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In the last 15 years, the therapeutical options for the treatment of chronic inflammatory diseases in rheumatology have increased a lot. Nevertheless, some patients do not respond or respond partially to the current therapies--including to the biologics therapy. Tofacitinib (Xeljanz) is now on the Swiss market. It inhibits the JAK pathway. Tofacitinib--as monotherapy or with methotrexate--improves the control of rheumatoid arthritis (RA). In a comparative study, tofacitinib was as effective as adalimumab. Further, tofacitinib reduced structural damages in RA and is considered as an alternative, in case of non-response, to anti-TNF and probably to other biologics therapy. The side effects are upper respiratory tract and opportunist infections and tuberculosis. Blood count, lipids, kidney function, liver tests, CK and blood pressure have to be monitored.

Aim: To describe drugs used in renal cell carcinoma., Method: Pubmed search for efficacy, mode of action and side effects for each molecule. Additional data were searched from the French regulatory agencies websites (HAS and ANSM)., Results: Since 2007, a total of three different therapeutic classes in the management of metastatic renal cell carcinoma are available. These three classes are tyrosine kinase inhibitors with sunitinib and sorafenib, the anti-VEGF antibodies (bevacizumab which is associated with alpha interferon in the treatment of advanced kidney cancer) and mTOR inhibitors with temsirolimus and everolimus. These targeted therapies are a major progress in the treatment of patients with metastatic kidney cancer. The side effects encountered with these molecules are numerous but serious side effects are less than 5% of all reported side effects., Conclusions: A better understanding of molecular mechanisms has enabled the development of new therapies for the treatment of metastatic renal cell carcinoma. In the future, a personalized approach taking into account the biology of each tumor could be created to provide a more targeted treatment., (Copyright © 2013. Published by Elsevier Masson SAS.)

Atorvastatin is a second generation synthetic statin, introduced in Belgium in May 1998. Its mechanism of action is similar to that of the other statins, i.e. the inhibition of HMG Co-A reductase, the key enzyme in cholesterol synthesis, which leads to the increase of LDL receptors. The prolonged half-life (20-30 H) of atorvastatin and its active metabolites, induces a prolonged inhibition of HMG Co-A reductase and a reduction of hepatitic apo B production. The biological efficacy of atorvastatin is high: 41 to 61% lowering of LDL depending of the dose. Atorvastatin is indicated in primary hypercholesterolemia, mixed hyperlipidemia and homozygous familial hypercholesterolemia. If necessary, a resin or even a fibrate may be added. The safety profile is good. The most common adverse effects are gastro-intestinal and transient. Liver tests or muscle enzymes are rarely modified. If clinical proof of reduction of CV morbidity and mortality in primary and secondary prevention is obtained, atorvastatin shall represent a major step forward in the treatment of hypercholesterolemia.

A conformational analysis has been performed with SYBYL starting from the energy optimized (Tripos force field) X-ray conformation of (R,S)-pinacidil. The geometry of four selected low energy conformers has been reoptimized using the AM1 semiempirical Molecular Orbital method (MOPAC 5.0), and the total energy of the optimized conformers has been compared. In spite of an apparent structural dissimilarity, a good analogy has been found between the calculated isopotential map of diazoxide and that of at least one selected low energy conformer of pinacidil. It has been suggested that, unlike cromakalim, the low but observable activity of pinacidil on pancreatic B-cells could be explained by adoption for this compound of a conformation having a diazoxide-like stereoelectronical imprint which could assume a similar interaction on the same biological receptor.

Ro 5-3335 is a new benzodiazepine highly active in vitro (IC50 = 0.1-1.0 microM [corrected]) against HIV-1 viruses of AIDS resistant or non-resistant to zidovudine (AZT). It is also active against HIV-2. Ro 5-3335 is original by its mechanism of action, acting on the trans-activation factor of transcription (TAT) and non on the reverse transcriptase. Such as, it could prevent proviral DNA to express in both evolutive and silent AIDS resistant or non-resistant to AZT or to other anti-reverse transcriptase series. In addition, in antagonizing extracellular TAT's actions, Ro 5-3335 could alleviate the syndrome commonly associated with AIDS as Kaposi's syndrome. In rodent test, Ro 5-3335 has no diazepam-like central effects and presents in comparison to AZT a more favorable therapeutic index. In dog, the elimination half-life, peak concentration and availability are 2 h, 0.8 microM and 85% respectively, after a 1 mg.kg-1 oral dose of Ro 5-3335. Theoretically, Ro 5-3335 and now its analogue Ro 24-7429 seem to possess all virtues to antagonize evolutive and latent AIDS. Its arrival is timely to cope with the ever increasing resistance phenomena, lengthy development of AIDS vaccines, exponential contamination of populations worldwide and last but not least possibly to impede evolutions of the disease. Ability to manipulate TAT-mediated activation of HIV-1 genes paves the ways to study conceivable corrections of abnormal gene expressions of neurotransmitters, hormones, oncogenes and key enzymes.

The discovery of endothelial regulatory properties in the modulation of the vascular response to pharmacological agents and its fundamental role in the phenomenon of flow-dependence has enabled the demonstration of the mode of action of coronary vasodilators on the large epicardial vessels where most coronary spasm occurs. Nitrate derivatives are remarkably selective in their effects on the large vessels which dilate in an endothelial-independent manner, which makes them very effective in the prevention and treatment of coronary spasm occurring, for example, during angioplasty. On the other hand, arterial vasodilators, like calcium antagonists or potassium agonists have decreased vasodilatory effects on these conductance vessels in the presence of endothelial lesions as their action is partially or entirely endothelium-dependent. By their additive coronary vasodilator effects, the association of these two groups of vasodilators provides greater therapeutic efficacy in the prevention of angina whatever its cause.

The purpose of the present work is the contribution of hydrophobic fragmental constant, molecular connectivity and parachor in the study of the relationship between chemical structure and biological activity. The results obtained in this series of benzylidenes-pyrrols have shown high correlation between these parameters and the antifungal activity of these compounds.

Potassium channel activators (PCAs) open the membrane potassium channels, thus increasing the cell potassium efflux. This results in hyperpolarization of the cell membrane, the main result of which is a reduction of the penetration of calcium into cells. The resulting decrease of intracellular Ca++ produces relaxation of the smooth muscle fibres, notably in blood vessels. In animals, PCAs reduce total peripheral resistance and lower blood pressure. These vasodilator and hypotensive effects are accompanied by reflex tachycardia and stimulation of the renin-angiotensin system and they are antagonized by glibenclamide, an antagonist of ATP-dependent potassium channels. Very recent experimental data have shown that in the ischaemic myocardium PCAs tend to improve the balance between oxygen supply and demand and to exert a cardioprotective effect. Up to now, the only use of PCAs has been in arterial hypertension, and the only drugs used are pinacidil, minoxidil and diazoxide. Unfortunately, the PCAs that are available at present are rather poorly tolerated, which limits their development in this particular field. However, their combination with beta-blockers and/or diuretics reduces the incidence of their side-effects and improves their effectiveness. A synergistic effect between PCAs and angiotensin-converting enzyme inhibitors is probable.

Quantitative structure-activity relationships (QSAR) have been derived for twenty two 5-benzylidene furanones, pyrrolones and thiophenones having antifungal activity against Candida albicans. The correlation with the parabolic (Hansch) or bilinear (McFarland-Kubinyi) models are superior to those with the linear models (Free-Wilson or Fujita-Ban), while no significant differences exist between the parabolic and bilinear models. Lipophilicity was necessary for good in vitro activity of these compounds.

The antifungal activity against Neurospora crassa of some 5-benzilidene pyrrolone and furanone derivatives was realised. Relations between the structure and this biological activity are established with Fujita-Ban and Hansch methods. The preponderant part of lipophilicity, resonance effect and E or Z configurations have been showed.

The systemic and regional (kidney, mesentery, hindlimb) hemodynamic effects of (a) two potassium agonists: cromakalim (1 to 8 micrograms.kg-1.min-1/15 min) and SR 44866 (0.125 to 2 micrograms.kg-1.min-1/15 min) and (b) a calcium antagonist, nicardipine (0.5 to 2 micrograms.kg-1.min-1/15 min) have been investigated by the pulsed doppler technique, and compared in the anesthetized normotensive rat. The two potassium agonists and nicardipine lowered blood pressure (BP) and total peripheral resistance (TPR) dose-dependently and slightly increased heart rate. Cardiac output (QC) remained unchanged. SR 44866 was as potent as nicardipine in reducing BP and about three to four times more potent than cromakalim (the DE20s, doses producing a 20 p. 100 decrease in BP, being: SR 44866: 0.7 micrograms.kg-1.min-1, cromakalim: 2.8 micrograms.kg-1, nicardipine: 0.8 micrograms.kg-1.min-1). At these equihypotensive doses, the three drugs (a) similarly decreased TPR (SR 44866: -16 p. 100, cromakalim: -17 p. 100, nicardipine: -19 p. 100, (b) reduced mesenteric vascular resistance (MVR) (SR 44866: -18 p. 100, cromakalin: -20 p. 100, nicardipine: -21 p. 100) and renal vascular resistance (RVR) (SR 44866: -16 p. 100, cromakalim: -21 p. 100, nicardipine: -13 p. 100 to the same extent as TPR, but (c) SR 44866 and nicardipine reduced hindlimb vascular resistance (HVR) to a larger extent than TPR (SR 44866: -25 p. 100, nicardipine: -25 p. 100.(ABSTRACT TRUNCATED AT 250 WORDS)

The derivatives in question are prepared by reaction of substituted anilines with 1,4-ketones in an acidic medium. The diketones are themselves obtained either using Friedel and Crafts reaction with levulinic acid chloride, or by Stetter's method reacting Mannich bases with aryl aldehydes in the presence of sodium cyanide. The results of test of acute toxicity and of analgesic and anti-inflammatory activity are reported.

In order to increase the pharmacological activities of the molecules described in the first part of the paper, an acetic or a 2-propionic group was introduced in to the fundamental structure, either on the aromatic ring, on the pyrrole nitrogen or on carbon 3 of the heterocycle. Moreover, a 4-chlorobenzoyl group was fixed on carbon 3 of the pyrrole via condensation of 4-chloroaniline with 4-chlorobenzoyl triketones. The structure of the adducts was demonstrated both by N.M.R. spectra and by using another unambiguous synthetic route. Finally, derivatives with the salicylic substructure on the nitrogen of the pyrrole are described. Their analgesic and anti-inflammatory properties are reported as well as some effects on the central nervous system.