J Vet Intern Med 2006;20:1074–1079

Evaluation of the Clinical Efficacy of Benazepril in the Treatment of Chronic Renal Insufficiency in Cats Hisashi Mizutani, Hidekazu Koyama, Toshifumi Watanabe, Hitoshi Kitagawa, Masakazu Nakano, Keita Kajiwara, and Jonathan N. King Background: Chronic renal insufficiency (CRI) is a common disease in cats. Angiotensin-converting enzyme inhibitors (ACEI) have beneficial effects in humans with CRI by reducing the loss of protein in the urine and increasing life expectancy. Hypothesis: The ACEI benazepril has beneficial effects on survival, clinical variables, or both as compared with placebo in cats with CRI. Animals: 61 cats with naturally occurring CRI. Methods: The cats were enrolled into a prospective, randomized, double-blind, placebo-controlled clinical trial. Cats received placebo or 0.5–1 mg/kg benazepril once daily for up to 6 months. Results: Urine protein/urine creatinine ratios were significantly (P , .05) lower with benazepril as compared with placebo at days 120 and 180. Three cats with placebo and 1 cat with benazepril were removed prematurely from the study because of deterioration of CRI or death. Cats were classified into 4 stages of CRI according to the International Renal Interest Society (IRIS) classification scheme. Incidence rates of cats with IRIS classification stage 2 or stage 3 that remained in stage 2 or 3 without progressing to stage 4 were higher with benazepril (93 6 5%) as compared with placebo (73 6 13%). Clinical Importance: These results suggest a potential for benazepril to delay the progression of disease, extend survival time, or both in cats with CRI. Key words: ACEI; Benazepril; Cat.

Introduction Chronic renal insufficiency (CRI) is a common disease in cats.1,2 Data generated in induced CRI in cats, dogs, and rats, and in human clinical trials have revealed that angiotensin-converting enzyme inhibitors (ACEI) have beneficial effects in the treatment of CRI by reducing systemic and glomerular hypertension, reducing the loss of protein in the urine, and increasing life expectancy.1–9 The principle mechanism of action of ACEI is reduction of the enzymatic transformation of angiotensin I to angiotensin II. Glomerulosclerosis with proliferation and hypertrophy of mesangial cells induced by glomerular hypertension is considered one of contributing factors for CRI, and angiotensin II contributes to glomerular hypertension and the development of glomerulosclerosis.5 Benazepril is a prodrug that is metabolized in vivo by the liver to benazeprilat, a potent and selective inhibitor of ACE.10 Dosages of benazepril hydrochloride (HCl) of 0.5 mg/kg and above cause maximal inhibition of

From the Division of Veterinary Internal Medicine, Nippon Veterinary and Life Science University, Tokyo, Japan (Mizutani, Koyama); and the Department of Surgery I, School of Veterinary Medicine, Azabu University, Kanagawa, Japan (Watanabe); and the Laboratory of Veterinary Internal Medicine, Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan (Kitagawa); and the Novartis Animal Health, Tokyo, Japan (Nakano, Kajiwara); and the Novartis Animal Health, Inc, Basel, Switzerland (King). Reprint requests: Hisashi Mizutani, Division of Veterinary Internal Medicine, Nippon Veterinary and Life Science University, Kyonan-cho 1-7-1, Musashino-shi, Tokyo 180-8602, Japan; e-mail: [email protected]. Submitted August 9, 2005; Revised March 3, 2006; November 22, 2005; Accepted April 4, 2006. Copyright E 2006 by the American College of Veterinary Internal Medicine 0891-6640/06/2005-0003/$3.00/0

plasma ACE activity in cats throughout a 24-hour period.10 Benazepril reduced systemic and glomerular hypertension in an experimental model of renal insufficiency in cats, the optimal dose being 0.5 mg/kg.3 Beneficial effects of benazepril have been proven in human CRI, including reduction in urine protein and prolongation of survival time.7,8,11 Only preliminary data have been published at present from clinical trials with ACEI in CRI in cats.a,b The present prospective, randomized, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and tolerability of benazepril HCl at dosages ranging from 0.5 to 1.0 mg/kg once daily in the treatment of naturally occurring CRI in cats.

Materials and Methods Trial Design The study was a multicenter, double-blind, parallel-group, placebo-controlled, prospective clinical trial in cats with naturally occurring CRI. Cats that satisfied the inclusion criteria and did not satisfy the exclusion criteria were randomized to receive once daily either benazepril HCl, at dosages ranging from 0.5 to 1.0 mg/ kg, or a matched placebo. The test treatment and placebo had an identical appearance to keep the investigators and cat owners blinded. Cats included in the study were examined by the veterinarian once 1 to 3 weeks before the start of the trial on the starting date (day 0) and on days 7, 30, 60, 120, and 180 after the start of the trial. The trial ran from February 5, 1999 to October 20, 2003.

Animal Selection According to the inclusion criteria defined in the protocol, cats had to concurrently satisfy the following 2 conditions at the start of the trial: (1) plasma creatinine concentration $2.0 mg/dL or urine protein level $++ by the stick method and (2) urine specific gravity #1.025. These criteria had to be fulfilled at both day 0 and the preceding visit (1–3 weeks prior) to establish stability of the CRI. There were no restrictions on inclusion or exclusion criteria in relation to age, breed, or sex of the cats.

Benazepril for Renal Insufficiency The following were preadmission exclusion criteria: acute renal insufficiency or nephropathy within 28 days of the start of the trial, CRI of prerenal or postrenal origin, chronic heart failure (New York Heart Association class II, III, or IV), cystitis or presence of uroliths, diabetes mellitus with uncontrolled hyperglycemia, edema requiring diuretic therapy, chronic gastrointestinal disease judged likely to interfere with the absorption of benazepril, clinically significant hepatic disease, malignant neoplasia, female animals that were pregnant or were planned to become pregnant during the next 1 year, and cats requiring regular intravenous fluids.

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Blood Examination Plasma creatinine and urea (PUN) concentrations were measured to assess the effectiveness of the test treatments. Plasma total protein, albumin, alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), inorganic phosphate, electrolytes (Na, K, Ca, and Cl), blood erythrocyte and leukocyte counts, and hematocrit were analyzed to evaluate the general health condition of the cats. These examinations were carried out by automatic analyzers installed at each of the veterinary clinics.

Allocation of Cats to Treatment Groups

Urinalyses

Cats that were confirmed to satisfy the inclusion criteria and not to fulfill the exclusion criteria stated previously were allocated to receive either benazepril or placebo (‘‘benazepril group’’ or ‘‘placebo group,’’ respectively). Allocation to treatment group was randomized by preprepared allocation tables.

Urine specimens were collected from spontaneous urination, by expression of the bladder, or by urethral catheterization. Confirmation of urine protein with a stick method based on protein error of indicator principle and measurements of urine specific gravity with a gravimeter were conducted immediately after urine collection at the veterinary clinic. Samples of urine were frozen and analyzed later for quantitative determination of urine protein and urine creatinine concentrations by the pyrogallol red and enzymatic methods, respectively, at Sumitomo Metal Bio-Science, Inc. (Tokyo, Japan).

Benazepril Tablets and Placebo Tablets A quarter-divisible tablet containing 5 mg of benazepril HClc was used as the test drug. Benazepril tablets were administered at a dosage of 0.5 to 1.0 mg per kg body weight once daily according to the following scheme: body weight 1.25–2.5 kg, 0.25 tablet; 2.5– 5.0 kg, 0.5 tablet; 5.1–10 kg, 1 whole tablet. Equal amounts of placebo tablets were administered to the placebo group. Tablets were given once daily at approximately the same time each day, with or without feeding. The maximum treatment duration was defined as 6 months.

Prohibited Concomitant Drugs Use of the following concomitant drugs that were considered to have an action on the circulatory and urinary systems was prohibited during the trial to not complicate evaluation of the effect of the test compound: (1) antihypertensive drugs, diuretics (other than benazepril); (2) vitamin D and its derivatives; (3) nonsteroidal anti-inflammatory drugs, corticosteroids; (4) phosphorus chelating agents; (5) oral charcoal adsorbentd; and (6) antibiotics with nephrotoxic properties. In cats with previous administration of these drugs, these agents had to be withdrawn at least 1 week before starting the clinical trial.

Diet To minimize changes during the trial, owners were instructed to feed the cat the same diet during the 3-week selection phase and during the trial. Special prescription diets designed for the treatment of CRI were not permitted.

Clinical Examination Observations were made about general clinical condition (body weight, coat, neurologic signs, and respiration), digestive system (appetite, buccal cavity lesions, diarrhea, and vomiting), and urinary system (urination and water intake). The general clinical condition was graded according to the severity of signs on a 5-point scale: coma 5 1, severe asthenia 5 2, moderate asthenia 5 3, slight asthenia 5 4, and normal activity 5 5. The appetite was graded on a 5-point scale: complete anorexia 5 1, markedly reduced appetite 5 2, slightly reduced appetite 5 3, bulimia 5 4, and good appetite 5 5. The drinking behavior and urination were graded according to 4-point scales: cannot judge 5 0, above normal 5 1, below normal 5 2, and normal 5 3. Systemic blood pressure was not measured.

Adverse Events Adverse events were recorded at each visit after interviewing the cat owner and from results of clinical and blood examinations.

Efficacy Assessment Criteria The primary efficacy end points were urine protein (determined from the urine protein/urine creatinine ratio [UPC]) and PUN. The secondary efficacy end point was ‘‘renal survival,’’ defined as the time from inclusion in the trial to the occurrence of either of the following: (a) premature withdraw from the trial because of deterioration of CRI such that the veterinarian judged that hemodialysis or euthanasia of the cat was necessary or (b) death of the cat. As additional tertiary efficacy end points, changes over time in clinical signs of the cat (general clinical signs, signs affecting the digestive or urinary system), quality of life of the cat, and an overall assessment of efficacy were also evaluated.

Data Analysis In most cats data were normally distributed and therefore analysis of variance with repeated measures was used to test differences between the benazepril and placebo groups. However, the Friedman test was used for UPC and urine protein as these data were not normally distributed. The Mann-Whitney U test was used for the comparison between the 2 groups at each observation time, and the x2 test was used for frequency data. Survival data were analyzed by the Kaplan-Meier method and the log rank test. The effect of center was not tested.

Results Animals A total of 61 cats fulfilled the inclusion criteria, did not satisfy the exclusion criteria, and provided sufficient data to permit evaluation of the efficacy and tolerability of the test treatments. The 61 cats consisted of 22 intact males, 15 neutered males, 19 intact females, and 5 neutered females, with an average age of 11.7 years (range, 1–19 years) and an average body weight of 4.1 kg (range, 1.9–6.9 kg). The benazepril group test

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group consisted of 33 cats (14 intact males, 8 neutered males, 10 intact females, and 1 neutered female), aged 11.5 years (range, 1–19 years) and weighing 3.9 kg (range, 1.9–5.9 kg). The placebo group consisted of 28 cats (8 intact males, 7 neutered males, 9 intact females, and 4 neutered females), aged 11.9 years (range, 4– 18 years) and weighing 4.4 kg (range, 2.2–6.9 kg). Cats allocated to the 2 groups were matched at baseline with respect to clinical signs, plasma creatinine concentration or urine protein level, and urine specific gravity.

Clinical Chemistry Data from 2 cats with cystitis were deleted from the urine protein analyses (60, 120, and 180 days of the test for cat 9 and whole trial for cat 209). There was no significant change in UPC with time in the benazepril group (P 5 .69), whereas there was a significant increase in UPC with time in the placebo group (P 5 .015) (Fig 1). The UPC was significantly lower in the benazepril group at days 120 (P 5 .043) and 180 (P 5 .015). No significant effect of treatment or time was observed on plasma creatinine concentration (Fig 2). No significant effect of time or treatment was detected in PUN (Fig 3). There were no significant changes with time or differences between groups in total protein, albumin, ALT, ALP, AST, inorganic phosphate, electrolytes (Na, K, Ca, and Cl), blood erythrocyte and leukocyte counts, and hematocrit.

Fig 1. Ratio of urine protein/urine creatinine in cats with chronic renal insufficiency. Treatment 5 0.5–1 mg/kg benazepril HCl once daily. *P,.05 vs benazepril at that time point.

Survival The number of cats that died during the trial was zero (0%) in the benazepril group and 3 (11%) in the placebo group. The 3 cats died of renal insufficiency. One cat in the benazepril group was withdrawn from the trial for dialysis. Therefore, the number of cats dead or withdrawn from the trial in accordance with the renal survival criteria defined in the protocol was 1 cat (3%) in the benazepril group and 3 cats (11%) in the placebo group (P 5 .255, x2 test). As an additional analysis, results were analyzed from the time of treatment onset to worsening of clinical condition with the CRI staging system for plasma creatinine established by the International Renal Interest Society (IRIS).12 In the IRIS classification, cats with plasma creatinine ,1.6 mg/dL are stage 1, 1.6– 2.8 mg/dL are stage 2, 2.8–5.0 mg/dL are stage 3, and .5.0 mg/dL are stage 4.12 In stage 4 severe renal azotemia occurs, normal renal function is lost, and continuous fluid therapy or hemodialysis is required. Two different end points were analyzed for creatinine: (1) change from stage at enrollment to stage 4, death, or withdrawal of the cat from the trial because of worsening CRI and (2) change from stage 2 or 3 at enrollment to stage 4; cats that were in stage 4 at enrollment (4 cats in the benazepril group and 2 cats in the placebo group) were not included in the analysis. The cumulative survival rates at the termination of the trial were 88 6 6% in the benazepril group and 70 6 13% in the placebo group (P 5 .195) (Fig 4). When cats in stage 4 at enrollment were not included in the

Fig 2. Plasma creatinine concentration in cats with chronic renal insufficiency. Treatment 5 0.5–1 mg/kg benazepril HCl once daily. No significant differences between groups were detected.

Fig 3. Plasma urea concentration in cats with chronic renal insufficiency. Treatment 5 0.5–1 mg/kg benazepril HCl once daily. No significant differences between groups were detected.

Benazepril for Renal Insufficiency

Fig 4. Kaplan-Meier plots of time (days) from onset of treatment in cats with chronic renal insufficiency to worsening of clinical condition, defined as reaching International Renal Interest Society (IRIS) classification stage 4 (plasma creatinine concentration .5.0 mg/dL) when therapy was started in IRIS stage 2 or 3, death, or withdrawal from the trial because of worsening CRI. P 5 .195 (log-rank test).

analysis, the cumulative survival rates at the termination of the trial were 93 6 5% in the benazepril group and 73 6 13% in the placebo group (P 5 .196) (Fig 5).

Quality of Life and Assessment of Efficacy The change in quality of life for each cat was assessed by the veterinarian after questioning the owner as much improved, improved, same, or worse at each visit and at the termination of the trial. Although more cats were rated as improved with benazepril (11/32 or 34%) as compared with placebo (6/29 or 21%), differences did not approach statistical significance (P 5 .47, x2 test) (Fig 6). A global assessment of the efficacy of the test treatments was made by the veterinarian at the final visit according to very good, good, average, or insufficient (Fig 7). Differences between groups reached statistical significance (P 5 .022, x2 test) with good efficacy more common in the benazepril group (11/32,

Fig 5. Kaplan-Meier plots of time (days) from onset of treatment in cats with chronic renal insufficiency in International Renal Interest Society (IRIS) stage 2 (plasma creatinine concentration 1.6–2.8 mg/dL or stage 3 (plasma creatinine concentration 2.8– 5 mg/dL) required to reach IRIS classification stage 4 (plasma creatinine concentration .5.0 mg/dL). P 5 .196 (log-rank test).

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Fig. 6. Quality of life for cats with chronic renal insufficiency assessed at the final visit as represented by proportion of cats in each category. P 5 .47 (x2 test).

34%) as compared with the placebo group (3/27, 11%). The number of cats rated with insufficient efficacy was also higher (7/27, 26%) with placebo as compared with benazepril (2/32, 6%).

Other Clinical Signs There was a significant difference in body weight between the groups before the start of the trial, but no significant difference between groups was noted throughout the trial. Appetite, vomiting, drinking behavior, and urination were evaluated by 3- to 5-point scales, and there were no significant differences between groups during the trial for any parameter (x2 test).

Adverse Events Adverse events were recorded on a total of 7 occasions in 5 cats (benazepril, 3 occasions, 3 cats; placebo, 4 occasions, 2 cats). Three events were rated by the veterinarian as being unrelated to test treatment: very mild blood in the feces (benazepril), severe dyspnea caused by inhalation pneumonia (benazepril), and very severe asthenia leading to death (placebo). In 1 cat (placebo) with severe vomiting, anorexia, and weakness on 3 separate occasions resulting finally in death, the veterinarian could not judge the relation to the test treatment. Our assessment is that the adverse events in the placebo cats (resulting in death) were probably related to worsening CRI.

Fig 7. Clinical efficacy of benazepril in cats with chronic renal insufficiency at the final visit. Data are proportion of cats in each group. P 5 .022 (x2 test).

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There was only 1 adverse event judged by the veterinarian as being likely related to the test treatment. This cat had moderately severe diarrhea and staggering gait after 86 days of benazepril administration. Benazepril administration was continued, and the cat was administered antibiotics and recovered fully by day 100. A bacterial diarrhea was suspected. Since no increase in prevalence of any bacterial infection with benazepril has been reported, it is unlikely that benazepril was the cause of the diarrhea. Benazepril might cause a staggering gait via excessive reduction in blood pressure; however, it is difficult to judge if the staggering behavior was caused by bacterial diarrhea, CRI, or a decrease in blood pressure. The investigator judged that the signs in this cat were probably unrelated to benazepril.

Discussion The strengths of this study include that it was a prospective, randomized, placebo-controlled clinical trial in cats with naturally occurring CRI. The principle weakness is that we only included 61 cats and followed them for 6 months, and therefore the study was underpowered to detect significant differences between benazepril and placebo for some end points, notably survival time. In addition, systemic blood pressure was not measured because reliable methods were not used routinely in Japan at the time the trial began. Therefore, we could neither stage cats according to their blood pressure with the IRIS staging system12 nor examine effects of treatment on blood pressure. Statistically significant effects were observed for 2 end points, urine protein and an overall assessment of efficacy. Benazepril significantly (P , .05) reduced UPC as compared with placebo at later time points (days 120 and 180) and inhibited the worsening of proteinuria that was observed with time in the placebo group. In addition, the overall efficacy of treatment was rated by the veterinarian at the end of trial as statistically significantly (P 5 .022) better with benazepril than with placebo. The number of cats rated with good efficacy was higher with benazepril (34%) than placebo (11%), and the number of cats rated with insufficient efficacy was lower with benazepril (6%) than with placebo (26%). In addition to these statistically significant results, nonsignificant trends were observed for several end points: both plasma creatinine and urea concentrations were lower at the end of trial with benazepril as compared with placebo, quality of life was higher with benazepril than placebo, the number of cats with treatment failure during the trial (death or withdrawal because of worsening CRI) was lower with benazepril (3%) than with placebo (11%), and the number of cats progressing from IRIS stage 2 or 3 to stage 4 during the trial was lower with benazepril (93%) as compared with placebo (73%). These results suggest that benazepril may have inhibited the progression of CRI. However, the trial was underpowered, both in number of cats (61) and treatment duration (6 months), to reliably test these end points. The results described above are consistent with previous work with benazepril and other ACEI in

CRI. Benazepril has been shown to inhibit proteinuria in humans with CRI and increase survival time, notably in the large AIPRI study.7,8 Benazepril has been reported to reduce proteinuria in cats with CRI in preliminary reports of 2 clinical studies.a,b The reduction in proteinuria may be caused by several actions of benazepril, notably reduction in glomerular hypertension and improved function of the glomerular basement membrane. Treatment of glomerular hypertension with return of glomerular capillary pressure to normal has been described previously in experimental CRI in cats.3 Proteinuria has been identified as an independent risk factor for the progression of disease in CRI in humans and therefore should be treated, ACEI being the most effective therapies for reducing urine protein.13,14 Data in cats also suggest that proteinuria is a risk factor for a poor prognosis.15,a,e,f In preliminary retrospective studies in cats with CRI, hypertension, or both,a,e,f higher levels of proteinuria were associated with shorter survival. In an experimental model of CRI in cats, proteinuria was associated with nephron hypertrophy, increased intraglomerular pressure, and hyperfiltration.15 Most of the cats in this study had low levels of proteinuria. Although previously it was understood that only higher levels of proteinuria (UPC . 0.43) were relevant clinically, recent data suggest that lower levels of proteinuria are relevant.e,g In a preliminary study in clinically healthy nonazotemic cats, survival times were significantly longer in animals with a mean UPC value of 0.11 as compared with the group with a mean UPC value of 0.30.g Although the results of this study suggest a possible benefit of benazepril in improving survival time or delaying worsening of CRI in cats, no effect was proven since statistical significance was not reached. The relative low number of cats (61) and short treatment time (6 months) were probably insufficient to test with sufficient power the effect of benazepril on these end points. Interestingly, in the human AIPRI study, plasma creatinine concentrations were slightly higher at the start of therapy with benazepril as compared with placebo, presumably because of slight reduction in glomerular filtration rate (GFR) secondary to reduced glomerular hypertension.7 Nevertheless, benazepril inhibited the progression of CRI and led to lower creatinine concentrations at later time points.7 A similar profile was noted in these cats for plasma creatinine with slightly higher concentrations with benazepril before day 60 followed by lower concentrations after day 60, although effects were not statistically significant. In an experimental model of CRI in cats, benazepril certainly reduced glomerular hypertension; however, GFR was in fact increased because benazepril increased the filtration efficiency of the nephrons.3 Nevertheless, the results support the finding in humans that mild increases in plasma creatinine at the start of therapy are not a reason to stop therapy with benazepril.7 A statistically significant benefit of benazepril on the veterinarian’s assessment of overall efficacy and a nonsignificant trend to improved quality of life with

Benazepril for Renal Insufficiency

benazepril was observed. These results suggest improved well-being or quality of life of the cats treated with benazepril. Possible mechanisms of action for these effects are reduced systemic hypertension or improved appetite with benazepril. Benazepril has been shown to have a small systemic antihypertensive effect in cats with experimental CRI, although it had comparatively greater effect on the intrarenal blood pressure.3 In addition, in healthy young cats, benazepril significantly increased appetite and body weight.h Benazepril appeared to be well tolerated in the cats, with no differences from placebo in adverse events, plasma biochemistry, or blood CBC parameters. In conclusion, some beneficial effects of benazepril were proven statistically in this clinical trial in cats with naturally occurring CRI (reduction of proteinuria and assessment of overall efficacy). The results also suggest a possible benefit of benazepril in inhibiting the progression of CRI and prolonging survival time in cats with CRI, but this was not proven statistically. Further trials with more cats, longer treatment times, or both are needed to test for these actions.

Footnotes a

Gunn-Moore D, for the BENRIC study group. Influence of proteinuria on survival time in cats with chronic renal insufficiency. J Vet Intern Med 2003;17:405 (Abstract) b Watanabe T, Mishina M, Wakao Y. Studies with the ACE inhibitor benazepril in an experimental model and in clinical cases of renal insufficiency in cats. Proc 17th ACVIM 1999;718 c Fortekor 5, Novartis Animal Health Inc, Basel, Switzerland d Covalzin, Sankyo Lifetech Co, Ltd, Tokyo, Japan e Syme HM, Elliot J. Urinary protein excretion in cats with renal failure and/or hypertension. J Vet Intern Med 2003;17:405 (Abstract) f Syme HM, Elliot J. Relation of survival time and urinary protein excretion in cats with renal failure and/or hypertension. J Vet Intern Med 2003;17:405 (Abstract) g Walker D, Syme HM, Markwell P, et al. Predictors of survival in healthy, non-azotaemic cats. J Vet Intern Med 2004;18:417 (Abstract) h Witte S, Goldenthal E, King JN. Effects of long term treatment with benazepril HCl in healthy cats. J Vet Intern Med 2003;17:436 (Abstract)

Acknowledgments The authors gratefully acknowledge Prof Katsuya Kito at Gifu University, Dr Tomiya Uchino at Animal ME Research Center, Dr Toru Kurita at Tendo Animal Hospital, Dr Koji Nishida at Nishida Veterinary Clinic, Dr Keiji Kamakura at Kamakura Animal Hospital, Dr Masahiko Noya at Noya Animal Hospital, Dr Hiroto Maeda at Maeda Veterinary Clinic, Dr Hitoshi Nagawa at Nagawa Animal Hospital, Dr Yasuhito Kuwahara at Kuwahara Animal Hospital, Dr Kosuke Takazawa at Takazawa Animal Hospital, Dr Masaaki Akatsuka at

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Akatsuka Pet Clinic, Dr Koichi Fujii at Fujii Animal Hospital, Dr Takahiro Minato at Minato Animal Hospital, Dr Daisuke Murayama at Murayama Daisuke Animal Hospital, Dr Kiyoshi Okusa at Okusa Animal Hospital, Dr Masaoki Otaku at Otaku Animal Hospital, Dr Masaru Sato at Sato Veterinary Clinic, Dr Eiji Shimizu at Youga Animal Hospital, Dr Hirohide Kamimura at Champion Animal Hospital, and Dr Kazuo Yamauchi at Yamauchi Animal Center for participating in the trial with great cooperation.

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