[The flexible fiberoptic bronchoscopy report: medico-legal issues]. / Le compte rendu de bronchoscopie souple: éléments de réflexion médicojuridique.

INTRODUCTION: The flexible bronchoscopy report is one of the tools permitting exchange of medical information in respiratory medicine and is an integral part of the medical record. Currently, there is no consensus on its content, and consequently, there are no recommendations. METHODS AND RESULTS: A survey was carried out involving experts from the Groupe d'Endoscopie de Langue Française (GELF--Endoscopy Research Group of the French Language Society of Pneumology) and a lawyer from the legal affairs and patient's rights department of the Paris public hospital system. Thirty-four questions distributed in eight chapters were asked in an eight-part questionnaire covering: 1) general administration, 2) environmental safety, 3) medical and anatomical description of the examination, 4) tolerance/complications of the examination, 5) conclusion, 6) image and video sequence capture, 7) administrative data for archiving, 8) disposable elements used during the examination. The results showed as many areas of convergence as they did divergence, between physicians, and between physicians and lawyer. CONCLUSION: Collective consideration is required to harmonize the writing of bronchoscopy reports, to provide a tool that is not only consensual and complete, but also valid and sound from the medicolegal viewpoint.

Fused bicyclic Gly-Asp beta-turn mimics with potent affinity for GPIIb-IIIa. Exploration of the arginine isostere.

6-[4-Amidinobenzoyl]amino]-tetralone-2-acetic acid is a potent antagonist of GPIIb-IIIa. Substitution in the meta position of the benzamidine, or replacement with a heteroaryl amidine was tolerated in this series. Use of an acyl-linked 4-alkyl piperidine as an arginine isostere also provided active compounds. Compounds from this series provided substantial systemic exposure in the rat following oral administration.

Fused bicyclic Gly-Asp beta-turn mimics with specific affinity for GPIIb-IIIa.

Disubstituted isoquinolones 2 and 3 have affinity for GPIIb-IIIa and represent leads for further structural evaluation. Structure-activity studies centered on the bicyclic beta-turn mimic contained in these molecules indicated that this moiety could accommodate a variety of modifications. Specifically, monocyclic, 6, 5-bicyclic, and 6,7-bicyclic structures provide compounds with affinity for GPIIb-IIIa. Within the 6,6-series, isoquinoline, tetralin, tetralone, and benzopyran nuclei yield potent antagonists that are specific for GPIIb-IIIa. Attachment of the arginine isostere (benzamidine) to the supporting nucleus can be accomplished with an ether or amide linkage, although the latter enhances activity. Several compounds in this series provided measurable blood levels after oral dosing. Conversion of the acid moiety in these molecules to an ester generally provided compounds which gave greater systemic exposure after oral administration. Absolute bioavailabilities in the rat for the ethyl ester prodrug derivatives of the tetralin, tetralone, and benzopyran analogues of 3 were 28%, 23%, and 24%, respectively.

Use of conformationally restricted benzamidines as arginine surrogates in the design of platelet GPIIb-IIIa receptor antagonists.

The use of 5,6-bicyclic amidines as arginine surrogates in the design of a novel class of potent platelet glycoprotein IIb-IIIa receptor (GPIIb-IIIa) antagonists is described. The additional conformational restriction offered by the bicyclic nucleus results in 20-400-fold increases in potency compared to the freely flexible, acyclic benzamidine counterpart. The design, synthesis, structure-activity relationships (SAR), and in vitro activity of this novel class of GPIIb-IIIa antagonists are presented.

Phenethylthiazolylthiourea (PETT) compounds as a new class of HIV-1 reverse transcriptase inhibitors. 2. Synthesis and further structure-activity relationship studies of PETT analogs.

Phenylethylthiazolylthiourea (PETT) derivatives have been identified as a new series of non-nucleoside inhibitors of HIV-1 RT. Structure-activity relationship studies of this class of compounds resulted in the identification of N-[2-(2-pyridyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea hydrochloride (trovirdine; LY300046.HCl) as a highly potent anti-HIV-1 agent. Trovirdine is currently in phase one clinical trials for potential use in the treatment of AIDS. Extension of these structure-activity relationship studies to identify additional compounds in this series with improved properties is ongoing. A part of this work is described here. Replacement of the two aromatic moieties of the PETT compounds by various substituted or unsubstituted heteroaromatic rings was investigated. In addition, the effects of multiple substitution in the phenyl ring were also studied. The antiviral activities were determined on wild-type and constructed mutants of HIV-1 RT and on wild-type HIV-1 and mutant viruses derived thereof, Ile100 and Cys181, in cell culture assays. Some selected compounds were determined on double-mutant viruses, HIV-1 (Ile 100/Asn103) and HIV-1 (Ile100/Cys181). A number of highly potent analogs were synthesized. These compounds displayed IC50's against wild-type RT between 0.6 and 5 nM. In cell culture, these agents inhibited wild-type HIV-1 with ED50's between 1 and 5 nM in MT-4 cells. In addition, these derivatives inhibited mutant HIV-1 RT (Ile 100) with IC50's between 20 and 50 nM and mutant HIV-1 RT (Cys 181) with IC50's between 4 and 10 nM, and in cell culture they inhibited mutant HIV-1 (Ile100) with ED50's between 9 and 100 nM and mutant HIV-1 (Cys181) with ED50's between 3 and 20 nM.

Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. 1. Synthesis and basic structure-activity relationship studies of PETT analogs.

A novel series of potent specific HIV-1 inhibitory compounds is described. The lead compound in the series, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (1), inhibits HIV-1 RT using rCdG as the template with an IC50 of 0.9 microM. In MT-4 cells, compound 1 inhibits HIV-1 with an ED50 of 1.3 microM. The 50% cytotoxic dose in cell culture is > 380 microM. The chemical structure-activity relationship (SAR) was developed by notionally dividing the lead compound in four quadrants. The SAR strategy had two phases. The first phase involved optimization of antiviral activity through independent variation of quadrants 1-4. The second phase involved the preparation of hybrid structures combining the best of these substituents. Further SAR studies and pharmacokinetic considerations led to the identification of N-(2-pyridyl)-N'-(5-bromo-2-pyridyl)-thiourea (62; LY300046.HCl) as a candidate for clinical evaluation. LY300046.HCl inhibits HIV-1 RT with an IC50 of 15 nM and in cell culture has an ED50 of 20 nM.

Synthesis and biological evaluation of a series of parenteral 3'-quaternary ammonium cephalosporins.

The preparation and biological evaluation of a series of 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-methoximinoacetamido]cep halosporins, substituted at the 3'-position with monocyclic or bicyclic nitrogen-containing heterocycles are described. The resulting family of parenteral compounds displays a broad spectrum of antibacterial activity. Some compounds exhibit a similar level of Gram-negative activity to that of the "third-generation" cephalosporins with increased staphylococcal activity. The in vitro and in vivo antimicrobial activity, structure-activity relationships, beta-lactamase stability, and in vitro and in vivo pharmacological evaluations are presented.