Search

Herein we describe the discovery of IDX21437 35b, a novel RPd-aminoacid-based phosphoramidate prodrug of 2'-α-chloro-2'-β-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection.

A novel assembly of two structurally related 14-membered ring macrocyclic hepatitis C virus protease inhibitors is presented. Key to their successful construction was an ultimate ring-closing metathesis step on the respective highly functionalized dienyl-ureas. In the case of IDX316, this procedure significantly outperformed the original macrocyclizations in terms of reaction conditions, impurity profile, product isolation, and basic efficiency metrics. Simple nonchromatographic purification methods achieved sub-10-ppm ruthenium content in the isolated product. Overall yields to IDX316 from all five starting materials ranged from 11 to 40%, and the estimated process mass intensity was improved by a factor of 50 relative to the original unscalable discovery-based routes. Application of similar methodology in the case of IDX320 and first scale-up to half-kilogram batch sizes was demonstrated.

SUMMARY Plasma concentrations of cimetidine and ranitidine were measured after oral administration (n= 5 for cimetidine, n= 5 for ranitidine) or intravenous administration (n= 6 for cimetidine, n= 4 for ranitidine) in habitual smokers, once when cigarettes were smoked and again on a separate day when cigarettes were prohibited. After oral administration plasma concentrations of both drugs rose more rapidly and peak plasma concentrations were achieved earlier when cigarettes were smoked. However, plasma concentrations of the drugs subsequent to the peak were significantly lower when cigarettes were smoked. Cigarette smoking had no effect on plasma blood concentrations of either drug when administered intravenously. In eight healthy smokers cigarette smoking increased the gastric emptying of a liquid test meal by 28% compared with non-smoking control rates. In habitual smokers cigarette smoking alters the blood concentrations of antisecretory drugs in a manner which appears attributable to an increase in the rate of gastric emptying. The observed changes in drug disposition may contribute to the loss of gastric secretory inhibition observed in duodenal ulcer patients who are smokers.

The evolving challenge of managing patients with congestive heart failure is the need to develop new therapeutic strategies. The cellular, molecular, and genetic approaches investigated aim to reinforce the weak, failing heart muscle while restoring its functional potential. This approach is principally cellular therapy (i.e. cellular cardiomyoplasty), the preferred therapeutic choice because of its clinical applicability and regenerative capacity. Different stem cells: bone marrow cells, skeletal and smooth muscle cells, vascular endothelial cells, mesothelial cells, adipose tissue stroma cells, dental stem cells, and embryonic and fetal cells, have been proposed for regenerative medicine and biology. Stem cell mobilization with G-CSF cytokine was also proposed as a single therapy for myocardial infarction. We investigated the association of cell therapy with electrostimulation (dynamic cellular cardiomyoplasty), the use of autologous human serum for cell cultures, and a new catheter for simultaneous infarct detection and cell delivery. Our team conducted cell-based myogenic and angiogenic clinical trials for chronic ischemic heart disease. Cellular cardiomyoplasty constitutes a new approach for myocardial regeneration; the ultimate goal is to avoid the progression of ventricular remodeling and heart failure for patients presenting with ischemic and non-ischemic cardiomyopathies.

In numerous legal Systems (we shall consider the French, Belgian, English, American and Louisianian legal Systems), the issue of price certainty in contracts of sale is to be tied to the principle of freedom of contract (principe de l'autonomie de la volonté). This study demonstrates that the application of such principle must be adapted, or even questioned, in a contemporaneous commercial context where complexity and length call for a more flexible approach. We shall see whether or not such resuit has been reached at the national as well as at the international levels. A greater generalization in the use of standards should resuit into greater uniformity of legal attitudes the diversity of which is finally less important than it first appears., La Constitution espagnole de 1978, dont on va célébrer le 10e anniversaire, comporte une institution originale : la Délégation permanente (« Diputaciàn permanente »). Cet organe collégial composé de parlementaires (il y a une délégation permanente par chambre, soit une à la Chambre des députés et une au Sénat) est chargée d'assurer la continuité de l'Assemblée dans les périodes d'inter-sessions et exerce par délégation certaines compétences. Inconnue dans le droit politique français, cette institution répond à la volonté de redonner au Parlement un rôle qu'il avait perdu sous le franquisme, et de renouer avec une certaine tradition constitutionnelle espagnole. Si l'organisation et le fonctionnement des deux délégations sont proches, leurs pouvoirs respectifs ne sont pas identiques, traduisant un bicamérisme inégalitaire., Silie Salanson Noele. La délégation permanente dans la Constitution espagnole du 29 décembre 1978. In: Revue internationale de droit comparé. Vol. 40 N°4, Octobre-décembre 1988. pp. 833-855.