Effect of benazepril and pimobendan on serum angiotensin‐converting enzyme activity in dogs

To support their combined use, the objective of the study was to evaluate the effects of benazepril and pimobendan on serum angiotensin‐converting enzyme (ACE) activity in dogs. A total of 48 healthy beagle dogs were randomized into four groups (n = 12 per group) in a parallel‐group design study: A (control, placebo twice daily (BID)); B (0.5–1.0 mg/kg benazepril once daily (SID) in the morning, placebo in the evening); C (0.25–0.5 mg/kg benazepril BID); D (0.25–0.5 mg/kg benazepril and 0.125–0.25 mg/kg pimobendan, both BID). The test items were administered orally for 15 days. Serum ACE activity was measured on days 1 and 15. Groups B, C and D had significantly lower average serum ACE activity compared to baseline and to the control group, on both days 1 and 15. There were no significant differences in average ACE activity between groups B, C and D. Noninferiority of group C to B was demonstrated. In conclusion, 0.25–0.5 mg/kg benazepril administered BID produced noninferior inhibition of serum ACE activity compared to 0.5–1.0 mg/kg benazepril dosed SID. Pimobendan had no significant effect on benazepril's action on serum ACE activity. The results support the use of benazepril BID in dogs and in combination with pimobendan.     

Comparative adverse cardiac effects of pimobendan and benazepril monotherapy in dogs with mild degenerative mitral valve disease: a prospective, controlled, blinded, and randomized study

BACKGROUND: Pimobendan (PIMO) is an inodilator that may have some beneficial effects in canine degenerative mitral valve disease (MVD). However, little information is available about its cardiac effects in dogs without systolic myocardial dysfunction. HYPOTHESIS: Compared to benazepril (BNZ), an angiotensin-converting enzyme inhibitor, PIMO may worsen valve regurgitation in early canine MVD. ANIMALS: Twelve Beagles with asymptomatic MVD were randomized into 2 groups (n = 6) receiving BNZ or PIMO at dosages of 0.25 mg/kg PO q24h and q12h respectively, for 512 days. METHODS: The study followed a blinded, randomized, prospective, and parallel group design. After day 512, the dogs were necropsied, and cardiac histopathology was performed in a blinded manner. RESULTS: A significant treatment effect was observed as soon as day 15 with increased systolic function in the PIMO group by comparison to baseline value as assessed by fractional shortening (P < .0001) and tissue Doppler variables (P = .001). Concurrently, the maximum area and peak velocity of the regurgitant jet signal increased (P < .001), whereas these variables remained stable in the BNZ group. Histologic grades of mitral valve lesions were more severe in the PIMO group than in the BNZ group. Moreover, acute focal hemorrhages, endothelial papillary hyperplasia, and infiltration of chordae tendinae with glycosaminoglycans were observed in the mitral valves of dogs from the PIMO group but not in those of the BNZ group. CONCLUSIONS AND CLINICAL IMPORTANCE: PIMO has adverse cardiac functional and morphologic effects in dogs with asymptomatic MVD. Additional investigation in dogs with symptomatic MVD is now warranted.     

The normal electroretinogram in adult healthy Shih Tzu dogs using the HMsERG

Electroretinography (ERG) is a reliable diagnostic tool for the diagnosis of retinal disease. It measures electric potentials occurring in the retina in response to light stimulation. In this study, we examined the normal electroretinogram using the Handheld Multispecies ERG (HMsERG) in Shih Tzu dogs. ERG recordings were performed in twelve eyes of six healthy Shih Tzu dogs. Dogs were anesthetized with a combination of medetomidine and ketamine. Proparacaine eye drops were also applied as a topical anesthetic. Tropicamide eye drops were applied for mydriasis. After 20 min of dark adaptation, we recorded the amplitudes and implicit times of the b-waves of the rod, standard rod and cone (Std R&C), high-intensity rod and cone (Hi-int R&C), and cone systems, and responses of the cones and inner retina by flicker light stimulation (cone flicker). Results showed that mean the amplitudes of a-waves of Std R&C, Hi-int R&C, and the cone responses were 141.25 µV, 173.00 µV, and 12.92 µV, respectively. The b-waves of the rod responses ranged from 141.58 to 155.25 µV; the Std R&C was 314.75 µV, the Hi-int R&C was 329.42 µV, the cones were 37.75 µV, and the flicker responses were 64.08 µV. The b/a ratios for the Std R&C, Hi-int R&C, and the cone response were 2.29, 1.94, and 3.71, respectively. Mean implicit time of the a-wave of the Std R&C was 15.12 ms, of Hi-int R&C was 13.42 ms, and of the cone response was 7.22 ms. The b-wave of the rod responses ranged from 68.12 to 72.68 ms, of Std R&C were 37.28 ms, of Hi-int R&C were 41.90, of the cone responses were 38.12 ms, and of the cone flicker responses were 22.80 ms. We believe that these parameters can be used as reference "normal" ERGs ranges for Shih Tzu dogs using the HMsERG under medetomidine and ketamine anesthesia.     

Effects of dexmedetomidine alone or in combination with opioids on intraocular pressure in healthy Beagle dogs

ObjectiveTo evaluate the effects of dexmedetomidine alone or in combination with different opioids on intraocular pressure (IOP) in dogs.Study designExperimental, prospective, crossover, randomized, blinded study.AnimalsA total of six Beagle dogs (two males and four females) aged 2 years and weighing 15.9 ± 2.9 kg (mean ± standard deviation).MethodsDogs were distributed randomly into seven treatments (n = 6 per treatment) and were administered dexmedetomidine alone (10 μg kg^–1; Dex) or in combination with butorphanol (0.15 mg kg^–1; DexBut), meperidine (5 mg kg^–1; DexMep), methadone (0.5 mg kg^–1; DexMet), morphine (0.5 mg kg^–1; DexMor), nalbuphine (0.5 mg kg^–1; DexNal) or tramadol (5 mg kg^–1; DexTra). All drugs were administered intramuscularly. IOP was measured before drug injection (time 0, baseline) and every 15 minutes thereafter for 120 minutes (T15–T120).ResultsThere were significant reductions in IOP compared with baseline in treatments Dex and DexMep at times T30–T120, and in treatment DexMet at T15–T90. IOP decreased compared with baseline in treatments DexBut, DexNal and DexTra at all evaluation times. No changes in IOP were seen in treatment DexMor. The mean IOP values in treatment DexMet at T105–T120 were higher than those for other treatments.Conclusions and clinical relevanceDexmedetomidine alone or in combination with butorphanol, meperidine, methadone, nalbuphine or tramadol resulted in decreased IOP for 120 minutes in dogs. The magnitude of the reduction was small and lacked clinical significance.     

The pharmacokinetics of pimobendan enantiomers after oral and intravenous administration of racemate pimobendan formulations in healthy dogs

Pimobendan is a benzimidazole‐pyridazinone derivative, marketed as a racemic mixture for the management of canine heart failure. Pharmacokinetics of the enantiomers of pimobendan and its oral bioavailability have not been described in dogs. The aim of this study was to describe pharmacokinetics of three formulations of pimobendan in healthy dogs: the licensed capsule product, and novel liquid and intravenous formulations. A three‐period, nested randomized two‐treatment crossover design was used. Pimobendan was administered p.o. at 0.25 and i.v. at 0.125 mg/kg. Blood and plasma samples were analysed by liquid chromatography–mass spectrometry. Noncompartmental modelling was used to describe the pharmacokinetics. Parameters were compared between formulations using a general linear model. Bioequivalence of the oral formulations was tested using CI90 for AUC_(0–∞) and C_max. Bioavailability of pimobendan after oral dosing was 70%. Liquid and capsule formulations were bioequivalent only for AUC. The positive enantiomer of pimobendan (PE) had a larger volume of distribution than the negative enantiomer (NE) (281 ± 48 vs. 215 ± 68 mL/kg; P = 0.003) and a shorter half‐life (21.7 vs. 29.9 min; P = 0.004). The NE was distributed more quickly than the PE into blood cells. Enantiomers of pimobendan have differing absorption, distribution and elimination. The pharmacokinetics of pimobendan in healthy dogs was described.     

Safety of orally administered,USP‐compliant levothyroxine sodium tablets in dogs

The safety of synthetic levothyroxine sodium tablets (Thyro‐Tabs® Canine; LLOYD , Inc.) in dogs was evaluated in a randomized, sham‐dose controlled, parallel‐group study. Young, healthy, euthyroid Beagle dogs were randomized into four groups (four females and four males per group) and received single daily doses of 0×, 2× (0.044 mg/kg), 6× (0.132 mg/kg), or 10× (0.22 mg/kg) the labeled starting dose of 0.022 mg kg^?1 day^?1 for 182 days. Every 2 weeks, physical examinations, electrocardiology examinations, and sample collections for thyroid panel, hematology, serum biochemistry, coagulation panel, and urinalysis were performed. At the end of the study, the dogs were euthanized and full necropsies performed. The most overt finding was the expected dose‐dependent increase in serum concentrations of total and free thyroxine with dose‐dependent suppression of the hypothalamic–pituitary–thyroid axis as evidenced by decreased serum thyroid‐stimulating hormone concentrations, decreased thyroid+parathyroid/body weight ratios, and a trend for decreased pituitary weight/brain weight ratios. Clinical signs of thyrotoxicosis (excitation, tachypnea, tachycardia) in the treated dogs were sporadic with no dose–response relationship. Other findings statistically associated with levothyroxine treatment were generally mild and not clinically important. In summary, doses of levothyroxine sodium up to 10× the labeled starting dose were well tolerated in healthy dogs.     

Sedative and analgesic effects of two subanaesthetic doses of ketamine in combination with methadone and a low dose of dexmedetomidine in healthy dogs

ObjectiveTo evaluate the sedative, analgesic and recovery characteristics of two subanaesthetic ketamine doses in combination with dexmedetomidine and methadone for intramuscular sedation in healthy Beagles.Study designRandomized, blinded, crossover, experimental study.AnimalsSix healthy adult Beagles.MethodsDogs were randomly given three treatments: dexmedetomidine (3 μg kg^–1) and methadone (0.3 mg kg^–1) combined with ketamine at 1 and 2 mg kg^–1 (K1 and K2, respectively) or saline (K0), intramuscularly. Sedation score, response to tail clamping and rectal temperature were recorded at baseline, 5, 15, 25, 35, and 45 minutes posttreatment. Pulse rate (PR), respiratory rate, oxygen haemoglobin saturation and noninvasive blood pressure were also recorded at baseline and every 5 minutes until 45 minutes posttreatment. Onset and duration of recumbency, response to venous catheterization and recovery quality were also assessed. Sedation and physiological variables were compared between treatments and within treatments compared to baseline (analysis of variance). Nonparametric data were analysed with the Friedman and Cochran’s Q tests; p < 0.050.ResultsIncreased sedation was found at 15 (K0 and K1), 25 (all treatments) and 35 (K1) minutes compared with baseline. Sedation score, onset (3–12 minutes) and duration of recumbency (29–51 minutes) were similar between treatments. Recovery quality was considered acceptable in all cases. Response to tail clamping was inconsistent within treatments with no differences between them. None of the dogs responded to venous catheterization. There were no differences between treatments in physiological variables, except for PR which was higher in K2 than in K0. Oxygen supplementation was required in five and three dogs administered saline and ketamine, respectively.Conclusions and clinical relevanceThe addition of 1 or 2 mg kg^–1 of ketamine to methadone and dexmedetomidine combination did not enhance sedation or antinociception in healthy dogs. Recovery quality was unaffected.     

Comparison of the postoperative analgesic effects of cimicoxib,buprenorphine and their combination in healthy dogs undergoing ovariohysterectomy

Objective

To determine the noninferior postoperative analgesic efficacy of cimicoxib compared to buprenorphine following elective ovariohysterectomy in healthy bitches.

Pharmacokinetics and cardiovascular effects following a single oral administration of a nonaqueous pimobendan solution in healthy dogs

Pimobendan is an inodilator used in the treatment of canine congestive heart failure (CHF). The aim of this study was to investigate the pharmacokinetics and cardiovascular effects of a nonaqueous oral solution of pimobendan using a single‐dose, operator‐blinded, parallel‐dose study design. Eight healthy dogs were divided into two treatment groups consisting of water (negative control) and pimobendan solution. Plasma samples and noninvasive measures of cardiovascular function were obtained over a 24‐h period following dosing. Pimobendan and its active metabolite were quantified using an ultra‐high‐performance liquid chromatography–mass spectrometer (UHPLC‐MS) assay. The oral pimobendan solution was rapidly absorbed [time taken to reach maximum concentration (T_max) 1.1 h] and readily converted to the active metabolite (metabolite T_max 1.3 h). The elimination half‐life was short for both pimobendan and its active metabolite (0.9 and 1.6 h, respectively). Maximal cardiovascular effects occurred at 2–4 h after a single oral dose, with measurable effects occurring primarily in echocardiographic indices of systolic function. Significant effects persisted for <8 h. The pimobendan nonaqueous oral solution was well tolerated by study dogs.     

Effect of EDTA on morphology of neutrophils of healthy dogs and dogs with inflammation

Increased basophilia and foamy vacuolation in the cytoplasm of neutrophils in smears made within 1 hour of blood collection suggest inflammatory disease. Due to the mild increase in foamy vacuolation which occurred with time in EDTA, the significance of mildly vacuolated neutrophils in smears prepared a few hours after blood collection is questionable. However, moderate or severe foamy vacuolation should be considered clinically significant. In vitro morphologic changes in neutrophils from healthy dogs in EDTA include clear, discrete vacuoles in the cytoplasm, uneven distribution of cytoplasmic granules, irregular cell membrane and pyknosis. These neutrophils generally lack basophilia, have minimal foamy vacuolation of the cytoplasm and are morphologically different from neutrophils associated with severe inflammation.     

The profile of urinary lipid metabolites in healthy dogs

Polyunsaturated fatty acids, including arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), are converted to hundreds of lipid mediators by cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome P450 (CYP), or through non-enzymatic processes, and they reflect inflammatory states of the body. We comprehensively analyzed lipid metabolites in dog urine using a liquid chromatograph-mass spectrometry (LC-MS/MS) to describe their metabolic characteristics. We detected 31 AA-derived metabolites, four EPA-derived metabolites, and a DHA-derived metabolite in all urine samples. Among AA-derived metabolites, 15, 5, 3, and 8 were generated by COX, LOX, CYP, and non-enzymatic oxidation respectively. This study will be the first step to use profiles of urinary lipid metabolites for better understanding and diagnosis of canine diseases.     

Screening of bacterial DNA in bile sampled from healthy dogs and dogs suffering from liver- or gallbladder-associated disease

Although the biliary system is generally aseptic, gallbladder microbiota has been reported in humans and some animals apart from dogs. We screened and analyzed the bacterial deoxyribonucleic acid in canine gallbladders using bile sampled from 7 healthy dogs and 52 dogs with liver- or gallbladder-associated disease. PCR screening detected bacteria in 17.3% of diseased dogs (9/52) and none in healthy dogs. Microbiota analysis of PCR-positive samples showed that the microbial diversity differed between liver- and gallbladder-associated disease groups. Thus, a specific bacterial community appears to occur at a certain frequency in the bile of diseased dogs.     

Safety study of a beef-based chewable tablet formulation of ivermectin and pyrantel pamoate in growing dogs, pups, and breeding adult dogs.

To determine the safety of a new combination of ivermectin and pyrantel (as pamoate salt) in a novel beef-based chewable tablet formulation, 3 tolerance trials were conducted and included growing dogs, pups, and breeding adult dogs. Growing dogs, given the combination orally for 5 consecutive days at recommended dosages (5 mg of pyrantel/kg of body weight, 6 micrograms of ivermectin/kg) or at twice the pyrantel dosage in combination with the recommended dosage of ivermectin, had no adverse effects. The combination also was administered to 6-week-old pups at 1, 3, and 5 times the recommended dose on 3 successive days for 3 times in 1 month. Compared with age-matched controls, treatment had no effect on clinical status, growth rate, or gross or histologic features. Breeding male and female dogs given the combination at 3 times the recommended dose for extended periods had no adverse effects, and prevalence of abnormalities in the offspring was not greater than that in nonmedicated controls.     

Efficacy of a topical antimicrobial-anti-inflammatory combination in the treatment of pyotraumatic dermatitis in dogs

Abstract The efficacy of a topical antimicrobial-corticosteroid combination for the treatment of pyotraumatic dermatitis in dogs, was investigated. An open-ended, double-blind, randomized trial design was used. Forty dogs were divided into two vehicle-treated control groups and three treatment groups. The dogs in the respective treatment groups were treated with emulsions of either neomycin, prednisolone or a neomycin-prednisolone combination. Lesions were shaved and cleaned before treatment commenced, whereafter the allocated emulsion was applied twice daily for 7 days. Lesions were evaluated for surface area and degree of pruritus and inflammation. Skin biopsy specimens for bacterial culture and histopathological examination were taken. Staphylococcus aureus was the predominant organism isolated. The antimicrobial-corticosteroid combination emulsion resulted in the quickest recovery, followed by the antimicrobial drug alone. Prednisolone alone gave significantly poorer results. Dogs in all groups, including the control groups, recovered completely within 7 days. Résumé L'efficacité d'un topique associant antimicrobien et corticoide dans le traitement de la dematite pyotraumatique du chien a étéétudiée. Une étude randomisée, ouverte, en double aveugle, a été réalisée. Quarante chiens ont été divisés en deux groupes controles traités seulement à l'aide du véhicule et trois groupes traités respectivement soit par l'émulsion de néomycine seule, de prednisolone seule ou par l'association néomycine-prednisolone. Les lésions ont été tondues et nettoyées avant la mise en place du traitement, après quoi l'émulsion a été appliquée deux fois par jour pour sept jours. Les lésions ont étéévaluées quant à leur extension et le degré de prurit et d'inflammation. Des biopsies cutanées ont été réalisées pour culture bactériologique et examen histopathologique. Le principal agent isolé est le staphyloccoque doré. L'émulsion associant antimicrobien et corticoide a entrainé la guérison la plus rapide, suivi par l'antimicrobien utilisé seul. La prednisolone utilisée seule a donné les plus mauvais résultats. Les chiens de tous les groupes, y compris les groupes controles, ont été complètement guéris en sept jours. [Schroeder, H., Swan, G. E., Berry, W. L., Pearson, J. Efficacy of a topical antimicrobial-anti-inflammatory combination in the treatment of pyotraumatic dermatitis in dogs (Efficatité d'un topique associant antimicrobien et antiinflammatoire dans le traitement de la dermatite pyotraumatique du chien). Veterinary Dermatology 1966; 7 : 163–170.] Résumén Se investigó la eficacia de un preparado tópico combinado antimicrobiano-corticoesteroideo en el tratamiento de la dermatitis piotraumática canina. Se utilizó un ensayo de final abierto, doble-ciego y al azar. Cuarenta perros se dividieron en dos grupos control tratados con un vehiculador y tres grupos a los que se aplicó el tratamiento. Los perros en los respectivos grupos de tratamiento fueron tratados con emulsiónes de en neomicina o prednisolona o con una combinación de neomicina-prednisolona. Se afeitaron y lavaron las lesiones antes del inicio del tratamiento, y después se aplicó la emulsión asignada dos veces al día durante 7 días. Se evaluaron las lesiones según el área afectada y el grado de prurito e inflamación. Se tomaron biopsias cutáneas para cultivo bacteriano y examen histopatológico. Staphylococcus aureus fue el organismo que predominó en los aislamiento. La emulsión con combinación de antibiótico-corticoesteroide fue la que cursó con una recuperación más rápida, seguido del antimicrobiano solo. El tratamiento unicamente con prednisolona dio resultados significativamente peores. Los perros de todos los grupos, incluyendo los de los grupos control, se recuperaron dentro de los 7 días de tratamiento. [Schroeder, H., Swan, G. E., Berry, W. L., Pearson, J. Efficacy of a topical antimicrobial-anti-inflammatory combination in the treatment of pyotraumatic dermatitis in dogs (Eficacia de un tratamiento antimicrobiano-antiinflamatorio topico combinado en la dermatitis piotraumatica canina). Veterinary Dermatology 1966; 7 : 163–170.] Zusammenfassung Die Wirksamkeit einer lokalen Antibiotikum-Kortikoid-Kombination für die Behandlung der pyotraumatischen Dermatitis des Hundes wurde untersucht. Es wurde das Modell einer offenen, randomisierten Doppelblindstudie verwendet. 40 Hunde wurden in zwei Vehikel-behandelte Kontroll-und drei Behandlungsgruppen eingeteilt. Die Hunde der drei Behandlungsgruppen wurden mit Emulsionen von Neomycin, Prednisolon oder einer Neomycin-Prednisolon-Kombination behandelt. Die Hautveränderungen wurden geschoren und gereinigt bevor die Behandlung begann. Dann wurde die entsprechende Emulsion zweimal täglich sieben Tage lang aufgetragen. Die Hautveränderungen wurden nach Größe der Oberfläche und Grad des Juckreizes und der Entzündung beurteilt. Es wurden Hautbioptate für bakteriologische Kulturen und histopathologische Untersuchungen entnommen. Als vorherrschender Keim wurde Staphylococcus aureus isoliert. Die Antibiotikum-Kortikoid-Kombination brachte die schnellste Abheilung, gefolgt von der ausschließlich antibiotischen Therapie. Prednisolon als Monotherapie ergab signifikant schlechtere Resultate. Die Hunde in alien Gruppen, einschließlich der Kontrollgruppen, gesundeten innerhalb von 7 Tagen vollständig. [Schroeder, H., Swan, G.E., Berry, W.L., Pearson, J. Efficacy of a topical antimicrobial-antiinflammatory combination in the treatment of pyotraumatic dermatitis in dogs (Wirksamkeit einer lokalen antimikrobiellen-entzündungshemmenden Kombination bei der Behandlung der pyotraumatischen Dermatitis des Hundes). Veterinary Dermatology 1996; 7 : 163–170.]