Zolpidem involvement on memory and hypnotic effect of ethanol in chronically ethanol-treated rats.
(41/1949)
Multiple (10x) treatment of zolpidem (1.0 or 2.0 mg/kg, orally, p.o.) led to different effects in chronically ethanol-treated and control rats. In control rats, after repeated zolpidem administration, a weaker, when compared to single administration, hypnotic effect of ethanol was observed, which may be the result of tolerance developed towards the inhibitory effect of zolpidem. However, in chronically ethanol-treated rats, the multiple zolpidem treatment led to prolongation of ethanol-induced sleep similar to the values observed in non-zolpidem-treated control animals. This suggests that zolpidem multiple administration may inhibit tolerance towards ethanol in chronically ethanol-treated rats. In the experiment with zolpidem, there were effects on performance in a memory test and the impairment of passive avoidance task after multiple drug treatment when compared to the effects after single administration in control rats. In contrast, in chronically ethanol-treated rats, amplification of latency (especially after 2.0 mg/kg) was observed. The possible relationship between ethanol-induced sedation and latency values would be consistent with a higher contribution of the inhibitory effect of zolpidem, than a direct influence on memory processes in chronically ethanol-treated rats. (+info)
Cytochrome P-450 3A4 and 2C8 are involved in zopiclone metabolism.
(42/1949)
Zopiclone is a widely prescribed, nonbenzodiazepine hypnotic that is extensively metabolized by the liver in humans. The aim of the present study was to identify the human cytochrome P-450 (CYP) isoforms involved in zopiclone metabolism in vitro. Zopiclone metabolism was studied with different human liver microsomes and a panel of heterologously expressed human CYPs (CYP1A2, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4). In human liver microsomes, zopiclone was metabolized into N-desmethyl-zopiclone (ND-Z) and N-oxide-zopiclone (NO-Z) with the following K(m) and V(m) of 78 +/- 5 and 84 +/- 19 microM, 45 +/- 1 and 54 +/- 5 pmol/min/mg for ND-Z and NO-Z generation, respectively. Ketoconazole (CYP3A inhibitor) inhibited approximately 40% of the generation of both metabolites, sulfaphenazole (CYP2C inhibitor) inhibited the formation of ND-Z, whereas alpha-naphtoflavone (CYP1A), quinidine (CYP2D6), and chlorzoxazone (CYP2E1) did not affect zopiclone metabolism. The generation of ND-Z and NO-Z were highly correlated to testosterone 6beta-hydroxylation (CYP3A activity, r = 0.95 and 0.92, respectively; p =.0001), and ND-Z was highly correlated to CYP2C8 activity (paclitaxel 6alpha-hydroxylase; r = 0.76, p =.004). Recombinant CYP2C8 had the highest enzymatic activity toward zopiclone metabolism into both its metabolites, followed by CYP2C9 and 3A4. CYP3A4 is the major enzyme involved in zopiclone metabolism in vitro, and CYP2C8 contributes significantly to ND-Z formation. (+info)
The role of codeine phosphate premedication in fibre-optic bronchoscopy under insufficient local anaesthesia and midazolam sedation.
(43/1949)
Midazolam is widely used as a sedative agent to produce amnesia in patients undergoing fibre-optic bronchoscopy. However, if a patient does not receive sufficient local anaesthesia, continuous severe cough and physical movement may interrupt the procedure and reduce its safety. We therefore examined whether codeine phosphate is a useful premedication for bronchoscopy. The study design was a randomized comparison between codeine phosphate and a placebo in patients undergoing light local anaesthesia and midazolam sedation. We used low dose local anaesthesia (5 ml of nebulized 2% xylocaine) on the assumption of insufficient local anaesthesia. Patients were allocated to receive codeine phosphate 0.4 mg kg-1 or a saline placebo 60 min before they were sedated with i.v. midazolam. If the patients exhibited severe cough during bronchoscopy, intrabronchial supplemental local anaesthesia (2% xylocaine solution in 1 ml increments) was instilled via a bronchoscope to the trachea and segmental bronchi to suppress the cough. The dose of supplemental xylocaine was assessed and the requirements were significantly lower in the codeine group compared to the placebo group: 36.4 +/- 10.2 mg vs. 95.1 +/- 24.6 mg, respectively. After bronchoscopy, patients were interviewed by a doctor to assess their willingness to undergo a repeat procedure if one was clinically indicated, but no significant difference was observed between the two groups. If local anaesthesia is insufficient, midazolam together with codeine phosphate premedication is useful for both the patient and the bronchoscopist. (+info)
Patient-controlled sedation using propofol in elderly patients in day-case cataract surgery.
(44/1949)
Patient-controlled sedation (PCS) with propofol has been used successfully as an adjunct to local anaesthetic procedures. We studied a group of elderly patients (mean age 75.4 yr) undergoing cataract surgery and attempted to increase patient acceptability and comfort of local anaesthesia. Propofol was self-administered in a dose of 0.25 mg kg-1 for patients more than 60 yr of age, with a lockout period of 3 min. A total of 14 of 20 patients used PCS; eight of 20 used the PCS only once and another six had three tries or less. Despite this, 18 of 20 patients claimed they found the PCS useful. However, while it is possible to administer PCS successfully to elderly patients undergoing cataract surgery and produce a decrease in the level of anxiety, we found it unacceptable because of head movement in two patients. These patients received only two and three divided doses, to a maximum of 29 and 30 mg, respectively. There were no other adverse events. (+info)
Effect of dietary taurine on endogenous hypercholesterolemia in rats fed on phenobarbital-containing diets.
(45/1949)
The effect of dietary taurine on endogenous hypercholesterolemia induced by a phenobarbital-containing diet was investigated. Supplemented taurine did not affect the concentrations of serum cholesterol, but further potentiated the accumulation of hepatic cholesterol in the hypercholesterolemic state induced by phenobarbital. It is suggested that taurine might amplify the hepatic cholesterogenesis in phenobarbital-induced hypercholesterolemia. (+info)
Organization of rat circadian rhythms during daily infusion of melatonin or S20098, a melatonin agonist.
(46/1949)
Daily administration of melatonin or S20098, a melatonin agonist, is known to entrain the free-running circadian rhythms of rats. The effects of the duration of administration on entrainment were studied. The animals demonstrated free-running circadian rhythms (running-wheel activity, body temperature, general activity) in constant darkness. Daily infusions of melatonin or S20098 for 1, 8, or 16 h entrained the circadian rhythms to 24 h. Two daily infusions of 1 h (separated by 8 h) entrained the activity peak within the shorter time interval. The entraining properties of melatonin and S20098 were similar and were affected neither by pinealectomy nor by infusion of 1- or 8-h duration. However, with 16-h infusion, less than half of the animals became entrained. Once entrained, the phase angle between the onset of infusion and the rhythms (onset of activity or acrophase of body temperature) increased with the duration of infusion. Before entrainment, the free-running period increased with the duration of infusion, an effect that was not predictable from the phase response curve. (+info)
Electroencephalographic effects of thiopentone and its enantiomers in the rat: correlation with drug tissue distribution.
(47/1949)
1. To better understand the pharmacology of the thiopentone enantiomers, we studied their quantitative electroencephalographic effects and their distribution into vital tissues. 2. Adult Wistar rats were infused with rac-, R- or S-thiopentone at 4 mg kg(-1)min(-1) until death ensued. The EEG signal was acquired continuously; serial arterial plasma and terminal tissue thiopentone concentrations were measured enantiospecifically. Relevant drug tissue : plasma distribution coefficients and plasma concentration-EEG effect relationships were determined. 3. Doses (mg kg(-1)) (mean+/-s.e.mean) for anaesthesia (toe pinch) and lethality (respiratory failure), respectively, decreased in the order R-thiopentone (55.8+/-2.4 and 176.2+/-11.2)> rac-thiopentone (39.3+/-2.1 and 97.5+/-3.9)> S-thiopentone (35.6+/-1.9 and 74.2+/-5.2); plasma drug concentrations (microg ml(-1)) decreased in the order R-thiopentone (66.3+/-4.5 and 89.8+/-5.2)> rac-thiopentone (56.7+/-2.0 and 77. 8+/-2.8)> S-thiopentone (55.0+/-1.9 and 64.1+/-2.8). 4. Initial EEG activation was similar for all thiopentone forms. Plasma drug concentrations for the same extent of EEG deactivation reflected the potency order. 5. After infusion of rac-thiopentone, tissue : plasma distribution coefficients were higher for R- than for S-thiopentone in brain and visceral regions, but not in fat or muscle. After infusion of the separate enantiomers, the relative heart : brain distribution ratio was for S-thiopentone was double that for R-thiopentone. 6. The therapeutic index of R-thiopentone (3.16+/-0. 14) was more advantageous than either rac-thiopentone (2.52+/-0.13) or S-thiopentone (2.10+/-0.14), possibly due to the relatively greater distribution into CNS tissues than heart. The data suggest that R-thiopentone could make a satisfactory single enantiomer substitute for rac-thiopentone. (+info)
Tenckhoff catheter salvage by closed stiff-wire manipulation without fluoroscopic control.
(48/1949)
OBJECTIVE: To describe the results of Tenckhoff catheter salvage by a modified, closed, stiff-wire manipulation technique without the use of general anesthesia or fluoroscopy, and compare this with previously described techniques. DESIGN: Retrospective study in patients treated with continuous ambulatory peritoneal dialysis (CAPD) over a 41-month period. SETTING: Renal unit in an inner city hospital. PATIENTS: Eighteen patients using CAPD who had 22 episodes of outflow failure due to radiologically confirmed malposition of straight two-cuff Tenckhoff catheters. INTERVENTIONS: Closed stiff-wire manipulation of malpositioned Tenckhoff catheter without the use of general anesthesia or fluoroscopy. MAIN OUTCOME MEASURES: Initial success rate of manipulation, catheter and technique (CAPD) survival, and procedure-related complications. RESULTS: Catheter manipulation was technically successful in 21 of 22 cases. An additional six episodes of malposition occurred ranging from 2 to 630 days after the primary manipulation (median 7 days). A second manipulation was carried out in four cases that resulted in long-term success in two. Three patients were forced to discontinue CAPD for reasons other than catheter malposition, and the overall success rate at 1 month (patient successfully performing CAPD) was 59.1% (+/-0.1%). No major complications were experienced during the procedure and no episodes of peritonitis occurred. CONCLUSION: The technique described is relatively straightforward, does not require fluoroscopy or general anesthetic, and its success is comparable to previously reported methods of Tenckhoff catheter salvage. We would recommend this technique of catheter salvage in patients with Tenckhoff catheter malposition in whom conservative treatment has failed. (+info)