bluuebunny/crossref_metadata_2025_split huggingface dataset:
Involvement of human liver cytochrome P4502B6in the metabolism of propofol
Authors: Oda Yutaka , Hamaoka Naoya , Hiroi Toyoko , Imaoka Susumu , Hase Ichiro , Tanaka Kazuo , Funae Yoshihiko , Ishizaki Takashi , Asada Akira 
Published: March 2003

Aims  To determine the cytochrome P450 (CYP) isoforms involved in the oxidation of propofol by human liver microsomes.Methods  The rate constant calculated from the disappearance of propofol in an incubation mixture with human liver microsomes and recombinant human CYP isoforms was used as a measure of the rate of metabolism of propofol. The correlation of these rate constants with rates of metabolism of CYP isoform‐selective substrates by liver microsomes, the effect of CYP isoform‐selective chemical inhibitors and monoclonal antibodies on propofol metabolism by liver microsomes, and its metabolism by recombinant human CYP isoforms were examined.Results  The mean rate constant of propofol metabolism by liver microsomes obtained from six individuals was 4.2 (95% confidence intervals 2.7, 5.7) nmol min−1 mg−1 protein. The rate constants of propofol by microsomes were significantly correlated with S‐mephenytoin N‐demethylation, a marker of CYP2B6 (r =0.93, P < 0.0001), but not with the metabolic activities of other CYP isoform‐selective substrates. Of the chemical inhibitors of CYP isoforms tested, orphenadrine, a CYP2B6 inhibitor, reduced the rate constant of propofol by liver microsomes by 38% (P < 0.05), while other CYP isoform‐selective inhibitors had no effects. Of the recombinant CYP isoforms screened, CYP2B6 produced the highest rate constant for propofol metabolism (197 nmol min−1 nmol P450−1). An antibody against CYP2B6 inhibited the disappearance of propofol in liver microsomes by 74%. Antibodies raised against other CYP isoforms had no effect on the metabolism of propofol.Conclusions  CYP2B6 is predominantly involved in the oxidation of propofol by human liver microsomes.
Effect of MAO‐A inhibition on the pharmacokinetics of almotriptan, an antimigraine agent in humans
Authors: Fleishaker Joseph C. , Ryan Kristi K. , Jansat Josep M. , Carel Barabara J. , Bell David J. A. , Burke Moira T. , Azie Nkechi E. 
Published: March 2003

Aims  To assess the effect of a reversible MAO‐A inhibitor, moclobemide, on the single‐dose pharmacokinetics of almotriptan and assess the clinical consequences of any interaction.
Methods
Twelve healthy volunteers received the following treatments in a randomized, open‐label, two‐way crossover design (with a 1 week washout between treatments): (A) one 150 mg moclobemide tablet every 12 h for 8 days and one 12.5 mg almotriptan tablet on the morning of day 8; and (B) one 12.5 mg almotriptan tablet on day 8. Plasma almotriptan was quantified by h.p.l.c.‐MS‐MS, while urinary concentrations were measured by h.p.l.c.‐u.v. Vital signs, ECGs, and adverse events were evaluated after almotriptan administration. Treatment effects on pharmacokinetics and vital signs were assessed by analysis of variance.
Results
Mean almotriptan AUC was higher (483 ± 99.9 vs 352 ± 75.4 ng ml−1 h, P = 0.0001) and oral clearance was lower (26.6 ± 4.00 vs 36.6 ± 5.89 l h−1, P = 0.0001) when almotriptan was administered with moclobemide. Mean half‐life was longer (4.22 ± 0.78 vs 3.41 ± 0.45 h, P = 0.0002) after coadministration with moclobemide. Renal clearance of almotriptan was unaffected by moclobemide. No serious adverse events occurred and no clinically significant vital sign changes were observed.
Conclusions
Moclobemide increased plasma concentrations of almotriptan on average by 37%, but the combined administration of these two compounds was well tolerated. The degree of interaction was much less than that seen previously for sumatriptan or zolmitriptan given with moclobemide.
Inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes
Authors: Yeo Karen Rowland , Yeo Wilfred W. 
Published: March 2003

Aims  To determine the effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes and to compare their inhibitory potencies and CYP3A4 inactivation parameters with those reported previously for mibefradil.Methods  Simvastatin metabolism was investigated in human liver microsomes in the presence and absence of verapamil or diltiazem (0.1–250 µm). Kinetics of CYP3A4 inactivation by verapamil and diltiazem were determined using testosterone as the substrate.Results  When verapamil was coincubated with simvastatin, IC50 values ranged from 23 to 26 µm for all major metabolites. The IC50 values ranged from 4.8 to 5.6 µm on preincubation of verapamil for 30 min in the presence of an NADPH‐generating system. Corresponding IC50 values for diltiazem ranged from110–127 µm and from 21–27 µm, respectively. Verapamil and diltiazem inhibited testosterone 6β‐hydroxylation in a time‐ and concentration‐dependent manner, key features of mechanism‐based inactivation. Values for the inactivation parameters kinact and KI were 0.15 ± 0.04 min−1 (mean ± s.d.) and 2.9 ± 0.6 µm, respectively, for verapamil and 0.07 ± 0.01 min−1 and 3.3 ± 1.5 µm, respectively, for diltiazem.Conclusions  The IC50 values for coincubation of verapamil and diltiazem were 46‐ and 220‐fold higher, respectively, than those reported previously for mibefradil, and 16‐ and 71‐fold higher, respectively, for preincubation. Thus, the results of this study suggest that verapamil and diltiazem are less likely than mibefradil to cause acute drug interactions with simvastatin in vivo. However, verapamil and diltiazem are moderate mechanism‐based inhibitors of CYP3A4 and therefore may still cause significant inhibition of simvastatin metabolism in vivo during chronic therapy.
Serum cystatin C is not a better marker of creatinine or digoxin clearance than serum creatinine
Authors: O'Riordan S. , Ouldred E. , Brice S. , Jackson S. H. D. , Swift C. G. 
Published: March 2003

Aims  To assess whether cystatin C, a new serum marker of renal function, is a better index of creatinine or digoxin clearance than serum creatinine in older people.Methods  Twenty‐two volunteers over the age of 65 years (mean 73±5) were recruited from a healthy elderly volunteer database. None of the volunteers was taking digoxin or other medication known to interfere with digoxin kinetics or assay. Digoxin was infused at a dose of 7–10 µg kg−1 and blood samples were taken over the following 48 h and assayed for serum digoxin. Serum cystatin C, creatinine and creatinine clearance were measured and a calculated creatinine clearance was estimated using the Cockcroft Gault formula. Digoxin clearance was calculated using a pharmacokinetic software package. All values were log transformed to normalize their distribution.Results  Of the 22 volunteers enrolled into the study, 18 completed the study. Serum cystatin C ranged between 0.72 and 1.89 mg l−1 and serum creatinine ranged from 69.6 to 153.9 µmol l−1. Measured creatinine clearance ranged from 38 to 123 ml min−1 and calculated creatinine clearance from 29.5 to 88.0 ml min−1. Digoxin clearance ranged from 51.0 to 103.5 ml min−1. Cystatin C correlated extremely well with creatinine (r=0.93, P<0.001, 95% CI 0.82, 0.97) and with creatinine clearance (r=0.67, P=0.002, 95% CI 0.3, 0.87). Neither serum cystatin C nor serum creatinine correlated with digoxin clearance (r=0.25, P=0.31, 95% CI −0.25, 0.64 and r=0.44, P=0.068, 95% CI −0.03, 0.75, respectively). Measured creatinine clearance, however, did correlate well with digoxin clearance (r=0.55, P=0.018, 95% CI 0.11, 0.81).Conclusions  Serum cystatin C and serum creatinine show very similar correlations with creatinine and digoxin clearances. Serum cystatin C does not offer any advantages in this respect. It remains to be seen whether cystatin C offers any advantage over creatinine in elderly people in other respects.
Lead poisoning: case studies
Authors: Gordon J. N. , Taylor A. , Bennett P. N. 
Published: March 2003

Early clinical features of lead toxicity are non‐specific and an occupational history is particularly valuable.Lead in the body comprises 2% in the blood (t1/2 35 days) and 95% in bone and dentine (t1/2 20–30 years). Blood lead may remain elevated for years after cessation from long exposure, due to redistribution from bone.Blood lead concentration is the most widely used marker for inorganic lead exposure. Zinc protoporphyrin (ZPP) concentration in blood usefully reflects lead exposure over the prior 3 months.Symptomatic patients with blood lead concentration >2.4 µmol l−1 (50 µg dl−1) or in any event >3.8 µmol l−1 (80 µg dl−1) should receive sodium calciumedetate i.v., followed by succimer by mouth for 19 days.Asymptomatic patients with blood lead concentration >2.4 µmol l−1 (50 µg dl−1) may be treated with succimer alone.Sodium calciumedetate should be given with dimercaprol to treat lead encephalopathy.
Clinical Pharmacology: Principles and practice of drug therapy in medical education
Authors: Whiting Brian , Holford Nicholas H. G. , Begg Evan J. 
Published: March 2003

Educational reform has taken place in many Medical Schools. A traditional passive approach has been replaced by a more active, student‐centred approach, founded on Problem‐Based Learning. This has not been without risk because many well‐structured courses have been abandoned, and this is of particular significance to the principles and practice of drug therapy.Here we outline an approach which could be incorporated into a medical curriculum and suggest some guidelines and a list of questions that should be asked in clinical situations involving drug therapy.
Effects of oral monosodium (l)‐glutamate on insulin secretion and glucose tolerance in healthy volunteers
Authors: Chevassus Hugues , Renard Eric , Bertrand Gyslaine , Mourand Isabelle , Puech Raymond , Molinier Nathalie , Bockaert Joël , Petit Pierre , Bringer Jacques 
Published: March 2003

Aims  To investigate the effects of glutamate on insulin secretion and glucose tolerance in humans.Methods  Monosodium (l)‐glutamate (10 g) was given orally in a double‐blind placebo‐controlled cross‐over study to 18 healthy volunteers, aged 19–28 years, with an oral (75 g) glucose load.Results  The 75 min insulin response (AUC(0,75 min)), up to tmax of glutamate kinetics, was significantly correlated with the AUC(0,75 min) of glutamate concentrations (r=0.485, P=0.049). Glucose tolerance was not affected.Conclusions  Oral (l)‐glutamate enhances glucose‐induced insulin secretion in healthy volunteers in a concentration‐dependent manner.
Pharmacokinetics and safety of JTE‐522, a novel selective cyclooxygenase‐2 inhibitor, in healthy male volunteers
Authors: Ikeda Yasuhiko , Umemura Kazuo , Kondo Kazunao , Nakashima Mitsuyoshi , Kobayashi Takuo , Takahashi Mitsuru 
Published: March 2003

Aims  The pharmacokinetics and safety profile of JTE‐522, 4‐(4‐cyclohexyl‐2 methyloxazol‐5‐yl)‐2‐fluorobenzensulphonamide, a novel selective cyclooxygenase‐2 inhibitor were investigated in healthy male volunteers.Methods  Initially, as a pilot study, five groups of two subjects were given oral doses of 3–100 mg of JTE‐522. After safety assessment, subjects were given 150 and 200 mg of JTE‐522. The effect of food‐intake on the pharmacokinetics of JTE‐522 at a dose of 150 mg was examined. In the multiple‐dose study, subjects were given 150 mg of JTE‐522 once a day for 7 days. Concentrations of unchanged JTE‐522 in plasma, blood and urine were determined by high performance liquid chromatography (h.p.l.c.). Concentrations of metabolites were estimated with h.p.l.c. chromatograms and calibration curves for quantification of unchanged JTE‐522.Results  In the course of this study, no serious abnormality attributable to the test drug was observed, suggesting that JTE‐522 was well tolerated in healthy subjects. In a single‐dose study, the concentrations of JTE‐522 in blood were much higher than the corresponding concentrations in plasma. JTE‐522 was readily distributed to blood cells and percentage distribution into blood cells was more than 99.0%. However, the values of Cmax in blood at doses of 100, 150, 200 mg JTE‐522 were 15241, 20445 ± 3918 (16333–24556), 20965 ± 3260 (17544–24386) ng ml−1, respectively. These findings suggest that JTE‐522 has a high affinity for blood cells and the distribution into blood cells is limited at the higher doses of over 100 mg. In a multiple dose study, pharmacokinetic parameters including t1/2 and AUC after the fourth administration were comparable with that of the seventh administration. Thus, these findings suggest the absence of accumulation on the multiple‐dosing of JTE‐522.Conclusions  These results indicate that JTE‐522 has an acceptable pharmacokinetic profile for clinical use without any serious adverse events as we verified in healthy young male volunteers.
MDR1 genotypes do not influence the absorption of a single oral dose of 1 mg digoxin in healthy white males
Authors: Gerloff Thomas , Schaefer Melanie , Johne Andreas , Oselin Kersti , Meisel Christian , Cascorbi Ingolf , Roots Ivar 
Published: March 2003

Aims  A noncoding single nucleotide polymorphism (SNP) in exon 26 3435C > T of the highly polymorphic MDR1 gene has been demonstrated to alter digoxin absorption after induction of the MDR1 gene product P‐glycoprotein by rifampicin or after multiple oral dosing. The aim of the study was to investigate the effects of the major known MDR1 SNPs on the absorption of digoxin after a single oral dose in a large sample without drug pretreatment.Methods  Fifty healthy white male subjects between the age of 18 and 40 years were enrolled. Following an overnight fast, all subjects received a single oral dose of 1 mg digoxin. Venous blood samples were taken at intervals up to 4 h post dose to obtain a pharmacokinetic profile.Results  AUC(0,4 h), Cmax and tmax, used as indices of digoxin absorption, were not significantly different in any of the genotype groups tested. In particular, there was no significant difference between homozygous carriers of the C and T allele in exon 26 3435 (AUC(0,4 h) 9.24 and 9.38 µg l−1 h, Cmax 4.73 and 3.81 µg l−1, tmax 0,83 and 01.14 h).Conclusions  This lack of effect of the major MDR1 SNPs on digoxin absorption might be explained by saturation of the maximum transport capacity of intestinal Pgp at the dose used.
Bioanalysis of the novel peptide anticancer drug kahalalide F in human plasma by h.p.l.c. under basic conditions coupled with positive turbo‐ionspray tandem mass spectrometry
Authors: Stokvis E. , Rosing H. , López‐Lázaro L. , Jimeno J. M. , Supko J. G. , Schellens J. H. M. , Beijnen J. H. 
Published: March 2003

Kahalalide F (KF) is a cyclic depsipeptide derived from the marine mollusc Elysia rufescens. Anti‐cancer activity of KF was observed both in vitro and in vivo especially against prostate cancer cell lines [1]. In order to support the Phase I study a method was developed and validated for the quantitative determination of KF in human plasma using high performance liquid chromatography (h.p.l.c.) coupled with positive turbo‐ionspray tandem mass spectrometry ((h.p.l.c.)‐TISP‐MS/MS). Miniaturized LC combined with mass spectrometric detection was essential to obtain the required selectivity and sensitivity. The use of trifluoroacetic acid, conventionally used in the mobile phase in the LC analysis of peptides, was omitted due to its signal suppressing effects on electrospray ionization. An alternative approach was followed employing a basic mobile phase using a stationary phase that is stable under basic conditions. KF remained positively charged under these conditions while the mobile phase background remained low.The method involves a solid phase extraction (SPE) on C18 columns as sample pre‐treatment followed by LC‐MS/MS analysis. The LC separation was performed on a Zorbax Extend C18 column (150×2.1 mm i.d., particle size 5 µm) with acetonitrile‐10 mm ammonium acetate in water (85 : 15, v/v) as the mobile phase, pumped at a flow‐rate of 0.20 ml min−1. A butyric acid analogue of KF was used as the internal standard.A lower limit of quantitation (LLQ) of 1 ng ml−1 was obtained using a 500 µl sample volume with a linear dynamic range up to 1000 ng ml−1. Accuracies were within 15.1% for the LLQ and within 9.0% for other quality control samples. Precisions did not exceed 9.9%. The drug was found to be stable in the biomatrix for at least 9 months at −20° C and for at least 24 h at ambient temperatures. The results demonstrate that an accurate, selective and sensitive bioanalytical method has been developed for KF analysis in human plasma. The method was successfully applied in a Phase I clinical study of KF. At the starting dose of 20 µg m−2 a Cmax of 1.75 ng ml−1 was obtained.
Diabetes mellitus increases the in vivo activity of cytochrome P450 2E1 in humans
Authors: Wang Zaiqi , Hall Stephen D. , Maya Juan F. , Li Lang , Asghar Ali , Gorski J. C. 
Published: March 2003

Aims  Cytochrome P450 2E1 (CYP2E1) is thought to activate a number of protoxins, and has been implicated in the development of liver disease. Increased hepatic expression of CYP2E1 occurs in rat models of diabetes but it is unclear whether human diabetics display a similar up‐regulation. This study was designed to test the hypothesis that human diabetics experience enhanced CYP2E1 expression.Methods  The pharmacokinetics of a single dose of chlorzoxazone (500 mg), used as an index of hepatic CYP2E1 activity, was determined in healthy subjects (n = 10), volunteers with Type I (n = 13), and Type II (n = 8) diabetes mellitus. Chlorzoxazone and 6‐hydroxychlorzoxazone in serum and urine were analysed by high‐performance liquid chromatography. The expression of CYP2E1 mRNA in peripheral blood mononuclear cells was quantified by reverse transcriptase‐polymerase chain reaction.Results  The mean ± s.d. (90% confidence interval of the difference) chlorzoxazone area under the plasma concentration‐time curve was significantly (P ≤ 0.05) reduced in obese Type II diabetics (15.7 ± 11.3 µg h ml−1; 9, 22) compared with healthy subjects (43.5 ± 16.9 µg h ml−1; 16, 40) and Type I diabetics (32.8 ± 9.2 µg h ml−1; 9, 25). There was a significant two‐fold increase in the oral clearance of chlorzoxazone in obese Type II diabetics compared with healthy volunteers and Type I diabetics. The protein binding of chlorzoxazone was not significantly different between the three groups. In contrast, Type 1 diabetics and healthy volunteers demonstrated no difference in the oral clearance of chlorzoxazone. The urinary recovery of 6‐hydroxychlorzoxazone as a percentage of the administered dose was not different between healthy, Type I and obese Type II diabetics. The elimination half‐life of chlorzoxazone did not differ between the three groups. CYP2E1 mRNA was significantly elevated in Type I and obese Type II diabetics compared with healthy volunteers. The oral clearance of chlorzoxazone, elimination half‐life, Tmax, and Cmax were not significantly influenced by weight, body mass index, serum glucose, serum cholesterol, or glycosylated haemoglobin.Conclusions  There was a marked increase in hepatic CYP2E1 activity in obese Type II diabetics as assessed by chlorzoxazone disposition. Increased expression of CYP2E1 mRNA in peripheral blood mononuclear cells was found in both types of diabetes mellitus. Adverse hepatic events associated with Type II diabetes may be in part a result of enhanced CYP2E1 expression and activity.
Population pharmacokinetics of theophylline during paediatric extracorporeal membrane oxygenation
Authors: Mulla Hussain , Nabi Fazal , Nichani Sanjiv , Lawson Graham , Firmin R. K. , Upton David R. 
Published: March 2003

Aims  To determine the population pharmacokinetics of theophylline during extracorporeal membrane oxygenation (ECMO) from routine monitoring data.Methods  Retrospective data were collected from 75 term neonates and children (age range 2 days to 17 years) receiving continuous infusions of aminophylline (mean rate 9.2 ± 2.6 µg kg−1 min−1) during ECMO. A total of 160 plasma concentrations (range 1–8 per patient), sampled at time intervals ranging from 10 h to 432 h, were included. Population PK analysis and model building were carried out using WinNonMix Professional (Version 2.0.1). Cross‐validation was used to evaluate the validity and predictive accuracy of the model.Results  A one‐compartment model with first order elimination combined with an additive error model was found to best describe the data. Of the covariables tested, bodyweight significantly influenced clearance and volume of distribution, whereas age was an important determinant of clearance, as adjudged by the differences in the −2 × log likelihood (P < 0.005) and the residual error value. The final model parameters were estimated as: clearance (l h−1) = 0.023 × bodyweight (kg) + 0.000057 × age (days) and volume of distribution (l) = 0.57 × bodyweight (kg). The interindividual variability in clearance and volume of distribution was 38% and 40%, respectively. The residual error corresponded to a standard deviation of 3.6 mg l−1. Cross‐validation revealed a median (95% confidence interval) model bias of 9.4% (2.9, 16.5%) and precision of 29.5% (24.8, 36.0%).Conclusions  The estimated clearance is significantly lower, and volume of distribution higher, than previously reported in non‐ECMO patients of similar age. These differences are probably a result of the expanded circulating volume during ECMO and altered renal and hepatic physiology in this critically ill group. Large interindividual variability reflects the heterogeneous nature of patients treated on ECMO.
Changes in the pattern of sensitization to common contact allergens in Denmark between 1985–86 and 1997–98, with a special view to the effect of preventive strategies
Authors: Johansen J.duus , Menné T. , Christophersen J. , Kaaber K. , Veien N. 
Published: March 2003

AbstractThe objective of the present study is to describe any changes in the prevalence of sensitization to common contact allergens in patch-tested patients over a 12-year period. Attention is given to possible effects of preventive strategies introduced in Denmark regarding nickel and chromate sensitization during that period, and particular areas of concern are identified. Members of the Danish Contact Dermatitis Group collected patch-test results from consecutive eczema patients as well as information about exposures and demographic variables over a 6-month period in 1985–86. The investigation was repeated in 1997–98 in the same clinics, at the same time of year, using identical methods and patch-test substances, including nickel sulphate 5%, potassium dichromate 0·5% and fragrance mix 8%. Nickel was the most common contact allergen in both study periods, followed by the fragrance mix. In children 0–18 years of age, the frequency of nickel allergy decreased from 24·8% in the first study period to 9·2% in the second study period (P &lt; 0·0008). Fragrance mix allergy doubled in frequency from 4·1% in 1985–86 to 9·9% in 1997–98, an increase that affected all age groups. Contact allergy to potassium dichromate decreased significantly from 3·0% in the first period to 1·2% in the second period (P = 0·001). The decrease was seen in both sexes and was most pronounced among those of working age. No other significant changes were found in the frequency of sensitization to common allergens over the 12-year observation period.