Evaluation of twice-daily, low-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism

OBJECTIVE: To evaluate the effects of twice-daily oral administration of a low-dose of trilostane treatment and assess the duration of effects after once-daily trilostane administration in dogs with naturally occurring hyperadrenocorticism (NOH). DESIGN: Prospective study. ANIMALS: 28 dogs with NOH. PROCEDURES: 22 dogs received 0.5 to 2.5 mg of trilostane/kg (0.23 to 1.14 mg/lb) orally every 12 hours initially. At intervals, dogs were reevaluated; owner assessment of treatment response was recorded. To assess drug effect duration, 16 of the 22 dogs and 6 additional dogs underwent 2 ACTH stimulation tests 3 to 4 hours and 8 to 9 hours after once-daily trilostane administration. RESULTS: After 1 to 2 weeks, mean trilostane dosage was 1.4 mg/kg (0.64 mg/lb) every 12 hours (n = 22 dogs; good response [resolution of signs], 8; poor response, 14). Four to 8 weeks later, mean dosage was 1.8 mg/kg (0.82 mg/lb) every 12 or 8 hours (n = 21 and 1 dogs, respectively; good response, 15; poor response, 5; 2 dogs were ill). Eight to 16 weeks after the second reevaluation, remaining dogs had good responses (mean dosages, 1.9 mg/kg [0.86 mg/lb], q 12 h [n = 13 dogs] and 1.3 mg/kg [0.59 mg/lb], q 8 h [3]). At 3 to 4 hours and 8 to 9 hours after once-daily dosing, mean post-ACTH stimulation serum cortisol concentrations were 2.60 and 8.09 Pg/dL, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs with NOH, administration of trilostane at low doses every 12 hours was effective, although 2 dogs became ill during treatment. Drug effects diminished within 8 to 9 hours. Because of potential adverse effects, lower doses should be evaluated.     

Kinetic study of serum gentamicin concentrations in baboons after single-dose administration

This study establishes preliminary pharmacokinetic data on the use of gentamicin sulfate administered IM to baboons. Serum concentrations greater than or equal to 12 micrograms/ml are generally agreed to cause toxicosis in human beings. On the basis of preliminary test results suggesting that the manufacturer's recommended dosage for dogs of 4.4 mg/kg of body weight caused potentially toxic serum concentrations, a dosage of 3 mg/kg was chosen to conduct a single-dose kinetic study in 6 baboons. Using a single-compartment model, the gentamicin serum half-life for IM administration of 3 mg of gentamicin/kg was 1.58 hours, and serum concentrations remained below the potentially toxic concentrations reported for human beings. We suggest that a dosage of 3 mg/kg is safer than a dosage of 4.4 mg/kg administered IM to baboons. Minimal inhibitory concentrations for 2 Pseudomonas aeruginosa isolates were less than or equal to 1 micrograms/ml. On the basis of our measured elimination half-life of 1.58 hours, it is reasonable to suppose that dosing q24 h will be inadequate to maintain therapeutic serum concentrations. We calculate that serum concentrations will remain at or above our measured minimal inhibitory concentration for P aeruginosa (1 micrograms/ml) for 100% of the treatment time if the animal is dosed q 6h, 78% for dosing q 8h, and 52% for dosing q 12h. Therefore, we suggest 3 mg/kg, q 8h or q 6h as appropriate dosing schedules for the use of gentamicin sulfate administered IM to baboons.     

Pharmacokinetic evaluation of enrofloxacin administered orally to healthy dogs.

Enrofloxacin was administered orally to 6 healthy dogs at dosages of approximately 2.75, 5.5, and 11 mg/kg of body weight, every 12 hours for 4 days, with a 4-week interval between dosage regimens. Serum and tissue cage fluid (TCF) concentrations of enrofloxacin were measured after the first and seventh treatments. The mean peak serum concentration occurred between 1 and 2.5 hours after dosing. Peak serum concentrations increased with increases in dosage. For each dosage regimen, there was an accumulation of enrofloxacin between the first and seventh treatment, as demonstrated by a significant (P = 0.001) increase in peak serum concentrations. The serum elimination half-life increased from 3.39 hours for the 2.75 mg/kg dosage to 4.94 hours for the 11 mg/kg dosage. Enrofloxacin accumulated slowly into TCF, with peak concentrations being approximately 58% of those of serum. The time of peak TCF concentrations occurred between 3.8 hours and 5.9 hours after drug administration, depending on the dosage and whether it was after single or multiple administrations. Compared with serum concentrations (area under the curve TCF/area under the curve serum), the percentage of enrofloxacin penetration into TCF was 85% at a dosage of 2.75 mg/kg, 83% at a dosage of 5.5 mg/kg, and 88% at a dosage of 11 mg/kg. All 3 dosage regimens of enrofloxacin induced continuous serum and TCF concentrations greater than the minimal concentration required to inhibit 90% (MIC90) of the aerobic and facultative anaerobic clinical isolates tested, except Pseudomonas aeruginosa.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum and skin concentrations after multiple-dose oral administration of trimethoprim-sulfadiazine in dogs.

Six healthy adult mixed breed dogs were each given 5 oral doses of trimethoprim (TMP)/sulfadiazine (SDZ) at 2 dosage regimens: 5 mg of TMP/kg of body weight and 25 mg of SDZ/kg every 24 hours (experiment 1) and every 12 hours (experiment 2). Serum and skin concentrations of each drug were measured serially throughout each experiment and mean serum concentrations of TMP and SDZ were determined for each drug for 24 hours (experiment 1) and 12 hours (experiment 2) after the last dose was given. In experiment 1, mean serum TMP concentration was 0.67 +/- 0.02 micrograms/ml, and mean skin TMP concentration was 1.54 +/- 0.40 micrograms/g. Mean serum SDZ concentration was 51.1 +/- 12.2 micrograms/ml and mean skin SDZ concentration was 59.3 +/- 9.8 micrograms/g. In experiment 2, mean serum TMP concentration was 1.24 +/- 0.35 micrograms/ml and mean skin TMP concentration was 3.03 +/- 0.54 micrograms/g. Mean serum SDZ concentration was 51.6 +/- 9.3 micrograms/ml and mean skin SDZ concentration was 71.1 +/- 8.2 micrograms/g. After the 5th oral dose in both experiments, mean concentration of TMP and SDZ in serum and skin exceeded reported minimal inhibitory concentrations of TMP/SDZ (less than or equal to 0.25/4.75 micrograms/ml) for coagulase-positive Staphylococcus sp. It was concluded that therapeutically effective concentrations in serum and skin were achieved and maintained when using the manufacturer's recommended dosage of 30 mg of TMP/SDZ/kg (5 mg of TMP/kg and 25 mg of SDZ/kg) every 24 hours.     

Pharmacokinetics of zonisamide and drug interaction with phenobarbital in dogs

The purposes of the present study were to elucidate the pharmacokinetics of zonisamide, determine the presence of a drug interaction with phenobarbital, and evaluate how long any interaction lasted after discontinuation of phenobarbital in dogs. Five dogs received zonisamide (5 mg/kg, p.o. and i.v.) before and during repeated oral administration of phenobarbital (5 mg/kg, bid, for 30–35 days). Zonisamide (5 mg/kg, p.o.) was also administered 8, 10, and 12 weeks after discontinuation of phenobarbital. Blood was sampled until 24 h after each zonisamide administration and serum concentrations of zonisamide were determined. Repeated phenobarbital decreased the maximum serum concentration, area under the serum concentration vs. time curve, apparent elimination half-life, and bioavailability of zonisamide. Total clearance increased. Time to maximum serum concentration and volume distribution were not changed. The maximum serum concentration and area under the serum concentration vs. time curve of zonisamide continued to be low until 10 weeks after the discontinuation of phenobarbital. They were restored to the same serum concentration as before phenobarbital administration 12 weeks after the discontinuation of phenobarbital. These data suggested that repeated administration of a clinical dose of phenobarbital enhanced the clearance of zonisamide and the enhanced clearance lasted at least 10 weeks after the discontinuation of phenobarbital. Caution may be necessary when zonisamide is given with phenobarbital and when antiepileptic therapy is changed from phenobarbital to zonisamide.     

Serum concentrations of acute-phase proteins in dogs with leishmaniosis during short-term treatment

OBJECTIVE: To evaluate changes in serum concentrations of acute-phase proteins in dogs with leishmaniosis during short-term therapy in accordance with 2 treatment protocols and determine whether concentrations of acute-phase proteins could be used to monitor the initial response of dogs to treatment. ANIMALS: 12 dogs naturally infected with Leishmania infantum. PROCEDURE: Dogs were allocated into 2 groups. Dogs of group 1 were treated by use of meglumine antimonate (100 mg/kg, SC, q 24 h) administered concurrently with allopurinol (15 mg/kg, PO, q 12 h) for 20 days and then with allopurinol alone at the same dosage for the subsequent 30 days. Dogs of group 2 were treated by administration of allopurinol alone (15 mg/kg, PO, q 12 h) for 60 days). Blood samples were obtained before and during treatment for measurement of serum concentrations of acute-phase proteins and determination of CBC counts, serum biochemical analyses, and electropherograms. RESULTS: All dogs evaluated in the study had increased concentrations of C-reactive protein, haptoglobin, and ceruloplasmin at the time of diagnosis of leishmaniosis. Mean concentration of serum amyloid A before treatment was also increased, but some of the dogs had concentrations of serum amyloid A that were within the reference range. Concentrations of C-reactive protein and ceruloplasmin decreased significantly in all dogs at the end of the study period. CONCLUSIONS AND CLINICAL RELEVANCE: Measurement of concentrations of selected acute-phase proteins, such as C-reactive protein or ceruloplasmin, could be used to evaluate the initial response of dogs with leishmaniosis to treatment.     

Mitotane (o, p''-DDD) Treatment of 200 Dogs with Pituitary-Dependent Hyperadrenocorticism

Two hundred dogs with pituitary dependent hyperadrenocorticism (PDH) were treated with mitotane at an initial daily dosage of 21 to 69 mg/kg (mean = 45.2 mg/kg) for 5 to 14 days. During the induction period, 194 of the dogs also were given daily maintenance dosages of a glucocorticoid. Fifty of the dogs exhibited one or more adverse effects during initial induction, including weakness, vomiting, anorexia, diarrhea, and ataxia. After completion of the induction period, repeat ACTH stimulation testing revealed significant decreases in mean serum cortisol concentrations when compared with initial values. Twenty-five dogs, however, still responded to exogenous ACTH with serum cortisol concentrations above normal resting range, necessitating daily treatment for an additional 5 to 55 days. In contrast, 70 of the 200 dogs had low post-ACTH serum cortisol concentrations after the induction period. These subnormal serum cortisol concentrations generally increased spontaneously to within normal resting range 2 to 6 weeks after cessation of mitotane. In 184 dogs, mitotane was continued at an initial mean maintenance dosage of 49 mg/kg administered weekly in two to three divided doses. Of these dogs, 107 had one or more relapses of hyperadrenocorticism during treatment. In the 75 dogs that had one relapse, the median maintenance dosage was increased by approximately 35%, whereas the median maintenance dosage in the 32 dogs having two or more relapses was eventually increased by 225% over the initial dosage. After a mean maintenance treatment time of 2.0 years, the final maintenance dosage required in the 184 dogs ranged from 26.8 to 330 mg/kg/week.(ABSTRACT TRUNCATED AT 250 WORDS)     

Therapeutic serum concentrations of primidone and its metabolites, phenobarbital and phenylethylmalonamide in epileptic dogs

Fifteen dogs with idiopathic epilepsy were included in a 9-month clinical trial to determine the therapeutic serum concentrations of primidone and its active metabolites, phenobarbital and phenylethylmalonamide. Dogs with a seizure frequency greater than 1/mo or with a record of multiple seizures greater than 1/day were chosen for the study. Each dog was given primidone 3 times daily at dosages intended to maximize seizure control and to minimize undesired side effects. Maintenance period blood samples were taken from fasted dogs 7 hours after dosing in the 3rd, 5th, 7th, and 9th months of the trial to determine therapeutic serum concentrations of primidone and its metabolites. Two blood samples also were taken from all dogs 7 hours after dosing, during an enforced drowsy period, to establish upper limits of desirable serum concentrations of the drug. Seizure frequencies during the trial were controlled in 13 dogs, 7 of which had no seizures during the 9-month trial. The mean percentage reduction in seizure frequency from pretrial frequency was 85%. Two dogs appeared refractory to primidone therapy. Serum phenobarbital was the best metabolite of primidone to use to assess therapeutic serum concentrations. The therapeutic antiepileptic serum concentration of phenobarbital was found to be between 25 and 40 micrograms/ml of serum. Serum phenobarbital concentrations greater than 40 micrograms/ml resulted in side effects in most dogs.     

Prospective study of zonisamide therapy for refractory idiopathic epilepsy in dogs

O bjectives : Investigation of the efficacy of zonisamide as an add-on therapy in dogs with refractory epilepsy.
M ethods : Thirteen dogs fulfilled the inclusion criteria of poor seizure control despite adequate serum levels of phenobarbital, potassium bromide or both. One further dog was treated with zonisamide as monotherapy because of severe blood dyscrasia due to phenobarbital treatment. Various seizure parameters were evaluated retrospectively for a four month period without zonisamide and prospectively for the same time period under zonisamide add-on therapy. The study time period was extended by up to 17 months to evaluate long-term outcome.
R esults : Data of 11 dogs could be evaluated: nine of them were responders. The median reduction of seizure frequency of all dogs on zonisamide add-on therapy was 70 per cent (range 14 to 100 per cent). Only transient central nervous system side effects were reported. No further increase of liver enzymes occurred. In three of the responder dogs, seizure control subsided after individual time periods (between 69 days and seven months).
C linical S ignificance : In dogs with refractory epilepsy, zonisamide may have a beneficial effect on seizure control. In three responder dogs, seizure activity relapsed possibly because of an induction of tolerance. Limiting factors are the high costs.     

Long-term efficacy of trilostane administered twice daily in dogs with pituitary-dependent hyperadrenocorticism

Trilostane is considered an efficacious and safe medication for canine pituitary-dependent hyperadrenocorticism (PDH). Its recommended frequency of administration is once daily. In this prospective study, the efficacy, toxicity, and long-term outcome of trilostane administered twice daily per os were evaluated in 44 dogs with PDH. Mean initial dose was 3.1 mg/kg q 12 hours, and mean final dose was 3.2 mg/kg q 12 hours. The final total daily dose was lower than previously reported for once-daily administration. The mean survival time for affected dogs was 930 days.     

Effects of short-term trimethoprim-sulfamethoxazole administration on thyroid function in dogs

OBJECTIVE: To determine how rapidly trimethoprim-sulfamethoxazole affects serum total thyroxine (T4) and thyroid-stimulating hormone (TSH) concentrations in euthyroid dogs and how quickly hormone concentrations return to reference values following discontinuation of administration. DESIGN: Prospective study. ANIMALS: 7 healthy euthyroid dogs. PROCEDURE: Dogs were given trimethoprim-sulfamethoxazole (26.5 to 31.3 mg/kg [12 to 14.2 mg/lb], PO, q 12 h) for a maximum of 6 weeks. A CBC and Schirmer tear test were performed and serum total T4 and TSH concentrations were measured weekly. Administration of trimethoprim-sulfamethoxazole was discontinued if total T4 concentration was less than the lower reference limit and TSH concentration was greater than the upper reference limit or if persistent neutropenia developed. RESULTS: Six dogs had total T4 concentrations less than the lower reference limit within 3 weeks; T4 concentration was decreased after 1 week in 3 of these 6 dogs. In these 6 dogs, TSH concentration was greater than the upper reference limit within 4 weeks. In 1 dog, T4 and TSH concentrations were not affected, despite administration of trimethoprim-sulfamethoxazole for 6 weeks. Neutropenia developed in 4 dogs. In 1 dog, the neutropenia resolved while trimethoprim-sulfamethoxazole was still being administered. In the other 3, neutrophil counts returned to reference values 1 week after drug administration was discontinued. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that administration of trimethoprim-sulfamethoxazole at a dosage of 26.5 to 31.3 mg/kg, PO, every 12 hours can substantially alter serum total T4 and TSH concentrations and neutrophil counts in dogs within as short a time as a few weeks.     

Effects of sulfamethoxazole-trimethoprim on thyroid function in dogs

OBJECTIVE: To evaluate effects of trimethoprim-sulfamethoxazole (T/SMX) on thyroid function in dogs. ANIMALS: 6 healthy euthyroid dogs. PROCEDURE: Dogs were administered T/SMX (14.1 to 16 mg/kg, PO, q 12 h) for 3 weeks. Blood was collected weekly for 6 weeks for determination of total thyroxine (TT4), free thyroxine (fT4), and canine thyroid-stimulating hormone (cTSH) concentrations. Schirmer tear tests were performed weekly. Blood was collected for CBC prior to antimicrobial treatment and at 3 and 6 weeks. RESULTS: 5 dogs had serum TT4 concentrations equal to or less than the lower reference limit, and 4 dogs had serum fT4 less than the lower reference limit after 3 weeks of T/SMX administration; cTSH concentrations were greater than the upper reference limit in 4 dogs. All dogs had TT4 and fT4 concentrations greater than the lower reference limit after T/SMX administration was discontinued for 1 week, and cTSH concentrations were less than reference range after T/SMX administration was discontinued for 2 weeks. Two dogs developed decreased tear production, which returned to normal after discontinuing administration. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that administration of T/SMX at a dosage of 14.1 to 16 mg/kg, PO, every 12 hours for 3 weeks caused decreased TT4 and fT4 concentrations and increased cTSH concentration, conditions that would be compatible with a diagnosis of hypothyroidism. Therefore, dogs should not have thyroid function evaluated while receiving this dosage of T/SMX for >2 weeks. These results are in contrast to those of a previous study of trimethoprim-sulfadiazine.     

Pharmacokinetics of single-dose intravenous or intramuscular administration of gentamicin in roosters

Healthy mature roosters (n = 10) were given gentamicin (5 mg/kg of body weight, IV) and, 30 days later, another dose IM. Serum concentrations of gentamicin were determined over 60 hours after each drug dosing, using a radioimmunoassay. Using nonlinear least-square regression methods, the combined data of IV and IM treatments were best fitted by a 2-compartment open model. The mean distribution phase half-life was 0.203 +/- 0.075 hours (mean +/- SD) and the terminal half-life was 3.38 +/- 0.62 hours. The volume of the central compartment was 0.0993 +/- 0.0097 L/kg, volume of distribution at steady state was 0.209 +/- 0.013 L/kg, and the total body clearance was 46.5 +/- 7.9 ml/h/kg. Intramuscular absorption was rapid, with a half-life for absorption of 0.281 +/- 0.081 hours. The extent of IM absorption was 95 +/- 18%. Maximal serum concentration of 20.68 +/- 2.10 micrograms/ml was detected at 0.62 +/- 0.18 hours after the dose. Kinetic calculations predicted that IM injection of gentamicin at a dosage of 4 mg/kg, q 12 h, and 1.5 mg/kg, q 8 h, would provide average steady-state serum concentrations of 6.82 and 3.83 micrograms/ml, with minimal steady-state serum concentrations of 1.54 and 1.50 micrograms/ml and maximal steady-state serum concentrations of 18.34 and 7.70 micrograms/ml, respectively.     

Estimation of intestinal permeability in healthy dogs using the contrast medium iohexol

Background: Iohexol is a nonradioactive marker that has been used successfully to test intestinal permeability in humans with inflammatory bowel disease. There is evidence in dogs that iohexol shares a similar permeability pathway as ⁵¹chromium‐EDTA, the gold standard marker. Objective: The objective of this study was to determine an optimal oral iohexol dosage for an intestinal permeability serum test (IPST) and to use the test to estimate intestinal permeability in healthy dogs. Methods: Eight clinically healthy dogs free of gastrointestinal, liver, and pancreatic disease were used in the study. Dosages of 0.25, 0.5, 1.0, 2.0, and 4.0 mL/kg of Omnipaque‐350 (iohexol) were administered to 2 dogs at weekly intervals. Iohexol concentration was determined in serum samples obtained hourly for 6 hours after administration by high‐performance liquid chromatography. Using the optimal dosage, iohexol was administered to 8 dogs twice, 6–36 days (mean 10 days) apart, and coefficients of variation (CVs) for iohexol concentration were calculated. Results: A dosage of 2.0 mL/kg was chosen as optimal for the IPST, based on ease of iohexol detection in serum, intestinal contrast, and clinical effects of iohexol. Following administration of this dose to healthy dogs, mean (±SD) serum iohexol concentrations were 8.74±4.38, 11.89±5.67, 12.40±5.47, 9.23±5.54, 7.61±5.13, and 5.27±2.67 μg/mL at 1, 2, 3, 4, 5, and 6 hours after iohexol administration, respectively. CVs between the 2 test days were 28–45%. Conclusions: Using the iohexol dosage established in this study, the iohexol IPST was easy to perform as a marker for intestinal permeability in dogs. Further studies to establish reference intervals and evaluate the diagnostic value of the iohexol IPST in dogs with gastrointestinal disease are warranted.     

Cisplatin Therapy in 41 Dogs With Malignant Tumors

Forty-one dogs with a variety of histopathologically diagnosed, measurable tumors were treated with cisplatin (cis-diamminedichloroplatinum, Platinol, Bristol Laboratories, Syracuse, NY 13221-4755) as a single agent at a dosage of 60 mg/m2 given intravenously at 3-week intervals. In an attempt to avoid renal toxicity of cisplatin, saline diuresis was induced and maintained for 4 hours before and 2 hours following cisplatin administration. The dogs received one to ten doses of cisplatin. To determine response to therapy and to monitor toxicity of the drug, the dogs were evaluated with physical examinations including tumor measurements, radiography, complete blood counts, platelet counts, urinalyses, serum urea nitrogen concentrations, and serum creatinine concentrations. An overall response rate of 19% was observed. Complete remission occurred in one of 11 dogs with squamous cell carcinomas and one of one dog with a mediastinal undifferentiated carcinoma. Partial remissions were documented in one of 11 dogs with squamous cell carcinomas, two of three dogs with metastatic osteosarcomas, one of three dogs with nasal adenocarcinomas, and one of one dog with a thyroid adenocarcinoma. Toxic side effects were primarily gastrointestinal in nature, with vomiting occurring 1-6 hours after cisplatin administration in 27 of 41 dogs. Severe anorexia occurred in three dogs, and hemorrhagic diarrhea was observed in one dog. One dog developed grand mal seizures and died 3 hours following therapy. Granulocytopenia was documented in six dogs, and thrombocytopenia was observed in four dogs. One dog showed an increase in serum urea nitrogen and creatinine concentrations, but this patient had known pre-existing renal disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum disposition of exogenous progesterone after intramuscular administration in bitches

Progesterone was administered IM to 6 adult anestrous bitches at a dosage of 2 mg/kg of body weight. Serum progesterone concentrations were measured prior to progesterone administration and for 72 hours thereafter. The serum progesterone concentration time data were analyzed by use of a pharmacokinetics modeling computer program. The mean (+/- SD) peak serum progesterone concentration (34.3 +/- 7.8 ng/ml) was reached at 1.8 +/- 0.2 hours after progesterone administration. The mean serum progesterone concentration was 6.9 +/- 1.4 ng/ml at 24 hours and 2.0 +/- 0.4 ng/ml at 48 hours after progesterone administration. By 72 hours after administration, mean serum progesterone concentration was 0.9 +/- 0.2 ng/ml, which was comparable to serum progesterone concentrations prior to injection. The mean half-life of the absorption phase was 0.5 hours (range, 0.3 to 0.7 hours). The mean half-life of elimination was 12.1 hours (range, 9.5 to 13.8 hours). By analysis of the data, it was established that a dosage of 3 mg/kg, when the hormone was given IM to dogs once a day, would maintain serum progesterone concentration greater than 10 ng/ml.     

Effects of administration of glucocorticoids and feeding status on plasma leptin concentrations in dogs

OBJECTIVE: To investigate effects of short- and long- term administration of glucocorticoids, feeding status, and serum concentrations of insulin and cortisol on plasma leptin concentrations in dogs. ANIMALS: 20 nonobese dogs. PROCEDURE: For experiment 1, plasma leptin concentrations and serum concentrations of insulin and cortisol were monitored for 24 hours in 4 dogs administered dexamethasone (0.1 mg/kg, IV) or saline (0.9% NaCl) solution for fed and nonfed conditions. For experiment 2, 11 dogs were administered prednisolone (1 mg/kg, PO, q 24 h for 56 days [7 dogs] and 2 mg/kg, PO, q 24 h for 28 days [4 dogs]) and 5 dogs served as control dogs. Plasma leptin and serum insulin concentrations were monitored weekly. RESULTS: For experiment 1, dexamethasone injection with the fed condition drastically increased plasma leptin concentrations. Furthermore, injection of saline solution with the fed condition increased plasma leptin concentrations. These increases in plasma leptin concentrations correlated with increases in serum insulin concentrations. Dexamethasone injection with the nonfed condition increased plasma leptin concentrations slightly but continuously. Injection of saline solution with the nonfed condition did not alter plasma leptin concentrations. For experiment 2, prednisolone administration at either dosage and duration did not alter plasma leptin concentrations in any dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Dexamethasone injection and feeding increased plasma leptin concentrations in dogs. In addition, dexamethasone administration enhanced the effect of feeding on increases in plasma leptin concentrations. Daily oral administration of prednisolone (1 or 2 mg/kg) did not affect plasma leptin concentrations in dogs.     

Serum and tissue fluid norfloxacin concentrations after oral administration of the drug to healthy dogs

Norfloxacin, a 4-quinolone antibiotic, was administered orally to 4 healthy dogs at dosages of 11 and 22 mg/kg of body weight, every 12 hours for 4 days, with a 4-week interval between dosing regimens. Serum and tissue cage fluid (TCF) norfloxacin concentrations were measured at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after the first and seventh dose of each dosing regimen. When administered at a dosage of 11 mg/kg, the mean peak serum concentration (Cmax) was 1.0 microgram/ml at 1 hour, the time of mean peak concentration (Tmax) after the first dose. After the seventh dose, the Cmax was 1.4 micrograms/ml at Tmax of 1.5 hours. The Tmax for the TCF concentration was 5 hours, with Cmax of 0.3 microgram/ml and 0.7 microgram/ml after the first and seventh dose, respectively. When administered at a dosage of 22 mg/kg, the serum Tmax was 2 hours after the first dose, with Cmax of 2.8 micrograms/ml. After the seventh dose, the serum Tmax was 1.5 hours, with Cmax of 2.8 micrograms/ml. The Tmax for the TCF concentration was 5 hours after the first and seventh doses, with Cmax of 1.2 micrograms/ml and 1.6 micrograms/ml, respectively. After the seventh dose, the serum elimination half-life was 6.3 hours for a dosage of 11 mg/kg and was 6.7 hours for a dosage of 22 mg/kg. For serum concentration, the area under the curve from 0 to 12 hours (AUC0----12) was 8.77 micrograms.h/ml and 18.27 micrograms.h/ml for dosages of 11 mg/kg and 22 mg/kg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low concentrations of cerebrospinal fluid GABA correlate to a reduced response to phenobarbital therapy in primary canine epilepsy

In this study, we investigated whether pretreatment cerebrospinal fluid (CSF) neurotransmitter concentrations of gamma-aminobutyric acid (GABA) and glutamate (GLU) were correlated with response to phenobarbital treatment in dogs with primary epilepsy. Eleven untreated dogs, 6 males and 5 females, with a median age of onset of seizures of 3 years (range: 0.5-5 years) were selected for therapy based on progressive or serious seizure patterns. The median interval between the first observed seizure and start of phenobarbital therapy was 485 days (range: 101-1,765 days). All dogs were purebred, with the exception of I male dog. Oral phenobarbital was started at 2.5 mg/kg every 12 hours. Trough serum phenobarbital concentrations were measured at 15, 45, 90, 180, 360, 540, and 720 days after the start of treatment. There was no difference in the mean trough serum concentration or in the mean number of seizures recorded between each time period of phenobarbital measurement over the 2-year evaluation. No correlation was found between CSF GLU, GABA, or GLU: GABA ratio and the total number of seizures recorded before or after initiation of phenobarbital therapy. Lower CSF GABA concentration, however, was correlated with a lower seizure frequency difference (the total number of seizures before phenobarbital therapy minus the total number of seizures after phenobarbital therapy for an identical time period of evaluation) and lower percentage reduction in seizures: ([total number of seizures before phenobarbital therapy minus the total number of seizures after phenobarbital therapy] divided by the total number of seizures before phenobarbital therapy) x 100. There was no correlation between CSF GLU and the seizure frequency difference and percentage reduction in seizures. A negative correlation between the CSF GLU:GABA ratio and seizure frequency difference was found. Thus, dogs with an initial lower CSF GABA concentration before phenobarbital therapy did not respond as well as did dogs with a higher CSF GABA concentration.     

Bromide Therapy in Refractory Canine Idiopathic Epilepsy

On a retrospective basis, the response to adding chronic oral bromide (BR) to phenobarbital (PB) administration in 23 refractory canine idiopathic epileptics between 1986 and 1991 was studied. The mean age for an observed first seizure was 24 months (range 7 to 72) for all dogs. Thirteen (57%) dogs were males with no breed predisposition observed. All dogs were diagnosed as having idiopathic epilepsy based on normal metabolic and neurologic diagnostic evaluations. Dogs were evaluated before BR therapy for a mean time of 22 months (range 5 to 75 months). Seventeen dogs (74%) received multiple antiepileptic drugs (AEDs) before BR therapy. All animals were maintained on PB at least 4 months before the onset of BR therapy, with a mean trough serum concentration of 37.8 mcg/mL and no improvement in seizure severity or recurrence. Twelve dogs presented with generalized isolated seizures and 11 with generalized cluster seizures (two or more seizures within 24 hours) as their first seizure. The effects of BR therapy were evaluated for a mean time of 15 months (range 4 to 33), with 17 dogs (74%) followed for 12 or more months. The mean BR serum concentration for the 0 to 4 months time period was 117 mg/dL compared with 161 mg/dL for the greater than 4 months period. Overall, response to BR therapy was associated with a reduction in the total number of seizures in 83% of the dogs when compared with their respective pre-BR period. For those followed for 1 year after BR, there was a 53% reduction in the number of seizures compared with the previous 12 months. Furthermore, owners reported a decrease in seizure intensity (65% of dogs) and change to a less severe seizure type (22% of dogs) in those dogs that continued to have seizures. Seizure-free status was obtained in 26% of the dogs with protection continuing up to 31 months in one dog. No correlations could be determined between response to BR and either age of onset of the first seizure or interval from the first AED therapy to BR therapy. Adverse effects of concomitant BR and PB therapy were polydipsia (56% of dogs), polyphagia (30% of dogs), excessive sedation (30% of dogs), and generalized ataxia (17% of dogs). As a result of BR treatment, the PB dosage was reduced in eight dogs (35%). In conclusion, concomitant BR and PB was well tolerated in dogs of this study and was effective in treating refractory canine idiopathic epilepsy, regardless of prior interval of seizure activity or previous treatment. (Journal of Veterinary Internal Medicine 1993; 7:318–327. Copyright © 1993 by the American College of Veterinary Internal Medicine.)