Evaluation of Serum Thyroid‐Stimulating Hormone Concentration as a Diagnostic Test for Hyperthyroidism in Cats

Background

In humans, measurement of serum thyroid‐stimulating hormone (TSH) concentration is commonly used as a first‐line discriminatory test of thyroid function. Recent reports indicate that canine TSH (cTSH) assays can be used to measure feline TSH and results can help diagnose or exclude hyperthyroidism.

Objectives

To investigate the usefulness of cTSH measurements as a diagnostic test for cats with hyperthyroidism.

Animals

Nine hundred and seventeen cats with untreated hyperthyroidism, 32 euthyroid cats suspected of having hyperthyroidism, and 131 clinically normal cats.

Methods

Prospective study. Cats referred to the Animal Endocrine Clinic for suspected hyperthyroidism were evaluated with serum T₄, T₃, free T₄ (fT ₄), and TSH concentrations. Thyroid scintigraphy was used as the gold standard to confirm or exclude hyperthyroidism.

Results

Median serum TSH concentration in the hyperthyroid cats (<0.03 ng/mL) was significantly (P < .001) lower than concentrations in clinically normal cats (0.05 ng/mL) or euthyroid cats with suspected thyroid disease (0.06 ng/mL). Only 18 (2.0%) hyperthyroid cats had measurable TSH concentrations (≥0.03 ng/mL), whereas 114 (69.9%) of the 163 euthyroid cats had detectable concentrations. Combining serum TSH with T₄ or fT ₄ concentrations lowered the test sensitivity of TSH from 98.0 to 97.0%, but markedly increased overall test specificity (from 69.9 to 98.8%).

Conclusions and Clinical Importance

Serum TSH concentrations are suppressed in 98% of hyperthyroid cats, but concentrations are measurable in a few cats with mild‐to‐moderate hyperthyroidism. Measurement of serum TSH represents a highly sensitive but poorly specific test for diagnosis of hyperthyroidism and is best measured in combination with T₄ and fT ₄.     

EVALUATION OF QUANTITATIVE THYROID SCINTIGRAPHY FOR DIAGNOSIS AND STAGING OF DISEASE SEVERITY IN CATS WITH HYPERTHYROIDISM: COMPARISON OF THE PERCENT THYROIDAL UPTAKE OF PERTECHNETATE TO THYROID‐TO‐SALIVARY RATIO AND THYROID‐TO‐BACKGROUND RATIOS

Thyroid scintigraphy is commonly used for evaluation of cats with hyperthyroidism, with the thyroid‐to‐salivary ratio (T/S) being the most common method to quantify the degree of thyroid activity and disease. Calculation of thyroid‐to‐background ratios (T/B) or percent thyroidal uptake of ^99mTcO^?₄ (TcTU) has only been reported in a few studies. The purpose of this prospective, cross‐sectional study was to evaluate a number of quantitative scintigraphic indices as diagnostic tests for hyperthyroidism, including the T/S, three different T/B, TcTU, and estimated thyroid volume. Of 524 cats referred to our clinic for evaluation of suspected hyperthyroidism, the diagnosis was confirmed (n = 504) or excluded (n = 20) based on results of a serum thyroid panel consisting of thyroxine (T₄), triiodothyronine (T₃), free T₄ (fT₄), and thyroid‐stimulating hormone (TSH) concentrations. In the hyperthyroid cats, median values for TcTU, T/S, and three T/B ratios were all significantly higher (P < 0.001) than values in euthyroid suspect cats or clinically normal cats. All scintigraphic parameters were relatively sensitive and specific as diagnostic tests for hyperthyroidism, but the T/S ratio had the highest test accuracy. The T/S ratio correlated strongly with the TcTU (r = 0.85). However, the TcTU had a higher and more significant correlation (P < 0.01) with serum T₄ (r = 0.76 vs. 0.64), T₃ (r = 0.77 vs. 0.64), and estimated thyroid volume (r = 0.62 vs. 0.38). Overall, calculation of TcTU is an accurate diagnostic test, but also appears to be the best parameter to predict the functional volume and metabolic activity of the feline adenomatous thyroid gland.     

Use of the Thyrotropin Releasing Hormone Stimulation Test to Diagnose Mild Hyperthyroidism in Cats

We evaluated serum T₄ and T₃ concentrations before and after administration of thyrotropin releasing hormone (TRH) in 35 cats with mild to moderate hyperthyroidism. 15 cats with nonthyroidal disease, and 31 clinically normal cats. The TRH stimulation test was performed by collecting blood for serum T₄ and T₃ determinations before and 4 hours after IV administration of 0.1 mg/kg TRH. Mean basal serum thyroid hormone concentrations in hyperthy-roid cats were significantly (P < .05) higher than concentrations in normal cats and in those with nonthyroidal disease, but there was considerable overlap among the 3 groups. After administration of TRH, mean serum T₄ concentrations increased significantly in all groups of cats, whereas mean T₃ concentrations increased significantly in normal cats and in those with nonthyroidal disease, but not in cats with hyperthyroidism. The absolute difference between mean basal and TRH-stimulated serum concentrations of T₄ in cats with hyperthyroidism (10.7 nmol/L) was significantly lower than the difference in the cats with nonthyroidal disease (20.0 nmol/L) and in clinically normal cats (28.3 nmol/L), but there was considerable overlap in values among groups. The mean value for relative change in serum T₄ concentration after TRH was significantly lower incats with hyperthyroidism (18.9%) than in those with nonthyroidal disease (110.0%) and in clinically normal cats (130.2%). Serum T₄ concentrations increased by > 50% in all normal cats and cats with nonthyroidal disease, whereas only 4(11.4%) of the 35 hyperthyroid cats had an increase of > 50% after TRH administration. On the basis of canonical discriminate analysis, the mean discriminant function score was significantly higher in the hyperthyroid cats (D = 63.8) than in cats with nonthyroidal disease (D = 5.9) or clinically normal cats (D = 0.7). All cats having a discriminant function score > 30 were hyperthyroid, whereas all cats with a value < 20 were euthyroid. Adverse side effects associated with administration of TRH were common and included transient vomiting, salivation, tachypnea, and defecation. Results of this study indicate that the TRH stimulation test is a useful aid in the diagnosis of hyperthyroidism in cats when basal serum T₄ concentrations are high-normal or only slightly high. As a diagnostic test, the TRH stimulation test compares favorably with the T₃ suppression test but requires less time and is more convenient to perform.     

Circadian variations of serum thyroxine, free thyroxine and 3,5,3'triiodothyronine concentrations in healthy dogs

This study was to determine the daily fluctuation of serum thyroxine (tT₄), free thyroxine (fT₄), 3,5,3''-triiodothyronine (T₃) concentrations in healthy dogs. Thyroid function of these dogs was evaluated on the basis of results of TSH response test. Samples for the measurement of serum tT₄, fT₄, and T₃ concentrations were obtained at 3-hour intervals from 8 : 00 to 20 : 00. Serum tT₄, fT₄, and T₃ concentrations were measured by the enzyme chemiluminescent immunoassay (ECLIA). Mean T₃ concentrations had no significant differences according to the sample collection time during the day. Mean tT₄ and fT₄ concentrations at 11 : 00 were 3.28 ± 0.86 µg/dl and 1.30 ± 0.37 ng/dl, respectively and mean tT₄ and fT₄ at 14:00 were 3.54 ± 1.15 µg/dl and 1.35 ± 0.12 ng/dl, respectively. These concentrations were significantly high compared with tT₄ and fT₄ concentrations at 8:00, which were 1.75 ± 0.75 µg/dl and 0.97 ± 0.25 ng/dl, respectively (p < 0.05). According to the sample collection time, mean tT₄ and fT₄ concentrations changed with similar fluctuation during the day. Based on these results, it was considered that measurement of serum tT₄ and fT₄ concentrations from 11 : 00 to 14 : 00 might more easily diagnose the canine hypothyroidism in practice.     

Effect of Long-distance Road Transport on Thyroid and Adrenal Function and Haematocrit Values in Limousin Cattle: Influence of Body Weight Decrease

The purpose of this study was to evaluate the effect of long-distance road transport as a relevant stressor on total and free iodothyronines, cortisol levels and haematocrit values in 10 male Limousin cattle. Serum T₃,T₄,fT₃,fT₄ and cortisol concentrations were analysed by immunoenzymatic assays. Serum cortisol levels and haematocrit modifications were also evaluated on the basis of percentage body weight decrease. The results showed a general increase of total and free iodothyronines and cortisol levels after short-and long-distance road transport and a decrease 15 days after transport, as compared to basal values. Significant positive correlations between T₃ and T₄, between T₃ and fT₃, and between T₄ and fT₄ were found. These results suggest that transport stress induces an increase in the activity of thyroid and adrenal function in Limousin cattle that is evident after even a short-distance road transport and continues to increase after long-distance transport.     

Changes of Circulating Total and Free Iodothyronine in Horses After Competitive Show Jumping With Different Fence Height

The effect of exercise on circulating T₃, T_4, free (f) T₃, and fT₄ concentrations were studied before and after competitive show jumping in 24 trained jumper horses with an age range of 11–13 years and having the same level of show experience. All horses, randomly divided into three groups paired by gender, participated in three competition levels with the same circuit design over 10 fences, with five upright and five cross-pole fences .The three fence height groups were group I (n = 8), 1.10 m; group II (n = 8), 1.20 m; and group III (n = 8), 1.30 m. Repeated measures analysis of variance showed a statistically significant effect of competitive exercise on fT₃ changes in all groups, whereas the effect of competitive exercise on T₃ changes was exclusively seen in group III. Two-way repeated measures analysis of variance showed that the effect of fence height (P = .0002) and performance results were significant (P = .0486) only for T₃ changes. Performance also affected fT₃ changes (P = .0152). No significant correlation was found between total and free iodothyronines. These results suggest a dependence of T₃ and fT₃ changes on exercise-related variables and performance results and that the thyroid response is different with respect to the different exercise-related variables, such as the varying level of difficulty and performance results.     

Pharmacokinetics of clomipramine in dogs following single-dose and repeated-dose oral administration

OBJECTIVE: To determine pharmacokinetics of clomipramine and its principle metabolite (desmethylclomipramine) in the plasma of dogs following single-dose and repeated-dose oral administration at various dosages. ANIMALS: 9 male and 9 female Beagles. PROCEDURES: Clomipramine was administered orally at a dose of 1, 2, or 4 mg/kg to 3 male and 3 female dogs, first as a single dose and then, after an interval of 14 days, twice daily for 10 days. Plasma clomipramine and desmethylclomipramine concentrations were measured by use of a gas chromatography with mass-selection method. RESULTS: Dose-related accumulation was detected following repeated-dose administration. Accumulation ratios after administration of clomipramine at dosages of 1, 2, and 4 mg/kg twice daily were 1.4, 1.6, and 3.8, respectively, for clomipramine and 2.1, 3.7, and 7.6, respectively, for desmethylclomipramine. Terminal half-life increased slightly (1.6-fold for clomipramine and 1.2-fold for desmethylclomipramine) with repeated-dose administration but remained short in all groups (< or = 4 hours). Steady state was reached within 4 days in all animals. Ratios of the areas under the concentration versus time curves from time 0 to 12 hours for clomipramine and desmethylclomipramine were 3.9, 3.1, and 1.5 after repeated administration at dosages of 1, 2, and 4 mg/kg every 12 hours, respectively. Areas under the concentration versus time curve, mean residence times, and terminal half-lives were not significantly different between male and female dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Repeated administration of clomipramine results in higher concentrations of clomipramine than desmethylclomipramine in dogs.     

Evaluation of the effects of clomipramine on canine thyroid function tests

To evaluate the effect of long-term clomipramine administration on the hypothalamic-pituitary-thyroid axis in healthy dogs, 14 healthy adult dogs were enrolled in a prospective study. Clomipramine (3 mg/kg PO q12h) was administered to all dogs beginning on day 0, and continued for 112 days. Serum total thyroxine (T4), free thyroxine (fT4), 3,5,3'-triiodothyronine (T3), 3,3',5'-triiodothyronine (reverse T3; rT3), and thyroid-stimulating hormone (TSH) were measured on days 0, 7, 28, 42, 56, and 112. Thyrotropin-releasing hormone (TRH) response tests were performed concurrently. Significant decreases were noted in serum T4, f4, and rT3 concentrations beginning on day 28 through the end of the study period. The lowest mean (+/-SEM) concentrations of T4 (26 +/- 1.2 to 17 +/- 0.5 nmol/L) and rT3 (1.21 +/- 0.13 to 0.83 +/- 0.08 nmol/L) occurred at day 112, whereas the lowest mean fT4 (29 +/- 2.4 to 18 +/- 1.7 pmol/L) was found on day 56 of clomipramine treatment. The effect of treatment over time on serum T3 concentration also was significant, but the deviation in T3 from baseline was variable. No significant effect of clomipramine treatment was noted on either pre- or post-TRH TSH concentrations. The 35 and 38% decreases in serum T4 and fT4 concentrations, respectively, during clomipramine administration may lead to a misdiagnosis of hypothyroidism. Although no evidence of hypothyroidism was noted in this study population, subclinical hypothyroidism may have occurred. A longer duration of treatment might further suppress thyroid function, and concurrent illness or other drug administration might exacerbate clomipramine's effects.     

Influence of Isoflurane General Anesthesia or Anesthesia and Surgery on Thyroid Function Tests in Dogs

Background: Anesthesia and surgery affect thyroid function tests in humans but have not been studied in dogs. Hypothesis: Anesthesia and anesthesia with surgery will affect thyroid function tests in dogs. Animals: Fifteen euthyroid dogs. Methods: Prospective, controlled, interventional study. Dogs were assigned to one of 3 groups: control, general anesthesia, and general anesthesia plus abdominal exploratory surgery. Dogs in the anesthesia and surgery groups were premedicated with acepromazine and morphine, induced with propofol, and maintained on isoflurane. Samples for measurement of serum thyroxine (T₄), free T₄ (fT₄) by equilibrium dialysis, triiodothyronine (T₃), reverse T₃ (rT₃), and thyroid‐stimulating hormone concentrations were collected from each dog immediately before premedication, at multiple times during anesthesia, surgery, 4, 8, 12, 24, 36, and 48 hours after anesthesia, once daily for an additional 5 days, and once 14 days after anesthesia. Sampling was performed at identical times in the control group. Results: Serum T₄ decreased significantly from baseline in the surgery and anesthesia groups compared with the control group at 0.33 (P= 0.043) and 1 hour (P= 0.018), and 2 (P= 0.031) and 4 hours (P= 0.037), respectively, then increased significantly in the surgery group compared with the control group at 24 hours (P= 0.005). Serum T₃ decreased significantly from baseline in the anesthesia group compared with the control group at 1 hour (P= 0.034). Serum rT₃ increased significantly from baseline in the surgery group compared with the control and anesthesia groups at 8 (P= 0.026) and 24 hours (P= 0.0001) and anesthesia group at 8, 12, 24, and 36 hours (P= 0.004, P= 0.016, P= 0.004, and P= 0.014, respectively). Serum fT₄ increased significantly from baseline in the surgery group compared to the control at 24 hours (P= 0.006) and at day 7 (P= 0.037) and anesthesia group at 48 hours (P= 0.023). Conclusions and Clinical Importance: Surgery and anesthesia have a significant effect on thyroid function tests in dogs.     

Evaluation of Thyroid‐Stimulating Hormone,Total Thyroxine,and Free Thyroxine Concentrations in Hyperthyroid Cats Receiving Methimazole Treatment

Background

Iatrogenic hypothyroidism (IH) after treatment of hyperthyroidism can impair renal function. No study compared the efficacy of measurement of serum free thyroxine by equilibrium dialysis (fT4ed) or thyroid‐stimulating hormone (TSH) concentrations for monitoring cats receiving methimazole.

Objectives

To (1) compare the ability of total T4 and fT4ed concentrations in conjunction with TSH to define thyroid function in hyperthyroid cats receiving methimazole, (2) determine the prevalence of IH in cats receiving methimazole, and (3) examine the relationship between thyroid axis hormones and serum creatinine concentration.

Animals

One hundred and twenty‐five serum samples from hyperthyroid cats receiving methimazole and total T4 concentrations ≤3.9 μg/dL.

Methods

Total T4, fT4ed, and TSH concentrations were measured to evaluate thyroid status and serum creatinine concentration was measured to assess renal function. A low total T4 or fT4ed concentration in combination with an increased TSH concentration defined IH.

Results

Forty‐one cats (33%) had increased TSH concentrations. Of cats with total T4 and fT4ed concentrations below the reference range, 68% and 73%, respectively, had TSH concentrations above the reference range. Only 18% of cats with a normal TSH concentration had an increased serum creatinine concentrations as compared to 39% of those with increased TSH concentrations (P < .001).

Conclusions

Free T4ed does not identify more cats with potential IH as compared to total T4. The IH prevalence was approximately 20%. Measurement of TSH may be more helpful in indicating that azotemia, if present, is at least in part related to IH. Investigation is needed to define TSH assay utility in identifying possible subclinical IH.     

Pharmacokinetics of clomipramine in dogs following single-dose intravenous and oral administration

OBJECTIVE: To determine pharmacokinetics of clomipramine and its principle metabolite (desmethylclomipramine) in the plasma of dogs after IV or oral administration of a single dose. ANIMALS: 6 male and 6 female Beagles. PROCEDURES: Clomipramine was administered IV (2 mg/kg), PO (4 mg/kg) after food was withheld for 15 hours, and PO (4 mg/kg) within 25 minutes after dogs were fed. Plasma clomipramine and desmethylclomipramine concentrations were measured by use of a gas chromatography with mass-selection method. RESULTS: Time to peak plasma concentrations of clomipramine and desmethylclomipramine following oral administration was 1.2 hours. For clomipramine, after IV administration, elimination half-life was 5 hours, mean residence time was 3 hours, and plasma clearance was 1.4 L/h/kg. Values for mean residence time and terminal half-life following oral administration were similar to values obtained following IV administration, and systemic bioavailability was approximately 20% for clomipramine and 140% for desmethylclomipramine, indicating fast absorption of clomipramine from the gastrointestinal tract and extensive first-pass metabolism. Administration of clomipramine with food did not alter the area under the concentration versus time curve for desmethylclomipramine but resulted in a 25% increase for clomipramine. Clomipramine and desmethylclomipramine were extensively bound (> 96%) to serum proteins. There were no significant differences in area under the concentration versus time curve between male and female dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that there should not be any clinically important differences in efficacy regardless of whether clomipramine is administered with or without food.     

Use of clomipramine in the treatment of anxiety-related and obsessive-compulsive disorders in cats

Objective To evaluate the efficacy and tolerance of a treatment protocol for anxiety-related and obsessive-compulsive disorders in cats.
Design A study was undertaken to assess the clinical response in cats diagnosed with anxiety-related or obsessive-compulsive disorders to a treatment regimen that included clomipramine and behaviour modification.
Procedure The study group of 11 cats was acquired through referral. A detailed behavioural and clinical history was obtained. Presenting signs were urine spraying in seven cases, overgrooming in three and excessive vocalisation in one. Clomipramine was administered orally once daily. The mean starting dose was 0.4 mg/kg. If necessary, the dose was adjusted according to the clinical response of each cat. A behaviour modification program was designed and the owner instructed on its implementation. Cats were to continue on medication for at least 1 month after clinical signs disappeared, then medication withdrawal was to be attempted by decreasing the clomipramine dose progressively at weekly intervals while the behaviour modification program continued.
Results In all cases the presenting clinical sign was largely improved or disappeared. One cat was removed from the study by the owner. Four cats became lethargic at higher doses, but this resolved when the clomipramine dose was reduced. The average maintenance dosage was 0.3 mg/kg once daily. Clomipramine withdrawal was attempted in two cases: the behaviour returned in one case and the medication was reinstated at 0.3 mg/kg twice daily.
Conclusion Clomipramine was effective in controlling the signs of anxiety-related and obsessive-compulsive disorders in 10 of 10 assessable cases when used in combination with behaviour modification. Clomipramine was well tolerated.     

Effect of a Limited Iodine Diet on Iodine Uptake by Thyroid Glands in Hyperthyroid Cats

Background

The effect of feeding a limited iodine diet on radioactive iodine uptake in the thyroid glands of hyperthyroid cats is unknown.

Objectives

To determine how feeding limited dietary iodine affects radioactive iodine uptake by the thyroid glands of hyperthyroid cats.

Animals

Eight geriatric cats with spontaneous hyperthyroidism.

Methods

Prospective study of eight client owned hyperthyroid cats fed a commercially available iodine limited diet for 6 months. Clinical signs were evaluated and TT4 and fT4 were measured during consumption of the diet. Uptake of ¹²³I was determined before and 8–16 weeks after exclusive consumption of the diet.

Results

Clinical signs of hyperthyroidism resolved in all cats, but there was no significant increase in body weight. TT4 and fT4 decreased into the reference range by 8–16 weeks in all cats. Mean TT4 before consumption of the diet was 9.7 μg/dL (SD 5.2) and after consumption of the diet was 3.1 μg/dL (SD 0.9). Scintigraphy revealed unilateral uptake of isotope in 5 cats and bilateral uptake in 3 cats. Mean percentage uptake of ¹²³I by the thyroid gland at 8 hours after isotope administration was 16.2 (SD 11.8) before diet consumption and 34.6 (SD 11.7) 8–16 weeks after exclusive consumption of the diet. The percentage increase was variable between cats (38–639%).

Conclusions and clinical importance

Limited iodine diets increase iodine uptake in the autonomous thyroid glands of hyperthyroid cats. Further studies are necessary to determine if consumption of a limited iodine diet changes sensitivity of the thyroid gland to ¹³¹I treatment.     

The prevalence of hypocobalaminaemia in cats with spontaneous hyperthyroidism

Objectives : To determine the prevalence of hypocobalaminaemia in cats with moderate to severe hyperthyroidism and to investigate the relationship between cobalamin status and selected haematologic parameters. Methods : Serum cobalamin concentrations were measured in 76 spontaneously hyperthyroid cats [serum thyroxine (T₄) concentration ≥100 nmol/L] and 100 geriatric euthyroid cats. Erythrocyte and neutrophil counts in hyperthyroid cats with hypocobalaminaemia were compared with those in hyperthyroid cats with adequate serum cobalamin concentrations (≥290 ng/L). Results : The median cobalamin concentration in hyperthyroid cats was lower than the control group (409 versus 672 ng/L; P=0·0040). In addition, 40·8% of hyperthyroid cats had subnormal serum cobalamin concentrations compared with 25% of controls (P=0·0336). Weak negative correlation (coefficient: –0·3281) was demonstrated between serum cobalamin and T₄ concentrations in the hyperthyroid population, and the median cobalamin concentration was lower in cats with T₄ above the median of 153 nmol/L compared with cats with T₄ below this value (P=0·0281). Hypocobalaminaemia was not associated with neutropenia or anaemia in hyperthyroid cats. Clinical Significance : This study indicates that a substantial proportion of cats with T₄≥100 nmol/L are hypocobalaminaemic and suggests that hyperthyroidism directly or indirectly affects cobalamin uptake, excretion or utilisation in this species.     

Carbimazole therapy of feline hyperthyroidism

The efficacy and safety of carbimazole (CBZ) was studied in a series of 45 hyperthyroid cats. CBZ was used before surgical thyroidectomy in 34 cats, at a dose of 5 mg administered orally every eight hours. Biochemical euthyroidism, as assessed by a decrease in serum total thyroxine (T₄) concentrations into the reference range, was achieved in 31 cats (91 per cent) within a mean (± SD) of 5–7 (± 2–9) days (range, three to 15 days). Clinical evidence of euthyroidism tended to lag behind biochemical evidence but was usually apparent after 14 days. Continuing therapy tended to decrease serum total T₄ but not serum total triiodothyronine (T₃) concentrations below the reference range but clinical evidence of hypothyroidism was not apparent. In five additional cats, 5 mg CBZ was administered three times between 08.00 and 20.00 hours. Euthyroidism was achieved in only one cat after 14 days, emphasising the need for eight hourly dosing. Clinically observable side effects developed in five cats (13 per cent), two to three weeks after commencing therapy and included vomiting (n y 2) and vomiting and anorexia (n = 3). In three cases withdrawal of CBZ was required. Mild and transient haematological abnormalities developed in two cats (one case each of lymphocytosis and leucopenia). There were significant decreases in serum concentrations of alanine aminotransferase and alkaline phosphatase in those cats achieving euthyroidism (P < 0–001 in each case) but not in those that remained hyperthyroid despite CBZ therapy (P ± 0–05 in each case). CBZ was used as the sole therapy for the condition in eight cats for between four and 65 weeks. A consistent dosage of 5 mg CBZ administered twice daily was necessary to maintain euthyroidism. Adverse reactions were not noted. Chronic medical management tended to depress serum total T₄ concentrations below the reference range. Corresponding serum total T₃ concentrations remained within the reference range on 15 (88 per cent) of 17 occasions and may explain why the animals appeared clinically euthyroid. CBZ appears to be a safe and effective drug both in the short and long term management of feline hyperthyroidism and can be recommended as the current drug of choice in the UK.     

Pharmacokinetics of clomipramine and desmethylclomipramine after single-dose intravenous and oral administrations in cats

A cross-over study was performed in six adult spayed cats to determine the pharmacokinetics of clomipramine and its metabolite, desmethylclomipramine (DCMP) after intravenous (0.25 mg/kg) and oral (0.5 mg/kg) single-dose administrations. Plasma clomipramine and DCMP were measured by high-performance liquid chromatography at regular intervals for up to 30 h. Intravenous clomipramine best fit a two-compartmental model yielding an elimination rate constant of 0.037-0.09 h(-1) from which a mean half-life of 12.3 h was calculated. Mean clomipramine AUC(0--infinity) (ngxh/mL), clearance (L/hxkg), V(ss) (L/kg) and MRT (h) values were 652.5, 0.393, 5.0, and 13.5, respectively. Compartmental modeling for clomipramine, after oral administration, and DCMP after both administrations, produced wide parameter estimates and plots of residuals indicated poor goodness of fit. Noncompartmental analysis yielded mean AUC(0--30 h) (ngxh/mL), C(max) (ng/mL) and T(max) (h) of 948.3, 87.5 and 6.2 for clomipramine, and 613.8, 34.8, and 12.8 for DCMP respectively after oral administration. Clomipramine bioavailability was 90%. The present study showed marked pharmacokinetic variability for clomipramine and DCMP through biphasic absorption and potential genetic variability in clomipramine metabolism. It was concluded that population pharmacokinetics would allow better characterization of clomipramine variability that may explain the variability in clinical response noted in cats.     

Single and multiple dose pharmacokinetics of a novel mirtazapine transdermal ointment in cats

Single and multiple dose pharmacokinetics (PK) of mirtazapine transdermal ointment applied to the inner ear pinna of cats were assessed. Study 1 was a randomized, cross‐over single dose study (n = 8). Cats were treated once with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner ear pinna (treatment) or administered orally (control) and then crossed over after washout. Plasma was collected predose and at specified intervals over 96 hr following dosing. Study 2 was a multiple dose study (n = 8). Cats were treated daily for 14 days with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner pinna. Plasma was collected on Day 13 predose and at specified intervals over 96 hr following the final dose. In Study 1, single transdermal administration of mirtazapine resulted in mean T_max = 15.9 hr, C_max = 21.5 ng/mL, AUC_0‐24 = 100 ng*hr/mL, AUC_0‐∞ = 260 ng*hr/mL and calculated half‐life = 26.8 hr. Single oral administration of mirtazapine resulted in mean T_max = 1.1 hr, C_max = 83.1 ng/mL, AUC_0‐24 = 377 ng*hr/mL, AUC_0‐∞ = 434 ng*hr/mL and calculated half‐life = 10.1 hr. Mean relative bioavailability (F) of transdermal to oral dosing was 64.9%. In Study 2, daily application of mirtazapine for 14 days resulted in mean T_max = 2.1 hr, C_max = 39.6 ng/mL, AUC_0‐24 = 400 ng*hr/mL, AUC_0‐∞ = 647 ng*hr/mL and calculated half‐life = 20.7 hr. Single and repeat topical doses of a novel mirtazapine transdermal ointment achieve measurable plasma concentrations in cats.     

Control of urine marking by use of long-term treatment with fluoxetine or clomipramine in cats

OBJECTIVES: To determine whether clomipramine differs from fluoxetine in reducing feline urine marking; whether reduction of marking continues in cats treated >8 weeks; whether recurrence of marking, after abrupt drug withdrawal, is less in cats treated >8 weeks; and whether cats that are successfully treated but resume marking after drug withdrawal can be successfully treated again with the same drug regimen. DESIGN: Positive-controlled, double-masked clinical trial. ANIMALS: 22 neutered cats (2 females, 20 males) > or =1 year old with objectionable urine marking. PROCEDURE: Cats that marked vertically > or =3 times/wk were treated with fluoxetine (1 mg/kg [0.45 mg/lb], q 24 h, PO) or clomipramine (0.5 mg/kg [0.23 mg/lb], q 24 h, PO) for 16 weeks, and efficacy was compared. Recurrence of marking was determined after abrupt withdrawal of fluoxetine at 16 or 32 weeks. Reduction in marking in cats treated with fluoxetine for 8 weeks after returning to marking following drug withdrawal was compared with the initial 8 weeks of successful treatment. RESULTS: Efficacy of fluoxetine and clomipramine was similar. Treatment >8 weeks revealed increasing efficacy in reduction of marking. Return of marking after termination of fluoxetine administration occurred in most cats. Cats successfully treated initially with fluoxetine responded similarly to repeated treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Clomipramine and fluoxetine were equivalent in treating urine marking. Longer treatment increased efficacy. Most cats return to marking after abrupt drug withdrawal. A second course of treatment can be expected to be as effective as the first.     

Placebo-controlled double-blind clomipramine trial for the treatment of anxiety or fear in beagles during ground transport

The purpose of this explorative study was, first, to document changes in physiological parameters and behavior observed in dogs following ground transport and, second, to measure the effects on the above variables of a short-term administration of clomipramine, anecdotally already prescribed in private veterinary practice to reduce fear, anxiety, or both. Twenty-four beagles were randomly allocated to either clomipramine (2 mg/kg, q12h for 7 d) or placebo treatment, and then transported 3 times in a truck for 1 hour. Physiological parameters (cortisol, neutrophil:lymphocyte (N:L) ratio, heart rate) and behavior were recorded and analyzed. Clomipramine significantly reduced plasma cortisol (P < 0.05) following transport and tended (P = 0.07) to reduce N:L ratio. Clomipramine tended to only reduce "moving and panting" and drooling. Short-term administration of clomipramine appears to slightly reduce fear, anxiety, or both during transport. More research is needed to confirm the efficacy of this treatment and the appropriate dosage.     

Physiopathological Effects of the Administration of Chronic Cyanide to Growing Goats – A Model for Ingestion of Cyanogenic Plants

Ingestion of cyanogenic plants, such as cassava and sorghum, has been associated with goitre and tropical pancreatic diabetes in both humans and animals. Thus, the objective of the present study was to determine the toxic effects on the thyroid and pancreas in growing goats of prolonged exposure to potassium cyanide (KCN). Thirty-four male goats were divided into five groups dosed with KCN at 0 (control), 0.3, 0.6, 1.2 or 3.0 mg/kg daily for 5 months. Blood samples were obtained in order to determine the glucose, cholesterol, thyroxine (T₄), triiodothyronine (T₃) and thiocyanate concentrations and for haematological studies; pancreas and thyroid gland were collected for histopathological study. The group receiving the highest dose of cyanide showed lower body weight gains and carcase weights and a decrease in plasma T₃ concentrations compared to the control group. Reabsorption vacuoles in follicular colloid and normocytic normochromic anaemia were observed in the experimental animals. Inhibition of peripheral conversion of T₄ to T₃ is suggested. However, no diabetogenic effects were observed.