Owner preference for insulin delivery device and glycaemic control in diabetic dogs.

OBJECTIVES: To assess treatment satisfaction and owner preference for two delivery devices (VetPen, MSD Animal Health, and U40 insulin syringes) and the effect on glycaemic control in diabetic dogs treated with porcine insulin zinc suspension. MATERIALS AND METHODS: Randomised prospective cross-over study with two arms, each of 8 weeks. Twenty client-owned diabetic dogs on insulin treatment by U40 syringe were enrolled. Dogs were randomly assigned to receive insulin by syringe or pen injector for 2 months, followed by 2 months of the other injection method. Treatment satisfaction and owners' insulin delivery device preference were assessed using a questionnaire. Glycaemic control was assessed using a clinical score, serum fructosamine and glycated haemoglobin (HbA1c%) at the time of the enrolment (T0) and the end of each arm of treatment (T2 and T4). RESULTS: Treatment satisfaction differed for the two types of the delivery device when the order that each device was used was taken into consideration. Owners who used the syringe first did not have a significant preference for an injection device. In contrast, owners who used the pen injector first expressed a significant preference for VetPen compared to syringes. No significant differences in the number of dogs of Groups 1 and 2 with good and poor glycaemic control at T2 and T4 were detected. CLINICAL SIGNIFICANCE: Overall treatment satisfaction and preference for the two delivery methods were similar. However, VetPen was preferred by owners who were randomised to use this device first. Glycaemic control did not appear to be affected by the insulin delivery device used.

Efficacy of a non-updated, Matrix-C-based equine influenza subunit-tetanus vaccine following Florida sublineage clade 2 challenge.

Assessing the ability of current equine influenza vaccines to provide cross-protection against emerging strains is important. Horses not vaccinated previously and seronegative for equine influenza based on haemagglutination inhibition (HI) assay were assigned at random to vaccinated (n=7) or non-vaccinated (control, n=5) groups. Vaccination was performed twice four weeks apart with a 1 ml influenza subunit (A/eq/Prague/1/56, A/eq/Newmarket/1/93, A/eq/Newmarket/2/93), tetanus toxoid vaccine with Matrix-C adjuvant (EquilisPrequenza Te). All the horses were challenged individually by aerosol with A/eq/Richmond/1/07 three weeks after the second vaccination. Rectal temperature, clinical signs, serology and virus excretion were monitored for 14 days after challenge. There was no pain at the injection site or increases in rectal temperature following vaccination. Increases in rectal temperature and characteristic clinical signs were recorded in the control horses. Clinical signs were minimal in vaccinated horses. Clinical (P=0.0345) and total clinical scores (P=0.0180) were significantly lower in the vaccinated than in the control horses. Vaccination had a significant effect on indicators of viraemia - the extent (P=0.0006) and duration (P=<0.0001) of virus excretion and the total amount of virus excreted (AUC, P=0.0006). Vaccination also had a significant effect (P=0.0017) on whether a horse was positive or negative for virus excretion during the study. Further research is needed to fully understand the specific properties of this vaccine that may contribute to its cross-protective capacity.

Pharmacokinetics of total thyroxine after repeated oral administration of levothyroxine solution and its clinical efficacy in hypothyroid dogs.

BACKGROUND: Oral levothyroxine (l-T4 ) supplementation is commonly used to treat hypothyroid dogs. OBJECTIVES: Investigate the plasma profile and pharmacokinetics of total thyroxine (tT4 ) after PO administration of a l-T4 solution and its clinical efficacy in hypothyroid dogs. ANIMALS: Ten dogs with naturally occurring hypothyroidism. METHODS: After hypothyroidism diagnosis and supplementation with l-T4 solution PO q24h at 20 µg/kg BW for minimum 4 weeks, the plasma profile and pharmacokinetics of tT4 were determined over 34 hours and the clinical condition of the dogs was evaluated. RESULTS: Before dosing for pharmacokinetic evaluation, mean tT4 concentration was 23 ± 9 nmol/L. l-T4 was absorbed rapidly (tmax , 5 hours), reaching a mean maximal tT4 concentration of 56 ± 11 nmol/L. The apparent terminal half-life was 11.8 hours. Clinical signs of hypothyroidism improved or resolved in all dogs after 4 weeks of treatment. The dosage of 20 µg/kg PO q24h was judged appropriate in 5 dogs, and 4 dogs required slight increases (9-16%). Twice daily treatment, with a 30% increase in dosage, was necessary for 1 dog. CONCLUSIONS AND CLINICAL IMPORTANCE: The pharmacokinetics of l-T4 in hypothyroid dogs was similar to that reported in healthy euthyroid dogs. Clinical and hormonal responses to l-T4 solution were rapid in all dogs. The starting dosage of 20 µg/kg PO q24h was suitable for maintenance supplementation in 50% of the dogs, minor dosage modification was required in 4 other dogs, and treatment q12h was required in 1 dog.

Clinical efficacy and safety of a once-daily formulation of carbimazole in cats with hyperthyroidism.

OBJECTIVE: Evaluation of efficacy and safety of a novel controlled-release formulation of carbimazole in feline hyperthyroidism. METHODS: A multicentre, self-controlled study in 44 client-owned cats with history and clinical signs of hyperthyroidism, and total thyroxine concentration greater than or equal to 50 nmol/l. Treatment was started at 15 mg once daily, response assessed after 10 days, and 3, 5, 8, 26 and 53 weeks and dose adjusted as required. RESULTS: The median dose of carbimazole was 10 mg (range 10 to 15 mg) and 15 mg (5 to 25 mg) once daily after 3 and 53 weeks, respectively. Median total thyroxine concentration dropped significantly from 118 nmol/l (50 to 320 nmol/l) at presentation to 33 nmol/l (n=40) after 10 days, 31 nmol/l (n=34) at 3 weeks and 21 nmol/l (n=18) at 53 weeks. Clinical signs improved or resolved in almost all cats within three weeks after starting treatment. Twenty-one adverse reactions possibly (20) or probably (1) related to treatment were reported. During treatment, increased blood urea nitrogen concentration was observed in 25 per cent of the cats, eosinophilia in 20 per cent and lymphopenia in 16 per cent, while liver enzymes tended to improve. CLINICAL SIGNIFICANCE: Once daily administration of controlled-release carbimazole tablets was effective and had expected tolerance in hyperthyroid cats during short- and long-term treatment.

Pharmacokinetics of cimetidine in dogs after oral administration of cimetidine tablets.

Long-term oral treatment with cimetidine is recommended to reduce vomiting in dogs with chronic gastritis. Despite this, few studies have specifically examined the plasma disposition and pharmacokinetics of cimetidine in dogs, particularly following repeated oral administration. The pharmacokinetics of cimetidine following oral administration as tablets was investigated in healthy dogs. Cimetidine was absorbed rapidly post-treatment (t(max) = 0.5 h). A mean absolute bioavailability of 75% was calculated following a single oral administration of 5 mg cimetidine/kg body weight. After intravenous administration, a plasma half-life of 1.6 h was calculated. Repeated oral administration at the recommended dose rate and regime (5 mg/kg body weight three times daily) for 30 consecutive days did not lead to any accumulation of cimetidine in plasma. Food intake concomitant with oral administration of cimetidine delayed (t(max) = 2.25 h) and decreased the rate and extent of absorption (AUC) by about 40%. Cimetidine was well absorbed in fasted dogs. Administration of food decreased the bioavailability of cimetidine by 40%. Cimetidine does not accumulate over time in plasma when administered long term to dogs.

Clinical evaluation of a novel liquid formulation of L-thyroxine for once daily treatment of dogs with hypothyroidism.

BACKGROUND: A liquid solution of levothyroxine (L-T4) is available for treatment of canine hypothyroidism. HYPOTHESIS: Once daily oral administration of a liquid L-T4 solution is effective and safe for controlling hypothyroidism in dogs. ANIMALS: Thirty-five dogs with naturally occurring hypothyroidism. METHODS: Dogs received L-T4 solution PO once daily at a starting dosage of 20 microg/kg body weight (BW). The dose was adjusted every 4 weeks, based on clinical signs and peak serum total T4 (tT4) concentrations. Target peak serum tT4 and thyroid stimulating hormone (TSH) concentrations, 4-6 hours posttreatment, were 35-95 nmol/L and < 0.68 ng/mL, respectively. Dogs were followed for up to 22 weeks after establishment of the maintenance dose. RESULTS: Clinical signs of hypothyroidism improved or resolved in 91% of dogs after 4 weeks of L-T4 treatment at 20 microg/kg once daily. The maintenance dose was established in 76, 94, and 100% of dogs after 4, 8, and 12 weeks of treatment, respectively. This was 20 microg L-T4/kg BW for 79% of the dogs, 30 microg/kg BW for 15%, and 10-15 microg/kg BW in the remaining 6%, once daily. Thereafter, median peak tT4 and TSH concentrations were 51 nmol/L and 0.18 ng/mL, respectively, and remained stable during the 22-week follow-up; clinical signs did not recur. CONCLUSIONS AND CLINICAL IMPORTANCE: All of the hypothyroid dogs had rapid clinical and hormonal responses to supplementation with the PO-administered L-T4 solution. The starting dosage of 20 microg L-T4/kg BW once daily was suitable for 79% of dogs.

Pharmacokinetics and pharmacodynamics of ramipril and ramiprilat in healthy cats.

The pharmacokinetics of ramipril and its active metabolite, ramiprilat, was determined in cats following single and repeated oral doses of ramipril (Vasotop tablets) (once daily for 9 days) at dose rates of 0.125, 0.25, 0.5 and 1.0 mg/kg. The pharmacodynamic effects were assessed by measuring plasma angiotensin-converting enzyme (ACE) activity. Maximum ramipril concentrations were attained within 30 min following a single dose and declined rapidly (concentrations were below the limit of quantification 4 h after treatment). Peak ramiprilat concentrations were detected at approximately 1.5 h. The apparent terminal half-life (t((1/2)beta)) was > or =20 h irrespective of the dose. Ramiprilat accumulated in plasma (ratio of accumulation 1.3 to 1.9 depending on the dose rate) following repeated administration. Steady-state conditions were attained after the second dose. Excretion was predominant in faeces (87%) and to a lesser extent in urine (11%). The rate and extent of absorption of ramipril as well as its conversion to ramiprilat were not significantly influenced by the presence of food in the gastrointestinal tract. Plasma-ACE activity was almost completely abolished 0.5-2.0 h after treatment, irrespective of the dose rate. Significant inhibition of ACE activity of 54.7 to 82.6% (depending on the dosage) was still present 24 h after treatment. Treatment was well-tolerated in all cats. Ramipril at a dose rate of 0.125 mg/kg once daily produces significant and long-lasting inhibition of ACE activity in healthy cats. The appropriateness of this dosage regime needs to be confirmed in diseased cats.

Pharmacokinetics of controlled-release carbimazole tablets support once daily dosing in cats.

Carbimazole, a prodrug of methimazole, is used in the treatment of hyperthyroidism in cats. The pharmacokinetics of methimazole was investigated in healthy cats following oral administration of 15 mg of carbimazole as a controlled-release tablet (Vidalta), Intervet). The controlled-release tablet did not produce a pronounced concentration peak and methimazole was present in the circulation for a sustained period, compared with a conventional tablet formulation. The time to reach peak concentrations after carbimazole administration was quite long (t(max) 6 h). The absolute bioavailability of carbimazole was around 88 +/- 11%. Repeated oral administration daily for 13 consecutive days did not lead to accumulation of methimazole in plasma. The extent of absorption of carbimazole was about 40% higher when administered to cats that had been fed compared to fasted cats. The relative oral bioavailability of methimazole following administration of the controlled-release tablets was similar to that of a conventional release formulation (83 +/- 21%). The pharmacokinetics of this controlled-release formulation of carbimazole supports its use as a once daily treatment (both as a starting dose and for maintenance therapy) for cats with hyperthyroidism.

Pharmacokinetics of total thyroxine in dogs after administration of an oral solution of levothyroxine sodium.

Oral L-thyroxine (L-T4) supplementation is used to replace thyroid hormone concentrations in dogs with hypothyroidism. The pharmacokinetics of L-T4 following administration of a solution (Leventa) was investigated in healthy dogs. L-T4 was absorbed fairly rapidly (t(max) 3 h). A mean bioavailability of 22% was calculated following a single oral administration of 40 microg L-T4/kg body weight. Repeated oral administration at the same dose for 14 consecutive days did not lead to any accumulation of T4 in serum. After intravenous administration of L-T4, a serum half-life of 11.6 h was calculated. Food intake concomitant with L-T4 oral administration delayed L-T4 absorption and decreased its rate and extent by about 45%. The relative bioavailability of L-T4 following administration of a tablet formulation was about 50% of that of the L-T4 solution. The pharmacokinetic properties of liquid L-T4 after oral administration support the use of a dose rate of 20 microg/kg once daily, as a starting dose for replacement therapy in dogs with hypothyroidism.

Vedaprofen therapy in cats with upper respiratory tract infection or following ovariohysterectomy.

OBJECTIVES: The antipyretic and analgesic efficacy of vedaprofen (at a dose of 0.5 mg/kg) was evaluated after repeated once-daily administration (for three or five days) to 80 cats with upper respiratory tract disease or 302 cats undergoing ovariohysterectomy. METHODS: Both clinical trials were randomised, double blinded and placebo controlled. RESULTS: In the upper respiratory tract disease trial, vedaprofen produced a significant reduction in rectal temperature when compared with cats administered antimicrobial treatment only. This antipyretic activity lasted at least four hours after administration on the first day of treatment (day 0) and at least eight hours on day 1 and day 2. Significantly more cats in the treatment group were classified as having returned to normal on day 5, day 6 and day 7 compared with the placebo group. In the ovariohysterectomy trial, scores for behaviour (on day 1, day 2 and day 3) and appetite (on day 1 and day 2) were significantly better in the vedaprofen group than in the placebo-treated cats. CLINICAL SIGNIFICANCE: Vedaprofen produced a clinically relevant reduction in body temperature and a more rapid return to normality in cats with upper respiratory tract disease. Vedaprofen treatment also resulted in more rapid recovery, presumably through the relief of pain and inflammation, in cats that had undergone soft tissue surgery.

Compatibility of a bivalent modified-live vaccine against Bordetella bronchiseptica and CPiV, and a trivalent modified-live vaccine against CPV, CDV and CAV-2.

Eight puppies (group 1) were vaccinated once with a bivalent modified-live vaccine against infectious tracheobronchitis by the intranasal route and at the same time with an injectable trivalent vaccine against canine parvovirus, canine distemper virus and canine adenovirus; a second group of eight puppies (group 2) was vaccinated only with the intranasal bivalent vaccine, and a further eight puppies (group 3) were vaccinated only with the injectable trivalent vaccine. Three weeks later they were all challenged with wildtype Bordetella bronchiseptica and canine parainfluenza virus by the aerosol route, and their antibody responses to the five vaccine organisms were determined. Oronasal swabs were taken regularly before and after the challenge for the isolation of bacteria and viruses, and the puppies were observed for clinical signs for three weeks after the challenge. There were no significant differences in the puppies' titres against canine parvovirus, canine distemper virus and canine adenovirus type 2 between the groups vaccinated with or without the bivalent intranasal vaccine. After the challenge the mean clinical scores of the two groups vaccinated with the intranasal vaccine were nearly 90 per cent lower (P=0.001) than the mean score of the group vaccinated with only the trivalent injectable vaccine, and the puppies in this group all became culture-positive for B bronchiseptica and canine parainfluenza virus. There were only small differences between the rates of isolation of B bronchiseptica from groups 1, 2 and 3, but significantly lower yields of canine parainfluenza virus were isolated from groups 1 and 2 than from group 3.

Double-blind, placebo-controlled study of the efficacy of nandrolone laurate in the treatment of dobermanns with subclinical hepatitis.

Twenty-one three-year-old dobermanns with subclinical hepatitis were treated with nandrolone laurate or a placebo in a double-blind trial. The dogs were scored clinically before and after four months of treatment and they were evaluated by clinical biochemistry and liver biopsies. After the treatment no significant differences were observed between the two groups in any of the clinical biochemistry values; eight of the 21 dogs had no histological evidence of hepatitis and five other dogs had improved, but there was no significant difference between the responses of the two groups.

Protection of dogs for 13 months against Bordetella bronchiseptica and canine parainfluenza virus with a modified live vaccine.

Twelve specific pathogen-free (spf) puppies were vaccinated intranasally with a bivalent, modified live vaccine against infectious tracheobronchitis (group 1) and six puppies of the same age and from the same source served as unvaccinated controls (group 2). Both groups were challenged with wild-type Bordetella bronchiseptica and canine parainfluenza virus by the aerosol route 56 weeks after group 1 had been vaccinated, and at the same time six 10-week-old spf puppies from the same source (group 3) were also challenged. Oronasal swabs were taken regularly before and after the challenge, for the isolation of bacteria and viruses, and the dogs were observed for clinical signs for three weeks after the challenge. The control dogs became culture-positive for B bronchiseptica and canine parainfluenza virus, but the isolation yields from the vaccinated group were significantly lower (P<0.05). The mean clinical scores of the vaccinated group were 61 per cent lower than the scores of group 2 (P=0.009), and 90 per cent lower than the scores of group 3 (P=0.001).

The pharmacokinetics of vedaprofen and its enantiomers in dogs after single and multiple dosing.

Vedaprofen is a chiral nonsteroidal anti-inflammatory drug that has been developed as a gel formulation for oral administration to dogs and horses. The pharmacokinetics of vedaprofen and its enantiomers were studied in beagle dogs after single (intravenous solution and oral gel) and multiple (oral gel) dosing at a dosage of 0.5 mg/kg body weight. Plasma concentrations of vedaprofen and its enantiomers were analysed by HPLC. The plasma protein binding of vedaprofen was studied by ultrafiltration. The absorption of vedaprofen was rapid (tmax 0.63 +/- 0.14 h) and almost complete after oral administration (bioavailability 86 +/- 7%). The terminal half-lives after intravenous and oral administration, 16.8 +/- 2.2 and 12.7 +/- 1.7 h respectively, were of the same order of magnitude. Enantioselective analysis showed that the R(-) enantiomer predominated in plasma. The change in the plasma time course of the plasma R(-)/S(+) enantiomer concentration ratio over time was similar after single intravenous and oral dosing, with R(-)/S(+) ratios in the AUC of 1.7 +/- 0.5 and 1.9 +/- 0.2 respectively. Plasma protein binding of vedaprofen and its enantiomers was high (> 99.5%). Vedaprofen is absorbed rapidly from the gastrointestinal tract, has a high bioavailability and does not accumulate in plasma in dogs following repeated oral administration.

Aspects of pharmacodynamics and biotransformation of the glucocorticoid resocortol butyrate.

Aspects of the biotransformation and pharmacodynamics of the novel glucocorticoid resocortol butyrate (RCB) and its metabolites were assessed in vitro and in vivo in comparison with selected reference compounds. The main route of biotransformation of ((3)H)-RCB in the skin and the liver was 5alpha-reduction of the A-ring followed by reduction of the 3-carbonyl group. In the liver, metabolism was much more rapid than in the skin and 5beta-reduction also occurred. RCB had a relative binding affinity for the glucocorticoid receptor similar to that of triamcinolone acetonide, about 1.5 times that of dexamethasone, three times that of betamethasone valerate (BMV) and 10-14 times that of cortisol. The metabolites of RCB displayed only low to very low affinities for the receptor. The suppression of the hypothalamic-pituitary-adrenal axis was investigated in placebo- and positive-controlled studies in dogs by measurement of basal and corticotrophin-releasing hormone (CRH) stimulated plasma cortisol concentrations. The AUC of the plasma cortisol vs. time curve following CRH stimulation, a measure of adrenal suppression, was reduced significantly after topical application of BMV compared with the pretreatment values. The AUC in the RCB group was not reduced significantly. Adrenocorticotrophic hormone concentrations were not affected. Oral administration of RCB did not suppress adrenocortical function, whereas BMV induced almost complete suppression of basal and CRH-induced cortisol concentrations. The pharmacodynamics of RCB makes it a relatively safe glucocorticosteroid for topical application.

Treatment of canine pyoderma with ibafloxacin and marbofloxacin--fluoroquinolones with different pharmacokinetic profiles.

Dogs with superficial or deep pyoderma (n = 228) presented to first opinion veterinarians (n = 20) were treated orally with either ibafloxacin, at a dosage of 15 mg/kg, or marbofloxacin, at a dosage of 2 mg/kg, once daily for 3-16 weeks. On initial presentation, 35% of the cases were classified as having recurrent pyoderma and 40% as having deep pyoderma. Staphylococci (mainly Staphylococcus intermedius) were isolated from over 90% of the cases. The average treatment periods were 41 +/- 26 and 38 +/- 21 days in the ibafloxacin and marbofloxacin groups, respectively. One week after the cessation of treatment, 74 and 81% of dogs (P > 0.05) in the ibafloxacin and marbofloxacin groups, respectively, were classified as having responded to treatment. One month after the cessation of treatment, 70% of the dogs in each group were still classified as cured or improved, and 3 and 11% (P < 0.05) in the ibafloxacin and marbofloxacin groups, respectively, were classified as having relapsed. Despite having different pharmacokinetic profiles, ibafloxacin and marbofloxacin produced similar results when used under field conditions at the recommended dosages.

Pharmacokinetics of oestriol after repeated oral administration to dogs.

The aim of the present study was to investigate the pharmacokinetics of oestriol in plasma in the dog after repeated oral administration of oestriol tablets, a preparation intended for the treatment of urinary incontinence in the bitch. The study was performed in six healthy, entire, adult female beagle dogs. The bitches were treated once daily with two tablets, containing 1 mg oestriol per tablet, for seven consecutive days (days 1-7). Blood samples were taken from the jugular vein before treatment, frequently on days 1, 3 and 7 of the treatment period and daily just before (C(trough)) and 1 h after dosing (C(t=1h)). During the washout period samples were taken at a 24 h interval up to four days post-treatment. Oestriol concentrations were determined in plasma by radioimmunoassay. Pharmacokinetic parameters, AUC, C(max) and t(max), were determined from the plasma concentration-time curves using non-compartmental methods. The between animal variation in C(max) and the AUC was high. Individual values of the C(max) varied from 206 pg/ml (day 1) to 1128 pg/ml (day 7) and the AUC(0-24h) from 789 pg x h/ml (day 1) to 5718 pg x h/ml (day 7). t(max) occurred within 1 h. The mean C(trough) value was slightly above the pre-treatment level ( 38+/-2 pg/ml vs. 18+/-5 pg/ml). Within 48 h after the last treatment the concentrations had returned to the pre-treatment values. C(max) and C(trough) did not increase during the treatment period, indicating that no accumulation occurred. A shoulder in the concentration-time curve around 8-12 h after treatment strongly suggested the existence of enterohepatic recirculation (EHR). The average relative contribution of the EHR to the AUC(0-24h) was estimated to be 22%, 38% and 44% on days 1, 3 and 7, respectively. These mean values were calculated from five animals per time point, because one dog failed to show EHR on days 1 and 3 and was therefore excluded from the calculations.