Comparison of volume-controlled and pressure-controlled ventilation during laparoscopic gastric banding in morbidly obese patients.

BACKGROUND: There are no guidelines on ventilation modes in morbidly obese patients. We investigated the effects of volume-controlled (VCV) and pressure-controlled ventilation (PCV) on gas exchange, respiratory mechanics, and cardiovascular responses in laparoscopic gastric banding procedures. METHODS: After Institutional Review Board approval, 24 adult consenting patients scheduled for laparoscopic gastric banding were studied. Anesthesia was standardized using remifentanil, propofol, rocuronium, and sevoflurane. All patients started with VCV with a tidal volume of 10 ml kg(-1) ideal body weight, respiratory rate adjusted to obtain an end-tidal carbon dioxide of 35-40 mmHg, positive end-expiratory pressure of 5 cmH2O, an inspiratory pause of 10% and an inspiratory/expiratory ratio of 1:2. Fifteen minutes after pneumoperitoneum, the patients were randomly allocated to two groups. In Group VCV (n = 12), ventilation was with the same parameters. In Group PCV (n = 12), the airway pressure was set to provide a tidal volume of 10 ml kg(-1) ideal body weight without exceeding 35 cm H2O. Respiratory rate was adjusted to keep an end-tidal carbon dioxide of 35-40 mmHg. Arterial blood samples were drawn after surgical positioning and 15 min after allocation. Analysis of variance (ANOVA) was used for statistical analysis. RESULTS: With constant minute ventilation, VCV generates equal airway pressures and cardiovascular effects with a lower PaCO2 as compared to PCV (42.5 (5.2) mmHg versus 48.9 (4.3) mmHg, p < 0.01 ANOVA). Arterial oxygenation remained unchanged. CONCLUSIONS: VCV and PCV appear to be an equally suited ventilatory technique for laparoscopic procedures in morbidly obese patients. Carbon dioxide elimination is more efficient when using VCV.

Intraoperative high-dose-rate brachytherapy (IBT) for locally unresectable intraabdominal malignancy.

PURPOSE: Intraoperative high-dose-rate brachytherapy (IBT) has been successfully used in locally advanced unresectable intraabdominal malignancy. We retrospectively evaluated the safety, feasibility, and general outcome of IBT following cytoreductive surgery. PATIENTS AND METHODS: After radical resection, the target area to be treated by IBT was determined jointly by the surgeon and the radiation oncologist. A silicon template was used to position parallel hollow catheters spaced 1 cm apart against the area of interest. IBT doses were prescribed at 1 cm depth from the template surface and calculated using standard plans. Radiation was administered in a dedicated shielded room. RESULTS: Between August 2001 and February 2006, 10 patients (colorectal cancer n = 6, cervix cancer n = 1, extramedullar plasmocytoma n = 1, liposarcoma n = 1 and sacrococcygeal teratocarcinoma n = 1) were treated. The mean delivered IBT dose was 8 Gy (range 7.5-20). No postoperative mortality was seen, while major complications developed in one (10%) patient with a rectovaginal fistula and intraabdominal abscess. Five of the six colorectal cancer patients developed local recurrence while 3 also developed distant metastases. The mean disease-free and overall survival in this group was 8.5 months (range 4-15) and 25.5 months (range 10-48) respectively. Palliation of symptoms was observed in 89 % of cases. CONCLUSION: IBT combined with debulking surgery is feasible and can be safely performed. While cure is rarely achieved, IBT offers the potential to prolong local control and survival in locally unresectable intraabdominal cancer. Therefore, IBT can be considered as a valuable adjuvant in the therapeutic and palliative armamentarium in these selected patients.

Surgery for gastrointestinal endometriosis: indications and results.

BACKGROUND: Although gastrointestinal endometriosis is an uncommon and often unexpected finding, the best treatment requires removal of all endometriotic lesions. The purpose of our study was to report our experience with the diagnosis and treatment of bowel endometriosis. MATERIAL AND METHODS: From January 1997 to January 2004, 13 patients (mean 35.7y ; range 21-55y) were operated for bowel endometriosis. We noted: age, history of endometriosis, previous pregnancies, preoperative investigations and symptoms, operative procedure and intraoperative findings. Follow-up varied between one month postoperative examination and seven years. RESULTS: Presenting symptoms of the cases were: acute appendicitis (3), dysmenorrhoea (7), constipation (6), pelvic pain (2), rectal bleeding (3) and dyspareunia (2). Operative management was performed in accordance with the anatomical distribution. Seven patients had a history of previous operations and multifocal involvement was present in 61.5% of cases. At a median follow-up of 12.2 months, 83.3% had complete relief of their initial complaints, with only one reoperation needed. The pregnancy rate after surgery was 66.6%. Preoperative tests were: ultrasound for ovarian endometriomas, coloscopy, barium enema, vaginal palpation for detecting rectovaginal involvement, MRI and CT scan. These tests predicted the extension of endometriotic process correctly in 50% of the cases. CONCLUSIONS: Endometriosis of the sigmoid and rectum is rare but can give rise to severe gastrointestinal and pelvic symptoms. Preoperative investigations are not infallible in predicting the extent of the disease, sometimes placing the surgeon before a dilemma, because it involves mostly young women in the reproductive phase of life. The colorectal surgeon, therefore, should seek the advice of an experienced gynaecologist and vice versa. Removal of all endometriotic lesions is mandatory for obtaining an optimal relief of symptoms.

Influence of stiripentol on cytochrome P450-mediated metabolic pathways in humans: in vitro and in vivo comparison and calculation of in vivo inhibition constants.

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 6 beta-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 stripentol 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 6 beta-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 mumol/L, whereas the corresponding in vitro value was 80 mumol/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.

Interactions of etifoxine with the chloride channel coupled to the GABA(A) receptor complex.

This study examined the nature of the interactions of etifoxine, an anxiolytic and anticonvulsant compound, with the GABA(A) receptor/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 GABA(A) receptor chloride channel site. In vivo studies demonstrated an anticonvulsant effect of etifoxine (50 and 75 mg/kg, i.p.) against the clonic convulsions induced by TBPS in CD1 mice. Flumazenil (10 and 40 mg/kg, i.p.), an antagonist of benzodiazepine sites at GABA(A) receptors, had no effect on the action of etifoxine. These findings suggest that etifoxine exerts its effect by interacting with the Cl- channel of GABA(A) receptors and probably by facilitating GABAergic inhibition.

Functional modulation of gamma-aminobutyric acid(A) receptors by etifoxine and allopregnanolone in rodents.

We looked for an interaction between etifoxine and the neurosteroid allopregnanolone at central gamma-aminobutyric acid (GABA(A)) receptors. Etifoxine (2 microM) did not affect the affinity of allopregnanolone (IC(50)=108 nM) for its site in preparations of Sprague-Dawley rat cerebral cortex membranes, as determined by the inhibition of [(35)S] t-butylbicyclophosphorothionate binding, a specific ligand of the GABA(A) receptor chloride channel site. Etifoxine and allopregnanolone were anticonvulsants, blocking the clonic convulsions induced by bicuculline (an antagonist of the GABA(A) receptor) in CD1 mice. A combination of subactive doses of the two compounds showed additive anticonvulsant effects. These results suggest that etifoxine and allopregnanolone bind to distinct putative recognition sites at or near the chloride channel site. Functionally, their binding may have an additive effect by enhancing GABA(A) inhibitory transmission.

Endotoxins modify muscle fatigue characteristics.

To test the hypothesis that endotoxins can directly modify muscle fatigue characteristics, in vitro experiments were performed on rat muscles 48 hours after injection of lipopolysaccharides (LPS) from Klebsiella pneumoniae. Resistance to fatigue was quantified by measuring tension production during repetitive electrical stimulation of the isolated epitrochlearis muscle. LPS treatment did not significantly modify initial force production whereas fatigability of the muscle was increased. This in vitro preparation should be used for testing antifatigue drugs.

[Complete pre-peritoneal endoscopic closure of inguinal hernias]. / Vollständig präperitonealer endoskopischer Leistenhernienverschluss.

BACKGROUND: Considering the high recurrence rate after conventional inguinal hernia repair, the totally preperitoneal endoscopic inguinal hernia repair has been used. METHODS: The present experience of the authors embraces 1085 patients with a total of 1717 inguinal hernias, including 200 recurrences. The operative technique is described with emphasis on pitfalls and tricks. RESULTS: Analysis of the data concerning the first 403 patients with 1 year complete follow-up reveals a mean (SEM) operating time of 42 (1.2) min for unilateral and 58 (1.0) min for bilateral hernia repair. Mean (SEM) postoperative hospital stay was 2 (0.04) days. Complication rates during and after operation were 0.3% and 3.3% respectively. The morbidity rate at 1 month after operation was 3.5%. The recurrence rate was 0.3% at 1-year follow-up. CONCLUSION: Totally preperitoneal endoscopic inguinal hernia repair is safe and reproducible for any type of primary or recurrent inguinal hernia, even in patients with previous subumbilical surgery or severe systemic disease. Careful follow-up is mandatory to assess the late recurrence rate.

[Astemizole: its pharmacokinetics and pharmacologic properties]. / L'astémizole: données pharmacologiques et pharmacocinétiques.

Astemizole (Hismanal) is a chemically novel compound selected from a series of piperidinylaminobenzimidazoles. Further preclinical pharmacological investigations were initiated by experiences with other drugs in the same field. The aim of this review is to illustrate new pharmacological data on astemizole. Astemizole showed the lowest ED50 and the longest duration in mast cell-mediated shock. Binding characteristics to histamine H1 receptors were specificity, selectivity and long duration. Lack of effects on the wakefulness-sleep cycles was evidenced. An equal bioavailability of the drug was demonstrated with different formulations, dosing and food intake. High plasma levels of desmethylastemizole, the major metabolite, and longer half-life than for astemizole, contribute partly to the antihistamine activity. On chronic administration relative amounts of both molecules in the peripheral compartment are most likely responsible for the expected pharmacological effect. The time-course of kinetics shows, the peak plasma levels of the unchanged astemizole followed by a gradual take-over by desmethylastemizole. In patients with hepatic or renal insufficiency the pharmacokinetic background was similar to healthy volunteers.

[Non-sedative antihistaminics and binding to central and peripheral H1 histamine receptors]. / Antihistaminiques non-sédatifs et liaison aux récepteurs histaminergiques-H1 centraux et périphériques.

Four non-sedating antihistamines (astemizole, cetirizine, loratadine and terfenadine) were investigated for in vitro and ex vivo binding to histamine-H1 receptors in guinea-pig cerebellum and lung. In vitro, all the drugs dissociated slowly from H1 receptors (half-times greater than or equal to 100 min), Ki,app-values decreased with longer incubation times for potent lipophylic agents (astemizole and terfenadine) Ki,app-values were lower with more dilute tissue suspensions. In optimized assay conditions astemizole showed a Ki,app-value of 0.2 microM. Terfenadine, cetirizine and loratadine bound with 30-, 80- and 100-times lower affinity to H1 receptors. The occupancy of lung and cerebellar H1 receptors was investigated after oral administration of various dosages of the drugs and at several times after drug administration, using ex vivo binding techniques. Astemizole was a very potent compound showing complete differentiation between lung and cerebellar receptor occupation (with 0.63 mg/kg: 70% of lung H1 receptors were occupied, with less than 10% of cerebellar H1 receptor occupancy). A 7-times higher dose of terfenadine was required to induce the same effect. Astemizole produced a rapid and complete occupancy of lung receptors, which was maintained up to 72 h after administration. In contrast, terfenadine produced a peak effect at 1 h and was completely eliminated from lung receptors in 24 h. Loratadine and cetirizine only poorly differentiated between lung and cerebellar receptor occupancy (at 2.5 mg/kg: 70 and 60% of lung receptor occupancy, 50 and 70% of cerebellar receptor occupancy).(ABSTRACT TRUNCATED AT 250 WORDS)

Phenazone potentiates the local anaesthetic effect of lidocaine in mice.

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.

Effects of citrulline malate on bacterial lipopolysaccharide induced endotoxemia in rats.

The administration of endotoxins to rats as lipopolysaccharides (LPS) induces a state of exhaustion, in which the main symptoms are febrile hyperthermia, reduced food intake, decreased body weight, and reduced muscle performance in treadmill tests. Underlying the physiological and behavioral disturbances due to the LPS is the activation of macrophages that release cytokines (interleukin-1, tumor necrosis factor a) and NO. The cellular responses are intended to maintain homeostasis. Provision of citrulline as citrulline malate (CAS 54940-97-5, Stimol), an antifatigue substance, improved muscle performance, but had no effect on the body temperature or on the body weight of these animals weakened by LPS. The presence of citrulline in the NO synthesis pathway, or its participation in the speeded up elimination of ammonia and lactates, the main products of muscle metabolism, might explain the effects of citrulline malate in rats treated with LPS.

Citrulline malate limits increase in muscle fatigue induced by bacterial endotoxins.

Citrulline malate is known to improve performance in weakened muscles. The present experiment was designed to test the hypothesis that citrulline malate can limit the effect of endotoxins on muscle fatigability. Endotoxemia was induced in rats by injection of lipopolysaccharides from Klebsiella pneumoniae. Resistance to fatigue was quantified by measuring tension production during repetitive electrical stimulation of the isolated epitrochlearis muscle. Oral treatment by citrulline malate was found to increase resistance to fatigue in infected rats, whereas twitch tension was not modified. This demonstrates the efficacy of citrulline malate for limiting an increase in muscle fatigue elicited with bacterial endotoxins.

Nefopam reduces thermal hypersensitivity in acute and postoperative pain models in the rat.

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 x kg(-1) by intraperitoneal or subcutaneous administration, at 60 mg x kg(-1) by oral dosing, and from 3 mg x kg(-1) after intravenous injection. In the postoperative pain model, at 30 mg x kg(-1) nefopam 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.

Tissue distribution and antifungal effect of liposomal itraconazole in experimental cryptococcosis and pulmonary aspergillosis.

We studied the tissue distribution and in vivo antifungal effect of itraconazole, incorporated into pure dipalmitoylphosphatidylcholine (DPPC) multilamellar liposomes and administered intravenously. Eighty percent of the itraconazole was associated with DPPC. Drug levels in lung, brain, and liver, obtained after intravenous administration of tritiated itraconazole, were higher when the drug was administered intravenously as liposomal than when it was dissolved in cyclodextrin. Administration of the liposomal formulation also led to higher and sustained levels of intact itraconazole in serum. Efficacy was assessed in DBA/2 mice infected intravenously with 3 x 10(6) Cryptococcus neoformans, an inoculum responsible for early fatal pneumonia, or 3 x 10(5) C. neoformans, leading to delayed meningitis. In pneumonia, 20 mg/kg of liposomal itraconazole was more effective on survival than the same dose given intravenously in cyclodextrin or twice the dose administered orally dissolved in polyethylene glycol 200. In meningitis, liposomal itraconazole was also more efficient than the drug dissolved in cyclodextrin. These results were confirmed by colony counts in the brain and lung of infected mice. In immunosuppressed OF1 mice infected after inhalation of Aspergillus fumigatus spores, liposomal itraconazole (20 mg/kg x 3) was the only effective treatment. We conclude that intravenous liposomal delivery of itraconazole enhances both concentrations in infected tissues and the in vivo efficacy of the drug. Such passive targeting of antifungal agents other than amphotericin B might be helpful in the treatment of severe systemic mycoses, especially in the case of lung or brain involvement.

Nefopam enantiomers: preclinical pharmacology/toxicology and pharmacokinetic characteristics in healthy subjects after intravenous administration.

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(R) 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 LD(50) values of nefopam enantiomers after oral or intravenous administration in male and female rats or mice. There were no significant differences in AUC(0-infinity), C(max), 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.

Disposition of stiripentol in the pregnant and non-pregnant female rat.

1. The disposition of stiripentol labelled with 14C and 3H on two positions has been studied in the pregnant and non-pregnant female rat after p.o. administration of a 200 mg/kg dose. 2. For both labelled species radioactivity was eliminated mainly in the faeces (69% within 72 h). Urinary excretion was rather low (22% within 72 h). No significant difference was found between the disposition of the two labelled species. 3. For both labelled species concentrations of radioactivity reached a plateau in the plasma and tissues between 1 and 6 h after administration. The liver, fat, mammary gland and adrenal gland were the most extensively-labelled organs. The affinity for the mammary gland was significantly greater in pregnant rats and for the adrenal gland was significantly greater in the non-pregnant rats. The fact that the concentration in the placenta was higher than in the foetus demonstrated that this membrane acts as a barrier for the penetration of the drug in the amniotic fluid. 4. Chromatographic analysis of the faeces and urine showed that an important portion of the dose remained unabsorbed through the gastrointestinal tract. The absorbed fraction undergoes an extensive first-pass metabolism involving mainly the oxidative cleavage of the methylenedioxy ring. Comparison with the results of other work conducted on the non-pregnant rat demonstrated that pregnancy did not affect the disposition and metabolic process.

Disposition and metabolism of 2,6-dimethylbenzamide N-(5-methyl-3-isoxazolyl) (D2916) in male and female rats.

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.