bluuebunny/crossref_metadata_2025 huggingface dataset:
The induction effect of rifampicin on activity of mephenytoin 4′‐hydroxylase related to M1 mutation of CYP2C19 and gene dose
Authors: Feng Hua‐Jun , Huang Song‐Lin , Wang Wei , Zhou Hong‐Hao
Published: March 2003

Aims
 To determine the induction effect of rifampicin on the activity of 4′‐hydroxylase in poor metabolizers (PMs) with m1 mutation of S‐mephenytoin 4′‐hydroxylation and the relationship of the effect with gene dose.

Methods
 Seven extensive metabolizers (EMs) of S‐mephenytoin 4′‐hydroxylation and five PMs with m1 mutation were chosen to take rifampicin 300 mg day−1 orally for 22 days. Prior to and after rifampicin treatment, each subject was given racemic mephenytoin 100 mg. The 4′‐hydroxymephenytoin (4′‐OH‐MP) excreted in the 0–24 h urine and mephenytoin S/R ratio in the 0–8 h urine were determined by h.p.l.c. and GC, respectively.

Results
 In all EMs, the excretion of 4′‐OH‐MP in the 0–24 h urine was increased by 146.4±17.9%, 0–8 h urinary mephenytoin S/R ratio was decreased by 77.3±8.8%, the percentage increase in the 0–24 h excretion of 4′‐OH‐MP in those CYP2C19 homozygous (wt/wt) was greater than that in those heterozygous (wt/m1 and wt/m2 ) (203.9±42.5%vs 69.6±4.1%). 0–8 h urinary mephenytoin S/R ratio of those PMs with m1 mutation was decreased by 9.6%, the amount of 4′‐OH‐MP excreted in the 0–24 h urine was increased by 80.1±48.0%.

Conclusions
 The activity of 4′‐hydroxylase of PMs with m1 mutation of S‐mephenytoin 4′‐hydroxylation can be induced by rifampicin and the inducing effect of rifampicin on 4′‐hydroxylase is gene dependent.
The population pharmacokinetics of recombinant‐ and urinary‐human follicle stimulating hormone in women
Authors: Karlsson Mats O. , Wade Janet R. , Loumaye Ernest , Munafo Alain
Published: March 2003

Aims
 To characterize the pharmacokinetics of recombinant‐human follicle stimulating hormone (r‐hFSH) and urinary‐human follicle stimulating hormone (u‐hFSH) using population pharmacokinetic analysis and deconvolution techniques.

Methods
 Sparse data were available from 62 female patients who received u‐hFSH intramuscularly (i.m.) and 60 female patients who received r‐hFSH subcutaneously (s.c.) as part of an in vitro fertilisation and embryo transfer (IVF‐ET) procedure. The dose of u‐hFSH and r‐hFSH was 225 International Units (IU) FSH/day for the first 5 days of treatment. The dose of u‐hFSH/r‐hFSH on subsequent days depended upon the ovarian response. Intensively sampled data were also available from 12 female volunteers who received r‐hFSH, 150 IU, on three occasions: intravenously (i.v.), i.m. and s.c., each separated by 1 week of wash‐out. The volunteers then received multiple r‐hFSH doses by the s.c. route: 150 IU once daily for 7 days. Intensively sampled data were available from a further 12 female volunteers who received u‐hFSH, 150 IU, given by the i.v. and i.m. routes.

Results
 Analysis of the intensively sampled r‐hFSH and u‐hFSH data sets found that disposition could be described using a two‐compartment model and that absorption was rate limiting and essentially a first order process, for both compounds. The population estimate of clearance (CL) after i.v. administration was 0.60 and 0.44 l h−1 for r‐hFSH and u‐hFSH respectively. The calculated mean residence times (MRT) for r‐hFSH and u‐hFSH were 16 and 18 h, respectively. The different bioavailabilities (F ) and mean absorption times (MAT) determined after i.m. and s.c. administration ranged from 0.60 to 0.77 and from 27 h to 48 h, depending on compound, administration route, data type and method of analysis. Population analysis of the sparse patient data found that a one compartment model with first order absorption was adequate to describe the r‐hFSH and u‐hFSH data. The population estimates of apparent clearance (CL/F ) were 0.71 and 0.33 l h−1 for r‐hFSH and u‐ hFSH respectively. Urinary‐hFSH CL/F increased linearly with weight and was 0.33 l h−1 at the average weight of 58.5 kg. No other covariates (age, weight, height, creatinine clearance, body mass index, race) were found to influence the FSH disposition parameters. The sparse data population estimates of intersubject variability in CL/F for r‐hFSH and u‐hFSH were essentially the same, 26% and 25%, respectively.

Conclusions
 The population analysis indicates that the variability in CL/F is moderate, consequently, so would be the variability in exposure, given a fixed dosage regimen.
A pharmacokinetic and pharmacodynamic study of intravenous vs oral artesunate in uncomplicated falciparum malaria
Authors: Batty Kevin T. , Anh Thu Le Thi , Davis Timothy M. E. , Ilett Kenneth F. , Xuan Mai Truong , Canh Hung Nguyen , Phuc Tien Nguyen , Powell Shane M. , Van Thien Huynh , Quang Binh Tran , Kim Nguyen Van
Published: March 2003

Aims
 To obtain comprehensive pharmacokinetic and pharmacodynamic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following i.v. and oral administration of ARTS to patients with acute, uncomplicated falciparum malaria.

Methods
 Twenty‐six Vietnamese patients with falciparum malaria were randomized to receive either i.v. ARTS (120 mg; group 1) or oral ARTS (100 mg; group 2), with the alternative preparation given 8 h later in an open crossover design. Mefloquine (750 mg) was administered at 24 h. Plasma concentrations of ARTS and DHA were determined by h.p.l.c. assay. Pharmacokinetic parameters were calculated by non‐compartmental methods. The time to 50% parasite clearance (PCT50 ) was calculated by linear interpolation of parasite density determinations. Linear least squares and multiple linear regression analyses were used to evaluate pharmacokinetic‐pharmacodynamic relationships.

Results
 Following i.v. bolus, ARTS had a peak concentration of 29.5 μm (11 mg l−1 ), elimination t1/2=2.7 min, CL=2.33 l h−1 kg−1 and V=0.14 l kg−1. The Cmax for DHA was 9.3 μm (2.64 mg l−1 ), t1/2=40 min, CL=0.75 l h−1 kg−1 and V=0.76 l kg−1. Following oral ARTS, relative bioavailability of DHA was 82%, Cmax was 2.6 μm (0.74 mg l−1 ), t1/2=39 min, and MAT=67 min. Overall, the PCT50 and fever clearance time (FCT) were 6.5 h and 24 h, respectively. There was no correlation between PCT50 or FCT and AUC, Cmax or MRT for DHA.

Conclusions
 Despite rapid clearance of ARTS and DHA in patients with uncomplicated falciparum malaria, prompt parasite and fever clearance were achieved. High relative bioavailability of DHA following oral ARTS administration, and clinical outcomes comparable with those after i.v. ARTS, support the use of the oral formulation in the primary care setting.
The influence of transdermal oestradiol replacement therapy and medroxyprogesterone acetate on serum lipids and lipoproteins
Authors: Bhathena R. K. , Anklesaria B. S. , Ganatra A. M. , Pinto Rosaline
Published: March 2003

Aims
 The objective of this study was to examine the effects of continuous transdermal oestradiol with or without sequential oral medroxyprogesterone acetate on serum lipids and lipoproteins in menopausal women.

Methods
 Sixty‐two healthy menopausal women, attending at two menopause clinics in Western India, were recruited for this study over a period of 1 year. Group 1 included 38 hysterectomised women being treated with continuous transdermal oestradiol only (50 μg daily). Group 2 included 24 menopausal women with an intact uterus being treated with transdermal oestradiol (50 μg daily) and medroxyprogesterone acetate (10 mg daily for the first 12 days of each calendar month). Women maintained on 50 μg oestradiol throughout 6 months (group 1: n=22; group 2: n=16) were reviewed for changes in serum lipids and lipoproteins at the end of 6 months (group 1), and between days 8 and 12 of the seventh month (combined phase of treatment) (group 2).

Results
 In group 1, there was a small reduction in the concentrations of total cholesterol (−5.5%, P=0.04) and a small but not significant reduction in LDL‐cholesterol (−5.7%, P=0.16). In group 2, there were no significant changes in total cholesterol (−4.2%, P=0.43) and LDL‐cholesterol (−3.9%, P=0.57). HDL‐cholesterol levels did not change significantly with unopposed transdermal oestradiol (+3.0%, P=0.53), or with additional sequential medroxyprogesterone acetate (−3.8%, P=0.32). Serum triglyceride concentrations decreased significantly in both the groups (−13.9%, P=0.01, and −13.4%, P=0.008, respectively). Serum lipid changes did not differ between the groups.

Conclusions
 Transdermal oestrogen therapy appears to be of particular benefit for women with hypertriglyceridaemia. There were no significant adverse effects of medroxyprogesterone acetate on serum lipids and lipoproteins.
Gut wall metabolism of verapamil in older people: effects of rifampicin‐mediated enzyme induction
Authors: Fromm Martin F. , Dilger Karin , Busse Dagmar , Kroemer Heyo K. , Eichelbaum Michel , Klotz Ulrich
Published: March 2003

Aims
 To investigate prehepatic metabolism of verapamil and its inducibility by rifampicin in older subjects.

Methods
 Eight older subjects (67.1±1.2 years mean±s.d.) received racemic, unlabelled verapamil orally for 16 days (120 mg twice daily). Rifampicin (600 mg daily) was coadministered from day 5 to 16. Using stable isotope technology (i.e. intravenous coadministration of 10 mg deuterated verapamil) during verapamil steady‐state without (day 4) and with rifampicin (day 16) bioavailability, prehepatic and hepatic extraction of verapamil were determined. The effects of verapamil on AV‐conduction were measured by the maximum PR interval prolongation (%).

Results
 Bioavailability of the cardiovascularly more active S‐verapamil decreased from 14.2±4.3% on day 4 to 0.6±0.5% on day 16 (P<0.001). As a consequence, effects of orally administered verapamil on the AV‐conduction were nearly abolished (14.4±9.4%vs 2.7±2.6%, P<0.01). This could be attributed to a considerable increase of prehepatic extraction during treatment with rifampicin (41.7±22.1%vs 91.6±6.6%, P<0.01) and to a minor extent to induction of hepatic metabolism (73.7±9.4%vs 91.6±5.3%, P<0.01).

Conclusions
 Prehepatic metabolism of verapamil occurred in the group of older people investigated. Induction of gut wall metabolism most likely was the major reason for the loss of verapamil effect during treatment with rifampicin in this group of older subjects.
Molecular effects of sulphonylurea agents in circulating lymphocytes of patients with non‐insulin‐dependent diabetes mellitus
Authors: Rabbone I. , Piccinini M. , Curto M. , Mostert M. , Gamba S. , Mioletti S. , Bruno R. , Rinaudo M. T.
Published: March 2003

Aims
 In circulating lymphocytes of NIDDM patients pyruvate dehydrogenase (PDH), the major determinant in glucose consumption through oxidative pathways, is poorly active. The aim of this study is to examine whether sulphonylurea drug treatment revives PDH activity in circulating lymphocytes from NIDDM patients.

Methods
 Twenty normal‐weight individuals with NIDDM were enrolled in this study. They had maintained their glycaemic levels close to normal by means of a restricted diet that had no longer been successful in the proceeding 2 months. The treatment protocol consisted in 160 mg gliclazide daily for 5 weeks. Twenty healthy subjects, matched for age, body mass index and gender, were enrolled as a control group. Patients, before and after treatment, as well as controls were tested for PDH activity in their circulating lymphocytes. Nine other untreated patients and nine healthy subjects, with the above mentioned characteristics, were recruited for the assay of PDH activity in their circulating lymphocytes before and after exposure, in vitro, to gliclazide, to insulin, and to gliclazide and insulin in combination.

Results
 In gliclazide‐treated NIDDM patients, PDH activity in circulating lymphocytes recovered. In vitro, in circulating lymphocytes of untreated patients and controls insulin at 5 μU ml−1 was ineffective and highly effective, respectively, in raising enzyme activity; gliclazide at 10 ng ml−1 was ineffective on PDH in both groups, but in combination with insulin at 5 μU ml−1 in both groups PDH was as active as in cells of controls exposed to insulin only. In cells of controls, gliclazide alone at 25–50 ng ml−1 caused enzyme activation, whereas above 50 ng ml−1 it caused inhibition; in cells of patients below 50 ng ml−1 it had no effects, but at 50 ng ml−1 and above raised enzyme activity to the basal level of controls.

Conclusions
 This study suggests that free gliclazide concentrations determine recovery of PDH activity in circulating lymphocytes of treated patients through drug‐mediated enhanced insulin control over PDH or through the drug alone.
Constipation as an adverse effect of drug use in nursing home patients: an overestimated risk
Authors: Van Dijk K. N. , De Vries C. S. , Van Den Berg P. B. , Dijkema A. M. , Brouwers J. R. B. J. , De Jong‐van den Berg L. T. W.
Published: March 2003

Aims
 To investigate whether results from case control and cross sectional studies which suggest an association between laxative use and other drug use could be confirmed in a cohort study of nursing home patients.

Methods
 A prospective cohort study of 2355 nursing home patients aged 65 years and over was performed to estimate the incidence relative risk of constipation associated with drug use. The study was conducted with prescription sequence analysis of each resident's detailed pharmacy records and data on morbidity and mobility.

Results
 Use of drugs, which according to the summaries of product characteristics (SPC) and the literature on adverse drug effects have moderately to strongly constipating properties, was associated with a relative risk of 1.59 (95% CI 1.24–2.04) for the occurrence of constipation during exposure time. Use of drugs with mildly to moderately constipating effects was not associated with laxative use (RR 1.13; 95% CI 0.93–1.38). Stratification on the level of age, gender, type of nursing (psychogeriatric or somatic), morbidity, number of medications taken and mobility showed no confounding effects of these variables on outcome measurements. These variables all acted as effect modifiers. Effect of age and number of medications taken on the relative risk was nonlinear.

Conclusions
 Although an association between drugs that exhibit moderately to strongly constipating effects and occurrence of constipation was found, the risk was not as high as seen in previous studies. The high prevalence of constipation in nursing home patients is only partly due to adverse drug effects.
Midazolam pharmacokinetics following intravenous and buccal administration
Authors: Schwagmeier R. , Alincic S. , Striebel H. W.
Published: March 2003

Aims
 Midazolam has good anxiolytic qualities and is a well established premedication agent before anaesthesia or short surgical procedures. The objective of the present study was to determine pharmacokinetic data from individual plasma concentration profiles obtained following intravenous and buccal administration of midazolam.

Methods
 Eight young healthy volunteers received single doses of 5 mg midazolam i.v. and after a period of 1 week buccally in a cross over manner. Blood samples were obtained up to 480 min. The measurement of plasma midazolam concentrations was by gas‐chromatography.

Results
 The maximum plasma concentration was 55.9 ng ml−1 (range 35.6–77.9 ng ml−1 ) at 30 min (range 15–90 min) following buccal administration. AUC was calculated to be 15 016 ng ml−1 min (s.d. 3778 ng ml−1 min) following i.v. and 11191 ng ml−1 min (s.d. 1777 ng ml−1 min) following buccal midazolam. This gave a mean midazolam bioavailabilty of 74.5%.

Conclusions
 The pharmacokinetic data presented in this study demonstrate a high bioavailability and reliable plasma concentrations following buccal midazolam. The clinical benefit of buccal midazolam may be in particular patient controlled premedication or sedation in adults.
An approach for dose finding of drugs in infants: sedation by midazolam studied using the continual reassessment method
Authors: Fabre Emmanuelle , Chevret Sylvie , Piechaud Jean‐François , Rey Elisabeth , Vauzelle‐Kervroedan Françoise , D’Athis Phillippe , Olive Georges , Pons Gérard
Published: March 2003

Aims
 No drug has been demonstrated to provide simultaneously appropriate sedation, safety and lack of disturbance of the measured parameters during cardiac catheterization in infants. The objective of this study was to estimate the dose of midazolam, administered rectally, that would provide a 90% probability of adequate sedation in infants during cardiac catheterization. A sedation score ≥4 (six‐point scale) 30 to 60 min after dosing was rated as a success.

Methods
 A double‐blind, continual reassessment method using a Bayesian approach has been used. Sixteen infants were administered a single midazolam dose, within a 0.1 to 0.6 mg kg−1 dose range.

Results
 Consecutive failures led to allocation of the highest dose to 15 out of 16 patients. The final estimated probability of failure of the 0.6 mg kg−1 dose was 81% (95% CI: 78.5 to 84%). The time to reach a score ≥4 was longer than expected and the median duration‐time at score ≥4 was shorter (15 min) than expected.

Conclusions
 Delayed absorption and low rectal bioavailability may explain these data. Higher doses or different routes of administration may lead to the expected sedation, but the safety of doses higher than 0.6 mg kg−1 administered rectally has not been evaluated. The therapeutic strategy for sedation of this category of infants in the hospital has now been changed based on the present results in that rectal midazolam has been abandoned in this indication.
The influence of drug input rate on the development of tolerance to frusemide
Authors: Wakelkamp Monique , Alván Gunnar , Scheinin Harry , Gabrielsson Johan
Published: March 2003

Understanding the impact of drug input rate on its pharmacokinetic‐pharmacodynamic relationship may lead to a more optimal drug therapy. The aim of the present study was to investigate the influence of the rate of administration on tolerance development to frusemide, by giving the drug at four different infusion rates.

 Eight healthy volunteers were given 10 mg of frusemide on four different occasions, as a constant‐rate intravenous infusion during 10, 30, 100 and 300 min, respectively. Urinary volume and contents of frusemide and sodium were measured in samples collected over 8 h.

 The four different infusion rates systematically influenced the frusemide excretion rate versus diuretic and natriuretic response relationship. Counter‐clockwise hysteresis occurred for the most rapid infusion rate, whereas a progressive clockwise hysteresis was observed for the slower infusions, indicating development of tolerance. For each subject, diuresis and natriuresis were modeled for all four treatments simultaneously, using a feedback tolerance model. It was not possible to describe the data using a model without tolerance. The time course of tolerance development showed remarkable differences between the infusion rates. The intensity of maximum tolerance development was significantly less for the slowest infusion rate compared with the more rapid infusions and it appeared significantly later. However, no differences in diuretic or natriuretic response were found between the treatments.

 The direction of the hysteresis loop is dependent on the input rate of frusemide. After the administration of a single low dose of frusemide, the time course of tolerance, rather than the integrated time course of tolerance, is influenced by the drug input rate.
Tacrolimus whole blood concentrations correlate closely to side‐effects in renal transplant recipients
Authors: Böttiger  , Brattström  , Tydén  , Säwe  , Groth
Published: March 2003

Aims To evaluate the relationship between tacrolimus whole blood concentrations and side‐effects and rejections in 14 renal transplant recipients.

Methods Tacrolimus was measured by MEIA in whole blood in samples collected repeatedly during the first year after transplantation. Retrospectively, tacrolimus trough concentrations on the days with adverse events (n=172) or rejection (n=28) were related to the total distribution of the concentration values (n=656).

Results Side‐effects (one or more) were noted in connection with 76% of tacrolimus concentrations above 30 ng ml−1, with 41% of concentrations within the interval of 20–30 ng ml−1, with 26% of the concentrations within the interval of 10–20 ng ml−1 and with only 5.3% on the concentrations lower than 10 ng ml−1. No relation to the tacrolimus concentration was seen for rejection episodes.

Conclusions We conclude that therapeutic drug monitoring may be helpful in the management of tacrolimus therapy and that tacrolimus whole blood trough concentrations (MEIA) should preferably be kept below 20 ng ml−1 to avoid side‐effects, such as nephro‐and neurotoxicity and infections. The lower limit of the therapeutic range has yet to be defined.
Genetic polymorphism of (S)‐mephenytoin 4′‐hydroxylation in populations of African descent
Authors: Xie  , Kim  , Stein  , Wilkinson  , Wood
Published: March 2003

Aims  The frequency of CYP2C19 poor metabolizers (PMs) in populations of African descent has been reported to range from 1.0% to 35.4%. In order to determine with greater certainty the frequency of CYP2C19 PMs in such black populations we have performed a meta‐analysis of the studies.

Methods Relevant data on the frequency of both the PM phenotype of probe drugs (mephenytoin, omeprazole, and proguanil), and the distribution frequencies of CYP2C19 alleles and genotypes in black populations were summarized and reanalysed using a meta‐analytical approach.

Results Of nine reported studies two were excluded because of significant heterogeneity (χ2=115, P<0.0001). The combined data from the remaining seven studies showed that the frequency of the PM phenotype in 922 healthy unrelated black Africans and black Americans ranged from 1.0% to 7.5% (n=7 for combined data) with an overall frequency being 3.9% (36 of 922; 95%CI: 2.7%–5.2%). The frequency of the PM genotypes in blacks was 3.7% (36 of 966; 95%CI: 2.5%–4.9%), in agreement with the frequency of the PM phenotype. In the extensive metabolizers (EMs) 29% (271 of 930) were heterozygotes (wt/m ). The observed frequencies of the three Mendelian genotypes were 0.68 for wt/wt, 0.28 for wt/m, and 0.04 for m/m. The allelic distribution was appropriate at 82.3% (95%CI: 80.5%‐83.9%) for CYP2C19*1, 17.3% (95%CI:15.7%–19.0%) for CYP2C19*2 (m1 ), and 0.4% (95%CI: 0.1%–0.7%) for CYP2C19*3 (m2 ) in these populations.

Conclusions We conclude that subjects of African ancestry have a low frequency of the CYP2C19 PM phenotype and genotype; that the defective CYP2C19 alleles are uncommon, and that a small proportion of heterozygotes exists in the EM subpopulation.
Inhibition of the CYP3A4‐mediated metabolism and P‐glycoprotein‐mediated transport of the HIV‐1 protease inhibitor saquinavir by grapefruit juice components
Authors: Eagling  , Profit  , Back
Published: March 2003

Aims Cytochrome P450 3A4 (CYP3A4) and P‐glycoprotein (P‐gp) are both expressed in the intestinal mucosa and present a barrier to oral drug delivery. CYP3A4 and P‐gp share both overlapping tissue distribution and substrate specificity. Grapefruit juice interactions with CYP3A4 substrates are well documented and occur as a consequence of down regulation of intestinal CYP3A4. The aim of the present study was to screen grapefruit juice components against the CYP3A4‐mediated metabolism and P‐gp mediated transport of the HIV‐1 protease inhibitor saquinavir.

Methods Five grapefruit juice components: quercetin, naringin, naringenin, 6′,7′‐dihydroxybergamottin and bergamottin were screened as potential inhibitors of the metabolism of saquinavir by human liver microsomes. The known CYP3A4 inhibitor ketoconazole was also screened for inhibitory potential. These compounds were also screened as modulators of P‐gp activity by assessing the directional transport of saquinavir across Caco‐2 cell monolayers which express P‐gp. The effect of verapamil, a known modulator of P‐gp function, was also determined in these cell lines.

Results On preincubation, 6′,7′‐dihydroxybergamottin and bergamottin inhibited the metabolism of saquinavir, with IC50 values of 0.33±0.23 μm and 0.74±0.13 μm, respectively (n=3). Ketoconazole achieved an IC50 of 0.55±0.12 μm (n=4). The other compounds studied failed to reach IC50 at concentrations of up to 100 μm. The transport of saquinavir in the basolateral→apical (BL→AP) direction exceeded that in the apical →basolateral direction (AP→BL), with apparent permeability coefficients of 199.2±15.8×10−7 cm s−1 and 8.00±1.13×10−7 cm s−1, respectively (n=3) which is indicative of a polarized efflux mechanism. The ratio of BL→AP/AP→BL for saquinavir was 25, but in the presence of verapamil and ketoconazole this ratio was reduced to 3.6 and 4.0, respectively (n=3), indicating extensive inhibition of P‐gp mediated saquinavir efflux. Of the grapefruit juice components studied only naringin and 6′,7′‐dihydroxybergamottin had any appreciable effect, reducing the ratio to 7.6 and 7.1, respectively (n=3); but this was due solely to increased AP→BL transport.

Conclusions Grapefruit juice components inhibit CYP3A4‐mediated saquinavir metabolism and also modulate, to a limited extent, P‐gp mediated saquinavir transport in Caco‐2 cell monolayers. The in vivo effects of grapefruit juice coadministration are most likely the result of effects on CYP3A4 (inhibition and down regulation) and only to a minor extent on modulation of P‐gp function.
Enhanced cholesterol reduction by simvastatin in diltiazem‐treated patients
Authors: Rowland Yeo  , Yeo  , Wallis  , Ramsay
Published: March 2003

Aims To investigate whether an interaction between diltiazem and the 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor simvastatin may enhance the cholesterol‐lowering response to simvastatin in diltiazem‐treated patients.

Methods One hundred and thirty‐five patients attending the Sheffield hypertension clinic who started consecutively on simvastatin for primary or secondary prevention of coronary heart disease (CHD) during the 2 years June, 1996—May 1998 were surveyed. From the clinic records we extracted and recorded absolute and percentage cholesterol responses to the starting dose of simvastatin and coprescription of diltiazem.

Results The cholesterol reduction for the 19 patients on diltiazem was 33.3% compared with 24.7% in the remaining 116 patients (median difference 8.6%, 95% CI 1.1–12.2%, P<0.02). The interindividual variability of cholesterol response to simvastatin was greater for patients not taking diltiazem than for those patients taking diltiazem. The ratio of the variances in response for the nondiltiazem group relative to the diltiazem group was 1.34 at 10 mg simvastatin daily (not significant, 95% CI 0.16–4.11), and 3.42 at 20 mg daily (P<0.01, 95% CI 1.26–7.18). Concurrent diltiazem therapy (P<0.04), age (P=0.001) and starting dose of simvastatin (P=0.002) were found to be significant independent predictors of percentage cholesterol response.

Conclusions Patients who take both simvastatin and diltiazem may need lower doses of simvastatin to achieve the recommended reduction in cholesterol. The pharmacokinetic and pharmacodynamic aspects of this interaction need further study to confirm an enhanced effect on cholesterol reduction, and exclude an increased risk of adverse events.
Effects of cytochrome P450 inducers on 17α‐ethinyloestradiol (EE2) conjugation by primary human hepatocytes
Authors: Li  , Hartman  , Lu  , Collins  , Strong
Published: March 2003

Aims Our objective was to elucidate further the underlying mechanism responsible for therapeutic failures observed with concomitant administration of the oral contraceptive 17α‐ethinyloestradiol (EE2 ) and rifampicin.

Methods We investigated both oxidative and direct conjugative [3H]‐EE2 metabolism by human liver S9 fraction and the effect of known enzyme‐inducing drugs using a human hepatocyte induction model in vitro.

Results Cofactor dependent [3H]‐EE2 metabolism by human liver S9 fraction produced 2‐hydroxy‐[3H]‐EE2, 2‐methoxy‐[3H]‐EE2, and direct [3H]‐EE2 sulphate and glucuronide conjugates. Only two detectable metabolites of [3H]‐EE2 were produced by the S9 fraction in the presence of all cofactors: [3H]‐EE2–3‐sulphate (75.7±7.6% s.d.) and 2‐methoxy‐3H‐EE2 (2.6%±0.5% s.d.). Human hepatocytes extensively metabolized [3H]‐EE2 to its glucuronide and sulphate conjugates. Small amounts of a 2‐methoxy‐[3H]‐EE2 3‐conjugate, ≤10%, was observed but no. 2‐hydroxy‐[3H]‐EE2 was detected. An unexpected finding in our study was increased [3H]‐EE2–3‐sulphate production (1.5–3.3 fold, n=3 donor livers) by hepatocytes pretreated with rifampicin compared to control hepatocytes. No statistically significant increase in [3H]‐EE2–3‐sulphation was observed in hepatocytes pretreated with 3‐methylcholanthrene, phenobarbitone, dexamethasone, or omeprazole over nontreated hepatocytes. To our knowledge, this is the first observation of sulphotransferase induction by rifampicin in human hepatocytes in vitro resulting in increased [3H]‐EE2 sulphation.

Conclusions Our data indicate that the major EE2 metabolic products formed by human hepatocytes in vitro are direct EE2 conjugates with EE2 oxidation representing minor pathways. Further studies are required to establish the mechanism of sulphotransferase induction and the clinical relevance of our findings.
The pharmacokinetic modelling of GI198745 (dutasteride), a compound with parallel linear and nonlinear elimination
Authors: Gisleskog Per Olsson , Hermann David , Hammarlund‐Udenaes Margareta , Karlsson Mats O.
Published: March 2003

Aims To characterize the pharmacokinetics of the dual 5α‐reductase inhibitor GI198745 (dutasteride) to allow for more accurate predictions of GI198745 concentrations after different dosing schedules.

Methods In this randomized, single‐blind, parallel group study, 32 healthy male volunteers received single oral doses of GI198745 ranging from 0.01 to 40 mg. Data were analysed by nonlinear mixed effects modelling using NONMEM where both linear and nonlinear pharmacokinetic models were examined.

Results The time course of GI198745 serum concentrations indicated concentration dependent elimination, with the apparent half‐life increasing with dose. Data were best described by a two‐compartment model with first order absorption and parallel linear and nonlinear elimination pathways. Drug absorption was rapid, and was followed by a short distribution phase. A high volume of distribution (511 l) and a low linear clearance (0.58 l h−1 ) combined to give a half‐life of up to 5 (1–7) weeks at high concentrations. As concentrations declined towards Km (0.96 ng ml−1 ), the proportion eliminated by the relatively rapid saturable elimination pathway, with a maximum clearance of 6.2 l h−1, increased and the half‐life reduced to about 3 days. The estimated inter individual variability for the linear clearance was high (CV=70%).

Conclusions GI198745 pharmacokinetics are well described by a pharmacokinetic model with parallel linear and nonlinear elimination. Simulations using this model show that at daily doses of 0.1 mg the steady state drug concentrations, and the rate at which these are achieved, are mainly influenced by the nonlinear pathway, while at daily doses above 1 mg they are almost entirely influenced by the linear pathway.
A comparison of the use, effectiveness and safety of bezafibrate, gemfibrozil and simvastatin in normal clinical practice using the New Zealand Intensive Medicines Monitoring Programme (IMMP)
Authors: Beggs Peter W. , Clark David W.J. , Williams Sheila M. , Coulter David M.
Published: March 2003

Aims Because of the importance of treating dyslipidaemia in the prevention of ischaemic heart disease and because patient selection criteria and outcomes in clinical trials do not necessarily reflect what happens in normal clinical practice, we compared outcomes from bezafibrate, gemfibrozil and simvastatin therapy under conditions of normal use.

Methods A random sample of 200 patients was selected from the New Zealand Intensive Medicines Monitoring Programme’s (IMMP) patient cohorts for each drug. Questionnaires sent to prescribers requested information on indications, risk factors for ischaemic heart disease, lipid profiles with changes during treatment and reasons for stopping therapy.

Results 80% of prescribers replied and 83% of these contained useful information. The three groups were similar for age, sex and geographical region, but significantly more patients on bezafibrate had diabetes and/or hypertension than those on gemfibrozil or simvastatin. After treatment and taking the initial measure into account, the changes in serum lipid values were consistent with those generally observed, but with gemfibrozil being significantly less effective than expected. More patients (15.8%) stopped gemfibrozil because of an inadequate response compared with bezafibrate (5.4%) and simvastatin (1.6%). Gemfibrozil treatment was also withdrawn significantly more frequently due to a possible adverse reaction compared with the other two drugs.

Conclusions In normal clinical practice in New Zealand gemfibrozil appears less effective and more frequently causes adverse effects leading to withdrawal of treatment than either bezafibrate or simvastatin.
Dose linearity study of selegiline pharmacokinetics after oral administration: evidence for strong drug interaction with female sex steroids
Authors: Laine Kari , Anttila Markku , Helminen Antti , Karnani Hari , Huupponen Risto
Published: March 2003

Aims The purpose of this study was to characterize the dose relationship of selegiline and desmethylselegiline pharmacokinetics within the selegiline dose range from 5 to 40 mg.

Methods Eight female subjects, of whom four were using oral contraceptives, ingested a single dose of 5 mg, 10 mg, 20 mg or 40 mg of selegiline HCl in an open four‐period randomized study. Concentrations of selegiline and desmethylselegiline in serum were measured by gas chromatography for 5 h. As it became evident that the use of oral steroids had a drastic effect on selegiline concentrations, the pharmacokinetic analyses were performed separately for oral contraceptive users and those not receiving any concomitant medication.

Results The total AUC and Cmax of selegiline were 10‐to 20‐fold higher in those subjects taking oral steroids compared with subjects with no concomitant medication; this finding was consistent and statistically significant at all the four dose levels. The dose linearity of selegiline pharmacokinetics failed to be demonstrated in both groups. The AUC and Cmax of desmethylselegiline were only moderately higher (about 1.5‐fold; P=NS at each dose level) in the subjects taking oral steroids than in those not receiving concomitant medication. The AUC values of desmethylselegiline increased in a dose linear manner in subjects with no concomitant medication, but not in the oral steroid group. The metabolic ratio (AUC(desmethylselegiline)/AUC(selegiline)) was several‐fold lower in the group receiving oral steroids compared with the no‐concomitant‐medication group (P<0.005 at all the four dose levels).

Conclusions Concomitant use of oral contraceptives caused a drastic (20‐fold) increase in the oral bioavailability of selegiline. The highly significant difference in the metabolic ratio between the groups provides evidence that the mechanism of the interaction between selegiline and female sex steroids involves reduced N‐demethylation of selegiline. The present results suggest that concomitant use of selegiline with exogenous female sex steroids should be avoided or the dosage of selegiline should be reduced in order to minimize the risks of selegiline related adverse drug reactions.
Functional significance of a C→A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine
Authors: Sachse Christoph , Brockmöller Jürgen , Bauer Steffen , Roots Ivar
Published: March 2003

Aims The cytochrome P450 enzyme CYP1A2 metabolises several drugs and carcinogens. We wanted to determine how much of the variability of CYP1A2 activity is explained by a newly discovered gene polymorphism in intron 1.

Methods A single nucleotide polymorphism in intron 1 of the CYP1A2 gene at position 734 downstream of the first transcribed nucleotide was identified by DNA sequence analysis. The functional significance of this C/A polymorphism was assessed in 185 healthy Caucasian non‐smokers and in 51 smokers by genotyping and phenotyping using caffeine (100 mg oral dose).

Results Out of the total sample, 46% were homozygous for the variant A, 44% were heterozygous, and 10% were homozygous for the variant C. The ratio of 1,7‐dimethylxanthine (17X) plus 1,7‐dimethyluric acid divided by caffeine in 0–5 h urine samples from 185 non‐smokers did not differ significantly between the three CYP1A2 genotypes. In the 51 smokers, analysis of variance revealed significant differences in the 5 h plasma 17X/caffeine ratios between the genotypes (P=0.008, F‐test). The mean ratio was 1.37 in carriers of the A/A genotype, 0.88 in heterozygotes and 0.82 in carriers of C/C. The mean difference between the A/A and C/A groups was 0.48 (95% confidence interval 0.15–0.81; P=0.01).

Conclusions The A/A genotype, which may represent a CYP1A2 high inducibility genotype, may either be a direct cause of increased CYP1A2 activity, or be genetically linked to polymorphisms conferring high inducibility. Further studies are needed to define the role of this polymorphism on the pharmacokinetics of drugs metabolised by CYP1A2 and in the activation of carcinogens.
Metabolic interactions between mibefradil and HMG‐CoA reductase inhibitors: an in vitro investigation with human liver preparations
Authors: Prueksaritanont Thomayant , Ma Bennett , Tang Cuyue , Meng Yuan , Assang Carol , Lu Ping , Reider Paul J. , Lin Jiunn H. , Baillie Thomas A.
Published: March 2003

Aims To determine the effects of mibefradil on the metabolism in human liver microsomal preparations of the HMG‐CoA reductase inhibitors simvastatin, lovastatin, atorvastatin, cerivastatin and fluvastatin.

Methods Metabolism of the above five statins (0.5, 5 or 10 μm ), as well as of specific CYP3A4/5 and CYP2C8/9 marker substrates, was examined in human liver microsomal preparations in the presence and absence of mibefradil (0.1–50 μm ).

Results Mibefradil inhibited, in a concentration‐dependent fashion, the metabolism of the four statins (simvastatin, lovastatin, atorvastatin and cerivastatin) known to be substrates for CYP3A. The potency of inhibition was such that the IC50 values (<1 μm ) for inhibition of all of the CYP3A substrates fell within the therapeutic plasma concentrations of mibefradil, and was comparable with that of ketoconazole. However, the inhibition by mibefradil, unlike that of ketoconazole, was at least in part mechanism‐based. Based on the kinetics of its inhibition of hepatic testosterone 6β‐hydroxylase activity, mibefradil was judged to be a powerful mechanism‐based inhibitor of CYP3A4/5, with values for Kinactivation, Ki and partition ratio (moles of mibefradil metabolized per moles of enzyme inactivated) of 0.4 min−1, 2.3 μm and 1.7, respectively. In contrast to the results with substrates of CYP3A, metabolism of fluvastatin, a substrate of CYP2C8/9, and the hydroxylation of tolbutamide, a functional probe for CYP2C8/9, were not inhibited by mibefradil.

Conclusions Mibefradil, at therapeutically relevant concentrations, strongly suppressed the metabolism in human liver microsomes of simvastatin, lovastatin, atorvastatin and cerivastatin through its inhibitory effects on CYP3A4/5, while the effects of mibefradil on fluvastatin, a substrate for CYP2C8/9, were minimal in this system. Since mibefradil is a potent mechanism‐based inhibitor of CYP3A4/5, it is anticipated that clinically significant drug–drug interactions will likely ensue when mibefradil is coadministered with agents which are cleared primarily by CYP3A‐mediated pathways.
The effect of bosentan on the pharmacokinetics of digoxin in healthy male subjects
Authors: Weber Cornelia , Banken Ludger , Birnboeck Herbert , Nave Stephane , Schulz Rainer
Published: March 2003

Aims To investigate the effect of multiple oral dose treatment with the endothelin receptor antagonist bosentan on the pharmacokinetics of digoxin in healthy subjects.

Methods This was an open‐label, randomized, two‐way crossover study in 18 evaluable young male subjects. They received, on two occasions which were separated by at least 2 weeks washout period, 0.375 mg digoxin once daily for 13 days following a loading dose of 0.375 mg given twice on the day before the once daily dosing regimen started. On one occasion treatment with 500 mg bosentan twice daily was started on the eighth day of digoxin treatment and continued for 1 week. Serum concentrations of digoxin were determined up to 24 h postdose on day 8 (first day of bosentan treatment) and day 14 (last day of bosentan treatment) of the digoxin treatment period. Plasma concentrations of bosentan were measured at two time points after the first bosentan dose and up to 12 h after the last morning dose of bosentan. Safety was assessed by adverse events, clinical laboratory tests, blood pressure and pulse rate measurements and ECG recordings.

Results Steady‐state of digoxin was always achieved after 7 days of treatment. Serum concentrations of digoxin were within the usual therapeutic range. Average steady‐state Cmax and Ctr were 2–2.1 μg l−1 and 0.65–0.69 μg l−1, respectively, when given alone. Bosentan did not lead to statistically significant changes in Cmax and Ctr of digoxin. AUC (0,24h) of digoxin, however, was slightly reduced after 1 week of treatment with bosentan. The reduction was 12% on average with a narrow 95% confidence interval of 0‐23%. Bosentan pharmacokinetic parameters after 1 week of treatment were as expected with a mean Cmax of 3260 μg l−1 and a mean AUC (0,12h) of 12 600 μg l−1 h.

Conclusions Treatment with bosentan 500 mg twice daily for 1 week did not show clinically relevant effects on the pharmacokinetics of digoxin in healthy human subjects
Comparison of antiplatelet activity of microencapsulated aspirin 162.5 mg (Caspac XL), with enteric coated aspirin 75 mg and 150 mg in patients with atherosclerosis
Authors: Brown Nigel , May Jane A. , Wilcox Robert G. , Allan Linda M. , Wilson Adrian M. , Kiff Peter S. , Heptinstall Stan
Published: March 2003

Aims A new formulation, low dose microencapsulated aspirin, permits slow absorption of aspirin and presystemic acetylation of platelet cyclo‐oxygenase within the portal circulation, potentially avoiding deleterious effects on gastric and systemic prostaglandin synthesis. The objective of this study was to determine whether the administration of microencapsulated aspirin was as effective as enteric coated (EC) aspirin as an inhibitor of platelet function in patients with atherosclerosis.

Methods One hundred and four patients were enrolled and randomised after a run in period of at least 14 days on aspirin EC 75 mg (day 0), to receive either microencapsulated aspirin 162.5 mg (n=34), aspirin EC 150 mg (n=36) or continue on aspirin EC 75 mg (n=34) for 28 days. Serum thromboxane B2 and collagen‐induced platelet aggregation and release of 5‐hydroxytryptamine (EC50 values) were measured on days 0 and 28. Aggregation/release EC50s were then repeated in the presence of a large dose of aspirin added in vitro to determine the EC50 at the maximum level of platelet inhibition.

Results Median thromboxane B2 levels were low after 14 days run‐in therapy with aspirin EC 75 mg, but significant further reductions were seen on day 28 in patients randomised to microencapsulated aspirin 162.5 mg (P=0.0368) and aspirin EC 150 mg (P=0.0004) compared with those remaining on aspirin EC 75 mg. Median EC50 s on day 28 showed small but significant increases from baseline (day 0) in aggregation in patients randomised to microencapsulated aspirin 162.5 mg (0.62–0.85, P=0.0482) and in both aggregation and release in patients randomised to aspirin EC 150 mg (0.95–1.20, P=0.0002, 8.4–11.7, P<0.0001, respectively) signifying enhanced antiplatelet activity. No changes were seen in patients continuing on aspirin EC 75 mg. Results following addition of high dose aspirin in vitro suggest that mechanisms other than thromboxane synthesis may be operative in the long term effects of microencapsulated aspirin 162.5 mg and aspirin EC 150 mg over aspirin EC 75 mg.

Conclusions The results show good inhibition of thromboxane B2 synthesis and subsequent platelet activity by all preparations of aspirin, although both microencapsulated aspirin 162.5 mg and aspirin EC 150 mg are slightly more effective than aspirin EC 75 mg. A randomised trial is now required to determine whether microencapsulated aspirin is associated with fewer gastric side‐effects.
The prevalence and incidence of medical conditions in healthy pharmaceutical company employees who volunteer to participate in medical research
Authors: Singh  , Williams
Published: March 2003

Aims Although clinical research in healthy volunteers is commonly performed there have been few studies of the value of the medical screening of subjects. The aim of this study was to investigate the prevalence and incidence of medical conditions found during the medical screening of ‘healthy’ subjects employed in a pharmaceutical company who volunteered to participate in medical research.

Methods This was a retrospective study of the medical notes of all the subjects who volunteered for membership of the Zeneca Clinical Pharmacology Unit’s healthy volunteer panel over a 4 year period from 1990 to 1994. The prevalence of medical conditions found at presentation was determined. The incidence of medical conditions during the 4 year observation period was also ascertained. Medical screening included a full medical history and examination, clinical chemistry, haematology and urinalysis screens, pulmonary function tests, ECGs, 24 h ambulatory cardiac monitoring and a request for information from the volunteer’s General Practitioner.

Results Prevalence‐1293 subjects volunteered to join the panel of which 156 subjects (12%) were not accepted at presentation including 141 (10.9%) for medical reasons. The most medical common reasons were; previously diagnosed medical conditions (3.3%), cardiovascular abnormalities (1.9%), abnormal liver function tests (1.9%), anaemia (1.2%), hyperlipidaemia (1.1%), excess alcohol intake (0.6%) and thyroid disease (0.5%). Incidence—36 of the 1137 volunteers (0.8% per year) accepted onto the panel subsequently developed medical conditions of which the most common were; anaemia (0.29% per year), cardiovascular abnormalities (0.13% per year) and vasovagal syncope (0.13% per year).

Conclusions This study demonstrates the importance of medical screening before healthy volunteers participate in clinical research.
The efficacy of a novel adenosine agonist (WAG 994) in postoperative dental pain
Authors: Seymour  , Hawkesford  , Hill  , Frame  , Andrews
Published: March 2003

Aims To determine the comparative efficacy of a new novel adenosine agonist (WAG 994) in postoperative pain after third molar surgery.

Methods One hundred and twenty‐two patients with postoperative pain after third molar surgery were randomised in a placebo double‐blind trial with an active control group. In the early postoperative period patients received either a single dose of WAG 994 1 mg, ibuprofen 400 mg or matched placebos. Pain intensity score was recorded on serial visual analogue scales over a 6 h investigation period. Similarly, pain relief was completed on a 4 point categorical scale at each evaluation point. Patients had access to escape analgesic and if these were taken, the time and dosage were recorded. A sparse sampling technique was used to investigate the relationship between analgesic effects and plasma concentrations of WAG 994.

Results All three treatment groups were matched for various demographic variables. For all efficacy measures, WAG 994 was not significantly different from placebo (P >0.05), whereas ibuprofen 400 mg was significantly superior to placebo (P<0.001). No significant relationships (P<0.05) were found between WAG 994 pharmacokinetic variables and efficacy measures.

Conclusion WAG 994, an adenosine agonist, did not show efficacy in the management of postoperative pain after third molar surgery. Although this pain responds well to nonsteroidal anti‐inflammatory drugs, it appears to be resistant to compounds that interact with purinergic receptors.