Safety of Simparica Trio® (sarolaner, pyrantel, moxidectin) in heartworm-infected dogs.

BACKGROUND: Assessment of the safety of heartworm preventatives in dogs with pre-existing patent heartworm (Dirofilaria immitis) infections is necessary because rapid adult worm and microfilarial death can lead to severe clinical complications, including thromboembolism and anaphylactic shock in dogs. The aim of this study was to determine the clinical safety of Simparica Trio® (sarolaner, pyrantel, moxidectin) in heartworm-infected dogs and the degree of microfilaricidal and adulticidal activity of three consecutive monthly treatments of Simparica Trio. METHODS: Twenty-four laboratory Beagle dogs were implanted with 10 male and 10 female D. immitis (ZoeKY isolate), and once infection was patent, they were randomized equally among three groups to receive no treatment, 1× or 3× the maximum recommended label dose of Simparica Trio. Dogs in the treated groups received Simparica Trio on days 0, 28 and 56. In-life assessments included body weight, physical examinations, clinical observations, daily general health observations, a quantitative estimate of food consumption and blood collections for pharmacokinetic (PK) analysis, microfilariae (MF) counts and D. immitis antigen testing. At the end of the study the heart, lungs and pleural and peritoneal cavities were examined for adult D. immitis worms. RESULTS: Simparica Trio was generally well tolerated. Emesis occurred at low frequency in all groups including control. Abnormal stool occurred occasionally in the 1× and 3× groups throughout the 3-month study. Fever (> 104 °F/40 °C) was recorded in one 1× and one 3× dog 1 day after the first dose and resolved by the following day. No severe hypersensitivity reactions occurred. The mean number of circulating microfilariae (MF) counts in the control group increased from 12,000/ml at study start (Day 0) to > 20,000/ml at Day 28 and remained > 20,000/ml for the duration of the study. The least squares means of circulating MF were reduced by 69.8% on Day 1 and 97.4% on Day 7 for the 1× group and remained at > 99% lower than the control group for the remainder of the study. Similarly, least squares means of circulating MF were reduced by 85.3% on Day 1 and 93.9% on Day 7 for the 3× group and remained > 98% lower than the control group for the remainder of the study. At the end of the study, the mean number of implanted adult worms recovered was < 10 per sex in all groups with 90%, 85% and 75% of live adult heartworms recovered in control, 1× and 3× treatment groups, respectively. Low numbers of dead adult worms were recovered in 1× and 3×, with none in control. Following each dose, the moxidectin and sarolaner AUC and Cmax had close to dose proportional increases. CONCLUSIONS: This study demonstrated that Simparica Trio (sarolaner, pyrantel, moxidectin) was well tolerated when administered to heartworm-positive dogs at 1× and 3× the maximum recommended dose at 28-day intervals for 3 consecutive months. Simparica Trio significantly reduced microfilaria counts in both treatment groups, without significant clinical consequences. At the doses administered, Simparica Trio had minor adulticidal activity but resulted in no clinical sequelae.

Effects of intravenous hyperosmotic sodium bicarbonate on arterial and cerebrospinal fluid acid-base status and cardiovascular function in calves with experimentally induced respiratory and strong ion acidosis.

The objectives of this study were to determine the effects of hyperosmotic sodium bicarbonate (HSB) administration on arterial and cerebrospinal fluid (CSF) acid-base balance and cardiovascular function in calves with experimentally induced respiratory and strong ion (metabolic) acidosis. Ten healthy male Holstein calves (30-47 kg body weight) were instrumented under halothane anesthesia to permit cardiovascular monitoring and collection of blood samples and CSE Respiratory acidosis was induced by allowing the calves to spontaneously ventilate, and strong ion acidosis was subsequently induced by i.v. administration of L-lactic acid. Calves were then randomly assigned to receive either HSB (8.4% NaHCO3; 5 ml/kg over 5 minutes, i.v.; n=5) or no treatment (controls, n=5) and monitored for 1 hour. Mixed respiratory and strong ion acidosis was accompanied by increased heart rate, cardiac index, mean arterial pressure, cardiac contractility (maximal rate of change of left ventricular pressure), and mean pulmonary artery pressure. Rapid administration of HSB immediately corrected the strong ion acidosis, transiently increased arterial partial pressure of carbon dioxide (P(CO2)), and expanded the plasma volume. The transient increase in arterial P(CO2) did not alter CSF P(CO2) or induce paradoxical CSF acidosis. Compared to untreated control calves, HSB-treated calves had higher cardiac index and contractility and a faster rate of left ventricular relaxation for 1 hour after treatment, indicating that HSB administration improved myocardial systolic function. We conclude that rapid i.v. administration of HSB provided an effective and safe method for treating strong ion acidosis in normovolemic halothane-anesthetized calves with experimentally induced respiratory and strong ion acidosis. Fear of inducing paradoxical CSF acidosis is not a valid reason for withholding HSB administration in calves with mixed respiratory and strong ion acidosis.

Effects of dietary sodium chloride intake on renal function and blood pressure in cats with normal and reduced renal function.

OBJECTIVE: To determine effects of variations in dietary intake of sodium chloride (NaCl) on systemic arterial blood pressure (ABP) in cats with normal and reduced renal function. ANIMALS: 21 adult cats (7 with intact kidneys [control cats; group C], 7 with unilateral renal infarction with contralateral nephrectomy [remnant-kidney model; group RK], and 7 with unilateral renal infarction and contralateral renal wrapping and concurrent oral administration of amlodipine [remnant-wrap model; group WA]). PROCEDURE: All cats were sequentially fed 3 diets that differed only in NaCl content (50, 100, or 200 mg of Na/kg); each diet was fed for 7 days. The ABP was recorded continuously by radiotelemetry, and renal function (glomerular filtration rate [GFR]) was determined on the sixth day of each feeding period. RESULTS: Dietary supplementation with NaCl did not affect ABP, but it increased GFR in groups C and WA. The renin-angiotensin-aldosterone axis was activated in groups RK and WA at the lowest NaCl intake, but supplementation with NaCl suppressed this activation in group WA. The lowest NaCl intake was associated with hypokalemia and a high fractional excretion of potassium that decreased in response to supplementation with NaCl. Arterial baroreceptor resetting was evident after chronic hypertension but was not modified by dietary supplementation with NaCl. CONCLUSIONS AND CLINICAL RELEVANCE: Low NaCl intake was associated with inappropriate kaliuresis, reduced GFR, and activation of the renin-angiotensin-aldosterone axis without evidence of a beneficial effect on ABP. Therefore, this common dietary maneuver could contribute to hypokalemic nephropathy and progressive renal injury in cats.

Evaluation of a technique of inducing hypertensive renal insufficiency in cats.

OBJECTIVE: To compare 2 techniques of inducing combined renal insufficiency and systemic hypertension in cats. ANIMALS: 22 cats 6 to 12 months of age. PROCEDURES: Cats were randomly assigned to 1 of 3 groups. Control (C) group cats had 2 intact kidneys, remnant kidney (RK) group cats underwent unilateral partial renal infarction and contralateral nephrectomy, and remnant-wrap (W) group cats underwent unilateral partial renal infarction and partial abtation and wrapping of the contralateral kidney. Systemic arterial blood pressure (BP) was measured continuously by use of implanted radiotelemetric devices. Renal function was assessed via determination of glomerular filtration rate, measurement of serum creatinine and BUN concentrations, and determination of urine protein-to-creatinine ratio (UP/C). Serum aldosterone concentration and plasma renin activity were measured on day 75. RESULTS: Systolic BP was significantly higher in groups RK and W than in group C, and systolic BP was significantly higher in group W than in group RK. Serum aldosterone concentration and plasma renin activity were significantly higher in group W, compared with groups C and RK. Glomerular filtration rate was significantly lower in groups RK and W, compared with group C. Histologic indices of renal injury and UP/C were significantly higher in group W, compared with groups C and RK. CONCLUSIONS AND CLINICAL RELEVANCE: Hypertensive renal insufficiency in group W was characterized by marked sustained systemic hypertension, decreased renal function, proteinuria, activation of the renin-angiotensin-aldosterone axis, and renal structural injury. Results support the hypothesis that marked systemic hypertension, activation of the renin-angiotensin-aldosterone axis, and proteinuria may damage the kidney of cats with preexisting renal insufficiency.

Effects of the calcium channel antagonist amlodipine in cats with surgically induced hypertensive renal insufficiency.

OBJECTIVE: To determine whether amlodipine besylate decreases systemic arterial blood pressure (BP) and reduces the prevalence of complications in cats with induced hypertensive renal insufficiency. ANIMALS: 20 cats with partial nephrectomy. PROCEDURE: Following reduction in renal mass, 10 cats were administered 0.25 mg of amlodipine/kg, PO, q 24 h (group A). Ten cats served as a control group (group C). Systolic BP (SBP), diastolic BP (DBP), and mean BP (MBP), physical activity, and pulse rate were measured continuously for 36 days by use of radiotelemetric devices. RESULTS: Compared with values for clinically normal cats, SBP, DBP, and MBP were significantly increased in cats of group C. Cats in group A had significant reductions in SBP, DBP, and MBP, compared with values for cats in group C. Albuminuria but not urine protein-to-creatinine ratio was significantly correlated (R2 = 0.317) with SBP in hypertensive cats. Prevalence of ocular lesions attributable to systemic hypertension in group C (7 cats) was greater than that observed in group A (2). Two cats in group C were euthanatized on day 16 because of nuerologic complications attributed to systemic hypertension. One normotensive cat in group A was euthanatized because of purulent enteritis of unknown cause on day 27. CONCLUSIONS AND CLINICAL RELEVANCE: Amlodipine had an antihypertensive effect in cats with coexistent systemic hypertension and renal insufficiency. Its use may improve the prognosis for cats with systemic hypertension by decreasing the risk of ocular injury or neurologic complications induced by high BP.

In vivo evaluation of vaccine efficacy against challenge with a contemporary field isolate from the α cluster of H1N1 swine influenza virus.

Influenza A virus vaccines currently contain a mixture of isolates that reflect the genetic and antigenic characteristics of the currently circulating strains. This study was conducted to evaluate the efficacy of a trivalent inactivated swine influenza virus vaccine (Flusure XP) in pigs challenged with a contemporary α-cluster H1N1 field isolate of Canadian swine origin. Pigs were allocated to vaccinated, placebo, and negative-control groups and monitored for respiratory disease for 5 d after challenge. On the challenge day and 5 d after challenge the serum of the vaccinated pigs had reciprocal hemagglutination inhibition antibody titers 40 for all the vaccine viruses but ≤ 20 for the challenge virus. Gross lesions were present in the lungs of all pigs that had been inoculated with the challenge virus, but the proportion of lung tissue consolidated did not differ significantly between the placebo and vaccinated pigs. However, the amount of virus was significantly reduced in the nasal secretions, lungs, and bronchoalveolar lavage fluid in the vaccinated pigs compared with the placebo pigs. These results indicate that swine vaccinated with Flusure XP were partially protected against experimental challenge with a swine α-cluster H1N1 virus that is genetically similar to viruses currently circulating in Canadian swine.

Les vaccins actuels contre l'influenza A contiennent un mélange d'isolats qui reflète les caractéristiques génétiques et antigéniques des souches actuellement en circulation. La présente étude a été réalisée afin d'évaluer l'efficacité d'un vaccin inactivé trivalent contre le virus de l'influenza porcin (Flusure XP) chez des porcs challengés avec un isolat terrain du virus de l'influenza de la grappe α du type H1N1 provenant d'un porc d'origine canadienne. Des porcs ont été répartis dans un des trois groupes suivants : vacciné, placebo ou témoin négatif; et examinés pour problèmes respiratoires pendant 5 jours après le challenge. Le jour du challenge et le 5e jour suivant le challenge, on retrouvait dans le sérum des porcs vaccinés des titres réciproques d'anticorps hémagglutinants 40 pour tous les virus vaccinaux mais ≤ 20 pour le virus ayant servi au challenge. Des lésions macroscopiques étaient présentes dans les poumons de tous les porcs qui avaient été inoculés avec le virus servant pour le challenge, mais il n'y avait pas de différence significative dans la proportion de tissu pulmonaire consolidé entre le groupe vacciné et le groupe placebo. Toutefois, la quantité de virus était réduite de manière significative dans les sécrétions nasales, les poumons et le liquide des lavages broncho-alvéolaires des porcs vaccinés comparativement aux porcs du groupe placebo. Ces résultats indiquent que les porcs vaccinés avec Flusure XP étaient partiellement protégés contre une infection expérimentale avec un virus H1N1 porcin de la grappe α qui est génétiquement similaire aux virus qui circulent actuellement chez les porcs canadiens.(Traduit par Docteur Serge Messier).