Imidazole as an anti-epileptic: an overview

Imidazole is incorporated into many important biological molecules. The major revolution in the field of imidazole derivatives with antiepileptic properties came with the synthesis of Denzimol and Nafimidone, which leads in its effectiveness among other molecules. The pharmacophore and substitution necessary to elevate the pharmacological effect of these derivatives in curing epilepsy are presented in this review, which can serve the medicinal chemist working on epileptic research to focus on this untouched class of molecules and enlarge its category and synthesize more active and potent anticonvulsant agents.     

Replacement of an NH(3) by an iminoether in transplatin makes an antitumor drug from an inactive compound

To investigate the modifications of antitumor activity and DNA binding mode of transplatin after replacement of one nonleaving group NH(3) by an iminoether group, trans-[PtCl(2)(Z-HN=C(OMe)Me)(NH(3)] and trans-[PtCl(2)(E-HN=C(OMe)Me)(NH(3)] complexes (differing in the Z or E configuration of iminoether, and abbreviated mixed Z and mixed E, respectively), have been synthesized. In a panel of human tumor cell lines, both mixed Z and mixed E show a cytotoxic potency higher than that of transplatin, the mean IC(50) values being 103, 37, and 215 microM, respectively. In vivo mixed Z is more active and less toxic than mixed E in murine P388 leukemia and retains its efficacy against SK-OV-3 human cancer cell xenograft in nude mice. In the reaction with naked DNA, mixed Z forms monofunctional adducts that do not evolve into intrastrand cross-links but close slowly into interstrand cross-links between complementary guanine and cytosine residues. The monofunctional mixed Z adducts are removed by thiourea and glutathione. The interstrand cross-links behave as hinge joints, increasing the flexibility of DNA double helix. The mixed Z, transplatin, and cisplatin interstrand cross-links, as well as mixed Z monofunctional adducts are not specifically recognized by HMG1 protein, which was confirmed to be able to specifically recognize cisplatin d(GpG) intrastrand cross-links. These data demonstrate that the DNA interaction properties of the antitumor-active mixed Z are very similar to those of transplatin, thus suggesting that clinical inactivity of transplatin could not depend upon its peculiar DNA binding mode.     

Corticosterone - an anxiogenic or an anxiolytic agent?

Corticosterone (3–12 mg kg^?1, i.p., giving rise to plasma corticosterone concentrations from 26.7 to 89.0 μg/100 ml) failed to have a significant anxiogenic action. Instead, corticosterone (3 mg kg^?1) had a significant anxiolytic effect in the social interaction test of anxiety. Adrenalectomized rats had very low levels of social interaction; but adrenalectomized rats that had been given replacement corticosterone therapy did not differ from the shamoperated controls. Thus, corticosterone appears to have the opposite effect to that previously reported for ACTH. Possible mechanisms for the observed results are discussed.     

Corticosterone -- an anxiogenic or an anxiolytic agent?

Corticosterone (3--12 mg kg-1, i.p., giving rise to plasma corticosterone concentrations from 26.7 to 89.0 micrograms/100 ml) failed to have a significant anxiogenic action. Instead, corticosterone (3 mg kg-1) had a significant anxiolytic effect in the social interaction test of anxiety. Adrenalectomized rats had very low levels of social interaction; but adrenalectomized rats that had been given replacement corticosterone therapy did not differ from the sham-operated controls. Thus, corticosterone appears to have the opposite effect to that previously reported for ACTH. Possible mechanisms for the observed results are discussed.     

Zoledronic acid: an unending tale for an antiresorptive agent

Importance of the field: Therapy with zoledronic acid (ZOL) is a standard for patients with malignant bone disease. However, the antitumor effects of ZOL are demonstrated only in the preclinical setting and, therefore, they require pharmacological and molecular optimization. ZOL blocks protein isoprenylation, a pleiotropic and basic biochemical process within the cells regulating the activity of several proteins involved in survival and proliferating pathways.

Areas covered in this review: The present review will cover different areas of research from pharmacology to cell biology and molecular biology regarding both direct and indirect anticancer effects of ZOL in humans. The challenge in demonstrating the clinical activity of ZOL is mainly based on its pharmacokinetic properties, which are discussed in detail.

What the reader will gain: New data about the modes to overcome the limitations of ZOL and the following therapeutic strategies to implement its anticancer activity are described: i) development of pharmacological combinations; ii) finding of new molecular targets of ZOL; and iii) development of new pharmacological formulations of ZOL.

Take home message: In conclusion, ZOL has still underestimated anticancer properties that require further investigation in both preclinical and clinical settings.     

Zearalenone,an Estrogenic Mycotoxin,Is an Immunotoxic Compound

The aim of this study was to assess the toxic effects of zearalenone (ZEA) on the immune function. Ovariectomised rats were treated daily by gavage with 3.0 mg/kg of ZEA for 28 days. Body weight gain, food consumption, haemotological parameters, lymphoid organs, and their cellularities were evaluated. Moreover, acquired immune responses and macrophage activity were also assessed. ZEA promoted reduction in body weight gain, which is not fully explained by diminished food consumption. Despite no effect on haematological parameters, ZEA caused thymic atrophy with histological and thymocyte phenotype changes and decrease in the B cell percentage in the spleen. With respect to acquired and innate immune responses, no statistically significant differences in delayed-type hypersensitivity were noticed; however, in the ZEA-treated rats, antibody production and peroxide release by macrophages were impaired. The observed results could be related to ZEA activity on ERs; thus, ZEA is an immunotoxic compound similar to estrogen and some endocrine disruptors.     

The Development of an Assertiveness Program on an Alcoholism Unit

This article describes the integration of an assertion training component into an overall treatment program for alcoholism on an inpatient unit. The usefulness of assertion training is delineated, particularly with regard to relapse prevention. Specific techniques that work well with an alcoholic population are described. Suggestions for the staffing of an assertion training group are made.     

Carum induced hypothyroidism: an interesting observation and an experiment

Carum carvi is a widely available herb that has been used as a food additive and as a medication in traditional medicine for many years. Its potential biological effects include analgesic, anti-inflammatory, anti-anxiety and antispasmodic activities. We report a patient with papillary thyroid carcinoma who were under treatment with levothyroxine and experienced an elevated TSH level by ingestion of Carum carvi. TSH level was increased to 60.3 mIU/L with no change in levothyroxine dosage and decreased to normal range after discontinuation of the Carum carvi. Observing this dramatic change in TSH level by carum ingestion, carum carvi capsules was produced and one of the researcher tried the medication on herself with a dose of 40 mg/kg/day. She had a history of hypothyroidism and was taking 100 ugr/day of levothyroxine. TSH was markedly increased 2 weeks after ingestion of Carum carvi and returned to normal range 5 months after discontinuation of it. This case report shows the effect of consumption of Carum carvi in increasing TSH level in hypothyroid patients treating with levothyroxine. The exact mechanism of action of carum carvi remains unknown.     

Venlafaxine exhibits an anti-inflammatory effect in an inflammatory co-culture model

Growing evidence indicates immunoregulatory effects of various antidepressants. Through the interaction of the nervous and immune systems, the norepinephrine-serotonin system was shown to modulate inflammatory CNS diseases. Thus, we examined the norepinephrine-serotonin reuptake inhibitor venlafaxine in an astroglia-microglia co-culture model which allows mimicking of an inflammatory milieu by increasing the cultured microglial fraction. Astrocytic membrane resting potential and intercellular coupling, two markers becoming severely impaired under inflammation, were assessed with the patch-clamp technique. We measured IL-6, IL-10, IFN-gamma and TGF-beta concentrations and analysed phenotypic changes of microglia. We found (i) a reversal of the inflammation-induced depolarization effect on the membrane resting potential, (ii) an augmentation of TGF-beta release with a concomitant reduction in the secretion of pro-inflammatory IL-6 and IFN-gamma, and (iii) a significant change of microglial phenotype from activated to resting morphology. Our data clearly indicate anti-inflammatory properties of venlafaxine which might be a result of monoamine-mediated immunomodulation.     

Narkosestudien an Seetieren

Ohne Zusammenfassung     

Cycloadditionsreaktionen an Iminiumverbindungen

Cycloaddition Reactions of Iminium Compounds Iminium compounds 1 react in [2⊕ + 1]-cycloaddition reactions with the nucleophile carbene 2b , but not with methylene carbene (2a). On the other hand, 2a adds to the enamine 5. With 2,3-dimethylbutadiene (10) only less crowded carbiminium structures give products of a “Diels-Alder addition”.     

Alkylierungen an Trialkylsulfonyldiamiden

Alkylations of Trialkylsulfonyldiamides Trimethylsulfonyldiamide was reacted with chloromethyl ethyl ether or chloromethyl alkyl thioethers under the conditions of phase transfer catalysis to yield 1 and 3–5 , respectively. Aminomethylation to 7 and 9–11 was possible with formaldehyde and secondary amines. While 2-chloroethyl benzyl ether did not react, the alkyl ethyl thioethylamides 12 and 13 and the dialkylaminoethyl compounds 15–19 could be obtained. With other trialkylsulfonyldiamides the compounds 2 and 8 , with (3-chloropropyl)diethylamine and trimethylsulfonyldiamide or 1-ethyl-3,3-dimethylsulfonyldiamide 20 and 21 were synthesized.     

Untersuchungen an Lichtschutzmitteln

Ohne Zusammenfassung