Plasma concentrations of an angiotensin-converting enzyme inhibitor, benazepril, and its active metabolite, benazeprilat, after repeated administrations of benazepril in dogs with experimental kidney impairment

In order to examine the safety of an angiotensin-converting enzyme (ACE) inhibitor in dogs with impaired renal excretion route, benazepril was administered orally, and plasma concentrations of benazeprilat, the active metabolite of benazepril, were determined in dogs with renal mass reduction (1/4th kidney) created by right-side nephrectomy and ligation of branches of the left renal arteries. Five dogs were administered benazepril orally at a given dose (0.5 mg/kg body weight) and 4 other dogs received 20 times that dose (10 mg/kg body weight) once daily for 15 consecutive days before (intact kidney period) and after (1/4th kidney period) creation of kidney impairment. Six control dogs received surgical treatment, but no drug. After creating a 1/4th kidney, plasma urea nitrogen and creatinine concentrations increased to approximately 30 mg/dl and 2.0 mg/dl, respectively, and renal plasma flow and glomerular filtration rate decreased to 37% and 30% of pre-treatment values, respectively. However, these parameters did not change significantly during the 1/4th kidney period both in the 0.5 mg/kg and 10 mg/kg groups. In the 0.5 mg/kg group, plasma benazeprilat concentrations increased to approximately 20 ng/ml to 340 ng/ml 2 hr after each administration, and there were no significant differences between the plasma benazeprilat concentrations during the intact and 1/4th kidney periods. In the 10 mg/kg group, plasma benazeprilat concentrations varied in the individual dog, but did not increase with the days of administration, and were not significantly different on each administration day between the intact and 1/4th kidney periods in either dose group. The AUCs(0-24) of plasma benazeprilat concentrations determined on the 15th administration day were not different between the intact and 1/4th kidney periods in dogs of either dose group. Plasma ACE activities decreased after drug administration in dogs of both groups. Benazepril seemed to have a high safety, and the adjustment of dosage regimen might not be needed in dogs with mild to moderate renal function impairment because the drug was excreted both from the kidneys and liver.     

Effects of the angiotensin converting enzyme inhibitor benazepril in cats with induced renal insufficiency

OBJECTIVE: To determine effects of the angiotensin converting enzyme inhibitor benazepril in cats with induced renal insufficiency. ANIMALS: 32 cats. PROCEDURE: Renal mass was surgically reduced, and cats were assigned to 1 of 4 eight-cat groups. Group 1 received placebo, whereas groups 2, 3, and 4 received benazepril hydrochloride orally once daily for approximately 6.5 months at the following doses: group 2, 0.25 to 0.50 mg/kg of body weight; group 3, 0.50 to 1.00 mg/kg; and group 4, 1.00 to 2.00 mg/kg. Arterial blood pressures, glomerular filtration rate (GFR), and renal plasma flow were determined before treatment and during the treatment period. Other determinants of renal hemodynamics were measured by use of micropuncture techniques. Renal biopsy specimens were examined microscopically. RESULTS: Compared with cats that received placebo, mean systolic arterial blood pressure was significantly less and GFR significantly greater in cats that received benazepril. Glomerular capillary pressure and the ratio of efferent to afferent arteriolar vascular resistance were also significantly less in treated cats. However, histologic differences in renal specimens were not detected. CONCLUSIONS AND CLINICAL RELEVANCE: Treatment with benazepril sustained single nephron GFR in remnant nephrons of cats with induced renal insufficiency. Administration of benazepril was also associated with a small but significant reduction in degree of systemic hypertension and an increase in whole kidney GFR. Benazepril may be an effective treatment to slow the rate of progression of renal failure in cats with renal disease.     

Evaluation of the effects of inhibition of angiotensin converting enzyme with enalapril in dogs with induced chronic renal insufficiency

OBJECTIVE: To determine whether the angiotensin converting enzyme inhibitor enalapril would lower systemic arterial and glomerular capillary pressure and reduce the magnitude of renal injury in a canine model of renal insufficiency. ANIMALS: 18 adult dogs that had renal mass reduced by partial nephrectomy. PROCEDURE: After surgical reduction of renal mass and baseline measurements, dogs in 2 equal groups received either placebo (group 1) or enalapril (0.5 mg/kg, PO, q 12 h; group 2) for 6 months. RESULTS: Values for systemic mean arterial blood pressure determined by indirect and direct measurement after 3 and 6 months of treatment, respectively, were significantly lower in group 2 than in group 1. During treatment, monthly urine protein-to-creatinine ratios were consistently lower in group 2 than in group 1, although values were significantly different only at 3 months. At 6 months, significant reduction in glomerular capillary pressure in group 2 was detected, compared with group 1, but glomerular filtration rate in group 2 was not compromised. Glomerular hypertrophy, assessed by measurement of planar surface area of glomeruli, was similar in both groups. Glomerular and tubulointerstitial lesions were significantly less in group 2, compared with group 1. CONCLUSIONS AND CLINICAL RELEVANCE: Data suggest that inhibition of angiotensin converting enzyme was effective in modulating progressive renal injury, which was associated with reduction of glomerular and systemic hypertension and proteinuria but not glomerular hypertrophy. Inhibition of angiotensin converting enzyme may be effective for modulating progression of renal disease in dogs.     

Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study

Background: Myxomatous mitral valve disease (MMVD) continues to be an important cause of morbidity and mortality in geriatric dogs despite conventional therapy. Hypothesis: Pimobendan in addition to conventional therapy will extend time to sudden cardiac death, euthanasia for cardiac reasons, or treatment failure when compared with conventional therapy plus benazepril in dogs with congestive heart failure (CHF) attributable to MMVD. Animals: Two hundred and sixty client‐owned dogs in CHF caused by MMVD were recruited from 28 centers in Europe, Canada, and Australia. Methods: A prospective single‐blinded study with dogs randomized to PO receive pimobendan (0.4–0.6 mg/kg/d) or benazepril hydrochloride (0.25–1.0 mg/kg/d). The primary endpoint was a composite of cardiac death, euthanized for heart failure, or treatment failure. Results: Eight dogs were excluded from analysis. One hundred and twenty‐four dogs were randomized to pimobendan and 128 to benazepril. One hundred and ninety dogs reached the primary endpoint; the median time was 188 days (267 days for pimobendan, 140 days for benazepril hazard ratio = 0.688, 95% confidence limits [CL] = 0.516–0.916, P= .0099). The benefit of pimobendan persisted after adjusting for all baseline variables. A longer time to reach the endpoint was also associated with being a Cavalier King Charles Spaniel, requiring a lower furosemide dose, and having a higher creatinine concentration. Increases in several indicators of cardiac enlargement (left atrial to aortic root ratio, vertebral heart scale, and percentage increase in left ventricular internal diameter in systole) were associated with a shorter time to endpoint, as was a worse tolerance for exercise. Conclusions and Clinical Importance: Pimobendan plus conventional therapy prolongs time to sudden death, euthanasia for cardiac reasons, or treatment failure in dogs with CHF caused by MMVD compared with benazepril plus conventional therapy.     

Distribution of enrofloxacin and its active metabolite, using an in vivo ultrafiltration sampling technique after the injection of enrofloxacin to pigs

The objective of this study was to determine the pharmacokinetics (PK) of enrofloxacin in pigs and compare to the tissue interstitial fluid (ISF). Six healthy, young pigs were administered 7.5 mg/kg enrofloxacin subcutaneously (SC). Blood and ISF samples were collected from preplaced intravenous catheters and ultrafiltration sampling probes placed in three different tissue sites (intramuscular, subcutaneous, and intrapleural). Enrofloxacin concentrations were measured using high-pressure liquid chromatography with fluorescence detection, PK parameters were analyzed using a one-compartment model, and protein binding was determined using a microcentrifugation system. Concentrations of the active metabolite ciprofloxacin were negligible. The mean ± SD enrofloxacin plasma half-life, volume of distribution, clearance, and peak concentration were 26.6 ± 6.2 h (harmonic mean), 6.4 ± 1.2 L/kg, 0.18 ± 0.08 L/kg/h, and 1.1 ± 0.3 μg/mL, respectively. The half-life of enrofloxacin from the tissues was 23.6 h, and the maximum concentration was 1.26 μg/mL. Tissue penetration, as measured by a ratio of area-under-the-curve (AUC), was 139% (± 69%). Plasma protein binding was 31.1% and 37.13% for high and low concentrations, respectively. This study demonstrated that the concentration of biologically active enrofloxacin in tissues exceeds the concentration predicted by the unbound fraction of enrofloxacin in pig plasma. At a dose of 7.5 mg/kg SC, the high tissue concentrations and long half-life produce an AUC/MIC ratio sufficient for the pathogens that cause respiratory infections in pigs.     

QT instability,an indicator of augmented arrhythmogenesis,increases with the progression of myxomatous mitral valve disease in dogs

Objectives

To investigate QT instability in dogs with myxomatous mitral valve disease (MMVD) and to determine if this is associated with arrhythmogenesis.

Efficacy of AHR-13268, an antiallergenic compound, in the management of pruritus caused by atopic disease in dogs.

Twenty-nine pruritic, atopic dogs were entered into a double-blind, placebo-controlled, crossover study to evaluate the efficacy of an investigational antiallergenic compound, AHR-13268. Fourteen dogs were evaluated by a veterinary dermatologist (at intervals) and the owner (daily). Fifteen dogs were evaluated only by the owner. The mean (+/- SE) owner scores for pruritus, erythema, and lesions with placebo treatment (higher score = worse signs) were 3.24 (+/- 0.12), 2.73 (+/- 0.12), and 2.61 (+/- 0.09), respectively. With drug treatment, the corresponding scores were 2.89 (+/- 0.12), 2.50 (+/- 0.12), and 2.25 (+/- 0.09). Scores for pruritus and lesions (but not erythema) were significantly better with drug treatment than with placebo treatment. Investigator scores showed similar trends, but the differences were not great enough to be statistically significant. Overall, 11/29 (38%) owners reported their dogs had moderate or better improvement from drug capsules, and 4/29 dogs (14%) improved on placebo capsules. A variety of adverse effects were reported following both drug (9/29 dogs) and placebo (8/29 dogs) capsule administration, but were mild and well tolerated. Results of this study indicate that AHR-13268 has potential for empiric treatment of allergic inhalant dermatitis in some dogs.     

MRI features can help to confirm a diagnosis of progressive myelomalacia,but may not be accurate in dogs lacking characteristic clinical signs at the time of imaging

Progressive myelomalacia (PMM) is a fatal sequela of acute thoracolumbar intervertebral disc extrusion in dogs, with unpredictable onset in the days after the inciting injury. No single reliable diagnostic test is currently available. Magnetic resonance imaging (MRI) features such as T2-weighted spinal cord hyperintensity and loss of subarachnoid signal in a half-Fourier single-shot turbo spin echo (HASTE) sequence have been associated with PMM, but are sometimes present in other dogs with severe deficits. Magnetic resonance imaging findings in 22 dogs with a clinical or histopathologic diagnosis of PMM and 38 deep pain-negative paraplegic dogs were compared in a retrospective case-control study. Length of T2-weighted hyperintense spinal cord change and HASTE signal loss were significantly associated with clinically evident PMM (P = .0019 and P = .0085), however, there were no significant differences between groups when analysis was restricted to dogs not yet showing clinical signs of PMM. The PMM group also had significantly shorter compressive lesions than the control group (P = 0.026), suggesting a possible role of more severe focal pressure at the extrusion site. A segment of total loss of contrast enhancement in the venous sinuses and meninges, a feature not previously described, was more common in the PMM group and the difference approached significance (P = 0.054). Findings show that MRI features can support the diagnosis in dogs with clinical evidence of PMM, and absence of these features supports absence of PMM at time of imaging. However, their absence does not reliably differentiate dogs with imminent progressive myelomalacia from other dogs with severe deficits following intervertebral disc extrusion.     

Effect of the 5-lipoxygenase inhibitor, fenleuton, on antigen-induced neutrophil accumulation and lung function changes in horses with chronic obstructive pulmonary disease

The leukotrienes (LT) LTD₄ and LTB₄ have been shown to cause bronchoconstriction and neutrophil accumulation, respectively, in horse lungs. Such changes are characteristic of the equine allergic respiratory disease, chronic obstructive pulmonary disease (COPD). To further investigate the role of these putative mediators in the pathogenesis of equine COPD the effect of a 5-lipoxygenase inhibitor, fenleuton, on antigen-induced changes in horses with this condition has been examined. Six horses with COPD underwent a series of four antigen challenges, one month apart, with placebo pre-treatment on three occasions and fenleuton (4 days oral dosing 5 mg/kg) pre-treatment on one occasion. Three horses received fenleuton prior to the second challenge and three horses received the drug prior to the fourth antigen challenge. Changes in radiolabelled neutrophil distribution, lung function and peripheral leucocyte counts were monitored on each occasion for 7 h following the start of antigen challenge. Antigen challenge caused an increase in radioactive counts over the lungs and a decrease in peripheral leucocyte count. Neither response was affected by fenleuton pre-treatment. Mean maximal changes in pleural pressure (ΔP_plmax) and respiratory rate were also unaffected by fenleuton pre-treatment. However, in the two horses which responded to antigen-challenge with a particularly marked increase in ΔP_plmax (>15 cm H₂O), prior administration of fenleuton reduced the response by 64 and 63%. These results suggest that 5-lipoxygenase inhibitors warrant further investigation as bronchodilators in equine COPD.     

Assessment of disease severity and outcome of dietary, antibiotic, and immunosuppressive interventions by use of the canine IBD activity index in 21 dogs with chronic inflammatory bowel disease

Recently, the canine IBD activity index (CIBDAI) was developed for evaluation of the severity of illness, therapeutic strategies, and efficacy of therapy.The aim of the present study was to assess the severity of illness and the therapeutic strategy in dogs with IBD by the use of CIBDAI, serum albumin concentration, and histologic score (HPEG). Furthermore the use of CIBDAI and the efficacy of therapy in a prospective study during a 3 month treatment period were evaluated. Twentyone dogs with inflammatory bowel disease (lymphocytic-plasmacytic enteritis and enterocolitis) were examined in this study. In 11 dogs with IBD the severity of illness was assessed as low, according to CIBDAI and HPEG (CIBDAI score 4 or between 5 and 10 with HPEG score between 1 and 1.5). Six dogs were treated with hypoallergenic diet (Group D), five dogs were treated with hypoallergenic diet and metronidazole (15.6-22,3 mg/kg/day) (Group M). In 10 dogs with IBD the severity of illness was assessed as high (CIBDAI <10, or CIBDAI between 5 and 10 with HPEG score between 2 and 3 or hypoalbuminemia (< or = 2.5 g/dl)). This group (Group I) was treated with immunosuppressive therapy.Treatment consisted of prednisolone (n=10; 0.9-2 mg/kg/day), azathioprine (n=5; 0.9-2.3 mg/kg/day), sulfasalazine (n=4; 18.2-25 mg/kg/day) and hypoallergenic diet (n=10). Efficacy of therapy was evaluated prospectively 3 times in a 12 weeks treatment period. Remission (CIBDAI score < 4) indicated good therapeutic response, chronic or recurrent disease (CIBDAI score persistent or recurrent > or =4) indicated poor therapeutic response. Age, CIBDAI score and HPEG score were significantly different in IBD dogs with low severity of illness (age: median 60 months; CIBDAI score: median 5; HPEG score: median (1) and IBD dogs with high severity of illness (age: median 90 months; CIBDAI score: median 9.5; HPEG score: median 2.25) (p = 0.0101 and p = 0.0099, respectively). The presence of hypoalbuminemia was not significantly different between these two groups (p = 0.3108). There was no significant correlation between CIBDAI score and serum albumin concentration (r = 0.0394; p = 0.0802) or between CIBDAI score and HPEG score (r = 0.2587; p = 0.2574). In the treatment groups, HPEG score was only significantly different between D-group and group I (p < 0.01). The CIBDAI score decreased significantly in group I after 4 weeks of treatment (median 4th week: 3; p < 0.05), and in the D-group after 8 weeks of treatment (median 8" week 1; p < 0.05). No significant decrease of CIBDAI score was seen in the M-group (median 12th week: 1.75; p > 0.05). All dogs in group D, four of five dogs in group M, and six from ten dogs in group I went into remission. Poor therapeutic response (1 dog in group M and 5 dogs in group I; one dog died) was seen in 6 dogs, where as 15 dogs showed good therapeutic response. There was no significant association between efficacy of therapy and age (p = 0.8455), CIBDAI score (p = 0.3293), or serum albumin concentraton (p = 0.8455). Poor therapeutic response was weekly associated with HPEG score > or =2 (p = 0.0635). Using CIBDAI in dogs with IBD as a single parameter to assess the severity of illness and the therapeutic response, misinterpretations are possible.The assessment of the severity of illness by the combination of CIBAI, HPEG, and serum albumin concentration is leading to adaequate therapeutic results. Dogs with low grade IBD benefit from hypoallergenic diet, whereas dogs with high grade IBD benefit from immunosuppressive therapy. The effect of antibiotic treatment is questionable.     

Concentrations of strontium,barium, cadmium,copper, zinc,manganese, chromium,antimony, selenium,and lead in the liver and kidneys of dogs according to age,gender, and the occurrence of chronic kidney disease

This study was conducted to measure the concentrations of strontium (Sr), barium (Ba), cadmium (Cd), copper (Cu), zinc (Zn), manganese (Mn), chromium (Cr), antimony (Sb), selenium (Se), and lead (Pb) in canine liver, renal cortex, and renal medulla, and the association of these concentrations with age, gender, and occurrence of chronic kidney disease (CKD). Tissues from 50 dogs were analyzed using inductively coupled plasma mass spectrometry. Cu, Zn, and Mn levels were highest in the liver followed by the renal cortex and renal medulla. The highest Sr, Cd, and Se concentrations were measured in the renal cortex while lower levels were found in the renal medulla and liver. Female dogs had higher tissue concentrations of Sr (liver and renal medulla), Cd (liver), Zn (liver and renal cortex), Cr (liver, renal cortex, and renal medulla), and Pb (liver) than male animals. Except for Mn and Sb, age-dependent variations were observed for all element concentrations in the canine tissues. Hepatic Cd and Cr concentrations were higher in dogs with CKD. In conclusion, the present results provide new knowledge about the storage of specific elements in canine liver and kidneys, and can be considered important reference data for diagnostic methods and further investigations.     

In vitro killing of Escherichia coli, Staphylococcus pseudintermedius and Pseudomonas aeruginosa by enrofloxacin in combination with its active metabolite ciprofloxacin using clinically relevant drug concentrations in the dog and cat

Enrofloxacin is a fluoroquinolone antibacterial agent used to treat infections in companion animals. Enrofloxacin's antimicrobial spectrum includes Gram positive and Gram-negative bacteria and demonstrates concentration-dependent bacteriocidal activity. In dogs and cats, enrofloxacin is partially metabolized to ciprofloxacin and both active agents circulate simultaneously in treated animals at ratios of approximately 60-70% enrofloxacin to 30-40% ciprofloxacin. We were interested in determining the killing of companion animal isolates of Escherichia coli, Staphylococcus pseudintermedius and Pseudomonas aeruginosa by enrofloxacin and ciprofloxacin combined using clinically relevant drug concentrations and ratios. For E. coli isolates exposed to 2.1 and 4.1μg/ml of enrofloxacin/ciprofloxacin at 50:50, 60:40 and 70:30 ratios, a 1.7-2.5log(10) reduction (94-99% kill) was seen following 20min of drug exposure; 0.89-1.7log(10) (92-99% kill) of S. pseudintermedius following 180min of drug exposure; 0.85-3.4log(10) (98-99% kill) of P. aeruginosa following 15min of drug exposure. Killing of S. pseudintermedius was enhanced in the presence of enrofloxacin whereas killing of P. aeruginosa was enhanced in the presence of ciprofloxacin. Antagonism was not seen when enrofloxacin and ciprofloxacin were used in kill assays. The unique feature of partial metabolism of enrofloxacin to ciprofloxacin expands the spectrum of enhanced killing of common companion animal pathogens.     

Effects of acepromazine and dexmedetomidine,followed by propofol induction and maintenance with isoflurane anaesthesia,on the microcirculation of Beagle dogs evaluated by sidestream dark field imaging: an experimental trial

ObjectiveTo investigate the effects of intramuscularly administered acepromazine or dexmedetomidine on buccal mucosa microcirculation in Beagle dogs.Study designExperimental, blinded, crossover study.AnimalsA group of seven Beagle dogs aged 7.5 ± 1.4 years (mean ± standard deviation).MethodsMicrocirculation was assessed on buccal mucosa using sidestream dark field videomicroscopy. After baseline measurements, 5 μg kg^–1 dexmedetomidine or 30 μg kg^–1 acepromazine were administered intramuscularly. After 10, 20 and 30 minutes, measurements were repeated. At 40 minutes after premedication, anaesthesia was induced with propofol intravenously and maintained with isoflurane. Measurements were repeated 50, 60 and 65 minutes after the injection of the investigated drugs. Analysed microcirculatory variables were: Perfused de Backer density, Perfused de Backer density of vessels < 20 μm, Proportion of perfused vessels and Proportion of perfused vessels < 20 μm. Heart rate (HR), systolic, diastolic (DAP) and mean (MAP) arterial pressures were recorded at the same time points. Macro- and microcirculatory variables were analysed using a linear mixed model with baseline as a covariate, treatment, trial period and repetition as fixed effects and time and dog as random effect. Results are presented as effect size and confidence interval; p values < 0.05 were considered significant.ResultsAfter acepromazine, Perfused de Backer density was greater during sedation and anaesthesia [3.71 (1.93–5.48 mm mm^–2, p < 0.0001) and 2.3 (0.86–3.75 mm mm^–2, p < 0.003)], respectively, than after dexmedetomidine. HR was significantly lower, whereas MAP and DAP were significantly higher with dexmedetomidine during sedation and anaesthesia (p < 0.0001 for all) compared with acepromazine.Conclusions and clinical relevanceThe sedative drugs tested exerted a significant effect on buccal mucosal microcirculation with a higher Perfused de Backer density after the administration of acepromazine compared with dexmedetomidine. This should be considered when microcirculation is evaluated using these drugs.     

An experimental contribution to the epizootiology of viral hemorrhagic septicemia of rabbits (rabbit hemorrhagic disease, RHD)--transmission by flies

In experiments adapted to natural conditions it was established that--a conjunctival infection with about 100 RHD-virus particles was successful--in a milieu without flies transmission over a distance of only 50 cm did not take place--iridescent flies (Phormia spp.) seven hours after contamination with RHD-virus material from died rabbits transmitted RHD to susceptible rabbits in an isolated cage. It ist supposed that transmission in this way will be an epizootiological important one for spreading in narrow distances.     

A randomized, double-blind, placebo-controlled study to evaluate the effect of EFF1001, an Actinidia arguta (hardy kiwi) preparation, on CADESI score and pruritus in dogs with mild to moderate atopic dermatitis

Canine atopic dermatitis (AD) is common and new therapies are beneficial. This multicentric, randomized, double-blind, placebo-controlled study tested the efficacy of Actinidia arguta (hardy kiwi) (EFF1001) in dogs with mild/moderate AD. The study was divided into two stages. Stage 1 lasted 6 weeks. In the first 2 weeks prednisolone [days 1–3: 0.2 mg/kg twice daily (BID), days 4–14: 0.2 mg/kg every other day (EOD)] was administered. Responsive dogs were placed on prednisolone 0.2 mg/kg EOD + assigned test article [either placebo or EFF1001 (30 mg/kg)] once daily for 4 weeks. Stage 1 responders were advanced to stage 2, which involved 4 weeks of just EFF1001. Clinicians scored lesions using Canine Atopic Dermatitis Extent and Severity Index (CADESI) and owners scored pruritus using a Pruritus Visual Analogue Scale. Seventy-seven dogs were enrolled, 76 were randomized on day 14, and 57 (57/76 = 75%) completed stage 1 (27 in EFF1001 and 30 in placebo). At the end of stage 1, 35 of 57 dogs (35/57 = 61%) responded (18 in EFF1001 and 17 in placebo) and advanced to stage 2. At completion of stage 1, CADESI scores did not significantly differ between groups while pruritus decreased in EFF1001 group and approached significance. At completion of stage 2, 19 dogs (19/35 = 54%) responded (15/19 = 79% had received EFF1001 and 4/19 = 21% placebo in stage 1). After completing stage 2, dogs placed on EFF1001 throughout the study were 3.5 times more likely to either maintain or improve scores than those that started it in stage 2. It is concluded that EFF1001 is beneficial adjunctive therapy after prolonged use.