First-in-man study with a novel PEGylated recombinant human insulin-like growth factor-I.

OBJECTIVE: This study is a first time assessment of safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 in human, in comparison with unmodified rhIGF-I. DESIGN: The study was conducted as a single-center, randomized, double-blinded, placebo-controlled, single ascending dose, parallel group study in a clinical research unit in France. A total of 62 healthy volunteers participated in this clinical trial. RO5046013 was given as single subcutaneous injection, or as intravenous infusion over 48h, at ascending dose levels. The active comparator rhIGF-I was administered at 50µg/kg subcutaneously twice daily for 4days. Safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 were evaluated. RESULTS: PEGylation resulted in long exposure to RO5046013 with a half-life of 140-200h. Exposure to RO5046013 increased approximately dose proportionally. RO5046013 was safe and well tolerated at all doses, injection site erythema after SC administration was the most frequent observed AE. No hypoglycemia occurred. Growth hormone (GH) secretion was almost completely suppressed with rhIGF-I administration, whereas RO5046013 caused only a modest decrease in GH at the highest dose given IV. CONCLUSIONS: PEGylation of IGF-I strongly enhances half-life, reduces the negative GH feedback and hypoglycemia potential, and therefore offers a valuable alternative to rhIGF-I in treatment of relevant diseases.

Population prevalence of Down's syndrome in the United Kingdom.

BACKGROUND: Aim was to estimate the age and sex-stratified prevalence of Down's syndrome (DS) in the United Kingdom (UK) general population using a large primary care database. METHOD: Data source was the Clinical Practice Research Datalink. We divided the number of individuals with a record of DS present on 01/07/2014 by the total number of individuals, and computed Wilson's confidence intervals. Prevalence by age and sex was represented using local linear smoothing plots. RESULTS: On July 1(st) 2014, 1159 females and 1317 males with DS were present in the data, corresponding to a prevalence of 5.9 per 10 000 (95% CI: 5.5; 6.2) in females and 6.8 (6.5; 7.2) per 10 000 in males. Prevalence of DS was increased in individuals aged 40 to 55 years compared to adjacent age groups. CONCLUSIONS: A relative peak prevalence of DS at age 40-55 years may be attributed to the combined effects of a rise in life expectancy and the still limited availability of selective abortion.

Effect of calcium supplements on the oral bioavailability of moxifloxacin in healthy male volunteers.

OBJECTIVE: To investigate the effect of concomitant calcium administration on the pharmacokinetics and tolerability of moxifloxacin. DESIGN: This was a nonblinded, randomised, single dose, crossover study in healthy male volunteers. PARTICIPANTS: 12 healthy male Caucasians (age 24 to 45 years) were enrolled in the study. METHODS: In each of the 2 study periods, each volunteer received a single oral morning dose of moxifloxacin 400mg after an overnight fast. In 1 of the study periods, Ca2+ 500mg (Calcium-Sandoz Forte) was administered immediately before, and 12 and 24 hours after, moxifloxacin (total of 3 doses of Ca2+). The 2 study periods were separated by a washout period of at least 2 weeks. RESULTS: Moxifloxacin was well tolerated throughout the study. There was no difference in the area under the plasma concentration-time curve from zero to infinity [AUCinfinity; geometric mean (SD)] of moxifloxacin [32.2 (1.24) vs 33.0 (1.26) mg/L x h, with vs without Ca2+]. Maximum plasma concentration (Cmax) [2.29 (1.27) vs 2.71 (1.33) mg/L, with vs without Ca2+] slightly decreased by approximately 16% and the time to Cmax [median (range)] tended to be slightly prolonged [2.5 (0.8 to 3) vs 0.9 (0.5 to 2.5) hours, with vs without Ca2+]. CONCLUSIONS: The extent of absorption of moxifloxacin is not affected by concomitant Ca2+ intake, whereas the rate of absorption is slightly reduced, an effect not considered to be of clinical relevance. Hence, moxifloxacin may be administered together with Ca2+ without dosage adjustments or special recommendations.

Cyclosporine pharmacokinetics and pharmacodynamics in African American and white subjects.

BACKGROUND: Renal allograft survival is lower in African American patients compared with white patients. Interethnic differences in cyclosporine (INN, ciclosporin) pharmacokinetics in renal transplant recipients have been described but have not been well characterized. Pharmacodynamic responses to cyclosporine have not been compared among ethnic groups. METHODS: Healthy men were studied after 5 days on a controlled diet. Cyclosporine concentrations were determined in whole blood drawn at intervals over 24 hours after administration of a microemulsion cyclosporine formulation (4 mg/kg; 9 African American subjects and 9 white subjects) and after a standard cyclosporine formulation (4 mg/kg; 10 African American subjects and 10 white subjects). Inhibition of phytohemagglutinin-P-stimulated interleukin-2 production in whole blood drawn 4 hours after cyclosporine was used as a pharmacodynamic measure to compare the effect of cyclosporine in African American and white subjects. RESULTS: The microemulsion cyclosporine formulation (area under the cyclosporine concentration-time curve, 7432 +/- 560 ng. h/mL in African American subjects and 7043 +/- 454 ng. h/mL in white subjects) was more bioavailable than the standard formulation (area under the cyclosporine concentration-time curve, 4828 +/- 319 ng. h/mL in African American subjects and 4538 +/- 301 ng. h/mL in white subjects); this resulted in an approximately 50% greater area under the cyclosporine concentration-time curve (P < .001 in both ethnic groups). There were no differences between African American subjects and white subjects in any pharmacokinetic measurement, with both the standard and the microemulsion cyclosporine formulations. Inhibition of phytohemagglutinin-P-stimulated interleukin-2 production 4 hours after the administration of cyclosporine was similar in African American subjects (70% +/- 5% inhibition) and white subjects (64% +/- 7% inhibition; P = .5). CONCLUSIONS: The pharmacokinetics and pharmacodynamics of cyclosporine were similar in a matched group of African American and white subjects studied under controlled conditions. Environmental factors may contribute more than genetic variability to the lower bioavailability of cyclosporine reported in African American renal transplant recipients.

Increased drug delivery to the brain by P-glycoprotein inhibition.

BACKGROUND: Although the antidiarrheal loperamide is a potent opiate, it does not produce opioid central nervous system effects at usual doses in patients. On the basis of in vitro studies demonstrating that loperamide is a substrate for the adenosine triphosphate-dependent efflux membrane transporter P-glycoprotein, we postulated that inhibition of P-glycoprotein with quinidine would increase entry of loperamide into the central nervous system with resultant respiratory depression. METHODS: To test this hypothesis, a 16-mg dose of loperamide was administered to eight healthy male volunteers in the presence of either 600 mg quinidine, a known inhibitor of P-glycoprotein, or placebo. Central nervous system effects were measured by evaluation of the respiratory response to carbon dioxide rebreathing as a measure of opiate-induced respiratory depression. RESULTS: Loperamide produced no respiratory depression when administered alone, but respiratory depression occurred when loperamide (16 mg) was given with quinidine at a dose of 600 mg (P < .001). These changes were not explained by increased plasma loperamide concentrations. CONCLUSION: This study therefore demonstrates first the potential for important drug interactions to occur by a new mechanism, namely, inhibition of P-glycoprotein, and second that the lack of respiratory depression produced by loperamide, which allows it to be safely used therapeutically, can be reversed by a drug causing P-glycoprotein inhibition, resulting in serious toxic and abuse potential.

CYP3A activity in African American and European American men: population differences and functional effect of the CYP3A4*1B5'-promoter region polymorphism.

OBJECTIVE: Cytochrome P4503A (CYP3A) activity exhibits considerable interindividual variability. Possible differences in CYP3A activity were investigated in European American and African American men with the use of midazolam as an in vivo probe. METHODS: Midazolam was simultaneously administered intravenously (1 mg, [15N3]-labeled) and orally (2 mg, unlabeled in capsule form) to 15 young healthy European American men and a similar group of men of African American descent. Plasma concentration-time curves were measured. The subjects were subsequently genotyped with respect to the CYP3A4*B1 polymorphism (A-290G) in the 5'-promoter (nifedipine-specific element) region. RESULTS: The oral bioavailability of midazolam was about equally determined by intestinal and hepatic extraction with CYP3A activity at the former site exhibiting greater variability. Oral bioavailability was related to intestinal metabolism (r = 0.98), whereas hepatic CYP3A activity contributed little to the interindividual variability (r = 0.03). A lower systemic clearance (265+/-54 versus 310+/-56 mL/min; P = .04), but not oral clearance, was observed in African Americans. With one exception, the African Americans possessed a variant CYP3A4*1B allele (4 heterozygotes A/G and 10 homozygote G/G), whereas all of the European Americans were wild-type homozygotes (A/A). Hepatic CYP3A activity and the systemic clearance of midazolam were about 30% lower in G/G homozygotes than in A/A homozygotes (252+/-53 versus 310+/-54 mL/min; P = .02), and a gene-dose effect was present (P = .01). There was no genotype/phenotype relationship with respect to the oral clearance of midazolam. CONCLUSION: Comparison of CYP3A activity between populations is complicated by frequency distribution differences in the regulatory CYP3A4*1B polymorphism and lower hepatic CYP3A activity associated with the variant allele. However, this reduction is modest; therefore no major and clinically important difference in CYP3A activity is present between Americans of African or European descent.

Mibefradil is a P-glycoprotein substrate and a potent inhibitor of both P-glycoprotein and CYP3A in vitro.

Mibefradil, a calcium T- and L-channel blocker developed for use in hypertension, was recently removed from the market after reports of severe drug-drug interactions. Mibefradil is known to inhibit various cytochrome P450 enzymes involved in drug metabolism, particularly CYP3A. However, the extent and the severity of the observed drug interactions in humans suggest that inhibition of additional systems important to drug disposition, such as the drug transporter P-glycoprotein (P-gp), may also have contributed to the severity of the mibefradil interactions. A polarized epithelial cell line, LLC-PK1, which does not express P-gp, and the derived L-MDR1 cell line, which overexpresses human P-gp, were used to study the effects of mibefradil on drug transport. A markedly greater basal-to-apical versus apical-to-basal transport of [H3]mibefradil was seen in the L-MDR1, but not in the LLC-PK1 cells, suggesting that the drug is a substrate of P-gp. Using a human intestinal cancer-derived cell line Caco-2, which constitutively expresses P-gp, mibefradil was shown to be a potent inhibitor of P-gp-mediated digoxin transport, with an IC50 of 1.6 microM. Additionally, the effect of mibefradil on CYP3A was assessed using human liver microsomes. Mibefradil inhibited CYP3A-mediated nifedipine oxidase activity with an IC50 of 0.8 microM, and a Ki of 0.6 microM. Thus, mibefradil is not only a P-gp substrate, but also a potent inhibitor of both P-gp and CYP3A. These data suggest that the severity of drug interactions seen with mibefradil use is due to the dual inhibition of both P-gp and CYP3A.

Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes.

HIV protease inhibitors have proven remarkably effective in treating HIV-1 infection. However, some tissues such as the brain and testes (sanctuary sites) are possibly protected from exposure to HIV protease inhibitors due to drug entry being limited by the membrane efflux transporter P-glycoprotein, located in the capillary endothelium. Intravenous administration of the novel and potent P-glycoprotein inhibitor LY-335979 to mice (1-50 mg/kg) increased brain and testes concentration of [(14)C]nelfinavir, up to 37- and 4-fold, respectively, in a dose-dependent fashion. Similar effects in brain levels were also observed with (14)C-labeled amprenavir, indinavir, and saquinavir. Because [(14)C]nelfinavir plasma drug levels were only modestly increased by LY-335979, the increase in brain/plasma and testes/plasma ratios of 14- to 17- and 2- to 5-fold, respectively, was due to increased tissue penetration. Less potent P-glycoprotein inhibitors like valspodar (PSC-833), cyclosporin A, and ketoconazole, as well as quinidine and verapamil, had modest or little effect on brain/plasma ratios but increased plasma nelfinavir concentrations due to inhibition of CYP3A-mediated metabolism. Collectively, these findings provide "proof-of-concept" for increasing HIV protease inhibitor distribution into pharmacologic sanctuary sites by targeted inhibition of P-glycoprotein using selective and potent agents and suggest a new therapeutic strategy to reduce HIV-1 viral replication.

P-glycoprotein and cytochrome P-450 3A inhibition: dissociation of inhibitory potencies.

Many P-glycoprotein (P-gp) inhibitors studied in vitro and in vivo are also known or suspected to be substrates and/or inhibitors of cytochrome P-450 3A (CYP3A). Such overlap raises the question of whether CYP3A inhibition is an intrinsic characteristic of P-gp inhibitors, a matter of concern in the development and rational use of such agents. Thus, the purpose of the present study was to determine whether the ability to inhibit P-gp and CYP3A is, in fact, linked and whether specific P-gp inhibitors with limited ability to inhibit CYP3A can be identified. Therefore, the potency of a series of 14 P-gp inhibitors was assessed by measuring their inhibition of the transepithelial flux across Caco-2 cells of digoxin, a prototypical P-gp substrate. CYP3A inhibition was determined from the impairment of nifedipine oxidation by human liver microsomes. Determination of the apparent Ki values for CYP3A inhibition and the IC50s for P-gp and CYP3A inhibition allowed comparison of the relative inhibitory potency of the compounds on the two proteins' function. The IC50s for P-gp inhibition ranged from 0.04 to 3.8 microM. All compounds inhibited CYP3A with apparent Ki values of between 0.3 and 76 microM and IC50s between 1.5 and 50 microM. However, no correlation was found between the extent of P-gp inhibition and CYP3A inhibition, and the ratio of the IC50 for CYP3A inhibition to the IC50 for P-gp inhibition varied from 1.1 to 125. These results demonstrate that, although many P-gp inhibitors are potent inhibitors of CYP3A, a varying degree of selectivity is present. The development and use of P-gp inhibitors with minimal or absent CYP3A inhibitory effects should decrease the impact of drug interactions on the therapeutic use of such compounds.

Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein.

PURPOSE: CYP3A and P-gp both function to reduce the intracellular concentration of drug substrates, one by metabolism and the other by transmembrane efflux. Moreover, it has been serendipitously noted that the two proteins have many common substrates and inhibitors. In order to test this notion more fully, systematic studies were undertaken to determine the P-gp-mediated transport and inhibitory characteristics of prototypical CYP substrates. METHODS: L-MDR1, LLC-PK1, and Caco-2 cells were used to evaluate established CYP substrates as potential P-gp substrates and inhibitors in vitro, and mdr1a deficient mice were used to assess the in vivo relevance of P-gp-mediated transport. RESULTS: Some (terfenadine, erythromycin and lovastatin) but not all (nifedipine and midazolam) CYP3A substrates were found to be P-gp substrates. Except for debrisoquine, none of the prototypical substrates of other common human CYP isoforms were transported by P-gp. Studies in mdr1a disrupted mice confirmed that erythromycin was a P-gp substrate but the CYP3A-inhibitor ketoconazole was not. In addition, CYP3A substrates and inhibitors varied widely in their ability to inhibit the P-gp-mediated transport of digoxin. CONCLUSIONS: These results indicate that the overlap in substrate specificities of CYP3A and P-gp appears to be fortuitous rather than indicative of a more fundamental relationship.

Effect of CYP3A inhibition on vesnarinone metabolism in humans.

OBJECTIVE: To identify the cytochrome P450 (CYP) enzymes involved in the conversion of vesnarinone to it main primary metabolite OPC-18692 and to investigate the effect of CYP3A inhibition on the pharmacokinetics of vesnarinone in vivo. METHODS: Formation of the primary vesnarinone metabolite OPC-18692 was measured in microsomes from AHH-1 TK +/- cells heterologously expressing CYP1A1, CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, or CYP3A4. The pharmacokinetics of vesnarinone and OPC-18692 were defined for 12 health white men after oral administration of 60 mg vesnarinone before and after CYP3A inhibition, which was produced by pretreatment with erythromycin. CYP3A inhibition was verified with erythromycin breath test. RESULTS: In vitro, expressed CYP2E1 and CYP3A4 produced significant amounts of OPC-18692 with the higher formation rate observed by CYP3A4 (12.3 pmol/pmol VYP3A4 per 2 hours versus 1 pmol/pmol CYP2E1 per 2 hours). In vivo, the area under the concentration-time curve extrapolated to infinity (AUC[infinity]) of vesnarinone after pretreatment with erythromycin increased from 133 +/- 26 micrograms.hr/ml to 202 +/- 47 micrograms.hr/ml (p < 0.001), and the half-life increased from 36.5 +/- 9.6 hours to 46.2 +/- 9.2 hours (p < 0.01). Clearance decreased from 372 +/- 68 ml/min to 256 +/- 49 ml/min (p < 0.001). These changes in the disposition of vesnarinone were accompanied by a decrease in plasma concentration of the metabolite OPC-18692 so that the AUC(0-48) was reduced from 1311 +/- 513 micrograms.hr/ml to 850 +/- 148 micrograms.hr/ml (p < 0.001). The total amount of vesnarinone excreted in the urine up to 168 hours after administration increased after erythromycin pretreatment (p < 0.001). Although renal clearance did not change, OPC-18692 was not detectable in the urine. The erythromycin breath test showed significant inhibition after pretreatment with erythromycin (p < 0.001). CONCLUSIONS: CYP2E1 and CYP3A4 are involved in the phase I metabolism of vesnarinone. Inhibition of CYP3A activity in vivo increases the plasma concentration of vesnarinone and delays its elimination in humans so that monitoring of its plasma levels may be helpful in preventing concentration-related toxicity when CYP3A activity is impaired. Whether CYP3A induction and altered CYP2E1 activity may also change the in vivo disposition of vesnarinone remains to be determined.

Relationship between hepatic cytochrome P450 3A content and activity and the disposition of midazolam administered orally.

It was recently shown by others that the clearance of midazolam/kg body weight after iv administration correlates with hepatic cytochrome P450 (CYP or P450) 3A content in liver transplant patients. However, after po administration midazolam undergoes significant first-pass metabolism, with significant intestinal extraction. The relationship between hepatic CYP3A and midazolam disposition after po administration had not previously been investigated. The aim of this study was to compare intraindividually hepatic CYP3A content and activity with the in vivo pharmacokinetics of midazolam (7.5 mg) administered po. For 15 patients scheduled for partial liver resection, the AUC values for the observed time period (AUC0-5hr) and to infinity (AUCinf) and the clearance were determined. In a macroscopically normal area of resected liver tissue, the microsomal CYP3A4 content (nanomoles per nanomole of total P450) was measured by immunoblot analysis and parameters (apparent Vmax, apparent KM, and intrinsic clearance) for the microsomal alpha-hydroxylation of midazolam were determined. Clearance/kg in vivo correlated with the apparent Vmax (r2 = 0.45, p < 0.01) and the CYP3A4 content (r2 = 0.29, p < 0.05). We conclude that interindividual variability in the pharmacokinetics of po administered midazolam is in part determined by interindividual variability in the hepatic microsomal Vmax for the alpha-hydroxylation of midazolam. However, the relationship between the disposition of midazolam administered po and hepatic CYP3A content is weaker than that reported after iv administration, indicating the importance of the contribution of intestinal CYP3A to the in vivo disposition of midazolam administered po.

The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors.

Currently available HIV-1 protease inhibitors are potent agents in the therapy of HIV-1 infection. However, limited oral absorption and variable tissue distribution, both of which are largely unexplained, complicate their use. We tested the hypothesis that P-glycoprotein is an important transporter for these agents. We studied the vectorial transport characteristics of indinavir, nelfinavir, and saquinavir in vitro using the model P-glycoprotein expressing cell lines L-MDR1 and Caco-2 cells, and in vivo after intravenous and oral administration of these agents to mice with a disrupted mdr1a gene. All three compounds were found to be transported by P-glycoprotein in vitro. After oral administration, plasma concentrations were elevated 2-5-fold in mdr1a (-/-) mice and with intravenous administration, brain concentrations were elevated 7-36-fold. These data demonstrate that P-glycoprotein limits the oral bioavailability and penetration of these agents into the brain. This raises the possibility that higher HIV-1 protease inhibitor concentrations may be obtained by targeted pharmacologic inhibition of P-glycoprotein transport activity.

The relationship between cytochrome P4502E1 activity and plasma fluoride levels after sevoflurane anesthesia in humans.

UNLABELLED: We determined whether the perianesthetic plasma fluoride levels after sevoflurane anesthesia in humans were correlated with the metabolic ratio (MR) of 6-hydroxychlorzoxazone to chlorzoxazone, an in vivo probe for cytochrome P4502E1 (CYP2E1) activity. Thirty ASA physical status I or II patients scheduled for extraabdominal surgery were randomized to a chlorzoxazone (n = 20) or a control group (n = 10). Patients in the chlorzoxazone group received 500 mg chlorzoxazone orally on the morning of the day of surgery. Chlorzoxazone and its 6-hydroxymetabolite concentrations were measured in plasma 2 h after drug administration. Anesthesia was induced with propofol, fentanyl, and atracurium intravenously and maintained with sevoflurane (inspired concentration 1-3 vol%). Plasma fluoride concentrations were determined before the induction of anesthesia, at the cessation of sevoflurane, and 2, 4, 6, 10, and 24 h thereafter. The area under the plasma fluoride concentration-time curve (AUC) was calculated up to 24 h after sevoflurane cessation. MR correlated significantly with the plasma fluoride AUC (r2 = 0.28, P < 0.025), the elimination constant calculated for the postanesthetic 10- to 24-h period (r2 = 0.30, P < 0.025), and the plasma fluoride levels 24 h after the cessation of sevoflurane (r2 = 0.48, P < 0.05). A comparison between groups indicated that the administration of chlorzoxazone itself did not alter the postanesthetic fluoride kinetics. Thus, the interindividual variability in perianesthetic plasma fluoride levels after sevoflurane anesthesia is reflected by differences in the MR of chlorzoxazone and hence is related to the interindividual variability in CYP2E1 activity. We conclude that although the predictive value is limited, this study provides a reasonable basis for examining renal function after sevoflurane anesthesia in a subgroup of patients with a high preoperative metabolic ratio of chlorzoxazone. IMPLICATIONS: CYP2E1 metabolizes sevoflurane as measured by the metabolic ratio of chlorzoxazone. Patients with a high ratio may be used to justify examining renal function in patients receiving sevoflurane.

[A comparative study of the use of sevoflurane and propofol in ambulatory surgery]. / Eine vergleichende Untersuchung zum Einsatz von Sevofluran und Propofol bei tageschirurgischen Eingriffen.

UNLABELLED: Cost-containment strategies increase the demand for day-case surgery. In outpatients, a short time of stay in the post-anaesthesia care unit and a short interval to discharge home are of great importance. After general anaesthesia, mental and psychomotor functions are impaired to varying degrees by different anaesthetics. Therefore, the choice of anaesthetic may influence the discharge times of outpatients. In this study, the recovery characteristics of sevoflurane versus propofol anaesthesia were compared in adult outpatients. METHODS: With ethics committee approval and written informed consent, a total of 50 patients undergoing day-case ophthalmological or urological surgery were randomised into two groups. After a priming dose of vecuronium 0.015 mg/kg, anaesthesia was induced in all patients with propofol 2.0-2.5 mg/kg and fentanyl 2 micrograms/kg. Suxamethonium 1 mg/kg was used to provide muscle relaxation for endotracheal intubation. According to the randomisation, anaesthesia was maintained with either sevoflurane 1-3 vol.% (group 1, n = 25) or propofol (group 2, n = 25). The immediate postoperative recovery was assessed by the time to the appropriate response to different verbal commands. The quality of the overall postoperative recovery was classified by visual analogue scales, the digit-symbol substitution test (DSST), a modified Aldrete score, and the time until the ability to sit upright and walk. Overall side effects and postoperative behaviour were evaluated by a telephone interview on the day after surgery. RESULTS: Neither the study groups nor the duration of surgical procedures differed significantly. The total doses of anaesthetic used were 1.7 +/- 1.1 MAC-h sevoflurane and 631 +/- 261 mg propofol, respectively. The time intervals from the end of anaesthesia to extubation of the trachea were significantly shorter after sevoflurane than after propofol (6.6 +/- 2 min vs. 9.8 +/- 6 min). Similar results were obtained for the intervals to eye opening (7.2 +/- 2 min vs. 12.6 +/- 9 min) and hand squeezing (8 +/- 2 min vs. 13.8 +/- 11 min). The recovery of cognitive functions was significantly faster after sevoflurane when compared to propofol as evidenced by the DSST. The modified Aldrete score was significantly better in the sevoflurane group at all assessment times. Except for 30 min after anaesthesia, when sevoflurane patients complained of significantly more nausea, VAS scores were not different. No significant difference in the ability to sit and walk was found. The side effects did not differ between both groups. CONCLUSION: The results indicate that in urological and ophthalmological day surgery, the early recovery and the return of mental and psychomotor function in the first 60 min after anaesthesia is faster following sevoflurane than after propofol. No differences in ambulation times became evident. Sevoflurane may offer clinical advantages over propofol when used for maintenance of anaesthesia during outpatient surgical procedures.

Lignocaine metabolite formation: an indicator for liver dysfunction and predictor of survival in surgical intensive care patients.

Formation of the lignocaine metabolite monoethyl-glycine-xylidide (MEGX) by hepatic cytochrome P450 enzymes is a new method for evaluating liver function. The purpose of this study was to compare MEGX formation with other liver function parameters in surgical intensive care unit patients. The study include 29 critically ill patients who had been admitted to the unit for more than 3 days with a median APACHE III score-predicted mortality > 30%. On day 4, lignocaine was given intravenously at a dose of 1 mg.kg-1 over 2 min and MEGX formation was measured 15 min later. Eighty-nine percent of the patients had MEGX values below 90 micrograms.l-1 indicating impaired liver function. Eleven patients died, 18 patients survived. The group of patients with fatal outcome had significantly lower MEGX values (median: 23 micrograms.l-1) than the group of survivors (median: 53 micrograms.l-1, p < 0.01). Bilirubin values were elevated in the non-survivor group (median: 2.8 mg.dl-1) compared to the survivors (median: 0.9 mg.dl-1, p < 0.05). There was no significant difference between two groups in the other liver function tests. We conclude from our results that the MEGX test can be considered an indicator for hepatic dysfunction and predictor of survival in critically ill patients.

Recovery characteristics following anaesthesia with sevoflurane or propofol in adults undergoing out-patient surgery.

The aim of the study was to compare recovery characteristics in adult patients following general anaesthesia either with the new investigational volatile agent sevoflurane or with propofol. Accordingly, two groups of 25 adults undergoing outpatient surgery were entered into a prospective, randomised study. Patients who received sevoflurane were extubated at an earlier stage than those receiving propofol (6.6 vs. 9.8 min), and the times to eye opening (7.2 vs. 12.6 min) and hand squeezing (8.2 vs 13.8 min) were also shorter. As measured by the digit-symbol substitution test, patients regained the pre-operative level of cognitive function significantly earlier after sevoflurane anaesthesia. Modified Aldrete scores were also higher in this group within the first hour after anaesthesia than in the propofol group. Sevoflurane appears to be a useful alternative to propofol in outpatient anaesthesia.

Midazolam is metabolized by at least three different cytochrome P450 enzymes.

Distribution volumes and metabolism determine the pharmacokinetics of midazolam. Cytochrome P450 3A4 has been considered a significant enzyme in its metabolism. Using heterologously expressed cytochrome P450 enzymes, we have confirmed the additional involvement of cytochromes P450 3A3 and 3A5 in the hydroxylation of the midazolam. Whereas cytochrome P450 3A3 metabolized midazolam to the same extent as cytochrome P450 3A4, cytochrome P450 3A5 increased its metabolism by a factor of 2.7. The relationship of alpha- to 4-hydroxylation of midazolam was approximately 1.3 for cytochromes P450 3A3 and 3A4, and approximately 8.8 for 3A5. The primary location of cytochromes P450 3A3 and 3A4 is the liver in contrast with cytochrome P450 3A5, which occurs predominantly in the kidney. Therefore, further in vivo study is required to prove conclusively that enzymes in the kidney are involved in the metabolism of midazolam. Nitrendipine itself is metabolized by cytochrome P450 3A enzymes and this was shown to inhibit human liver microsomal hydroxylation of midazolam and preferentially alpha-hydroxylation by about 77%. 4-Hydroxylation was inhibited to 32% of control by nitrendipine. In contrast with inhibition of 4-hydroxylation, alpha-hydroxylation would appear to be competitively inhibited. These findings may be relevant to drug interactions in combined therapy.