Telmisartan for the treatment of hypertension in dogs

Abstract

This invention relates to telmisartan or a pharmaceutically acceptable salt thereof as a medicament for treating hypertension in dogs, wherein the therapeutically effective dose of telmisartan is administered at a daily dose that varies during the treatment period.

Description

[Technical Field] This invention relates to a method of using telmisartan or a pharmaceutically acceptable salt thereof to treat hypertension in a dog requiring such treatment, wherein the method comprises administering a therapeutically effective amount of telmisartan to the dog, wherein the therapeutically effective amount of telmisartan is administered at a daily dose that varies during the treatment period. [Previous Technology] Systemic hypertension (SHT) is defined as sustained systolic blood pressure (SBP) exceeding 140 mmHg, although interbreed hybrid blood pressure differences in dogs have been described [1-4]. SHT identification has improved in recent years, thus improving the management of various diseases. SHT causes tissue damage, which leads to kidney damage, resulting in proteinuria, retinopathy and hypertensive encephalopathy. These are called target organ damage (TOD). The prevalence of hypertension is not fully determined and varies from 1% to 10% in dogs [3]. Primary or idiopathic SHT is considered a rare disease in dogs because only a very small number of cases are diagnosed and there is no identifiable cause[4], but secondary SHT is relatively common and is associated with various conditions (such as primary aldosteronism, hyperadrenocorticism, pheochromocytoma, chronic kidney disease (CKD) and hyperthyroidism) and some 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. When SBP exceeds 180 mmHg, the serious consequences of SHT are retinopathy, intraocular hemorrhage, and hypertensive encephalopathy, while in cats and most breeds of dogs, the threshold for tissue damage is considered to be 160 mmHg [4, 10]. Other conditions (including left ventricular hypertrophy

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

[12] ) may be the cause or consequence of SHT. In addition, secondary SHT is considered another progression factor of underlying disease. The ACVIM Consensus Statement guidelines propose different strategies for managing hypertension in dogs and cats, including ACEIs, calcium channel blockers (CCBs), beta blockers, and diuretics. Monotherapy and daily dose administration are the first-line treatments for controlling SHT, but some patients are refractory and require a combination of different drugs to achieve good control of SBP[3]. Due to the role of the renin-angiotensin-aldosterone system (RAAS) in its development, ACEIs are widely used as first-line treatment for SHT in dogs, but they provide incomplete blockade of angiotensin II production, which can lead to poor control of SHT. This phenomenon (called "aldosterone breakthrough") is due to the release of angiotensin II at sites other than those controlled by ACE, and is independent of the dose of ACEI administered.

[14] When dogs are refractory to ACEIs, switching or using amlodipine (a CCB) as an adjunct therapy is an alternative treatment [6, 15]; however, aldosterone breakthrough can also occur with combination therapy of amlodipine and ACEIs

[16] . Although diuretics are often given to hypertensive individuals, they are not the first-line drugs for livestock patients, mainly because dehydration and volume loss can prove problematic in CKD, but they can be used in hypertensive animals with significant volume overload (e.g., those with edema)[3]. If the chosen antihypertensive agent is not completely effective, the usual approach is to increase the dose or add another medication [13,17]. However, certain combinations such as ACEIs and angiotensin II receptor blockers (ARBs) must be used with caution or avoided, as recent publications on humans indicate a higher risk of kidney failure in these cases [13, 18, 19]. Telmisartan (an ARB) is a new drug for veterinary use to reduce proteinuria associated with CKD in cats

[20] . In dogs, daily oral doses of telmisartan have been shown to produce vasodilation, diuresis, and sodium excretion without affecting potassium or creatinine excretion, and to prevent potassium deficiency by inhibiting aldosterone release in a dose-dependent manner [21, 22]. The standard recommended dose for controlling proteinuria in dogs is 1 mg / kg

[13] . Effects of a daily dose of 1 mg / kg on blood pressure in dogs have also been reported

[23] . In addition, a combination of telmisartan and amlodipine at a daily dose of 1.0 mg / kg body weight has been used in dogs to control systemic hypertension refractory to standard hypertension therapy

[24] . In another case study, it was demonstrated that surgery, 0.43 mg / kg telmisartan and 0.3 mg / kg amlodipine were used to successfully manage refractory proteinuria and systemic hypertension in an 11-year-old Yorkshire terrier with renal cell carcinoma

[25] . International patent application WO 2019 / 008077 teaches a dosing regimen for sartans used to prevent or treat hypertension in cats, wherein the initial dose is 1.0 to 5.0 mg / kg body weight and is reduced in subsequent periods. Therefore, there is an urgent need for alternative and sustainable antihypertensive options for canine patients with systemic hypertension. [Summary of the Invention] It has been found that hypertension, especially systemic hypertension (SHT), in dogs can be treated by administering a therapeutically effective dose of telmisartan. The therapeutically effective dose of telmisartan is administered at a daily dose that varies during the treatment period. The daily dose of telmisartan during the first time period of the treatment period is at least 1.0 mg / kg body weight, and the daily dose of telmisartan increases during the second time period after the first time period of the treatment period. Therefore, one objective of this invention is to provide a new treatment approach for treating systemic hypertension in dogs. Therefore, the present invention relates to a method of using telmisartan or a pharmaceutically acceptable salt thereof for treating hypertension in dogs requiring such treatment, wherein the method comprises administering a therapeutically effective amount of telmisartan to the dog, wherein the therapeutically effective amount of telmisartan is administered at a daily dose that varies during the treatment period, wherein the daily dose of telmisartan is at least 1.0 mg / kg body weight during a first time period during the treatment period, and wherein the daily dose of telmisartan is increased during a second time period following the first time period during the treatment period. Furthermore, this invention relates to telmisartan or a pharmaceutically acceptable salt thereof, used as a medicament for treating hypertension in non-refractory dogs treated with ACE inhibitors. In another embodiment of the invention, a method for treating hypertension in a dog requiring the treatment is provided, wherein the method comprises 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 a daily dose that varies during the treatment period, wherein the daily dose of telmisartan is at least 1.0 mg / kg body weight during a first time period during the treatment period, and wherein the daily dose of telmisartan is increased during a second time period following the first time period during the treatment period. In another embodiment, the present invention provides a method for treating hypertension in dogs that are not refractory to treatment with ACE inhibitors, the method comprising administering a therapeutically effective amount of telmisartan or a pharmaceutically acceptable saline thereof to the dog requiring the treatment. Furthermore, the present invention relates to a pharmaceutical composition for treating hypertension in dogs requiring such treatment, comprising telmisartan of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Implementation Method

[26] : As used in this article, the term "non-refractory to ACE inhibitor treatment" refers to dogs with hypertension that can be treated with ACE inhibitors, but with lower efficacy than telmisartan. Conversely, ACE inhibitors cannot reduce persistently high systolic blood pressure (SBP) in dogs refractory to ACE inhibitors. In the non-refractory subgroup of dogs, the efficacy of ACE inhibitors in reducing SBP values ​​was 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, more than 50%, more than 60%, or more than 70% lower than telmisartan. In a preferred embodiment, the telmisartan and / or method according to the invention relates to the treatment of a non-refractory subgroup of dogs. However, the administration method according to the invention can advantageously be administered to both subgroups, namely non-refractory and refractory dogs. According to the present invention, dogs intended to be treated with telmisartan are preferably pet dogs of any breed, including any kind of mixed breed. Depending on the breed or size of the mixed breed, they may develop hypertension at any age, but more usually at 5 years or older, preferably 7 to 18 years, and especially 10 to 16 years. Generally, smaller breeds will develop the disease at a slightly later age than larger breeds, preferably 12 to 18 years, while larger breeds may develop it at 10 to 16 years. As used herein, the terms "with" or "in combination with" encompass both separate and sequential administration of telmisartan and another drug. For example, when the drugs are administered sequentially, telmisartan or another drug may be administered first. When administered simultaneously, the drugs may be administered in the same or different pharmaceutical compositions. Adjunctive therapy (i.e., one drug is used as the primary treatment and another drug is used to assist the primary treatment) is also an embodiment of the present invention. One or more active ingredients may be formulated individually or in a single combination. When combined in the same formulation, it should be understood that the two compounds must be stable and compatible with each other and with the other components of the formulation. The formulations of this invention include those suitable for oral, non-enteric (including subcutaneous (e.g., by injection or by storage tablets), intradermal, intrathecal, intramuscular (e.g., by storage and intravenous)), rectal, and local (including transcutaneous, buccal, and sublingual) administration, or in a form suitable for inhalation or blowing. The most suitable route of administration may depend on the patient's condition and disease. Preferably, the compositions of this invention are formulated for oral administration. Formulations can be readily presented in unit dosage forms and can be prepared by any method well known in pharmaceutics, such as that described in "Remington: The Science and Practice of Pharmacy", Lippincott Williams and Wilkins, 21st ed., (2005). Suitable methods include steps involving the combination of the active ingredient with a carrier constituting one or more excipients. Generally, formulations are prepared by homogenizing and fully combining the active ingredient with a liquid carrier or a finely ground solid carrier, or both, and then shaping the product into the desired formulation as needed. It should be understood that when the two active ingredients are administered independently, each can be administered in different ways. Suitable formulations for oral administration may be in the form of discrete units, such as capsules, tablets, or lozenges, specifically chewable lozenges, each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions. The active ingredient may also be in the form of pills, granules, or pastes. Alternatively, the active ingredient may be incorporated into oral liquid formulations, such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs. Formulations containing the active ingredient may also be presented as dry products, prepared with water or another suitable medium before use. These liquid formulations may contain conventional additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose, glucose / syrup, gelatin, hydroxymethylcellulose, carboxymethylcellulose, aluminum stearate gel, and / or hydrogenated edible fats), emulsifiers (e.g., lecithin, sorbitan monooleate, and / or gum arabic), non-aqueous mediums (e.g., edible oils, such as almond oil, fractionated coconut oil, esters, propylene glycol, and / or ethanol), and preservatives (e.g., methylparaben or propylparaben and / or sorbic acid). In addition, oral formulations may contain one or more flavoring agents that enhance the dog’s compliance with chewing and swallowing the medicine. Ideally, telmisartan is administered orally in the form of chewable tablets or as an aqueous solution containing benzyl alkyl chloride (as in the product Semintra®, which is commercially available from Boehringer Ingelheim Vetmedica GmbH, Ingelheim Germany). Specifically, this document discloses the following items: a) A method of treating hypertension in dogs requiring such treatment with telmisartan or a pharmaceutically acceptable salt thereof, wherein the method comprises administering a therapeutically effective amount of telmisartan to the dog, wherein the therapeutically effective amount of telmisartan is administered at a daily dose varying during the treatment period, wherein the daily dose of telmisartan is at least 1.0 mg / kg body weight during a first time period during the treatment period, and the daily dose of telmisartan is increased during a second time period following the first time period during the treatment period. b) Telmisartan according to item a), wherein hypertension is correlated with elevated urinary protein-to-creatinine concentration (UPC) levels. c) Telmisartan according to item a) or b), wherein it is a sodium or potassium salt thereof. d) Telmisartan according to any one of items a) to c), for treating dogs that are not refractory to ACE inhibitors. e) Telmisartan according to any one of items a) to c), for treating dogs refractory to ACE inhibitors. f) Telmisartan according to any of items a) to e), wherein the daily therapeutically effective dose is in the range of 1.0 to 10.0 mg / kg, preferably 1.0 to 4.0 mg / kg, specifically 1.0 to 3.5 mg / kg, and optimally 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 during the second time period is increased by an increment in the range of 0.25 to 2.50 mg / kg body weight. h) Telmisartan according to any of items a) to g), wherein the daily dose of telmisartan during the first time period of the treatment period is 1.0 to 1.5 mg / kg body weight, and the daily dose of telmisartan during the second time period is 1.75 to 3.50 mg / kg body weight. i) Telmisartan according to any of items a) to h), wherein the daily dose of telmisartan is reduced in increments ranging from 0.25 to 2.50 mg / kg body weight after the second time period. j) Telmisartan according to any of items a) to i), wherein the daily dose of telmisartan is reduced after the second time period following measurement of the dog's systolic blood pressure (SBP).k) Telmisartan according to any of items a) to j), wherein after the second time period, the daily dose of telmisartan is reduced when the measured systolic blood pressure (SBP) of the dog decreases 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, relative to the baseline SBP measured before the first time period. l) Telmisartan according to any of items a) to k), which is administered to the dog requiring this treatment together with at least one other drug. m) Telmisartan according to item l), wherein the other drug is selected from the group consisting of: calcium channel blockers, preferably amlodipine; cardiotonics-calcium sensitizers, preferably pimobendan or levosimendan; ACE inhibitors, preferably ramipril, benazepril, or enalapril, specifically enalapril. n) Telmisartan according to any of items a) to m), 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, this period of time is measured in days, such as 10 days, 20 days, 30 days, 60 days, 90 days, 120 days, or more than 120 days until the SBP value remains well below the threshold for hypertension. A significantly higher proportion of dogs treated with telmisartan showed a reduction in SBP of almost 20% on day 30, while dogs treated with enalapril showed an increase in SBP of more than 10%, as shown in Figure 2. As shown in Figure 1, dogs treated with telmisartan showed a greater average reduction in SBP from day 30 to day 90 compared to dogs treated with enalapril. Furthermore, the combination of telmisartan and enalapril from day 90 to day 120 achieved an average SBP reduction of more than 40 mmHg in dogs treated with telmisartan from day 0 to day 90. o) A method for treating hypertension in dogs requiring such treatment, wherein the method comprises administering to the dog a therapeutically effective dose of telmisartan or a pharmaceutically acceptable saline thereof, wherein the therapeutically effective dose of telmisartan is administered at a daily dose varying during the treatment period, wherein the daily dose of telmisartan is at least 1.0 mg / kg body weight during a first time period during the treatment period, and wherein the daily dose of telmisartan is increased during a second time period following the first time period during the treatment period. p) The method according to item o), wherein hypertension is correlated with elevated urinary protein versus creatinine concentration (UPC) levels.q) The method according to item o) or p) includes administering an effective amount of sodium or potassium salt of telmisartan. r) The method according to any of items o) to q) is used to treat dogs that are non-refractory or refractory to ACE inhibitors. s) The method according to any of items o) to r) wherein the daily therapeutic effective dose of telmisartan is in the range of 1.0 to 10.0 mg / kg, preferably 1.0 to 4.0 mg / kg, specifically 1.0 to 3.5 mg / kg, and more preferably 1.0 to 3.0 mg / kg body weight. t) The method according to any of items o) to s) wherein the daily dose of telmisartan is increased in increments ranging from 0.25 to 2.50 mg / kg body weight during the second time period. u) The method according to any of items o) to t) wherein the daily dose of telmisartan is decreased in increments ranging from 0.25 to 2.50 mg / kg body weight after the second time period. v) According to the method of any one of items o) to u), wherein after the second time period, when the measured SBP value of the dog is reduced by at least 20% relative to the baseline SBP value of the dog measured before the first time period, the daily dose of telmisartan is reduced. w) According to the method of any one of items o) to v), wherein the method further comprises administering at least one other drug to the dog requiring this treatment. x) According to the method of any one of items o) to w), wherein the other drug is selected from the group consisting of: calcium channel blockers, cardiotonics-calcium sensitizers, and ACE inhibitors. y) According to the method of any one of items o) to x), wherein the other drug is selected from the group consisting of: amlodipine, pimoxendan, levosimendan, ramipril, benazepril, and enalapril, specifically enalapril. z) According to the method of any of items o) to y), 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, this period of time is measured in days, such as 10 days, 20 days, 30 days, 60 days, 90 days, 120 days, or more than 120 days until the SBP value remains well below the critical value for hypertension. The present invention will now be generally described, and will be more readily understood with reference to the following examples, which are included only for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention. Example Experimental Methods and Design: A prospective, cluster-randomized, double-blind clinical trial was conducted. Fifty-four customer-owned dogs with persistent pathological renal proteinuria were recruited over a two-year period. Example 1: Animals. Dogs with hypertension and non-hypertensive CKD, exhibiting both azotemia and non-azotemia, were prospectively recruited from patients brought to the hospital (N = 54). Dogs included as cases were confirmed to have persistent pathological renal proteinuria due to CKD; to be classified as such, the following criteria would need to be met. Inclusion criteria. The UPC (Upper Criterion for Inclusion) of animals was approximately 2.0 (for patients with azotemia; IRIS grade 1) or approximately 0.5 (for patients without azotemia; IRIS grades 2–4), recorded in each of two urine samples collected two weeks apart. Abdominal ultrasound findings were consistent with CKD (bilateral small and irregular kidneys) and also indicated the absence of renal spurs. Exclusion Criteria. Animals will be excluded if one or more of the following are identified: evidence of bleeding, inflammation, or bacteria in urine sediment analysis; positive urine culture when identifying proteinuria; positive canine heartworm antigen test within 3 months of identifying proteinuria and / or not currently receiving regular monthly canine heartworm prophylaxis; medical history, physical examination, or clinicopathological findings suggestive of acute kidney injury, infectious nephropathy, or lower urinary tract infection; systolic hypotension (SBP < 120 mm Hg); moderate to severe hyperkalemia (serum K > 6.5 mmol / L); history of oral ACEI and / or corticosteroids within one month (ACEi) or two weeks (corticosteroids) prior to examination; and concomitant diseases related to proteinuria that can be treated to reduce proteinuria (e.g., systemic lupus erythematosus, ehrlichiosis, vesicle formation). Dogs suspected or diagnosed with hyperadrenocorticism and diabetes will be included if their conditions are considered adequately manageable with medication. Patient grouping was used for pool randomization: Once enrolled and based on the presence / severity of azotemia, dogs were grouped according to the International Renal Interest Society (IRIS) CKD classification scheme. Dogs classified as IRIS 2–4 (serum creatinine ≥1.4 mg / dL and inappropriately diluted urine [USG <1.030]) were considered to have azotemia (AZ), and those classified as IRIS 1 (creatinine <1.4 mg / dL) were considered to have non-AZ. Within each of these groups, dogs were then stratified according to IRIS recommendations regarding arterial blood pressure (AP) subclassification. According to this scheme, dogs with a sustained mean indirect arterial systolic blood pressure (BP) <150 mm Hg were classified as AP0 (lowest risk of target organ damage). Dogs with a sustained mean indirect arterial systolic blood pressure (BP) ≥150 mm Hg were classified as AP1–3 (at risk of target organ damage). This will identify four groups: 1. AZ (IRIS levels 2-4), IRIS AP1-3 subclasses; 2. AZ (IRIS levels 2-4), IRIS AP0 subclass; 3. non-AZ (IRIS level 1), IRIS AP1-3 subclasses. Once a patient is assigned to one of the four groups, each patient is randomly assigned to receive either enalapril (n=27) or telmisartan (n=27) based on a randomized clustering scheme, as described below, with the aim of ensuring that an equal number of patients are included in each of the two treatment groups. Baseline. At enrollment (Day 0), all owners were required to read / sign a consent form for their pet's participation in the study. The following baseline data were collected for each case: full physical examination (performed by one researcher), fundus examination, blood pressure measurement, serum chemistry tests, urinalysis, abdominal ultrasound, UPC, and urine culture. Results of screening tests (if performed within 2 weeks of enrollment) were used as baseline information. Baseline UPC was defined as the average of two measurements taken 2 weeks prior to enrollment. ARB / ACEi therapy. On day 0, each dog was randomly assigned in a double-blind manner to receive either telmisartan (TEL group, n=27) at 1 mg / kg PO q 24 h (oral every 24 hours) or enalapril (ENAL group, n=27) at 0.5 mg / kg PO q 12 h (oral every 12 hours). Telmisartan or enalapril was assigned at the appropriate dose. Appropriate contact numbers for emergency situations were provided to the owner. Enalapril is readily available, and telmisartan was provided in aqueous solution by Boehringer Ingelheim Vetmedica Inc., St. Joseph, MO, and was commercially available from Semintra®. Antihypertensive / Other Therapies. Dogs classified as AP3 (SBP ≥ 180 mmHg; sighthounds ≥ 200 mmHg) were concurrently administered a calcium channel blocker (CCB; amlodipine, 0.1 mg / kg PO q 24 hours). Co-administration of RAAS inhibitors with CCBs is common in human patients and was recommended by a panel of veterinary experts and has shown effectiveness in laboratory models of proteinuria. Prior to enrollment, all dogs had started or maintained a commercially available low-phosphorus and low-protein diet for at least one month. The diet remained unchanged during the study period. Fish oil therapy was permitted if the dogs had received this supplement for >1 month at enrollment. Monitoring: The monitoring protocol followed the recommendations of the IRIS Canine GN Study Group Standard Therapy Panel. All dogs were re-examined on day 7, at which time physical examination, serum creatinine (sCr), and serum potassium (K) were assessed. An increase in sCr >30% from baseline, or the identification of moderate / severe hyperkalemia (serum K >6.5 mmol / L) or systolic hypotension (sBP <120) prompted investigators to disclose the patient and remove them from the study. For dogs reliably identified with a mean SBP of approximately 180 mm Hg (i.e., classified as AP3), amlodipine was up-titrated to 0.1 mg / kg PO BID (orally twice daily). Subsequently, AP3-classified dogs were re-examined every 7 days to ensure therapeutic efficacy and adjust antihypertensive therapy. If the average SBP measurement remains at approximately 180 mm Hg at each visit, the amlodipine dose for the dogs is increased in increments of 0.05 mg / kg BID (twice daily) up to a maximum dose of 0.3 mg / kg BID. SBP and sCr are rechecked 7 days after any adjustment. Final Phase I Visit. On day 30, all dogs underwent a physical examination, SBP, serum biochemistry, urinalysis, and UPC measurement. At this time and at all subsequent time points, the urine used for UPC measurement will consist of a pooled sample, which is a combination of three randomly collected samples collected and refrigerated by the owner the previous day. Target endpoint. The target endpoint for Period I is the percentage decrease in SBP and the percentage change in UPC (ΔUPC). Conclusion: Compared with dogs treated with enalapril, dogs treated with telmisartan showed a mean change in SBP of at least 30 mmHg on day 30, as shown in Figure 2. Example 2 Specific Objectives #2 and #3 (Phase II and III; Interim Phase) The Phase II study compared the efficacy of enalapril and telmisartan as part of a regimen allowing for up-titering, while Phase III evaluated the combination in dogs with persistent proteinuria at the highest individual dose of each drug. Each of the 54 dogs was retained in the treatment group assigned in Phase I. In these groups, if proteinuria persisted and the monthly UPC was approximately 0.5, up-titering of the study drug followed by combination therapy was implemented. ARB / ACEi therapy. Phase II (days 31-90): For dogs with a UPC <0.5 identified on day 30, treatment continued with telmisartan at a dose of 1 mg / kg PO q24 h or enalapril at a dose of 0.5 mg / kg PO BID until the end of the study (day 120). For dogs with a UPC ~0.5 identified on day 30, the study drug dose was titrated monthly up by increasing the dose by 1 mg / kg PO q24 h (TEL group) or 0.5 mg / kg BID (ENAL group) until the target UPC <0.5 or the "ceiling dose" of either drug was reached (3 mg / kg PO q24 h for telmisartan or 1.5 mg / kg PO BID for enalapril), whichever occurred first. Phase III (Days 91-120): Dogs with a UPC <0.5 at or before day 90 continued treatment with telmisartan or enalapril at doses sufficient to control proteinuria until the end of the study. Dogs with a UPC of approximately 0.5 at day 90 were given additional treatment with enalapril at a dose of 0.5 mg / kg BID or telmisartan at a dose of 1 mg / kg q 24 h, respectively, in the TEL and ENAL groups. Combination therapy continued for one month until the end of the study. Monitoring. If the treatment regimen for an individual dog is changed on day 30, it should be re-examined one week later (day 37) to assess SBP, sCr, and serum potassium levels. An increase in creatinine >30% or the identification of moderate / severe hyperkalemia (serum potassium >6.5 mmol / L) prompts the investigator to disclose the patient and remove them from the study. If mild hyperkalemia is identified (serum potassium 6.1-6.5 mmol / L), no titration to the next dose is performed regardless of UPC. Dogs with persistent proteinuria were subsequently monitored monthly using SBP, UPC, and urinalysis (i.e., on days 60 and 90). Urine cultures were performed if active urine sediment was identified. For dogs with persistent proteinuria requiring uptiter, SBP, sCr, and serum potassium were rechecked one week after adjustment (days 67 and 97), with the criteria for identification and further uptitering as described above. Dogs with UPC <0.5 at any time point were rechecked only at the end of the study (day 120). Final visit: On day 120, all dogs underwent a full physical examination, SBP, serum renal biochemistry, urinalysis (bladder biopsy), and UPC measurement. Target endpoints. The target endpoints for Phase II include baseline AUPC and the percentage of patients who achieved a 50% reduction in UPC or a reduction to <0.5 after a total of 3 months of treatment, as well as an average reduction in SBP of approximately 20% from baseline. The target endpoints for Phase III include baseline AUPC, AUPC after one month of treatment (UPC day 90 - UPC day 120), and an average reduction in SBP of at least 40% from baseline. Conclusion. As shown in Figures 1 and 2, compared with dogs treated with enalapril, dogs treated with telmisartan showed greater average changes in SBP from day 30 to day 90, with the telmisartan-treated dogs showing the greatest change on day 90. Furthermore, the combination of telmisartan and enalapril from day 90 to day 120 resulted in a mean SBP reduction of more than 70 mmHg and achieved a mean SBP reduction of >40% in the group of dogs treated with telmisartan, as shown in Tables I and II below. Table 1: Average Changes in SBP of Active Ingredient [mmHg] Day 30: SBP Change [mmHg] Day 60: SBP Change [mmHg] Day 90: SBP Change [mmHg] Day 120: Enalapril +20.00 +1.00 +3.00 -32.00 Telmisartan -31.50 -31.00 -37.00 -76.00 21. Telmisartan was administered after SBP measurement on Day 90. 2. Enalapril was administered after SBP measurement on Day 90. Table 2: Average Changes in SBP% of Active Ingredient [%] Day 30: SBP Change [%] Day 60: SBP Change [%] Day 90: SBP Change [%] Day 120: Enalapril +12.90 +0.65 +1.94 -20.65 Telmisartan -18.88 -18.42 -22.58 -42.7021 was administered after the SBP measurement on day 90, along with telmisartan 2 and enalapril 2 after the SBP measurement on day 90. As shown in Figure 3, compared with dogs treated with enalapril, dogs treated with telmisartan who had hypertension with a SBP of at least 150 mmHg on day 0 and were receiving amlodipine and other medications showed greater changes in mean SBP from baseline on days 30, 60 and 90. Furthermore, the absolute mean SBP of dogs receiving telmisartan was significantly lower than that of dogs treated with enalapril, as shown in Figure 4. However, 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. The mean SBP of dogs treated with telmisartan decreased continuously from an initial 163 mmHg to 132 mmHg on day 90 during the treatment period, as shown in Table III. Table III Mean SBP Active ingredient SBP [mmHg] Day 0 SBP [mmHg] Day 30 SBP [mmHg] Day 60 SBP [mmHg] Day 90 Enalapril 163.17 153.80 153.00 158.00 Telmisartan 163.57 140.86 138.60 132.33 References The following publications are incorporated herein by reference in their entirety, as if each individual publication specifically and individually indicated to be incorporated by reference. In case of conflict, the application (including any definition herein) shall prevail. [1] Bodey AR, Michell AR. Epidemiological study of blood pressure in domestic dogs. J Small Anim Pract 1996; 37:116-25. [2] Brown S. Pathophysiology of systemic hypertension. In: Ettinger SJ, Feldman EC, eds. Textbook of veterinary internal medicine. Diseases of the dog and cat, vol. I. 6th edn. St. Louis (MO): Elsevier Saunders, 2005:472-6. 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Brief Description of the Drawings

Claims

1. Use of telmisartan or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating hypertension in dogs requiring such treatment, wherein the agent comprises a therapeutically effective amount of telmisartan, wherein the therapeutically effective amount of telmisartan is administered at a daily dose varying during a treatment period, wherein the daily dose of telmisartan is at least 1.0 mg / kg body weight during a first time period of the treatment period, and the daily dose of telmisartan is increased during a second time period following the first time period of the treatment period, wherein a proteinuria-to-creatinine ratio (UPC) is identified as at least 0.5, wherein the daily dose of telmisartan is increased in the second time period by an increase ranging from 0.25 to 2.50 mg / kg body weight.

2. As requested in item 1, wherein the hypertension is associated with systemic chronic kidney disease (CKD), elevated proteinuria-to-creatinine ratio (UPC) levels, and / or hyperthyroidism.

3. As requested in paragraph 1 or 2, wherein the pharmaceutically acceptable salt is a sodium or potassium salt of telmisartan.

4. As requested in item 1 or 2, wherein the hypertension is idiopathic hypertension.

5. As requested in paragraph 1 or 2, wherein the daily dose of telmisartan is 1.0 to 1.5 mg / kg body weight during the first time period of the treatment period, and the daily dose of telmisartan is 1.75 to 3.50 mg / kg body weight during the second time period.

6. For the purposes requested in paragraph 1 or 2, wherein the daily dose of telmisartan is reduced in increments ranging from 0.25 to 2.50 mg / kg body weight after the second time period.

7. As requested in item 1 or 2, wherein the daily dose of telmisartan is reduced when the dog's systolic blood pressure (SBP) is measured after the second time period.

8. For the purposes of claim 1 or 2, wherein after the second time period, when the measured systolic blood pressure (SBP) value of the dog is reduced 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, the daily dose of telmisartan is reduced.

9. As claimed in claim 1 or 2, wherein the agent is administered to the dog requiring the treatment together with at least one other drug.

10. As claimed in claim 9, wherein the other drug is selected from the group consisting of: calcium channel blockers, preferably amlodipine; cardiotonic-calcium sensitizers, preferably pimobendan or levosimendan; and ACE inhibitors, preferably ramipril, benazepril, or enalapril.

11. As requested in paragraph 1 or 2, wherein the hypertension is non-refractory when treated with ACE inhibitors.

12. For the purposes of claim 1 or 2, wherein the daily dose of telmisartan is 1.0 to 1.5 mg / kg body weight during the first time period of the treatment period and the daily dose of telmisartan is 1.75 to 4.0 mg / kg body weight during the second time period.

13. As claimed in claim 9, wherein the other drug is selected from the group consisting of: calcium channel blockers, cardiotonics-calcium sensitizers and ACE inhibitors.

14. As claimed in claim 13, wherein the other drug is selected from the group consisting of: amlodipine, pimoxendan, levosimendan, ramipril, benazepril and enalapril.

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