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Exposure to environmental pollutants such as polychlorinated biphenyls (PCBs) is now taken into account to partly explain the worldwide decline of amphibians. PCBs induce deleterious effects on developing amphibians including deformities and delays in metamorphosis. However, the molecular mechanisms by which they express their toxicity during the development of tadpoles are still largely unknown. A proteomics analysis was performed on developing Xenopus laevis tadpoles exposed from 2 to 5 days postfertilization to either 0.1 or 1 ppm Aroclor 1254, a PCB mixture. Two-dimensional DIGE with a minimal labeling method coupled to nanoflow liquid chromatography-tandem mass spectrometry was used to detect and identify proteins differentially expressed under PCBs conditions. Results showed that 59 spots from the 0.1 ppm Aroclor 1254 condition and 57 spots from the 1 ppm Aroclor 1254 condition displayed a significant increase or decrease of abundance compared with the control. In total, 28 proteins were identified. The results suggest that PCBs induce mechanisms against oxidative stress (peroxiredoxins 1 and 2), adaptative changes in the energetic metabolism (enolase 1, glycerol-3-phosphate dehydrogenase, and creatine kinase muscle and brain types), and the implication of the unfolded protein response system (glucose-regulated protein, 58 kDa). They also affect, at least at the highest concentration tested, the synthesis of proteins involved in normal cytogenesis (-tropomyosin, myosin heavy chain, and -actin). For the first time, proteins such as aldehyde dehydrogenase 7A1, CArG binding factor-A, prolyl 4-hydroxylase β, and nuclear matrix protein 200 were also shown to be up-regulated by PCBs in developing amphibians. These data argue that protein expression reorganization should be taken into account while estimating the toxicological hazard of wild amphibian populations exposed to PCBs.

Exposure to environmental pollutants such as polychlorinated biphenyls (PCBs) is now taken into account to partly explain the worldwide decline of amphibians. PCBs induce deleterious effects on developing amphibians including deformities and delays in metamorphosis. However, the molecular mechanisms by which they express their toxicity during the development of tadpoles are still largely unknown. A proteomics analysis was performed on developing Xenopus laevistadpoles exposed from 2 to 5 days postfertilization to either 0.1 or 1 ppm Aroclor 1254, a PCB mixture. Two-dimensional DIGE with a minimal labeling method coupled to nanoflow liquid chromatography-tandem mass spectrometry was used to detect and identify proteins differentially expressed under PCBs conditions. Results showed that 59 spots from the 0.1 ppm Aroclor 1254 condition and 57 spots from the 1 ppm Aroclor 1254 condition displayed a significant increase or decrease of abundance compared with the control. In total, 28 proteins were identified. The results suggest that PCBs induce mechanisms against oxidative stress (peroxiredoxins 1 and 2), adaptative changes in the energetic metabolism (enolase 1, glycerol-3-phosphate dehydrogenase, and creatine kinase muscle and brain types), and the implication of the unfolded protein response system (glucose-regulated protein, 58 kDa). They also affect, at least at the highest concentration tested, the synthesis of proteins involved in normal cytogenesis (α-tropomyosin, myosin heavy chain, and α-actin). For the first time, proteins such as aldehyde dehydrogenase 7A1, CArG binding factor-A, prolyl 4-hydroxylase β, and nuclear matrix protein 200 were also shown to be up-regulated by PCBs in developing amphibians. These data argue that protein expression reorganization should be taken into account while estimating the toxicological hazard of wild amphibian populations exposed to PCBs.

For biotherapeutic agents, there is a lack of information on dose–response relationships and mechanism of action. The present study was designed to address these issues for Saccharomyces boulardiiusing the rat model of castor oil-induced diarrhea. A single dose of Saccharomyces boulardiiat 12 × 1010CFU/kg of viable cells given 1 hr before castor oil administration significantly reduced the onset of diarrhea. Repeated ingestion of the yeast, twice daily between 1.2 and 12 × 1010CFU/kg for 5 days before castor oil, showed a dose–response relationship. The percentage of rats with diarrhea decreased and a stronger protection was afforded by the repeated treatment. The mechanism of action of Saccharomyces boulardiiin this model was investigated with two classes of antagonists, naloxone and L-arginine. The effect of Saccharomyces boulardiiwas not inhibited by naloxone but was significantly reduced by L-arginine. This last result suggests a novel mechanism of action for Saccharomyces boulardiiinvolving a possible inhibition of nitric oxide production by the yeast.

The activity of nefopam, a centrally acting compound, not structurally related to other analgesics, was examined in acute and postoperative thermal pain models in the rat. Its antinociceptive potency was evaluated using heat noxious stimuli either in intact or in injured animals after skin and muscular incisions. In the hot plate and in the plantar tests, nefopam after acute administration by different routes exhibited a dose-dependent attenuation of the nociceptive responses at 10–30 mg kg −1by intraperitoneal or subcutaneous administration, at 60 mg kg −1by oral dosing, and from 3 mg kg −1after intravenous injection. In the postoperative pain model, at 30 mg kg −1nefopam augmented the endpoint to thermal threshold, 60 and 90 minutes after administration compared to the threshold recorded after the incision. In the same conditions, morphine and tramadol displayed antinociceptive activities. As the plantar test provides a good index of nociception in humans, these results point out the usefulness of nefopam for attenuating moderate to severe pain, and for postoperative analgesia. In conclusion, nefopam has shown potent properties to reduce thermal hypersensitivity after acute or postoperative pain in rats.

AbstractThis study was made to prospectively assess the results of our first 237 consecutive patients who underwent laparoscopic or laparoscopic-assisted colorectal procedures. Between May 1995 and July 1999, two hundred thirty seven laparoscopic (assisted) colorectal procedures were performed : 97 sigmoidectomies, 31 right hemicolectomies, 26 rectosigmoidectomies, 23 abdominoperineal rectum amputations and 60 other procedures. The following parameters were recorded and analysed : patients gender, age, diagnosis, procedure, conversion to open surgery, peroperative and postoperative complications, duration of procedure, mortality and length ol hospitalization. There were 104 men (44%) and 133 women (56%) with a mean age of 62 years. Hundred and fifty-one operations were performed for benign indications (diverticular disease (51,6%), benign colonic polyps (17,5%) and others (30,9%)) and 86 for cancer (palliative and curative). The conversion rate was 4%. Postoperative complications occurred in 65 patients (27%). In 20% of these cases re-operation was necessary. The most common cause was bowel obstruction. Surgery lasted an average of 110 minutes. Mean overall hospital stay was 11 days. Sixty per cent left the hospital within eight days after operation. The 60-day mortality rate was 2,9%.The feasibility and safety of laparoscopic colorectal surgery has been established in a variety of procedures for different indications. Care must be taken in the case of acute diverticulitis which in our series is associated with higher minor and major complication rate and conversion rate. Although our results for malign cases are good, the definitive incidence of neither port-site metastasis nor local recurrence is known and no long-term results after laparoscopic surgery for carcinoma are available, we believe that curative procedures for cancer should continue to be carried out only within the framework of prospective studies unless the patient is more than 75-year old, is in bad general condition or when a palliative procedure has to be performed.

To justify the inclusion of phenazone, independently of its anti-inflammatory properties, in combination with a local anaesthetic, such as lidocaine, in some ear drop medications, we have studied the effect of this compound on the local anaesthetic activity of lidocaine in an animal model, that of sciatic nerve blockade in mice. Lidocaine and phenazone were tested alone and in combination at various concentrations. The local anaesthetic activity was estimated as the loss of motor activity of the hindlimb after topical injection of the drugs in the region of the sciatic nerve. Lidocaine, at concentrations ranging from 0.03 to 0.25%, induced a concentration-dependent anaesthetic effect. Phenazone alone had no effect at 0.25–1%. When combined, the two compounds acted synergistically. The local anaesthesia induced by lidocaine plus phenazone was significantly more intense and longer lasting than that induced by lidocaine alone. Phenazone enhanced the potency of lidocaine in this animal model. It is suggested that the potentiated local anaesthetic effect of the combination may be partly due to enhanced local bioavailability of lidocaine.

Nefopam (NEF) is a potent analgesic compound administered as a racemic mixture. Previous in vitro and in vivo studies with nefopam enantiomers have shown that (+)nefopam [(+)NEF] is substantially more potent than (−)nefopam [(−)NEF]. Differences between enantiomers have also been suggested in metabolic studies in vitro. The impact of these differences in vivo is not known because there is little or no information on the relative plasma concentrations of the enantiomers or on their kinetics. In this study, individual enantiomers of nefopam were synthesized and examined for acute toxicity in male and female rats and mice. Pharmacologic properties of enantiomers were examined using in vitro binding assays and antinociceptive tests in rats and mice. Additionally, a pharmacokinetic study was conducted in human volunteers. Subjects were administered 20 mg nefopam as Acupan® either as a 5- or 20-min intravenous infusion. In a control phase, subjects were administered only vehicle. Blood samples were collected through the following 24 h. Plasma samples were analyzed for individual enantiomers using a chiral assay developed for this purpose. The pharmacologic differences of previous studies were confirmed in receptor binding assays and in the hot plate and the formalin tests in mice. Neither enantiomer demonstrated substantial activity in the tail flick test in rats. No significant differences were revealed between LD50 values of nefopam enantiomers after oral or intravenous administration in male and female rats or mice. There were no significant differences in AUC0-∞, Cmax, or half-life between enantiomers following intravenous administration. Based on these findings, there is currently no compelling rationale to justify administering or monitoring individual enantiomers. Chirality 12:153–159, 2000. © 2000 Wiley-Liss, Inc.

THIS study examined the nature of the interactions of etifoxine, an anxiolytic and anticonvulsant compound, with the GABAAreceptor/chloride channel complex. In membrane preparations of Sprague–Dawley rat cerebral cortex, etifoxine competitively inhibited the binding of [35S]t-butylbicyclophosphoro-thionate (TBPS), a specific ligand of the GABAAreceptor chloride channel site. In vivostudies demonstrated an anticonvulsant effect of etifoxine (50 and 75 mg/kg, i.p.) against the clonic convulsions induced by TBPS in CD1mice. Flumazenil (10 and 40 mg/kg, i.p.), an antagonist of benzodiazepine sites at GABAAreceptors, had no effect on the action of etifoxine. These findings suggest that etifoxine exerts its effect by interacting with the Cl−channel of GABAAreceptors and probably by facilitating GABAergic inhibition.

Disposition and metabolism of the new anticonvulsant 2,6-dimethylbenzamide N-(5-methyl-3-isoxazolyl) (D2916) was studied in male and female rats after oral administration of14C-labeled material. D2916 was well absorbed in both sexes and distributed to all tissues, with maximal drug concentrations found in elimination and metabolization organs, as well as in fatty tissues. Striking differences in pharmacokinetic parameters of total radioactivity were observed between males and females: females had higher brain concentrations and longer blood and tissue half-lives. The study of blood, bile, urine, and brain metabolites showed that D2916 follows two degradation pathways related to hydroxylation of methyl groups. Males prefer to hydroxylate one of the methyl groups of the phenyl ring, and females prefer to hydroxylate the methyl of the isoxazolyl ring forming the active metabolite D3187. These findings suggest a sex difference in the location of the hydroxylation of the D2916 molecule and can explain the longer anticonvulsant effect observed in the female rat that is related both to an orientation of the metabolism toward the formation of the active metabolite and to a better ability to this metabolite to cross the blood-brain barrier, compared with the unchanged drug.

Disposition and metabolism of the new anticonvulsant 2,6-dimethylbenzamide N-(5-methyl-3-isoxazolyl) (D2916) was studied in male and female rats after oral administration of 14C-labeled material. D2916 was well absorbed in both sexes and distributed to all tissues, with maximal drug concentrations found in elimination and metabolization organs, as well as in fatty tissues. Striking differences in pharmacokinetic parameters of total radioactivity were observed between males and females; females had higher brain concentrations and longer blood and tissue half-lives. The study of blood, bile, urine, and brain metabolites showed that D2916 follows two degradation pathways related to hydroxylation of methyl groups. Males prefer to hydroxylate one of the methyl groups of the phenyl ring, and females prefer to hydroxylate the methyl of the isoxazolyl ring forming the active metabolite D3187. These findings suggest a sex difference in the location of the hydroxylation of the D2916 molecule and can explain the longer anticonvulsant effect observed in the female rat that is related both to an orientation of the metabolism toward the formation of the active metabolite and to a better ability to this metabolite to cross the blood-brain barrier, compared with the unchanged drug.

Objective: The spectrum of cytochrome P450 inhibition of stiripentol, a new anticonvulsant, was characterized in vitro and in vivo.Methods: Stiripentol was incubated in vitro with (R)-warfarin, coumarin, (S)-warfarin, (S)-mephenytoin, bufuralol, p-nitrophenol, and carbamazepine as probes for CYPs 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4, respectively. Caffeine demethylation and the 6β-hydroxycortisol/cortisol ratio were monitored in vivo before and after 14 days of treatment with stiripentol as measures of CYP1A2 and CYP3A4 activity, and dextromethorphan O- and N-demethylation were used to measure CYP2D6 and CYP3A4 activity, respectively. In vivo inhibition constants for CYP3A4 were calculated with use of data that previously documented the interaction between stiripentol and carbamazepine.Results: In vitro, stiripentol inhibited CYPs 1A2, 2C9, 2C19, 2D6, and 3A4, with inhibition constant values at or slightly higher than therapeutic (total) concentrations of stiripentol, but it did not inhibit CYPs 2A6 and 2E1 even at tenfold therapeutic concentrations. In vivo inhibition of caffeine demethylation and dextromethorphan N-demethylation were consistent with inhibition of CYP1A2 and CYP3A4, respectively. The 6β-hydroxycortisol/cortisol ratio did not provide a reliable index of CYP3A4 inhibition. Inhibition of CYP2D6-mediated O-demethylation was not observed in vivo. With use of carbamazepine, in vivo inhibition constants for CYP3A4 ranged between 12 and 35 μmol/L, whereas the corresponding in vitro value was 80 μmol/L.Conclusions: Stiripentol appears to inhibit several CYP450 enzymes in vitro and in vivo. In vivo inhibition constants show that stiripentol inhibition of CYP3A4 is linearly related to plasma concentration in patients with epilepsy.

Gives directions on how to make a mini pinwheel quilt that's perfect for a baby quilt or wallhanging. Includes pattern.