Telmisartan for treatment of hypertension in dogs

Abstract

To provide a new therapeutic approach for the treatment of dogs against systemic hypertension.SOLUTION: The present invention relates to telmisartan or a pharmaceutically acceptable salt thereof as a medicament for the treatment of hypertension in dogs, wherein the therapeutically effective amount of telmisartan is administered in a daily dosage amount that is varied over a treatment period.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to telmisartan or a pharmaceutically acceptable salt thereof for use in a method for the treatment of hypertension in a dog in need of such treatment, the method comprising administering a therapeutically effective amount of telmisartan to the dog, said therapeutically effective amount of telmisartan being administered in various daily doses throughout the treatment period. [Background technology]

[0002] Although differences in blood pressure between dog breeds have been described, systemic hypertension (SHT) is described as a sustained systolic arterial blood pressure (SBP) above 140 mmHg [ 1 – 4 ]. Recognition of SHT is increasing in later life due to improved management of different diseases. SHT damages tissues, causing kidney damage and leading to proteinuria, retinopathy, and hypertensive encephalopathy, which are called target organ damage (TOD). The prevalence of hypertension is not fully established and varies from 1 to 10% in dogs [3]. Primary or idiopathic SHT is considered a rare condition in dogs due to the fact that only a few cases are diagnosed without any identified cause [4], whereas secondary SHT is relatively common and is associated with different disorders such as primary aldosteronism, hyperadrenocorticism, pheochromocytoma, chronic kidney disease (CKD), hyperthyroidism, as well as several medications such as glucocorticoids, mineralocorticoids, erythropoietin, nonsteroidal anti-inflammatory drugs, and tyrosine kinase inhibitors [3, 5–9]. Idiopathic SHT is considered a health risk factor in itself. Severe consequences of SHT have been described when SBP exceeds 180 mmHg, including retinopathy, intraocular hemorrhage, and hypertensive encephalopathy, with the threshold for tissue injury estimated to be 160 mmHg in most breeds of cats and dogs [4, 10]. Other conditions, including left ventricular hypertrophy

[11] , proteinuria, and further loss of functional renal tissue

[12] , can also be causes or consequences of SHT. Additionally, secondary SHT is thought to be an additional factor in the progression of the underlying disease. The ACVIM consensus statement guidelines for the management of hypertension in dogs and cats suggest different strategies, including ACEIs, calcium channel blockers (CCBs), β-blockers, diuretics, etc. Monotherapy and daily dose administration are the first-line treatments for controlling SHT, but some patients are resistant to treatment and require the combination of different drugs to achieve good control of SBP [3].

[0003] Because the renin-angiotensin-aldosterone system (RAAS) is involved in the development of SHT in dogs, ACEIs are widely used as first-line treatment for SHT. However, ACEIs can only incompletely block the production of angiotensin II, which may lead to inadequate control of SHT. This phenomenon, called "aldosterone breakthrough," occurs when angiotensin II is released from a site other than that regulated by ACEI, independent of the ACEI dose

[14] . Amlodipine, a CCB, is an alternative treatment when dogs become resistant to ACEIs, either by switching or as add-on therapy [6, 15], although aldosterone breakthrough can also occur with the combination of amlodipine and ACEIs

[16] . Although diuretics are frequently administered to humans with hypertension, these agents are not the drugs of first choice for veterinary patients, and although dehydration and volume loss may prove to be primarily problematic in CKD, they can be useful in hypertensive animals with demonstrable volume overload (e.g., animals with edema) [3].

[0004] If the selected antihypertensive agent is not completely effective, the usual approach is to increase the dosage or add additional drugs [ 13 , 17 ]. However, certain combinations, such as the combination of an ACEI with an angiotensin II receptor blocker (ARB), should be used with caution or avoided, as recent publications in humans have shown a higher risk of renal failure in these cases [ 13 , 18 , 19 ]. Telmisartan, a type of ARB, is a novel drug used in veterinary medicine to reduce proteinuria associated with CKD in cats

[20] .

[0005] In dogs, oral administration of telmisartan once daily has been shown to cause vasodilation, diuresis, and natriuresis, and to dose-dependently inhibit aldosterone release and prevent potassium depletion without affecting potassium or creatinine excretion [21, 22]. The standard recommended dose for the management of proteinuria in dogs is 1 mg / kg

[13] . A daily dose of 1 mg / kg has also been reported to have an effect on blood pressure in dogs

[23] . Additionally, a daily dose of 1.0 mg / kg body weight of telmisartan has been used in combination with amlodipine in dogs to control systemic hypertension that is refractory to standard hypertensive therapy

[24] . Another case study described successful management of treatment-resistant proteinuria and systemic hypertension with telmisartan at 0.43 mg / kg and amlodipine at 0.3 mg / kg in an 11-year-old Yorkshire terrier undergoing surgery for renal cell carcinoma

[25] . International patent application WO2019 / 008077 teaches a dosing scheme for sartans for the prevention or treatment of hypertension in cats, with an initial dose of 1.0-5.0 mg / kg body weight, which is subsequently reduced over time. Therefore, additional antihypertensive and sustainable options are urgently needed for canines suffering from systemic hypertension. Summary of the Invention [Problem to be solved by the invention]

[0006] It has now been found that hypertension, particularly systemic hypertension (SHT), can be treated in dogs by administering a therapeutically effective amount of telmisartan, wherein the therapeutically effective amount of telmisartan is administered at various daily dosages throughout a treatment period, wherein the daily dosage of telmisartan is at least 1.0 mg / kg body weight during a first period during the treatment period, and the daily dosage of telmisartan is increased during a second period following the first period during the treatment period. It is therefore an object of the present invention to provide a new therapeutic approach for the treatment of systemic hypertension in dogs. [Means for solving the problem]

[0007] Accordingly, the present invention relates to telmisartan or a pharmaceutically acceptable salt thereof for use in a method for treating hypertension in a dog in need of such treatment, the method comprising administering a therapeutically effective amount of telmisartan to the dog, wherein the therapeutically effective amount of telmisartan is administered at various daily dosages throughout a treatment period, wherein the daily dosage of telmisartan is at least 1.0 mg / kg body weight during a first period during the treatment period and the daily dosage of telmisartan is increased during a second period following the first period during the treatment period. Furthermore, the present invention relates to telmisartan or a pharmaceutically acceptable salt thereof as a pharmaceutical agent for the treatment of hypertension in dogs that is non-refractory to treatment with ACE inhibitors.

[0008] In a further embodiment of the present invention, there is provided a method for treating hypertension in a dog in need of such treatment, comprising administering to the dog a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of telmisartan is administered at various daily dosages throughout a treatment period, wherein the daily dosage of telmisartan is at least 1.0 mg / kg body weight during a first period during the treatment period, and wherein the daily dosage of telmisartan is increased during a second period following the first period during the treatment period. In a further embodiment, the present invention provides a method for the treatment of hypertension in a dog that is non-refractory to treatment with an ACE inhibitor, the method comprising administering a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof to a dog in need of such treatment. Furthermore, the present invention relates to a pharmaceutical composition for use in a method for treating hypertension in a dog in need of such treatment, said pharmaceutical composition comprising telmisartan according to the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. [Brief explanation of the drawings]

[0009] [Figure 1] Figure 1 shows the change in mean SBP from baseline from days 30 to 120 in dogs that had hypertension on day 0 and were not receiving amlodipine. Dogs received one dose of either enalapril or telmisartan on day 90 in addition to their first dose of drug. [Figure 2] Figure 2 shows the percentage change in mean SBP from baseline from days 30 to 120 in dogs with hypertension on day 0 and not receiving amlodipine. Dogs received one dose of either enalapril (····E) or telmisartan (−··-T) on day 90 in addition to their initial drug administration. [Figure 3] Figure 3 shows the change in mean SBP from baseline from days 30 to 90 in dogs that were hypertensive on day 0 and were receiving amlodipine. [Figure 4] Figure 4 shows the mean SBP in mmHg from day 0 to day 90 in dogs that had hypertension on day 0 and were not receiving amlodipine. DETAILED DESCRIPTION OF THE INVENTION

[0010] Before describing the embodiments of the present invention, it should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to a "preparation" includes a plurality of such preparations, and a reference to a "carrier" is a reference to one or more carriers and equivalents thereof known to those skilled in the art. Unless otherwise defined, 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 given ranges and values may vary by 1-5% unless otherwise indicated or known to those skilled in the art; therefore, the term "about" has been omitted from the description. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated by reference for the purpose of describing and disclosing the substances, excipients, carriers, and methodologies reported in the publications as being capable of being used in connection with the present invention. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention. The solution to the above technical problem is achieved by the description and embodiments characterized in the claims.

[0011] In accordance with the present invention, a method for treating hypertension in a dog in need of such treatment is described herein, the method comprising administering to the dog a therapeutically effective amount of telmisartan, wherein the therapeutically effective amount of telmisartan is administered at various daily dosages throughout a treatment period, starting with an initial dose of at least 1.0 mg / kg body weight. For example, during a first period during the treatment period, the daily dosage of telmisartan may be 1.0-1.5 mg / kg body weight, and the daily dosage of telmisartan is increased during a second period following the first period during the treatment period.

[0012] As used herein, the term "pharmaceutically acceptable salt" includes metal salts or addition salts that can be used in dosage forms.For example, the pharmaceutically acceptable salts of the compounds provided herein may be acid addition salts, base addition salts, or metal salts, and can be synthesized from parent compounds containing basic or acidic residues by conventional chemical methods.Such salts are generally prepared by reacting the non-acid or non-basic form of these compounds with an equivalent amount of an appropriate base or acid in water or an organic solvent or a mixture of both.Non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred.Examples of acid addition salts include mineral acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.; and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate. Examples of alkali addition salts include inorganic salts such as ammonium salts, and organic alkali salts such as diethylamine, ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine, glutamine, and basic amino acid salts. Examples of metal salts include sodium, potassium, calcium, magnesium, aluminum, and lithium salts.

[0013] As used herein, the term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically acceptable and do not typically cause allergic reactions or similar side effects such as stomach discomfort, dizziness, etc. when administered to humans. As used herein, the term "pharmaceutically acceptable" preferably means approved by a federal or state regulatory agency, listed in the United States Pharmacopoeia or another pharmacopoeia, or generally recognized for its use in animals, preferably mammals, more specifically dogs. As used herein, the term "high blood pressure" refers to high blood pressure against the arterial walls when the heart contracts and empties, and when it relaxes and fills with blood. The term includes systemic and idiopathic hypertension.

[0014] The term "systemic hypertension" applies to a sustained increase in systolic blood pressure (SBP greater than 140 mmHg), which can generally be categorized into one of three types: (i) it can be caused by environmental or situational stressors, (ii) it can occur in association with other disease processes that increase blood pressure (i.e., secondary hypertension), or (iii) it can occur in the absence of other underlying causative disease processes (i.e., idiopathic hypertension). According to the ACVIM consensus statement

[26] , canine "systemic hypertension" can be classified based on the risk of target organ damage (TOD) as follows:

[0015] As used herein, the term "non-resistant to ACE inhibitor treatment" refers to dogs suffering from hypertension that can be treated with an ACE inhibitor, but less effectively than telmisartan. Conversely, the persistently high systolic arterial blood pressure (SBP) of ACE inhibitor-resistant dogs cannot be reduced with the help of an ACE inhibitor. In non-treatment-resistant subpopulations of dogs, treatment with ACE inhibitors was 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, more than 50%, more than 60%, or more than 70% less effective than telmisartan for reducing SBP levels. In a preferred embodiment, telmisartan and / or methods according to the invention relate to the treatment of non-treatment-resistant subpopulations of dogs, although the administration scheme according to the invention can advantageously be administered to both non-treatment-resistant and treatment-resistant subpopulations of dogs. Dogs treated with telmisartan according to the present invention are preferably pet dogs of any breed, including any type of mixed breed. Depending on the breed and size of the mixed breed, hypertension can occur at any age, more often from 5 years of age onwards, preferably between 7 and 18 years of age, and especially between 10 and 16 years of age. Small breeds generally develop the disease at a later age than large breeds, preferably between 12 and 18 years of age, which may be affected between 10 and 16 years of age.

[0016] As used herein, the term "together with" or "in combination with" covers both separate and sequential administration of telmisartan and another drug. For example, when drugs are administered sequentially, either telmisartan or the other drug may be administered first. When drugs are administered simultaneously, the drugs may be administered in the same or different pharmaceutical compositions. Adjunctive therapy, i.e., when one drug is used as a primary treatment and the other drug is used to support the primary treatment, is also an embodiment of the present invention. The active ingredient(s) may be used as separate formulations or as a single combined formulation. If combined in the same formulation, it will be understood that the two compounds must be stable and compatible with each other and the other ingredients of the formulation.

[0017] Formulations of the present invention include those suitable for oral, parenteral (e.g., subcutaneous, intradermal, intrathecal, e.g., by injection or depot, including intramuscular and intravenous, e.g., by depot), rectal, topical (including cutaneous, buccal, and sublingual), or inhalation or insufflation administration. The optimal route of administration may depend on the patient's condition and disorder. Preferably, the compositions of the present invention are formulated for oral administration.

[0018] The formulations may be conveniently presented in unit dosage form, e.g., as described in "Remington: The Science and Practice of Pharmacy," Lippincott Williams and Wilkins, 21 stIt may be prepared by any method well known in the field of pharmacy, such as described in "The Journal of Pharmaceutical Sciences, Vol. 1, No. 1, pp. 2005-2009." Suitable methods include the step of bringing into association the active ingredient with a carrier that constitutes one or more excipients. Generally, the formulation is prepared by uniformly and intimately bringing into association the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. It will be understood that when two active ingredients are administered independently, each active ingredient may be administered by a different means. Formulations suitable for oral administration may be presented as discrete units such as capsules, wafers, tablets, etc., each containing a predetermined amount of the active ingredient, particularly as chewable tablets; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0019] Alternatively, the active ingredient may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs. Formulations containing the active ingredient may be presented as a dry product for constitution with water or another suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxymethylcellulose, carboxymethylcellulose, aluminum stearate gel, and / or hydrogenated edible fats and oils), emulsifiers (e.g., lecithin, sorbitan monooleate, and / or acacia gum), non-aqueous vehicles (e.g., edible oils such as almond oil, fractionated coconut oil, oily esters, propylene glycol, and / or ethyl alcohol), preservatives (e.g., methyl or propyl p-hydroxybenzoates and / or sorbic acid). Additionally, the oral dosage form may contain one or more flavoring agents, which may increase compliance in dogs treated by chewing and swallowing the medication. Most preferably, telmisartan is administered orally in the form of a chewable tablet or in the form of an aqueous solution containing benzalkonium chloride, such as the product Semintra® available from Boehringer Ingelheim Vetmedica GmbH, Ingelheim, Germany.

[0020] In particular, the following items are disclosed herein: a) Telmisartan or a pharmaceutically acceptable salt thereof for use in a method for treating hypertension in a dog in need of such treatment, said method comprising administering a therapeutically effective amount of telmisartan to the dog, said therapeutically effective amount of telmisartan being administered at various daily dosages throughout a treatment period, wherein during a first period during the treatment period the daily dosage of telmisartan is at least 1.0 mg / kg body weight, and during a second period during the treatment period following the first period the daily dosage of telmisartan is increased. b) Telmisartan according to item a), wherein the hypertension is associated with an elevated urinary protein creatinine concentration (UPC) level. c) Telmisartan according to item a) or b), which is a sodium salt or a potassium salt. d) Telmisartan according to any of items a) to c) for the treatment of dogs that are non-refractory to treatment with ACE inhibitors. e) Telmisartan according to any of items a) to c) for the treatment of dogs that are resistant to treatment with ACE inhibitors. f) Telmisartan according to any one of items a) to e), wherein the daily therapeutically effective amount is in the range of 1.0 to 10.0 mg / kg body weight, preferably 1.0 to 4.0 mg / kg body weight, particularly 1.0 to 3.5 mg / kg body weight, and most preferably 1.0 to 3.0 mg / kg body weight. g) Telmisartan according to any of items a) to f), wherein the daily dose of telmisartan is increased in the second period by an increment in the range of 0.25 to 2.50 mg / kg body weight.

[0021] h) Telmisartan according to any one of items a) to g), wherein the daily dose of telmisartan is 1.0 to 1.5 mg / kg of body weight during a first period of the treatment period and 1.75 to 3.50 mg / kg of body weight during a second period. i) Telmisartan according to any of items a) to h), wherein the daily dose of telmisartan is reduced after the second period by an increment in the range of 0.25 to 2.50 mg / kg body weight. j) Telmisartan according to any one of items a) to i), wherein the daily dose of telmisartan is reduced when systolic blood pressure (SBP) values are measured in the dog after the second period.

[0022] k) The telmisartan according to any of items a) to j), wherein the daily dose of telmisartan is reduced if the systolic blood pressure (SBP) value measured in the dog after the second time period has decreased by at least 10 mmHg or at least 20 mmHg, or by 10 to 150 mmHg, 10 to 100 mmHg, 10 to 80 mmHg, 10 to 50 mmHg, 10 to 30 mmHg, 10 to 20 mmHg, 20 to 150 mmHg, 20 to 100 mmHg, 20 to 80 mmHg, 20 to 50 mmHg, or 20 to 30 mmHg, compared to the baseline SBP value measured in the dog before the first time period. l) Telmisartan according to any of items a) to k), administered together with at least one other drug to a dog in need of such treatment.

[0023] m) Telmisartan according to item l), wherein the other drug is selected from the group consisting of calcium channel blockers, preferably amlodipine, cardiac calcium sensitizers, preferably pimobendan or levosimendan, ACE inhibitors, preferably ramipril, benazepril or enalapril, in particular enalapril.

[0024] n) Telmisartan according to any of items a) to m), wherein the SBP of treated dogs is reduced by at least 50%, or at least 40%, 30%, or 20% over a period of time, preferably measured in days, such as 10 days, 20 days, 30 days, 60 days, 90 days, 120 days, or more than 120 days until SBP values are consistently well below the hypertensive threshold. As shown in Figure 2, the majority of dogs treated with telmisartan showed a decrease in SBP of approximately 20% at 30 days, whereas SBP in dogs treated with enalapril increased by more than 10%.

[0025] As shown in Figure 1, the mean reduction in SBP in telmisartan-treated dogs was greater than that in enalapril-treated dogs from days 30 to 90. In addition, the combination of telmisartan and enalapril from days 90 to 120 reduced the mean SBP in telmisartan-treated dogs from days 0 to 90 by more than 40 mmHg.

[0026] o) A method for treating hypertension in a dog in need of such treatment, comprising administering to the dog a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of telmisartan is administered at various daily dosages throughout a treatment period, wherein the daily dosage of telmisartan is at least 1.0 mg / kg body weight during a first period during the treatment period, and wherein the daily dosage of telmisartan is increased during a second period following the first period during the treatment period. p) The method according to item n), wherein the hypertension is accompanied by an elevated urinary protein-to-creatinine concentration (UPC) level. q) The method according to item o) or p), which comprises administering an effective amount of the sodium or potassium salt of telmisartan. r) The method according to any of items o) to q) for the treatment of dogs that are non-resistant or resistant to treatment with an ACE inhibitor. s) The method according to one of items o) to r), wherein the daily therapeutically effective amount of telmisartan is in the range of 1.0 to 10.0 mg / kg body weight, preferably 1.0 to 4.0 mg / kg body weight, particularly 1.0 to 3.5 mg / kg body weight, most preferably 1.0 to 3.0 mg / kg body weight. t) The method according to one of items o) to s), wherein the daily dose of telmisartan is increased in a second period by an increment in the range of 0.25 to 2.50 mg / kg body weight. u) The method according to one of items o) to t), wherein the daily dose of telmisartan is reduced after the second period by an increment in the range of 0.25 to 2.50 mg / kg body weight. v) The method according to one of items o) to u), wherein the daily dose of telmisartan is reduced if the SBP value measured in the dog after the second time period has decreased by at least 20% compared to the baseline SBP value measured in the dog before the first time period. w) The method according to one of items o) to v), further comprising administering at least one other drug to a dog in need of such treatment. x) The method according to one of items o) to w), wherein the other drug is selected from the group consisting of calcium channel blockers, cardiac calcium sensitizers, and ACE inhibitors. y) The method according to one of items o) to x), wherein the other drug is selected from the group consisting of amlodipine, pimobendan, levosimendan, ramipril, benazepril and enalapril, in particular enalapril.

[0027] z) The method of any one of items o) to y), wherein the SBP of the treated dog is reduced by at least 50%, or at least 40%, 30%, or 20% over a period of time, preferably measured in days, of 10, 20, 30, 60, 90, 120 days, or a period of more than 120 days until the SBP values are consistently well below the hypertensive threshold. Having generally described the invention, it will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0028] Example Experimental methods and design A prospective, block-randomized, double-blind clinical trial was conducted. Fifty-four client-owned dogs with persistent pathological renal proteinuria were recruited over a 2-year period. [Example]

[0029] animal Asphyxiated and non-asphyxiated dogs with hypertensive and non-hypertensive CKD (N = 54) were prospectively recruited from patients presenting to the hospital. Dogs included as cases had confirmed persistent pathological renal proteinuria due to CKD and met the following criteria to be classified as such: Inclusion criteria: Eligible animals had UPC levels of approximately 2.0 (non-asphyxiated patients; IRIS stage 1) or approximately 0.5 (asphyxiated patients; IRIS stages 2-4) documented in two urine samples collected two weeks apart. Abdominal ultrasound also demonstrated findings consistent with CKD (both small, irregular kidneys) and the absence of renal tumors.

[0030] Exclusion criteria Animals will be excluded if one or more of the following are identified: evidence of hemorrhage, inflammation, or bacteria on urine sediment analysis; a positive urine culture at the time of proteinuria identification; a positive heartworm antigen test within 3 months of proteinuria identification and / or not currently receiving regular monthly heartworm prophylaxis; historical, physical examination, or clinical pathology findings suggestive of acute kidney injury, infectious nephropathy, or lower urinary tract infection; systolic hypotension (SBP <120 mmHg); moderate to severe hyperkalemia (serum potassium >6.5 mmol / L); history of oral ACEi and / or corticosteroids within 1 month (ACEi) or 2 weeks (corticosteroids) prior to the study; or an intercurrent illness associated with proteinuria, the treatment of which may alleviate proteinuria (e.g., systemic lupus erythematosus, ehrlichiosis, neoplasia). Dogs with suspected or confirmed hyperadrenocorticism and diabetes mellitus were included if the disease was considered adequately controlled by medical therapy.

[0031] Grouping of patients for block randomization Once enrolled, dogs were grouped according to the International Renal Institutions Research Association (IRIS) classification scheme for CKD based on the presence / severity of azotemia. Those classified as IRIS stages 2–4 (serum creatinine ≥ 1.4 mg / dL with inadequately diluted urine [USG < 1.030]) were considered azotemic (AZ), whereas those classified as IRIS stage 1 (creatinine < 1.4 mg / dL) were considered non-azotemic (non-AZ). Within each of these two groups, dogs were stratified based on the IRIS recommendations for arterial pressure (AP) substaging. According to this scheme, dogs with a sustained mean indirect arterial systolic pressure < 150 mmHg were classified as AP0 (minimal risk of target organ damage). Dogs with a sustained mean indirect arterial systolic pressure ≥ 150 mmHg were classified as AP1–3 (at risk of target organ damage). Therefore, four groups were identified: 1.AZ (IRIS stages 2-4), IRIS substages AP1-3 2.AZ (IRIS stages 2-4), IRIS substage AP0 3. Non-AZ (IRIS stage 1), IRIS substage AP1-3 4. Non-AZ (IRIS stage 1), IRIS substage AP0 After being assigned to one of these four groups, each patient was assigned based on a randomized block scheme to receive either enalapril (n=27) or telmisartan (n=27), as described below. The purpose of the grouping was to ensure that the two treatment groups contained equal numbers of patients.

[0032] Baseline At the time of enrollment (day 0), all owners were asked to read and sign a document consenting to their pet's participation in the study. The following baseline data were collected for each case: complete physical examination (performed by one of the investigators), fundus examination, blood pressure measurement, blood chemistry panel, urinalysis, abdominal ultrasound, UPC, and urine culture. Screening test results could be used as baseline information if performed within 2 weeks of study enrollment. Baseline UPC was defined as the mean of two measurements taken 2 weeks apart prior to enrollment.

[0033] ARB / ACEi therapy On day 0, dogs were randomly assigned in a double-blind manner to receive either telmisartan 1 mg / kg orally every 24 hours (group TEL, n=27) or enalapril 0.5 mg / kg orally every 12 hours (group ENAL, n=27). Randomization and distribution of telmisartan or enalapril was performed at the appropriate dose. Owners were provided with appropriate emergency contact telephone numbers. Enalapril is readily available, and telmisartan is supplied in aqueous solution by Boehringer Ingelheim Vetmedica Inc., St. Joseph, Missouri, and is marketed as Semintra®. Antihypertensives / Other Therapies Dogs classified as AP3 (SBP ≥ 180 mmHg; ≥ 200 mmHg in sight hounds) were concurrently administered a calcium channel blocker (CCB; amlodipine; 0.1 mg / kg orally every 24 hours). The combination of RAAS inhibitors with CCBs is common in human patients, recommended by a veterinary expert committee, and shown to be effective in experimental models of proteinuria. All dogs had been initiated or continued on a commercially formulated diet low in phosphorus and protein for at least 1 month prior to enrollment. Dietary composition remained stable throughout the study. Fish oil treatment was permitted, provided the dogs had been receiving this supplement for more than 1 month at the time of enrollment.

[0034] monitoring Monitoring procedures followed the recommendations of the Standard Therapy Subgroup of the IRIS Canine GN Study Group. All dogs were reexamined on day 7, during which physical examination, SBP, serum creatinine (sCr), and serum potassium (K) were assessed. A 30% increase in sCr compared to baseline or moderate / severe hyperkalemia (serum potassium >6.5 mmol / L) or systolic hypotension (SBP <120) prompted investigators to unmask the patient and remove them from the study. For dogs with a reliably identified mean SBP of approximately 180 mmHg (i.e., if the dog was classified as AP3), amlodipine was titrated to 0.1 mg / kg orally twice daily. Subsequently, dogs classified as AP3 were reexamined at 7-day intervals to ensure therapy effectiveness, with adjustments to antihypertensive therapy. At each study visit, assuming the mean SBP measurement remained approximately 180 mmHg, the dog's amlodipine dose was increased in increments of 0.05 mg / kg twice daily to a maximum dose of 0.3 mg / kg twice daily. SBP and sCr were retested 7 days after any adjustments were made.

[0035] Final Phase 1 Study Visit All dogs undergo physical examination, SBP, serum biochemistry, urinalysis, and UPC measurement on day 30. At this and subsequent time points, urine for UPC measurement consists of a pooled sample made by combining three free-collected specimens collected by the owner the previous day and stored refrigerated. Objective evaluation items The objective endpoints in phase 1 were reduction in SBP and percent change in UPC (ΔUPC). conclusion As shown in Figure 2, the mean change in SBP in dogs treated with telmisartan was reduced by at least 30 mmHg at day 30 compared with dogs treated with enalapril. [Example]

[0036] Specific Objectives No. 2 and No. 3 (Phase 2 and Phase 3, Interim Phase) Phase 2 of this study compared the efficacy of enalapril and telmisartan when used as part of a protocol that allowed for titration of both drugs. Phase 3 evaluated the combination in dogs whose proteinuria persisted at the highest dose of each drug alone. Each of the 54 dogs remained in the treatment group to which they were assigned in Phase 1. Within these groups, if proteinuria UPCs remained at approximately 0.5 on monthly retests, titration of the study drug followed by combination therapy was implemented.

[0037] ARB / ACEi therapy Phase 2 (31-90 days) For dogs identified with a UPC of less than 0.5 on day 30, treatment continued with telmisartan at a dose of 1 mg / kg orally every 24 hours or enalapril at a dose of 0.5 mg / kg orally twice daily until the end of the study (day 120). For dogs identified with a UPC of approximately 0.5 on day 30, the dose of study drug was titrated monthly in increments of 1 mg / kg orally every 24 hours (TEL group) or 0.5 mg / kg orally twice daily (ENAL group) until the target UPC of less than 0.5 was reached or until the "ceiling dose" of either drug was reached (3 mg / kg orally every 24 hours for telmisartan or 1.5 mg / kg orally twice daily for enalapril), whichever occurred first. Phase 3 (91-120 days) For dogs identified with a UPC of less than 0.5 before day 90, treatment continued with telmisartan or enalapril at a dose sufficient to cause control of proteinuria until the end of the study. For dogs identified with a UPC of approximately 0.5 on day 90, enalapril at a dose of 0.5 mg / kg twice daily or telmisartan at a dose of 1 mg / kg every 24 hours was added to dogs in the TEL and ENAL groups, respectively. Combination therapy continued for one month until the end of the study.

[0038] monitoring If an individual dog's treatment regimen was changed on day 30, he / she was reexamined 1 week later (day 37), at which time SBP, sCr, and serum potassium levels were assessed. A more than 30% increase in creatinine or moderate / severe hyperkalemia (serum potassium >6.5 mmol / L) prompted the investigator to unmask the patient and remove the patient from the study. If mild hyperkalemia (serum potassium 6.1-6.5 mmol / L) was identified, no escalation to the next dose was performed, regardless of UPC.

[0039] Thereafter, dogs with persistent proteinuria were monitored monthly (i.e., on days 60 and 90) by SBP, UPC, and urinalysis. If an active urinary sediment was identified, a urine culture was performed. For dogs with persistent proteinuria requiring drug titration, SBP, sCr, and serum potassium were retested 1 week after adjustment (days 67 and 97) and unmasked according to the criteria outlined above, followed by further dose titration. Dogs with a UPC of less than 0.5 identified at any time point had their monitoring parameters retested only at the end of the study (day 120). Final research visit On day 120, all dogs undergo a complete physical examination, measurement of SBP, serum renal biochemistry, urinalysis (cystocentesis) and UPC. Objective evaluation items Phase 2 objective endpoints included the proportion of patients achieving a 50% reduction in ΔUPC and UPC or a reduction in UPC to <0.5 from baseline, and a mean reduction in SBP of approximately 20% from baseline after a total of 3 months of treatment. Phase 3 objective endpoints included ΔUPC from baseline, ΔUPC over the treatment month (UPC at day 90 minus UPC at day 120), and a mean reduction in SBP of at least 40% from baseline. Conclusions: As shown in Figures 1 and 2, the mean change in SBP between days 30 and 90 was greater in telmisartan-treated dogs compared with enalapril-treated dogs, with the telmisartan-treated dogs achieving a greater change at day 90.

[0040] In addition, as shown in Tables I and II below, the combination of telmisartan and enalapril from Day 90 to Day 120 reduced mean SBP by more than 70 mmHg, achieving an average reduction in SBP of more than 40% in the group of telmisartan-treated dogs.

[0041] TIFF2025115405000001.tif51156

[0042] TIFF2025115405000002.tif46156

[0043] As shown in Figure 3, in dogs with hypertension, with an SBP of at least 150 mmHg on day 0, that received amlopudipine and additional medications, the mean SBP change from baseline was greater in dogs treated with telmisartan at days 30, 60, and 90 compared with dogs treated with enalapril.

[0044] Furthermore, the absolute mean SBP of dogs administered telmisartan was much lower than that of dogs treated with enalapril, as shown in Figure 4. As shown in Table III, the SBP of dogs treated with enalapril decreased from 163 mmHg to 153 mmHg on day 30 but increased again on days 60 and 90, whereas the mean SBP values of dogs treated with telmisartan steadily decreased over the course of treatment, from an initial 163 mmHg to 132 mmHg on day 90.

[0045] TIFF2025115405000003.tif34156

[0046] References The following publications are incorporated herein by reference in their entireties as if each individual publication were specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0047] TIFF2025115405000004.tif208158 TIFF2025115405000005.tif225157 TIFF2025115405000006.tif49161

Claims

1. 1. A method for treating hypertension in a dog in need of such treatment, comprising administering a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof to the dog, wherein the therapeutically effective amount of telmisartan is administered at various daily dosages throughout a treatment period, wherein the daily dosage of telmisartan is at least 1.0 mg / kg body weight during a first period during the treatment period, and wherein the daily dosage of telmisartan is increased during a second period following the first period during the treatment period.

2. 2. The telmisartan of claim 1, wherein the hypertension is accompanied by generalized chronic kidney disease (CKD), elevated urinary protein creatinine ratio (UPC) levels and / or hyperthyroidism.

3. 3. Telmisartan according to claim 1 or 2, in the form of its sodium or potassium salt.

4. The telmisartan according to any one of claims 1 to 3, wherein the hypertension is idiopathic hypertension.

5. 5. The telmisartan according to any one of claims 1 to 4, wherein the daily therapeutically effective amount is in the range of 1.0 to 10.0 mg / kg body weight.

6. The method of any one of claims 1 to 5, wherein the daily dosage of telmisartan is increased in the second period by increments ranging from 0.25 to 2.50 mg / kg body weight.

7. 7. The method of claim 1, wherein the daily dose of telmisartan is 1.0 to 1.5 mg / kg body weight during a first period of the treatment period and 1.75 to 3.50 mg / kg body weight during a second period of the treatment period.

8. Telmisartan according to any one of claims 1 to 7, wherein the daily dosage of telmisartan is reduced after the second period by increments ranging from 0.25 to 2.50 mg / kg body weight.

9. The method of any one of claims 1 to 8, wherein the daily dose of telmisartan is reduced when systolic blood pressure (SBP) values are measured for the dog after the second period of time.

10. 11. The telmisartan of any one of claims 1 to 10, wherein the daily dose of telmisartan is reduced if the systolic blood pressure (SBP) value measured in the dog after the second time period is reduced by at least 10 mmHg or at least 20 mmHg, or by 10-150 mmHg, 10-100 mmHg, 10-80 mmHg, 10-50 mmHg, 10-30 mmHg, 10-20 mmHg, 20-150 mmHg, 20-100 mmHg, 20-80 mmHg, 20-50 mmHg, or 20-30 mmHg, compared to the baseline SBP value measured in the dog before the first time period.

11. Telmisartan according to any one of claims 1 to 11, administered together with at least one other drug to a dog in need of such treatment.

12. 12. Telmisartan according to claim 11, wherein the other drug is selected from the group consisting of calcium channel blockers, preferably amlodipine, cardiac calcium sensitizers, preferably pimobendan or levosimendan, ACE inhibitors, preferably ramipril, benazepril or enalapril.

13. Telmisartan or a pharmaceutically acceptable salt thereof as a pharmaceutical agent for the treatment of hypertension in dogs that is non-refractory to treatment with ACE inhibitors.

14. A method for treating hypertension in a dog in need of such treatment, comprising administering to the dog a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of telmisartan is administered at various daily dosages throughout a treatment period, wherein the daily dosage of telmisartan is at least 1.0 mg / kg body weight during a first period during the treatment period, and wherein the daily dosage of telmisartan is increased during a second period following the first period during the treatment period.

15. 15. The method of claim 14, wherein the hypertension is associated with generalized chronic kidney disease (CKD), elevated urinary protein creatinine ratio (UPC) levels and / or hyperthyroidism.

16. 15. The method of claim 14, comprising administering an effective amount of the sodium or potassium salt of telmisartan.

17. 15. The method of claim 14, wherein the hypertension is idiopathic hypertension.

18. 15. The method of claim 14, wherein the daily therapeutically effective amount of telmisartan is in the range of 1.0 to 10.0 mg / kg body weight.

19. 15. The method of claim 14, wherein the daily dosage of telmisartan is increased in the second period by an increment ranging from 0.25 to 2.50 mg / kg body weight.

20. 20. The method of claim 19, wherein during a first period of the treatment period, the daily dosage of telmisartan is 1.0 to 1.5 mg / kg body weight, and during a second period of the treatment period, the daily dosage of telmisartan is 1.75 to 4.0 mg / kg body weight.

21. 15. The method of claim 14, wherein the daily dosage of telmisartan is reduced after the second period by an incremental amount ranging from 0.25 to 2.50 mg / kg body weight.

22. 15. The method of claim 14, wherein the daily dosage of telmisartan is reduced when systolic blood pressure (SBP) values are measured for the dog after the second period of time.

23. 23. The method of claim 22, wherein the daily dose of telmisartan is reduced if the systolic blood pressure (SBP) value measured for the dog after the second time period is reduced by at least 10 mmHg or at least 20 mmHg, or by 10-150 mmHg, 10-100 mmHg, 10-80 mmHg, 10-50 mmHg, 10-30 mmHg, 10-20 mmHg, 20-150 mmHg, 20-100 mmHg, 20-80 mmHg, 20-50 mmHg, or 20-30 mmHg, compared to the baseline SBP value measured for the dog before the first time period.

24. 15. The method of claim 14, further comprising administering at least one other drug to a dog in need of such treatment.

25. 25. The method of claim 24, wherein the other drug is selected from the group consisting of calcium channel blockers, cardiac calcium sensitizers, and ACE inhibitors.

26. 26. The method of claim 25, wherein the other drug is selected from the group consisting of amlodipine, pimobendan, levosimendan, ramipril, benazepril, and enalapril.

27. A method for the treatment of hypertension in dogs that is non-resistant to treatment with ACE inhibitors, comprising administering a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof to a dog in need of such treatment.

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