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An infant girl with choanal atresia, athelia, minor anomalies, and mild to moderate mental retardation was born to a woman treated for hyperthyroidism throughout pregnancy with methimazole and propranolol. The patient's defects may be due to methimazole teratogenicity or could represent a previously undescribed syndrome affecting ectodermal structures.
We report on 2 newborn infants with esophageal atresia and tracheoesophageal fistula (EA + TEF) born to hyperthyroid mothers receiving methimazole (Tapazol) before and during their entire pregnancies. Both mothers were euthyroid during gestation and developed hydramnios diagnosed during weeks 34 and 33 of gestation. Premature delivery (36.2 weeks of gestation) occurred in one case, and both newborn infants were small for date with palpable goiter; one of them had other associated malformations. Hypothyroidism was diagnosed by laboratory tests in both cases. Corrective surgery was undertaken, but both newborn infants developed septicemia and renal insufficiency and died in the first week of life. The EA + TEF and a normally placed enlarged thyroid gland were confirmed at necropsy. These cases represent a previously unreported example of the association of maternal ingestion of methimazole during pregnancy and EA + TEF.
BACKGROUND: The interferon-gamma-inducible chemokine CXCL10 is highly expressed in infiltrating inflammatory cells, and in thyrocytes in patients with Graves' disease. The aim of this study was to measure serum levels of CXCL10 in relation to thyroid function and treatment. METHODS: Serum levels of CXCL10 were measured in 22 patients with Graves' disease when hyperthyroid, when euthyroid under methimazole therapy, and 3 days after near-total thyroidectomy. They were compared with levels in three groups of age- and sex-matched controls: 44 subjects with no thyroid disorder, 44 patients with euthyroid autoimmune thyroiditis and 20 with toxic nodular goitre. RESULTS: Basal serum levels of CXCL10 in patients with Graves' disease were higher than levels in patients with toxic nodular goitre or no thyroid disorder, and similar to levels in patients with autoimmune thyroiditis (mean(s.d.) 167(121), 100(24), 78(46) and 142(107) pg/ml respectively; P < 0.010). Among patients with Graves' disease, serum levels of CXCL10 were significantly higher in those aged over 50 years (P = 0.010), with a hypoechoic pattern at thyroid ultrasonography (P < 0.001) or with hypervascularity (P = 0.001). CXCL10 levels in patients with Graves' disease decreased significantly when euthyroidism was achieved by methimazole therapy (P < 0.010), and a further decrease was observed after thyroidectomy (P < 0.010). CONCLUSION: Serum levels of CXCL10 are higher in newly diagnosed hyperthyroid patients with Graves' disease than in those with toxic nodular goitre, and decrease when euthyroidism is achieved with antithyroid therapy. This high level may be related to the active inflammatory phase of Graves' disease. A further reduction of CXCL10 levels after thyroidectomy indicates that it is produced mainly in the thyroid in patients with autoimmune thyroid disease.
BACKGROUND: During radiolabeled metaiodobenzylguanidine (MIBG) administration in children with neuroblastoma, the thyroid is protected from (123/131)I uptake by potassium iodide. Despite this protection, up to 64% of patients develop thyroid dysfunction. The authors introduce a new method of radiation protection for the thyroid gland. METHODS: In a prospective cohort study, 34 children with neuroblastoma who received MIBG were given thyroxine, methimazole, and potassium iodide for protection of the thyroid gland. Protection started 1 day before the start of diagnostic 123I-MIBG and was continued until 4 weeks after the last therapeutic 131I-MIBG dose. Follow-up measurements were performed every 3 months after the protection was stopped. Visualization of the thyroid on MIBG images was reviewed by three nuclear medicine physicians. Results were compared with a historic control group of children who had received potassium iodide for thyroid protection during MIBG administration. RESULTS: After a mean follow-up of 19 months, there were 23 evaluable patients. Thyroid function was normal in 86% of survivors compared with 44% of children in the historic control group (P=0.011; Pearson chi-square test). Scintigraphic visualization of the thyroid diminished substantially after the new protection (21.5% vs. 5.3%, respectively; P=0.000). CONCLUSIONS: The results of the current study indicate that compared with potassium iodide alone, combined thyroxine, methimazole, and potassium iodide protect the thyroid more effectively against radiation damage from (123/131)I during diagnostic and therapeutic MIBG administration in children with neuroblastoma.
In normal, nonmedicated volunteers and in patients with thyroid disorders the plasma half-lives of antipyrine, propylthiouracil, and methimazole were determined after single oral doses. The plasma half-liver plus or minus S.D. of antipyrine, propylthiouracil, and methimazole were 11.9 plus or minus 1.4 hr, 6.7 plus or minus 1.0 hr, and 9.3 plus or minus 1.4 hr, respectively, in normal volunteers, but were shortened to 7.7 plus or minus 1.2 hr, 4.3 plus or minus 0.7 hr, and 6.9 plus or minus 0.6 hr, respectively, in hyperthyroid patients. In hypothyroid patients the plasma half-lives of these drugs were prolonged to 26.4 plus or minus 4.0 hr, 24.7 plus or minus 34.5 hr, and 13.6 plus or minus 4.8 hr, respectively. Return to the euthyroid state restored plasma half-lives to or toward normal. Alterations in plasma drug half-lives during thyroid dysfunction appear to result mainly from accelerated hepatic microsomal drug metabolism in hyperthyroidism and retarded drug biotransformation during hypothyroidism.
A series of five 6-alkyl- and 6-aryl-mesoionic 1-methylimidazo[2,1-b][1,3]thiazine-5,7-diones was synthesized and found to produce 1-methyl-3H-imidazole-2-thione (methimazole) upon alkaline hydrolysis or treatment with amine or thiol reagents. The alkaline hydrolysis followed a second-order rate expression, being dependent on both substrate and hydroxide-ion concentrations. The rate constants for the five derivatives fell within 6-15 x 10(-2) liter/mole min at 40 degrees. These compounds were stable in aqueous acidic solutions and in human serum or rat liver homogenate under conditions producing rapid hydrolysis of the methimazole prodrug 1-carbethoxy-2-methylimidazole-2-thione (carbimazole).
This study investigated T-cell activation markers HLA-DR and CD69 in both naive (CD45RA+) and memory (CD45RA-) CD4+ as well as CD8+ T cells in peripheral blood of patients with autoimmune thyroiditis (AT, N = 28) or hyperthyroid untreated Graves' disease (GDH, N = 34) using three-color flow cytometry. It was demonstrated that patients with AT, but not those with GDH, expressed increased amounts of HLA-DR antigen compared to healthy subjects (HS, N = 26) on total CD4+ (AT: 14.1%; GDH: 11.3%; HS: 10.9%) and CD8+ cells (AT: 31.9%; GDH: 23.5%; HS: 19.4%) as well as on CD45RA- CD4+ cells (AT: 11.2%; GDH: 7.7%; HS: 7.9%). In GDH (+71%) and AT (+91%) only the proportion of HLA-DR+ CD45RA+ CD8+ cells was increased vs HS. Furthermore, euthyroid GD patients on methimazole (GDE, N = 22) displayed greater HLA-DR+ expression on total and CD45RA- cells within both CD4+ (+37 and 40%, respectively) and CD8+ cells (+47 and 93%, respectively) than GDH. In addition, total and CD45RA+ CD4+ and CD8+ cells were increased vs HS. In contrast, proportions of CD69 positive T cells were increased in AT and GDH on total CD4+ (+97 and 74%, respectively) and CD8+ (+95 and 68%, respectively) cells and all subsets thereof (except for CD45RA- cells in GDH), but normalized upon thyrostatic treatment. We conclude that patients with autoimmune thyroid disease harbor an almost twofold greater proportion vs HS of (a) HLA-DR+ CD45RA+ CD8+ T cells, and of (b) CD69 on total CD4+ and CD8+ cells, and an even more marked elevation on their CD45RA+ subset in AT and untreated GD. In addition, (c) thyrostatic treatment by methimazole in GD is accompanied by a further increase in circulating HLA-DR+ CD4+ and CD8+ cells and their CD45RA- subsets, but decreased CD69 expression. These data suggest association of HLA-DR expression with ongoing autoimmunity, while increased CD69 expression relates in part also to elevated thyroid hormone concentration in GDH.
Whether melanogenesis occurs in adult eyes is still a matter of controversy. It has been widely held that the pigment epithelial cells are fully melanized at birth, and that the uveal melanocytes cease their melanin production in the very young individual. Therefore there should be no turnover of melanin in the adult eye. A number of studies have, however, demonstrated that the enzyme involved in melanin synthesis, tyrosinase, seems to be active also in the adult eye. The recent observation that a prostaglandin analogue, used in glaucoma therapy, caused increased iridal pigmentation in the treated eye, but not in the untreated eye, of adult monkeys and in humans, indicate that the adult eye at least has the capacity to produce melanin. In the present study 3H-methimazole, a false melanin precursor, was administered to a series of DBA-mice, 3 weeks to one year of age. The eyes were removed 24 hr after a single i.p. injection of 3H-methimazole. Using microautoradiography the incorporation of radioactivity was studied in X-ray film covered sections comprising the entire eye. A very selective accumulation of radioactivity was seen in uveal melanocytes and in the pigment epithelial cells in the iris and the ciliary body. The level in the retinal pigment epithelium was low in the eyes of all ages. No uptake was seen in any non-pigmented ocular tissue. The most pronounced accumulation was seen in the pigment epithelium and melanocytes in the iris of the young mice, but some activity was seen in these cells also in the older mice. The presence of immature melanosomes seen in electron micrographs from iridal pigment cells and melanocytes of one year old mice indicate that new melanosomes are formed in these cells also in adult animals. The results of this study thus strongly indicate that there seems to be an active melanin synthesis in the adult eye of the mouse, most pronounced in iridal melanocytes and in the iridal pigment epithelium.
The histopathology of the olfactory mucosal lesion associated with ip administration of 2,6-dichlorobenzonitrile (dichlobenil) and 3,3'-iminodipropionitrile (IDPN) has been well documented. Whether there is an olfactory deficit associated with the partial loss of the olfactory mucosa (localized around the dorsal medial meatus of the nasal cavity) has yet to be determined. Dichlobenil (100 mg/kg) or IDPN (200 mg/kg) was administered ip to adult male Long-Evans rats previously trained in an olfactory task to find a food pellet buried in approximately 7.5 cm of bedding in a 0.61 x 1.2 x 0.61-m Plexiglass chamber. As a positive control, another group received 300 mg/kg ip of 1-methyl-2-mercaptoimidazole (methimazole), a dosing regimen which destroys nearly all of the olfactory mucosa. All three compounds caused a transient increase in the mean latency to find the pellet, with the magnitude of the effect positively correlated with the extent of the olfactory lesion. In order to determine whether these deficits resulted from olfactory dysfunction or impaired cognitive function (a deficit previously attributed to IDPN exposure), another group of rats was dosed as above and tested in another spatial memory task, the Morris water maze (MWM), which is less dependent upon olfactory function. No performance deficit was detected in the MWM. These data suggest that the transient olfactory deficit in the dichlobenil-, IDPN-, and methimazole-treated rats is attributable to defective olfactory function.
Cholestatic jaundice caused by imidazole derivates is a rare complication of antithyroid therapy. Only 20 such cases have been reported in the literature since the introduction of methimazole in 1949 and of carbimazole in 1953. We present a further case of methimazole-induced cholestatic liver injury, mimicking sclerosing cholangitis, where the etiology has been proven by a clear chronological relationship and the lack of other causative factors.
A newly developed method for extracting and measuring methimazole in biological fluids was used to study the pharmacokinetics of methimazole in two euthyroid and eight hyperthyroid subjects. The volume of distribution approximated total body water; the biological half-life was 2-3 h in euthyroid and about 6 h in hyperthyroid patients. Total clearance was lower in hyperthyroid patients than in euthyroid subjects, and it did not increase after thyroid function was normalized. Bioavailability in euthyroid subjects was greater than 1 but only 0.5 in hyperthyroid subjects. The reasons for these observed differences are not known.
Portal hypertension is accompanied by a hyperdynamic circulatory state that shares some similarities with thyrotoxicosis. This study was conducted in order to investigate the hemodynamic effects of hypothyroidism in a rat model with portal hypertension induced by partial portal vein ligation (PVL). Four groups of 10 rats each were studied: normal control and hypothyroid rats, and PVL control and hypothyroid rats. Hypothyroidism was induced by methimazole 0.04% in drinking water. Hemodynamic measurements were performed using the radioactive microsphere technique. Induction of hypothyroidism was confirmed by elevated TSH levels. In the PVL groups, hypothyroidism ameliorated the hyperdynamic circulation. Portal venous inflow and portal pressure dropped significantly: 7.1 +/- 0.2 vs 4.8 +/- 0.3 ml/min/100 g body wt (P < 0.01) and 13.4 +/- 0.9 vs 10.9 +/- 0.8 mm Hg; (P < 0.01), respectively. In normal rats, hypothyroidism was manifested by a hypodynamic circulatory state. These results demonstrate that hypothyroidism induced by methimazole is followed by amelioration of the hyperdynamic circulation, normalization of portal venous inflow, and reduction of portal pressure.
The antithyroid drug, methimazole (1-methyl-2-thiolimidazole), is a powerful chelator of cupric ion. This is reflected in its ability to selectively inhibit certain copper oxidases. Uricase, ascorbic oxidase and monoamine oxidase are not affected. Ceruloplasmin oxidase is slightly inhibited and tyrosinase is markedly inhibited by methimazole.
In this study we compared the functions of normal peritoneal macrophages with those from methimazole-induced hypothyroid C57BL/6 mice. Methimazole (MMI) suppressed the expression of the tumor necrosis factor (TNF) gene in peritoneal macrophages (MAM) at both transcriptional and translational levels. The kinetics of TNF synthesis by MAM following in vivo and in vitro lipopolysaccharide (LPS) challenge were different, but both treatments resulted in significant decreases (P < 0.05) in TNF mRNA and protein after 60 min. Similarly, the production of reactive nitrogen and oxygen intermediates by MAM were significantly (P < 0.05) lower compared with control macrophages (CAM). In addition, the serum TNF protein was significantly lower (P < 0.05) in MMI-treated mice following intravenous LPS challenge for 90 min. These data suggested that peritoneal macrophages were inactivated in MMI-induced hypothyroid mice.
For many years, breast-feeding was forbidden if methimazole (MMI) was being used. However, a few studies have demonstrated the relative safety of MMI. The purpose of this study was to evaluate thyroid function of breast-fed infants whose lactating mothers became hypothyroid while taking methimazole. Between 1990 and 2001, 134 thyrotoxic lactating mothers received MMI while breast-feeding. MMI therapy was initiated between 2-8 months postpartum, 10-30 mg for the first month and 5-10 mg from the second until the twelfth month. In 16 mothers, TSH was increased at the end of one month of MMI therapy (Group 1). Infants of 18 mothers whose serum TSH was normal at the end of the first month were included as controls (Group 2). Mothers and their infants were clinically evaluated and serum T4, T3 and TSH were measured before and at 1, 2, 4, 8 and 12 months after MMI therapy. Serum MMI was measured in 8 infants 2 h after breast-feeding. Mean +/- SD of FT4I and FT3I were not statistically different between the two groups of mothers before MMI therapy. In all 34 mothers thyroid indices decreased one month after MMI therapy; FT4I: Group 1 from 19.8 +/- 4.3 to 6.0 +/- 4.8 (p<0.001) and Group 2 from 20.3 +/- 4.7 to 11.4 +/- 4.1 (p<0.001); FT3I: Group 1 from 602 +/- 56 to 146 +/- 52 (p<0.001) and Group 2 from 562 +/- 42 to 186 +/- 39 (p<0.001). The difference in FT4I, FT3I and TSH (20 +/- 18 vs 2.1 +/- 1.1 mU/l, p<0.001) between the 2 groups was significant at the end of the first month of MMI therapy. There was no significant difference in thyroid function of infants of these two groups one month after MMI therapy and all tests remained within the normal range during 12 months of treatment of their lactating mothers. Serum MMI levels were less than 0.03 in 6 and 0.03 and 0.035 microg/ml in the other 2 infants. The results further indicate the safety of MMI therapy in breast-feeding thyrotoxic women.
The outcome of radioiodine therapy of Graves' hyperthyroidism was retrospectively evaluated in 274 consecutive patients treated from 1975 to 1984. At 1-yr follow-up, permanent hypothyroidism occurred in 36.9% of patients and the cumulative incidence of hypothyroidism progressively increased up to 79.3% after 7-10 yr. At the end of the follow-up period, 148 patients (54%) were hypothyroid, 115 (42%) euthyroid and 11 (4%) still hyperthyroid. The prevalence of hypothyroidism was significantly higher in patients with small goiters (less than or equal to 50 g) than in those with large goiters (greater than 90 g). Moreover, hypothyroidism was more frequent in patients with high thyroglobulin antibodies titers (greater than or equal to 1:25,600) than in those with low titers or negative tests, and occurred earlier in the former group than in the latter ones Correction of thyrotoxicosis was obtained after the administration of a single dose of 131I in 187 patients (63.6%); 69 patients required two doses and 11 three or more doses. Seven patients refused further treatment with 131I after the first dose. In an effort to identify possible factors affecting the efficacy of 131I therapy, we evaluated the results obtained after the administration of the first dose of radioiodine. We found that large goiters, rapid iodide turnover and adjunctive therapy with methimazole shortly after radioiodine were associated with a higher rate of persistence of thyrotoxicosis, whereas an increased prevalence of hypothyroidism was observed in patients with small goiters and in those not treated with methimazole up to one week after 131I.(ABSTRACT TRUNCATED AT 250 WORDS)
The best-known adverse hematologic reaction of methimazole is agranulocytosis. Aplastic anemia is extremely rare. The prognosis within the entity of aplastic anemias is surprisingly good, despite the severe and prolonged course of the disease. The present article reports the case of a 74-yr-old female patient who exhibited aplastic anemia with severe clinical symptoms 8 weeks after the initiation of methimazole administration. The hemorrhagic symptoms were aggravated by a coumarin overdose. Supportive hemotherapy and antibiotic treatment were supplemented with recombinant human granulocyte colony-stimulating factor and high-dosage corticosteroids. The granulocyte count normalized on day 5 of treatment, the platelet count exceeded the critical value on day 11, and on day 25 the patient was discharged in remission.
We have expanded our early observation that a potent Graves' IgG preparation induces HLA-DR expression on thyroid cells, by showing that four randomly-selected Graves' IgG's were also capable of inducing DR antigens on thyroid cells. The effect of Graves' IgG was specific to thyroid cells, as it did not induce MHC Class II molecule expression on endothelial cells whereas interferon-gamma and immune complexes did so. The anti-thyroid drug methimazole was capable of rapidly reducing Graves' IgG-induced DR expression but to a much lesser extent than brought about by interferon-gamma. We conclude that Graves' IgG propagates thyroid-specific autoaggression by continued induction of DR antigens and than an important means whereby methimazole brings about remission is by reducing this induction.