Effects of long-term oral administration of levothyroxine sodium on glucose dynamics in healthy adult horses

OBJECTIVE: To determine the effects of long-term oral administration of levothyroxine sodium (L-T(4)) on glucose dynamics in adult euthyroid horses. ANIMALS: 6 healthy adult mares. PROCEDURES: Horses received L-T(4) (48 mg/d) orally for 48 weeks. Frequently sampled IV glucose tolerance test procedures were performed on 3 occasions (24-hour intervals) before and at 16, 32, and 48 weeks during the treatment period. Data were assessed via minimal model analysis. The repeatability of measurements was evaluated. RESULTS: During treatment, body weight decreased significantly from the pretreatment value; mean +/- SD weight was 49 +/- 14 kg, 43 +/- 7 kg, and 25 +/- 18 kg less than the pretreatment value at weeks 16, 32, and 48, respectively. Compared with pretreatment findings, 1.8-, 2.4-, and 1.9-fold increases in mean insulin sensitivity (SI) were detected at weeks 16, 32, and 48, respectively; SI was negatively correlated with body weight (r = -0.42; P < 0.001). During treatment, glucose effectiveness increased and the acute insulin response to glucose decreased. Overall mean within-horse coefficients of variation were 5% and 29% for plasma glucose and serum insulin concentrations, respectively, and 33%, 26%, and 23% for SI, glucose effectiveness, and the acute insulin response to glucose, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Long-term administration of L-T(4) was associated with weight loss and increased SI in adult euthyroid horses, although other factors may have confounded results. Levothyroxine sodium may be useful for the treatment of obesity and insulin resistance in horses, but further studies are required.     

Effects of oral administration of levothyroxine sodium on serum concentrations of thyroid gland hormones and responses to injections of thyrotropin-releasing hormone in healthy adult mares

OBJECTIVE: To determine the effects of levothyroxine sodium (L-T4) on serum concentrations of thyroid gland hormones and responses to injections of thyrotropin-releasing hormone (TRH) in euthyroid horses. ANIMALS: 12 healthy adult mares. PROCEDURE: 8 horses received an incrementally increasing dosage of L-T4 (24, 48, 72, or 96 mg of L-T4/d) for weeks 1 to 8. Each dose was provided for 2 weeks. Four additional horses remained untreated. Serum concentrations of total triiodothyronine (tT3), total thyroxine (tT4), free T3 (fT3), free T4 (fT4), and thyroid-stimulating hormone (TSH) were measured in samples obtained at weeks 0, 2, 4, 6, and 8; 1.2 mg of TRH was then administered i.v., and serum concentrations of thyroid gland hormones were measured 2 and 4 hours after injection. Serum reverseT3 (rT3) concentration was also measured in the samples collected at weeks 0 and 8. RESULTS: Treated horses lost a significant amount of weight (median, 19 kg). Significant treatment-by-time effects were detected for serum tT3, tT4, fT3, fT4, and TSH concentrations, and serum tT4 concentrations were positively correlated (r, 0.95) with time (and therefore dosage) in treated horses. Mean +/- SD serum rT3 concentration significantly increased in treated horses (3.06 +/- 0.51 nmol/L for week 8 vs 0.74 +/- 0.22 nmol/L for week 0). Serum tT3, tT4, fT3, and TSH concentrations in response to TRH injections differed significantly between treated and untreated horses. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of levothyroxine sodium increased serum tT4 concentrations and blunted responses toTRH injection in healthy euthyroid horses.     

Effects of long-term oral administration of levothyroxine sodium on serum thyroid hormone concentrations, clinicopathologic variables, and echocardiographic measurements in healthy adult horses

OBJECTIVE: To determine the effects of long-term oral levothyroxine sodium (L-T(4)) administration on serum thyroid hormone concentrations, thyroid gland function, clinicopathologic variables, and echocardiographic examination measurements in adult euthyroid horses. ANIMALS: 6 healthy adult mares. PROCEDURES: Horses received L-T(4) (48 mg/d) orally for 48 weeks. Every 4 weeks, physical examinations were performed; blood samples were collected for CBC, plasma biochemical analyses, and assessments of serum total triiodothyronine (tT(3)) and thyroxine (tT(4)) concentrations. Plasma creatine kinase MB activity and cardiac troponin I concentration were also measured. Echocardiographic examinations were performed before and at 16, 32, and 48 weeks during the treatment period. RESULTS: During the treatment period, mean body weight decreased significantly; heart rate varied significantly, but the pattern of variation was not consistent. Significant time effects were detected for certain clinicopathologic variables, but mean values remained within reference ranges. Cardiac troponin I was only detectable in 8 of 24 plasma samples (concentration range, 0.01 to 0.03 ng/mL). Serum creatine kinase MB activity did not change significantly over time. Compared with the pretreatment value, 5.4-, 4.0-, and 3.7-fold increases in mean serum tT(4) concentrations were detected at 16, 32, and 48 weeks, respectively. Some cardiac measurements changed significantly over time, but mean values remained within published reference ranges. Mean fractional shortening was lower than the pretreatment mean value at 16 and 32 weeks. CONCLUSIONS AND CLINICAL RELEVANCE: In horses, long-term oral administration of 48 mg of L-T(4)/d significantly increased serum tT(4) concentrations and did not appear to adversely affect health.     

Effects of rice bran oil on plasma lipid concentrations, lipoprotein composition, and glucose dynamics in mares

Plasma lipid concentrations, lipoprotein composition, and glucose dynamics were measured and compared between mares fed diets containing added water, corn oil (CO), refined rice bran oil (RR), or crude rice bran oil (CR) to test the hypothesis that rice bran oil lowers plasma lipid concentrations, alters lipoprotein composition, and improves insulin sensitivity in mares. Eight healthy adult mares received a basal diet fed at 1.5 times the DE requirement for maintenance and each of the four treatments according to a repeated 4 x 4 Latin square design consisting of four 5-wk feeding periods. Blood samples were collected for lipid analysis after mares were deprived of feed overnight at 0 and 5 wk. Glucose dynamics were assessed at 0 and 4 wk in fed mares by combined intravenous glucose-insulin tolerance tests. Plasma glucose and insulin concentrations were measured, and estimated values of insulin sensitivity (SI), glucose effectiveness, and net insulin response were obtained using the minimal model. Mean BW increased (P = 0.014) by 29 kg (range = 10 to 50 kg) over 5 wk. Mean plasma concentrations of NEFA, triglyceride (TG), and very low-density lipoprotein (VLDL) decreased (P < 0.001) by 55, 30, and 39%, respectively, and plasma high-density lipoprotein and total cholesterol (TC) concentrations increased (P < 0.001) by 15 and 12%, respectively, over 5 wk. Changes in plasma NEFA (r = 0.58; P < 0.001) and TC (r = 0.44; P = 0.013) concentrations were positively correlated with weight gain over 5 wk. Lipid components of VLDL decreased (P < 0.001) in abundance over 5 wk, whereas the relative protein content of VLDL increased by 39% (P < 0.001). Addition of oil to the basal diet instead of water lowered plasma NEFA and TG concentrations further (P = 0.002 and 0.020, respectively) and increased plasma TC concentrations by a greater magnitude (P = 0.072). However, only plasma TG concentrations and VLDL free cholesterol content were affected (P = 0.024 and 0.009, respectively) by the type of oil added to the diet. Mean plasma TG concentration decreased by 14.2 mg/dL over 5 wk in the CR group, which was a larger (P < 0.05) decrease than the one (-5.3 mg/dL) detected in mares that received water. Consumption of experimental diets lowered S(I), but glucose dynamics were not affected by oil supplementation. Addition of oil to the diet altered blood lipid concentrations, and supplementation with CR instead of water specifically affected plasma TG concentrations and VLDL free cholesterol content.     

Effects of hypothyroidism and withholding of feed on plasma lipid concentrations,concentration and composition of very-low-density lipoprotein,and plasma lipase activity in horses

OBJECTIVE: To evaluate selected concentrations of blood lipids and lipase activities in euthyroid and hypothyroid horses deprived of feed for 96 hours. ANIMALS: 4 healthy adult mares and 4 thyroidectomized adult mares. PROCEDURE: Horses were deprived of feed for 96 hours. Blood samples were collected at 24-hour intervals and analyzed to determine concentrations of non-esterified fatty acid (NEFA), triglyceride (TG), total cholesterol (TC), and very-low-density lipoprotein (VLDL) as well as composition of VLDL. Plasma lipase activities were measured after feed was withheld for 96 hours and 12 days after resumption of feeding. RESULTS: Time significantly affected plasma NEFA, VLDL, TG, and TC concentrations in both groups of horses. During the 96-hour period, mean plasma concentrations of NEFA and VLDL increased 10-fold in euthyroid horses and increased 5-fold and 9-fold, respectively, in hypothyroid horses. Mean plasma TG concentrations increased 8-fold in both groups, and plasma TC concentrations significantly increased by 33 and 30%, respectively. Composition of VLDL was significantly affected by feed deprivation in euthyroid horses. Activities of lipoprotein lipase and hepatic lipase were significantly higher in feed-deprived horses. Activity of hepatic lipase was significantly lower in hypothyroid horses than in euthyroid horses. CONCLUSIONS AND CLINICAL RELEVANCE: Hypothyroidism did not significantly alter the magnitude of the response of blood lipids to feed deprivation. Thyroid hormones may reduce variability in blood lipid concentrations but do not determine susceptibility to hyperlipemia. Hypothyroidism does not appear to be a factor in the pathogenesis of hyperlipemia in horses.     

Single-dose oral pharmacokinetics of pergolide mesylate in healthy adult mares

This pilot study evaluated protection of an equine autogenous bacterin-toxoid vaccine against Corynebacterium pseudotuberculosis infection. Twenty-four BALB/c mice were inoculated with two doses of bacterin-toxoid vaccine or two injections of a placebo. Clinical, microbiologic, and pathologic outcomes were assessed after intradermal infection with one of two equine-origin C. pseudotuberculosis strains. Mice receiving bacterin-toxoid from fast-growing C. pseudotuberculosis showed significant protection from challenge infection, as evidenced by a higher survival rate, fewer gross and histopathologic lesions, and lower bacterial levels on culture. Successful protection via a vaccine against equine internal abscesses might provide supplementary management options against an important, potentially fatal disease.     

Effects of pre‐operative administration of medetomidine on plasma insulin and glucose concentrations in healthy dogs and dogs with insulinoma

ObjectiveTo investigate the effect of medetomidine on plasma glucose and insulin concentrations in dogs with insulinoma and in healthy dogs undergoing anesthesia and surgery.AnimalsTwenty–five dogs with insulinoma and 26 healthy dogs.MethodsIn dogs with insulinoma, medetomidine (5 μg kg^?1) was randomly included (n = 12) or omitted (n = 13) from the pre–anesthetic medication protocol, which typically contained an opioid and an anticholinergic. Healthy dogs received medetomidine (5 μg kg^?1; n = 13) or acepromazine (0.04 mg kg^?1; n = 13) plus an opioid (morphine 0.5 mg kg^?1) and an anticholinergic (atropine 0.04 mg kg^?1) as pre–anesthetic medications. Pre–anesthetic medications were given intramuscularly. Plasma glucose and insulin concentrations were measured before (sample 1) and 30 minutes after pre–anesthetic medication (sample 2), and at the end of surgery in dogs with insulinoma or at 2 hours of anesthesia in healthy dogs (sample 3). Glucose requirement to maintain intra–operative normoglycemia in dogs with insulinoma was quantified and compared. Data were analyzed with anova and Bonferroni post–test, t–tests or chi–square tests as appropriate with p < 0.05 considered significant. Data are shown as mean ± SD.ResultsMedetomidine significantly decreased plasma insulin concentrations and increased plasma glucose concentrations in healthy dogs and those with insulinoma. These variables did not change significantly in the dogs not receiving medetomidine. In the dogs with insulinoma, intra–operative glucose administration rate was significantly less in the animals that received medetomidine compared to those that did not.ConclusionsPre–anesthetic administration of medetomidine significantly suppressed insulin secretion and increased plasma glucose concentration in dogs with insulinoma and in healthy dogs undergoing anesthesia and surgery.Clinical relevanceThese findings support the judicious use of medetomidine at low doses as an adjunct to the anesthetic management of dogs with insulinoma.     

Effects of anesthesia, surgery, and intravenous administration of fluids on plasma antidiuretic hormone concentrations in healthy dogs

OBJECTIVE: To evaluate effects of anesthesia, surgery, and intravenous administration of fluids on plasma concentrations of antidiuretic hormone (ADH), concentration of total solids (TS), PCV, arterial blood pressure (BP), plasma osmolality, and urine output in healthy dogs. ANIMALS: 22 healthy Beagles. PROCEDURE: 11 dogs did not receive fluids, and 11 received 20 ml of lactated Ringer's solution/kg of body weight/h. Plasma ADH adn TS concentrations, PCV, osmolality, and arterial BP were measured before anesthesia (T0) and after administration of preanesthetic agents (T1), induction of anesthesia (T2), and 1 and 2 hours of surgery (T3 and T4, respectively). Urine output was measured at T3 and T4. RESULTS: ADH concentrations increased at T1, T3, and T4, compared with concentrations at T0. Concentration of TS and PCV decreased at all times after administration of preanesthetic drugs. Plasma ADH concentration was less at T3 in dogs that received fluids, compared with those that did not. Blood pressure did not differ between groups, and osmolality did not increase > 1% from To value at any time. At T4, rate of urine production was less in dogs that did not receive fluids, compared with those that did. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma ADH concentration increased and PCV and TS concentration decreased in response to anesthesia and surgery. Intravenous administration of fluids resulted in increased urine output but had no effect on ADH concentration or arterial BP. The causes and effects of increased plasma ADH concentrations may affect efficacious administration of fluids during the perioperative period in dogs.     

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 μg 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 μg/kg once daily, as a starting dose for replacement therapy in dogs with hypothyroidism.     

Evaluation of plasma concentration after intravenous and intramuscular penicillin administration over 24 hr in healthy adult horses

Penicillin is administered intravenously (IV) or intramuscularly (IM) to horses for the prevention and treatment of infections, and both routes have disadvantages. To minimize these shortcomings, a 24‐hr hybrid administration protocol (HPP) was developed. Our objective was to determine penicillin plasma concentrations in horses administered via HPP. Venous blood was collected from seven healthy horses administered IV potassium penicillin G at 0 and 6 hr and IM procaine penicillin G at 12 hr. Blood was collected at 2‐hr intervals from 0 to 20 hr and at 24 hr. Plasma penicillin concentrations were measured using liquid chromatography and mass spectrometry. Penicillin susceptibility from equine isolates was examined to determine pharmacodynamic targets. The MIC₉₀ of penicillin for 264 isolates of Streptococcus sp. was ≤0.06 μg/ml. For the 24‐hr dosing interval, the mean plasma penicillin concentration was >0.07 μg/ml. Five horses (72%) exceeded 0.06 μg/ml for 98% of the dosing interval, and two horses exceeded this value for 52%–65% of the dosing interval. The HPP achieved mean plasma penicillin concentrations in healthy adult horses above 0.07 μg/ml for a 24‐hr dosing interval. However, individual variations in plasma concentrations were apparent and deserve future clinical study.     

Effect of probenecid administration on cephapirin pharmacokinetics and concentrations in mares

Cephapirin (20 mg/kg of body weight, IV) was administered before and after 3 doses of probenecid (25, 50, or 75 mg/kg, intragastrically, at 12-hour intervals) to 2 mares. Clearance and apparent volume of distribution, based on area under the curve, were negatively correlated with probenecid dose. Clearance of cephapirin was decreased by approximately 50% by administration of 50 mg of probenecid/kg. Serum, synovial fluid, peritoneal fluid, CSF, urinary, and endometrial concentrations of cephapirin were determined after 5 doses of cephapirin (20 mg/kg, IM, at 12-hour intervals) without and with concurrently administered probenecid (50 mg/kg, intragastrically) to 6 mares, including the 2 mares given cephapirin, IV. Highest mean serum cephapirin concentrations were 16.1 +/- 2.16 micrograms/ml at 0.5 hour after the 5th cephapirin dose [postinjection (initial) hour (PIH) 48.5] in mares not given probenecid and 23.7 +/- 1.30 micrograms/ml at 1.5 hours after the 5th cephapirin dose (PIH 49.5) in mares given probenecid. Mean peak peritoneal fluid and synovial fluid cephapirin concentrations were 6.2 +/- 0.57 micrograms/ml and 6.6 +/- 0.58 micrograms/ml, respectively, without probenecid administration and 12.3 +/- 0.46 micrograms/ml and 10 +/- 0.78 micrograms/ml, respectively, with concurrent probenecid administration. Mean trough cephapirin concentrations for peritoneal and synovial fluids in mares given probenecid were 2 to 3 times higher than trough concentrations in mares not given probenecid. Overall mean cephapirin concentrations were significantly higher for serum, peritoneal fluid, synovial fluid, and endometrium when probenecid was administered concurrently with cephapirin (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of oral administration of lactulose in healthy horses

Lactulose (1-4-galactosidofructose) was administered to seven healthy, mature horses at a dosage of 333 mg/kg, by mouth, three times daily for 11 days. There was a significant (P<0.05) reduction in the concentration of blood ammonia during the period after first administration, with a mean reduction of 3 umol/L. Although fecal pH tended to increase after the administration of lactulose, the change was not statistically significant (P>0.05). There were no substantial changes in the results of physical examinations during the periods before, during and after administration in six horses. One horse developed signs of laminitis on the sixth day of administration, was removed from the study and responded well to treatment for laminitis.     

Effects of dexamethasone on glucose dynamics and insulin sensitivity in healthy horses

OBJECTIVE: To determine effects of dexamethasone on glucose dynamics and insulin sensitivity in healthy horses. ANIMALS: 6 adult Standardbreds. PROCEDURES: In a balanced crossover study, horses received dexamethasone (0.08 mg/ kg, IV, q 48 h) or an equivalent volume of saline (0.9% NaCl) solution (control treatment) during a 21-day period. Horses underwent a 3-hour frequently sampled IV glucose tolerance test (FSIGT) 2 days after treatment. Minimal model analysis of glucose and insulin data from FSIGTs were used to estimate insulin sensitivity (Si), glucose effectiveness (Sg), acute insulin response to glucose (AIRg), and disposition index. Proxies for Si (reciprocal of the inverse square of basal insulin concentration [RISQI]) and beta-cell responsiveness (modified insulin-to-glucose ratio [MIRG]) were calculated from basal plasma glucose and serum insulin concentrations. RESULTS: Mean serum insulin concentration was significantly higher in dexamethasone-treated horses than control horses on days 7, 14, and 21. Similarly, mean plasma glucose concentration was higher in dexamethasone-treated horses on days 7, 14, and 21; this value differed significantly on day 14 but not on days 7 or 21. Minimal model analysis of FSIGT data revealed a significant decrease in Si and a significant increase in AIRg after dexamethasone treatment, with no change in Sg or disposition index. Mean RISQI was significantly lower, whereas MIRG was higher, in dexamethasone-treated horses than control horses on days 7, 14, and 21. CONCLUSIONS AND CLINICAL RELEVANCE: The study revealed marked insulin resistance in healthy horses after 21 days of dexamethasone administration. Because insulin resistance has been associated with a predisposition to laminitis, a glucocorticoid-induced decrease in insulin sensitivity may increase risk for development of laminitis in some horses and ponies.     

Fibronectin concentration in plasma of mares and neonatal foals

Plasma fibronectin concentrations were measured in clinically healthy mares and their neonatal foals, using a modified human fibronectin competitive enzyme-linked immunosorbent assay. Ranges of plasma fibronectin were established in clinically healthy horses, and the assay was reliable and reproducible. Plasma fibronectin concentrations were similar in mares and foals, both before and after colostrum ingestion.     

Plasma concentration, mammary excretion and side-effects of phenylbutazone after repeated oral administration in healthy cows

Seven clinically healthy dairy cows were each given 2.5 gphenylbutazone (approximately 5 mg/kg body weight) by oral administration twice daily for 8 days. The concentrations of phenylbutazone in plasma and milk and several blood parameters were studied. The minium plasma concentration during steady state was 100.4 ± 7.3 μg/ml. During the same period the milk concentration never exceeded 1% of the plasma concentration. The elimination half-life in plasma was 38.6 ± 3.7 h. Five days after administration had been discontinued, the milk concentration was 0.05 ± 0.01 μg/ml. All seven cows were clinically healthy throughout the experiment. The most pronounced side-effect of the blood parameters studied was a decreased concentration of leucocytes to about two-thirds of the control value. This might have a pronounced influence on the effectiveness of the immune system. There was also a significant decrease in total bilirubin indicating a decrease in the breakdown of erythrocytes.     

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.