Treatment of Hyperthyroidism with a Small Single Daily Dose of Methimazole

Shiroozu, Akiyo; Okamura, Ken; Ikenoue, Hiroshi; Sato, Kaori; Nakashima, Toshiro; Yoshinari, Mototaka; Fujishima, Masatoshi; Yoshizumi, Takayuki

doi:10.1210/jcem-63-1-125

Cited by 69 publications

(57 citation statements)

References 15 publications

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“…Although the incidence of agranulocytosis with lowdose MMI was one-tenth that of the high-dose regimen, the clinical effectiveness of the regimens was similar [1][2][3]5], suggesting that there is no longer a convincing rationale for continuing high-dose MMI. Despite convincing evidence for the effectiveness of low-dose MMI, many patients referred to our clinic had been placed on high-dose MMI, perhaps because Japanese reference books recommend an initial dose of 30 mg. We do not have data for the other major antithyroid drug, propylthiouracil (PTU), because it is not our first choice for treatment of Graves' disease.…”

Section: Discussionmentioning

confidence: 99%

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The Relation of Initial Methimazole Dose to the Incidence of Methimazole-induced Agranulocytosis in Patients with Graves' Disease

et al. 2007

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Abstract. The relation between the incidence of methimazole (methylmercaptoimidazole; MMI)-induced agranulocytosis and initial MMI dose was evaluated in a group of 514 patients with Graves' disease who were treated between 1995 and 2005. One hundred and forty-six (28.40%) patients had received an initial dose of 30 mg MMI and 277 (53.89%) patients had been treated with 15 mg MMI. Nine patients (1.75%) developed agranulocytosis due to MMI treatment. Six (4.11%) of 146 patients who received an initial dose of 30 mg MMI, two (4.54%) of 44 patients given an initial dose of 20 mg MMI, and one (0.36%) of 277 patients given an initial dose of 15 mg MMI developed agranulocytosis. There was a statistically significant difference in agranulocytosis incidence between patients receiving an initial dose of 30 mg MMI and those who received an initial dose of 15 mg. Although 8 (4.10%) of 195 patients in the high-dose group (20 mg or higher) developed agranulocytosis, only 1 (0.31%) of 319 patients in the low-dose group (15 mg or lower) did. In conclusion, the incidence of agranulocytosis with low-dose MMI therapy was ten times lower than that of the high-dose regimen.

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Section: Discussionmentioning

confidence: 99%

“…Shirooze et al [1] and Okamura et al [2] reported that the effectiveness of low-dose methimazole (methylmercaptoimidazole; MMI) for the treatment of hyperthyroidism was no less than that of 30 mg MMI. In addition, a European prospective randomized study [3] reported that 10 mg and 40 mg MMI regimens were equally effective.…”

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confidence: 99%

The Relation of Initial Methimazole Dose to the Incidence of Methimazole-induced Agranulocytosis in Patients with Graves' Disease

et al. 2007

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“…Although the plasma half-life of MMI is about 3-6 h [13,14], the plasma concentration may have little bearing on the duration of its action. MMI is accumulated by the thyroid [15], and a single dose of 15-30 mg of MMI may exert an antithyroid effect for more than 24 h [9,16].…”

Section: Discussionmentioning

confidence: 99%

“…In 1986, Shiroozu et al [9] reported that a single daily dose of 15 mg of MMI was as effective as 10 mg administered 3 times daily or 30 mg administered once daily. Several studies have since revealed the efficacy of a small single daily dose of MMI for the initial control of thyrotoxicosis.…”

Section: Discussionmentioning

confidence: 99%

Treatment of Hyperthyroidism with a Small Single Daily Dose of Methimazole: A Prospective Long-Term Follow-Up Study.

et al. 1997

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Abstract.A prospective long-term follow-up study was performed with conventional divided doses (group C:10 mg 3 times daily, N=58) and a small single daily dose (group S:15 mg once daily, N=54) of methimazole (MMI) for the treatment of Graves' hyperthyroidism. Within 8 weeks, almost 80% of the patients in both groups became euthyroid. The mean time required to achieve a euthyroid state was 5.6 ± 2.7 weeks in group C and 5.8 ± 3.1 in group S. TSH binding inhibitor immunoglobulin (TBII) levels before therapy were 44.2 ± 22.7% and 47.1 ± 23.9% in group C and group S, respectively. A similar gradual fall in TBII levels was observed in both groups over a two-year period of treatment. MMI doses were gradually reduced to a maintenance dose (5 mg daily) after the patients became euthyroid. The patients were treated for 28 ± 9 months and were followed up after therapy was stopped (observation period in patients who remained in remission was 12-130 (75 ± 34) months and the interval to relapse in reccured cases was 1-98 (20 ± 27) months).The rates of recurrence in group C were 41% at 1 yr, 54% at 2 yrs, 56% at 4 yrs and 61% at 6 yrs. In group S, these were 44%, 53%, 56% and 63%, respectively. No differences between relapse rates were observed with the two different dosage regimens. Adverse effects occurred more frequently in group C patients (24%) than in group S patients (13%). These results show that there is no difference in the clinical and immunological course or in the long-term remission rate of Graves' hyperthyroidism when the treatment is initiated with either a small single daily dose (15 mg) or the conventional regimen (10 mg 3 times daily).

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“…Methimazole is used in the treatment of hyperthyroid conditions in humans at doses of 0.2-2 mg/ kg/day po (6,17,31 ). The drug belongs to the thioureylene class of antithyroid drugs, specifically, the thioamides (16).…”

Section: Introductionmentioning

confidence: 99%

Olfactory Toxicity of Methimazole: Dose-Response and Structure-Activity Studies and Characterization of Flavin-Containing Monooxygenase Activity in the Long-Evans Rat Olfactory Mucosa

et al. 1995

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Methimazole is a compound administered to humans for the treatment of hyperthyroidism and is used experimentally as a model substrate for the flavin-containing monooxygenase (FMO) system. Previous results from this laboratory demonstrated that methimazole is an olfactory system toxicant, causing nearly complete destruction of the olfactory epithelium in the male Long-Evans rat following a single ip dose of 300 mg/kg.The present studies were undertaken to determine the dose-response relationship for methimazole-induced olfactory mucosal damage and to determine whether or not similar damage occurs as a result of oral administration, mimicking the relevant route of human exposure. We also investigated the mechanism of olfactory toxicity of methimazole by means of a structure-activity study and began the characterization of the form(s) of FMO present in the olfactory mucosa of the male Long-Evans rat. Dose-response analysis demonstrated that methimazole causes olfactory mucosal damage at doses of 25 mg/kg ip and greater. The results of gavage studies showed that a single oral dose of 50 mg/kg also caused olfactory mucosal damage. Two structurally related compounds, methylimidazole and methylpyrrole, were not olfactory toxicants, suggesting that a reactive intermediate generated in the course of metabolizing methimazole to an S-oxide is the olfactory toxic species. Microsomal incubation studies revealed the presence ofmethimazole S-oxidation activity in olfactory mucosal microsomes at levels comparable to those in liver. An anti-mouse liver FMO antibody reacted on Western blots with olfactory mucosal microsomes. These findings demonstrate a doseresponse for the olfactory toxicity of methimazole and suggest that characterization of human olfactory mucosal FMO activity may be necessary to assess the potential for human risk associated with therapeutic exposure to methimazole.

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Treatment of Hyperthyroidism with a Small Single Daily Dose of Methimazole

Cited by 69 publications

References 15 publications

The Relation of Initial Methimazole Dose to the Incidence of Methimazole-induced Agranulocytosis in Patients with Graves' Disease

The Relation of Initial Methimazole Dose to the Incidence of Methimazole-induced Agranulocytosis in Patients with Graves' Disease

Treatment of Hyperthyroidism with a Small Single Daily Dose of Methimazole: A Prospective Long-Term Follow-Up Study.

Olfactory Toxicity of Methimazole: Dose-Response and Structure-Activity Studies and Characterization of Flavin-Containing Monooxygenase Activity in the Long-Evans Rat Olfactory Mucosa

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