Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/401—Proline; Derivatives thereof, e.g. captopril
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• 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, wherein the method comprises administration of a therapeutically effective amount of telmisartan to the dog, wherein the therapeutically effective amount of telmisartan is administered in a daily dosage amount that is varied over a treatment period.
• SHT Systemic hypertension
• SBP sustained systolic arterial blood pressure
• SHT recognition has increased in the last years improving the management of different diseases. SHT causes injury to tissues causing kidney damage resulting in proteinuria, retinopathy and hypertensive encephalopathy. These are called the target organ damage (TOD). The prevalence of hypertension is not perfectly established and varies from 1 to 10 per cent in dogs [ 3]
• SHT Primary or idiopathic SHT is considered a rare condition in dogs due to the fact that only few cases have been diagnosed without an identifiable cause [4], but secondary SHT is relatively common and associated with different disorders as primary aldosteronism, hyperadrenocorticism, pheochromocytoma, chronic kidney disease (CKD) and hyperthyroidism as well as with some medications like glucocorticoids, mineralocorticoids, erythropoietin, non-steroidal anti-inflammatory drugs and inhibitors of tyrosine kinase [3, 5- 9] ⁇
• Idiopathic SHT is considered a health risk factor in itself. Severe consequences of SHT, described when SBP is over 180 mmHg, are retinopathy, intra-ocular hemorrhage and hypertensive encephalopathy, while the threshold for tissue injury is assumed to be 160 mmHg in cats and most breeds of dogs [4, 10] Other conditions, including left ventricular hyper-trophy [1 1], proteinuria and further loss of functional kidney tissue [12], can be a cause or consequence of SHT. In addition, secondary SHT is considered an additional progression factor of the underlying disease.
• ACVIM Consensus Statement guidelines for the management of hypertension in dogs and cats propose different strategies including ACEI, calcium channel blockers (CCB), beta- blockers and diuretics.
• Monotherapy and daily dose administration is the first choice to control SHT, but some patients are refractory and need a combination of different drugs to achieve good control of SBP [3]
• ACEIs are widely used as first-line treatment for SHT in dogs due to the role of the renin- angiotensin-aldosterone system (RAAS) in its development, but they provide an incomplete block of angiotensin II production that can result in poor control of SHT.
• RAAS renin- angiotensin-aldosterone system
• Amlodipine, a CCB, either by switching or as add-on therapy, is the alternative treatment when dogs are refractory to ACEI [6, 15]; however, aldosterone breakthrough may also occur in combined treatments with amlodipine and ACEI [16]
• an antihypertensive agent of choice is not completely effective, the usual approach is to increase the dosage or add an additional drug [13, 17]
• certain combinations like ACEI and angiotensin II receptor blocker (ARB) must be used with caution or avoided, as recent publications in humans showed a higher risk of kidney failure in these cases [13, 18, 19]
• Telmisartan an ARB, is a novel drug used in veterinary medicine to reduce proteinuria associated with CKD in cats [20]
• telmisartan produces vasodilation, diuresis and natriuresis without influencing potassium or creatinine excretion, and prevents potassium depletion by inhibiting the release of aldosterone in a dose-dependent manner
• the standard recommended dose in the management of proteinuria in dogs is 1 mg/kg [13] It has also been reported to have an effect on blood pressure in dogs at a 1 mg/kg daily dose [23]
• a daily dose of 1.0 mg/kg of body weight of telmisartan has been used in combination with amlodipine in dogs to control systemic hypertension refractory to standard hypertension therapy [24]
• the International patent application WO 2019/008077 teaches an administration scheme of sartans for prophylaxis or treatment of hypertension in a cat, where the initial dosage is 1.0 to 5.0 mg/kg of bodyweight and is decreased in a subsequent period.
• dogs can be treated against hypertension, in particular systemic hypertension (SHT) by administering therapeutically effective amounts of telmisartan, wherein the therapeutically effective amount of telmisartan is administered in a daily dosage amount that is varied over a treatment period, the daily dosage amount of telmisartan for a first period of time during the treatment period is at least 1.0 mg/kg of body weight, and the daily dosage amount of telmisartan is increased for a second period of time subsequent the first period of time during the treatment period.
• SHT systemic hypertension
• one objective of the present invention consists in providing a new therapeutic approach for the treatment of dogs against systemic hypertension.
• the 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, wherein the method comprises administration of a therapeutically effective amount of telmisartan to the dog, wherein the therapeutically effective amount of telmisartan is administered in a daily dosage amount that is varied over a treatment period, the daily dosage amount of telmisartan for a first period of time during the treatment period is at least 1.0 mg/kg of body weight, and the daily dosage amount of telmisartan is increased for a second period of time subsequent the first period of time during the treatment period. Furthermore, the invention relates to telmisartan or a pharmaceutically acceptable salt thereof as a medicament for the treatment of hypertension in dogs, which are non-refractory to the treatment with ACE inhibitors.
• a method for the treatment of hypertension in a dog in need of such treatment, wherein the method comprises administration of a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof to the dog, wherein the therapeutically effective amount of telmisartan is administered in a daily dosage amount that is varied over a treatment period, the daily dosage amount of telmisartan for a first period of time during the treatment period is at least 1.0 mg/kg of body weight, and the daily dosage amount of telmisartan is increased for a second period of time subsequent the first period of time during the treatment period.
• the invention provides a method for the treatment of hypertension in dogs, which are non-refractory to the treatment with ACE inhibitors, which method comprises administration of a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof to a dog in need of such a treatment.
• the invention relates to a pharmaceutical composition for use in a method for the treatment of hypertension, in a dog in need of such treatment, which comprises telmisartan or a pharmaceutically acceptable salt thereof according to the invention and a pharmaceutically acceptable carrier.
• FIG. 1 is a plot of the average SBP change from baseline, from day 30 to day 120 in dogs with hypertension at day 0, which did not receive amlodipine; on day 90 the dogs received a dose of either enalapril or telmisartan in addition to the initial drug administered.
• FIG. 2 is a plot of the average percent SBP change from baseline, from day 30 to day 120 in dogs with hypertension at day 0, which did not receive amlodipine; on day 90 the dogs received a dose of either enalapril (- ⁇ - E) or telmisartan (— ⁇ — T) in addition to the initial drug administered.
• FIG. 3 depicts the average SBP change from baseline, from day 30 to day 90 in dogs with hypertension at day 0, which received amlodipine.
• FIG. 4 depicts the average SBP in mmHg from day 0 to day 90 in dogs with hypertension at day 0, which did not receive amlodipine.
• telmisartan a therapeutically effective amount of telmisartan to the dog
• the therapeutically effective amount of telmisartan being administered in a daily dosage amount that is varied over a treatment period starting with an initial dose of at least 1.0 mg/kg of bodyweight.
• the daily dosage amount of telmisartan for a first period of time during the treatment period can be 1.0 to 1.5 mg/kg of body weight, where the daily dosage amount of telmisartan is increased for a second period of time subsequent the first period of time during the treatment period.
• the term“pharmaceutically acceptable salts” includes the metal salts or the addition salts which can be used in dosage forms.
• the pharmaceutically acceptable salts of the compounds provided herein can be acid addition salts, base addition salts or metal salts, and can be synthesized from parent compounds containing a basic or acid residue by means of conventional chemical processes.
• Such salts are generally prepared, for example, by reacting the free acid or base forms of these compounds with a stoichiometric amount of the suitable base or acid in water or in an organic solvent or in a mixture of both.
• Non-aqueous media are generally preferred, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.
• acid addition salts include mineral acid additions salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p- toluenesulfonate.
• mineral acid additions salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate
• organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p- toluenesulfonate.
• alkali addition salts include inorganic salts such as, for example, ammonium salts and organic alkaline salts such as, for example, diethylamine, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glutamine and basic amino acid salts.
• organic alkaline salts such as, for example, diethylamine, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glutamine and basic amino acid salts.
• metal salts include, for example, sodium, potassium, calcium, magnesium, aluminium and lithium salts.
• the term “pharmaceutically acceptable” relates to molecular entities and compositions that are physiologically tolerable and do not normally cause an allergic reaction or a similar adverse reaction, such as gastric discomfort, dizziness and the like, when administered to humans.
• the term“pharmaceutically acceptable” preferably means that it is approved by a regulatory agency of the federal or state government or listed in the US pharmacopoeia or another pharmacopoeia, generally recognized for its use in animals, preferably in mammals and more particularly in dogs.
• hypertension refers to refers to an elevated pressure of the blood against the walls of arteries during the time the heart contracts and empties itself of blood as well as during the time the heart relaxes and fills with blood and in.
• the term embraces systemic hypertension and idiopathic hypertension.
• systemic hypertension is applied to sustained increases in systolic blood pressure (SBP > 140 mmHg), and generally can be categorized into 1 of 3 types: (i) it may be caused by environmental or situational stressors, (ii) it may occur in association with other disease processes that increase BP (ie, secondary hypertension), or (iii) it may occur in the absence of other potentially causative disease processes (ie, idiopathic hypertension).
• non-refractory to the treatment with ACE inhibitors refers to dogs suffering from hypertension, which can be treated with an ACE inhibitor, but with less efficacy than telmisartan. To the contrary the high values of sustained systolic arterial blood pressure (SBP) of dogs that are refractory to ACE inhibitors cannot be lowered with the aid of ACE inhibitors.
• SBP sustained systolic arterial blood pressure
• the efficacy of treatment with an ACE inhibitor is 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, more than 50%, more than 60%, or more than 70% less effective than telmisartan for lowering their SBP values.
• the telmisartan and/or the method according to the invention relates to the treatment of the non-refractory subpopulation of dogs.
• the administration scheme according to the invention may advantageously be administered to both the subpopulations, the non-refractory as well as to refractory dogs.
• the dogs to be treated with telmisartan according to the invention are preferably pet dogs of any breed including any kind of mongrel. Depending on the size of the breed or mongrel they may suffer from hypertension at an any age, but more frequently at an age of 5 years or more, preferably from 7 to 18 years, in particular from 10 to 16 years. Small breeds will as a rule suffer at a later age, preferably from 12 to 18, from this disease than big ones, which may be affected at an age of 10 to 16 years.
• telmisartan covers both separate and sequential administration of telmisartan and another drug.
• the agents when the agents are administered sequentially, either the telmisartan or the other drug may be administered first.
• administration is simultaneous, the agents may be administered either in the same or a different pharmaceutical composition.
• Adjunctive therapy i.e. where one agent is used as a primary treatment and the other agent is used to assist that primary treatment, is also an embodiment of the present invention.
• the one or more active ingredients may be used either as separate formulations or as a single combined formulation. When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation.
• Formulations of the invention include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingual) or in a form suitable for administration by inhalation or insufflation administration.
• the most suitable route of administration may depend upon the condition and disorder of the patient.
• the compositions of the invention are formulated for oral administration.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy e.g. as described in“Remington: The Science and Practice of Pharmacy”, Lippincott Williams and Wilkins, 21 st Edition, (2005).
• Suitable methods include the step of bringing into association active ingredients with a carrier which constitutes one or more excipients.
• formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. It will be appreciated that when the two active ingredients are administered independently, each may be administered by a different means.
• Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, in particular chewable tablets, each containing a predetermined amount of active ingredient; as powder or granules; as a solution or suspension in an aqueous liquid or non-aqueous liquid; or as an oil-in-water liquid emulsion or water-in-oil liquid emulsion.
• the active ingredients may also be presented a bolus, electuary or paste.
• the active ingredients may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs.
• Formulations containing the active ingredients may also 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, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel and/or hydrogenated edible fats), emulsifying agents (e.g. lecithin, sorbitan mono-oleate and/or acacia), non-aqueous vehicles (e.g.
• suspending agents e.g. sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel and/or hydrogenated edible fats
• emulsifying agents
• edible oils such as almond oil, fractionated coconut oil, oily esters, propylene glycol and/or ethyl alcohol), and preservatives (e.g. methyl or propyl p-hydroxybenzoates and/or sorbic acid).
• the oral formulation may contain one or more flavoring agents, which enhance the compliance of the dog to be treated to chew and swallow the medication.
• telmisartan is administered orally in form of a chewable tablet or as an aqueous solution containing benzalkonium chloride as in the product Semintra®, which is commercially available from Boehringer Ingelheim Vetmedica GmbH, Ingelheim Germany.
• 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, wherein the method comprises administration of a therapeutically effective amount of telmisartan to the dog, wherein the therapeutically effective amount of telmisartan is administered in a daily dosage amount that is varied over a treatment period, the daily dosage amount of telmisartan for a first period of time during the treatment period is at least 1.0 mg/kg of body weight, and the daily dosage amount of telmisartan is increased for a second period of time subsequent the first period of time during the treatment period.
• telmisartan according to any of the items a) to f), wherein the daily dosage amount of telmisartan is increased for the second period of time by an incremental amount ranging from 0.25 to 2.50 mg/kg of body weight.
• telmisartan according to any of the items a) to g), wherein the daily dosage amount of telmisartan for a first period of time during the treatment period is 1.0 to 1.5 mg/kg of body weight, and the daily dosage amount of telmisartan for the second period of time is 1.75 to 3.50 mg/kg of body weight.
• telmisartan according to any of the items a) to h), wherein the daily dosage amount of telmisartan is decreased after the second period of time by an incremental amount ranging from 0.25 to 2.50 mg/kg of body weight.
• telmisartan according to any of the items a) to i), wherein the daily dosage amount of telmisartan is decreased after the second period of time upon a systolic blood pressure (SBP) value measured for the dog.
• SBP systolic blood pressure
• telmisartan according to any of the items a) to j), wherein the daily dosage amount of telmisartan is decreased when a systolic blood pressure (SBP) value measured for the dog decreases after the second period of time 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 in relation to a baseline SBP value measured for the dog prior to the first period of time.
• SBP systolic blood pressure
• said period of time is period measured in days, such as 10 days, 20 days, 30 days, 60 days, 90 days, 120 days or more than 120 days up to a point in time when the SBP values are constantly well below the threshold of hypertension.
• telmisartan-treated dogs show a reduction of almost 20% in SBP at day 30, whereas the SBP in enalapril-treated dogs increased even by more than 10 % as shown in FIG. 2.
• the average reduction in SBP is greater from day 30 to day 90 for telmisartan treated dogs compared to enalapril treated dogs.
• the combination of telmisartan and enalapril from day 90 to day 120 achieves a reduction of more than 40 mmHg of the average SBP in dogs which were treated with telmisartan from day 0 to day 90.
• a method for the treatment of hypertension in a dog in need of such treatment comprises administration of a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof to the dog, wherein the therapeutically effective amount of telmisartan is administered in a daily dosage amount that is varied over a treatment period, the daily dosage amount of telmisartan for a first period of time during the treatment period is at least 1.0 mg/kg of body weight, and the daily dosage amount of telmisartan is increased for a second period of time subsequent the first period of time during the treatment period.
• telmisartan ranges from 1.0 to 10.0 mg/kg, preferably from 1.0 to 4.0 mg/kg, in particular from 1.0 to 3.5 mg/kg, most preferred from 1.0 to 3.0 mg/kg of body weight.
• Inclusion criteria Included animals had an UPC level of approximately 2.0 (for non- azotemic patients; IRIS stage 1) or approximately 0.5 (for azotemic patients; IRIS stages 2- 4), documented in each of two urine samples collected 2 weeks apart. Abdominal ultrasound findings consistent with CKD (bilaterally small, irregular kidneys) and absence of renal neoplasia have also been documented.
• Exclusion criteria Animals have been excluded if one or more of the following are identified: evidence of hemorrhage, inflammation or bacteria on urine sediment analysis; positive urine culture at the time of identification of proteinuria; positive heartworm antigen test within 3 months of identification of proteinuria and/or not currently receiving regular monthly heartworm preventive; historical, physical examination or clinical pathologic 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 having received oral ACEi and/or corticosteroids in the month (ACEi) or 2 weeks (corticosteroids) preceding examination; concurrent illness associated with proteinuria, the treatment of which might result in mitigation of proteinuria (e.g, systemic lupus erythematosis, ehrlichiosis, neoplasia).
• Dogs with suspected or confirmed hyper- adrenocorticism and diabetes mellitus have been included if their disease is considered well controlled with medical therapy.
• Patient grouping for block randomization Once included in the study and based on the presence/degree of azotemia, dogs have been grouped according to the International Renal Interest Society (IRIS) classification scheme for CKD. Those classified as IRIS stages 2-4 (serum creatinine >1.4 mg/dL with inappropriately dilute urine [USG ⁇ 1.030]) have been considered azotemic (AZ), and those classified as IRIS stage 1 (creatinine ⁇ 1.4 mg/dL) have been considered non-azotemic (non-AZ).
• IRIS International Renal Interest Society
• dogs will then be stratified according to IRIS recommendations for arterial pressure (AP) substaging.
• AP arterial pressure
• dogs with persistent average indirect arterial systolic BP ⁇ 150 mm Hg will be classified as AP0 (minimal risk for target organ damage).
• Those with persistent average indirect arterial systolic BP>150 mm Hg have been classified as AP1-3 (at risk for target organ damage).
• IRIS Stages 2-4 IRIS substage AP1-3 3. non-AZ (IRIS Stage 1), IRIS substage AP1 -3
• IRIS Stages 2-4 IRIS substage AP0 4. non-AZ (IRIS Stage 1), IRIS substage AP0
• Baseline On inclusion (day 0), all owners have been required to read/sign a form consenting to their pets’ participation in the study.
• the following baseline data have been collected for each case: full physical examination (performed by one of the study investigators), fundic examination, blood pressure measurement, serum chemistry panel, urinalysis, abdominal ultrasound, UPC and urine culture.
• the results of screening tests, if performed within 2 weeks of inclusion in the study, may be used as baseline information.
• Baseline UPC has been defined as the average of two measurements, taken 2 weeks apart, prior to enrollment.
• a calcium channel blocker (CCB; amlodipine, 0.1 mg/kg PO q 24 hours) has been administered contemporaneously.
• Co-administration of RAAS-inhibitors and CCB is common in human patients, recommended by a panel of veterinary experts and shown to be efficacious in a laboratory model of proteinuria. All dogs have been started or maintained on a commercially available diet formulated to be low in phosphorus and protein, for at least 1 month prior to enrollment. During the study period, diet remained constant. Treatment with fish oil has been allowed, provided that the dog has been receiving this supplement for >1 month at the time of enrollment.
• dogs classified as AP3 have been rechecked at 7-day intervals to ensure efficacy of therapy with adjustment of antihypertensive therapy.
• SBP measurements remained at about 180 mm Hg, then the dog’s amlodipine dose have been increased in increments of 0.05 mg/kg BID to a maximum dose of 0.3 mg/kg BID.
• SBP and sCr have been rechecked 7 d following any adjustments.
• the objective endpoints of phase I was the reduction of the SBP and the percentage change in UPC (AUPC).
• Phase II of this study compared the efficacy of enalapril and telmisartan when these drugs were used as part of protocols that allow their up-titration, and phase III will evaluate their combination in dogs whose proteinuria persisted in the face of the highest doses of each drug alone.
• Each of the 54 dogs will remain in the treatment group to which he/she was assigned in phase I.
• up-titration of study drugs, followed by combination therapy have been performed if proteinuria persisted with UPC at about 0.5 on monthly rechecks.
• Phase II (days 31 -90 ' ): For those dogs in which UPC ⁇ 0.5 was identified on day 30, treatment continued with telmisartan at a dose of 1 mg/kg PO q 24 h or enalapril at a dose of 0.5 mg/kg PO BID until the end of the study (day 120).
• the dose of study drug has been up-titrated monthly in increments of 1 mg/kg PO q 24 h (TEL group) or 0.5 mg/kg BID (ENAL group) until a target UPC ⁇ 0.5 was attained OR a “ceiling dose” (3 mg/kg PO q 24 h for telmisartan or 1 .5 mg/kg PO BID for enalapril) of either drug is reached, whichever occurs first.
• Phase III (days 91 -1201: For those dogs in which UPC ⁇ 0.5 was identified on or before day 90, treatment continued with telmisartan or enalapril at the dose producing proteinuria control until the end of the study. For those in which UPC approximately 0.5 was identified on day 90, enalapril at a dose of 0.5 mg/kg BID or telmisartan at a dose of 1 mg/kg q 24 h has been added for dogs in the TEL and ENAL groups, respectively. Combination therapy continued for 1 month, until the end of the study.
• the objective endpoints for phase II included AUPC from baseline and percentage of patients achieving 50% reduction or decrease to ⁇ 0.5 of UPC following a total of 3 months of therapy, as well as an average reduction of SBP by about 20 % from baseline.
• Phase Ill s objective endpoints included AUPC from baseline, AUPC over the month of therapy (UPCday90 - UPCday120) and an average reduction of SBP by at least 40 % from baseline.
• the combination of Telmisartan and Enalapril from day 90 to day 120 lowers the average SBP by more than 70 mmHg and achieves in average a > 40 % reduction of the SBP in the group of dogs that were treated with telmisartan as shown in the following tables I and II.
• telmisartan has been administered after SBP measurement on day 90
• additional enalapril has been administered after SBP measurement on day 90
• telmisartan has been administered after SBP measurement on day 90
• additional enalapril has been administered after SBP measurement on day 90
• the average SBP change from baseline was greater at day 30, day 60, and day 90 in dogs that were hypertensive with SBP of at least 150mmHg at day 0, which received amlopdipine and the extra drug, in telmisartan treated dogs compared to those treated with enalapril.
• the absolute average SBP of dogs that received telmisartan was much lower than of those dogs which were treated with enalapril as shown in FIG. 4.
• the SBP of the dogs treated with enalapril was reduced from 163 mmHg to 153 mmHg on day 30, but increased again on days 60 and 90
• the average SBP values of the dogs treated with telmisartan was constantly lowered during the period of treatment from initially 163 mmHg to 132 mmHg on day 90 as shown in table III
• 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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