Six healthy, adult horses, with normal (mean +/- SEM) baseline serum concentrations of total triiodothyronine (T3, 1.02 +/- 0.16 nmol/L), free T3 (FT3, 2.05 +/- 0.33 pmol/L), total thyroxine (T4, 19.87 +/- 1.74 nmol/L), free T4 (FT4, 11.55 +/- 0.70 pmol/L), total reverse T3 (rT3, 0.68 +/- 0.06 nmol/L), and cortisol (152.75 +/- 17.50 nmol/L), were judged to be euthyroid on the basis of response to a standardized thyroid-stimulating hormone response test. Serum concentrations of T3, FT3, T4, FT4, rT3, and cortisol were determined immediately before and every 24 hours during a 4-day period of food deprivation, when water was available ad libitum. Similar variables were measured 72 hours after refeeding. Decreases (to percentage of baseline, prefood deprivation value) in circulating T3 (42%), T4 (38%), FT3 (30%), and FT4 (24%) concentrations were maximal after 2, 4, 2, and 4 days of food deprivation, respectively (P < 0.05). Increases (compared with baseline, prefood deprivation value) in rT3 (31%) and cortisol (41%) concentrations were maximal after 1 and 2 days of food deprivation, respectively (P < 0.05). Refeeding resulted in increase in serum T4 and FT4, and decrease in rT3 and cortisol concentrations toward baseline values, after 72 hours (P < 0.05). Refeeding did not effect a return of T3 or FT3 concentration to baseline values after 72 hours (P < 0.05). Food deprivation appears to cause changes in serum concentrations of T3, FT3, T4, FT4, rT3, and cortisol in horses that are similar to those in human beings. This effect of food deprivation should be considered when results of serum thyroid hormone and cortisol assays are interpreted in the face of clinical disease. These results further emphasize the invalidity of making a clinical diagnosis of hypothyroidism on the basis of baseline, serum thyroid hormone concentrations in horses, especially if the horses have been anorectic or inappetent.

A bolus dose of methimazole (MMI) was administered IV over 1 minute to 5 healthy adult dogs at a dosage (40 mg/kg of body weight) known to impart protection against cisplatin-induced renal disease. Blood and urine samples for pharmacokinetic analysis were collected over a 24-hour period. Physical examination, CBC, determination of serum thyroid hormone concentrations, and serum biochemistry analysis were performed over a 10-day period to evaluate short-term toxicoses. At this dosage, MMI appears to be safe and well tolerated in dogs; only 1 of the 5 dogs had mild and transient increases in serum activity of hepatic enzymes. In addition, MMI did not alter serum thyroid hormone concentrations. Half-life of 8.82 hours and mean residence time of 12.18 hours were determined for MMI. Renal clearance of native MMI, along with sulfate and glucuronide conjugates, represented only 20% of total systemic clearance. Results of this study provide further information concerning clinical use of MMI in dogs and may contribute to better understanding of the mechanism of MMI protection against chemically induced nephrotoxicosis.

Twelve mature (5 sexually intact males, 4 castrated males, and 3 females) mixed-breed dogs were surgically thyroidectomized and used in a Latin-square design pharmacokinetic study of orally administered L-thyroxine. The dogs were treated with 44, 22, and 11 Kg of L-thyroxine/kg as a single morning dose or in divided doses, morning and evening. Serum concentration of thyroxine (T4) was evaluated to determine a number of pharmacokinetic variables for comparison. Mean steady-state concentrations (C(SS)) were determined from the area under the curve. Variables were analyzed for comparisons between dosages by use of ANOVA. Concentration at steady state was highest for dogs of the 44-micrograms/kg of body weight once-daily group and was lowest for dogs of the group given 11 micrograms/kg in 2 daily doses. Single daily administration resulted in higher C(SS), except at the 22-micrograms/kg/d dosage. Clearance was faster for the 22- and 44-micrograms/kg/d dosages than for the 11-micrograms/kg/d dosage. The half-life (t(1/2)) and mean residence time (MRT) also were shorter for the 44-micrograms/kg/d dosage, possibly indicating more rapid elimination of the drug at higher doses and dose-dependent kinetics. Perhaps, as the dogs' metabolism increased with higher iodothyronine concentrations, hormone degradation was accelerated. Interval (divided vs single dose) caused some expected changes: maximal concentration was higher and minimal concentration was lower when single administration was used. These undulations resulted in iodothyronine concentrations above the physiologic range for a number of hours, whereas concentration closer to physiologic ranges was achieved by use of divided doses. Delayed absorption (lag time) was seen in 37 of the 72 data sets, but was generally short, about 0.25 hour. Mean time to maximal concentration was 3 to 4 hours. At the higher dosages, serum total T4 concentration was high normal or above normal during most of the time after L-thyroxine administration, but serum concentration of total 3,5,3'-triiodothyronine did not remain within the normal range until the 44-micrograms/kg/d dosage was used. The customary dosage of 22 micrograms/kg/d (0.1 mg/10 lb/d) may not be adequate for most dogs. Pharmacokinetic variables appear to be highly dependent on the individual dog. Those with rapid absorption and higher concentration tended to have these characteristics at each dosage in this study. The pharmacokinetic variables, therefore, appear to be highly individualized, and dosages recommended for treatment of hypothyroidism should be considered to be only a starting point for the average dog. To avoid underdosing or overdosing, monitoring of treatment to adjust dose for individual dog kinetic variables seems to be imperative.

The objectives of this experiment were to determine serum concentrations of triiodothyronine (T3), thyroxine (T4), and free thyroxine (fT4) at rest, following thyroid-stimulating hormone (TSH) administration, and following phenylbutazone administration in healthy horses. This was done to determine which available laboratory test can best be used for diagnosis of hypothyroid conditions in horses. Serum T3, T4, and fT4 concentrations in serum samples obtained before and after TSH stimulation and following phenylbutazone administration for 7 days were determined. Baseline values ranged from 0.21 to 0.80 ng of T3/ml, 6.2 to 25.1 ng of T4/ml, and 0.07 to 0.47 ng of fT3/dl. After 5 IU of TSH was administered IV, serum T3 values increased to 6 times baseline values in 2 hours. Thyroxine values increased to 3 times baseline values at 4 hours and remained high at 6 hours. Free T4 values increased to 4 times baseline values at 4 hours and remained high at 6 hours. Administration of 4.4 mg of phenylbutazone/kg, every 12 hours for 7 days significantly decreased T4 and fT4 values, but did not significantly affect serum T3 concentrations, It was concluded that a TSH stimulation test should be performed when hypothyroidism is suspected. Measurement of serum fT4 concentrations, by the single-stage radioimmunoassay, does not provide any additional information about thyroid gland function over that gained by measuring T4 concentrations. Phenylbutazone given at a dosage of 4.4 mg/kg every 24 hours, for 7 days did significantly decrease resting T4 and fT4 concentrations, but did not significantly affect T3 concentrations in horses.

The influence of triiodothyronine (5 microgram/kg of body weight, SC, q 12 h for 7 days) on antipyrine (AP, 25 mg/kg, IV) plasma elimination and urinary metabolite excretion was studied in castrated male dwarf goats. After triiodothyronine treatment, a significant increase in AP elimination was found. However, the observed changes in clearances for production of AP metabolites (nor-AP, 3-hydroxy-methyl-AP; 4-hydroxy-AP, and 4,4'-dihydroxy-AP) do not suggest a clear selectivity of triiodothyronine toward any of the metabolic pathways of AP.

Effects of thyroid-stimulating hormone (TSH) and thyrotropin-releasing hormone (TRH) on plasma concentrations of thyroid hormones, and effects of ACTH and dexamethasone on plasma concentrations of cortisol, were studied in adult male ferrets. Thirteen ferrets were randomly assigned to test or control groups of eight and five animals, respectively. Combined (test + control groups) mean basal plasma thyroxine (T4) values were different between the TRH (1.81 +/- 0.41 microgram/dl, mean +/- SD) and TSH (2.69 +/- 0.87 microgram/dl) experiments, which were performed 2 months apart. Plasma T4 values significantly (P < 0.05) increased as early as 2 hours (3.37 +/- 1.10 microgram/dl) and remained high until 6 hours (3.45 +/- 0.86 microgram/dl) after IV injection of 1 IU of TSH/ferret. In contrast, IV injection of 500 microgram of TRH/ferret did not induce a significant increase until 6 hours (2.75 +/- 0.79) after injection, and induced side effects of hyperventilation, salivation, vomiting, and sedation. There was no significant increase in triiodothyronine (T3) values following TSH or TRH administration. Combined mean basal plasma cortisol values were not significantly different between ACTH stimulation (1.29 +/- 0.84 microgram/dl) and dexamethasone suppression test (0.74 +/- 0.56 microgram/dl) experiments. Intravenous injection of 0.5 IU of ACTH/ferret induced a significant increase in plasma cortisol concentrations by 30 minutes (5.26 +/- 1.21 microgram/dl), which persisted until 60 minutes (5.17 +/- 1.99 microgram/dl) after injection. Plasma cortisol values significantly decreased as early as 1 hour (0.41 +/- 0.13 microgram/dl), and had further decreased by 5 hours (0.26 +/- 0.15 microgram/dl) following IV injection of 0.2 mg of dexamethasone/ferret. These results indicate that IV injection of 1 IU of TSH/ferret is preferable to IV injection of 500 microgram of TRH/ferret for thyroid function testing in adult male ferrets. Results of this study also indicated that when TRH or TSH is used for the thyroid-stimulation test in male ferrets, plasma T4 concentrations, instead of T3, should be used as the indicator of thyroid response. Additionally, IV injection of 0.5 IU of ACTH and 0.2 mg of dexamethasone may be used in ferrets for the ACTH stimulation and dexamethasone-suppression tests, respectively.

Pituitary function and short-term clinical effects after transsphenoidal hypophysectomy were investigated in clinically normal dogs. In study, I, 8 dogs were given polyionic fluids IV during the first 12 hours after surgery. In study II, 4 dogs were given polyionic fluids IV and glucocorticoid supplementation for 7 days. Pituitary function was assessed by evaluating basal ACTH concentrations and results of a growth hormone stimulation test before and 1 and 12 weeks after hypophysectomy, an ACTH stimulation test, a thyrotropin-releasing hormone-stimulation test, and a modified water deprivation/vasopressin response test before and 1, 4, 8, and 12 weeks after hypophysectomy. Gross and histologic evaluations of the surgery site, thyroid and adrenal glands, and skin were done at 12 weeks after surgery. Four dogs from study I died within 27 hours after hypophysectomy. Postmortem examinations of these dogs revealed liver and lung congestion compatible with circulatory collapse. None of the dogs in study II died. For the surviving dogs in both studies, diabetes insipidus developed immediately after hypophysectomy and resolved within 2 weeks. Hypernatremia also developed immediately after hypophysectomy and resolved by 1 week. Production of ACTH was evident at 1 and 12 weeks after hypophysectomy in all dogs, and results of ACTH stimulation tests after surgery were not notably different from results obtained before surgery. Results of thyrotropin-releasing hormone stimulation and growth hormone-stimulation tests supported the diagnosis of hypothyroidism and hyposomatotropism attributable to hypophysectomy. Histologic examination revealed thyroid atrophy, epidermal and dermal atrophy, and normal adrenal glands in all dogs and remnants of the hypophysis in 2 dogs from study I. Continued ACTH production suggested that complete hypophysectomy was not accomplished in any dog.

OBJECTIVE To investigate the effect of high doses of orally administered levothyroxine sodium (LT4) on serum concentrations of triiodothyronine (T3) and thyroxine (T4) in euthyroid horses. ANIMALS 12 healthy adult horses. PROCEDURES 10 horses initially received water (vehicle) or 240 mg (5X treatment) or 480 mg (10× treatment) of LT4, and blood samples were collected at baseline (0 hours) and 0.5, 1, 2, 4, 6, 8, 10, 12, 18, 24, 48, 72, 96, and 120 hours after treatment to measure serum T3 and T4 concentrations. Three horses then received 480 mg of LT4 for 14 days, and T4 concentration was measured on days 0, 14, 21, 28, and 35. Changes in T3 and T4 concentrations were compared over time and among treatments. RESULTS One-time administration of LT4 resulted in variable but significant increases in both T3 and T4 concentrations for up to 120 hours; however, T3 and T4 concentrations rarely exceeded reference intervals with either treatment. Prolonged administration of 480 mg of LT4 resulted in a 15-fold increase in T4 concentration after 14 days, but concentration returned to day 0 values within 21 days after LT4 administration was discontinued. CONCLUSIONS AND CLINICAL RELEVANCE In euthyroid horses, administration of a high dose of LT4 resulted in mild increases in thyroid hormone concentrations; however, prolonged administration of high doses of LT4 resulted in markedly increased thyroid hormone concentrations that returned to pretreatment values within 3 weeks after discontinuation of LT4 administration. These results indicated complex kinetics of LT4 and suggested a possible saturation of T4 excretion in euthyroid horses.

Newborn foals of mares grazing on Acremonium coenophialum-infected fescue pasture throughout gestation or from gestation day 300 to parturition had increased gestation duration and decreased serum triiodothyronine concentration. Pregnant mares were allotted to 4 treatments: grazing continuously on endophyte-free (E-) fescue, grazing continuously on endophyte-infected (E+) fescue, grazing on E+ fescue from gestation day 300 to parturition, and grazing on E+ fescue from conception to gestation day 300. Morphometric studies indicated that foals born to mares exposed to endophyte late in gestation had large, distended thyroid follicles lined by flat cuboidal epithelial cells. Mean triiodothyronine concentration in foals exposed to endophyte (395.2 ng/dl) was decreased (P < 0.01), compared with mean values in control foals (778.0 ng/dl). Thyroxine and reverse triiodothyronine concentrations were not significantly different among groups. Foal organ weight as a percentage of foal body weight was not significantly different among experimental groups.