Microsomal antibodies and antibodies directed toward the receptor for thyroid-stimulating hormone (TSH) decreased in parallel while patients with Graves' disease were taking carbimazole, whereas no significant changes were observed during treatment with placebo or propranolol. The changes in autoantibody levels during carbimazole treatment were independent of changes in serum thyroxine and could have been due to a direct effect of the drug on autoantibody synthesis. Evidence for this suggestion was provided when low doses of methimazole (the active metabolite of carbimazole) were found to inhibit thyroid-autoantibody production in cultured lymphocytes. Since thyroid lymphocytes are probably a major site of thyroid-antibody synthesis in Graves' disease and methimazole is concentrated in the thyroid during treatment, a local action of the drug on antibody production seems likely. This possibility could be important in the use of carbimazole to control hyperthyroidism.

https://www.nejm.org/doi/pdf/10.1056/NEJM198008073030603?listPDF=true

Carbimazole and the autoimmune response in Graves' disease.

The placental transfer of 35S-labelled methimazole (MMI), carbimazole and propylthiouracil (PTU) has been examined in the rat in late pregnancy and in patients undergoing therapeutic abortion. Although rapid equilibrium of fetal and maternal serum radioactivity (FS:MS ratio 1:1) occurred after iv administration of 35S-carbimazole or 35S-MMI in rats, a persistent fetal to maternal ratio of less than one was observed after 35S-PTU administration. Results from human studies after a single oral dose indicate that, as in the rat, the placenta appeared to be more permeable to 35S-MMI than to 35S-PTU as shown by the marked difference in fetal serum:maternal serum ratios and amounts accumulated in the fetus. Localization of radioactivity in the human fetal thyroid was also observed after administration of 35S-labelled MMI, carbimazole or PTU.

The placental transfer of propylthiouracil, methimazole and carbimazole.

S-oxidation of thioureylenes catalyzed by a microsomal flavoprotein mixed-function oxidase.

Ninety-three hyperthyroid patients were treated with 1 dose of iodine-131 (131I) during the past 10 years. Thirty-three were pretreated with propylthiouracil (PTU), 22 with methimazole (MMI), and 38 received no antithyroid drugs (ATD). ATD were discontinued 5-55 days before 131I therapy in three fourths of the cases and more than 4 months before therapy in one fourth of the cases. The frequency of cures in the 3 groups, 6-8 months after radioiodine therapy, was retrospectively studied. The cure rate among those who discontinued PTU for 5-55 days before 131I was significantly reduced (24%), compared with those who discontinued MMI for the same duration (61%) or those who received no ATD (66%). When PTU was discontinued for more than 4 months, the cure rate was similar to those who received no ATD. It is concluded that if ATD are used as initial therapy for hyperthyroidism, then PTU (but not MMI) may reduce the therapeutic efficacy of subsequent 131I. The reduction in cure rate was observed even when PTU was discontinued for as long as 55 days before 131I therapy. To our knowledge, this is the first report to compare, in one study, the effects of pretreatment with PTU and MMI on 131I therapy.

Pretreatment with propylthiouracil but not methimazole reduces the therapeutic efficacy of iodine-131 in hyperthyroidism

We investigated whether thyrotoxic patients treated with short-term antithyroid therapy would achieve prolonged remissions. Thirty-one previously untreated and nine previously treated patients with thyrotoxic Graves's disease received a single daily dose of methimazole or propylthiouracil. The drug was stopped at, or shortly after, the time they became euthyroid. Twelve of the 31 previously untreated patients remained in remission for 29±3.5 months (mean ±S.E.) after treatment for 4.5±0.3 months. Four of the nine previously treated have remained in remission for 13.0±2.1 months after treatment for 3.0±0.3 months. Of various possibilities analyzed, only a small goiter at the onset of therapy and tri-iodothyronine toxicosis were significantly favorable prognostic indicators that a remission would be maintained. The lasting remission rate is as good when antithyroid drugs are stopped as soon as the patient is euthyroid as when they are continued for one year or more. (N Engl J Med 297:173–176, 1977)

Short-Term Antithyroid Drug Therapy for the Thyrotoxicosis of Graves's Disease

Accumulation of 35S-radioactivity by the thyroid gland was found after administration of equimolar doses of 35S-labelled thiouracil, methylthiouracil, propyl thiouracil, methimazole and carbimazole to rats. Thin-layer chromatography showed an accumulation of the parent drug in the case of methimazole, propylthiouracil, methylthiouracil and thiouracil. When carbimazole was given, an accumulation of methimazole was demonstrated in the thyroid. Propylthiouracil administration produced the largest amount of drug in the thyroid and thiouracil the least. In man both 35S-radioactivity and the parent drug accumulated in the normal thyroid after administration of methimazole and propylthiouracil. When carbimazole was given, methimazole accumulated in the thyroid. In six thyroid tumors little or no accumulation of the antithyroid drug was found.

The acclumulation of 35 S-antithyroid drugs by the thyroid gland.

Propylthiouracil is concentrated by the thyroid gland in rats and man. Four 35 S compounds were demonstrated in the rat and human thyroid by thin-layer chromatography: sulphate, intact propylthiouracil, an unknown metabolite X and origin 35 S activity which is protein bound. Unbound 35 S compounds in plasma include propylthiouracil, the glucuronide conjugate of PTU, sulphate, and X. The thyroid concentration rather than the plasma level of propylthiouracil determines the duration of inhibition of organic binding of iodine in the thyroid. The effect of perchlorate and iodide on the thyroid concentrating mechanism for 35 S-propylthiouracil and 125 I-iodide was studied. The level of perchlorate and iodide which almost completely blocked the concentration of 125 I-iodide also partially reduced the concentration of 35 S-propylthiouracil. Iodide but not perchlorate decreased the rate of metabolism of 35 S-propylthiouracil in the thyroid gland.

Concentration of 35S-propylthiouracil by the thyroid gland and its relationship to anion trapping mechanism.

35S-methimazole (MMI), 35S-carbimazole or 35S-propylthiouracil (PTU) were given orally to fifty-five patients at various times up to 12 h before surgical thyroidectomy. The amount of 35S radioactivity and labelled drug in thyroid and plasma samples was measured. Intrathyroidal inhibition or organic binding of iodine by MMI, carbimazole and PTU was measured after intravenous administration of 131I, 132I or 125I-iodide. After administration of 35S-carbimazole or 35S-MMI the thyroid to serum (T/S) ratio of 35S radioactivity was greater in thyrotoxic glands than in non-toxic adenoma tissue. 35S-MMI was found in thyroid and plasma samples after administration of 35S-carbimazole. The T/S 35S-MMI was greater than 1 in most but not all patients. 35S radioactivity was also concentrated in the thyroid after administration of 35S-PTU. In thyrotoxic glands there was an 80% inhibition of iodine organification in patients receiving MMI and 60% for those receiving PTU. It is suggested that carbimazole and MMI can be given once or twice daily in some patients but PTU would be less suitable for this dose schedule.

J.H. Lazarus

Papers

The acclumulation of 35 S-antithyroid drugs by the thyroid gland.

Concentration of 35S-propylthiouracil by the thyroid gland and its relationship to anion trapping mechanism.

35-S-antithyroid drug concentration and organic binding of iodine in the human thyroid.