Xenobiotic metabolism and disposition in human lung: transcript profiling in non-tumoral and tumoral tissues.

The lung is directly exposed to a wide variety of inhaled toxicants and carcinogens. In order to improve our knowledge of the cellular processing of these compounds in the respiratory tract, we investigated the mRNA expression level of 380 genes encoding xenobiotic-metabolizing enzymes (XME), transporters, nuclear receptors and transcription factors, in pulmonary parenchyma (PP), bronchial mucosa (BM) and tumoral lung tissues from 12 patients with non-small cell lung cancer (NSCLC). Using a high throughput quantitative real-time RT-PCR method, we found that ADH1B, CYP4B1, CES1 and GSTP1 are the major XME genes expressed both in BM and PP.

[Developments in anti-malaria agents: chemical data, structure-activity relationships].

Various features of the evolution of a few antimalarial drugs including amodiaquine, dihydrofolate-reductase inhibitors, and artemisinin are described. The mechanism of action of artemisinin is detailed to explain the information of the main metabolites and drug design of certain compounds. Structure-activity and structure-neurotoxicity relations are reported.

Synthesis of new N-substituted pyrrolidin-2-ones as cyclic analog of gamma-aminobutyric acid.

Some new N-substituted pyrrolidin-2-ones, cyclic analogs of baclofen and of 3-(5-methylbenzo[b]furan-2-yl)-gamma-aminobutyric acid, have been prepared starting from corresponding pyrrolidinones and characterized.

A multicentric comparison of transabdominal versus totally extraperitoneal laparoscopic hernia repair using PARIETEX meshes.

The authors report a series of 1972 inguinal hernias treated between 1993 and 1997 by the insertion of a PARIETEX mesh via either a transabdominal-preperitoneal (TAPP) (1,290 procedures) or a totally extraperitoneal TEP approach (682 procedures). Pain scores were equivalent in both groups, while the hospital stay and time to return to normal activity was lower in the TEP group than in the TAPP group (p<0.001).

Isomers of substituted 3-benzo[b]furyl and 3-thienylaminobutyric acids as potent ligands of the GABA-B receptor: synthesis and preparative liquid chromatographic separation.

Baclofen (4-amino-3-(4-chlorophenyl)butyric acid) is the only selective agonist for GABA-B receptors. Its R-(-)-enantiomer is about 100 times more active than the S-(+)-enantiomer. In the search for new compounds that bind to GABA-B receptors, it is very important to clarify the structural requirements.

GABAB receptor antagonism by resolved (R)-saclofen in the guinea-pig ileum.

The GABAB receptor antagonist saclofen (3-amino-2-(4-chlorophenyl)propylsulphonic acid) has been resolved by chiral high-performance liquid chromatography. The enantiomer (R)-saclofen, but not (S)-saclofen, reversibly antagonised the (R,S)-baclofen-induced depression of cholinergic twitch contractions in the guinea-pig ileum with an apparent pA2 of 5.3.

Structure-affinity relationships of baclofen and 3-heteroaromatic analogues.

Substituting a furan, a thiophene, a benzo[b]furan, a benzo[b]thiophene, or a quinoline ring for the p-chlorophenyl moiety of baclofen has led to GABAB ligands with different affinities depending on the nature of the heteroaromatic ring, and on the nature and position of its substituent. As steric effects cannot account for all the affinity variations, we have studied the lipophilic and electronic properties of baclofen and selected 3-heteroaromatic analogues, gaining insight into the structural features necessary for GABAB affinity. Centrifugal partition chromatography (CPC) has been used to measure octan-1-ol water distribution coefficients, while ab initio molecular orbital (MO) calculations were performed to study electronic properties.

Thienyl-GABA derivatives as specific baclofen agonists in the rat and cat spinal cord in vivo.

The depression of the amplitude of extracellularly recorded monosynaptic excitatory field potentials in the lumbar spinal cord of pentobarbitone anaesthetised rats and cats by three thienyl derivatives of GABA: 4-amino-3-(2-thienyl)-butanoic acid; 4-amino-3-(2-thienyl-5-methyl)-butanoic acid and 4-amino-3-(2-thienyl-5-chloro)-butanoic acid was reversibly blocked by the (-)-baclofen antagonist 3-aminopropyl-diethoxymethyl-phosphinic acid (CGP 35348). These compounds, of which the most potent, the 5-chloro derivative, was weaker than (-)-baclofen, thus activate baclofen receptors in the cat and rat spinal cord.

Differing actions of beta-(2-thienyl)-gamma-aminobutyric acid in central and peripheral preparations.

In the guinea-pig isolated ileum, beta-(2-thienyl)-gamma-aminobutyric acid (BTG; 100-500 microM) reversibly and competitively (pA2 = 4.3 +/- 0.1) antagonised the baclofen-induced (5-100 microM) depression of cholinergic twitch contractions, but not that to adenosine or morphine.

Actions of thienyl analogs of baclofen in the guinea-pig isolated ileum.

In guinea-pig isolated ileal preparations, the 5-methylthien-2-yl (5d), 5-bromothien-2-yl (5f) and 5-chlorothien-2-yl (5h) analogs of baclofen depressed twitch responses to field stimulation in a dose-dependent manner. These actions were reversibly and competitively antagonised by 2-hydroxysaclofen but not by naloxone, phentolamine, propranolol or theophylline. The relative potencies (EC50 values) were baclofen (10 microM) greater than 5h (40 microM) greater than 5d (80 microM) greater than 5f (120 microM).

3-Thienyl- and 3-furylaminobutyric acids. Synthesis and binding GABAB receptor studies.

Baclofen (beta-(p-chlorophenyl)-GABA) is a selective agonist for the bicuculline-insensitive GABAB receptor. The search for new compounds that bind to the GABAB receptor is very important to clarify structural requirements. We report herein the synthesis and the binding studies of variously substituted 3-thienyl- and 3-furylaminobutyric acids.

Synthesis and schistosomicidal activity of 4-methyl-5-(aryl vinyl)-1,2-dithiole-3-thiones.

The synthesis of vinylogous of 1,2-dithiole-3-thione is described. The activity in experimental schistosomiasis (schistosomicidal activity) was tested with mice infected with Schistosoma mansoni. The reference compound was 4-methyl-5-(pyrazinyl)-1,2-dithiole-3-thione (oltipraz).

Synthesis of some 2-benzoxazolinone derivatives and their analgesic properties.

In this study, eight new 1-(2-benzoxazolinone-6-yl)-2-(4-arylpiperazine-1-yl)ethanol and -propanol derivatives have been prepared. Their structures have been elucidated by IR- and 1H-NMR-spectra and by elementary analysis. The analgesic activities of these compounds, using modified Koster's test have been investigated.

[Preparation of oxime, hydrazone and dichloroacetamide derivatives. Researches of antiparasitic activity].

Several oximes, hydrazones and dichloroacétamides were synthesized. The antiparasitic properties of these compounds were evaluated in vitro against two Protozoaires Entamoeba histolytica and Trichomonas vaginalis.

[Comparison of refractometric and ultraviolet detection methods in lactulose assay by high performance liquid chromatography].

Dosage of lactulose and determination of related sugars (lactose, fructose, galactose, épilactose) were undertaken by high performance liquid chromatography (HPLC). The present note described two modes of detection used simultaneously and compared: refractive index detector (RI) and multiwavelength ultraviolet detector (UV). HPLC is performed with an aminopropylsylil phase as stationary phase and an isocratic mobile phase containing acetonitrile and aqueous sodium phosphate.

Baclofen antagonism by 4-amino-3-(5-methoxybenzo[b]furan-2-yl) butanoic acid in the cat spinal cord.

When administered microelectrophoretically, 4-amino-3-(5-methoxybenzo[b]furan-2-yl)butanoic acid (MBFG) reversibly reduced the presynaptic depression by (-)-baclofen of the monosynaptic excitation of spinal interneurones by impulses in muscle low-threshold afferent fibres of the cat as well as the postsynaptic depression by (-)-baclofen of the firing of these neurones. MBFG, as an antagonist of (-)-baclofen, may be useful in investigating the structure-activity relationships of central and peripheral baclofen receptors.

Benzofuran analogues of baclofen: a new class of central and peripheral GABAB-receptor antagonists.

Two novel beta-(benzo[b]furan) analogues of baclofen (4-amino-3-benzo[b]furan-2-ylbutanoic acid, 9G, and 4-amino-3-(5-methoxybenzo[b]furan-2-yl)butanoic acid, 9H) antagonised the baclofen-induced depression of twitch contractions in the guinea-pig isolated ileum (estimated apparent pA2 3.9 and 4.1 respectively); both 9G and 9H also antagonised in a dose-dependent manner the baclofen-induced reduction of repetitive paroxysmal discharges in rat neo-cortical slice preparations maintained in Mg2+-free Krebs solution.

[Synthesis and antiparasitic activity of arylproprenones in the nitro-5-imidazole series].

The synthesis of new arylpropenones derived from 1-methyl-5-nitro imidazole is described. The investigation of some antiprotozoal properties has shown that compounds with the groups 4-hydroxyphenyl, 4-chlorophenyl or thiophenyl have trichomonacidal activity similar to that of metronidazole.

[Preparation and schistosomicidal activity of vinylogues of 1,3-dithio-3-thione].

The synthesis of vinylogues of 1,2-dithiol-3-thione is described. The activity in experimental schistosomiasis (schistosomicidal activity and, for the most interesting ones, on the egg-laying) was tested in mice with Schistosoma mansoni in comparison with oltipraz.

[Synthesis and antiparasitic activity of new nitro-5-imidazole derivatives].

Syntheses are given for derivatives of the type: 2-amino-1-[(1-methyl-5-nitro-2-imidazolyl) methyleneimino] imidazole, of new hydrazones of 1-methyl-5-nitroimidazole-2-carboxaldehyde and also for semicarbazones and a hydrazone of 1-methyl-5-nitro-2-(4-formyl-styryl)imidazole.

[Synthesis of new diheterocyclic derivatives of imidazole with antiparasitic activity].

A description is given of potential cyclic imidazoles such as 3,3-dichloro-2-methylenimino-acrylonitrile derived from nitro or non-nitro heterocycles, as well as the hydrazone, semicarbazone and arylpropenone derivatives of the 4-chloro-2-(5-nitro-2-thienyl) (V), 5-imidazole carboxaldehyde (IV) and the 5-bromothienyl analogue. The antiparasitic activity was tested in vitro against Trichomonas vaginalis and Entameba histolytica. Some of the nitro containing compounds showed trichomonacidal activity whereas one of the non-nitro compounds with potential imidazole structure showed clear amebacidal activity.

Synthesis and pharmacological evaluation of gamma-aminobutyric acid analogues. New ligand for GABAB sites.

Baclofen (beta-p-chlorophenyl-GABA) is the only selective agonist for the bicuculline-insensitive GABAB receptor. We report the synthesis of new GABA analogues and baclofen analogues. In vitro, two compounds, 4-amino-3-benzo[b]furan-2-ylbutanoic acid (9g) and 4-amino-3-(5-methoxybenzo[b]furan-2-yl)butanoic acid (9h), showed an affinity for the GABAB receptor.

[Antituberculous activity of cyclic analogs of ethambutol].

The activity of new cyclopentanoic and cyclohexanoic analogues of ethambutol on various strains of mycobacteria was determined. Three compounds were effective mainly on tuberculous strains; only one was like ethambutol, being effective on both tuberculous and saprophytic strains.