Biomedical subjects

J Buxeraud

Publications and source records attributed to J Buxeraud.

28 records · Page 2Linked to original sources

PubMed1993

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).

Animals↗

PubMed1993

[Antibacterial sulfonamides, antiparasitic and antifungal derivatives of imidazole: evaluation of their antithyroid effects in the rat].

Antithyroid action of some antibacterial, antiparasitic or antifungal agents, was studied by 2 in vitro and 3 in vivo experimentations in the rat. These drugs can upset thyroid hormone synthesis by forming a molecular complex with iodine, and/or by inhibiting thyroid peroxidase activity. Rats treated with these drugs showed an hypothyroidism, demonstrated both by a decrease in T4 concentration and an hyperactivity of thyroid gland by positive feed-back, whose consequence was the presence of cylindrical cells. We noticed this iatrogenic hypothyroidism with all the drugs experimented, by an increase in thyroid gland weight. But the increase of rats body weight, which should have appeared, was not shown. The use of anabolic steroid is now forbidden, therefore, such drugs could be used for breeding animals, in order to gain body weight. Detection of use of these drugs in breeding, to obtain this side effect, should be advised.

Animals↗

PubMed1992

Sites of action of 2-thiazoline-2-thiol on biogenesis of thyroid hormones.

2-Thiazoline-2-thiol is an antithyroid agent that strongly reduces thyroid hormone levels. Synthesis of these hormones is catalyzed in vivo by thyroid peroxidase. The interaction of this drug with molecular iodine and its effect on peroxidase activity were investigated. Iodine and 2-thiazoline-2-thiol form a complex of the charge transfer type of 1:1 stoichiometry characterized by a formation constant of 2,527 l.mole-1 at 20 degrees C. This drug was found to inhibit both horseradish peroxidase and lactoperoxidase (used as a model of thyroid peroxidase) in a competitive manner, giving inhibition constants of 5.7 mM and 0.13 mM, respectively. T3 and T4 levels were reduced significantly after a three-week administration of this drug to a group of 10 rats. Histological examination of the thyroid gland showed the presence of a cylindrical epithelium, which is indicative of hyperactivity of the gland. The results indicated that 2-thiazoline-2-thiol acts on both molecular iodine and thyroid peroxidase.

Animals↗

PubMed1991

Formation of molecular iodine during oxidation of iodide by the peroxidase/H2O2 system. Implications for antithyroid therapy.

The first step in the biogenesis of thyroid hormones is the oxidation of iodides taken up by the thyroid gland. Oxidation of I- by the H2O2/peroxidase system leads to the formation of iodinium ions I+ which bond to thyroglobulin by electrophilic substitution. However, it is not clear whether I- is transformed directly to I+ or whether it passes through a molecular iodine intermediate. This latter possibility is indicated by the oxidation potentials of the reactions. I2 can be detected in vitro from the formation of I3- ions, although this has yet to be confirmed in vivo. The present study was designed to determine, albeit indirectly, whether this reaction occurs in vivo. If I2 is produced, it may form charge transfer complexes with numerous drugs. We also investigated the action of various drugs on lactoperoxidase and assessed their antithyroid activity in the rat by assay of plasma levels of T3, T4, and TSH. We found a good correlation between the value of Kc, the formation constant of the complex of the drug with molecular iodine, and the antithyroid activity in vivo. This correlation was observed in four different classes of compound. The possibility that molecular iodine is produced in the thyroid gland has implications for antithyroid therapy.

Animals↗

PubMed1990

The mechanism of action of synthetic antithyroid drugs: iodine complexation during oxidation of iodide.

A number of compounds of pharmaceutical importance from a variety of chemical families, including thiocyanates, isothiocyanates, thiourea and derivatives, imidazoles, and various amines, were found to form charge transfer complexes with iodine. Parallel studies were carried out to investigate the actions of these drugs on lactoperoxidase and thyroid activity in vivo in the rat (assays of T3 and T4 and histology of the thyroid gland). The results showed that there was a good correlation between the value of Kc (the formation constant of the iodinated complex) and antithyroid activity in vivo. The higher the electron donor power of the compound, the higher the Kc value and the stronger the action on the thyroid. The results indicated that a number of drugs could have secondary antithyroid activity. Some compounds, such as levamisole, tetramethylthiourea, tetrahydrozoline, phenothiazines, and imipramines, with no action on peroxidase had high Kc values (tetramethylthiourea, 13,825 liters/M) and had strong antithyroid activity in the rat. These results suggest that synthetic antithyroid agents may act either on peroxidase and/or the molecular iodine which may be produced by oxidation of iodides (2I(-)----I2----2I+). It has been shown that oxidation of I- can occur in the absence of thyroglobulin. In the absence of a suitable receptor, significant amounts of I2 may, thus, accumulate. The action of such drugs on molecular iodine may have considerable pharmacological significance.

Absorption↗

PubMed1990

Spectroscopic analysis of charge transfer complexes between morpholine and iodine.

It has been demonstrated spectroscopically that many nitrogen-containing heterocyclic compounds can form charge transfer complexes with iodine. The complexes of morpholine with iodine were shown to be of the n-sigma type with a 1:1 stoichiometry. A strong donor-acceptor interaction was found (Kc = 1261 +/- 12 mol-1 at 20 degrees C in CCl4), considerably higher than those of complexes of aromatic compounds with iodine. The high value of the formation constant for this complex indicated that morpholine could serve as a starting point for the synthesis of novel anti-thyroid drugs.

Antithyroid Agents↗

PubMed1989

Spectroscopic analysis of charge transfer complex formation between neuroleptics and iodine.

Molecular interactions between iodine and various neuroleptics were investigated by UV/Vis spectroscopy. Iodine was found to form charge transfer complexes in a 1:1 stoichiometry and of n-sigma type with these molecules. The values of the formation constants Kc of these iodinated complexes indicate a strong donor-acceptor interaction. These drugs can therefore be expected to interfere with thyroid metabolism.

Antipsychotic Agents↗

PubMed1987

Drugs derived from thiazole and imidazole or with nitrogen-carbon-sulphur or tertiary amino groups. Prediction of secondary antithyroid activity by UV/visible spectroscopy.

The chemical structure of various drugs suggests their potential interference with thyroid metabolism by complexing molecular iodine in the thyroid gland. Spectroscopic analysis shows that such compounds form charge-transfer complexes with iodine in a 1:1 stoichiometry. The values of formation constant Kc indicate strong donor-acceptor interactions. Biochemical and histological studies carried out on the rat demonstrated that a correlation exists between the Kc values and the antithyroid activity. A mechanism of action of these molecules on thyroid function is proposed. The potential antithyroid activity of such compounds can therefore be predicted from the Kc values.

Animals↗

PubMed1984

Secondary antithyroid action of drugs in relation to structure.

Molecular interactions between iodine and disulfiram, clomethiazole, and tolnaftate were investigated by electron spectroscopy. Iodine forms charge transfer complexes with these molecules, with 1:1 stoichiometry and of the n-sigma type. The formation constants were compared with those obtained with antithyroid molecules. Only disulfiram appears to have any effect on the intrathyroid cycle of iodine.

Antithyroid Agents↗

PubMedDate not supplied

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.

Adult↗