Comparison of the efficacy of cloxacillin alone and cloxacillin combined with an internal teat sealant for dry-cow therapy.

All the quarters in the cows with high somatic cell counts in 10 herds were treated at drying off with either 600 mg cloxacillin or 600 mg cloxacillin and 4 g of an internal teat sealant containing 65 per cent bismuth subnitrate. The quarters were sampled daily for bacteriological tests for the three days before drying off and twice after calving to establish whether they were infected. Clinical mastitis cases were monitored from drying off until 100 days after calving. The odds of a quarter being bacteriologically negative after calving or developing clinical mastitis in the first 100 days after calving were investigated by multilevel logistic regression. The quarters treated with the internal sealant and cloxacillin were significantly more likely to be bacteriologically negative in the immediate period after calving and were significantly less likely to suffer clinical mastitis during the first 100 days after calving than the quarters treated with cloxacillin alone. There was more variation between cows than between herds in the underlying risk of an infection after calving, but there was more variation between herds than between cows in the underlying risk of clinical mastitis during the 100 days after calving.

Pharmacokinetics of danofloxacin 18% in lactating sheep and goats.

The pharmacokinetics of danofloxacin administered at 6 mg/kg bodyweight by the intravenous and subcutaneous (s.c.) routes were determined in sheep and goats. Milk concentrations were also determined following s.c. administration. Plasma and milk concentrations of danofloxacin were measured using high-performance liquid chromatography. The plasma concentration-time curves were analysed by noncompartmental methods. Danofloxacin had a similar large volume of distribution at steady state in sheep and goats of 2.19 +/- 0.28 and 2.43 +/- 0.13 L/kg, and a similar body clearance of 0.79 +/- 0.15 and 0.98 +/- 0.13 L/kg.h, respectively. Following s.c. administration, danofloxacin achieved a similar maximum concentration in sheep and goats of 1.48 +/- 1.54 and 1.05 +/- 0.09 mg/L, respectively at 1.6 h and had a mean residence time of 4.93 +/- 0.79 and 4.51 +/- 0.44 h, respectively. Danofloxacin had an absolute bioavailability of 93.6 +/- 13.7% in sheep and 97.0 +/- 15.7% in goats and a mean absorption time of 2.07 +/- 0.75 and 2.01 +/- 0.53 h, respectively. Mean danofloxacin concentrations in milk after s.c. administration to sheep were approximately 10 times higher than plasma at 12 h postdose and remained eight times higher at 24 h postdose. In goats, mean concentration of danofloxacin in milk were approximately 13 times higher than plasma at 12 h postdose and remained four times higher at 24 h postdose. Thus, danofloxacin 18% administered s.c. to lactating ewes and goats at a dose rate of 6 mg/kg was characterized by extensive absorption, high systemic availability and high distribution into the udder resulting in higher drug concentrations being achieved in milk than in plasma.

Efficacy of maropitant for preventing vomiting associated with motion sickness in dogs.

Maropitant is a neurokinin-1 inhibitor that acts to prevent and treat vomiting by blocking stimuli to the final common pathway in the emetic centre of the brain. The field efficacy and safety of a single oral dose of maropitant were investigated for the prevention of vomiting in dogs with a history of motion sickness resulting from transportation by car in two blinded, placebo-controlled studies. In an exploratory study designed as a two-way crossover trial with 17 dogs, 10 of the dogs given the placebo vomited during a car journey but only three of the dogs vomited under maropitant treatment. In a larger multicentred parallel design study, 69 of 105 dogs treated with the placebo vomited during the journey compared with 15 of 106 dogs treated with maropitant (P < 0.0001).

The pharmacokinetics of maropitant, a novel neurokinin type-1 receptor antagonist, in dogs.

Maropitant is the first NK1 receptor antagonist developed to treat and prevent emesis in dogs; it is administered by subcutaneous (s.c.) injection at 1 mg/kg, or orally (p.o.), in tablet form, at either 2 or 8 mg/kg depending on indication. The absolute bioavailability of maropitant was markedly higher (90.7%) following s.c. injection than after oral administration (23.7% at the 2 mg/kg dose and 37.0% at the 8 mg/kg dose). First-pass metabolism contributes to the low bioavailability of maropitant following oral administration. The difference in bioavailability between the two oral doses reflects the nonlinear kinetics characterizing the disposition of maropitant within the 2-8 mg/kg dose range. Systemic clearance of maropitant following intravenous (i.v.) administration was 970, 995 and 533 mL/h.kg at doses of 1, 2 and 8 mg/kg, respectively. Nonproportional kinetics were observed for p.o. administered maropitant at doses ranging from 2 to 16 mg/kg but dose proportionality was demonstrated at higher doses (20-50 mg/kg). Linearity was also demonstrated following s.c. administration at 0.5, 1 and 2 mg/kg. Maximum plasma drug concentration (Cmax) occurred 0.75 h (tmax) after s.c. administration at 1 mg/kg, and at 1.7 and 1.9 h after oral administration of 8 and 2 mg/kg doses, respectively. The apparent terminal half-life of maropitant was 7.75, 4.03 and 5.46 h after dosing at 1 mg/kg (s.c.), 2 mg/kg (p.o.) and 8 mg/kg (p.o.), respectively. Feeding status had no effect on oral bioavailability. Limited accumulation occurred following once-daily administration of maropitant for five consecutive days at 1 mg/kg (s.c.) or 2 mg/kg (p.o.). At the dose of 8 mg/kg (p.o.) once daily for two consecutive days, the mean AUC(0-24h) (second dose) was 218% that of the first dose value. Urinary recovery of maropitant and its main metabolite was minimal (<1%), thus supporting the evidence that maropitant clearance is primarily hepatic.

The anti-emetic efficacy of maropitant (Cerenia) in the treatment of ongoing emesis caused by a wide range of underlying clinical aetiologies in canine patients in Europe.

OBJECTIVES: The efficacy of maropitant (Cerenia; Pfizer Inc.) as an anti-emetic for use in dogs with ongoing emesis was evaluated in a two-phase multi-centric study conducted at veterinary clinics in France, Italy, Slovakia and the UK. METHODS: In phase I, dogs with ongoing emesis were randomised in a 1:1 ratio to either maropitant (32 dogs) or metoclopramide (34 dogs). In phase II, dogs were randomised in a 2:1 ratio to maropitant (77 dogs) or metoclopramide (40 dogs). Maropitant was administered subcutaneously at 1 mg/kg/day for up to five days. Metoclopramide was administered as recommended on the product labels as licensed at 0.5 to 1 mg/kg/day subcutaneously or orally with the daily dose divided over two to three administrations per day for up to three to five days. RESULTS: In phase I, 97 per cent of dogs treated with maropitant and 71 per cent of dogs treated with metoclopramide did not vomit after treatment (P<0.01). The mean number of emetic events after maropitant treatment was significantly reduced compared with that after metoclopramide treatment (P=0.01). In phase II, the occurrence of emesis was lower for maropitant during the first 24 hours (P<0.0001) and for each day thereafter. CLINICAL SIGNIFICANCE: A single daily dose of maropitant was more effective than metoclopramide administered two or three times daily in the treatment of emesis caused by various aetiologies in dogs.

Pharmacokinetics and lung tissue concentrations of tulathromycin in swine.

The absolute bioavailability and lung tissue distribution of the triamilide antimicrobial, tulathromycin, were investigated in swine. Fifty-six pigs received 2.5 mg/kg of tulathromycin 10% formulation by either intramuscular (i.m.) or intravenous (i.v.) route in two studies: study A (10 pigs, i.m. and 10 pigs, i.v.) and study B (36 pigs, i.m.). After i.m. administration the mean maximum plasma concentration (C(max)) was 616 ng/mL, which was reached by 0.25 h postinjection (t(max)). The mean apparent elimination half-life (t(1/2)) in plasma was 75.6 h. After i.v. injection plasma clearance (Cl) was 181 mL/kg.h, the volume of distribution at steady-state (V(ss)) was 13.2 L/kg and the elimination t(1/2) was 67.5 h. The systemic bioavailability following i.m. administration was >87% and the ratio of lung drug concentration for i.m. vs. i.v. injection was > or =0.96. Following i.m. administration, a mean tulathromycin concentration of 2840 ng/g was detected in lung tissue at 12 h postdosing. The mean lung C(max) of 3470 ng/g was reached by 24 h postdose (t(max)). Mean lung drug concentrations after 6 and 10 days were 1700 and 1240 ng/g, respectively. The AUC(inf) was 61.4 times greater for the lung than for plasma. The apparent elimination t(1/2) for tulathromycin in the lung was 142 h (6 days). Following i.m. administration to pigs at 2.5 mg/kg body weight, tulathromycin was rapidly absorbed and highly bioavailable. The high distribution to lung and slow elimination following a single dose of tulathromycin, are desirable pharmacokinetic attributes for an antimicrobial drug indicated for the treatment of respiratory disease in swine.

Fenbendazole pharmacokinetics, metabolism, and potentiation in horses.

The present study was designed to describe the pharmacokinetics and fecal excretion of fenbendazole (FBZ) and fenbendazole sulphoxide (FBZSO) and their metabolites in horses, to investigate the effects which concurrent feeding has on the absorption and pharmacokinetics of FBZ, and to determine the effect of coadministration of the metabolic inhibitor piperonyl-butoxide on the in vivo pharmacokinetics and in vitro liver microsomal metabolism of sulfide and sulfoxide benzimidazoles. The effect of piperonyl-butoxide on the enantiomeric genesis of the sulfoxide moiety was also investigated. Following administration of FBZSO and FBZ, the fenbendazole sulphone metabolite predominated in plasma, and the C(max) and area under the plasma curve (AUC) values for each moiety were larger (P < 0.001) following FBZSO than FBZ. In feces the administered parent molecule predominated. The combined AUC for active benzimidazole moieties following oral administration of FBZ (10 mg/kg) in horses was almost 4 times as high in unfed horses (2.19 microg x h/ml) than in fed horses (0.59 microg x h/ml), and coadministration of piperonyl-butoxide significantly increased the AUC and C(max) of active moieties following intravenous administration of FBZSO and oral administration of FBZ. When FBZSO was administered i.v. as a racemate, the first enantiomer of oxfendazole (FBZSO-1) predominated in plasma, however, following coadministration with piperonyl-butoxide, the second enantiomer of oxfendazole (FBZSO-2) predominated for 10 h. Piperonyl-butoxide significantly reduced the oxidative metabolism of FBZSO and FBZ in equine liver microsomes and altered the ratio of enantiomers FBZSO-1/FBZSO-2 from >4:1 to 1:1. It is concluded that in horses efficacy of FBZSO and FBZ could be improved by administration to unfed animals and coadministration with piperonyl-butoxide.

Efficacy and safety of selamectin against fleas on dogs and cats presented as veterinary patients in Europe.

Two controlled and masked multi-centre studies were conducted to examine the efficacy of a novel topical avermectin, selamectin, against natural flea infestations on 418 dogs and 345 cats. Veterinary patients with viable flea infestations were enrolled in the studies, which were conducted in United Kingdom, France, Germany, and Italy. Animals were allocated randomly in a 2:1 ratio to one of two treatments: either selamectin alone at a minimum dosage of 6mgkg(-1) or fenthion at recommended dose rates. Concurrent use of an environmental spray (containing methoprene and either pyrethrins or permethrin) was permitted only for fenthion-treated animals. In-contact cats and dogs (animals living in the same home) received the same treatment as the first animal enrolled from the household, if recommended by the veterinarian. Study day 0 was defined as the day of first treatment. Animals were treated on days 0, 30, and 60, and flea comb counts and clinical evaluations were conducted on days 0, 14, 30, 60, and 90. Analysis of variance of ln(flea count+1) showed that values were significantly lower for selamectin alone compared with fenthion (with or without the concurrent use of an environmental spray) in dogs on days 30, 60, and 90 (P<0.05) and in cats on days 14, 30, 60, and 90 (P<0.01). For selamectin, the reductions in geometric mean flea counts on days 14, 30, 60, and 90, compared with day 0, were 92.5, 90.7, 98.1, and 99.1%, respectively, for dogs and 92.8, 92.7, 97.7, and 98.4%, respectively, for cats. Selamectin was shown to be safe and highly effective in the control of naturally acquired flea infestations on dogs and cats presented as veterinary patients in Europe.

Efficacy and safety of selamectin against Sarcoptes scabiei on dogs and Otodectes cynotis on dogs and cats presented as veterinary patients.

A series of randomized, controlled and masked field studies was conducted in veterinary patients to evaluate the efficacy of selamectin, a novel avermectin, in the treatment of naturally occurring Sarcoptes scabiei infestations on dogs and Otodectes cynotis infestations on dogs and cats. A total of 342 dogs and 237 cats participated in these studies, which were conducted at 40 veterinary practices in the USA and Europe. Animals were randomly assigned to treatment with selamectin or a positive-control product (existing approved products). Selamectin was administered as a unit dose providing a minimum of 6mgkg(-1) (range: 6-12mgkg(-1)) in a topical preparation applied to the skin in a single spot on day 0 (O. cynotis in cats, n=144), or on days 0 and 30 (O. cynotis and S. scabiei in dogs, n=83 and n=122, respectively). The presence of parasites was assessed before treatment and at 30 days (for all studies) and 60 days (for O. cynotis and S. scabiei dog studies) after first treatment. The animals were also evaluated clinically at each assessment period. Based on skin scrapings, the efficacy of selamectin against S. scabiei infestations on dogs was >95% by day 30, and 100% by day 60. Against O. cynotis, selamectin eliminated mites in 94-100% of cats by day 30, and in 90% of dogs by day 60. The positive-control products achieved similar results. Thus, selamectin was safe and effective against ear mites in dogs and cats and sarcoptic mange in dogs when used in field (veterinary patient) studies in dogs and cats of a wide variety of ages and breeds.

Efficacy and safety of selamectin against gastrointestinal nematodes in cats presented as veterinary patients.

A series of randomized, controlled, masked, field (veterinary patient) studies were conducted in the USA and Europe to evaluate the efficacy of selamectin, a novel macrocyclic lactone of the avermectin subclass, in the treatment of naturally acquired gastrointestinal nematode infections in cats. After confirmation of ascarid and/or hookworm infection, 298 cats of various ages and breeds were randomly assigned to treatment with selamectin (n=202) or an existing commercially approved positive-control product (n=96). Unit doses of selamectin (providing a minimum dosage of 6mgkg(-1)) were administered topically to the skin in a single spot at monthly intervals. Quantitative fecal examinations were performed on days 0 (before treatment), 30, and 60. In the selamectin-treated cats, fecal ascarid egg counts were reduced by 99.6 to 100% on day 30, and by 99.9 to 100% on day 60. Fecal hookworm egg counts were reduced by 98.3% on day 30, and by 100% on day 60 in the selamectin-treated cats. The positive-control products achieved reductions in egg counts of 96.5 to 100% (ascarids) and 98.9 to 99.9% (hookworms). These studies have shown that monthly topical administration of selamectin is safe and highly effective in the treatment of naturally acquired ascarid and hookworm infections in cats.

Interaction between fenbendazole and piperonyl butoxide: pharmacokinetic and pharmacodynamic implications.

The effect of the cytochrome P450 inhibitor, piperonyl butoxide on the pharmacokinetics and anthelmintic efficacy of the benzimidazole compound fenbendazole was studied in sheep and goats. Pretreatment of goats with the inhibitor caused a greater than three-fold increase in the relative bioavailability of fenbendazole and fenbendazole sulphoxide. A pharmacokinetic dose titration study was carried out in sheep with fenbendazole (5 mg kg-1) and piperonyl butoxide administered orally at 0, 15, 31, 63, 125 and 250 mg kg-1. The AUC of fenbendazole and the sulphoxide were significantly increased when fenbendazole was co-administered with piperonyl butoxide at dose rates equal to or higher than 31 mg kg-1. Peak plasma concentrations (Cmax) and mean residence time (MRT) were also significantly increased. The efficacy of the combination was assessed in sheep against two species of benzimidazole-resistant abomasal nematodes; Ostertagia circumcincta and Haemonchus contortus. The percentage reduction in the total number of O. circumcincta worms was 7.9% (fenbendazole) and 97.8% (fenbendazole-piperonyl butoxide). For H. contortus, the percentage reduction was 84.8% (fenbendazole) and 99.0% (fenbendazole-piperonyl butoxide). The in-vitro S-oxidation of fenbendazole and fenbendazole sulphoxide was studied using microsomal preparations from rat liver. Piperonyl butoxide inhibited significantly the sulphoxidation and sulphonation of fenbendazole. It was concluded that piperonyl butoxide inhibited the oxidative conversion of fenbendazole into inactive metabolites and this resulted in a potentiated anthelmintic action.

Determination of rafoxanide and closantel in ovine plasma by high performance liquid chromatography.

A high performance liquid chromatographic method has been developed for the determination of rafoxanide and closantel in ovine plasma. Acetonitrile and chloroform were used for the extraction. The mean recoveries were 78.69% and 80.59% for rafoxanide and closantel, respectively. This method was applied to the characterization of rafoxanide plasma kinetics following oral administration of therapeutic doses to sheep.

Effect of early treatment with rafoxanide on antipyrine clearance in sheep infected with Fasciola hepatica.

1. The effect of the salicylanilide compound rafoxanide against immature stages of Fasciola hepatica was investigated in sheep using a series of antipyrine clearance tests and measuring glutamate dehydrogenase and gamma-glutamyl transferase activities in plasma. 2. Three animal groups were used. In two groups, sheep were infected with 200 metacercariae each. Four weeks after infection one of the two groups was treated with rafoxanide and the other was left untreated. The third group was unparasitized and also received rafoxanide. 3. Infection was confirmed by post-mortem examination of the livers of infected sheep. Infection did not alter the plasma disposition of rafoxanide. 4. The efficacy of rafoxanide, as assessed by the reduction in the number of adult flukes in treated animals compared with controls, was 85%. 5. Glutamate dehydrogenase activity fell dramatically 2 weeks after treatment but increased again at 12 weeks post-infection in the infected rafoxanide-treated group. 6. Antipyrine clearance decreased between 8 and 14 weeks post-infection in untreated sheep. In the infected rafoxanide-treated group plasma clearance of antipyrine remained unchanged until 10 weeks after rafoxanide administration when it decreased from the preinfection value of 5.09 to 3.90 ml.kg/min. Rafoxanide did not affect antipyrine disposition in uninfected sheep. 7. It was concluded that rafoxanide had an incomplete anthelmintic effect against immature stages of Fasciola hepatica, and that surviving parasites caused delayed liver damage which was reflected in an elevation in glutamate dehydrogenase activity and decreased plasma clearance of antipyrine.