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PubMed2004

Phenyl methimazole inhibits TNF-alpha-induced VCAM-1 expression in an IFN regulatory factor-1-dependent manner and reduces monocytic cell adhesion to endothelial cells.

Proinflammatory cytokine (e.g., TNF-alpha)-induced expression of endothelial cell adhesion molecules (ECAMs) on the lumenal surface of the vascular endothelium and a consequent increase in leukocyte adhesion are key aspects of pathological inflammation. A promising therapeutic approach to diminish aberrant leukocyte adhesion is, therefore, to inhibit cytokine-induced ECAM expression at the transcription level. Several studies suggest that methimazole, a compound used clinically to treat autoimmune diseases, such as Graves' disease, may also diminish pathological inflammation by suppressing ECAM expression. In this study we probed the hypothesis that a derivative of methimazole, phenyl methimazole (compound 10), can reduce cytokine-induced ECAM expression and consequent leukocyte adhesion. We found that compound 10 1) dramatically inhibits TNF-alpha-induced VCAM-1 mRNA and protein expression in human aortic endothelial cells (HAEC), has a relatively modest inhibitory effect on TNF-alpha induced E-selectin expression and has no effect on ICAM-1 expression; 2) significantly reduces TNF-alpha-induced monocytic (U937) cell adhesion to HAEC under in vitro flow conditions similar to that present in vivo; 3) inhibits TNF-alpha-induced IFN regulatory factor-1 binding to VCAM-1 promoter; and 4) reduces TNF-alpha-induced IRF-1 expression in HAEC. Combined, the results indicate that phenyl methimazole can reduce TNF-alpha-induced VCAM-1 expression in an IFN regulatory factor-1-dependent manner and that this contributes significantly to reduced monocytic cell adhesion to TNF-alpha-activated HAEC.

Cell Adhesion↗
PubMed1996

Association between the DRB1*08032 histocompatibility antigen and methimazole-induced agranulocytosis in Japanese patients with Graves disease.

OBJECTIVE: To determine the association between HLA class II genes and methimazole-induced agranulocytosis in patients with Graves disease. DESIGN: Case-control study. SETTING: Kuma Hospital, which specializes in thyroid diseases, in Kobe, Japan. SUBJECTS: 24 patients with Graves disease who had methimazole-induced agranulocytosis diagnosed by peripheral granulocyte counts of less than 0.5 x 10(9)/L, and 68 patients with Graves disease treated with methimazole, who were free from agranulocytosis. Controls were 525 healthy, unrelated Japanese student volunteers at Kyushu University in Japan. MEASUREMENTS: All HLA class II genes were analyzed for polymorphisms at the DNA level by using the polymerase chain reaction sequence-specific oligonucleotide probes method. The allele frequencies in the agranulocytotic Graves disease group were compared with those in the nonagranulocytotic Graves disease and control groups. RESULTS: A strong positive association was seen in DRB1*08032 between the agranulocytotic group and both the control and nonagranulocytotic Graves disease groups. CONCLUSION: The HLA DRB1*08032 allele was strongly associated with susceptibility to methimazole-induced agranulocytosis, suggesting that cellular autoimmunity may be involved in its development.

Agranulocytosis↗
PubMed1976

Leukocyte migration inhibition in vitro in untreated and methimazole-treated patients with Graves disease.

The leukocyte migration tests has been applied to investigate immune-reactivity of 43 untreated and methimazole-treated patients against thyroid crude antigen. A significant migration inhibition was observed in 21 untreated patients, while in 22 methimazole-treated patients the migration test was negative independently of T3 suppressibility. Migration inhibition against thyroid antigen and purified protein derivative (PPD) was reduced or abolished after preincubation with methimazole of leukocytes of untreated patients. It seems that methimazole-treatment influences not only thyroid iodine metabolism, but by means of a direct effect on lymphocytes it also decreases the pathological stimulation.

Adult↗
PubMed2000

Methimazole protection against oxidative stress induced by hyperthyroidism in Graves disease.

OBJECTIVE: To examine the dynamics of oxidative stress in patients with hyperthyroidism before and during the treatment with methimazole using the measurement of conjugated dienes, malondialdehyde, and Schiff bases in blood serum. METHODS: In eight female patients with diagnosed Graves disease and 8 healthy control subjects (7 females and one male) several parameters of oxidative stress (the level of conjugated dienes [CD], malondialdehyde [MDA] and Schiff bases [SB]) were estimated before and during the treatment with methimazole (Metizol -POLFA) as well as by hormonal and immunological tests. In addition, serum levels of TSH, free thyroxine (FT4), free triiodothyronine (FT3), antibodies against thyroperoxidase (anti-TPO) and thyroglobulin (anti-Tg) and low density lipoprotein-cholesterol fraction (LDL-Ch) were estimated. RESULTS: We observed increased concentrations of free thyroxine (FT4) and free triiodothyronine (FT3), as well as of antithyroperoxidase (anti-TPO) and antithyroglobulin (anti-Tg) antibodies. At the same time, TSH level was significantly suppressed. The concentrations of thyroid hormones and of TSH normalised after the methimazole treatment. The examined parameters, i.e., CD, MDA, and SB, were evaluated as proportions of each of them to the level of low density lipoproteins-cholesterol fraction (LDL-Ch). This fraction of cholesterol contains many polyunsaturated fatty acids, being a substrate for the peroxidation of lipids. Additionally, the CD/MDA ratio was calculated. CONCLUSIONS: The increase of the CD/LDL ratio in Graves hyperthyroidism and its normalisation in the course of the treatment with methimazole suggests that the drug can be protective against the oxidative stress induced by overproduction of thyroid hormones. The ratio of CD/MDA decreased in all the patients, as compared to the control group, showing a high speed of lipid peroxidation.

Antithyroid Agents↗
PubMed1992

[Effect of acute and chronic administration of L- thyroxine and methimazole on blood levels of tryptophane, serotonin and 5-hydroxyindoleacetic acid in plasma of rats].

The effects of hyperthyreosis induced by the administration of thyroxine and hypothyreosis induced by the administration of methimazole on the levels of tryptophane, serotonin and 5-hydroxyindoleacetic acid in low-platelet blood plasma have been studied in Wistar rats. Thyroxine administration (120 micrograms/kg/24 h, intraperitoneally) lasting 7 days caused a decrease in serotonin concentration by 38 per cent. The level of this amine in rats receiving thyroxine during three months was elevated by almost three times. Tryptophane concentration did not change following thyroxine administration. Methimazole administration lasting 14 days (oral dose 15 mg/kg/24 h) caused an increase in tryptophane concentration by 34 per cent and in serotonin concentration by 24 per cent. Long-term hypothyreosis induced by methimazole administration lasting three months caused an 39 per cent increase in tryptophane and 38 per cent increase in serotonin concentration. Neither hyperthyreosis induced by thyroxine administration nor hypothyreosis induced by methimazole++ caused any changes in the concentration of 5-hydroxyindoleacetic acid. The importance of serotonin in pathogenesis of clinical symptoms accompanying the states of deficit or excess of thyroid hormones needs further elucidation.

Animals↗
PubMedDate not supplied

[Pharmacokinetics of phenazone in patients with fast and slow euthyroidism after methimazole treatment].

Hyperthyroidic patients treated with methimazole were retrospectively divided into two groups, depending on the period of time required for euthyreosis: these attaining euthyreosis up to 28 days of therapy (A) and these in whom thyroid gland functioning is normalized after a 35-day therapy with full dose of methimazole (B). The study aimed at investigating whether clinical euthyreosis is related to the activity of microsomal enzymes in the liver using phenazone elimination test for this purpose. Phenazone elimination test was performed just before the treatment and after 8 weeks of methimazole administration. A decrease in kel and Clt as well as an increase in AUC were noted. These changes were more pronounced in patients of group A than those of group B. It might be concluded that phenazone pharmacokinetics is different in patients quickly attaining euthyreosis. The difference is probably due to the difference in biotransformation of methimazole in the liver in which microsomal enzymes play some role.

Adult↗
PubMed1989

Reduction of UV-induced erythema in normal subjects by applying methimazole.

Since free radicals are probably involved in the induction of erythema following ultraviolet (UV) irradiation, a study was conducted to investigate the influence of a topical application of methimazole (a free radical scavenger), before and at different times up to 2 h, after exposure to UV radiation. Seven subjects took part and erythema was assessed 6 h after exposure by a quantitative reflectance technique. Erythema was reduced at the sites that received methimazole 15 min prior to exposure and, although the trend was towards a decrease in erythema at the sites where methimazole was applied after exposure, the mean differences in these cases were not significant. It is believed that methimazole may have a useful role in the reduction of erythema following UV irradiation.

Administration, Cutaneous↗
PubMed1993

Plasma concentrations of atrial natriuretic peptide and cyclic guanosine monophosphate in patients with hyperthyroidism before and after short-term treatment with methimazole.

The aim of the study was to answer the question whether a rapid decrease in serum triiodothyronine (T3) and thyroxine (T4) levels resulting from the treatment with a full dose (3 x 20 mg daily) of methimazole applied in patients with thyrotoxicosis is associated with the parallel diminution of plasma atrial natriuretic peptide (ANP) and its second messenger-cyclic guanosine monophosphate (cGMP) concentrations. Sixteen patients with thyrotoxicosis of mean age 41.5 +/- 10.5 years participated in the study. Short-term (10 days) methimazole treatment resulted in a significant decrease in serum T3 and T4 concentrations to the values found in 14 healthy subjects serving as control group. Plasma ANP and cGMP levels also decreased significantly during the treatment attaining the normal range. A significant correlation was found between the decrease in serum T3 and T4 concentrations during the treatment and the decrease in plasma ANP level. The decrease in plasma ANP was not closely correlated with the reduction of cGMP levels. These results indicate that: 1) a steep decrease in serum thyroid hormone concentrations induced by a full methimazole treatment during ten days in patients with thyrotoxicosis due to Graves' disease was accompanied by the return of elevated plasma ANP levels to normal range; 2. diminution of serum concentrations of both T3 and T4 during the treatment was correlated with the decrease in plasma ANP; 3) reduction in plasma cGMP concentration associated with short-term methimazole treatment in thyrotoxicosis seems to depend not only on the diminution of plasma ANP level.

Adult↗
PubMed1993

Treatment of Graves' disease: effects of the administration of L-thyroxine associated with methimazole as a single daily dose.

OBJECTIVES: To reduce the number of tablets to be administered daily during antithyroid drug (ATD) treatment of Graves' disease (GD) and to evaluate the effectiveness of adding thyroxine after the patients had become euthyroid during methimazole therapy. PATIENTS AND METHODS: All patients were given gelatin capsules with 30 mg of methimazole 2 times per day for 4-6 weeks, followed by two capsules with 20 mg of methimazole and 75 micrograms of thyroxine to be taken once a day for 18-24 months. Thirty patients with Graves' disease without previous treatment for hyperthyroidism were included. Two were lost to follow-up and 28 (24 women and 4 men; age range 14-53 years; mean 34.2 years) were followed for 18 to 24 months with methimazole and thyroxine medication plus an additional 2 years after the treatment was suspended. After completion of the study the patients were, retrospectively, divided in two groups: group 1 (G1, n = 20) patients considered to be in remission, and group 2 (G2, n = 8) with persistent active Graves' disease. RESULTS: All patients in group 1 had a significant reduction in the glandular mass, as estimated by ultrasonographic studies (mean +/- SD 67 +/- 13 g to 18 +/- 3 g, p < 0.01) whereas subjects in group 2 had no significant reduction in glandular mass (67 +/- 14 g to 53 +/- 16 g). Thyroglobulin levels (mean +/- SD) in G1 were 54 +/- 55 micrograms/L at baseline and decreased to 15 +/- 9 micrograms/L (p < 0.001), and in G2 thyroglobulin concentrations did not decrease significantly after therapy (58 +/- 20 micrograms/L vs 44 +/- 22 micrograms/L). Also, levels of thyroid-stimulating hormone receptor inhibiting antibody (TRAb) only decreased in G1 (49-21% to 8 +/- 5%; p < 0.001). Nineteen patients (all from G1), were euthyroid 2 years after treatment withdrawal, indicating a remission rate of 67.8%. CONCLUSION: The administration of L-thyroxine during anti-thyroid drug treatment, with subsequent inhibition of thyroid-stimulating hormone secretion, may be an important factor in glandular mass reduction, decreasing both the production of antibodies to thyroid-stimulating hormone receptors and the frequency of recurrence of hyperthyroidism.

Adolescent↗
PubMed1982

Influence of hyperthyroidism on the kinetics of methimazole, propranolol, metoprolol and atenolol.

The kinetic profiles of oral methimazole 40 mg, propranolol 80 mg, metoprolol 100 mg and atenolol 100 mg were compared in hyperthyroid patients both during the hyper- and euthyroid states. for methimazole, neither the peak concentration (Cmax), the time to reach peak concentration (tmax), the elimination half-life (t 1/2) nor the area under the curve (AUC) value was affected by the hyperthyroid state. For propranolol and metoprolol, which undergo extensive presystemic clearance, the AUC values were lower (p less than 0.02) when the patients were hyperthyroid than when they had become euthyroid, but the t 1/2's were not significantly altered. For atenolol, there were no significant kinetic differences between the hyperthyroid and euthyroid states. The findings are compatible with the assumption that hyperthyroidism does not affect the kinetics of methimazole or atenolol, but that it may enhance presystemic clearance of propranolol and metoprolol.

Administration, Oral↗
PubMed1992

Intellectual capacity of subjects exposed to methimazole or propylthiouracil in utero.

Antithyroid drugs, considered the treatment of choice for hyperthyroidism during pregnancy, may have an adverse effect on intellectual development of the offspring. We examined the intellectual capacity of 31 subjects aged 4-23 years, born to women with Graves disease who received antithyroid drugs throughout pregnancy. Methimazole 40-140 mg/week (n = 15) or propylthiouracil 250-1400 mg/week (n = 16) was given. I.Q. was assessed using the Wechsler test appropriate for age. Twenty-five unexposed siblings served as controls. The exposed and unexposed groups did not differ with respect to the total I.Q. Both groups scored equally in verbal and performance skills and in each of six main subcategories of the tests. There was no difference between exposure to methimazole and propylthiouracil or between the higher (greater than 40 mg/week and greater than 600 mg/week, respectively) and lower dosages. All children were euthyroid at birth and none had goitre. We conclude that exposure to methimazole or propylthiouracil during pregnancy in doses sufficient to control maternal hyperthyroidism does not pose any threat to intellectual capacity of the offspring.

Adolescent↗
PubMed1994

Atrial natriuretic peptide and cyclic guanosine monophosphate plasma concentrations in patients with thyrotoxicosis and atrial fibrillation. Effect of short-term methimazole therapy.

Plasma immunoreactive atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP), serum thyroxine (T4), triiodothyronine (T3), and thyrotropin (TSH) concentrations were measured in 11 patients with thyrotoxicosis and atrial fibrillation (group 1), in 5 patients with thyrotoxicosis and sinus cardiac rhythm (group 2) and in 8 healthy subjects in comparable age. Patients with thyrotoxicosis were studied before and after treatment with methimazole (3 x 20 mg daily) during 10 days. During treatment sinus cardiac rhythm returned in 6 patients with initial fibrillation (group 1a) while 5 patients still presented atrial fibrillation at the end of the study (group 1b). All patients from group 2 maintained a sinus cardiac rhythm throughout the study. Median plasma concentrations of ANP and cGMP before treatment in patients from group 1 were higher: 43.8 pmol/l and 11.0 nmol/l, respectively than in patients from group 2: 20.0 pmol/l (p < 0.005) and 6.5 nmol/l (p < 0.01), respectively. In all groups of patients methimazole treatment resulted in a significant decrease of plasma ANP and cGMP concentrations in parallel to a reduction of serum T3 and T4 levels. After therapy, plasma ANP and cGMP levels in patients from group 1a were not significantly different from those in patients from group 2, while in patients from group 1b remained slightly elevated. Presented results suggest that atrial fibrillation in patients with thyrotoxicosis represents an important factor augmenting plasma ANP and cGMP levels, in addition to the stimulatory effect exerted by thyroid hormones. However, the marked reduction of serum thyroid hormones produced by short-term methimazole treatment in patients with thyrotoxicosis was associated with parallel decrease of plasma ANP and cGMP levels toward normal values. Therefore, the influence of thyroid hormones on plasma ANP and cGMP concentrations seems relatively more important than the effect of atrial fibrillation.

Adult↗
PubMedDate not supplied

Changes of circulating thyroid autoantibody levels during and after the therapy with methimazole in patients with Graves' disease.

The changes occurring in the levels of circulating thyroid microsomal antibody (M-Ab) and antithyroglobulin antibody (Tg-Ab) during antithyroid drug therapy were studied in 32 patients receiving methimazole for Graves' disease. M-Ab was determined by competitive binding radioassay and Tg-Ab by a sandwich radiometric method. Before treatment 25 subjects (78.1%) had abnormally elevated (greater than or equal to 75 U/ml) M-Ab levels. A more than 30% reduction of M-Ab concentration with respect to the pretreatment value was found in 16 (64.0%) of these patients within the first 3-5 months of therapy, in 23 (92.0%) within 8-11 months and in 21 (84.0%) at the end of treatment (16-18 months). No change was found in the 7 patients with initial M-Ab levels less than 75 U/ml. The reduction of M-Ab was more pronounced in the patients with good control of thyrotoxicosis than in those who were still hyperthyroid or were rendered hypothyroid during treatment. Twenty-three patients were followed after completion of the course of methimazole therapy, and 13 of them showed relapse of hyperthyroidism. A significant rise of M-Ab with respect to the values observed at the end of treatment occurred in all relapsing patients who had abnormally elevated M-Ab levels before therapy. With one exception, no M-Ab increase was found in the 10 nonrelapsing patients. However, no difference between relapsing and nonrelapsing patients was observed when the M-Ab changes occurring during treatment were considered. A similar trend during and after withdrawal of therapy was noted for Tg-Ab but, because of the relatively small percentage of positive subjects (25%), the results were less conclusive. The present data indicate that methimazole treatment induces a fall of thyroid antibodies in patients with Graves' disease, and that relapse of hyperthyroidism is associated with an increase of these antibodies. However, the antibody changes occurring during treatment showed no prognostic value in predicting the outcome of therapy.

Adolescent↗
PubMed1985

The effects of castration and/or methimazole feeding on the pituitary response to temperature extremes by cockerels.

The pituitary of goitrogen-treated White Leghorn cockerels is smaller in size than control birds and the pituitaries of castrated cockerels is nearly twice the size of control birds. The pituitary cells generated by these treatments may not be functional thyrotrophs or gonadotrophs and may not be able to respond to their usual stimuli. Low ambient temperature is a well-known stimulus to the thyroid gland acting through pituitary TSH. Cyclic-AMP-dependent protein kinase activity levels are used here as an index of cellular activity in the pituitary and thyroid glands. Castrated cockerels with or without methimazole treatment do not have an increased pituitary cAMP-dependent protein kinase activity in cold. Methimazole-treated birds have an exaggerated pituitary protein kinase response to cold stress when compared with controls. Pituitary cAMP-dependent protein kinase activity is paralleled by a similar activity increase in the thyroid gland of methimazole-treated cockerels and no increase in the thyroid of castrated birds. Castrated birds at all temperatures have an elevated thyroid cAMP-dependent protein kinase activity ratio which is interpreted as the result of removal of testosterone inhibition.

Animals↗
PubMed1995

Sister-chromatid exchanges in lymphocytes from methimazole-induced hypothyroid mice.

The inhibitory effect of an antithyroid drug on mouse T lymphocytes was investigated. Inbred C57BL/6 mice were provided with an antithyroid drug, methimazole, for 2, 4 and 6 weeks and the in vitro responses of the lymphocytes were studied. The proliferative responses of T lymphocytes from the spleen of methimazole (MMI)-treated mice significantly (p < 0.05) decreased following concanavalin A stimulation, and the inhibitory effect became prominent with the increased duration of MMI treatment. A concomitant increase in the frequency of induced sister-chromatid exchanges was also observed in these T lymphocytes. When the splenocytes were stimulated with concanavalin A for 24 h, their ability to produce interleukin-2 (IL-2) was significantly decreased (p < 0.05). The results indicated that methimazole interfered with the normal proliferation of T lymphocytes by suppressing the production of IL-2, a cytokine also known as T cell growth factor, as well as inducing a higher incidence of sister-chromatid exchange during cell division.

Animals↗
PubMed1985

The effects of thyroxine and methimazole treatment on the synthesis of prostacyclin (PGI2) in the rat.

The effects of thyroxine (T4) and methimazole administration on plasma prostacyclin (PGI2) levels in vivo and on PGI2 release by aortic rings incubated in vitro were investigated in rats. Male rats were given single injection of T4 (200 micrograms/100 g body wt) ip every 24 h for either 3, 7 or 14 days for hyperthyroid rats. For hypothyroid rats, a group of rats were given methimazole (0.01 % in drinking water) for 14 days. PGI2 concentrations were determined in plasma and also in the medium in which aortic rings were incubated. PGI2 was measured as 6-keto-PGF1 alpha by RIA. Plasma PGI2 levels in T4-treated groups were found to be significantly higher than those of control animals. Aortic rings obtained from rats given single injection of T4 for 7 and 14 days showed significant increases in release of PGI2 into the incubation medium. In contrast, rats given methimazole for 14 days showed a significant decrease in the production of PGI2 by aortic rings without any significant changes in plasma levels. Direct addition of T4 into the incubation medium did not cause any significant changes in PGI2 release by aortic rings obtained from control rats. These results suggest the regulatory role of thyroid hormone in PGI2 synthesis in vivo.

6-Ketoprostaglandin F1 alpha↗
PubMed2006

Methimazole increases H2O2 toxicity in human thyroid epithelial cells.

Hydrogen peroxide (H(2)O(2)) is necessary for thyroid hormone production and also for intracellular signalling purposes. Owing to its oxidative properties, however, it is harmful to cells, and deregulation of thyroid oxidative state has been implicated in the pathology of thyroid cancer. In this project, we studied the effects of H(2)O(2) on morphology and histochemical indicators of differentiated function (intracellular thyroglobulin), ability to generate NADPH (glucose-6-phosphate dehydrogenase (G6PD) activity) and vitality (apoptosis assay) in human thyroid epithelial cells. We further evaluated whether methimazole, an antithyroid drug reported to have antioxidative properties, could counteract the effects of H(2)O(2). Our data demonstrate tolerance to H(2)O(2) in concentrations less than 0.3mM and harmful effects at higher concentrations. 10mM methimazole sensitizes the cells towards H(2)O(2), possibly due to a dose-dependent inhibition of G6PD. Our data demonstrate the importance of this antioxidative system and point towards a relevant, but seldom recognized, influence of methimazole.

Antithyroid Agents↗
PubMed2004

Methimazole, thyroid hormone replacement, and lipogenic enzyme gene expression in broilers.

The purpose of this experiment was to determine the possible relationship between certain indices of lipid metabolism and specific gene expression in chickens fed methimazole to simulate hypothyroidism. Male broiler chickens (Gallus gallus) growing from 7 to 28 days of age were fed diets containing 18% crude protein and either 0 or 1 g methimazole per kilogram of diet. At 28 days, these two groups were further subdivided into groups receiving 18% crude protein diets containing either 0 or 1 mg triiodothyronine (T3) per kilogram. Birds were sampled at 28, 30, and 33 days. Measurements taken included in vitro lipogenesis (IVL), malic enzyme (ME) activity, isocitrate dehydrogenase, aspartate amino transferase, and the expression of the genes for ME, fatty acid synthase (FAS), and acetyl coenzyme carboxylase (ACC). Hypothyroidism decreased IVL and ME at 28 days of age; however, T3 supplementation for 2 days restored both IVL and ME. Paradoxically, continuing T3 replenishment for an additional 3 days decreased IVL but did not decrease ME activity. In contrast, supplemental T3 decreased IVL in euthyroid birds, regardless of the dosing interval, but had no effect on ME activity. Although methimazole decreased ME gene expression, there was only a transitory relationship between enzyme activity and gene expression when plasma T3 was restored with exogenous T3. These data may help to explain some of the apparent reported dichotomies in lipid metabolism elicited by changes in the thyroid state of animals. In addition, most metabolic changes in response to feeding T3 occurred within 2 to 5 days, suggesting that changes in intermediary metabolism preceded morphological changes. In conclusion, the thyroid state of the animal will determine responses to exogenous T3.

Animals↗