Effect of oral administration of prednisolone on thyroid function in dogs

To determine the effect of oral administration of prednisolone on thyroid function, 12 healthy Beagles were given 1.1 mg of prednisolone/kg of body weight every 12 hours for 22 days after 8 days of diagnostic testing of the dogs before treatment with prednisolone. Thyroid-stimulating hormone (TSH) and thyrotropin-releasing hormone (TRH) response tests were performed before treatment (days 1 and 8 of the study) and during treatment (days 21 and 28 of the study). Blood samples were collected daily at 8 AM and 2 and 8 PM to rule out normal daily hormone fluctuations as the cause of a potential decrease in serum triiodothyronine (T3), thyroxine (T4), and free T4 (fT4) concentrations. Serum T3, T4, and fT4 concentrations before treatment and 1 day and 21 days after the first prednisolone dose were compared by analyses of variance. Post-TSH and -TRH serum T3 and T4 concentrations before and during treatment were compared, using the Student t test for paired data. Oral administration of prednisolone significantly (P less than 0.005) decreased serum T3, T4, and fT4 concentrations in the 8 AM and 2 and 8 PM samples obtained 1 day and 21 days after the first prednisolone dose. Serum T4 and fT4 concentrations in 8 AM and 2 PM samples were significantly (P less than 0.05) lower 21 days after the first prednisolone dose than they were at 1 day after the first dose. Before treatment, serum T4 concentration in the 2 PM samples was significantly (P less than 0.05) higher than serum T4 concentration in 8 AM and 8 PM samples.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thrombocytopenia associated with administration of trimethoprim/sulfadiazine in a dog.

A diagnosis of trimethoprim/sulfadiazine-induced, immune-mediated thrombocytopenia in a dog was made, using a novel in vitro assay for thrombolytic activity. The assay quantifies thrombolytic activity by measuring the amount of platelet fragments in normal canine platelets before and after incubation with plasma from the thrombocytopenic dog. This report confirms previous reports of the development of thrombocytopenia after administration of trimethoprim/sulfadiazine, and describes a new assay that, after further validation, may be useful in the diagnosis of immune-mediated thrombocytopenia when an adequate sample of platelets cannot be obtained for quantification of platelet-associated IgG.     

Pharmacokinetics and oral bioavailability of sulfadiazine and trimethoprim in broiler chickens

Sulfonamides and trimethoprim are chemotherapeutics that are extensively used in various animal species. Little information about the pharmacokinetics of these compounds in chickens exists in the literature. In this study, a new commercial formulation of sulfadiazine in combination with trimethoprim was administered both intravenously and orally, according to a crossover design, to healthy, 7-week-old broilers. The plasma concentrations of the drugs were determined by validated high-performance liquid chromatographic methods, and pharmacokinetic parameters were calculated. After intravenous or oral administration of trimethoprim (6.67 mg/kg body weight) and sulfadiazine (33.34 mg/kg body weight), both active substances were rapidly eliminated from the plasma. There was a mean half-life of 1.61 h for trimethoprim and 3.2 h for sulfadiazine. The apparent volumes of distribution (2.2 and 0.43 L/kg, respectively, indicated that the tissue distribution of trimethoprim was more extensive than that of sulfadiazine. The oral bioavailability was approximately 80% for both components.     

The effect of age and diet on sulfadiazine/trimethoprim disposition following oral and subcutaneous administration to calves

Thirty milligrams per kilogram of sulfadiazine/trimethoprim (SDZ/TMP, Tribrissen) was given orally and subcutaneously (s.c.) to two groups of male, Holstein calves. One group was fed milk-replacer throughout the 13-week period of the study while the second group was weaned onto a chopped grain-fiber mixture when 5 weeks old. Serum and urine were assayed for concentrations of unchanged drug. Trimethoprim bioavailability, following oral administration at 1, 6 and 12 weeks of age, is higher in milk-fed calves (non-ruminants) than in grain-fiber-fed calves (ruminants); bioavailability decreases with increasing age in both groups of calves. Serum concentrations above 0.1 micrograms/ml (the level of sensitivity of the assay) could not be obtained in ruminating calves. The rate of SDZ absorption following oral administration, as determined by the Wagner-Nelson method, was very slow in all the calves in this study with average half-life values ranging from 8.2-12.67 h; absorption was slightly faster in ruminating calves. Absorption of SDZ is rate-limiting and determines the biological half-life of the drug; SDZ serum concentrations above 2 micrograms/ml were maintained in all calves for at least 24 h. Following s.c. administration of Tribrissen to 7-and 13-week-old calves, urinary excretion patterns indicated that TMP was slowly released from the injection site; serum concentrations were below 0.1 micrograms/ml. In contrast, absorption of SDZ was very rapid; values for tmax were 1.5-1.8 h. The pharmacokinetic parameters for SDZ were calculated according to a one-compartment open model; neither diet nor age had a significant effect on SDZ disposition following s.c. injection. Subcutaneous administration of 30 mg/kg Tribrissen, b.i.d., may be the best therapeutic regimen; even though measureable concentrations of TMP cannot be achieved in the serum following a single s.c. dose, TMP concentrations should accumulate and, because of its sustained release, provide almost continual potentiation of SDZ.     

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.     

Effect of oral melatonin administration on sex hormone, prolactin, and thyroid hormone concentrations in adult dogs.

OBJECTIVE: To determine the effect of oral melatonin (MT) administration on serum concentrations of sex hormones, prolactin, and thyroxine in dogs. DESIGN: Prospective study. ANIMALS: 8 male and 8 female adult sexually intact dogs. PROCEDURE: 5 male and 5 female dogs were treated with MT (1.0 to 1.3 mg/kg [0.45 to 0.59 mg/lb] of body weight), PO, every 12 hours for 28 days; the other 6 dogs were used as controls. Blood samples were collected on days 0, 14, and 28, and serum concentrations of estradiol-17 beta, progesterone, testosterone, androstenedione, 17-hydroxyprogesterone (17-HP), dihydroepiandrostenedione sulfate (DHEAS), prolactin, and thyroxine were determined. On day 5, serum MT concentrations were measured before and periodically for up to 8 hours after MT administration in 4 treated dogs. RESULTS: Female dogs treated with MT had significant decreases in serum estradiol, testosterone, and DHEAS concentrations between days 0 and 28. Male dogs treated with MT had significant decreases in serum estradiol and 17-HP concentrations between days 0 and 28. Serum MT concentrations increased significantly after MT administration and remained high for at least 8 hours. Prolactin and thyroxine concentrations were unaffected by treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Melatonin is well absorbed following oral administration and may alter serum sex hormone concentrations.     

Pharmacokinetics and bioavailability of sulfadiazine and trimethoprim following intravenous, intramuscular and oral administration in ostriches (Struthio camelus)

A pharmacokinetic and bioavailability study of sulfadiazine combined with trimethoprim (sulfadiazine/trimethoprim) was carried out in fifteen healthy young ostriches after intravenous (i.v.), intramuscular (i.m.) and oral administration at a total dose of 30 mg/kg body weight (bw) (25 and 5 mg/kg bw of sulfadiazine and trimethoprim, respectively). The study followed a single dose, three periods, cross‐over randomized design. The sulfadiazine/trimethoprim combination was administered to ostriches after an overnight fasting on three treatment days, each separated by a 2‐week washout period. Blood samples were collected at 0 (pretreatment), 0.08, 0.25, 0.50, 1, 2, 4, 6, 8, 12, 24 and 48 h after drug administration. Following i.v. administration, the elimination half‐life (t_1/2β), the mean residence time (MRT), volume of distribution at steady‐state (V_d(ss)), volume of distribution based on terminal phase (V_d(z)), and the total body clearance (Cl_B) were (13.23 ± 2.24 and 1.95 ± 0.19 h), (10.06 ± 0.33 and 2.17 ± 0.20 h), (0.60 ± 0.08, and 2.35 ± 0.14 L/kg), (0.79 ± 0.12 and 2.49 ± 0.14 L/kg) and (0.69 ± 0.03 and 16.12 ± 1.38 mL/min/kg), for sulfadiazine and trimethoprim, respectively. No significant difference in C_max (35.47 ± 2.52 and 37.50 ± 3.39 μg/mL), t_max (2.47 ± 0.31 and 2.47 ± 0.36 h), t_½β (11.79 ± 0.79 and 10.96 ± 0.56 h), V_d(z)/F (0.77 ± 0.06 and 0.89 ± 0.07 L/kg), Cl_B/F (0.76 ± 0.04 and 0.89 ± 0.07) and MRT (12.39 ± 0.40 and 12.08 ± 0.36 h) were found in sulfadiazine after i.m. and oral dosing, respectively. There were also no differences in C_max (0.71 ± 0.06 and 0.78 ± 0.10 μg/mL), t_max (2.07 ± 0.28 and 3.27 ± 0.28 h), t_½β (3.30 ± 0.25 and 3.83 ± 0.33 h), V_d(z)/F (6.2 ± 0.56 and 6.27 ± 0.77 L/kg), Cl_B/F (21.9 ± 1.46 and 18.83 ± 1.72) and MRT (3.68 ± 0.19 and 4.34 ± 0.14 h) for trimethoprim after i.m. and oral dosing, respectively. The absolute bioavailability (F) was 95.41% and 86.20% for sulfadiazine and 70.02% and 79.58% for trimethoprim after i.m. and oral administration, respectively.     

Effects of oral administration of meloxicam,carprofen, and a nutraceutical on thyroid function in dogs with osteoarthritis

The purpose of this study was to evaluate the effect of the administration of meloxicam; carprofen; and a slow-acting disease modifying osteoarthritis agent, that contains chondroitin sulfate, purified glucosamine, and manganese ascorbate (CS-G-M), on thyroid function in dogs. Forty-six healthy (except for osteoarthritis) euthyroid dogs were blindly assigned to 3 treatment groups: meloxicam, carprofen, and CS-G-M. Each group received the recommended dose of the drug for 60 days. Sixteen other osteoarthritic euthyroid dogs, which received a placebo, were used as a control group to validate the study. For all groups, blood samples were collected on days 0, 30, and 60 to evaluate the serum total and free thyroxine, and endogenous thyrotropin concentrations. There were no significant differences among the treatment groups at each time or within each group over a 60-day period for all parameters. Moreover, none of these values were within the hypothyroid range. Based on the results of this study, the administration of meloxicam, carprofen, and CS-G-M did not affect canine thyroid function evaluation.     

Effect of oral administration of carprofen on intraocular pressure in normal dogs

The aim of this study was to determine the effect of oral administration of carprofen on intraocular pressure in normal dogs. Twelve young adult beagle dogs were randomly assigned to treatment (n = 6) or control (n = 6) groups. After an 11‐day acclimation period, the treatment group received approximately 2.2 mg/kg carprofen per os every 12 h for 7 days, and the control group received a placebo gel capsule containing no drug per os every 12 h for 7 days. Intraocular pressure (IOP) was measured by a rebound tonometer at three time points per day (8 am, 2 pm, and 8 pm) during the acclimation (days 1–11) and treatment (days 12–18) phases and for 48 h (days 19–20) after the completion of treatment. There was no statistically significant change in IOP for either eye in the dogs receiving oral carprofen during the treatment phase (days 12–18). After day 4, no significant daily IOP changes were seen in control group dogs. Carprofen administered orally every 12 h for 7 days had no effect on IOP in normal beagle dogs. An acclimation period to frequent IOP measurements of at least 5 days is necessary to establish baseline IOP values and minimize possible anxiety‐related effects on IOP measurements.     

A comparative study of the pharmacokinetics of intravenous and oral trimethoprim/sulfadiazine formulations in the horse

The biopharmaceutical properties of four fuced trimethoprim/sulfonamide combinations were investigated in the horse. Eight fasted horses were dosed at 1 week intervals in a sequentially designed study with one intravenous (i.v.) and three oral trimethoprim/sulfadiazine (TMP/SDZ) formulations (1, 2 and 3) administered at a dose of 5 mg/kg trimethoprim (TMP) and 25 mg/kg sulfadiazine (SDZ). Plasma concentrations of each compound were monitored for 48 h. Pharmacokinetic parameters (volume of distribution, bioavailability and total body clearance) for TMP and SDZ were calculated and compared. After oral administration plasma concentrations of TMP and SDZ increased rapidly. With all three paste formulations, TMP peak plasma concentrations were attained within 2 h. SDZ mean peak plasma concentrations were reached at 2.59 ± 0.48 h for a commercial paste (l), and at 1.84 ± 0.66 h and 1.95 ± 0.61 h for the two self-made formulations (2 and 3). Mean peak plasma TMP concentrations (± SD) were 1.72 ± 0.36 μg/ml, 1.42 ± 0.37 μg/ml and 1.31 ± 0.36 μ g/d, and mean peak plasma SDZ concentrations 12.11 ± 4.5 5 μg/ml, 12.72 ± 3.47 μg/ml and 15.45 ± 4.74 μg/ml for preparations 1, 2 and 3. The bioavailability of TMP was 67.0 ± 20.3%, 57.7 ±21.6% and 60.9 f 18.9% and of SDZ 57.6 ± 14.8%, 59.3 ± 19.5% and 65.9 ± 5.8% for SDZ for 1, 2 and 3, respectively. Following i.v. administration TMP/SDZ plasma concentration ratios approached the optimal 1:20 ratio (It 10%) for about 5 h, but following the oral administrations this ratio was only achieved for a very short time-span. No adverse effects were seen following i.v. and oral administration. In considering the pharmacokinetic data in combination with in vitro antibacterial sensitivity data, it is concluded that treatment at a dose of 5 mg/kg TMP and 25 mg/kg SDZ with a dosing interval of 12 h can be regarded as therapeutically effective for susceptible bacteria (MIC₉₀ 0.25/4.75) for all three oral formulations. It is concluded that neither the formulation nor the addition of different excipients result in significantly different bioavailabilities.     

Repeated administration of trimethoprim/sulfadiazine in the horse--pharmacokinetics, plasma protein binding and influence on the intestinal microflora

Six healthy adult horses were given repeated administrations of trimethoprim/ sulfadiazine (TMP/SDZ) intravenously (i.v.) (2.5 mg/kg TMP and 12.5 mg/kg SDZ) and orally (p.o.) as a paste (5 mg/kg TMP and 25 mg/kg SDZ). Both formulations were given twice daily for 5 days, with a 3-week interval between i.v. and oral administration. The influence of the drug combination on the intestinal microflora was examined and the plasma concentrations, pharmacokinetic parameters and plasma protein binding were determined. There were no major changes in the bacterial intestinal flora and no clinical evidence of gastrointestinal disturbances following the i.v. and oral TMP/SDZ administration. An initial reduction in the number of coliform bacteria during the treatment was notable, though with no evident difference between i.v. and oral treatment. The minimum concentration during a dose interval at steady state (Cminss), the elimination half-life (t1/2beta) and the mean residence time (MRT) were significantly greater after oral administration compared to i.v. for both TMP and SDZ. The plasma protein binding was measured to be 20% for SDZ and 35% for TMP. Oral administration of TMP/SDZ in a dose of 30 mg/kg given twice daily in the form of paste appeared as a satisfactory method for obtaining plasma levels above MIC (minimum inhibitory concentration in vitro) values during the interdosing interval.     

Clinical efficacy of prophylactic administration of trimethoprim/sulfadiazine in a Streptococcus equi subsp. zooepidemicus infection model in ponies

Tissue chambers, implanted subcutaneously in the neck in six ponies, were inoculated with Streptococcus equi subsp. zooepidemicus in order to determine the clinical efficacy of prophylactic administration of trimethoprim/sulfadiazine (TMP/SDZ) against this infection. The TMP/SDZ treatment consisted of one intravenous (i.v.) injection of 5 mg/kg TMP and 25 mg/kg SDZ and the same dose of TMP/SDZ per os (p.o.), both given 3 h before inoculation. The oral dose was then repeated every 12 h for 5 days. TMP/SDZ concentrations in tissue chamber fluid (TCF) were above 10 times MIC at the moment of inoculation, and they were maintained at this level or higher throughout the duration of treatment. Trimethoprim/sulfadiazine treatment resulted in a marked reduction of viable bacteria in the tissue chamber but did not eliminate the infection, resulting in abscessation from day 19 onwards in all six ponies. This shows that, even when TCF is not yet purulent, TMP/SDZ is unable to eliminate the streptococci. Therefore, TMP/SDZ should not be the antimicrobial treatment of choice in infections in secluded sites in horses.     

Blood and tissue concentrations of trimethoprim following its administration alone and in combination with josamycin.

Following a single oral dose of trimethoprim (10 mg/kg b. wt.) in normal fowls, the highest serum concentration achieved 4 hours post-administration with value of 0.64 microgram/ml. The absorption half-life time was 0.64 hours. The elimination half life was 4.73 hours. During repeated oral administration of 10 mg/kg b. wt., once daily for five consecutive days, trimethoprim peaked in serum, 4 h after each dose. Trimethoprim persisted in all fowl's tissues for 96 hours after stopping of drug administration. After oral administration of josamycin (18 mg/kg b. wt.) and trimethoprim (10 mg/kg b. wt.) in normal fowls, a maximum serum concentration of trimethoprim was recorded at 2 hours with half-life of absorption (t0.5(ab)) valued 0.74 hour. The elimination half-life (t0.5 beta) was 4.37 hours. During repeated oral administration of josamycin (18 mg/kg b. wt.) and trimethoprim (10 mg/kg b. wt.) once daily for five consecutive days in normal fowls, the highest plasma concentrations of trimethoprim occurred 2 hours post each dose. The daily maximum plasma concentrations during the repeated oral administration of both tested drugs were nearly constant.     

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.     

Effect of anticonvulsant dosages of potassium bromide on thyroid function and morphology in dogs

A placebo-controlled experiment was performed to evaluate the effect of potassium bromide on the canine thyroid gland. Basal total thyroxine, free thyroxine, and basal thyrotropin serum concentrations were evaluated over a 6-month period in potassium bromide-treated and control dogs. A thyrotropin-releasing hormone stimulation test was also performed in all dogs at the beginning and conclusion of the study. Thyroid histopathology was compared between treated and control dogs at the end of the study. No difference was detected in any parameter between the two groups at the end of the study. A decline in thyroid hormone concentrations over the course of the study did occur in both groups of dogs. Potassium bromide does not appear to have a significant effect on canine thyroid function or morphology.     

Effect of the interval between feeding and drug administration on oral ampicillin absorption in dogs

Eight dogs of various breeds received single oral doses of 20 mg/kg bodyweight ampicillin at four different time intervals relative to feeding a meal. In treatment A the dogs were fasted for 12 hours before and after ampicillin administration. In treatment B the dogs received ampicillin immediately after, in treatment C one hour before and in treatment D two hours after the meal. Each dog received these treatments during a period of feeding dry and canned dog food according to an 8 × 8 Latin square design. Blood samples were taken at specified time intervals after drug administration by jugular venepuncture. Antibiotic concentrations in plasma were determined by microbiological assay. Non-compartmental pharmacokinetic parameters were calculated from the individual concentration-time curves and were compared by non-parametric statistic tests between treatments and types of food. With both dry and canned food ampicillin absorption was impaired when the drug and food were given at the same time (treatment B) as compared to the absorption in fasting dogs (treatment A and C). On dry food, drug absorption was also decreased in treatment D. It is recommended for clinical purposes to give ampicillin to fasted dogs, and to wait at least one hour before feeding. After a meal (dry food) waiting two hours until drug administration is not sufficient to avoid impaired ampicillin absorption.     

Short-term influence of prednisone and phenobarbital on thyroid function in euthyroid dogs.

The short-term effects of prednisone and phenobarbital on serum total thyroxine (tT4), free thyroxine (fT4), and thyroid stimulating hormone (TSH) were evaluated in euthyroid dogs. Twenty-six beagles were randomly divided into 3 groups receiving, respectively, a placebo, prednisone (1.2 to 2 mg/kg body weight, per os, every 12 hours for 3 weeks), or phenobarbital (1.8 to 3 mg/kg body weight for 1 week, then 2.7 to 4.5 mg/kg body weight, per os, every 12 hours for 2 weeks). Blood samples taken over a 6-week period were assayed for serum tT4, fT4, and TSH. Phenobarbital therapy in our study did not affect serum tT4, fT4, or TSH concentrations. Prednisone therapy, however, significantly decreased serum tT4 and fT4, but did not affect serum TSH concentrations.