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C Raby

Publications and source records attributed to C Raby.

At least 19 recordsLinked to original sources
PubMed1999

In vitro and in vivo study of the antithyroid side effects of trimeprazine.

Trimeprazine (TMP), a phenothiazine used as antipsychotic drug, was previously shown to induce a decrease in thyroid hormone serum levels in rats. Different mechanisms might be involved, mainly (i) a central mechanism, involving a reduction of thyroid-stimulating hormone (TSH) secretion; (ii) a peripheral mechanism, acting upon the synthesis of thyroid hormones, by inhibition of thyroperoxidase (TPO) or trapping of molecular iodine present in the thyroid gland. These different hypotheses were investigated in the present study, using in vitro and in vivo experiments. In vitro studies concerned TMP and its three main metabolites: trimeprazine sulphoxide (TSO), N-desmethyl trimeprazine (NDT), and 3-hydroxy-trimeprazine (3-OHT). TMP and TSO expressed a high affinity for iodine in vitro, contrary to NDT, which did not complex iodine. Only 3-OHT inhibited TPO in vitro. Administration of 5 mg/kg TMP ip twice daily for 11 days to Wistar rats induced a decrease of free triiodothyronine and free thyroxine (fT(3) and fT(4)) and a trend toward an increase of TSH serum levels. Thyroid concentrations of TMP, NDT, and TSO were significantly higher than serum levels, while 3-OHT was never detected. An iodine-supplemented diet administered to a group of rats treated with TMP significantly increased the thyroid concentration of TMP and TSO, but not that of NDT, while it did not affect the concentrations observed in serum and other organs. The increase in plasma TSH is not consistent with the central mechanism hypothesis, and the absence of TPO inhibition by TMP, TSO, and NDT contradicts the TPO inhibition hypothesis. On the contrary, three findings support the hypothesis of iodine trapping through formation of a complex with TMP and TSO: these molecules complex iodine in vitro, they accumulate in the thyroid, and their thyroid concentration is increased when the rats are fed an iodine-supplemented diet.

Animals↗
PubMed1998

Design and synthesis of m1-selective muscarinic agonists: (R)-(-)-(Z)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-methoxyphenyl)-2-propynyl)oxime maleate (CI-1017), a functionally m1-selective muscarinic agonist.

The synthesis and SAR of a series of (Z)-(+/-)-1-azabicyclo[2.2. 1]heptan-3-one, O-(3-aryl-2-propynyl)oximes are described. The biochemistry and pharmacology of 24Z (PD 142505) and its enantiomers are highlighted. 24Z is functionally an m1-selective muscarinic agonist. Efficacy and m1 selectivity reside in the R enantiomer, (R)-24Z (CI-1017).

3T3 Cells↗
PubMed1998

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.

Animals↗
PubMed1998

Phenothiazine-induced increase in thyroid autoantigens and costimulatory molecules on thyroid cells: a pathophysiological mechanism for drug-induced autoimmunity?

We have previously demonstrated (J Immunol 1995; 154:3593) that MHC class II antigens can be induced on thyroid epithelial cells (TEC) by alimemazine, a member of the phenothiazine group. Although this expression of MHC class II antigens on TEC confers the theoretical ability to behave as antigen-presenting cells (APC), the simultaneous expression of self antigens and co-receptor(s) must also occur for efficient presentation of self antigens. Therefore, we investigated whether alimemazine applied at pharmacologic doses would modify the expression of thyroid antigens, and simultaneously, the expression of intercellular adhesion molecule-1 (ICAM-1), B7, and LFA-1 co-receptors in human TEC in culture. Using polymerase chain reaction (PCR) amplification and Northern blot analysis, we showed that alimemazine induces increases in thyroglobulin (Tg) and thyroid-stimulating hormone receptor (TSH-R) cDNA, within the first 2 h following its addition. This phenomenon is followed 48 h later by an increase of Tg and TSH-R protein expression on the surface of TEC. Furthermore, increases in the expression of ICAM-1 and B7 co-receptors were concomitantly observed. These results suggest that alimemazine, a drug currently used in paediatrics, could play a role in the induction and perpetuation of thyroid autoimmune disorders by transforming TEC into functional APC.

Antigens↗
PubMed1998

Comparison of DNA enzyme immunoassay and line probe assays (Inno-LiPA HCV I and II) for hepatitis C virus genotyping.

Two methods for genotyping hepatitis C virus (DNA enzyme immunoassay [DEIA] and line probe assay [Inno-LiPA HCV I and II]) were compared on 120 samples and of these 87% were assigned to the same subtype by both assays. There were 15 subtyping discrepancies which involved 5% of type 1 isolates and 90% of type 2 isolates. Amplified products from the core and 5' untranslated regions (UTR) were sequenced to resolve conflicts. Type 1 discordant samples had a guanosine at position -99 in the 5' UTR, a characteristic of genotype 1b, and a core region typical of subtype 1a. The eight isolates classified as 2a/2c by LiPA and as subtype 2c by DEIA belonged to type 2.

Genotype↗
PubMed1998

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.

Animals↗
PubMed1997

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.

Animals↗
PubMed1997

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.

Animals↗
PubMed1996

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.

Antidepressive Agents, Tricyclic↗
PubMed1995

Phenothiazine induces de novo MHC class II antigen expression on thyroid epithelial cells. A new mechanism for drug-induced autoimmunity.

Autoimmune responses are initiated by MHC class II-restricted T cell responses directed against tissue-specific autoantigens. Furthermore, HLA-DR expression in thyroid epithelial cells is a prominent feature of autoimmune thyroid disease. In the present work, we were particularly interested in a phenothiazine, a neuroleptic and anti-depressant drug of pharmacologic importance named alimemazine. Our interest in this compound stems from previous findings of immune effects of this and other phenothiazines. We demonstrate that MHC class II Ags can be experimentally induced on thyroid cells by pharmacologic concentrations of alimemazine, a drug commonly used in psychiatry. In contrast, MHC class II Ags were not induced on the lymphoid cell lines Raji and Jurkat. Expression of MHC class II Ag on the surface of the cloned human thyroid cell hybridoma, GEJ, was demonstrated by flow cytometry. Moreover, by using Northern blot and Southern blot analyses, this finding was confirmed at the molecular level in GEJ and in murine thyroid epithelial cell cultures, respectively. The functional role of phenothiazine-, de novo-induced MHC class II Ags on thyroid cells was assessed by both syngeneic murine thyroglobulin-specific and allogeneic proliferative T cell responses. These results suggest that antidepressant drugs of the phenothiazine type could play a role in the induction and the perpetuation of thyroid autoimmune disorders, through induction of class II restriction elements on normally class II-negative thyroid epithelial cells.

Animals↗
PubMed1995

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.

Adult↗
PubMed1995

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.

Animals↗
PubMed1994

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.

Animals↗
PubMed1994

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.

Animals↗
PubMed1994

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.

Animals↗
PubMed1994

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).

Aspirin↗
PubMed1993

Biological evaluation of compounds with -NCS- group or derived from thiazole and imidazole. Activity on prostaglandin synthetase complex.

The effects of compounds with activity against thyroid peroxidase were tested on the activity of hydroperoxidase and cyclo-oxygenase of the prostaglandin synthetase complex in-vitro. Active compounds were found to inhibit the peroxidase, and the cyclo-oxygenase function. These compounds were also found to have anti-inflammatory activity as demonstrated by the reduction of carrageenan-induced oedema of the hind paw of the rat. Indomethacin and non-steroidal anti-inflammatory drugs tested under the same conditions were shown to have activity towards the cyclo-oxygenase rather than the peroxidase function of the prostaglandin synthetase complex. A common feature of the active compounds was the presence of an -NCS- linkage or free -SH group.

Animals↗