Anne Le Bouil

Effects of simvastatin, pentoxifylline and spironolactone on hepatic fibrosis and portal hypertension in rats with bile duct ligation

AIMS/METHODS Our aim was to study the antifibrotic and hemodynamic effects of simvastatin (SMV), pentoxifylline (PTX) and spironolactone (SPN), three drugs which may have antifibrotic and/or portal hypotensive properties, in a model of hepatic fibrosis and portal hypertension induced in rats by bile duct ligation. A blind study was performed in five groups of 53 Sprague-Dawley rats: sham, placebo (PL), SMV (2.5 mg x kg(-1) x J(-1)), PTX (50 mg x kg(-1) x J(-1)) and SPN (100 mg x kg(-1) x J(-1)). Drugs were administered by daily gavage over a 4-week period as soon as bile duct ligation was performed. At day 28, the following parameters were evaluated: area of hepatic fibrosis by image analysis after staining collagen with picrosirius and plasma concentrations of hyaluronate, splanchnic and systemic hemodynamics (radiolabeled microspheres). RESULTS Portal venous pressure (PL: 15.5+/-1.5, SMV: 15.8+/-2.5, PTX: 15.9+/-1.8, SPN: 13.5+/-2.1 mmHg, p<0.05) and porto-systemic shunts (PL: 30+/-31, SMV: 18+/-27, PTX: 25+/-24, SPN: 5+/-4%, p<0.05) were significantly reduced in the SPN group; other hemodynamic parameters were not significantly altered. There was a significant correlation between portosystemic shunts and portal pressure (r(s)=0.47, p<0.01). The area of fibrosis was not significantly different among the four groups of bile duct ligated rats (PL: 8.7+/-3.9, SMV: 7.1+/-3.6, PTX: 7.8+/-2.7, SPN: 6.6+/-3.3%) but was higher than in sham rats (1.5+/-0.5%, p<0.001). Hyaluronate was significantly higher in bile duct ligated rats (from 374+/-162 to 420+/-131 microg/l, among the four groups) than in sham rats (52+/-16 microg/l, p<0.0001). CONCLUSIONS In this model, none of the drugs prevented hepatic fibrosis. On the other hand, spironolactone decreased portal pressure and prevented porto-systemic shunts. Therefore, this drug may have beneficial effects in patients with early portal hypertension.

High-performance liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS) method for the simultaneous determination of diazepam, atropine and pralidoxime in human plasma

A high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS) procedure for the simultaneous determination of diazepam from avizafone, atropine and pralidoxime in human plasma is described. Sample pretreatment consisted of protein precipitation from 100microl of plasma using acetonitrile containing the internal standard (diazepam D5). Chromatographic separation was performed on a X-Terra MS C8 column (100mmx2.1mm, i.d. 3.5microm), with a quick stepwise gradient using a formate buffer (pH 3, 2mM) and acetonitrile at a flow rate of 0.2ml/min. The triple quadrupole mass spectrometer was operated in positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated over the concentration ranges of 1-500ng/ml for diazepam, 0.25-50ng/ml for atropine and 5-1000ng/ml for pralidoxime. The coefficients of variation were always <15% for both intra-day and inter-day precision for each analyte. Mean accuracies were also within +/-15%. This method has been successfully applied to a pharmacokinetic study of the three compounds after intramuscular injection of an avizafone-atropine-pralidoxime combination, in healthy subjects.

Suicide by Skull Stab Wounds: A Case of Drug-induced Psychosis

Suicide by stabbing to the head and/or driving sharp objects into the skull is of extreme rarity. This article reports the case of a 27-year-old man, who committed suicide by multiple knife stabs and cuts to the head, the torso, one shoulder and the forearms. Autopsy showed a perforating wound of the skull and the 10-cm long broken blade of the knife being still embedded in the right temporal lobe of the brain. The deceased had no history of psychiatric illness but was currently treated by mefloquine, a quinine derivative associated with a high rate of psychiatric adverse effects. Toxicological examination confirmed a recent intake of mefloquine together with chloroquine, another antimalarial drug. To our knowledge, this is the first report of a completed suicide with very strong evidence of mefloquine implication. Discussion focuses upon mefloquine-induced psychiatric disorders and highlights the importance of performing toxicological investigations in cases of unusual suicides.

Suicide spectaculaire lié à une prise de méfloquine

Resume Introduction Nous rapportons un cas de suicide spectaculaire survenu au decours d’une complication neuropsychiatrique liee a la prise de mefloquine. Les medecins doivent connaitre ces effets secondaires graves de la mefloquine et les evoquer devant la survenue de troubles psychiatriques soudains et atypiques ou devant des tableaux de suicide suspects. Observation Le corps d’un homme de 27 ans, ayant de multiples plaies par arme blanche, a ete decouvert a son domicile. Le rapport d’autopsie a permis d’etablir que le deces etait en rapport avec une plaie crânio-cerebrale grave provoquee par un coup de couteau intracrânien porte avec violence. Un homicide etait initialement suspecte. Un suicide lors d’un delire survenu a la suite de la prise de mefloquine ayant ete evoque, une analyse toxicologique a ete realisee et l’hypothese a ete confirmee. Discussion Depuis l’introduction de la mefloquine (Lariam®) en 1985, la survenue de complications psychiatriques graves a ete decrite. Une prophylaxie par mefloquine est recommandee lors de sejour dans les zones resistantes a la chloroquine. L’efficacite prouvee de cette prevention justifie le maintien de la prescription malgre le risque d’effets secondaires. Cependant, les medecins doivent connaitre ces graves effets secondaires neuropsychiatriques. En effet, devant un comportement inexplique, le diagnostic doit etre evoque afin de prevenir la survenue de complications plus graves. De meme, devant des tableaux de suicide atypique, une prise de mefloquine dans les mois precedents doit etre recherchee pres de la famille ou des amis. Des prelevements sanguins et urinaires doivent etre realises pour analyse toxicologique. Enfin, il est necessaire de respecter les recommandations de l’OMS concernant les contre-indications.

Skin vascular resistance in the standing position increases significantly after 7 days of dry immersion

Actual and simulated microgravity induces hypovolemia and cardiovascular deconditioning, associated with vascular dysfunction. We hypothesized that vasoconstriction of skin microcirculatory bed should be altered following 7 days of simulated microgravity in order to maintain cardiovascular homeostasis during active standing. Eight healthy men were studied before and after 7 days of simulated microgravity modeled by dry immersion (DI). Changes of plasma volume and orthostatic tolerance were evaluated. Calf skin blood flow (laser-Doppler flowmetry), ECG and blood pressure signal during a 10-min stand test were recorded, and skin vascular resistance, central hemodynamics, baroreflex sensitivity and heart rate variability were estimated. After DI we observed increased calf skin vascular resistance in the standing position (12.0 ± 1.0 AU-after- vs. 6.8 ± 1.4 AU-before), while supine it was unchanged. Cardiovascular deconditioning was confirmed by greater tachycardia on standing and by hypovolemia (-16 ± 3% at day 7 of DI). Total peripheral resistance and indices of cardiovascular autonomic control were not modified. In conclusion, unchanged autonomic control and total peripheral resistance suggest that increased skin vasoconstriction to standing involves rather local mechanisms-as venoarteriolar reflex-and might compensate insufficient vasoconstriction of other vascular beds.