to show the effective use of AT1 receptor antagonists for the treatment of nephropathy in type II diabetes Cupisi A et al, 2003, biomed Pharmacother, 57(3-4): 169-172; Rysava R et al, 2005, Press Monit; (10(4): 207-213; WO 92/10182). in cats, tubulointerstitial nephritis is reported as the primary cause of CRF (> 70%) whereas in humans and dogs, glomerulonephropathy is more pronounced than in cats glomerular injury is more commonly seen in dogs and humans and thus moderate to pronounced proteinuria due to loss of glomerular selective permeability is more common in dogs and humans Is considered to be an important predictor of disease progression in humans and dogs with idiopathic kidney disease, and the reduction in proteinuria associated with improved outcomes in clinical trials has been shown to block the renal protective effects of RAAS by ACE or ARB in humans with renal disease (Karalliede & Viberti, J human hypertension 2006). Due to the fact that proteinuria is less induced in cats by CRF derived from tubulointerstitial nephritis, it might be expected that a reduction in proteinuria in this species is less important as a renal protective effect in delaying the progression of CRF. However, in clinical field trials, an independent and significant correlation between proteinuria (measured as UPC) and survival in cats suffering from CRF has been reported. Surprisingly, this correlation was evident even in azotemic cats with only a small amount of proteinuria (UPC <0.25 according to IRIS, uploot 2006, J Vet lnd Med,20, 528-.
Thus, according to a preferred embodiment, the systemic disease is chronic kidney disease, preferably chronic renal failure, e.g. as defined in stages II to IV of table 2.
Diagnosis of reduced renal function, such as chronic renal failure, is based on the exclusion of prerenal and postrenal factors and standard blood pressure markers (e.g., urea and creatinine in plasma or serum). Abnormal concentrations of these parameters are described as azotemia. Standard urine markers for reduced renal function include specific gravity, proteinuria and other markers (Polzin DJ, Osborne CA, Ross, 2005: Chronic Kidney Disease, In: Ettinger SJ, Feldman EC (eds.) Textbook of Veterinary internal Medicine 6 th edition, W.B.Saunders Company, Philadelphia, USA). The International renal research organization (IRIS) has proposed a staging system for CRF patients based on azotemia (Polzin DJ,2006: Treating nonlinear clinical diagnosis: an evaluation-based assessment, Proceedings of The North American vessel Conference). The main class for staging is plasma creatinine [ mg/dl ], which is accomplished by two subcategories of urinary protein to creatinine ratio (UPC) and blood pressure [ mmHg ] independent of each stage. Using this application, feline patients can be staged along the continuum of progressive renal disease.
TABLE 2 phases of feline Chronic nephropathy
As described herein, a method for preventing or treating chronic renal failure in a cat comprises administering to the cat in need of such treatment a therapeutically effective amount of the angiotensin II receptor 1(AT-1) antagonist (sartan), and wherein the chronic renal failure is characterized by any one of the clinical manifestations as listed in table 2 or any combination thereof. For example, the present invention relates to a method for the prevention or treatment of cats having plasma creatine ≥ 1.6(mg/dl blood) and/or proteinuria ≥ 0.2 (subcategory UPC), wherein the method comprises administering to the cat in need of such treatment a therapeutically effective amount of the angiotensin II receptor 1(AT-1) antagonist (sartan).
A comprehensive list of angiotensin II receptor antagonists can be found on pages 2 to 22 of WO92/10182 and on pages 7 to 18 of WO 95/26188, all incorporated herein by reference. Angiotensin II receptor antagonists are described in particular in EP-A-253310, EP-A-323841, EP-A-324377, EP-A-420237, EP-A-443983, EP-A-459136, EP-A-475206, EP-A-502314, EP-A-504888, EP-A-514198, WO 91/14679, WO 93/20816, WO 02/092081, US 4,355,040, US 4,880,804 and US 6,028,091. Forms thereof are often referred to as sartan, such as candesartan (candesartan), eprosartan (eprosartan), irbesartan (irbesartan), losartan (losartan), olmesartan (olmesartan), tasosartan, telmisartan or valsartan (valsartan). Of these, irbesartan, losartan and telmisartan are particularly preferred according to the present invention. All such sartan, or pharmaceutical salts or polymorphs thereof, are well known to those skilled in the art and their use is within the meaning of the present invention.
Accordingly, the present invention relates to a method for preventing or treating cats suffering from systemic diseases, preferably chronic kidney disease, such as chronic renal failure, wherein the method comprises administering to the cat in need of such treatment a therapeutically effective amount of a vasopressin II receptor 1(AT-1) antagonist (sartan), and wherein the vasopressin II receptor 1(AT-1) antagonist (sartan) is selected from the group consisting of: candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan or valsartan, preferably losartan and telmisartan.
As disclosed in EP- ｃA-502314, telmisartan is an angiotensin II receptor antagonist developed for the treatment of hypertension and other medical indications. Its chemical name is 4' - [ 2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-ylmethyl ] -biphenyl-2-carboxylic acid, which has the following structure:
telmisartan is given the trade name Telmisartan
Thus, according to another embodiment, the present invention relates to a method for the prevention or treatment of a systemic disease in cats, such as chronic kidney disease, e.g. chronic renal failure, wherein the method comprises administering a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof, preferably telmisartan as mentioned above.
As already mentioned herein, it has been surprisingly found that the use of telmisartan is effective in inhibiting vasopressin II receptor stress responses in cats. In addition, it has been found that a dose of less than 0.05mg telmisartan per kg body weight of the cat produces about 75% inhibition of the blood pressure response in the majority of cats tested. In addition, studies have been conducted in laboratory cats to explore the angiotensin II-induced diastolic blood pressure elevation before and after telmisartan administration. This test was performed to evaluate the efficacy and duration of action of sartan, in particular telmisartan, in cats. When the target dose of telmisartan was compared with placebo, the diastolic blood pressure response was significantly reduced for an intravenous dose increase of vasopressin II about 24 hours after the last oral administration. Thus, it can be concluded that once daily administration of a target dose in a given cat can exhibit the desired pharmacodynamic effects and duration, despite the small elimination half-life and bioavailability.
Thus, according to another aspect, the present invention relates to a method for the prevention or treatment of a systemic disease, preferably chronic kidney disease, such as chronic renal failure, in a cat, wherein the method comprises administering to the cat in need of such treatment a therapeutically effective amount of a vasopressin II receptor 1(AT-1) antagonist (sartan), preferably telmisartan or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of such vasopressin II receptor 1(AT-1) antagonist is about 0.01 to about 10mg/kg body weight. Preferably, the therapeutically effective amount of such an angiotensin II receptor 1(AT-1) antagonist is from about 0.05 to about 8mg/kg body weight, even more preferably from about 0.1 to about 5mg/kg body weight, even more preferably from about 0.2 to about 4mg/kg body weight, even more preferably from about 0.3 to about 3mg/kg body weight, even more preferably from about 0.4 to about 2.5mg/kg body weight, even more preferably from about 0.5 to about 2mg/kg body weight, most preferably from about 0.75 to about 1.5mg/kg body weight. Thus, such therapeutically effective amounts of such angiotensin II receptor 1(AT-1) antagonists are, for example, 0.01, 0.02, 0.03, … 0.08, 0.09, 0.1, etc.; 0.11, 0.12, 0.125, 0.13, … 0.18, 0.19, 0.2, etc.; 0.21, 0.22, 0.23, … 0.28, 0.29, 0.3, etc. …; 0.81, 0.82, 0.83, … 0.88.88, 0.89, 0.9, etc.; 0.91, 0.92, 0.93, … 0.98.98, 0.99, 1.0, etc.; 1.01, 1.02, 1.03, … 1.08.08, 1.09, 1.1, etc.; … 1.2.2, 1.3, … 1.8.1, 8, 1.9, 2.0, etc.; 2.1, 2.2, 2.3, … 2.8.8, 2.9, 3.0, etc.; …, respectively; 8.1, 8.2, 8.3, … 8.8.8, 8.9, 9.0, etc.; 9.1, 9.2, 9.3, … 9.8.8, 9.9, 10mg/kg body weight. The angiotensin II receptor 1(AT-1) antagonist, preferably telmisartan, may be administered once, twice or three times a day in a daily dose as mentioned above.
In the case where the angiotensin II receptor 1(AT-1) antagonist is administered by a parenteral route, the angiotensin II receptor 1(AT-1) antagonist, preferably telmisartan, is administered AT a dose of about 0.01 to about 4mg/kg body weight. Preferably, the therapeutically effective amount of such an angiotensin II receptor 1(AT-1) antagonist is from about 0.05 to about 3mg/kg body weight, even more preferably from about 0.1 to about 2.5mg/kg body weight, even more preferably from about 0.15 to about 2.0mg/kg body weight, even more preferably from about 0.2 to about 1.5mg/kg body weight, most preferably from about 0.25 to about 1.25mg/kg body weight. Thus, such therapeutically effective amounts of such angiotensin II receptor 1(AT-1) antagonists are, for example, 0.01, 0.02, 0.03, … 0.08, 0.09, 0.1, etc.; 0.11, 0.12, 0.13, … 0.18, 0.19, 0.2, etc.; 0.21, 0.22, 0.23, … 0.28, 0.29, 0.3, etc. …; 0.81, 0.82, 0.83, … 0.88.88, 0.89, 0.9, etc.; 0.91, 0.92, 0.93, … 0.98.98, 0.99, 1.0, etc.; 1.01, 1.02, 1.03, … 1.08.08, 1.09, 1.1, etc.; … 1.1.1, 1.2, 1.3, … 1.8, 1.9, 2.0, etc.; 2.1, 2.2, 2.3, … 2.8.8, 2.9, 3.0, etc.; 3.1, 3.2, 3.3, … 3.8.8, 3.9, 4mg/kg body weight. The angiotensin II receptor 1(AT-1) antagonist, preferably telmisartan, may be administered once, twice or three times a day in a daily dose as mentioned above.
In the case of administration of an angiotensin II receptor 1(AT-1) antagonist, preferably telmisartan, by the oral, rectal, nasal or inhalation route, a dose of about 0.03 to about 10mg/kg body weight is preferred. Preferably, the therapeutically effective amount of such an angiotensin II receptor 1(AT-1) antagonist is from about 0.10 to about 8mg/kg body weight, even more preferably from about 0.20 to about 7.5mg/kg body weight, even more preferably from about 0.25 to about 7.0mg/kg body weight, even more preferably from about 0.25 to about 6.0mg/kg body weight, most preferably from about 0.25 to about 5mg/kg body weight. Thus, such therapeutically effective amounts of such angiotensin II receptor 1(AT-1) antagonists are, for example, 0.03, 0.04, 0.05, … 0.08, 0.09, 0.1, etc.; 0.11, 0.12, 0.13, … 0.18, 0.19, 0.2, etc.; 0.21, 0.22, 0.23, … 0.28, 0.29, 0.3, etc. …; 0.81, 0.82, 0.83, … 0.88.88, 0.89, 0.9, etc.; 0.91, 0.92, 0.93, … 0.98.98, 0.99, 1.0, etc.; 1.01, 1.02, 1.03, … 1.08.08, 1.09, 1.1, etc.; … 1.1.1, 1.2, 1.3, … 1.8, 1.9, 2.0, etc.; 2.1, 2.2, 2.3, … 2.8.8, 2.9, 3.0, etc.; …, respectively; 8.1, 8.2, 8.3, … 8.8.8, 8.9, 9.0, etc.; 9.1, 9.2, 9.3, … 9.8.8, 9.9, 10mg/kg body weight. Telmisartan can be administered once, twice or three times a day in a daily dose as mentioned above.
According to another aspect of the invention, the invention relates to a method for the prevention or treatment of a systemic disease in cats, such as chronic kidney disease, e.g. chronic kidney failure, wherein the method comprises administering to the cat in need of such treatment a therapeutically effective amount of a angiotensin II receptor 1(AT-1) antagonist (sartan), preferably telmisartan or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of such angiotensin II receptor 1(AT-1) antagonist is administered in a therapeutically effective amount resulting in a cumulative intravenous concentration of AT least 0.025mg/kg body weight (bw). Preferably, the angiotensin II receptor 1(AT-1) antagonist (sartan), preferably telmisartan, is administered to a cumulative intravenous concentration of AT least 0.05mg/kg bw, more preferably 0.1mg/kg bw, even more preferably 0.15mg/kg bw, even more preferably 0.2mg/kg bw, even more preferably 0.25mg/kg bw, even more preferably 0.40mg/kg bw, even more preferably 0.5mg/kg bw, even more preferably 0.75mg/kg bw, even more preferably 1mg/kg bw. The upper cumulative intravenous concentration of about 1mg/kg bw is well tolerated, however cumulative intravenous concentrations of up to 5, 4,3 and 2mg/kg bw as well as any other higher non-toxic cumulative intravenous concentrations of the angiotensin II receptor 1(AT-1) antagonist (sartan) are also within the meaning of the present invention. The upper nontoxic cumulative intravenous concentration can be estimated by standard techniques by those skilled in the art in view of the teachings given herein.
Optionally, the angiotensin II receptor 1(AT-1) antagonist (sartan), preferably telmisartan, may be administered in combination with other drugs such as Ca-channel blockers (e.g. Amlodipine (Amlodipine)), β -blockers (e.g. Atenolol (Atenols), carvedilol (Carvediol)), cardiotonic-Ca-sensitizing agents (e.g. Pimobendan (Pimobendan), Levosimendan (Levosimendan)), selective If-current inhibitors (selective If-current inhibitors) (i.e. Cilobradine (Cilobbradine)), Ivabradine (Ivabradine)), ACE inhibitors (e.g. ramipril (ramipril), nabepin (benazepril), enalapril (enalapril)), norgestrel (anti-1 (AT-1) antagonists (Amethiban), preferably, a pharmaceutically acceptable salt thereof, such as the angiotensin-1, a pharmaceutically acceptable antagonist (Amethopril), and other drugs such as a pharmaceutically acceptable inhibitor (e.g. a felbinapril, a felbinapril), a-norgestimatinib (Aminolide (Anagliadin (Anagliclazide), a-antagonist (e), a pharmaceutically acceptable substance (e, a pharmaceutically acceptable for example, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable antagonist (e) or a pharmaceutically acceptable inhibitor (e.g. a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable antagonist, a pharmaceutically acceptable salt thereof, such as a pharmaceutically acceptable antagonist, a pharmaceutically acceptable for example, a pharmaceutically acceptable antagonist, a pharmaceutically acceptable salt thereof, such as a vasopressin, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable antagonist, a vasopressin, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable antagonist, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt.
Telmisartan and other active compounds can be administered orally in a variety of different dosage forms, i.e., they can be formulated with a variety of pharmaceutically acceptable inert carriers into lozenges, capsules, troches, dragees, hard candies, powders, sprays, aqueous suspensions, elixirs, syrup forms, and the like. Such carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents. In addition, such oral pharmaceutical preparations may be suitably sweetened and/or flavored by means of various medicament types commonly employed for such purposes. In general, the compounds of the present invention are present in such oral dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, in amounts sufficient to provide the desired unit dosage. Other suitable dosage forms of the compounds of the invention include controlled release formulations and devices well known to those skilled in the art.
For oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, and preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc or similar types of compositions may also be used as fillers in soft and hard-filled gelatin capsules containing lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if desired, emulsifying agents and/or water, ethanol, propylene glycol, glycerin and various combinations thereof.
For the purpose of parenteral administration, solutions of the compounds in sesame or peanut oil or aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding pharmaceutically acceptable salts, may be employed. Such aqueous solutions should be suitably buffered, if necessary, and the liquid diluent isotonic with sufficient physiological saline or glucose. These particular aqueous solutions are particularly useful for intravenous, intramuscular, and subcutaneous injection purposes. In this regard, the sterile aqueous medium employed is readily obtained by standard techniques well known to those skilled in the art. For example, distilled water is typically used as the liquid diluent and the final formulation is passed through a suitable bacterial filter, such as a sintered glass filter or a diatomaceous earth or unglazed porcelain filter. Preferred filters of this type include the Berkefeld, Chamberland and Asbestos plate Metal Seitz (aspestos Disk-Metal Seitz) filters, in which fluid is drawn into a sterile container by means of a suction pump. The necessary steps should be taken throughout the preparation of such injectable solutions to ensure that the final product is obtained under sterile conditions.
Thus, for the purpose of transdermal administration, a particular compound or dosage form of a compound may include, for example, solutions, lotions, ointments, creams, gels, suppositories, rate-limiting sustained release formulations and devices. Such dosage forms comprise a particular compound or compounds and may comprise ethanol, water, penetration enhancers, and inert carriers such as gel-making materials, mineral oil, emulsifiers, benzyl alcohol, and the like.
Such preformulated combinations of active substances are typically incorporated into conventional galenic formulations such as plain or coated tablets, capsules, powders, suspensions or suppositories together with one or more formulation adjuvants such as mannitol, sorbitol, xylitol, sucrose, calcium carbonate, calcium phosphate, lactose, croscarmellose sodium (croscarmellose sodium), crospovidone, sodium starch glycolate, hydroxypropylcellulose (low substitution), maize starch, polyvinylpyrrolidone, copolymers of vinylpyrrolidone with other vinyl derivatives (copovidone), hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose or starch, magnesium stearate, sodium stearyl fumarate, talc, hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, polyvinylacetate, sodium, Water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxy-methyl cellulose or fatty substances such as hard fat or suitable mixtures thereof.
Lozenges may be obtained, for example, by mixing one or more active substances with one or more excipients and subsequently compressing them. The tablet may also be composed of several layers. Embodiments of the excipients are:
inert diluents such as mannitol, sorbitol, xylitol, sucrose, calcium carbonate, calcium phosphate and lactose;
disintegrants such as croscarmellose sodium salt (croscarmellose sodium carboxymethyl ether), crospovidone, sodium starch glycolate, hydroxypropylcellulose (low substitution), and corn starch;
binders such as polyvinylpyrrolidone, copolymers of vinylpyrrolidone and other vinyl derivatives (copovidone), hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose or starch;
lubricants such as magnesium stearate, sodium stearyl fumarate, and talc;
agents for achieving delayed release, such as hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetate phthalate and polyvinyl acetate; and
pharmaceutically acceptable colorants such as colored iron oxide.
Furthermore, if telmisartan is used in combination with another drug for preventing or treating a systemic disease, preferably chronic kidney disease, such as chronic renal failure, in cats, the pharmaceutical composition according to the invention may be a kit of parts comprising:
a first container containing a pharmaceutical composition comprising a therapeutically effective amount of telmisartan or a physiologically acceptable salt thereof and one or more pharmaceutically acceptable diluents and/or carriers; and
a second container containing another drug for the prevention or treatment of a systemic disease, preferably chronic renal failure, or a physiologically acceptable salt thereof, and one or more pharmaceutically acceptable diluents and/or carriers.
Preferably, the kit of parts comprises in a second container one or more Ca-channel blockers (e.g. amlodipine), β -blockers (e.g. atenolol, carvedilol), cardiotonic-Ca-sensitizers (e.g. pimobendan, levosimendan), selective If-current inhibitors (i.e. cilostamine, ivabradine), ACE inhibitors (e.g. ramipril, benazepril, enalapril), antiobesity agents (e.g. amphetamine derivatives, sibutramine, orlistat, rimonabant) and the like.
According to another aspect, the present invention also relates to the use of an angiotensin II receptor 1(AT-1) antagonist (sartan), preferably telmisartan, for the manufacture of a pharmaceutical composition comprising a therapeutically effective amount of such an angiotensin II receptor 1(AT-1) antagonist for the treatment of a systemic disease in cats.
Preferably, the systemic disease is selected from the group of: cardiovascular diseases such as Dilated Cardiomyopathy (DCM), Mitral Insufficiency (MI), Hypertrophic Cardiomyopathy (HCM); and other acquired or inherited heart diseases, systemic hypertension (e.g., hypertension associated with kidney disease), Chronic Kidney Disease (CKD), and other vascular diseases, metabolic disorders, such as diabetes. For example, the systemic disease is systemic hypertension associated with one or more of CKD, hyperthyroidism, controlled hypertension, and idiopathic hypertension.
Preferred sartan are those mentioned above by way of example. Most preferably telmisartan or any pharmaceutically acceptable salt thereof, such as
In another embodiment of the invention, the dosing of sartan (e.g., telmisartan) is adjusted during treatment of cats and is based on conditions associated with cats. The dose adjustments can be varied after certain treatment periods and the changes (e.g., improvements) measured in accordance with the physical condition of the cat. For example, in treating hypertension in a cat (e.g., hypertension associated with one or more of CKD, hyperthyroidism, controlled hypertension, and idiopathic hypertension), salbutan may be administered to the cat at an initial dose (e.g., any of the suitable doses as described above) and then varied after a certain period of time, wherein the dose variation may be based on the measured Systolic Blood Pressure (SBP) of the cat. The SBP of the cat may be measured in any suitable manner (e.g., using a blood pressure cuff wrapped around the tail or limbs of the cat). In example embodiments (e.g., such as certain examples described herein), an initial daily dose may be administered to a cat for a period of time, wherein the SBP of the cat is determined after such period of time. In the event that the measured SBP of the cat does not exceed the threshold, the daily dose may be reduced or titrated down to a smaller amount. In the event that the SBP of the cat remains below the threshold and/or drops even further below the threshold, further reduction of the daily dose or titration down may be effected on a dosing regimen. Alternatively, in other embodiments, the daily dose may also be increased or titrated upward in the event that the measured SBP for the cat is at a value that exceeds the threshold by a predetermined amount. The dosage may be administered in any suitable manner, such as those previously described herein (e.g., orally, parenterally, etc.), and may further be in any suitable form (e.g., solid or liquid) and in combination with any other suitable active ingredient or any other excipient or other substance as previously indicated herein.
According to another aspect of the invention, the invention pertains to a vasopressin II receptor 1(AT-1) antagonist (sartan), preferably telmisartan or a pharmaceutically acceptable salt thereof, for use in a method of treating hypertension in a cat, wherein a therapeutically effective amount of sartan is administered AT a daily dose that varies over a treatment period during which the daily dose of sartan for a first period of time is between 1.0 and 5.0mg/kg body weight and the daily dose of sartan for a second period of time after the first period of time is reduced during the treatment period. In a particular embodiment, the hypertension is hypertension associated with chronic kidney disease or hyperthyroidism or the hypertension is idiopathic hypertension.
In example embodiments, an initial dose of sartan to a cat for the treatment of hypertension may be administered in an amount of about 0.10 to about 8.0mg/kg, such as about 0.10 to about 5.0mg/kg, about 0.75 to about 5.0mg/kg, or about 1.0 to 3.0mg/kg (e.g., about 1.5mg/kg or about 2.0mg/kg), where such dose may be administered once daily, twice daily, or three times daily (threetimes/thrice). For example, the daily dose of sartan to be administered to a cat may be about 0.10 to about 8.0mg/kg, such as about 1.0 to about 4.0mg/kg, about 2.0 to about 3.0mg/kg, and the like. The reduction or titration down (and increase or titration up) of the daily dose between the first predetermined or specified period of time and the second (subsequent) specified period of time may be any suitable amount, such as a change or incremental change (i.e., an incremental increase or decrease, or in other words, an increase or decrease of a predetermined amount or step amount) of the daily dose in the range of about 0.05 to about 1.0mg/kg, or about 0.1 to about 0.5mg/kg, etc. For example, daily dose titration changes may be modified or adjusted by incremental or incremental (decrease or increase) or any other suitable incremental (i.e., any other fixed decrease or fixed increase) changes of about 1.0mg/kg, about 0.9mg/kg, about 0.8mg/kg, about 0.75mg/kg, about 0.5mg/kg, about 0.4mg/kg, about 0.3mg/kg, about 0.25mg/kg, about 0.2mg/kg, about 0.125mg/kg, about 0.1mg/kg, 0.05mg/kg between a first specified time period and a second (subsequent) specified time period.
The daily dosage of sartan administered to a cat may be adjusted over any selected number of time intervals. For example, the initial time period (e.g., the time period including the first day of treatment) for administering an initial daily dose of sartan to a cat for treating hypertension may be from about 1 day to about 30 days or more than 30 days, such as from about 5 days to about 28 days, from about 7 days to about 14 days, etc. At the end of the initial period, adjustment of the daily dose may be carried out for a second or subsequent period, which may be from about 1 day to about 30 days or more than 30 days, such as from about 5 days to about 28 days, from about 7 days to about 14 days, etc. Any other number of subsequent time periods of adjustment of the daily dose may further be administered as desired and based on the efficacy of the treatment. In some embodiments, the total treatment period over which cats may be treated with different daily doses (e.g., over certain time periods) may be at least about 120 days (e.g., the treatment period may last at least 3 months, at least 4 months, at least 5 months, at least 6 months, etc.).
Methods of treating or preventing hypertension in cats by administering salbutan (including changes in the dose of salbutan during the treatment period) have been determined to be effective in cats of different ages. However, no study has been conducted to determine the effect of such methods on cats less than 9 months of age. Thus, the treatment methods described herein are preferably used on cats at least 9 months of age (i.e., 9 months of age and older). In addition, the treatment methods described herein exclude cats less than 9 months of age.
As mentioned herein, for treating or preventing hypertension in cats by administering salbutan to the cat, SBP of the cat can be used as a criterion to decide whether to adjust the daily dosage of cats that can be administered. In example embodiments, it may be desirable to adjust the daily dose of sartan administered to a cat when the cat's SBP falls below (for downward titration or dose reduction) a first threshold or rises above (for upward titration or dose increase) a second threshold. For example, in the event that the SBP of the cat falls below or does not exceed the first threshold after the initial treatment period, the daily dose administered to the cat may be reduced by any amount (e.g., any of the dose increments as mentioned herein). The implementation threshold SBP value may be set, for example, within a range of about 120mmHg to about 170 mmHg. For example, the threshold SBP value may be set to not greater than about 170mmHg, not greater than about 165mmHg, not greater than about 160mmHg, not greater than about 155mmHg, not greater than about 150mmHg, not greater than about 145mmHg, not greater than about 140mmHg, not greater than about 135mmHg, not greater than about 130mmHg, not greater than about 125mmHg, not greater than about 120mmHg, or any value therebetween.
Alternatively, or in combination with establishing a threshold SBP value, a change in the SBP value or delta SBP value of the cat (where the change or delta is the difference between the two SBP values) may also trigger a change in the daily dose administered to the cat. For example, the change in SBP value that triggers a dose change to a cat can vary from about 10mmHg to about 150mmHg, from about 10mmHg to about 100mmHg, from about 10mmHg to about 80mmHg, from about 10mmHg to about 50mmHg, from about 10mmHg to about 30mmHg, from about 10mmHg to about 20mmHg, from about 20mmHg to about 150mmHg, from about 20mmHg to about 100mmHg, from about 20mmHg to about 80mmHg, from about 20mmHg to about 50mmHg, from about 20mmHg to about 30mmHg, or from about 5mmHg to about 30mmHg, such as from about 10mmHg to about 25mmHg, other embodiments are a change in value of at least about 5mmHg, at least about 10mmHg, at least about 15mmHg, at least about 20mmHg, at least about 25mmHg, or at.
In a preferred embodiment, the method of adjusting (varying the dosage) is carried out by administering salbutan to the cat in the form of a liquid formulation (e.g. any suitable liquid formulation of the type previously described herein). In such embodiments, a suitable dispenser may be provided to facilitate administration of different doses. However, the method of modulation can also be carried out by administering the sartan in the form of a solid formulation, for example in the form of a lozenge.
For liquid formulations, a kit of parts may be provided comprising: a container containing a liquid formulation of a pharmaceutical composition comprising a therapeutically effective amount of telmisartan or a physiologically acceptable salt thereof and one or more pharmaceutically acceptable diluents and/or carriers; and a suitable dispenser for dispensing doses to cats in different amounts according to the dosing regimen as described herein. In other words, a suitable dispenser is provided to facilitate dose changes (e.g., dose reduction/titration down or titration up/titration up) based on changes in the condition of the cat during the course of treatment (e.g., SBP changes).
Suitable dispensers for liquid formulations comprise: a syringe comprising printed indicia or graduated markings on the syringe barrel defining any suitable number of volume increments of liquid formulation for withdrawal within the syringe barrel for administration to a cat. In an example embodiment, the syringe has a size within the range of 1.0mL to 6.0mL or greater than 6.0mL (e.g., 2.0mL to 5.0mL) and further includes 0.05mL increments, 0.1mL increments, 0.25mL increments, 0.50mL increments, and/or any other suitable scale or incremental scale markings. Such volume increments of the syringe are suitable for enabling administration of the sartan to a cat at different doses (e.g., 0.1 to 8.0mg/kg) based on the weight of the cat by providing a liquid formulation having a suitable concentration of the sartan within the solution.
Some non-limiting embodiments of the titration down dose protocol (which are also described in more detail in examples 4-6) are as follows.
A. Salbutan (e.g., telmisartan) is administered to cats for the treatment or prevention of hypertension at a daily dose of 3.0mg/kg (e.g., twice daily dose of 1.5mg/kg at each dose), in liquid form (e.g., using 10mg/mL telmisartan solution, and 2mL dosing syringes demarcated in 0.10mL or less increments) for an initial period of 14 days. For example, at periodic veterinary visits (e.g., every 2 to 4 weeks), the daily dose is modified based on SBP measurements for the cats. The cat may have hypertension associated with Chronic Kidney Disease (CKD), hypertension associated with hyperthyroidism, controlled hypertension, and/or idiopathic hypertension. Initially (e.g., at or before the first veterinary interrogation on day 0), baseline SBP was measured for cats. After the initial 14 day treatment period (e.g., at the time of the second veterinary interrogation, such as at day 14 of the treatment period), the daily dose is reduced or titrated down to 2.0mg/kg (e.g., once daily dose). The daily dose may be further reduced depending on the SBP measurement of the cat (e.g., at the time of the third visit, such as at day 28 of the treatment period). For example, a reduction in SBP of at least 20mmHg relative to the baseline SBP value (obtained for cats prior to the initial period of administration of sartan) may result in a reduction in daily dose. Alternatively (or in combination with a measured reduction in SBP relative to baseline SBP), a reduction in SBP to a value that does not exceed a threshold (where the threshold is, for example, 120mmHg) may result in a reduction in daily dose. The daily dose may be reduced by about 1.0mg/kg or less than 1.0mg/kg (e.g., about 0.5mg/kg, about 0.4mg/kg, about 0.3mg/kg, about 0.25mg/kg, about 0.2mg/kg, about 0.15mg/kg, about 0.125mg/kg, about 0.1mg/kg, or about 0.05 mg/kg). Periodically, the dose may be further reduced by the same or different increments (e.g., at a second interrogation, a third interrogation, etc. of the treatment period) based on maintaining the SBP value at no more than the threshold and/or maintaining a cat with a reduction in SBP of at least about 20mmHg for a sufficient period of time (e.g., 14 days or less than 14 days). In this embodiment, the initial daily dose is 3.0mg/kg, and such daily dose can be reduced or titrated downward (based on a sufficient reduction in SBP) to a daily dose value in the range of 0.125mg/kg to 2.0 mg/kg. For example, the daily dose may be titrated downward from 3.0mg/kg → 2.0mg/kg → 1.0mg/kg → 0.5mg/kg, etc., wherein such downward titration is effected when the SBP value of the cat remains at no more than a threshold value (e.g., no more than 120mmHg) and/or at a value below at least about 20mmHg relative to the baseline SBP value for the cat after a certain period of time (e.g., 14 days or less than 14 days). In certain example embodiments, the daily dose for the cat may be set at 2.0mg/kg (e.g., a single daily dose) when the cat's SBP is maintained within 120-. The treatment period for the cat may be, for example, 26 weeks (i.e., 6 months), with an interrogation being made every 2 to 4 weeks to determine whether to adjust the daily dose of sartan based on the cat's SBP measurement (e.g., where the daily dose may be titrated down based on the cat's SBP value maintained at no more than 120 mmHg).
B. Sartan, such as telmisartan, is administered to cats at a daily dose of 2.0mg/kg, such as a once-two-daily dose, in liquid form (e.g., using a 4mg/mL telmisartan solution, and 5mL dosing syringes demarcated in 0.25mL or less increments) for the treatment or prevention of hypertension for an initial period of 28 days. For example, at periodic veterinary visits (e.g., every 2 to 4 weeks), the daily dose is modified based on SBP measurements for the cats. The cat may have hypertension associated with Chronic Kidney Disease (CKD), hypertension associated with hyperthyroidism, controlled hypertension, and/or idiopathic hypertension. After the initial period, if the cat has SBP not exceeding 160mmHg, the daily dose is reduced or titrated downward. The titration-down increment for a daily dose may be 1.0mg/kg or less than 1.0mg/kg (e.g., about 0.5mg/kg, about 0.4mg/kg, about 0.3mg/kg, about 0.25mg/kg, about 0.2mg/kg, about 0.15mg/kg, about 0.125mg/kg, about 0.1mg/kg, or about 0.05 mg/kg). For example, if the SBP of the cat does not exceed 160mmHg, the initial daily dose of 2.0mg/kg may be reduced or titrated down to 1.5 mg/kg. Further subsequent reductions or titrations down of the daily dose (e.g., 1.5mg/kg → 1.0mg/kg → 0.5mg/kg) may also be implemented in the treatment regimen when the SBP of the cat is maintained at no more than 160mmHg between the interrogations (e.g., between the current and previous interrogations) and at the current daily dose for a sufficient period of time (e.g., 2 to 4 weeks). In this embodiment, when the SBP value for the cat does not exceed the threshold (e.g., SBP does not exceed 160mmHg), the initial daily dose is 2.0mg/kg, and such daily dose can be reduced or titrated downward (based on SBP sufficiently reduced) to a daily dose value in the range of 0.125mg/kg to 2.0mg/kg (e.g., 0.5mg/kg to 2.0 mg/kg).
In some cases, if the cat's SBP has increased to or by an undesirable amount, the dose may be increased or titrated upward after the previous portion of the treatment period has been reduced or titrated downward. For example, consider a scenario where the daily dose of sartan for a cat is reduced from 3.0mg/kg daily to 1mg/kg daily (due to a reduction in SBP to no more than 120mmHg and/or at least 20mmHg relative to baseline SBP). In a subsequent time period (e.g., within 14 days of dose down titration), if the SBP of the cat is significantly increased (e.g., the current SBP is 120mmHg or greater than 120mmHg or the current SBP is no longer at least 20mmHg less than the baseline SBP), the daily dose of sartan for the cat may be increased or titrated up to a greater value (e.g., the initial amount, or to 3.0mg/kg or to 2.0 mg/kg). During the next time period when the SBP is measured in the cat, optional further adjustments (reductions or increases) of the daily dose may be made depending on the cat's response to dose changes (based on the currently measured SBP and previously measured SBP and/or baseline SBP).
As previously indicated, a kit of parts may be provided comprising: a container system for a liquid formulation of a pharmaceutical composition comprising a therapeutically effective amount of sartan (e.g. telmisartan or physiologically acceptable salts thereof) and one or more pharmaceutically acceptable diluents and/or carriers; and a suitable dispenser for dispensing doses to cats in different amounts according to a dosing regimen as described in embodiments herein (e.g., titration down, titration up, etc.). One example embodiment of a kit of parts is depicted in fig. 6A and 6B. Referring to fig. 6A, a kit of parts comprises: an injector comprising a
The syringe and container assembly may further have any dimensions (length, width, inside diameter, outside diameter, etc.) suitable for its intended purpose. By way of example, the
The
The corresponding geometry and dimensions of syringe
Drawings
FIG. 1 is a graph of the inhibition of blood pressure elevation by angiotensin II
Figure 2 is a graph of the change in systolic blood pressure for baseline values for the telmisartan (telmisartan) group and the placebo group of the study of examples 4 and 5.
Figure 3 depicts an overview of the study design of example 6.
Figure 4 is a box plot of the change in systolic blood pressure relative to baseline values for the telmisartan and placebo groups studied in example 6.
Figure 5 is a graph of systolic blood pressure change relative to baseline values for the telmisartan and placebo groups on days 14 and 28 of the study of example 6.
Fig. 6A and 6B depict one embodiment of a drug containing and administration system of a kit of parts for use with the methods described herein, wherein the system includes a piston and a container to store the drug.
Examples
The following examples are provided to further illustrate the invention; but should not be taken as limiting the scope of the invention disclosed herein.
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