AU2013203932B2 - Angiotensin II receptor antagonist for the treatment of systemic diseases in cats - Google Patents

Abstract

H:\fmt\Mntenvove\NRPortbl\DCC\FMT5066112 I.DOC.I 1/0412013 The present invention relates to a method of prophylaxis or treatment of systemic diseases in cats, wherein the method comprising administration of a therapeutically effective amount of angiotensin 11 receptor 1 (AT-1) antagonist (sartan) to a cat in need of such a treatment.

Description

H:\fntenvovcn\NRPortbl\DCC\FM 05066 12.1.DOC.I/04/2013 ANGIOTENSIN Il RECEPTOR ANTAGONIST FOR THE PREVENTION OR TREATMENT OF SYSTEMIC DISEASES IN CATS This is a divisional of Australian Patent Application No. 2007304216, the entire contents of 5 which are incorporated herein by reference. FIELD OF INVENTION: The present invention relates to the field of veterinary medicine, especially to the prophylaxis or treatment of systemic diseases in cats. In particular, the present invention 10 relates to a method of prophylaxis or treatment of systemic diseases in cats, wherein the method comprising administration of a therapeutically effective amount of angiotensin II receptor 1 (AT-1) antagonist (sartan) to a cat in need of such a treatment. BACKGROUND OF THE INVENTION: 15 The prevalence of renal disease is high in aged cats, whereas chronic renal failure is considered the most important one. The prevalence of chronic kidney disease (CKD) in cats is reported to reach up to 20% with 53% of cats were older than 7 years (Lefebre, Toutain 2004.J. Vet Pharm. Therap. 27, 265 - 281; Wolf AM North. Am. Vet. Congress 2006). Survival in cats with mild to moderate azotemia and extrarenal clinical signs {IRIS 20 stage 2 & 3) ranged from I to 3 years. Early management and therapy is considered to successfully influence prognosis for CKD (Wolf AM North Am. Vet Congress 2006). Chronic renal failure (CRF), at least in its final stage is, regardless of the underlying causes, characterized by irreversible structural lesions of the kidney. Thereby, progressive 25 irreversible lesions initially localized to one portion of the nephron (e.g. glomeruli, peritubular capillaries, tubules or interstitial tissue), are eventually responsible for the development of lesions in the remaining, but initially unaffected portions of nephrons due to their functional interdependencies. New nephrons cannot be formed to replace others irreversibly destroyed by disease . In a study of biopsy findings in cats with primary renal 30 azotemia, tubulointerstitial nephritis was observed in 70%, glomerulonephropathy occurred in 15%, lymphoma in 11 % and amyloidosis was observed in 2% of the samples. CRF is recognized by reduced kidney function or the presence of kidney damage (Polzin, Osborne, Ross 2005 in : Ettinger SJ, WO 2008/040774 PCT/EP2007/060531 -2 Feldman CE (eds.) Textbook of Veterinary Internal Medicine, 6th, Vol 2, Chapter 260, 1756 -1785). Angiotensin 11 plays an important part in pathophysiology, particularly as the most s potent agent for increasing blood pressure in humans. It is known that in addition to its effect of raising blood pressure Angiotensin 11 also has growth-promoting effects which contribute to left ventricular hypertrophy, vascular thickening, atherosclerosis, renal failure and stroke. In small animals, inhibition of the effects of Angiotensin ll, via either ACE inhibitors have been shown to exhibit renoprotectiv effects through their io simultaneous capacity to decrease blood pressure and control proteinuria. Current therapy aims to delay the progression of the disease in cats by improving renal function, especially glomerular function by maintaining glomerular perfusion. This includes dietary protein restriction, modification of dietary lipid intake, phosphate 1 restriction and treatment with angiotensin-converting enzyme (ACE) inhibitors (P.J. Barber (2004) The Kidney, in: Chandler EA, Gaskell CJ, Gaskell RM (eds.) Feline Medicine and Therapeutics, 3rd edition, Blackwell Publishing, Oxford, UK). ACE inhibitors, especially enalapril, benazepril, imidapril and ramipril, have been 20 initially developed in small animal medicine to control chronic heart failure (CHF). Based on the pathophysiological role of the renin-anglotensin-aldosterone system (RAAS) in progression of chronic heart failure and in progression of renal damage, these agents have been shown to be useful in the treatment of chronic kidney disease (CKD) in order to delay progression of disease and reduce morbidity and 2S suffering in small animals, including cats. Sound evidence for this is probably the recent approval of benazepril in Europe for the treatment of feline CRF (Lefebre Toutain, 2004 J Vet Pharm Therap 27, 265-281). However, the renoprotection of ACE inhibitor was likely mediated by the effect on proteinuria rather than by blood pressure reduction. This has been shown for ramipril, since the effect on blood 30 pressure was comparable to that of placebo while the protelnuria was reduced (Remuzzi et al., 2006 J Clin Invest 116, (2) 288-296).

H:\rec\ntrovn\NRPortbl\DCC\REC\735575I L.docx-13/01/2015 -3 From a clinical point of view, ACE inhibitors are not the preferred target to block the RAAS because of the lack of specificity for Angiotensin I and the "angiotensin escape " phenomenon; where alternate enzymatic pathways such a cathepsin, trypsin or the heart chymase can also convert Angiotensin I, Moreover, during long term treatment with ACE inhibitors, ACE activity is upregulated and Angiotensin I levels are high due the stimulated renin secretion (Burnier & Brunner 2000 The Lancet, 355 637-645). In one or more aspects the present invention may advantageously provide a new therapeutic approach for the treatment or prophylaxis of cats against chronic kidney disease. In one aspect the present invention provides use of an angiotensin || receptor 1 (AT-1) antagonist for the manufacture of a pharmaceutical composition comprising a therapeutically effective amount of said angiotensin || receptor 1 (AT-1) antagonist for the treatment of the metabolic disease diabetes mellitus in cats, wherein said angiotensin || receptor 1 (AT-1) antagonist is a sartan. In another aspect, the present invention provides a method for the prophylaxis or treatment of the metabolic disease diabetes mellitus in cats, wherein the method comprises administration of a therapeutically effective amount of angiotensin || receptor 1 (AT-1) antagonist to a cat in need of such a treatment, wherein said angiotensin || receptor 1 (AT-1) antagonist is a sartan. A further more general aspect of the present invention consists in providing a new therapeutic approach for the treatment or prophylaxis of cats against systemic diseases; preferably against systemic diseases which are related to Angiotensin II or associated with the renin-angiotensin-aldosterone system (RAAS). DESCRIPTION OF THE INVENTION: Description of Figures: Figure 1: Inhibition of blood pressure increase by angiotensin || receptor 1 antagonist Detailed Description of the Invention: Before the embodiments of the present invention it shall be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference H:VrmtnterwovnWRPortbl\DCCFKM\319931-1.do-15/07/2013 - 3a unless the context clearly dictates otherwise. Thus, for example, reference to "a preparation" includes a plurality of such preparations, reference to the "carrier" is a reference to one or more carriers and equivalents thereof known to those skilled in the art, and so forth. Unless defined otherwise, all technical and scientific terms used herein have 5 the same meanings 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 to 5 % unless indicated otherwise or known otherwise by the person skilled in the art, therefore, the term "about" was 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 10 invention, the preferred methods, devices, and WO 2008/040774 PCT/EP2007/060531 -4 materials are now described. All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the substances, excipients, carriers, and methodologies as reported in the publications which might be used in connection with the Invention. Nothing herein is to be construed as an 5 admission that the 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 the embodiments characterized in the claims. 10 To date, the use of angiotensin I receptor I antagonists (sartans) in cats is not described for any indication. Blockage of angiotensin Il receptor 1 is a treatment concept which differs from blockage of angiotensin converting enzyme as known from the ACE-inhibitors. Receptor blockage is more specific and complete and 15 further downstream in the physiologic cascade of the RAAS system. The present invention is based on various unexpected findings: It was surprisingly found that cats tolerate a pharmacodynamically effective dose of sartans. In a open-label study in nondiabetic, hypertensive human patients with 2 o proteinuric nephropathies the effects on renal outcome of low (80 mg once daily) and high dose (80 mg twice daily) telmisartan were compared. The results reinforced the concept that more effective RAAS inhibition achieved by a high dose of 160 mg daily. This dose corresponds to a plasma level of about 2800 t 2400 ng/ml (Cmax ± SD), which exceeds the no-effect doses in toxicities studies in animals such as dogs and 25 rats (Investigator broschure 1994, data on file) The resulting dose of about 2 to 3 mg/Kg body weight and day was thus expected to be toxic in cats. Pilot-toxicity studies have surprisingly shown, that such a dose (up to 3 mg/kg) is well tolerable in cats. 3 o Moreover, it was found that sartans effectively blocks the angiotensin Il receptor I also in cats. This finding was all the more unexpected, as the absolute bioavailability in cats is very low and the mean residence time and plasma half life are rather short in cats as compared to human beings. The oral bioavailability was calculated to WO 2008/040774 PCT/EP2007/060531 33,6% as compared to human beings. The mean tmax oral was 0,44 hours and the Cmx oral was 138,1 ng/ml. The mean t1/ 2 oral was 2,17 hours. The mean AUC -> oral was calculated to 150 (ng x h /ml), and the mean V/f oral was 20,4 I/kg, The mean AUC -+ ~intravenous was calculated to 385 (ng x h /ml). The mean t12 5 intravenous was 2,25 hours and the mean V/f oral was 8,8 I/kg. From this information, which was newly generated, it can be concluded that sartans, preferably telmisartan, can be used to treat cats with systemic diseases, preferably with chronic kidney disease, such as for example chronic renal failure, including chronic renal insufficiency. 10 Table 1: Abbreviations Abbreviation Pharmacokinetic parameters AUC area under the plasma concentration time curve C max maximum measured plasma concentration Volume of distribution (V) whereas f is V/f the absolute bioavailability MRT mean residence time t 1/2 terminal half-live t max time to reach Cmax Thus, according to one embodiment, the present invention relates to a method for the prophylaxis or treatment of a systemic disease in cats, wherein the method 15 comprising administration of a therapeutically effective amount of angiotensin II receptor 1 (AT-1) antagonist (sartan) to that cat in need of such a treatment. The term "systematic disease" as used herein means but is not limited to cardiovascular such as dilated cardiomyopathy (DCM), mitral valve insufficiency (MI), 20 hypertrophic cardiomyopathy (HCM); and other acquired or hereditary heart diseases, e.g. cardiopulmonary diseases, systemic hypertension for example hypertension associated with renal diseases, chronic renal failure and other vascular WO 2008/040774 PCT/EP2007/060531 diseases, or metabolic disorders such as diabetes mellitus. Thus, according to another aspect, the present invention relates to a method for the prophylaxis or treatment of a systemic disease in cats by the administration of therapeutically effective amount of said anglotensin 11 receptor 1 (AT-1) antagonist (sartan) to that 5 cat, wherein the systemic disease is selected from the group of cardiovascular diseases, such as dilated cardiomyopathy (DCM), mitral valve insufficiency (MI), hypertrophic cardiomyopathy (HCM) and other acquired or hereditary heart diseases, systemic hypertension, for example hypertension associated with renal diseases, chronic renal failure and other vascular diseases, metabolic disorders like diabetes lo mellitus, In humans, angiotensin Il receptor I (AT1 receptor antagonists (sartans) are known to significantly reduces proteinuria in both diabetic and non-diabetic patients, even in those with mild to moderate chronic renal failure (CRF). Moreover, there is published 15 evidence for the efficacious use of AT1 receptor antagonists for treatment of nephropathies in type l[ diabetes Cupisti A, et al., 2003, Biomed Pharmacother; 57 (3-4):169-172; Rysava R, et al., 2005, Press Monit; (10(4):207-213; W092/10182). In cats tubulointerstitial nephrits is reported to be the major causative (>70%) finding for CRF whereas in human beings and dogs glomerulonephropathy is more prominent 20 compared to cats, Glomerular lesions are more often seen in dogs and humans and consequently the clinical finding of moderate to marked proteinuria, resulting from loss of glomerular permselectivity, Is more common in dogs and humans. Tubulointerstitial nephritis as seen in cats showed less proteinuria. Proteinuria is recognized as an important predictor of disease progression in humans and dogs 25 with spontaneous kidney disease and reduction of proteinurla is associated with improved outcome in clinical trials to show the renoprotective effects of blocking the RAAS by either ACE or ARBs in human suffering from nephropathy (Karalliede & Viberti, J Human Hypertension 2006). Due to the fact that there is less proteinuria in cats because of the tubulointerstitial origin of CRF, the reduction of proteinuria as 30 renoprotective effect In delaying progression of CRF might be expected to be less important in this species. However, In a clinical field trial an independent and significant correlation between proteinuria (determined as UPC) and survival in cats suffering from CRF have been reported. Surprisingly, even in azotemic cats with only WO 2008/040774 PCT/EP2007/060531 -7 minor proteinuria (ace. to IRIS, UPC < 0.25) this correlation was evident (Syme, Elliot 2006, J Vet Intern Med, 20, 528-535). Thus, according to a preferred embodiment the systemic disease is chronic kidney 5 disease, preferably chronic renal failure, e.g. as defined as stage il to IV in Table 2. The diagnosis of reduced kidney function such as chronic renal failure is based on exclusion of pre- and postrenal causes and standard blood markers, e.g. urea and creatinine in plasma or serum. Abnormal concentrations of these parameters are 10 described as azotemia. Standard urine markers of reduced kidney function Include urine specific gravity, proteinuria and others (Poizin DJ, Osborne CA, Ross S, 2005: Chronic Kidney Disease, In: Ettinger SJ, Feldman EC (ed.) Textbook of Veterinary Internal Medicine 6 th edition, WB. Saunders Company, Philadelphia, USA). The international renal interest society (IRIS) has proposed a staging system based on 15 azotemia to define CRF patients (Po/zin DJ, 2006: Treating feline kidney disease: an evidence-based approach, Proceedings of The North American Veterinary Conference). The main category for staging being plasma creatinine [mg/dl], which is completed by two subcategories independent from stage, urine protein:creatinine ratio (UPC) and blood pressure [mmHg]. With the applied system, feline patients are 20 staged along a continuum of progressive kidney disease. Table 2. Stages of feline chronic kidney disease Stage Plasma Comments Subcategory Subcategory systolic creatinine UPC blood pressure (mmHg, (mg/dl) (Independent independent from stage) from stage) S <1.6 Non-azotemic: some < 0.2 = Non- < 150 = minimal risk of other renal abnormality proteinuric end-organ damage is present II 1.6 - 2.8 Mildly azotemic: usually 0.2 - 0.4 = 150-159 = low risk of _ mild clinical signs Borderline end-organ damage 1i1 2.9 -5.0 Moderately azotemic: proteinuric many extra-renal clinical 160-179 = moderate risk I signs > 0.4 = of end-organ damage IV > 5.0 Severly azotemic: Proteinuric Invasive life support ; 180 = high risk of end methods required organ damage WO 2008/040774 PCT/EP2007/060531 -8 Thus, according to a further embodiment, the present invention relates to a method for the prophylaxis or treatment of chronic renal failure in cats, wherein the method comprising administration of a therapeutically effective amount of angiotensin Il receptor 1 (AT-1) antagonist (sartan) to that cat in need of such a treatment and 5 wherein said chronic renal failure is characterized by any one of the clinical manifestations as listed in table 2, or any combination thereof- For example, the present invention relates to a method for the prophylaxis or treatment of cats having an plasma creatine of : 1.6 (mg/dl of blood), and/or having a proteinuric of 2 0.2 (subcategory UPC), wherein the method comprising administration of a 10 therapeutically effective amount of angiotensin 11 receptor 1 (AT-1) antagonist (sartan) to that cat in need of such a treatment. A comprehensive list of angiotensin 11 receptor antagonists can be found on pages 2 to 22 of WO 92110182 and pages 7 to 18 of WO 95/26188, which all are incorporated 15 herein by reference, Angiotensin Il receptor antagonists are described inter alla in EP-A-25331 0, EP-A-323841, EP-A-324377, EP-A-420237, EP-A-443983, EP-A-459136, EP-A-475206, EP-A-502314, EP-A-504888, EP-A-514198, WO 91/14679, WO 93/20816, WO 02/092081, US 4,355,040, US 4,880,804 and US 6,028,091. Forms which are frequently mentioned are sartans, such as 20 candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan or valsartan. Those which are particularly preferred according to the present invention are irbesartan, losartan und telmisartan. All of these sartans, or pharmaceutical salts or polymorphs thereof are well known to a person skilled in the art, and its use is within the meaning of the present invention. 25 Thus the present invention relates to a method for the prophylaxis or treatment of cats suffering from a systemic disease, preferably from chronic kidney disease, e.g. chronic renal failure, wherein the method comprising administration of a therapeutically effective amount of angiotensin Il receptor I (AT-1) antagonist 30 (sartan) to that cat in need of such a treatment and wherein the angiotensin I receptor I (AT-1) antagonist (sartan) is selected from the group consisting of: candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan or valsartan, preferably of irbesartan, losartan und telmisartan.

WO 2008/040774 PCT/EP2007/060531 -9 Telmisartan is an angiotensin 1i receptor antagonist developed for the treatment of hypertension and other medical indications as disclosed in EP-A-502314. Its chemical name is 4'-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-y) s benzimidazol-1-ylmethyl]-biphenyl-2-carboxylic acid having the following structure: N N N N HOOC Telmisartan is already sold on the market under the trade name Micardis* 10 (Boehringer Ingelhe(m, Germany) for treatment / prophylaxis of humans. It exists in two polymorphic forms as disclosed in WO 00/43370, US 6,358,986 and US 6,410,742. Sodium salts of telmisartan and its solvate, hydrate, and hemihydrate are disclosed in WO 03/037876. is Thus, according to a further embodiment, the present invention relates to a method for the prophylaxis or treatment of a systemic disease in cats, preferably of chronic kidney disease, e.g. chronic renal failure, wherein the method comprising administration of a therapeutically effective amount of telmisartan or pharmaceutically acceptable salt thereof, preferably of a telmisartan as mentioned above. More 20 preferably said telmisartan is Micardis*. As already mentioned above, It has been surprisingly found that use of telmisartan effectively Inhibits the angiotensin i receptor pressure response in cats. Moreover, it has been surprisingly found that doses of less than 0.05 mg telmisartan per kg body 25 weight of cat led to an inhibition of the blood pressure response of about 75% in the majority of the tested cats. Moreover, a study in laboratory cats was established to WO 2008/040774 PCT/EP2007/060531 -10 investigate the Angiotensin II Induced increase in diastolic blood pressure prior to and after administration of telmisartan. This test was established to estimate the potency as well as the duration of action of sartans, in particular of telmisartan in cats. Approximately 24 hours after the last oral dosing, diastolic blood pressure 5 responses to increasing intravenous doses of Angiotensin 11 were significantly reduced when the target dose of telmisartan was compared with Placebo. Thus It could be concluded that administration of the target dose, despite the short elimination half-life and bioavailability, in the cat given once daily is capable to exhibit the intended pharmacodynamic action and duration. 10 Thus, according to another aspect, the present invention relates to a method for the prophylaxis or treatment of a systemic disease in cats, preferably of chronic kidney disease, e.g. chronic renal failure, wherein the method comprising administration of a therapeutically effective amount of angiotensin Hl receptor 1 (AT-1) antagonist is (sartan), preferably telmisartan or pharmaceutically acceptable salt thereof, to that cat in need of such a treatment, wherein the therapeutically effective amount of such angiotensin II receptor 1 (AT-1) antagonist is about 0.01 to about 10 mg/kg of body weight. Preferably, said therapeutically effective amount of such angiotensin i receptor 1 (AT-1) antagonist is about 0.05 to about 8 mg/kg of body weight, even 20 more preferably about 0.1 to about 5 mg/kg of body weight, even more preferably about 0.2 to about 4 mg/kg of body weight, even more preferably about 0.3 to about 3 mg/kg of body weight, even more preferably about 0.4 to about 2.5 mg/kg of body weight, even more preferably about 0.5 to about 2 mg/kg of body weight, most preferred about 0.75 to about 1.5 mg/kg of body weight. Thus, said therapeutically 25 effective amount of such angiotensin Il receptor 1 (AT-1) antagonist is for example 0.01, 0.02, 0.03, ... 0.08, 0.09, 0.1, etc.; 0.11, 0.12, 0.13, ... 0.18, 0.19, 0.2, etc.; 0.21, 0.22, 0.23, ... 0.28, 0,29, 0.3 etc. ... ; 0.81, 0.82, 0.83, ... 0.88, 0.89, 0.9 etc.; 0.91, 0.92, 0.93, ... 0.98, 0.99, 1.0 etc.; 1.01, 1.02, 1.03, ... 1.08, 1.09, 1,1 etc.; 1.2, 1.3, ... 1.8, 1.9, 2.0 etc.; 2.1, 2.2, 2.3, ... 2.8, 2.9, 3.0 etc.; .... ; 8.1, 8.2, 8.3, 30 8.8, 8.9, 9.0 etc.; 9.1, 9.2, 9.3, ... 9.8, 9.9, 10 mg/kg of body weight. Angiotensin 11 receptor 1 (AT-1) antagonist, preferably telmisartan may be administered once twice or trice a day in a daily dosage as mentioned above.

WO 2008/040774 PCT/EP2007/060531 -11 In cases when angiotensin II receptor I (AT-1) antagonist is administered by parenteral route, said angiotensin 11 receptor 1 (AT-1) antagonist, preferably telmisartan is administered in a dosage of about 0.01 to about 4 mg/kg of body weight. Preferably, said therapeutically effective amount of such angiotensin II s receptor 1 (AT-1) antagonist is about 0.05 to about 3 mg/kg of body weight, even more preferably about 0.1 to about 2.5 mg/kg of body weight, even more preferably about 0.15 to about 2.0 mg/kg of body weight, even more preferably about 0.2 to about 1.5 mg/kg of body weight, most preferred about 0.25 to about 1.25 mg/kg of body weight. Thus, said therapeutically effective amount of such angiotensin 11 1a receptor I (AT-1) antagonist is for example 0.01, 0.02, 0.03, ... 0.08, 0.09, 0.1, etc.; 0.11, 0.12, 0.13, ... 0.18, 0.19, 0.2, etc.; 0.21, 0.22, 0.23, ... 0.28, 0.29, 0.3 etc. ... ; 0.81, 0.82, 0.83, ... 0.88, 0.89, 0.9 etc.; 0.91, 0.92, 0.93, ... 0.98, 0.99, 1.0 etc.; 1.01, 1.02, 1.03, ... 1.08, 1.09, 1.1 etc.; ... 1.1, 1.2, 1.3, ... 1.8, 1.9, 2.0 etc.; 2.1, 2.2, 2.3, ... 2.8, 2.9, 3.0 etc.; 3.1, 3.2, 3.3, ... 3.8, 3.9, 4 mg/kg of body weight. Angiotensin 11 15 receptor 1 (AT-1) antagonist, preferably telmisartan may be administered once twice or trice a day in a daily dosage as mentioned above. In cases when angiotensin I receptor 1 (AT-1) antagonist, preferably telmisartan is administered by oral, rectal, nasal or inhalative route a dosage of about 0.03 to about 20 10 mg/kg of body weight is preferred. Preferably, said therapeutically effective amount of such angfotensin Il receptor 1 (AT-1) antagonist is about 0.10 to about 8 mg/kg of body weight, even more preferably about 0.20 to about 7.5 mg/kg of body weight, even more preferably about 0.25 to about 7.0 mg/kg of body weight, even more preferably about 0.25 to about 6.0 mg/kg of body weight, most preferred about 25 0.25 to about 5 mg/kg of body weight. Thus, said therapeutically effective amount of such angiotensin 11 receptor I (AT-1) antagonist is for example 0.03, 0.04, 0.05, 0.08, 0.09, 0.1, etc.; 0.11, 0.12, 0.13, ... 0.18, 0.19, 0.2, etc.; 0.21, 0.22, 0.23, 0.28, 0.29, 0.3 etc. ... ; 0.81, 0.82, 0.83, ... 0.88, 0.89, 0.9 etc.; 0.91, 0.92, 0.93, 0.98, 0.99, 1.0 etc.; 1.01, 1.02, 1,03, ... 1.08, 1.09, 1.1 etc.; ... 1.1, 1.2, 1.3, ... 1.8, 30 1.9, 2.0 etc.; 2.1, 2.2, 2.3, ... 2.8, 2.9, 3.0 etc.; .... ; 8.1, 8.2, 8.3, ... 8.8, 8.9, 9.0 etc.; 9.1, 9.2, 9.3, ... 9.8, 9.9, 10 mg/kg of body weight. Telmisartan may be administered once twice or trice a day in a daily dosage as mentioned above.

WO 2008/040774 PCT/EP2007/060531 -12 According to another aspect of the invention, the present invention relates a method for the prophylaxis or treatment of a systemic disease in cats, preferably of chronic kidney disease, e.g. chronic renal failure, wherein the method comprising administration of a therapeutically effective amount of angiotensin I receptor 1 (AT-1) 5 antagonist (sartan), preferably telmisartan or pharmaceutically acceptable salt thereof, to that cat in need of such a treatment, wherein the therapeutically effective amount of such angiotensin I receptor 1 (AT-1) antagonist is administered in a therapeutically effective amount that result in an cumulative intravenous concentration of at least 0.025 mg/kg of body weight (bw) Preferably, said io angiotensin 11 receptor I (AT-1) antagonist (sartan), preferably telmisartan is administered to an cumulative intravenous concentration of at least 0.05 mg/kg of bw, more preferably of 0.1 mg/kg of bw, even more preferably 0.15 mg/kg of bw even more preferably 0.2 mg/kg of bw, even more preferably 0.25 mg/kg of bw, even more preferably 0.40 mg/kg of bw, even more preferably 0.5 mg/kg of bw, even more is preferably 0.75 mg/kg of bw, even more preferably 1 mg/kg of bw. Upper limits of cumulative intravenous concentration of about 1 mg/kg of bw are well tolerable, however, cumulative intravenous concentrations of up to 5, 4, 3 and 2 mg/kg of bw are also within the meaning of the present invention as well as any further higher non-toxic cumulative intravenous concentration of said angiotensin I receptor I (AT 20 1) antagonist (sartan). A person skilled in the art, In view of the teaching given herein, is entitled to estimate that upper non-toxic cumulative intravenous concentration by standard techniques. Optionally, the angiotensin I receptor 1 (AT-1) antagonist (sartan), preferably 25 telmisartan can be administered in combination with other drugs. Such other drugs are, for example Ca-channel blockers (e.g. Amlodipine), beta-blockers (e.g. Atenolol, Carvediol), cardiotonic-Ca-sensitising agents (e.g. Pimobendan, Levosimendan) , selective If-current inhibitors (i.e. Cilobradine, Ivabradine), ACE inhibitors (e.g. ramipril, benazepril, enalapril); anti-obesity drugs (such as Amphetamine derivatives, 30 Sibutramine, Orlistat, Rimonabat) and the like. Thus, according to another aspect, the present invention relates to a method for the prophylaxis or treatment of a systemic disease in cats, preferably of chronic kidney disease, e.g. chronic renal failure, wherein the method comprising administration of a therapeutically effective WO 2008/040774 PCT/EP2007/060531 -13 amount of angiotensin 11 receptor 1 (AT-1) antagonist (sartan), preferably telmisartan or pharmaceutically acceptable salt thereof, together wit another active substance, to that cat in need of such a treatment, wherein said further active substance is a Ca channel blocker (e.g. Amlodipine), beta-blocker (e.g. Atenolol, Carvediol), 5 cardiotonic-Ca-sensitising agent (e.g. Pimobendan, Levosimendan) , selective If current inhibitor (i.e. Cilobradine, Ivabradine), ACE Inhibitor (e.g. ramipril, benazepril, enalapril); an anti-obesity drug (such as Amphetamine derivatives, Sibutramine, Orlistat, Rimonabat) and the like. 10 Telmisartan and the other active compounds can be orally administered in a wide variety of different dosage forms, i.e., they may be formulated with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspensions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and 15 various non-toxic organic solvents. Moreover, such oral pharmaceutical formulations can be suitably sweetened and/or flavoured by means of various agents of the type commonly employed for such purposes. In general, the compounds of this invention are present In such oral dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, in amounts which are sufficient 20 to provide the desired unit dosages. Other suitable dosage forms for the compounds of this invention include controlled release formulations and devices well known to those who practice in the art. For purposes of oral administration, tablets containing various exciplents such as 25 sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicate, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatine and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc or compositions of a 30 similar type may also be employed as fillers in soft and hard-filled gelatine capsules; included lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or WO 2008/040774 PCT/EP2007/060531 -14 flavouring agents, colouring matter or dyes and, if so desired, emulsifying agents and/or water, ethanol, propylene glycol, glycerine and various like combinations thereof. 5 For purposes of parenteral administration, solutions of the compounds in sesame or peanut oil or in aqueous propylene glycol may be employed, as well as sterile aqueous solutions of the corresponding pharmaceutically acceptable salts. Such aqueous solutions should be suitably buffered if necessary, and the liquid diluent rendered isotonic with sufficient saline or glucose. These particular aqueous 1o solutions are especially suitable for intravenous, intramuscular and subcutaneous injection purposes, In this connection, the sterile aqueous media employed are readily obtained by standard techniques well known to those skilled in the art. For instance, distilled water is ordinarily used as the liquid diluent and the final preparation is passed through a suitable bacterial filter such as a sintered glass filter 15 or a diatomaceous earth or unglazed porcelain filter. Preferred filters of this type include the Berkefeld, the Chamberland and the Asbestos Disk-Metal Seitz filter, wherein the fluid is sucked into a sterile container with the aid of a suction pump. The necessary steps should be taken throughout the preparation of these inject-able solutions to insure that the final products are obtained in a sterile condition. 20 For purposes of transdermal administration, the dosage form of the particular compound or compounds may include, by way of example, solutions, lotions, ointments, creams, gels, suppositories, rate-limiting sustained release formulations and devices therefore. Such dosage forms comprise the particular compound or 25 compounds and may include ethanol, water, penetration enhancer and inert carriers such as gel-producing materials, mineral oil, emulsifying agents, benzyl alcohol and the like, These preformulated combinations of active substances are generally incorporated 3 o with one or more formulation adjuvants such as mannitol, sorbitol, xylitol, saccharose, calcium carbonate, calcium phosphate, lactose, croscarmellose sodium salt (cellulose carboxymethylether sodium salt, cross-linked), crospovidone, sodium starch glycolate, hydroxypropylcellulose (low-substituted), maize starch, WO 2008/040774 PCT/EP2007/060531 -15 polyvinylpyrrolidone, copolymers of vinylpyrrolidone with other vinyl derivatives (copovidone), hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose or starch, magnesium stearate, sodium stearylfumarate, talc, hyd roxypropy[methylcellu lose, carboxymethylcellulose, cellulose acetate phthalate, 5 polyvinyl acetate, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetyistearyl alcohol, carboxy methylcellulose or fatty substances such as hard fat or suitable mixtures thereof, Into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories. 10 Tablets may be obtained for example by mixing the active substance or substances with one or more exciplents and subsequently compressing them. The tablets may also consist of several layers. Examples of excipients are o inert diluents such as mannitol, sorbitol, xylitol, saccharose, calcium carbonate, is calcium phosphate and lactose; " disintegrants such as croscarmellose sodium salt (cellulose carboxymethylether sodium salt, cross-linked), crospovidone, sodium starch glycolate, hydroxypropylcellulose (low-substituted) and maize starch; " binders such as polyvinylpyrrolidone, copolymers of vinylpyrrolidone with other 2 0 vinyl derivatives (copovidone), hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose or starch; " lubricants such as magnesium stearate, sodium stearyl fumarate and talc; o agents for achieving delayed release such as hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetate phthalate and polyvinyl acetate; and 25 9 pharmaceutically permitted colourings such as coloured iron oxides. Furthermore, if telmisartan Is used in combination with another drug used for the prophylaxis or treatment of a systemic disease, preferably of chronic kidney disease, e.g. chronic renal failure in cats, the pharmaceutical composition according to the 3 0 invention may be a kit of parts which comprises (a) a first containment containing a pharmaceutical composition comprising a therapeutically effective amount of telmisartan or a physiologically WO 2008/040774 PCT/EP2007/060531 -16 acceptable salt thereof and one or more pharmaceutically acceptable diluents and/or carriers; and (b) a second containment containing another drug used for the prophylaxis or treatment of a systemic disease, preferably chronic renal failure, or a 5 physiologically acceptable salt thereof and one or more pharmaceutically acceptable diluents and/or carriers. A preferred kit of parts comprises one or more Ca-channel blockers (e.g. Amlodipine), beta-blockers (e.g. Atenolol, Carvedio[), cardiotonic- Ca-sensitising 10 agents (e.g. Pimobendan, Levosimendan), selective If-current inhibitors (i.e. Cilobradine, Ivabradine), ACE inhibitors (e.g. ramipril, benazepril, enalapril); anti obesity drugs (such as Amphetamine derivatives, Sibutramine, Orlistat, Rimonabat) and the like, in the second containment. is According to a further aspect, the present invention also relates to the use of an angiotensin Il receptor I (AT-1) antagonist (sartan), preferably of telmisartan for the manufacture of a pharmaceutical composition comprising a therapeutically effective amount of said angiotensin 11 receptor 1 (AT-1) antagonist for the treatment of a systemic disease in cats, 20 Preferably the systemic disease is selected from the group of cardiovascular diseases, such as dilated cardiomyopathy (DCM), mitral valve insufficiency (MI), hypertrophic cardiomyopathy (HCM) and other acquired or hereditary heart diseases, systemic hypertension, for example hypertension associated with renal diseases,, 25 chronic kidney disease and other vascular diseases, metabolic disorders like diabetes mellitus. As mentioned above, chronic kidney disease, preferably chronic renal failure is most preferred. Preferred sartans are those mentioned in an exemplarily manner supra. Most 30 preferred is the use of telmisartan or any pharmaceutically acceptable salt thereof, such as Micardis@. The preferred doses which can be used according to the Invention are those mentioned supra. Preferred administration routes are orally, bucally, parenterally, nasally, rectally or topically, whereas the oral administration WO 2008/040774 PCT/EP2007/060531 -17 being most preferred. Parenteral administration may include subcutaneous, intravenous, intramuscular and intrasternal injections and infusion techniques. 5 EXAMPLES The following examples serve to further illustrate the present invention; but the same should not be construed as a limitation of the scope of the invention disclosed herein. Example 1: 10 The aim of this exploratory study was to investigate the pharmacokinetic behaviour in plasma and the absolute bioavailability of telmisartan in male and female cats following a single oral or intravenous administration. Four clinically healthy male and female domestic short hair cats (HsdCpb: CADS) 15 with a body weight range of 2.6 - 4.2 kg were used in this study. The animals were randomly allocated to 2 groups, 2 animals per group. The study was designed as a 2x2 cross-over trial (i.e. two periods, days 1 and 15) in which the test article telmisartan was given by single oral or intravenous administration at a dose of 1 mg/kg body weight. 20 Blood samples were drawn at 0 h (i,e, prior to treatment), 5 (after i. v. injection only), 15, 30 and 60 min as well as 2, 4, 8, 24, 72 and 96 h after each treatment. Clinical observations were also conducted at these time points. Plasma samples were sent to the analytical laboratory and analysed there using a validated method. The plasma 25 levels measured In each animal were subjected to various pharmacokinetic calculations. The results of this study may be summarised as follows: 3 o No specific clinical signs were noted during the entire course of the study. Pharmacokinetic analyses for telmisartan revealed the following results: WO 2008/040774 PCT/EP2007/060531 -18 Route of Administration Parameter oral i.v. t max [hour] mean 0.438 C max [ng/ml] mean 138.10 AUC 0 + - mean 150.426 384.751 [ng-h/ml] AUC 0+' c- mean 138.598 375.945 [ng-h/mi] t %2 [hour] mean 2.169 2.252 ClIf or CI [ml/min-kg] mean 171.588 45.535 V/f or V [Il/kg] mean 20.453 8.856 MRT [hour] mean 1.969 0.789 The points estimate for the absolute bioavailability were 0.316 for AUC 0 --- + t and 0.336 for AUC 0 --- + - with respective 95% confidence intervals of 0.086 - 1.165 and 0.0,90 - 1.245. Individual data showed that the bioavailability was clearly lower in 5 animal no. 101 (i.e. 0.116 for AUC 0-> c) in comparison with the other animals (i.e. 0.387 - 0.582). The test article telmisartan was well tolerated after a single oral or intravenous administration to cats at a dose of 1 mg/kg body weight. 10 Mean plasma concentrations increased until 15 - 30 min after oral administration of telmisartan and declined rapidly afterwards. No quantifiable plasma concentrations could be found at 24 h after both routes, orally and intravenously. 15 The absolute bioavailability after oral administration was found to be 33%. Example 2: The aim of this study was to investigate the effects of an escalating intravenous dose 20 of telmisartan on the blood pressure response of anaesthetised cats after WO 2008/040774 PCT/EP2007/060531 - 19 administration of angiotensin 11. The originally intended endpoint of the study was to find a dose of telmisartan which inhibits 90% of the angiotensin blood pressure response. s Four clinically healthy adult male and female domestic short hair cats (HsdCpb: CADS) with a body weight range of 2.5 - 3.5 kg were used in this study. The animals were anaesthetised with sodium pentobarbital and anaesthesia was sustained by continuous infusion of diluted anaesthetic. A catheter was inserted into a carotid artery and connected to a pressure transducer for registration of the arterial pressure. 1o Another catheter was placed into the femoral vein for administration of angiotensin II (A2) or the test article telmisartan. The systolic and diastolic blood pressure [mmHg] in the carotid artery were recorded and analysed at discrete intervals as described below. 15 At first, the diastolic blood pressure was registered 6 times every 5 minutes. The mean of these 6 measurements were set as the baseline blood pressure. Then two bolus injections of A2 were administered at a dose of 0.1 pg/kg in an Interval of 10 min. The maximum increase in diastolic blood pressure obtained from the second A2 bolus relative to the baseline blood pressure was taken as the control angiotensin 11 2o blood pressure response (i.e. reference value). Five minutes after the reference value was obtained, the first injection of telmisartan was administered. Thirty minutes later the diastolic blood pressure was recorded, immediately followed by bolus injection of A2 at a dose of 0.1 pg/kg and the 2 5 maximum increase in diastolic blood pressure was obtained. This procedure was to be repeated accordingly until the intended endpoint of the experiment (i.e. an A2 pressure response s 10% of the control A2-pressure response corresponding to 90% inhibition) was reached. During the course of the experiment It had been shown that the dose of telmisartan had to be increased at single time points in order to 3 0 increase the effect. In addition, the endpoint of a 90% Inhibition could not be reached in 3 of 4 animals even after several consecutive steps as described above so that the experiment was terminated in these individual animals before. At the end of the WO 2008/040774 PCT/EP2007/060531 -20 experiment, the anaesthetised animals were euthanized with an overdose of sodium pentobarbital. The results of this study may be summarised as follows (see Figure 1): 5 The mean baseline diastolic blood pressure of the individual animals ranged from 82 - 99 mmHg and the control angiotensin Il-blood pressure response was between 34 and 63 mmHg, 10 After treatment with telmisartan, the response pattern was similar in 3 animals (i.e. animal nos. 102, 151, 152). In these animals the maximal inhibition of the blood pressure increase relative to the control angiotensin Il-blood pressure response was roughly 80 - 95% in contrast to 50% inhibition in animal no. 101. 15 However, the final cumulative dose of the test article was only 0.1mg/kg In this animal whereas this dose ranged between 0.34 and 0.4 mg/kg in the other animals. In animal no. 101 the maximum effect of 50% inhibition was reached at a cumulative dose of 0.05 mg/kg. In animal nos. 102 and 152 a 73% Inhibition was already 20 reached after the 1" dose of 0.04 and 0.02 mg/kg, respectively. In animal no. 151 the same inhibition of 73% was reached at a cumulative dose of 0.04 mg/kg. In all 4 animals, further escalation of the dose did not produce markedly higher effects which were appropriately related to the increase of the dose. 25 In conclusion, escalating intravenous doses of the test article telmisartan led to an inhibition of the diastolic blood pressure Increase in anaesthetised cats after administration of angiotensin 11. An inhibition of 73% was found at the cumulative dose of 0.04 mg/kg telmisartan in 3 30 of 4 animals. In one animal, a maximum inhibition of 50% was observed at a cumulative dose of 0.05 mg/kg. In all 4 animals, further dose escalations did not produce an appropriate dose response relationship.

WO 2008/040774 PCT/EP2007/060531 -21 Example 3: The aim of this blinded controlled, randomised exploratory study was to investigate the safety of telmisartan in male and female cats after repeated oral administration 5 over four weeks. Twelve clinically healthy approximately 1 year old male and female, domestic short hair cats (HsdCpb: CADS) with a body weight range of 2. 5 - 5. 1 kg were used in this study. The animals were allocated to 3 groups, 4 animals per group. All animals were 10 treated with the test article telmisartan or control article (i.e. placebo) once daily on days 0 to 27. The test/control article was administered orally at three different does levels of 0.0 (placebo; group 1), 1 (group II) and 3 (group Ill) mg telmisartan/kg body weight. The bottles with the test/control article looked identical with the exception of the animal no. in order to achieve blinding. 15 Blood samples for haematology and clinical chemistry were collected from the animals on days-1 (L.e. prior to the first treatment) and again on days 3, 7, 14, 28. Body weights were measured weekly and electrocardiography recording were made on days-1, 14, 21 and 28. A detailed physical examination including determination of 20 rectal temperature and respiratory rate was carried out on days -1, 7, 14, 22 and 28. Systolic blood pressure (once daily) and heart rate (twice daily) were determined five days per week beginning prior to treatment until necropsy. The palatability of the administered article was assessed at various time points throughout treatment using a scoring system. On day 28 of the study, all animals were subjected to necropsy 25 and stomach and kidneys were examined histopathologically. Relevant parameters were analysed using appropriate statistical procedures. The results of this study can be summarised as follows: 30 No clinical findings clearly attributable to the treatment with the test article were observed during the entire study period.

WO 2008/040774 PCT/EP2007/060531 - 22 Although no significant differences were found the results of the assessment of the palatability might indicate a slightly impaired palatability of the test article formulation. However, the palatability was predominantly good or acceptable in the animals of both treated groups Il and Ill. Physical and ECG examinations did not reveal treatment-related findings at all time points of investigation. No significant differences were found in the body weights, rectal temperature, 10 respiratory and heart rates during the course of the study. The systolic blood pressure was significantly lower in the treated groups II and Ill compared to the control group I on single occasions after initiation of treatment. In addition, differences of borderline significance were found including the time before 15 treatment. Changes from baseline did not reveal significant differences between treated groups and controls. However, the course of the mean values over time might suggest a tendency of a slight reduction of the systolic blood pressure in groups 11 and Ill compared to group I from day 20 onwards. 20 No treatment-related differences were found between treated groups and the concurrent controls in the haematological and clinical chemistry parameters including the differential leukocyte count on each day of examination during the study. Urinalysis did also not provide evidence of a treatment effect. 25 No animal showed any specific finding during necropsy. Histopathology revealed a few findings in stomach and kidneys but there were no histopathological findings considered to be associated with the treatment. 30 Due to the exploratory nature of this study the number of animals per treatment group was rather low, Taking this fact into consideration the results of the present study may permit the following conclusions: H:fml\lnienvoven\NRPodlbl\DCC\FMT\O1725 I.doc-I /04/2013 - 23 A slightly impaired palatability of the test article formulation containing telmisartan might be identified. The course of the mean values over time might suggest a tendency of a slight reduction of 5 the systolic blood pressure in the animals treated with telmisartan towards the end of the study period. The test article telmisartan was well tolerated after repeated oral administration over 4 weeks to cats at doses of 1 and 3 mg/kg body weight. 10 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. 15 The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour 20 to which this specification relates.

Claims (14)

1. Use of an angiotensin || receptor 1 (AT-1) antagonist for the manufacture of a pharmaceutical composition comprising a therapeutically effective amount of said angiotensin || receptor 1 (AT-1) antagonist for the treatment of the metabolic disease diabetes mellitus in cats, wherein said angiotensin || receptor 1 (AT-1) antagonist is a sartan.

2. The use according to claim 1, wherein the angiotensin || receptor 1 (AT-1) antagonist is selected from the group consisting of: candesartan, eprosartan, irbesartan, losartan, tasosartan, telmisartan, valsartan, and a pharmaceutically acceptable salt thereof.

3. The use according to claim 1 or 2, wherein angiotensin || receptor 1 (AT-1) antagonist is telmisartan or a pharmaceutically acceptable salt thereof.

4. The use according to any one of claims 1 to 3, wherein the therapeutically effective amount of the angiotensin || receptor 1 (AT-1) antagonist is about 0.01 to about

5.0 mg/kg of body weight. 5. The use according to any one of claims 1 to 4, wherein the pharmaceutical composition is administered to a subject in need thereof by parenteral route in a dosage of about 0.01 to about 1 mg angiotensin || receptor 1 (AT-1) antagonist per kg of body weight or by oral, rectal, nasal or inhalative route in a dosage of about 0.03 to about 5.0 mg angiotensin || receptor 1 (AT-1) antagonist per kg of body weight.

6. The use according to any one of claims 1 to 5, wherein the pharmaceutical composition is administered to a subject in need thereof in a therapeutically effective amount that results in a cumulative intravenous dose of the angiotensin || receptor 1 (AT-1) antagonist of at least about 0.025 mg/kg of body weight.

7. A method for the prophylaxis or treatment of the metabolic disease diabetes mellitus in cats, wherein the method comprises administration of a therapeutically H:\rec\ntr ovn\NRPortb\DCC\REC\735575I .docx-13/01/2015 - 25 effective amount of angiotensin || receptor 1 (AT-1) antagonist to a cat in need of such a treatment, wherein said angiotensin || receptor 1 (AT-1) antagonist is a sartan.

8. The method according to claim 7, wherein the angiotensin || receptor 1 (AT-1) antagonist is selected from the group consisting of: candesartan, eprosartan, irbesartan, losartan, tasosartan, telmisartan, valsartan, and a pharmaceutically acceptable salt thereof.

9. The method according to claim 7 or 8, wherein angiotensin || receptor 1 (AT-1) antagonist is telmisartan or a pharmaceutically acceptable salt thereof.

10. The method according to any one of claims 7 to 9, wherein the therapeutically effective amount of the angiotensin receptor 1 (AT-1) antagonist is about 0.01 to about 5.0 mg/kg of body weight.

11. The method according to any one of claims 7 to 10, wherein the angiotensin || receptor 1 (AT-1) antagonist is administered by parenteral route in a dosage of about 0.01 to about 1 mg/kg of body weight or by oral, rectal, nasal or inhalative route in a dosage of about 0.03 to about 5 mg/kg of body weight.

12. The method according to any one of claims 7 to 11, wherein the angiotensin || receptor 1 (AT-1) antagonist is administered in a therapeutically effective amount that results in a cumulative intravenous dose of at least 0.025 mg/kg of body weight.

13. The use according to claim 1 substantially as hereinbefore described with reference to any one of the Examples and/or Figures.

14. The method according to claim 7 substantially as hereinbefore described with reference to any one of the Examples and/or Figures.