Methimazole Treatment of 262 Cats With Hyperthyroidism

Transcription

1 Methimazole Treatment of 262 Cats With Hyperthyroidism Mark E. Peterson, DVM, Peter P. Kintler, DVM, and Arthur I. Hurvitz, CVM, PhD The efficacy and safety of the antithyroid drug methimazole were evaluated over a 3-year period in 262 cats with hyperthyroidism. In 181 of the cats, methimazole was administered for 7 to 130 days (mean, 27.7 days) as a preoperative preparation for thyroidectomy. The remaining 81 cats were given methimazole for 30 to 1,000 days (mean, 228 days) as sole treatment for the hyperthyroid state. After 2 to 3 weeks of methimazole therapy (10 to 15 mg/d), the mean serum thyroxine (T4) concentration decreased significantly (P < 0.001) from a pretreatment value of 12.1 Kg/dl to 2.1 Wg/dl. The final maintenance dose needed to maintain euthyroidism in the 81 cats that were given methimazole as sole treatment for hyperthyroidism ranged from 2.5 to 20 mg/d (mean, 11.9 mg/d). Clinical side effects developed in 48 (18.3%) cats (usually within the first month of therapy), which included anorexia, vomiting, lethargy, self-induced excoriation of the face and neck, bleeding diathesis, and icterus caused by hepatopathy. Mild hematolvgic abnormalities developed in 43 (16.4%) cats (usually within the first 2 months of treatment), which included eosinophilia, lymphocytosis, and slight leukopenia. In ten (3.8%) cats, more serious hematologic reactions developed including agranulocytosis and thrombocytopenia (associated with bleeding). These hematologic abnormalities resolved within 1 week after cessation of methimazole treatment. Immunologic abnormalities associated with methimazole treatment included the development of antinuclear antibodies in 52 of 238 (21.8%) cats tested and red cell autoantibodies (as evidenced by positive direct antiglobulin tests) in three of 160 (1.9%) cats tested. These immunologic reactions were not associated with evidence of immune-mediated hemolytic anemia or lupus-like syndrome in any of the cats. Tlie results of this study indicate that methimazole is effective in blocking excess thyroid hormone secretion in cats with hyperthyroidism. In addition, although not entirely free of adverse side effects, methimazole is a relatively safe antithyroid drug for use in the cat. (Journal of Veterinary Internal Medicine 1988; 2: ) IN RECENT YEARS, hyperthyroidism has become a common and well-recognized disorder of middle-aged to older cats.'-3 Medical treatment with antithyroid drugs of the thionamide class, which act to block thyroid hormone synthesis and thereby lower high circulating thyroid hormone concentrations, can be of great value in the long-term control of the hyperthyroid Antithyroid drugs also play an important role in preop- From the Departments of Medicine (Peterson, Kintzer) and Pathology (Hurvitz), The Animal Medical Center, and the Research Animal Resource Center (Peterson), Cornell University Medical College, New York, New York. Dr. Kintzer's present address is the Department of Medicine, School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts. The authors thank Ms. Kay Allyson, Ms. Irena Cavanagh, Ms. Lisa Esposito, Mr. Thomas Graves, and Ms. Katherine James for technical assistance. Reprint requests: Mark E. Peterson, DVM, The Animal Medical Center, 510 East 62nd Street, New York, NY erative preparation for successful thyroide~tomy.~-~ Advantages of long-term antithyroid drug treatment over other available treatment modalities (surgery and radioactive iodine) include absence of certain complications such as permanent hypothyroidism and postsurgical hyp~parathyroidism.~ In addition, unlike surgery or radioiodine, use of antithyroid drugs requires no advanced skills, training, or special licensing. Therefore, it is a practical treatment choice for most practitioner^.^ Propylthiouracil (PTU) and methimazole are the two thionamide antithyroid drugs available for use in the United States. We have previously reported that the use of PTU for the treatment of feline hyperthyroidism will, in most cases, effectively lower circulating thyroid hormone concentrations to within normal range.6 In the cat, however, PTU produces a high incidence of mild to severe side effects, which include vomiting, anorexia, lethargy, thrombocytopenia, immune-mediated hemolytic anemia, and the development of serum antinuclear 150

2 METHIMAZOLE TREATMENT OF CATS WITH HYPERTHYROIDISM n " Pre - Rx cs m 0 Post - Rx FIG. I. Serum T4 concentrations in 262 cats with hyperthyroidism before and 2 to 3 weeks after treatment with methimazole (10 to 15 mg/d). Horizontal lines indicate mean values. antibodie~.~.~ The complications associated with PTU treatment prompted a prospective evaluation of the efficacy and safety of methimazole in the cat. The purpose of this 3-year study is to report the results of methimazole treatment in 262 cats with hyperthyroidism. Materials and Methods From June 1983 through June 1986, we used methimazole* in the treatment of 262 hyperthyroid cats examined at The Animal Medical Center. In 181 (69%) of these 262 cats, methimazole was used as preoperative preparation for thyroidectomy, whereas the remaining 81 cats received methimazole as sole (primary) treatment of the hyperthyroid state. The choice of treatment (surgery versus long-term methimazole administration) was based on owner preference. Hyperthyroidism was tentatively diagnosed on the basis of history and results of physical examination, and was confirmed by demonstrating elevated serum concentrations of thyroxine (T4).I In 101 cats, serum triio- dothyronine (T3) also was determined to aid in diagnosis. The cats ranged in age from 5 to 20 years (mean f standard deviation [SD], 13.5? 2.5 years). Two hundred thirty-five cats (90%) were of mixed breeding (Domestic Long-haired and Short-haired). Other breeds included Siamese (n = 13), Persian (n = 7), Russian Blue (n = 3), Manx (n = 2), Burmese (n = I), and Maine Coon (n = 1). One hundred forty-one (54%) of the cats were female and 121 were male. All except nine females and eight males were neutered. Treatment with methimazole was initiated at a daily dosage of 10 to 15 mg orally administered in two to three divided doses. The cats were examined at 2-week to 3-week intervals during the first 3 months of treatment, and at 2-month to 3-month intervals thereafter. At the time of each examination, the owners were questioned regarding resolution of clinical signs and development of adverse side effects. To monitor for adverse reactions and evaluate the effectiveness of methimazole therapy, blood for a complete blood count (CBC), platelet count, direct antiglobulin test (DAT), and for determination of serum antinuclear antibodies (ANAs) and serum T4 concentration also was collected at examination time. in addition, serum biochemical testing was performed on cats in which severe illness developed (e.g., anorexia, vomiting, dehydration, and icterus) during methimazole treatment. In 50 of the cats in which a subnormal T4 concentration (<0.8 pg/dl) developed during treatment, a T3 concentration also was measured in the same serum sample. In those cats in which the drug was used as preoperative preparation, surgical thyroidectomy was performed once serum T4 concentrations had decreased to low or normal values (methimazole was discontinued on the day of surgery). In the cats in which methimazole was used as long-term therapy, the daily methimazole dose was adjusted by 2.5-mg to 5-mg increments as needed to maintain circulating T4 concentrations within low-normal range (0.8 to 2.5 PLg/dl). Serum T4 and T3 were measured by radioimmunoassay as previously rep~rted.~ Complete blood and platelet counts were performed using standard methods. Serum biochemical testing was performed using an autoanalyzer. Direct antiglobulin (Coombs') tests were performed using commercial feline IgG and C3 antiglobulin reagent.? Serum ANA were determined by indirect immunofluorescence using HeLA cells and either fluorescein-conjugated rabbitt or goat$ antiserum to cat IgG. All results are given as the mean +SD. Statistical analyses were performed using Student's paired and unpaired t tests. A P value of 0.05 or less was considered significant. lo * Tapazole, Eli Lilly and Co., Indianapolis, IN. t Miles Scientific, Division of Miles Laboratories, Naperville, IL. 4 Cappel Laboratories, Cochranville, PA.

3 131 PETERSON ET AL. Journal of Veterinary Internal Medicine Results After the first 2 to 3 weeks of therapy using a methimazole dosage of 10 to 15 mg/d, mean serum T4 concentration decreased significantly (P < 0.001) from a pretreatment value of 12.1 * 6.5 pg/dl to 2.1 k 3.2 pg/dl (Fig. 1). Serum T4 concentrations were below normal range in 92 (35.1%) of the 262 cats and remained above normal range in 33 (12.6%) cats at the time of this first recheck (Fig. 1). Of the cats with hyperthyroid values at the time of the initial recheck, the serum T4 concentrations decreased to normal or low values in all but two cats when reexamined 2 to 3 weeks later while receiving a dose of 15 mg/d (n = 25) or 20 mg/d (n = 8). These two cats remained clinically and biochemically hyperthyroid despite continued treatment with 20 mg of methimazole per day for periods of 50 and 60 days. Histopathologic examination of the excised thyroid lobes confirmed adenomatous hyperplasia in both of these cats. In 181 (69%) of the 262 cats, methimazole was administered for 7 to 130 days (mean, 27.7 * 17.9 days; median, 21 days) as preoperative preparation for thyroidectomy. The methimazole dosage in these cats ranged from 10 to 20 mg/d (mean, 14.7 f 2.1 mg/d; median, 15 mg/d). In all of these cats, this total daily methimazole dose was administered as two to three divided doses. The remaining 8 1 cats were given methimazole for 30 to 1,000 days (mean, 228 k 202 days; median, 160 days) as sole treatment of the hyperthyroid state. The final maintenance dosage required to maintain euthyroidism in these 8 1 cats ranged from 2.5 to 20 mg/d (mean, k 4.4 mg/d median, 10 mg/d). This total daily methimazole dose was given as either a single daily dose or divided into two daily doses. Only in one cat could long-term control of the hyperthyroid state be maintained with a dosage of 2.5 mg/d. The remaining 80 cats required a methimazole dosage of at least 5 mg/d. Daily administration of methimazole was necessary to maintain serum T4 concentrations within normal range. In 12 cats given long-term methimazole treatment in which the drug was discontinued for 2 days and serum T4 values again determined, circulating T4 increased into the hyperthyroid range in all cats (Fig. 2). The mean T4 value (9.5 -t 4.8 pg/dl) 2 days after cessation of methimazole was not significantly different than pretreatment concentrations (1 1.8 f 6.2 pg/dl). Figure 3 shows serial serum T4 concentrations determined in the 64 cats that were given methimazole as sole treatment of the hyperthyroid state for longer than 100 days. Although the mean serum T4 value remained within normal range at all testing intervals, 2 1 of the cats had T4 concentrations that were above normal on one to four occasions. In contrast, subnormal serum T4 concentrations developed in 30 cats on one to three occa \ - 0 a Y 12 v - t- E - 2 al * 8-4 " ~ Pre -Rx Post - R x Off-Rx FIG. 2. Serum T4 concentrations in 12 cats with hyperthyroidism before treatment, after treatment with methimazole, and 2 days after cessation of methirnazole therapy. sions during long-term treatment (Fig. 3). However, clinical signs of hypothyroidism were not observed in any of these cats. In accordance with this, serum T3 concentrations, determined in 50 samples with low serum T4 concentrations (mean, 0.4 * 0.7 pg/dl; normal, 0.8 to 4.0 pgldl), were normal and ranged from 33 to 115 ng/dl (mean, 65 f 17.6 ng/dl; normal, 25 to r ' (641 (641 (641 (641 (46) (33) (18) (71 (21 (2) Time (months) FIG. 3. Serum T4 concentrations in 64 cats with hyperthyroidism before and during long-term treatment with methimazole. Horizontal lines indicate mean values. Numbers in parentheses indicate number of cats treated during each time period.

4 VOI. 2. NO. 3 METHIMAZOLE TREATMENT OF CATS WITH HYPERTHYROIDISM 153 TABLE 1. Clinical Side Effects and Hematologic and Immunologic Abnormalities Associated With Methimaxole Treatment in 262 Cats With Hyperthyroidism Time When Signs Developed (Days) Dose When Signs Developed (mg/d) No. of Cats Sign ("/.I Range Mean t SD Median Range Mean f SD Median Anorexia Vomiting lethargy Excoriations Bleeding Hepatopathy Thrombocytopenia Agranulocytosis leukopenia Eosinophilia lymphocytosis ANA* Positive DATt 29 (1 1.1) 28 (10.7) 23 (8.8) 6 (2.3) 6 (2.3) 4 (1.5) 7 (2.7) 4 (1.5) 12 (4.7) 30 (1 1.3) 19 (7.2) 52 (21.8) 3 (1.9) f f f f k f f f f f f ? f I ? f f f f f 2.5 f 2.7 f f f f f f ANAs: antinuclear antibodies; DAT: direct antiglobulin test; SD: standard deviation. 'Determined in 239 cats. t Performed in 160 cats. ng/dl). All 64 cats that were treated with methimazole for longer than 100 days were judged by their owners to have a fair to excellent clinical response. Clinical side effects developed in 48 (1 8.3%) of the 262 cats and included anorexia, vomiting, lethargy, selfinduced excoriations of the face and neck, bleeding diathesis, and icterus associated with hepatopathy (Table 1). In most cats, gastrointestinal signs developed during the first month of therapy (Table 1) and resolved despite continued treatment. In eight cats, however, anorexia and vomiting persisted until methimazole treatment was discontinued. Similarly, although the facial and cervical excoriations that developed in six cats were partially responsive to treatment with glucocorticoids, cessation of methimazole was required in all cases. The bleeding diathesis (epistaxis or oral bleeding) associated with thrombocytopenia (see below) in five of six cats resolved within 5 days after cessation of methimazole. In the remaining cat, the cause of the bleeding diathesis (initiated by venipuncture) was unknown. In all of the cats in which bleeding developed, drug administration was stopped and none were rechallenged with methimazole. A hepatopathy developed in four cats within the first 2 months of treatment and was characterized by sharp increases in serum concentrations of alanine aminotransferase (500 to 2 I50 IU/l; normal, 10 to 80 IU/l), aspartate aminotransferase (200 to 349 IU; normal, 10 to 60 IU/l), alkaline phosphatase (165 to 422 IU/k normal, 10 to 80 IU/l), and total bilirubin (3.5 to 8.0 IU/l; normal, 0 to 0.5 IU/l), as well as clinical signs of anorexia, vomiting, lethargy, and icterus. After cessation of methimazole therapy, these clinical signs and abnormal biochemical findings resolved within 7 and 45 days, respectively. Rechallenge with the drug in one cat again induced clinical signs and serum biochemical abnormalities indicative of hepatic disease within 10 days. Results of liver biopsy examination, performed in one cat, showed hepatic degeneration and necrosis. Mild hematologic abnormalities developed in 43 (16.4%) of the 262 cats and included eosinophilia (> 1400 cellslpl), lymphocytosis (>6000 cells/pl), and leukopenia (4500 cells/pl) with a normal differential count (Table 1). These hematologic findings, which were usually noted in the first 1 to 2 months of treatment, were not associated with clinical disease and were usually transient despite continued therapy. More senous hematologic reactions developed in ten (3.8%) cats, and included agranulocytosis (severe leukopenia with a total granulocyte count <5OO/pl) and severe thrombocytopenia (platelet count <75,OOO/pl). Both agranulocytosis and thrombocytopenia developed in one cat (Table 1). In two of the seven cats with thrombocytopenia, overt bleeding had not yet occurred. These senous adverse effects developed within the first 3 months of treatment (Table I), but resolved by 7 days after cessation of methimazole administration in all cats. In one cat in which agranulocytosis developed, rechallenge with methimazole again produced severe neutropenia (44/p1) 7 days after reinstitution of the drug (Fig. 4). In general, the dose of methimazole that the cats were receiving at the time clinical and hematologic side effects developed ranged from 10 to 20 mg/d, with mean and median dosages of approximately 15 mg/d (Table 1). There did not appear to be a relationship between the development of these adverse effects and the daily methimazole dosage. Of the 160 cats tested, a positive DAT developed in three (1.9%) during treatment, consistent with the presence of anti-red blood cell (RBC) antibodies. Despite the formation of these autoantibodies, none of the cats showed any clinical or hematologic evidence of illness (i.e., hemolytic anemia).

5 154 PETERSON ET AL. Journal of Veterinaty Internal Medicine Serum ANAs were detected in 52 (21.8%) of the 238 cats that were evaluated (Table l), at titers ranging from I : I0 to 1 : 160 (median titer, I :20). The risk of developing ANAs appeared to increase with duration of methimazole treatment. In those cats treated for periods of greater than 6 months, approximately half had ANAs (Fig. 5). The risk of ANAs developing also appeared to be greater for cats treated with higher daily methimazole doses, since 37 of the 52 (71.2%) cats in which ANAs developed were receiving a dosage of greater than 15 mg/d and seven of the nine (78%) cats with a final maintenance dose of 20 mg/d had ANAs. In addition, the ANAs disappeared in seven of nine cats retested 3 to 12 weeks after their methimazole dose was decreased from 13.3 k 0.8 mg/d to 8.9 k 0.6 mg/d. Similarly, ANAs disappeared in all eight cats retested 2 to 8 weeks following thyroidectomy and the cessation of drug administration. In contrast, the ANAs persisted in 12 of the 13 cats with ANAs in which the methimazole dose was not decreased and drug treatment not discontinued. Of the 52 cats in which ANAs developed, no association between the development of ANAs and other clinical or hematologic side effects was noted. Thirty of these 52 cats had ANAs as their only side effect. None of the cats in which ANAs developed showed any signs of a lupus-like syndrome (i.e., dermatitis, glomerulonephritis, polyarthritis, hemolytic anemia, thrombocytopenia, or fever). Discussion The results of this study indicate that methimazole will effectively block thyroid hormone synthesis in most cats with hyperthyroidism, as reflected by the decreases in elevated serum thyroid hormone concentrations into the normal to low range. As compared with PTU, methimazole appears to be at least as effective in blocking thyroid hormone synthesis leading to lowered serum thyroid hormone concentrations.' In addition, although not entirely free of adverse side effects, methimazole is a relatively safe antithyroid drug for use in the cat, especially when compared with PTU.798 Therefore, methimazole can be considered the antithyroid drug of choice for both preoperative preparation and long-term treatment of feline hyperthyroidism. Several factors can influence the initial daily methimazole dosage and duration of treatment needed to restore euthyroidism in cats with hyperthyroidism. After absorption, methimazole is actively concentrated by the thyroid gland, where it acts to inhibit thyroid hormone synthesis. The drug does not block the release of stored thyroid hormone into the cir~ulation.~~" Therefore, the bioavailability (gastrointestinal absorption) of the drug, amount of absorbed drug that is concentrated within the thyroid gland, amount of preformed hormone stored within the thyroid gland, and the thyroid secretory rate, as well as the severity of hyperthyroidism and volume of I I I 'W ' Time (weeks) Normal Range FIG. 4. Total peripheral blood neutrophil concentrations in a cat showing the development of agranulocytosis during methimazole treatment. Note resolution of neutropenia after cessation of the drug and recurrence of agranulocytosis after rechallenge with methimazole. adenomatous thyroid tissue, are all factors that influence the initial methimazole dosage and time needed to reduce circulating thyroid hormone concentrations to within normal In accordance with this, although serum T4 concentrations fell to either normal or subnormal levels after the initial 2 to 3 weeks of me Time (months) FIG. 5. Percentage of cats in which serum ANAs developed during treatment with methimazole. Shaded bars represent the percentage of cats in which ANAs first developed during each time period. Unshaded bars represent total percentage of cats with ANAs during each time period. For example, of the 55 cats that did not have ANAs at the beginning of the 2-month to 4-month treatment interval, ANAs devdoped in nine cats during this period (shaded bar). Of the 65 cats treated during the same interval, 20 had ANAs. In 1 1 of these cats the ANAs developed before the 2-month to 4-month interval (unshaded bar). 1

6 VOl. 2. NO. 3 METHIMAZOLE TREATMENT OF CATS WITH HYPERTHYROIDISM 155 thimazole therapy ( 10 to 15 mg/d) in the majority of the cats of this study, T4 concentrations remained in the thyrotoxic range in approximately 10% of cases. Serum T, concentrations were normal in most of these cats when retested after a longer treatment period (2 to 3 weeks later), and, in some of the cases, after an increase in the methimazole dosage to 20 mg/d. In two cats, however, only slight decreases in the elevated serum T4 concentrations occurred after prolonged treatment despite an increase in the daily methimazole dosage to 20 mg. Although the cause(s) for this apparent resistance to methimazole is unclear, both of these cats had extremely elevated pretreatment serum T4 concentrations, as well as large thyroid nodules. It is possible that an even higher daily dosage of methimazole would have been required to adequately block thyroid hormone secretion from the large mass of adenomatous thyroid tissue in these two cats. Subnormal serum T4 concentrations developed on one or more occasions during methimazole treatment in many of the cats of this study. Despite low circulating T4 values, serum T3 concentrations usually remained within the normal range in these cats. Because T3 appears to be the most metabolically active thyroid horrnone,l'-i3 the normal serum T3 concentrations would explain the absence of clinical signs of hypothyroidism. The reason for the development of low serum T4 concentrations while maintaining normal serum T3 values in hyperthyroid cats during methimazole treatment is unknown. In both the normal and hyperthyroid states, a considerable amount (40% to 60%) of circulating T3 is derived from the peripheral deiodination of T4.1'.'2,'4 Therefore, the finding that the peripheral conversion of T4 to T3 is maintained during methimazole treatment, as the body attempts to prevent the development of hypothyroidism at the tissue level, may help explain these divergent serum thyroid hormone values.' ',I3-I6 In addition, antithyroid drugs impair iodine organification and cause intrathyroidal iodine deficiency, a situation in which the direct thyroidal secretion of T3 is favored.15 Mild clinical side effects associated with methimazole therapy in this study included anorexia, vomiting, and lethargy. Although these side effects were relatively common, they were seen less frequently than in previous studies with PTU.6-8 In most cats, these adverse signs were transient and resolved despite continued administration of the drug. Severe gastrointestinal signs persisted in some cats, however, necessitating discontinuation of the drug. Facial and cervical excoriations also developed in a few cats within the first 6 weeks of therapy. In all of these cats, the cutaneous lesions persisted with continued methimazole administration and resolved shortly after cessation of the drug. Hepatic toxicity is an uncommon but serious reaction that can develop with antithyroid drug treatment. In human patients, PTU treatment generally causes pri- marily cytotoxic hepatic damage whereas methimazole is most often associated with cholestatic jaundice (without evidence of hepatic necro~is).~,~'-~~ In contrast, a hepatopathy characterized by both hepatocellular and cholestatic alterations, based on icterus, biochemical indicators of liver disease, and results of liver biopsy examination, developed in four cats of this report. Similarly, the hepatopathy that can develop following treatment with PTU in cats also is characterized by both hepatic necrosis and chole~tasis.~.~ As in humans, clinical improvement usually occurs within a few days after cessation of methimazole (or PTU), but jaundice and abnormal serum biochemical tests indicative of liver disease may not resolve for several weeks. A variety of hematologic abnormalities may develop in cats during treatment with methimazole. Those abnormalities that do not appear to be associated with any adverse effects include eosinophilia, lymphocytosis, and transient leukopenia with a normal differential count. As with PTU more serious hematologic reactions, which develop in a few cats treated with methimazole, include severe thrombocytopenia and agranulocytosis. In contrast to PTU, in which immunemediated hemolytic anemia is the most frequent serious hematologic abn~rmality,~~~ direct antiglobulin (Coombs') reactivity was only found in a few cats and the associated anemia did not develop in these cats. As expected, most cats in which thrombocytopenia developed also showed concomitant overt bleeding (i.e., epistaxis or oral hemorrhage). In contrast to human patients, in which the development of agranulocytosis during treatment with an antithyroid drug is a lifethreatening syndrome characterized by fever, systemic toxicity, and bacterial infection^,^" neither fever nor any evidence of infection was detected in the cats of this study with agranulocytosis. This suggests that other defense mechanisms may compensate for the severe neutropenia in these cats. Hypoprothrombinemia associated with antithyroid drug treatment (PTU) has rarely been documented in human patients. The cause of the hypoprothrombinemia is unknown but may be related to the warfarin-like effect of the antithyroid drugs, since it can be partially reversed with large doses of vitamin K or fresh pla~ma.~ Although not documented in this study, hypoprothrombinemia may have contributed to the bleeding diathesis (not associated with thrombocytopenia) observed in one cat. In the cat, the presence of ANAs appears to be rare, and naturally occurring lupus-like syndromes (characterized by polyarthritis, glomerulonephritis, and dermatitis) have not been well-defined.22 In this study, ANAs developed in a high percentage of cats after treatment with methimazole. Drug-induced ANAs in the cat has been previously described only after administration of PTU.7*8 In humans, a variety of drugs can induce ANAs

7 156 PETERSON ET AL. Journal of Veterinab Internal Medicint and produce a lupus-like syndrome. However, the prevalence of ANAs is considerably higher than clinical signs of 1upus Following long-term treatment with hydralazine or procainamide (the two major drugs associated with lupus-like syndromes in humans), ANAs develop in over half of the patients, but overt clinical signs of lupus develop in less than 10% of the patient^.^^,^^ Similarly, although serum ANAs developed in approximately one half of the cats treated with methimazole for longer than 6 months, a lupus-like syndrome was not detected in any of the cats. This is similar to the findings in cats in which serum ANAs developed associated with PTU treatment.738 However, the potential for lupus development in cats with methimazole-induced ANAs still exists. The daily drug dosage should, therefore, be decreased to as low as possible (while still maintaining serum T4 values within the low-normal range) because ANA tests will become negative in many cats when the methimazole dosage is decreased. Recently, it has become clear that antithyroid drugs act as immunomodulators in addition to their role in inhibiting thyroid hormone In accordance with this, it is likely that immunologic responses are involved in many of the methimazole-induced side effects such as pruritis, eosinophilia, lymphocytosis, leukopenia, agranulocytosis, thrombocytopenia, and hepatopathy.4, By definition, allergic drug reactions require specific immunologic induction and are mediated by sensitized lymphocytes or antib~dies.~~ Although antiplatelet or antigraimlocytic antibodies were not measured in the cats in this study in which thrombocytopenia or agranulocytosis developed, such autoantibodies have been demonstrated in human patients The presence of autoantibodies on the surface of red cells was demonstrated in a few cats treated with methimazole (although, unlike PTU,6-8 associated hemolytic anemia did not develop), and serum ANAs were present in many of the cats treated for longer than a few months. Although some form of direct toxic damage is probably involved in methimazole-induced he pa to path^,^^.^^ immune-mediated mechanisms also may play a role in the pathogenesis of hepatotoxicity as evidenced by the finding of circulating autoantibodies and sensitization to antithyroid drugs (by in vitro peripheral lymphocyte studies) in human patients with drug-induced hepatopath~.~,'~ As with other immune-mediated drug reactions, clinical recovery was complete soon after cessation of methimazole treatment (i.e., thrombocytopenia, agranulocytosis, and hepatopathy resolved and serum ANA tests became negative), and rechallenge with the drug produced the reactions within a short time period. Based on our findings, we recommend the following guidelines for use of methimazole in the presurgical preparation or long-term treatment of cats with hyperthyroidism. Initially, the drug should be gven at a dose of 10 to 15 mg/d, depending on the severity of the hyper- thyroid state. This methimazole dosage ensures the rees. tablishment of euthyroidism within 2 to 3 weeks in most cats. During the first 3 months of treatment (when the most serious side effects associated with methimazole therapy develop), the cats should be examined every 2 to 3 weeks in order to make necessary dose adjustments and to monitor for adverse effects. At each of these rechecks, serum T4 concentrations and complete blood and platelet counts should be monitored. If little or no decrease in serum T4 concentrations occurs during this initial treatment period, the daily methimazole dosage should be gradually increased (in 5-mg increments), after poor compliance by owners or difficulty in giving the medication has been excluded as the cause of persistent hyperthyroidism. If the drug is given as preoperative preparation, surgical thyroidectomy can be performed once serum T4 concentrations decrease to low or normal values (usually within 2 to 4 week^).^ In such cases, it is not necessary to decrease the initial dosage of methimazole before surgery because of the development of low circulating T4 Concentrations. Surgical risks in these cats with subnormal circulating T4 concentrations do not appear to be increased, probably because normal serum T3 concentrations are maintained. In cats in which long-term methimazole treatment is planned, however, the goal of treatment is to maintain serum T4 values within the low-normal range with the lowest possible daily dosage since some side effects appear to develop less frequently with lower doses of methimazole. Therefore, if serum T4 concentrations fall to low or lownormal values during methimazole treatment, the daily methimazole dosage should be decreased by 2.5-mg to 5-mg increments and further testing peri'ormed at 2- week to 3-week intervals until the lowest daily dose is found that will effectively maintain serum T4 concentrations within the low-normal range. Although a few cases of feline hyperthyroidism can be effectively controlled on a long-term basis with a daily dosage as low as 2.5 to 5 mg, the great majority will require a dosage of 7.5 to 10 mg/d. Other cats may continue to require dosages of 15 to 20 mg/d to maintain serum T4 concentrations within normal range. If serious adverse effects develop during methimazole therapy, the drug should be stopped and supportive care given. Since most lifethreatening side effects (e.g., agranulocytosis and hepatopathy) usually appear to develop quickly after rechallenge with the drug, alternative therapy with either surgery or radioiodine should be considered in these case^.^'^ While divided doses of methimazole (given every 8 or 12 hours) tend to be most effective in controlling the hyperthyroid state, euthyroidism can often be maintained when the necessary dose is given only once daily Despite a serum half-life for methimazole of only 4 to 6 hours, studies in human hyperthyroid patients have shown that the drug has an intrathyroidal

8 VOI. 2. NO. 3 METHIMAZOLE TREATMENT OF CATS WITH HYPERTHYROIDISM 157 residence time of approximately 20 Since antithyroid drugs act to inhibit thyroid hormone synthesis only after they are concentrated within the thyroid gland, serum half-life of these drugs is of lesser importance than the intrathyroidal drug concentration for adequate control of the hyperthyroid state. In addition, many cat owners, especially those using methimazole on a long-term basis, may find a treatment regimen of once daily medication easier to maintain than having to give medication 2 or 3 times daily. The results of this study show that serum T4 concentrations return to hyperthyroid values within 2 days of cessation of methimazole treatment. Hence, administration of methimazole less frequently than once daily will result in failure to adequately control the hyperthyroid state. After the first 3 months of methimazole therapy, one should continue to measure serum T4 concentrations at 3-month to 6-month intervals in order to monitor dosage requirements and response to treatment. Although it does not appear to be necessary to continue to monitor complete blood and platelet counts during these rechecks, the cell counts should be performed if agranulocytosis or thrombocytopenia are suspected. In addition, although methimazole-induced lupus was not detected in any of the cats in this study in which ANAs developed, periodic monitoring of serum biochemical screening values and urinalysis, as well as serum ANA determinations, also are recommended if signs consistent with a lupus-like syndrome (e.g., polyarthritis, glomerulonephritis, or dermatitis) develop. References 1. Peterson ME, Kintzer PP, Cavanagh PG, et al. Feline hyperthyroidism: Pretreatment clinical and labo:.atory evaluation of 131 cases. J Am Vet Med Assoc 1983; 183: Peterson ME. Feline hyperthyroidism. Vet Clin North Am [Small Anim Prac] 1984; 14: Peterson ME, Turrel JM. Feline hyperthyroidism. In: Kirk RW, ed. Current Veterinary Therapy IX. Philadelphia: WB Saunders, 1986; Cooper DS. Antithyroid drugs. N Engl J Med 1984; 31 1: Birchard SJ, Peterson ME, Jacobson A. Surgical treatment of feline hyperthyroidism: Results of 85 cases. J Am Anim Hosp ASSOC 1984; 20: Peterson ME. Propylthiouracil treatment of feline hyperthyroidism. J Am Vet Med Assoc 1981; 179: Peterson ME, Hurvitz AI, Leib MS, et al. Propylthiouracil-associated hemolytic anemia, thrombocytopenia, and antinuclear antibodies in cats with hyperthyroidism. J Am Vet Med Assoc 1984; 184~ Aucoin DP, Peterson ME, Hurvitz AI, et al. Propylthiouracil-induced immune-mediated disease in cats. J Pharmacol Exp Ther 1985; 234: Peterson ME, Graves TK, Cavanagh I. Serum thyroid hormone concentrations fluctuate in cats with hyperthyroidism. J Vet Intern Med 1987; 1: Glantz SA. Primer of Biostatistics. 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