Antithyroid action of tamoxifen in the rat: in vivo and in vitro studies.

The influence of administration of tamoxifen (TAM) on thyroid metabolism was investigated. The potential action of TAM on iodine in the thyroid gland was evaluated by determination of the equilibrium constant of the charge transfer complex formed with molecular iodine and by computational studies. Adverse effects of TAM on thyroid function parameters were also investigated in female Wistar rats. Rats were treated for seven weeks with 5 mg/kg/day of TAM. Irrespective of the iodine content of the diet, administration of TAM led to goitre and a significant increase in levels of T4 and TSH. Similar results, albeit more marked, were observed after administration of an inhibitor of thyroid peroxidase. We also showed that TAM forms charge transfer complex with iodine (Kc = 876 liters/mol). We concluded that under our experimental conditions, TAM exerts antithyroid activity from an action on thyroid peroxidase. Nevertheless, when the exogenous iodine contribution is restricted, TAM may sequester iodine in the form of charge transfer complexes, thereby enhancing hypothyroidism.

Influence of dietary iodine on drug-induced hypothyrodism in the rat.

Several compounds of pharmaceutical importance from a variety of chemical families, for example chlorpromazine and clomipramine, have been found to form charge-transfer complexes with iodine. We have investigated the influence of dietary iodine on thyroid-gland dysfunction induced by clomipramine, chlorpromazine or 2-thiazoline-2-thiol. We suggest that iodine is partly diverted from its metabolic pathway by complexation with drugs, and so the urinary concentration of iodide is increased. Both chlorpromazine and clomipramine, at doses which do not inhibit thyroperoxidase, enhanced urinary iodine excretion when dietary iodine was restricted (3.944+/-0.96 microg/day for chlorpromazine-tested rats, 3.43+/-1.33 microg/day for clomipramine-tested rats, compared with 2.34+/-0.11 microg/day in control rats). Concurrently, these pharmaceutical compounds increased the level of free thyroid-stimulating hormone (TSH) in comparison with controls and induced histological modifications in, and enlargement of, the thyroid gland. We have demonstrated that drug-induced loss of iodine in the urine was associated with antithyroid action when iodine intake was limited.

Thyroid accumulation and adverse effects of imipramine and desipramine in rats after long-term administration.

The respective adverse effects of imipramine and desipramine on serum thyroid hormone levels and their accumulation in thyroid were investigated in male Wistar rats. Two groups of 30 rats were gavaged for 4 weeks with 30 mg/kg/day imipramine hydrochloride (IMI) or desipramine hydrochloride (DESI), while the control group (12 rats) received the arabic gum vehicle only. In the IMI-treated group, the serum thyroxine (T4) level significantly decreased (by 13%) and IMI and its metabolite DESI were accumulated in the thyroid, as pointed out by mean thyroid-to-serum concentration ratios close to 12 and 8, respectively. In the DESI-treated group, the mean thyroid-to-serum concentration ratio of the drug was close to 14, and significant decreases in both serum T4 (-20%) and triiodothyronine serum levels (-14%) were found. The accumulation of antidepressant drugs in the thyroid was more pronounced and the thyroid serum levels were even lower after DESI administration than after IMI administration. These results are in favour of an antithyroid action of IMI and DESI due to the formation of a complex in the thyroid between molecular iodine and the drugs or metabolites.

Relationship between psychotropic drugs and thyroid function: a review.

Some widely used psychoactive drugs, such as tricyclic antidepressants and antipsychotic phenothiazines exhibit iatrogenic effects on the thyroid. These side effects may arise from interactions at different steps of thyroid hormone biosynthesis. These drugs can induce a change in iodine capture by thyroid cells or can complex iodine, making it unavailable for thyroid hormone synthesis and thus decreasing thyroid hormone blood levels; they can also inhibit thyroid peroxidase activity and thus T3 and T4 synthesis or enhance deiodination of T4 to T3 or to Rt3 by stimulation of deiodinase activity. Moreover, tricyclic antidepressants interfere with the hypothalamic-pituitary-thyroid axis via the noradrenergic or serotonergic systems and might therefore decrease T4 or T3 blood levels, respectively. Phenothiazines can induce autoimmune hypothyroidism, as shown by an increase in the expression of the major histocompatibility complex antigen and by a production of antithyroglobulin or antithyroperoxidase antibodies. However, all these mechanisms are only speculative in humans, as they have only been demonstrated in vitro or in animal experiments. Clinically, thyroid function and affective disorders are closely linked. On one hand, the therapeutic response to antidepressants could be influenced by the thyroid status; on the other hand, the larger the thyroxin decrease induced by antidepressants, the better the therapeutic effect might be. Moreover, cotreatment with thyroid hormones and antidepressant drugs could allow either a decrease in the rate of treatment failure or a faster recovery from depression. As antipsychotic or antidepressant treatments are administered over long periods in humans, their thyroid toxic effects must be taken seriously.

Anti-inflammatory action of methimazole.

The anti-inflammatory activity of 1-methylimidazole-2-thiol (methimazole), the most widely used antithyroid drug, was investigated. Methimazole had a marked inhibitory action on prostaglandin H synthase (IC50 = 10 mumol/l), inhibiting the peroxidase (IC50 = 330 mumol/l), although the cyclo-oxygenase was slightly activated. Methimazole was less potent than indometacin (IC50 = 1.7 mumol/l) on prostaglandin H synthase, but was more potent than acetylsalicylic acid (IC50 = 160 mumol/l). Methimazole has been found to trap superoxide (O2.-) radicals and to decrease the level of blood prostaglandin E2.

Sensitive microanalysis of imipramine and desipramine in single rat thyroids by gas chromatography-mass spectrometry.

A new sensitive method for the quantitative determination of imipramine and desipramine in single rat thyroids using gas chromatography-mass spectrometry with selected ion monitoring, after enzymatic hydrolysis and liquid-liquid extraction has been developed. The technique was deemed suitable for microanalysis of single rat thyroids and for other solid tissues, using smaller sample sizes than usually required for traditional determination methods. The quantification was linear from 10 to 200 nmol/l (i.e., from 0.25 to 5 microg/g) for imipramine and from 100 nmol/l to 2000 nmol/l (i.e., from 2.4 to 47 microg/g) for desipramine, and the limits of detection (less than 25 ng/g tissue for both compounds) were better than those previously reported. Recoveries, repeatability and reproducibility of this technique were satisfactory. It has been successfully applied in a preliminary study of the concentration-time profiles of imipramine and desipramine in the thyroid of rats treated with either of these drugs.

Methimazole inhibits peripheral lymphocyte proliferation by inducing S-quiescent phase arrest.

The influence of methimazole (MTI) on the mitogenic proliferation of human blood lymphocytes was studied in vitro to evaluate the potential immunomodulatory activity of this antithyroid drug. The effects of the drug on the lymphocyte cell cycle were assessed by multiparametric flow cytometry. Although MTI induced an increase in the number of lymphocytes in the synthesis and G2M compartments, it failed to stimulate proliferation as the cells tended to accumulate in the quiescent S compartment. The effect was dose-dependent over a range from 0.1 to 100 mM. These in vitro results indicate that MTI possesses immunosuppressive activity.

Spectroscopic analysis of charge transfer complex formation and peroxidase inhibition with tricyclic antidepressant drugs: potential anti-thyroid action.

Inspection of the chemical structures of tricyclic antidepressant drugs indicates that they might interfere with the synthesis of thyroid hormones. This iatrogenic potential was demonstrated in vitro by the spectrophotometric detection in both the visible and UV regions of the formation of a complex between antidepressants and iodine. The values of Kc, the formation constant of the drug-iodine complex, were calculated. The concentration of antidepressant which led to a 50% inhibition (IC50) of horseradish peroxidase was also determined. The anti-thyroid activity of drugs can be evaluated from these two parameters, Kc and IC50. The results were compared to those obtained with methimazole, a reference anti-thyroid agent. Antidepressants derived from imipramine appeared to have anti-thyroid activity. This result is now awaiting confirmation in animal experiments.

Synthesis and inhibitory effects of 2-pyridyl-2-thiobenzoxazole and 2-pyridyl-2-thiobenzimidazole derivatives on arachidonic acid metabolism.

A series of new 2-pyridyl-2-thiobenzoxazole and 2-pyridyl-2-thiobenzimidazole compounds was prepared and investigated by a number of in vitro methods in order to determine their prostaglandin synthesis inhibitory activity. The most active compound decreases prostaglandin production and carrageenin edema, but has a less platelet antiaggregatory activity.

Lymphoproliferative activity of methimazole: free SH group dependency.

1. The comparative effects of methimazole (MTI), an antithyroid drug, and its S-methyl derivate (MMTI), were studied in vitro on the lymphoproliferative response to lectin in order to point out the free SH group importance. The cell cycle analysis was performed by flow cytometry after cellular DNA staining by propidium iodide. 2. We showed that MTI enhanced the PHA-induced DNA synthesis phase (P < 0.05 from 1 to 100 microns) whereas MMTI had no significant activity. The free SH group seems to be necessary to the MTI immunomodulatory activity.

Synthesis and antithyroid activity of 1,4,5-trialkyl 2-thioimidazole derivatives.

A series of compounds based on the structure of MTI (1-methyl-2-thioimidazole) were synthesized by condensation of alpha-hydroxyketones and alkylthioureas. The alpha-hydroxyketones were obtained by a radical reaction in the presence of sodium and the alkyl ester, while the alkylthioureas were prepared by nucleophilic addition of ammonia on an alkylisothiocyanate. The antithyroid activity of the 13 compounds prepared was evaluated in vitro by determination of the concentrations which led to a 50% inhibition (IC50) of the activity of thyroid peroxidase, and in vivo by assay of thyroid hormones levels and histological examination of the thyroid gland in rats treated chronically with the compounds. 1-methyl-4,5-dipropyl 2-thioimidazole (compound 10) was found to have the highest antithyroid activity of the 13 compounds synthesized.

Synthesis and inhibitory effects of 1,4,5-trialkyl-2-thioimidazole derivatives on platelet aggregation.

New 1,4,5-trialkyl-2-thioimidazole have been synthesized by the condensation of alpha-hydroxyketones and alkylthioureas. The in vitro platelet aggregation inhibiting effect of prepared compounds on human platelets was studied in the presence of ADP and collagen as inducers. The formation of thromboxane B2(TXB2) was inhibited. 1-isopropyl-4,5-dimethyl-2-thioimidazole has the greatest aggregation inhibiting effect, about 4 times that of aspirin. It highly inhibits the production of TXB2 (68.5% for a final concentration of 0.04 M).

1,4,5-trialkyl imidazole system anti-inflammatory properties of new substituted derivatives.

In an investigation of the anti-inflammatory properties of five-membered ring nitrogen-containing heterocyclic compounds, two series of derivatives of imidazole were prepared by altering the sites of substitution and by joining aliphatic chains to the nitrogen atom in the 1 position of the imidazole ring. Some of them were more potent inhibitors of carrageenan-induced edema than indomethacin. An electron spin resonance study indicated that these compounds possess anti-radical activity.

Antithyroid action of ketoconazole: in-vitro studies and rat in-vivo studies.

Inspection of the chemical structure of ketoconazole indicates that it may have antithyroid activity. The antithyroid action of this drug was demonstrated in-vitro and in-vivo. In-vitro, it was found to form a complex with iodine (formation constant Kc 141 L mol-1), and to inhibit lactoperoxidase (IC50 2 x 10(-4) M). Its effects in-vivo in the rat were assessed by assay of circulating-thyroxine, and from the histological appearance of the thyroid gland. Thyroid gland weight was increased in rats treated with ketoconazole.

Synthesis and antithyroid activity of pyridine, pyrimidine and pyrazine derivatives of thiazole-2-thiol and 2-thiazoline-2-thiol.

A series of compounds was synthesized by linking various derivatives of pyridine, pyrimidine or pyrazine to thiazole-2-thiol or to its partially hydrogenated derivative 2-thiazoline-2-thiol. The reactions of the compounds with molecular iodine and lactoperoxidase were examined in vitro. Their antithyroid activity was also examined in vivo in the rat. T4 and TSH levels were determined, and the thyroid gland was examined histologically. 2-(3-Hydroxy-2-pyridyl)-2-thiothiazoline had the highest antithyroid activity of the compounds tested (Kc = 14931.mol(-1),IC(50)0.65 x 10(-4) M, activity of thyroid gland).