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[An improved method for plasma methimazole assay and its clinical application].

An improved method for plasma methimazole assay using high performance liquid chromatography is described. The plasma samples were treated with sodium bisulfite and ammonium sulfate prior to extraction with chloroform. This pretreatment of the samples raised the extraction coefficient to 90%, while simple extraction yielded only 55%. The minimal detection limit was 0.02 microgram/ml, and the coefficient of variation at the level of 0.2 and 1.0 microgram/ml was less than 5%. Pharmacokinetics of methimazole was studied after a single oral dose (20 mg/m2) in six subjects including two healthy adults and four thyrotoxic children. Plasma levels of methimazole showed a peak concentration of 1.03 +/- 0.25 microgram/ml approximately one hour after the drug administration. Plasma half-life, area under the curve and distribution volume were 4.56 +/- 0.71 hr, 7.05 +/- 0.95 microgram/ml X hr, and 630 +/- 110 ml/kg respectively.

Adolescent↗

Thyroglobulin-rich colloid goitres: a result of the combined action of lithium and methimazole on the rat thyroid.

Naturally occurring euthyroid goitres in man and goitres produced in experimental animals by iodine deficiency or goitrogen feeding both have in common a thyroglobulin of low iodine content. The latter experimental goitres are always depleted of colloid and thyroglobulin. In contrast, natural goitres often contain excessive amounts of colloid which may accumulate because of endocytosis becoming refractory to TSH. We tested the hypothesis that minute doses of goitrogens could lower the iodine content of thyroglobulin without colloid depletion. We then examined whether such a low-dose 'classical' goitrogen could induce excessive colloid storage rather than depletion if acting in concert with lithium, a cation which blocks endocytosis. Rats on an adequate iodine intake were fed minimal doses of methimazole either alone or combined with lithium chloride. Chronic minimal-dose methimazole treatment lowered the iodine content of thyroglobulin without changing thyroglobulin content and thyroid weight. In contrast, addition of lithium to methimazole, produced goitres containing supranormal amounts of poorly iodinated thyroglobulin. We conclude that borderline doses of goitrogens can lower iodination of thyroglobulin without causing hyperplasia and colloid depletion. Thyroglobulin-rich goitres can be obtained by adding a second goitrogen which inhibits endocytosis. As an alternative to Marine's hypothesis of colloid goitre formation we suggest that inhibition of endocytosis, e g by goitrogens of the lithium type, could cause colloid and thyroglobulin accumulation in human iodine deficiency goitre.

Animals↗

Treatment of hyperthyroidism with a small single daily dose of methimazole.

A prospective randomized trial with the conventional divided doses (10 mg 3 times daily, N = 29) and a small single daily dose (15 mg once daily, N = 25) of methimazole for the treatment of Graves' hyperthyroidism was performed. Within 8 weeks, almost 80% of the patients in both groups became euthyroid. The mean time required to achieve the euthyroid state was 6.0 +/- 2.8 and 6.0 +/- 3.8 weeks, respectively. TSH binding inhibitor immunoglobulin was found in about 90% of the patients in both groups before methimazole treatment. However, a gradual fall of its levels was observed in nearly all patients after treatment. There was no difference in the mean levels of TSH binding inhibitor immunoglobulin between the two groups during therapy. We conclude that the single daily dose regimen of 15 mg of methimazole will control Graves' hyperthyroidism in most patients, and TSH binding inhibitor immunoglobulin levels decrease in this regimen in the same way as with the conventional divided dose regimen (10 mg 3 times daily).

Adult↗

Effects of methimazole treatment on growth hormone (GH) response to GH-releasing hormone in patients with hyperthyroidism.

In vitro studies have demonstrated that thyroid hormones can enhance basal and stimulated growth hormone secretion by cultured pituitary cells. However, both in man and in the rat the effects of high thyroid hormone levels on GH secretion are unclear. The aim of our study was to test the GH response to human GHRH in hyperthyroid patients and to evaluate the effects on GH secretion of short- and long-term pharmacological decrease of circulating thyroid hormones. We examined 10 hyperthyroid patients with recent diagnosis of Graves' disease. Twelve healthy volunteers served as controls. All subjects received a bolus iv injection of GHRH(1-29)NH2, 100 micrograms. Hyperthyroid patients underwent a GHRH test one and three months after starting antithyroid therapy with methimazole, 10 mg/day po. GH levels at 15, 30, 45, 60 min and GH peak after stimulus were significantly lower in hyperthyroid patients than in normal subjects. The GH peak was also delayed in hyperthyroid patients. After one month of methimazole therapy, most of the hyperthyroid patients had thyroid hormone levels in the normal range, but they did not show significant changes in GH levels after GHRH, and the GH peak was again delayed. After three months of therapy with methimazole, the hyperthyroid patients did not show a further significant decrease in serum thyroid hormone levels. However, mean GH levels from 15 to 60 min were significantly increased compared with the control study. The GH peak after GHRH was also earlier than in the pre-treatment study.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Effect of iodide on Fas, Fas-ligand and Bcl-w mRNA expression in thyroid of NOD mice pretreated with methimazole.

Nonobese diabetic (NOD) mice and a derived strain, NOD.H.2h4, have been used as a model for experimental spontaneous thyroiditis and thyroiditis induced by iodide excess after a goiter-inducing period. Some authors have proposed that iodide, given after methimazole or propylthiouracil, is capable of inducing apoptosis in thyroid cells and that anti-thyroid drugs can modulate the expression of apoptosis components such as Fas and its ligand (Fas-L). Here we evaluated the effect of potassium iodide (20 microg/animal for 4 days, i.p.) given to NOD mice at the 10th week of life after exposure to methimazole (1 mg/ml) in drinking water from the 4th to the 10th week of life. Fas, Fas-L and Bcl-w expression were analyzed semiquantitatively by RT-PCR immediately after potassium iodide administration (group MI44D) or at week 32 (MI32S). Control groups were added at 10 (C10) and 32 weeks (C32), as well as a group that received only methimazole (CM10). An increase in the expression of Fas-L and Bcl-w (P<0.01, ANOVA) was observed in animals of group MI44D, while Fas was expressed at higher levels (P = 0.02) in group C32 (72.89 +/- 47.09 arbitrary units) when compared to group C10 (10.8 +/- 8.55 arbitrary units). Thus, the analysis of Fas-L and Bcl-w expression in the MI44D group and Fas in group C32 allowed us to detect two different patterns of expression of these apoptosis components in thyroid tissue of NOD mice.

Animals↗

Insulin autoimmune syndrome after the third therapy with methimazole.

In 1986, a 26-year-old female had been diagnosed as having Graves' disease and had been treated with methimazole for four months. After the treatment with propylthiouracil for another four months, she had been treated with methimazole once again. She was in complete remission for two years. She again experienced symptoms of hyperthyroidism, and treatment with methimazole was started again. On the thirteenth day after treatment, she experienced hypoglycemic attacks with skin eruption. The plasma glucose was 57 mg/dl, 125I-Insulin binding 69%, free IRI 196 microU/ml. The patient had the HLA-DRB1*0406.

Adult↗

The effect of rapeseed meal and methimazole on levels of plasma hormones in growing broiler cockerels.

The effects of feeding a heat treated rapeseed meal, which has goitrogenic properties, on the concentrations of plasma pituitary and thyroid gland hormones was investigated in broiler cockerels of between 3 and 10 weeks of age. For purposes of comparison, two other groups were included in the study; one was fed the goitrogen, methimazole, and the other a normal control diet. The hormones measured were thyroxine (T4), triiodothyronine (T3), growth hormone (GH), prolactin, and luteinizing hormone (LH). In birds fed methimazole the thyroid glands were greatly enlarged, the concentrations of plasma T4 and T3 were depressed and the concentrations of growth hormone, prolactin, and LH were elevated. The high level of plasma LH in the birds fed methimazole was not due to the absence of sufficient concentrations of plasma testosterone to exert a negative feedback effect. Although the inclusion of rapeseed meal in the diet caused the thyroid glands to enlarge, the concentrations of all the hormones studied, with the exception of T3, were similar to those in the control birds. However, there was a tendency, which was more pronounced in birds of between 3 and 5 weeks of age, for rapeseed meal to depress the concentrations of plasma T4, GH, and LH and to increase the concentration of plasma prolactin. The most significant observation was that between 3 and 5 weeks of age the inclusion of rapeseed meal in the diet significantly (P less than .001) depressed the concentration of plasma T3.

Age Factors↗

Effects of methimazole on renal function in cats with hyperthyroidism.

The purpose of this study was to investigate the effects of methimazole on renal function in cats with hyperthyroidism. Twelve cats with naturally occurring hyperthyroidism and 10 clinically normal (i.e., control) cats were included in this study. All cats initially were evaluated with a history, physical examination, complete blood count, serum biochemistry profile, basal serum total thyroxine concentration, complete urinalysis, and urine bacterial culture. Glomerular filtration rate (GFR) was estimated by a plasma iohexol clearance (PIC) test. After initial evaluation, hyperthyroid cats were treated with methimazole until euthyroidism was achieved. Both groups of cats were then reevaluated by repeating the initial tests four to six weeks later. The mean (+/-standard deviation) pretreatment estimated GFR for the hyperthyroid cats was significantly higher (3.83+/-1.82 ml/kg per min) than that of the control cats (1.83+/-0.56 ml/kg per min). Control of the hyperthyroidism resulted in a significantly decreased mean GFR of 2.02+/-0.81 ml/kg per minute when compared to pretreatment values. In the hyperthyroid group, the mean increases in serum urea nitrogen (SUN) and creatinine concentrations and the mean decrease in the urine specific gravity after treatment were not statistically significant when compared to pretreatment values. Two of the 12 hyperthyroid cats developed abnormally high serum creatinine concentrations following treatment. These results provide evidence that cats with hyperthyroidism have increased GFR compared to normal cats, and that treatment of feline hyperthyroidism with methimazole results in decreased GFR.

Animals↗

[Bilateral renal agenesis (Potter's syndrome) in a girl born to a hyperthyroid mother who received methimazole in early pregnancy].

Bilateral kidney agenesias (Potter syndrome) in a newborn of a hyperthyroid woman receiving methimazole during early pregnancy. This is a clinical case of a hyperthyroid woman that received methimazole during early pregnancy who gave birth to a girl with bilateral kidney agenesis. The initial clinical data was the presence of oligohydramnios detected by an ultrasound (US) at 19 gestational weeks. Another US at the term of the gestation showed anhydramnios, absence of renal silhouettes and bladder, which was corroborated when the girl was born. She died two days after she was born. Sufficient evidence exists that the methimazole administered during the early pregnancy can cause diverse congenital malformations including Potter's syndrome.

Abnormalities, Multiple↗

Methimazole-induced lupus erythematosus: a case report.

A 15-year-old girl had a history of diffuse goiter and received methimazole treatment 2 months before admission to the hospital. She developed bilateral lower leg edema 5 days before admission and the laboratory examinations revealed leukopenia, anemia, proteinuria, and granular cast. Positive antinuclear antibodies and anti-double strand (anti-ds) DNA antibodies were noted, although complement levels were not reduced. Myeloperoxidase antineutrophil cytoplasmic antibody was positive. A renal biopsy disclosed that there was focal segmental glomerulosclerosis. Methimazole was discontinued, and she was treated with prednisolone and Plaquenil, after which the symptoms and laboratory tests became normal within 40 days. The prednisolone was discontinued after treatment for seven months. Currently, the anti-dsDNA, C3, C4, CBC, urinalysis, and thyroid function tests are within normal limits. With hydroxychloroquine and levothyroxine, she was free of symptoms after discontinuation of methimazole until now (about 21 months).

Adolescent↗

[Effect of intravenous methimazole on serum levels of thyroid hormones in patients with hyperthyroidism resistant to oral thyrostatic drugs].

The effectiveness of therapy involving intravenous administration of methimazole applied in patients with hyperthyroidism resistant to oral thyrostatic drugs has been investigated. Methimazole (Favistan, Asta) was administered intravenously to 3 patients (two women and one man, of ages 21, 24 and 67 years, respectively) in whom there was no remission of the disease after oral methimazole therapy lasting at least two months. Blood serum concentrations of thyroxine (T4), triiodothyronine (T3), reverse++ triiodothyronine (rT3) and triiodothyronine binding index (T3I) have been measured and free thyroxine index (FT4I) calculated before the treatment and on the 4-th, 7-th, 11-th, 14-th and 17-th day of the treatment. The mean value of T4 concentration decreased from 17.0 micrograms/dl before the treatment to 9.7 micrograms/dl after the treatment. T3 from 352 to 177 ng/dl, rT3 from 114 to 103ng/dl the value of T3I from 183 to 161%, and that of FT4I from 30 to 17, respectively. A significant fall of T3 level was observed on the 11-th day of the therapy, that of rT3 on the 14-th day, and that of FT4I on the seventh day. It was concluded that the resistance of some patients with hyperthyroidism to the oral thyreostatic therapy may be caused by the defective absorption of these drugs from the intestinal tract.

Administration, Oral↗

Validation of a developmental swimming test using Swiss Webster mice perinatally treated with methimazole.

The swimming method of Klaus and Hacker, developed for the AB/Jena and DBA2/Jena mouse strains, was evaluated for use with pre-weaned Swiss Webster (SW) mice. All SW mice completed the swimming pattern by postnatal day (PND) 16, but did not conform to all criteria depicted for each stage of the methodology. These swimming differences among strains required modification of the above method for the SW mouse. An expanded and revised swimming methodology included evaluation of limb movement and placement; body position; head position, including nostril and ear positions; and direction of movement. The revised methodology was validated on PND 4 through 20 with offspring of methimazole-treated or untreated SW dams. Methimazole, an antithyroid agent, was administered in drinking water (0.1 mg/ml; day 16 of pregnancy through day 10 postpartum). Untreated dams received tap water. Methimazole pups exhibited significant delays in swimming development on PND 9 through 16. This revised swimming methodology provides another preweaning test for the detection of behavioral teratogens for SW and probably other strains of mice.

Animals↗

Effect of perinatal methimazole exposure on enolase isozymes in the developing rat.

The induction of hypothyroidism by methimazole produces a delay in CNS development as well as behavioral deficits in rat pups. Methimazole (0.1 mg/ml) was administered via drinking water to dams from gestational day 17 to postnatal day 10. Rat pup body weight was reduced on postnatal day 15 (P15) and 30 (P30) while brain weight was decreased only at P15. Soluble brain protein was decreased at P15 and P30. Total enolase and neuron-specific plus hybrid enolase (NSE+H) specific activity and activity were reduced on P15, while non-neuronal enolase (NNE) activity but not specific activity was depressed. At postnatal day 30, total enolase and NSE+H activity were slightly reduced, but NNE activity and the specific activities of total enolase, NNE and NSE+H were similar to controls. The ratio of NSE+H to NNE was reduced at P15 but not P30. The alterations in enolase activity following methimazole administration suggest a delay in the development and maturation of the CNS at P15. These results provide a biochemical correlate of the developmental delays reported in hypothyroid rat pups.

Age Factors↗

Methimazole-induced agranulocytosis treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF): a case report.

Methimazole 5 mg three times daily was prescribed in 1994 spring to a woman, aged 53 years, with relapsed hyperthyroidism. The drug was discontinued six weeks after initiation because of leukopenia. Two weeks still later, the patient developed chills, high fever, and a sore throat. The leukocyte count was 1,100/mm3 with 23% granulocytes, 76% lymphocytes and 1% monocytes. The granulocyte count stopped decreasing only three weeks after the drug was discontinued when the recombinant human granulocyte colony-stimulating factor (rhG-CSF) was given; the patient recovered uneventfully. Thus we recommend that the peripheral leukocyte count of patients who receive methimazole therapy must be carefully monitored during the first three months. Furthermore, the use of rhG-CSF for methimazole-induced agranulocytosis abbreviates the period required for marrow recovery after cessation of this offensive drug.

Agranulocytosis↗

The effect of methimazole on the growth of the developing brushtail possum, Trichosurus vulpecula.

The brushtail possum, Trichosurus vulpecula, produces a single offspring 200 mg in body weight. The young grow slowly during the first half of pouch of life at approximately 1g/day. At day 96 post partum the growth rate increases dramatically and it has been suggested that this change in growth rate may result from the initiation of thyroid function in the young possum. To determine the role of the thyroid gland of the possum on growth, the production of hormones from the thyroid was inhibited by administration of the drug, methimazole. The drug was administered to adult and young possums at day 140 post partum for 28 days and to young at day 100 post partum for 42 days and the effects of this treatment on plasma concentrations of thyroxine and on growth were monitored. Methimazole was found to inhibit thyroxine production in 4 of the 6 adult possums although it had no effect on body weight. Similar treatment administered to nine young possums inhibited growth. The three surviving methimazole possum young treated at 100 days post partum weighed less than control possums after day 163 post partum. The four young treated at 140 days post partum also showed depression in growth rate. However, the depression was not as marked as that of the 100 day treated possums. It is highly likely therefore that the surge in growth rate in the possum at day 96 post partum is initiated by thyroxine produced by the thyroid gland of the young.

Animals↗

Recombinant human granulocyte colony-stimulating factor in treatment of methimazole-induced agranulocytosis.

OBJECTIVE: To describe a patient with methimazole-induced agranulocytosis who was treated with recombinant human granulocyte colony-stimulating factor (G-CSF). METHODS: A case report is presented, in which the clinical and laboratory findings are detailed and the response to treatment is discussed. Pertinent reports from the literature are reviewed. RESULTS: In a 24-year-old woman with Graves' disease who was treated with methimazole, a fever and sore throat developed; bone marrow examination revealed absence of granulocytes. After discontinuation of methimazole therapy, treatment with G-CSF was implemented in an attempt to hasten the reappearance of the granulocytes. The patient's granulocyte count reached 0.5 10(9)/L on the 9th hospital day and was more than 1.5 10(9)/L on the 10th day. Because the recovery time for thionamide-induced agranulocytosis typically ranges from 1 to 2 weeks and sometimes is even longer, G-CSF may have been beneficial in accelerating the return of the granulocytes. CONCLUSION: Only a small number of patients with thionamide-induced agranulocytosis have had G-CSF treatment, and most outcomes have generally supported a beneficial effect. More experience is needed with the use of G-CSF in such circumstances. Nevertheless, its use seems to be a reasonable therapeutic option for consideration in patients with thionamide-induced agranulocytosis.

Journal Article↗

Successful outcome with methimazole and lithium combination therapy for propylthiouracil-induced hepatotoxicity.

OBJECTIVE: To assess the efficacy and safety of combination therapy with methimazole and lithium carbonate in management of severe thyrotoxicosis and propylthiouracil-induced hepatotoxicity. METHODS: We present a case report of a patient with severe thyrotoxicosis and worsening liver dysfunction after propylthiouracil therapy, and we review the pertinent literature. RESULTS: In a 49-year-old man with severe thyrotoxicosis and propylthiouracil-induced hepatotoxicity, indices of liver function continued to increase despite discontinuation of propylthiouracil treatment. Adjunctive therapy with methimazole and lithium resulted in prompt remission of clinical manifestations and normalization of thyroid hormone indices, as well as a gradual reversal of liver dysfunction. CONCLUSION: Adjunctive therapy with methimazole and lithium is synergistic in promptly achieving a euthyroid state. Therefore, this combination therapy provides a safe and effective alternative option in patients with thyrotoxicosis associated with propylthiouracil-induced hepatotoxicity.

Journal Article↗

Choanal atresia and hypothelia following methimazole exposure in utero: a second report.

We report on a 3-year-old boy with bilateral choanal atresia, hypoplastic nipples, and developmental delay who had been exposed to carbimazole in utero because of maternal Graves disease. His combination of abnormalities and facial appearance strongly resembles that of a previously reported child exposed to methimazole (which is the active metabolite of carbimazole) in utero. We suggest that this represents a rare but distinct syndrome of methimazole teratogenicity, probably related to first-trimester exposure. Recognition of such teratogenic effects is clearly important for genetic counselling and for management of subsequent pregnancies.

Abnormalities, Multiple↗