Investigation on the clinical efficacy and safety of 0.1% tacrolimus ointment (Protopic) in canine atopic dermatitis: a randomized, double-blinded, placebo-controlled, cross-over study.

Topical tacrolimus is successfully used in people with atopic dermatitis. Preliminary studies in dogs with atopic dermatitis using tacrolimus in a compounded lotion formulation indicated that tacrolimus significantly decreased erythema and pruritus according to investigator, but no significant improvement was reported by the dog owners. The objectives of this study were to evaluate the clinical efficacy and safety of the commercially available 0.1% tacrolimus ointment (Protopic) in dogs with atopic dermatitis. The study was designed as a double-blinded, placebo-controlled, cross-over study. Selected dogs were allocated to either tacrolimus or placebo for 4 weeks. After 4 weeks there was a wash-out period of 2 weeks and treatments were switched. Twelve dogs completed the study. Clinical signs were scored. Blood samples were collected for complete blood count, chemistry panels and tacrolimus levels at week 0 and 4 of each treatment. Tacrolimus ointment significantly decreased severity of symptoms for both owners and investigators at the end of the trial. When the same dogs received the placebo, there were no differences between week 0 and week 4 scores. Dogs with localized disease responded better than dogs with generalized disease. Tacrolimus was detected in the blood of animals receiving the active ingredient. Levels were below the level of toxicity and no adverse effects were reported in any of the dogs. No changes in complete blood count and chemistry parameters were detected between groups or within groups. In conclusion, tacrolimus appears to be a safe alternative treatment in dogs with atopic dermatitis, especially in those with localized disease.

Investigation on the effects of topical therapy with 0.1% tacrolimus ointment (Protopic) on intradermal skin test reactivity in atopic dogs.

Tacrolimus ointment (TAC) is an effective treatment for atopic dermatitis in humans and dogs. The purposes of the present study were to evaluate the effect of 4 weeks of TAC on intradermal skin testing (IST), and in case of suppression, to investigate if reactivity returned to baseline by 2 or 4 weeks post treatment. Intradermal skin test was performed using saline, histamine, lipopolysaccharide (LPS, 0.4 mg mL(-1)), house dust (25 PNU mL(-1)) and house dust mite (1 : 40 000 w/v) at weeks 0, 4, 6 and 8 on nine dogs enrolled in a blinded, crossover, clinical trial, using 0.1% TAC or placebo once daily for 4 weeks. Reactions were evaluated at 15 min, and at 4 and 6 h. Ointment was applied after the 15-min evaluation on weeks 0 and 4. Data were analysed using the statistical software SAS System for Windows. At week 4, TAC did not affect 15-min IST, but some reactions in the TAC group were suppressed at 6 h compared to baseline. In the TAC group, 4-h IST reactivity was reduced 2 weeks after discontinuation but returned to baseline by 4 weeks. In conclusion, TAC has no effect on immediate reactions but decreased some late-phase reactions. Therefore, no withdrawal is recommended to evaluate only immediate reactions, but a 4-week withdrawal may be necessary for evaluation of late-phase reactions.

Double-blinded, placebo-controlled, cross-over pilot study on the efficacy of zileuton for canine atopic dermatitis.

Nine dogs meeting the diagnostic criteria for canine atopic dermatitis were enrolled in a double-blind, placebo-controlled, cross-over clinical trial. In this pilot study, zileuton (a 5-lipoxygenase inhibitor) given orally at 2 mg kg(-1) three times daily for 4 weeks significantly decreased erythema in dogs with atopic dermatitis but had no effect on pruritus. Zileuton was well tolerated and no adverse clinical signs were noted. However, one dog developed mild alanine aminotransaminase elevation, which resolved within 1 week of discontinuation of therapy. Monitoring of alanine aminotransaminase may be necessary in dogs receiving zileuton. Further studies with larger number of dogs are needed to evaluate the efficacy of zileuton as treatment for canine atopic dermatitis.

Intradermal skin test reactivity to histamine and substance P is blunted in dogs with atopic dermatitis.

Skin reactivity to intradermal injections (0.1, 0.5 and 1 nM) of substance P (SP) was evaluated in 20 clinically normal dogs and 20 dogs with atopic dermatitis (AD). Saline and histamine were used as negative and positive controls, respectively. Wheal diameters were measured. Reactions were evaluated for erythema and induration and a subjective score, on a scale from 0 to 4+, was given. Evaluations were performed at 3, 5, 10, 15 and 30 min after the injections. Wheal diameters for histamine and SP injections were significantly smaller in dogs with AD compared with clinically normal dogs. In both groups, reactions to the various concentrations of SP were not significantly different from each other and were always smaller than histamine reactions. Erythema was not seen with SP injections. In addition, subjective scores for SP injections were significantly lower in dogs with AD compared with controls. The results of this study are similar to those reported in human medicine, where a role for SP in AD is proposed and desensitization of receptors to both SP and histamine is hypothesized. Further studies are needed to investigate the role of SP in the pathogenesis of canine AD.

Sulphido-leukotriene production from peripheral leukocytes and skin in clinically normal dogs and house dust mite positive atopic dogs.

Pathogenesis of canine atopy has not been completely elucidated. In humans, sulphido-leukotrienes (s-LT) play a role in atopy, and increased production of s-LT occurs in the skin and peripheral leukocytes after allergen challenge. The study population included 16 clinically normal and 13 atopic dogs. All atopic dogs had in common a positive reaction (4+) to the intradermal injection of house dust mite (allergen of reference). Blood samples and skin biopsies were collected. Sulphido-LT synthesis by peripheral leukocytes after stimulation was measured, and no statistically significant difference was found between clinically normal and atopic dogs. Sulphido-LT concentrations in skin samples from stimulated and unstimulated sites were measured, and no statistically significant difference was detected between clinically normal and atopic dogs or between lesional and nonlesional skin within the atopic group. Clinical signs of atopic dogs were graded by owners and no correlation was found between their severity and cutaneous concentrations of s-LT. In this study there was no increase in s-LT synthesis in atopic dogs.

Pharmacokinetics of pentoxifylline in dogs after oral and intravenous administration.

OBJECTIVE: To evaluate the pharmacokinetics of pentoxifylline (PTX) and its 5-hydroxyhexyl-metabolite, metabolite 1 (M1), in dogs after IV administration of a single dose and oral administration of multiple doses. ANIMALS: 7 sexually intact, female, mixed-breed dogs. PROCEDURE: A crossover study design was used so that each of the dogs received all treatments in random order. A drug-free period of 5 days was allowed between treatments. Treatments included IV administration of a single dose of PTX (15 mg/kg of body weight), oral administration of PTX with food at a dosage of 15 mg/kg (q 8 h) for 5 days, and oral administration of PTX without food at a dosage of 15 mg/kg (q 8 h) for 5 days. Blood samples were taken at 0.25, 0.5, 1, 1.5, 2, 2.5, and 3 hours after the first and last dose of PTX was administered PO, and at 5, 10, 20, 40, 80, and 160 minutes after PTX was administered IV. RESULTS: PTX was rapidly absorbed and eliminated after oral administration. Mean bioavailability after oral administration ranged from 15 to 32% among treatment groups and was not affected by the presence of food. Higher plasma PTX concentrations and apparent bioavailability were observed after oral administration of the first dose, compared with the last dose during the 5-day treatment regimens. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, oral administration of 15 mg of PTX/kg results in plasma concentrations similar to those produced by therapeutic doses in humans, and a three-times-a-day dosing regimen is the most appropriate.

Comparison of anesthetic and cardiorespiratory effects of diazepam-butorphanol-ketamine, acepromazine-butorphanol-ketamine, and xylazine-butorphanol-ketamine in ferrets.

Ten ferrets were used in a crossover study to determine the sedative effects of intramuscularly administered diazepam (3 mg/kg body weight)-butorphanol (0.2 mg/kg body weight)-ketamine (15 mg/kg body weight); acepromazine (0.1 mg/kg body weight)-butorphanol (0.2 mg/kg body weight)-ketamine (15 mg/kg body weight); and xylazine (2 mg/kg body weight)-butorphanol (0.2 mg/kg body weight)-ketamine (15 mg/kg body weight). All of the ferrets became laterally recumbent following the administration of each drug combination. The xylazine-butorphanol-ketamine combination induced significantly longer (p less than 0.05) durations of tail-clamp analgesia (mean+/-standard deviation [SD], 81.0+/-19.1 min versus 20.5+/-25.4 min and 30.0+/-26.9 min), dorsal recumbency (mean+/-SD, 94.6+/-13.6 min versus 75. 6+/-34.7 min and 55.2+24.8 min), and muscle relaxation suitable for endotracheal intubation (mean+/-SD, 67.1+/-23.0 min versus 7.0+/-22.1 min and 9.5+/-15.4 min) than the diazepam-butorphanol-ketamine and acepromazine-butorphanol-ketamine combinations, respectively. The recovery time from dorsal recumbency to standing was not significantly different among the three treatment groups. The heart rate was significantly lower in the xylazine-butorphanol-ketamine group; however, systolic blood pressure was not significantly different among the treatment groups. Ventilatory function was more depressed in the diazepam-butorphanol-ketamine and xylazine-butorphanol-ketamine groups than in the acepromazine-butorphanol-ketamine group. A period (approximately 45 minutes) of hypoxia was observed in the xylazine-butorphanol-ketamine-treated ferret. Of the three combinations evaluated in ferrets, xylazine-butorphanol-ketamine was concluded to be the most effective anesthetic combination. However, hypoxemia and ventricular arrhythmias were observed in the xylazine-butorphanol-ketamine-treated ferrets, so the effectiveness of the xylazine-butorphanol-ketamine combination should be weighed against its cardiorespiratory side effects.

Effects of a microdose of medetomidine on diazepam-ketamine induced anesthesia in dogs.

OBJECTIVE: To evaluate cardiorespiratory and anesthetic effects of a microdose of medetomidine hydrochloride on diazepam-ketamine (DK) hydrochloride induced anesthesia in dogs. DESIGN: Randomized crossover study. ANIMALS: 6 two-year-old healthy female dogs. PROCEDURE: A study was designed to compare quality of anesthetic induction, recovery, analgesia, muscle relaxation, duration of immobilization, and ease of endotracheal intubation between diazepam-ketamine-medetomidine (DKM) and diazepam-ketamine induced anesthesia in 6 dogs. Diazepam (0.25 mg/kg [0.114 mg/lb] of body weight, i.v.) and ketamine (5 mg/kg [2.27 mg/lb], i.v.) with or without a microdose of medetomidine (5 micrograms/kg, i.v.) were administered to dogs. A baseline ECG was obtained, and baseline measurements of arterial blood gas tensions, arterial pressures, heart and respiratory rates, and minute volume were taken before drug administration. All measurements were repeated again 5, 10, 20, and 30 minutes after drug administration. Endotracheal intubation was attempted 1 minute after drug administration and then again 5, 10, 20, and 30 minutes after drug administration. Analgesia was evaluated by tail clamp and needle prick testing. RESULTS: Medetomidine improved quality of anesthetic induction, ease of endotracheal intubation, and extended duration of analgesia and lateral recumbency in anesthetized dogs. The addition of medetomidine to DK increased blood pressure and decreased heart and respiratory rates and minute volume. Hypoxemia was observed in 1 dog after DKM induced anesthesia. CLINICAL IMPLICATIONS: Administration of a microdose of medetomidine provides a useful adjunct to DK induced anesthesia in dogs. Oxygen insufflation is recommended for a minimum of the first 5 minutes of DKM induced anesthesia.

Evaluation of sedative and cardiorespiratory effects of diazepam-butorphanol, acepromazine-butorphanol, and xylazine-butorphanol in ferrets.

Ten ferrets were used in a crossover study to determine the sedative effects of intramuscularly (IM) administered diazepam (3 mg/kg body weight)-butorphanol (0.2 mg/kg body weight), acepromazine (0.1 mg/kg body weight)-butorphanol (0.2 mg/kg body weight), or xylazine (2.0 mg/kg body weight)-butorphanol (0.2 mg/kg body weight). All ferrets became laterally recumbent following the administration of each drug combination. The xylazine-butorphanol combination caused a significantly longer (p less than 0.05) duration of analgesia than the diazepam-butorphanol and acepromazine-butorphanol combinations. None of the ferrets could be intubated with any of the drug combinations. The time from induction to recovery was significantly shorter in the acepromazine-butorphanol-treated ferrets. A significantly lower heart rate was observed in the xylazine-butorphanol-treated ferrets; however, an acceptable systolic blood pressure was maintained. Ventilatory function was more depressed in the diazepam-butorphanol- and xylazine-butorphanol-treated ferrets than in the acepromazine-butorphanol-treated ferrets. Xylazine-butorphanol was found to be the best combination for use in ferrets.

Comparison of sedative and cardiorespiratory effects of diazepam, acepromazine, and xylazine in ferrets.

The sedative and cardiorespiratory effects of an intramuscular injection of diazepam (3 mg/kg body weight), acepromazine (0.1 mg/kg body weight), or xylazine (2 mg/kg body weight) in ferrets (n = 10, crossover design) was evaluated. Time from injection to assuming lateral recumbency was not significantly different between the three drugs. Duration of recumbency expressed as mean+/-standard deviation was significantly longer with xylazine (68.3+/-20.8 min) than with diazepam (43.2+/-8.2 min) or acepromazine (49.8+/-11.2 min). Sedation was graded to be the best in the xylazine-treated ferrets and worst in the diazepam-treated ferrets. Analgesia was judged only to be present following xylazine injection. Systolic blood pressure, oxyhemoglobin saturation, and end-expired carbon dioxide (CO2) were similar with all three drugs. It was concluded that, at the doses administered, xylazine provided better chemical restraint in the healthy ferret than either acepromazine or diazepam.

Comparison of anesthetic and cardiorespiratory effects of tiletamine-zolazepam-xylazine and tiletamine-zolazepam-xylazine-butorphanol in ferrets.

Nine ferrests were used in a crossover study to determine the anesthetic effects of intramuscular (i.m.) administration of a low dose of tiletamine-zolazepam (1.5 mg/kg body weight)-xylazine (1.5 mg/kg body weight); a high dose of tiletamine-zolazepam (3 mg/kg body weight)-xylazine (3 mg/kg body weight); and tiletamine-zolazepam (1.5 mg/kg body weight)-xylazine (1.5 mg/kg body weight)-butorphanol (0.2 mg/kg body weight). All ferrets became laterally recumbent within two minutes following the administration of each drug combination. The tiletamine-zolazepam-xylazine-butorphanol combination induced significantly longer (p less than 0.05) durations of tail clamp analgesia (mean +/- standard deviation [SD], 90.0 +/- 17.1 min versus 17.8 +/- 15.8 min and 41.9 +/- 26.3 min) and endotracheal intubation (mean +/- SD, 84.8 +/- 21.7 min versus 5.2 +/- 10.3 min and 26.3 +/- 29.8 min) than the low-dose tiletamine-zolazepam-xylazine and high-dose tiletamine-zolazepam-xylazine combinations, respectively. Heart rates and the times from dorsal recumbency to standing were not significantly different among the three treatment groups. However, systolic blood pressure was significantly lower in the tiletamine-zolazepam-xylazine-butorphanol group. Ventilatory function was more depressed in the tiletamine-zolazepam-xylazine-butorphanol group than in the low-dose tiletamine-zolazepam-xylazine and high-dose tiletamine-zolazepam-xylazine groups. A short period of hypoxia was observed in the tiletamine-zolazepam-xylazine-butorphanol-treated ferrets. Tiletamine-zolazepam-xylazine-butorphanol was found to be the best of the three combinations evaluated in these ferrets. The addition of butorphanol to the low-dose tiletamine-zolazepam-xylazine combination greatly enhanced the duration of analgesia, endotracheal intubation, and dorsal recumbency. However, since hypoxemia occurred during the tiletamine-zolazepam-xylazine-butorphanol anesthesia, oxygen (O2) insufflation is recommended. Doubling the dose of the low-dose tiletamine-zolazepam-xylazine increased the duration of analgesia and endotracheal intubation without prolonging the recovery when compared to the low-dose tiletamine-zolazepam-xylazine group.

Evaluation of the sedative and cardiorespiratory effects of medetomidine, medetomidine-butorphanol, medetomidine-ketamine, and medetomidine-butorphanol-ketamine in ferrets.

Ten ferrets were used in a crossover study to determine the anesthetic effects of intramuscular (I.M.) medetomidine (80 microg/kg body weight), medetomidine (80 microg/kg body weight)-butorphanol (0.1 mg/kg body weight), medetomidine (80 microg/kg body weight)-ketamine (5 mg/kg body weight), and medetomidine (80 microg/kg body weight)-butorphanol (0.1 mg/kg body weight)-ketamine (5 mg/kg body weight). All ferrets assumed lateral recumbency within four minutes and remained dorsally recumbent for 100 minutes, until atipamezole (400 microg/kg body weight, I.M.) administration. All four anesthetic combinations were effective for chemical restraint, with the most respiratory depression occurring in the medetomidine-butorphanol-ketamine group. The addition of butorphanol or ketamine to medetomidine significantly increased the duration of analgesia. The addition of ketamine to medetomidine-butorphanol expedited endotracheal intubation.