Biomedical subjects
Publications and source records attributed to C Riche.
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Three new limonoids, named haperforins C2 (1), F (2), and G (3), were isolated from a sample of Harrisonia perforata leaves collected in Central Vietnam. Their structures were determined by single-crystal X-ray diffraction analyses, and their NMR and mass spectral data are reported.
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[formula: see text] Cycloaddition between gamma,delta-unsaturated beta-enamino ester 9 and camphor-derived oxazoline N-oxide 8 afforded a single adduct, 14. Dipolarophile 9 proved to be very reactive despite the substitution on the double bond. Stereoselective sodium cyanoborohydride reduction of the imminium intermediate 14a gave rise stereoselectively to beta-amino ester derivative 15a. Oxidative acidic hydrolysis, oxidation of the resulting aldehyde 18, deprotection, and cyclization afforded the beta-lactam 23, a direct precursor of (+)-carpetimycin A.
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Bioassay-guided fractionation of a leaf extract of G. bracteata has yielded six new prenylxanthones, bractatin (1), isobractatin (2), 1-O-methylbractatin (3), 1-O-methylisobractatin (4), 1-O-methyl-8-methoxy-8,8a-dihydrobractatin (5), and 1-O-methylneobractatin (6). The structures of these compounds have been elucidated by spectroscopic means (NMR, MS), literature data, and X-ray crystallographic analysis of 2. These compounds possess significant cytotoxicity against the KB cell line.
Two new rearranged limonoids, named haperforine A (1) and haperforine E (2), were isolated from a sample of Harrisonia perforata leaves collected in Center Vietnam and their structures determined by X-ray diffraction analysis. The structure of a minor compound was established as 12-desacetylhaperforine A (3) by chemical correlation. Their NMR and mass spectroscopic properties are reported.
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PURPOSE: Penetration of piperacillin into the vitreous cavity after intravenous administration was investigated in humans. METHODS: Forty-five eyes undergoing vitrectomy between November 1993 and December 1994 were included. Each patient received a single intravenous dose of piperacillin 4 g 2 hours before ocular incision. A 0.2-mL vitreous sample was aspired at the beginning of vitrectomy, a blood sample was obtained, and piperacillin level was assessed. RESULTS: There were no detectable drug concentrations in 25 eyes. Mean vitreous drug concentration in the remaining evaluable eyes (n = 14) was 2.33 microg/mL (+/-0.76). We divided samples into two groups: 23 uninflamed (Group 1) and 16 inflamed (Group 2) eyes. Mean vitreous drug concentration was 0.42 microg/mL in Group 1 and 4.95 microg/mL in Group 2 (P < 0.2). Piperacillin concentration was higher than the minimum inhibitory concentration for gram-positive bacteria in 13% of uninflamed and 69% of inflamed eyes (P < 0.001). CONCLUSION: Studies show that intravenously administered piperacillin can penetrate the vitreous cavity in rabbits. Our study suggests that a single dose of piperacillin can produce intravitreal concentrations sufficient to kill gram-positive bacteria in inflamed eyes. The poor intraocular penetration of systemically administered piperacillin in uninflamed eyes raises questions about its usefulness as a prophylactic agent in ophthalmic surgery.
The aim of the present study was to evaluate the use of recombinant human cytochrome P-450 1A2 (rH-CYP1A2) in studies performed in vitro in order to predict metabolic drug-drug interactions occurring in man. In vitro metabolism of tacrine (a CYP1A2 probe) in the presence and absence of fluvoxamine, a CYP1A2 inhibitor, was investigated in human liver mircrosomes and with different rH-CYP. Vmax, Km and Ki determined with human liver microsomes were compared with those observed using rH-CYP1A2, assuming that 1 mg of liver microsomes contains, on average, 69 pmol of CYP1A2. The extent of tacrine metabolism inhibition procured by fluvoxamine with rH-CYP1A2, was compared with previous results observed in man. The Vax and Km for 1-hydroxytacrine formation rates obtained with rH-CYP1A2 were in good agreement with those observed in human liver microsomes (175+/-9 versus 140+/-60 pmol/min/mg for Vmax and 14+/-2 versus 16+/-2 microM for Km, respectively. The Ki of fluvoxamine on 1-hydroxytacrine formation rate observed with rH-CYP1A2 was similar to that observed with human liver microsome (0.35+/-0.05 versus 0.20+/-0.20 microM, respectively). Using the Km, Vmax and Ki determined with rH-CYP1A2, we calculated that fluvoxamine produced an inhibition of 1-, 2- and 4-hydroxytacrine formation rate of 91, 87 and 88%, respectively, in the range of tacrine and fluvoxamine concentrations observed in man. These percentages of inhibition calculated in vitro were in agreement with the percentage of fluvoxamine-dependent decrease in tacrine apparent oral clearance previously observed in man (83+/-13%). We conclude that human CYP1A2 expressed in yeast is a powerful tool to predict and to quantify drug-drug interactions in man.
Ritonavir, indinavir, and saquinavir, all human immunodeficiency virus-1 protease inhibitors with a potent antiviral effect during triple therapy, are extensively metabolized by liver cytochrome P450 3A4. As this P450 isoform is involved in the metabolism of about 50% of drugs, coadministration of protease inhibitors with other drugs may lead to serious effects due to enzyme inhibition. Among these drugs, methadone and buprenorphine, both metabolized by P450 3A4, are potential candidates to drug interactions. In this study, metabolic interactions between these protease inhibitors and methadone or buprenorphine were studied in vitro in a panel of 13 human liver microsomes. Ritonavir was the most potent competitive inhibitor with Ki about 50 and 20 nM for methadone and buprenorphine metabolisms, respectively. Indinavir and saquinavir also inhibited methadone N-demethylation (Ki about 3 and 15 microM, respectively) and buprenorphine N-dealkylation (Ki about 0.8 and 7 microM, respectively). The rank order of inhibition potency against metabolism of methadone and buprenorphine was ritonavir > indinavir > saquinavir. There is obvious potential for clinically significant drug interactions, particularly with ritonavir. In brief, caution should be advised if human immunodeficiency virus-1 protease inhibitors are coadministered with methadone and buprenorphine.
OBJECTIVE: Tacrine is extensively metabolized by cytochrome P4501A2 (CYP1A2). Fluvoxamine, a potent CYP1A2 inhibitor, may be coadministered with tacrine. The aim of this study was to examine the influence of fluvoxamine administration on the disposition kinetics of single-dose tacrine administration. METHODS: Thirteen healthy volunteers participated in this double-blind, randomized crossover study, which compared the effects of fluvoxamine (100 mg/day during 6 days) and placebo on the pharmacokinetics of a single oral dose of tacrine (40 mg). RESULTS: Fluvoxamine caused a significant increase in tacrine area under the plasma concentration versus time curve (AUC): arythmetic mean, 27 (95% confidence interval [CI], 19 to 38) ng.hr/ml versus 224 (95% CI, 166 to 302) ng. hr/ml. Fluvoxamine caused a decrease in the apparent oral clearance of tacrine from 1683 +/- 802 to 200 +/- 106 L/hr (mean +/- SD), which was explained by a decrease in its nonrenal clearance. Five subjects had gastrointestinal side effects during fluvoxamine administration. Fluvoxamine administration was associated with significant increases in the plasma AUC values of three monohydroxylated tacrine metabolites and in the total urinary recovery measurements of tacrine and its metabolites (9.1% +/- 4.6% versus 24.0% +/- 2.6% of recovery). These results may be attributable to fluvoxamine-dependent inhibition of CYP1A/, which is responsible of the biotransformation of tacrine into its monohydroxylated metabolites and further into dihydroxylated and reactive metabolites. CONCLUSION: Fluvoxamine inhibits the metabolism of tacrine. CYP1A2 may be the target of this inhibition. Fluvoxamine may modulate the hepatotoxicity of tacrine, depending on the relative contribution of tacrine and its reactive metabolites to this toxicity.
Collagenase from the fly larvae Hypoderma lineatum cleaves triple-helical collagen in a single region. It was crystallized at neutral pH in the absence of inhibitor and 1.8 A data were collected using synchrotron radiation and a Mark II prototype detector. The structure was solved by combining multiple isomorphous replacement methods and rotation translation function in real space. Refinement between 7 and 1.8 A using the program X-PLOR led to a final R factor of 16.9%. The overall fold is similar to that of other trypsin-like enzymes but the structure differs mainly by the presence of a beta-sheet at position 31-44. The two embedded molecules of the asymmetric unit are related by a pseudo twofold axis. The beta-sheet 31-44 of one molecule is involved in hydrogen bonds with binding-pocket residues of the other molecule. It thus completely prevents access to the active site. The specificity of this enzyme probably results from the position of Phe192 and Tyr99 at the entrance of the active site.
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Expression of P-glycoprotein, which confers multidrug resistance to a broad range of anticancer drugs, was studied in rat hepatocytes in culture. P-glycoprotein was localized in the plasma membrane by immunohistochemical staining and was evaluated by western blotting with C219 as primary antibody and quantification of the coloured spots. The conditions of culture (time in culture, cell density at seeding) had a strong effect on the expression of P-glycoprotein. Expression increases with time in culture. At 10 x 10(6) cells/75 cm2 flasks, which is the normal density seeding for hepatocytes in culture, the increase of P-glycoprotein was 17% between 4 and 24 hr in culture, 52% between 24 and 48 hr and 37% between 48 and 96 hr. At low density cell seeding (2 x 10(6) cells/75 cm2), the expression of P-glycoprotein was higher than at normal density from the first day in culture (+20%). This difference of expression was maintained until 96 hr of culture and was maximum at 48 hr (+44%). This P-glycoprotein was functional and this overexpression was correlated with a decrease of doxorubicin retention in hepatocytes.
Blood dyscrasias such as aplastic anaemia and leukopenia are described following the use of lindane for agricultural purposes or against ectoparasites in animal and human health. In order to determine the involvement of lindane in these effects, an in vitro model of haematotoxicity evaluation has been used. Culture of haematopoietic progenitors, Colony Forming Unit-Granulocyte and Macrophage (CFU-GM), have been performed in the presence of lindane with increasing concentrations. Results showed that lindane was cytotoxic for human progenitors. They were one thousand times more sensitive to the lindane than rat CFU-GM. This cytotoxicity was observed with lindane concentrations similar to those measured in human blood in cases of acute intoxication and in fat tissues of exposed populations.
OBJECTIVES: It has been suggested that omeprazole is an inducer of the cytochrome P450 1A, both in vitro and in vivo. To evaluate whether omeprazole treatment might affect the activity of P450 1A2, we performed a study of caffeine metabolism, which is mainly via P450 1A. METHODS: Thirteen subjects (one healthy volunteer and 12 patients) who were treated with omeprazole, 20 mg each morning for 4 wk, and a control group of 13 healthy volunteers, participated in the study. A test of caffeine metabolism was performed before treatment, 28 days after beginning treatment and, whenever possible, 28 days after treatment. Blood samples were analyzed for theobromine, paraxanthine, and theophylline, by high performance liquid chromatography. RESULTS: P4501A2 activity was determined as the ratio of (paraxanthine + theobromine + theophylline)/(metabolites + caffeine) which represents the total caffeine N-oxidative demethylations; this ratio was expressed as a percentage. For patients, on day 0, the percentage of total metabolism was 34.3% +/- 8.3; on day 28, it was 42.7% +/- 10.8; the difference was statistically significant (p < 0.01). No intra-individual variation of P450 1A2 activity was observed in the control group. CONCLUSIONS: These results demonstrate that omeprazole increases the metabolism of caffeine, especially N-1 and N-3 demethylation pathways, after 28 days of treatment with omeprazole, and suggest that omeprazole, when used for this period, is an inducer of hepatic cytochrome P4501A2.
"Almost half of...over-45s born in French overseas departments and living in mainland France had plans to return overseas by the year 2000. The desire to return is more clear-cut among the 50 to 54 year olds. The younger people have yet to think seriously about retirement, whilst a number of the oldest individuals have already made definite plans." Data are from a survey carried out in 1992. (SUMMARY IN ENG AND GER AND SPA)