bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of activated charcoal alone or given after gastric lavage in reducing the absorption of diazepam, ibuprofen and citalopram
Authors: Lapatto‐Reiniluoto O. , Kivistö K. T. , Neuvonen P. J.
Published: March 2003

Aims
 The efficacy of activated charcoal alone, and gastric lavage followed by charcoal in reducing the absorption of diazepam, ibuprofen and citalopram was studied in healthy volunteers.

Methods
 In a randomized cross‐over study with three phases, nine healthy volunteers were administered single oral doses of 5 mg diazepam, 400 mg ibuprofen and 20 mg citalopram, taken simultaneously after an overnight fast. Thirty minutes later, the subjects were assigned to one of the following treatments: 200 ml water (control), 25 g activated charcoal as a suspension in 200 ml water or gastric lavage followed by 25 g charcoal in suspension given through the lavage tube. Plasma concentrations of diazepam, ibuprofen and citalopram were determined up to 10 h.

Results
 The AUC(0,10 h) of diazepam was reduced by 27% (P<0.05) by both charcoal alone and charcoal combined with lavage. The increase in plasma diazepam concentration from 0.5 h onwards was prevented by both interventions (P≤0.05), whereas the Cmax of diazepam was not significantly affected by either treatment. The AUC(0, 10 h) of ibuprofen was reduced by 49% (P<0.05) after the combination treatment and by 30% (P<0.05) after charcoal alone, but there was no significant difference between these two treatments. Both charcoal alone and the combination treatment were equally effective in preventing the increase in plasma ibuprofen from 0.5 h onwards (P<0.01). The Cmax of ibuprofen was reduced by 45% (P<0.05) and by 21% (P=NS), respectively. The AUC(0,10 h) of citalopram was reduced by 51% (P<0.05) after both charcoal alone and charcoal combined with lavage, and the Cmax by 52% (P<0.05) and 54% (P<0.05), respectively. The increase in plasma citalopram concentration from 0.5 h onwards was reduced by about 50% (P<0.01) by both interventions.

Conclusions
 Activated charcoal alone and charcoal combined with lavage showed similar efficacy in preventing the absorption of diazepam, ibuprofen and citalopram. These results suggest that gastric lavage needs not be routinely performed before administration of charcoal.
Polypharmacy in a general surgical unit and consequences of drug withdrawal
Authors: Kennedy J. M. , Van Rij A. M. , Spears G. F. , Pettigrew R. A. , Tucker I. G.
Published: March 2003

Aims  To identify drug usage/withdrawal in surgical patients and the relative risk this imposes on postoperative surgical complications.

Methods  A prospective survey of patients’ medicines, oral intake (food/fluids/ medicines) and postoperative complications was carried out in the General Surgical Unit, Dunedin Hospital, Dunedin, New Zealand.

Results  One thousand and twenty‐five general surgical patients aged ≥ 16 years, were entered into the study. Half of the patients were taking medicines unrelated to surgery. On average these patients received 9 different drugs (range 1–47) from a selection of 251, of which 21% were released in the last 10 years. The mean number of these drugs taken increased with age, vascular surgery and other major procedures. The majority of patients (53%) were taking drugs for cardiovascular problems. Only 8% of admissions were on the drugs more traditionally recognized to be of importance to the surgery, i.e. steroids and diabetic therapy. With respect to risk, taking a drug unrelated to surgery was associated with an increased relative risk of a postoperative complication by 2.7 (95% C.I. 1.76–4.04) compared with those who were not taking any drug. Cardiovascular drugs contributed significantly to this risk; when they were excluded from analysis, the risk dropped to 1.8 (95% C.I. 1.14–2.93). Death may be more common in those taking ACE inhibitors. Drug withdrawal and complications were analysed and as the time without medicines increased (range 1–42 days) so did the complication rate (χ2 = 14.7, DF = 2, P = 0.007). Of those patients who were taking a cardiovascular medicine and were without their normal medicines for a period of time postoperatively, 12% suffered a cardiac complication.

Conclusions  Many patients admitted to a general surgical ward, are taking medicines unrelated to surgery. Drug therapy unrelated to surgery is a useful predictor for increased postoperative complications and one for which preventive action can be taken. This study provides evidence that withdrawal of regular medicines may add significant risk to the surgery and further complicate outcome. The longer patients were without their regular medicines the more nonsurgical complications they suffered. Reintroduction of patients’ regular medicines early in their postoperative course may decrease morbidity and mortality in‐patients.
Within‐ and between‐subject variations in pharmacokinetic parameters of ethanol by analysis of breath, venous blood and urine
Authors: Norberg Å. , Gabrielsson J. , Jones A. W. , Hahn R. G.
Published: March 2003

Aims To evaluate the prerequisites for using ethanol dilution to estimate total body water, we studied the within‐ and between‐subject variation in the parameter estimates of a two‐compartment model for ethanol pharmacokinetics with parallel Michaelis‐Menten and first‐order renal elimination. Because sampling of breath might be preferable in some clinical situations the parameter estimates derived from breath and venous blood were compared.

Methods On two occasions, ethanol 0.4 g kg−1was given by intravenous infusion to 16 volunteers after they had fasted overnight. The proposed model was fitted by means of nonlinear regression to concentration‐time data measured in the breath, venous blood and urine during 360 min. The model contained six parameters:VmaxandKm(Michaelis‐Menten elimination constants), CLd(intercompartmental distribution parameter),VCandVT(volumes of the central and tissue compartment, respectively) and CLR(renal clearance). The volume of distribution,Vss, was calculated as the sum ofVCandVT.

Results The mean ± total s.d. of the parameter estimates derived from blood data wereVmax95 ± 25 mg min−1,Km27 ± 19 mg l−1, CLd809 ± 232 ml min−1,VC14.5 ± 4.3 l,VT21.2 ± 4.4 l, CLR3.6 ± 2.0 ml min−1andVss35.8 ± 4.3 l. The variation within subjects amounted to 3%, 9%, 21%, 21%, 17%, 26% and 2%, respectively, of the total variation. Breath samples were associated with a similar or lower variation than blood, both within and between subjects. About 1.5% of the infused ethanol was recovered in the urine.

Conclusions The low within‐subject variation of the key parameterVss(only 2%) suggests that ethanol dilution analysed by the pharmacokinetic model applied here may be used as an index of the total body water. Breath samples yielded at least as good reproducibility in the model parameters as venous blood.
Validation of the diagnosis of venous thromboembolism in general practice database studies
Authors: Lawrenson R. , Todd J.‐C. , Leydon G. M. , Williams T. J. , Farmer R. D. T.
Published: March 2003

Aims
The study was conducted to determine whether the method for selecting cases of venous thromboembolism (VTE) from general practice databases significantly affected the findings of an epidemiological study.

Methods
Cases of VTE were identified from the UK General Practice Research Database (GPRD) by searching for codes for deep vein thrombosis (DVT) and pulmonary embolism (PE). These had to be supported by evidence of anticoagulation and be exposed to a combined oral contraceptive (COC) at the time of the event. Additional information about the event was sought from general practitioners who were requested to complete a questionnaire and to supply anonymised copies of hospital letters and discharge summaries.

Results
Of the 285 cases identified from the GPRD, additional information was available for 177 VTE events. This information showed that 84% of those events were supported by hospital investigations or a death certificate. Using only verified cases, rather than all GPRD identified events, did not alter the results of the epidemiological study.

Conclusions
The GPRD provides information of sufficiently high quality to allow valid epidemiological research of VTE events. Excluding cases without a database record of hospital admission would lead to valid events being overlooked, and an under‐estimate of the disease incidence.
Constriction to ETB receptor agonists, BQ‐3020 and sarafotoxin S6c, in human resistance and capacitance vessels in vivo
Authors: Strachan Fiona E. , Crockett Thomas R. , Mills Nicholas L. , Gray Gillian A. , Webb David J.
Published: March 2003

Aims
The aim of the study was to examine the effects of the ETB receptor selective agonists sarafotoxin S6c (SFTX6c) and BQ‐3020 on the forearm resistance and capacitance vessels in healthy subjects in vivo.

Methods
The local response to intra‐arterial or intravenous infusion of SFTX6c (5 pmol min−1) or BQ‐3020 (50 pmol min−1) was assessed, on separate occasions, in eight healthy men (aged 20–28 years). Data (mean ± s.e.mean) were examined by
anova. Results are expressed as percentage change from baseline at 90 min.

Results
SFTX6c and BQ‐3020 reduced forearm blood flow, following local intra‐arterial infusion (−25 ± 7% and −27 ± 7%, respectively; P < 0.001) and reduced hand vein diameter, following local intravenous infusion (−30 ± 8% and −16 ± 7%, respectively; P < 0.001).

Conclusions
We have shown that locally active infusions of the selective ETB receptor agonists SFTX6c and BQ‐3020 cause arterial constriction and venoconstriction in healthy human blood vessels in vivo. These results indicate that ETB receptor stimulation may mediate vasoconstriction in humans.
A model for size and age changes in the pharmacokinetics of paracetamol in neonates, infants and children
Authors: Anderson Brian J. , Woollard Gerald A. , Holford Nicholas H. G.
Published: March 2003

Aims
The aims of this study were to describe paracetamol pharmacokinetics in neonates and infants.

Methods
Infants in their first 3 months of life (n = 30) were randomised to sequentially receive one of three paracetamol formulations (dose 30–40 mg kg−1) over a 2 day period. The formulations were (a) elixir, (b) glycogelatin capsule suppository and (c) triglyceride base suppository. Approximately six blood samples were taken after each dose over the subsequent 10–16 h. Data were analysed using a nonlinear mixed effect model. These neonatal and infant data were then included with data from four published studies of paracetamol pharmacokinetics (n = 221) and age‐related pharmacokinetic changes investigated.

Results
Population pharmacokinetic parameter estimates and their coefficients of variation (CV%) for a one compartment model with first order input, lag time and first order elimination were volume of distribution 69.9 (18%) l and clearance 13.0 (41%) l h−1 (standardized to a 70 kg person). The volume of distribution decreased exponentially with a half‐life of 1.9 days from 120 l 70 kg−1 at birth to 69.9 l 70 kg−1 by 14 days. Clearance increased from birth (4.9 l h−1 70 kg−1) with a half‐life of 3.25 months to reach 12.4 l h−1 70 kg−1 by 12 months. The absorption half‐life (tabs) for the oral preparation was 0.13 (154%) h with a lag time (tlag) of 0.39 h (31%). Absorption parameters for the triglyceride base and capsule suppositories were tabs 1.34 (90%) h, tlag 0.14 h (31%) and tabs 0.65 (63%) h, tlag 0.54 h (31%), respectively. The tabs for elixir and capsule suppository in children under 3 months were 3.68 and 1.51 times greater than children over 3 months. The relative bioavailability of rectal formulations compared with elixir were 0.67 (30%) and 0.61 (23%) for the triglyceride base and capsule suppositories, respectively.

Conclusions
Total body clearance of paracetamol at birth is 62% and volume of distribution 174% that of older children. A target concentration above 10 mg l−1 in approximately 50% subjects can be achieved by a dose from 45 mg kg−1 day−1 at birth and up to 90 mg kg−1 day−1 in 5‐year‐old children. A reduced dose of 75 mg kg−1 day−1 in an 8‐year‐old child is sufficient because clearance is a nonlinear function of weight.
Intravenous diltiazem and CYP3A‐mediated metabolism
Authors: Masica Andrew L. , Azie Nkechi E. , Brater D. Craig , Hall Stephen D. , Jones David R.
Published: March 2003

Aims
To study whether intravenous diltiazem, a calcium channel blocker commonly prescribed for hypertension and stable angina, is an inhibitor of the CYP3A enzymes by using oral lovastatin, an HMG Co‐A reductase inhibitor, as a substrate.

Methods
Ten healthy volunteers were studied in a randomized two‐way crossover design. The two arms were 1) administration of a 20 mg dosage of lovastatin orally and 2) administration of a 20 mg dosage of lovastatin orally 1 h after an intravenous loading dosage and constant infusion of diltiazem. Blood samples were collected up to 25 h in order to quantify lovastatin and diltiazem concentrations in the separated serum. Lovastatin and diltiazem concentrations were quantified by GC‐MS and h.p.l.c., respectively.

Results
Intravenous diltiazem did not significantly affect the oral AUC, Cmax, t½, or tmax of lovastatin.

Conclusions
These data suggest that the interaction of lovastatin with diltiazem does not occur systemically and is primarily a first‐pass effect. Thus, drug interactions with diltiazem may become evident when a patient is moved from intravenous to oral dosing.
Relative bioavailability of salbutamol to the lung following inhalation when administration is prolonged
Authors: Silkstone V. L. , Tomlinson H. S. , Corlett S. A. , Chrystyn H.
Published: March 2003

Aims  Urinary salbutamol post‐inhalation has been shown to be an index of lung deposition. The possibility of using the urinary method for prolonged periods of inhalation (such as nebulized therapy) has been evaluated.

Methods  On separate study days volunteers received salbutamol 5 × 100 µg via either oral administration (ORAL), oral with 5 g oral charcoal (ORAL + C), inhaled from a metered dose inhaler (MDI) or MDI plus 5 g oral charcoal (MDI + C). Each dose was separated by 2 min, i.e. administration time of 8 min. Urine samples were provided at 0, 30, 40, 60 and 120 min postdose. Also seven subjects inhaled 5×100 µg doses from the MDI on five separate occasions and provided urine 0–30 min post dose.

Results  No salbutamol was detected in urine samples following ORAL + C. The mean (s.d.) amounts of salbutamol excreted in the urine in the first 30 min post ORAL, MDI and MDI + C were 0.42 (0.55), 11.01 (3.77) and 11.60 (3.68) µg, respectively. The ratio of urinary salbutamol following MDI and MDI + C to ORAL in the 0–30 min collection period was 26.2 and 27.8, and between 30 and 40 min postdose was 5.1 and 4.7, respectively. There was no difference between urinary salbutamol over the first 30 min following MDI and MDI + C with a mean ratio (90% confidence interval) of 95.6 (84.0, 107.2). The mean (s.d.) coefficient of variation for the 30 min urinary salbutamol elimination following inhalation of 5 × 100 µg doses from the MDI by seven subjects (on 5 separate study days) was 9.4 (2.3) %.

Conclusions  The 30 min urinary salbutamol method can be used for an inhalation period of up to 8 min to identify the relative bioavailability to the lung. Samples taken after this time period are affected by excretion of the oral absorbed fraction. Most nebulisers deliver their dose within this administration time.
The pharmacokinetics of trinitroglycerin and its metabolites in patients with chronic stable angina
Authors: Hashimoto Satoru , Yamauchi Eiko , Kobayashi Atsuko , Shigemi Kenji , Tsuruta Hiroshi , Yamashita Tomomitsu , Tanaka Yoshifumi
Published: March 2003

Aims
 To study the pharmacokinetics of trinitroglycerin (GTN) and its four metabolites in angina patients during their transient use of transdermal GTN tape following intravenous administration of GTN.

Methods
 Four patients received a GTN tape following intravenous administration of 0.1 µg kg−1 min−1 GTN, and the other four patients received two GTN tapes following intravenous administration of 0.2 µg kg−1 min−1 GTN.

Results
 Plasma concentrations of GTN in both groups during tape application showed a slight decrease for the hour after the application of the tape and then were con‐ stant for 24 h. In contrast, the concentrations of dinitroglycerins (GDNs) and mononitroglycerins (GMNs) depended on the duration of previous intravenous administration of GTN. Neither significant cardiovascular changes nor undesirable complications were observed during the study.

Conclusions
 The results suggest that appropriate replacement of intravenous GTN administration with transdermal tape application could maintain a therapeutic GTN level.
Pharmacodynamic and pharmacokinetic profile of S 17092, a new orally active prolyl endopeptidase inhibitor, in elderly healthy volunteers. A phase I study
Authors: Morain P. , Robin J. L. , De Nanteuil G. , Jochemsen R. , Heidet V. , Guez D.
Published: March 2003

Aims  The aim of this study was to characterize the pharmacodynamics and the pharmacokinetics of S 17092, a new orally active prolyl endopeptidase inhibitor following single and repeated administration in elderly healthy volunteers.

Methods  This was a double‐blind, randomized, placebo‐controlled, single and multiple dose study in elderly healthy male and female volunteers (n = 36). Four doses were investigated in sequential order: 100, 400, 800 and 1200 mg. Each dose was administered orally once a day in single administration and then, after a 1 week washout period, during 7 days. Pharmacodynamics were assessed by measurement of plasmatic prolyl endopeptidase (PEP) activity, quantitative electroencephalogram (EEG) and psychometric tests. S 17092 concentrations in plasma were quantified by high performance liquid chromatography with tandem mass spectrometric detection.

Results  PEP activity in plasma was dose‐dependently inhibited both after administration of a single dose and after repeated doses of S 17092. The mean maximal inhibition was obtained within 0.5–2 h after dosing, while inhibition lasted at least 12 h after dose administration. S 17092 appeared to be a centrally active substance as it induced statistically significant modifications in EEG compared with placebo. S 17092 at 100 mg exerted an acute increase in alpha band following single administration at 4 h and 8 h postdosing. When administered repeatedly over 7 days S 17092 did not appear to induce significant lasting central nervous system (CNS) effects. In psychometric tests, response times in the numeric working memory were significantly reduced compared with placebo, following the 800 mg dose. There were some beneficial residual effects of the 1200 mg dose on day 13: delayed word recall and word recognition sensitivity improved compared with the declines noted under placebo. Maximum measured concentration (Cmax) and area under the curve (AUC) parameters increased in proportion to the dose. The terminal half‐life (t½) values ranged between 9 and 31 h on day 1 and between 7 and 18 h on day 14. A high interindividual variability was observed at all dose levels. S 17092 was well tolerated with no clinically significant changes in laboratory or physical parameters observed at any dose.

Conclusions  S 17092 had a potent, dose‐dependent inhibitory effect on plasmatic PEP, increased alpha band EEG at the 100 mg dose and improved performance in two verbal memory tests at the 1200 mg dose while there were disruption to the vigilance task. The results obtained in elderly healthy subjects indicated that S 17092 is suitable for once‐daily dosing without any serious adverse events.
Enterocytic CYP3A4 in a paediatric population: developmental changes and the effect of coeliac disease and cystic fibrosis
Authors: Johnson Trevor N. , Tanner M. Stuart , Taylor Christopher J. , Tucker Geoffrey T.
Published: March 2003

Aims  To investigate the effects of age and disease states on the expression and activity of intestinal CYP3A4 in a paediatric population.

Methods  Duodenal biopsies and surgical sections were collected from 104 paediatric patients (age range 2 weeks to 17 years) and from 11 foetuses. An S9 fraction was prepared in each case. CYP3A4 expression was assessed by Western blotting and by immunohistochemistry; activity was measured by the rate of formation of 6β‐hydroxytestosterone from testosterone. Villin expression was used as a marker of enterocyte harvest to normalize CYP3A4 expression and activity data.

Results  In the 74 histologically normal paediatric biopsies there were statistically significant increases in CYP3A4 expression (r2 = 0.19, P = 0.001) and activity (r2 = 0.17, P = 0.02) with age. CYP3A4 was practically absent in fetal duodenum and was expressed at relatively low levels in neonates (P < 0.05 between neonates and children > 5 years). Active coeliac disease resulted in significant (P < 0.001) decreases in CYP3A4 expression and activity.

Conclusions  Duodenal CYP3A4 is present at significantly lower levels in neonates and in patients with active coeliac disease. This may have clinical significance with respect to the oral bioavailability of CYP3A4 substrates.
Influence of cirrhosis on lamotrigine pharmacokinetics
Authors: Marcellin P. , De Bony F. , Garret C. , Altman C. , Boige V. , Castelnau C. , Laurent‐Puig P. , Trinchet J. C. , Rolan P. , Chen C. , Mamet J. P. , Bidault R.
Published: March 2003

Aims  Lamotrigine, an antiepileptic drug, is cleared from the systemic circulation mainly by glucuronidation. The possibility of changes in the pharmacokinetics of lamotrigine in plasma owing to hepatic dysfunction has been evaluated.

Methods  Thirty‐six subjects, including 24 patients with various degrees of liver cirrhosis and 12 healthy volunteers received a single 100 mg dose of lamotrgine. Blood samples were taken for 7 days in all subjects, except nine with severe cirrhosis, who had a 29 day blood sampling period.

Results  The pharmacokinetics of lamotrigine were comparable between the patients with moderate cirrhosis (corresponding to Child‐Pugh grade A) and the healthy subjects. Plasma oral clearance mean ratios (90% confidence interval) in patients with severe cirrhosis without or with ascites (corresponding, respectively, to Child‐Pugh grade B and C) to healthy subjects were, respectively, 60% (44%, 83%) and 36% (25%, 52%). Plasma half‐life mean ratios (90% confidence interval) in these two patient groups to healthy subjects were, respectively, 204% (149%, 278%) and 287% (202%, 408%).

Conclusions  Lamotrigine administered as a single oral dose of 100 mg was well tolerated in all groups. Initial, escalation and maintenance doses should generally be reduced by approximately 50 or 75% in patients with Child‐Pugh Grade B or C cirrhosis. Escalation and maintenance doses should be adjusted according to clinical response.
Pharmacokinetic/pharmacodynamic model for prednisolone inhibition of whole blood lymphocyte proliferation
Authors: Magee Mindy He , Blum Robert A. , Lates Christian D. , Jusko William J.
Published: March 2003

Aims Mitogen‐inducedex vivowhole blood lymphocyte proliferation (WBLP) is a widely used method to assess lymphocyte responsiveness to immunosuppressive therapy. A three‐component complex model was developed to characterize effects of prednisolone on cell trafficking, transduction, and lymphocyte suppression.

Methods An oral dose (0.27 mg kg−1) of prednisone was given to 32 subjects. The study consisted of baseline and prednisone phases each with 32 h of sampling. Measurements included plasma prednisolone concentrations,in vitroandex vivoWBLP, and lymphocyte cell counts during baseline and prednisone phases.

Results The final model consists of a precursor‐dependent indirect response model with a first‐order periodic influx rate for lymphocyte trafficking. This accounts for the rebound phenomenon and the circadian rhythm seen in all individualex vivoWBLP effect‐time profiles. Prednisolone was modelled as inhibiting lymphocyte influx from the precursor to the blood pools. The direct suppressive effect of prednisolone on WBLP was modelled with the simple Imax model. A transduction step with rate constantktwas introduced to the simple Imax model to account for the delay (∼4 h) in reaching the maximum inhibition. The IC50values obtainedex vivowerecirca10 times lower thanin vitrovalues (3.76vs38.8 ng ml−1), suggesting additionalin vivofactors may have enhanced lymphocyte response to the inhibitory effect of prednisolone.

Conclusions This integrated PK/PD model enables evaluation of multicomponent direct and indirect inhibition ofex vivoWBLP by steroids and other immunosuppressants in relation to sex and race.
Effect of the catechol‐O‐methyltransferase inhibitor entacapone on the steady‐state pharmacokinetics and pharmacodynamics of warfarin
Authors: Dingemanse Jasper , Meyerhoff Carsten , Schadrack Jan
Published: March 2003

Aims  To investigate the influence of a multiple‐dose regimen with the catechol‐O‐methyltransferase inhibitor entacapone on the pharmacokinetics and pharmacodynamics of warfarin.

Methods  In a randomized, double‐blind, two‐way cross‐over study, 12 healthy subjects (gender ratio 1 : 1) received treatment for 1 week with either entacapone 200 mg four times daily or placebo during individually optimized treatment with warfarin (INR 1.4–1.8). The effect of entacapone on the steady‐state pharmacokinetics of both R‐ and S‐warfarin was determined and, in addition, INR values were measured. The key pharmacokinetic variables were AUCss, Cmax and tmax.

Results  Entacapone increased the exposure to R‐warfarin by 18% (90% CI: 111, 126%), and caused a 13% (6, 19%) increase in INR values. No effect was seen on the pharmacokinetics of the pharmacologically more potent S‐enantiomer. Safety and tolerability variables did not show any difference between the treatment phases.

Conclusions  In healthy subjects, entacapone displays a slight pharmacokinetic interaction with R‐warfarin but, based on the lack of a clinically relevant pharmacodynamic interaction, it appears that it can also be used safely in Parkinson's disease patients who are receiving warfarin.
Prior iontophoresis of saline enhances vasoconstriction to phenylephrine and clonidine in the skin of the human forearm
Authors: Drummond Peter D.
Published: March 2003

Aims  To determine whether postjunctional α1‐ and α2‐adrenoceptors mediate vasoconstrictor responses in the cutaneous vasculature of the human forearm.

Methods  Drugs were administered transdermally by iontophoresis in the forearm of 20 healthy participants. Phenylephrine and clonidine were administered at sites pretreated with the relevant antagonist (terazosin and rauwolscine), and at additional untreated sites and sites pretreated with saline. To enhance the contrast between sites, the forearm was heated to 42° C before flow was measured with the laser Doppler technique.

Results  After the iontophoresis of phenylephrine, blood flow at the site pretreated with terazosin was 24±37% (±95% confidence interval) greater than flow at the reference site, whereas flow was 53±24% lower than reference flow at the previously untreated site and 77±10% lower than reference flow at the site pretreated with saline (P<0.001). After the iontophoresis of clonidine, blood flow at the site pretreated with rauwolscine was 25±21% greater than flow at the reference site, whereas flow was 56±15% lower than reference flow at the previously untreated site and 72±8% lower than reference flow at the site pretreated with saline (P<0.001). The saline pretreatment enhanced vasoconstriction to phenylephrine (P<0.05) and clonidine (P=0.05).

Conclusions  Pre‐treatment with the appropriate antagonist blocked vasoconstrictor responses to phenylephrine and clonidine, consistent with the presence of both α‐adrenoceptor subtypes in cutaneous vessels of the human forearm. In addition, iontophoretic pretreatment with saline facilitated vasoconstrictor responses, suggesting that a nonspecific effect of iontophoresis may enhance drug penetration through the stratum corneum.
Single‐ and multiple‐dose pharmacokinetics of bosentan and its interaction with ketoconazole
Authors: van Giersbergen Paul L. M. , Halabi Atef , Dingemanse Jasper
Published: March 2003

Aims  The present study was conducted to characterize the single‐ and multiple‐dose pharmacokinetics of bosentan, a dual endothelin receptor antagonist, and to investigate a possible pharmacokinetic interaction with ketoconazole.

Methods  In a randomized, two‐way crossover study, 10 healthy male subjects received treatments A and B. Treatment A consisted of a single dose of 62.5 mg bosentan on day 1 followed by 62.5 mg twice daily for 5.5 days. Treatment B consisted of bosentan (62.5 mg twice daily) for 5.5 days plus concomitant ketoconazole (200 mg once daily) for 6 days. Plasma concentrations of bosentan and its three metabolites were measured on days 1 and 7 of treatment A and on day 6 of treatment B.

Results  Bosentan was absorbed and eliminated with a tmax of 4.5 h (range 3.5–6.0 h) and a t½ of 5.4 h (95% CI; 4.5, 6.6). Upon multiple dosing, the exposure to bosentan was reduced by 33% without change in tmax and t½. Concomitant administration of ketoconazole increased the Cmax and AUC of bosentan 2.1‐ (95% CI; 1.5, 2.7) and 2.3‐fold (95% CI; 1.8, 2.9), respectively. Exposure to the metabolites was low and represented less than 25% of that to bosentan both after single and multiple doses. In the presence of ketoconazole, formation of the metabolites was inhibited.

Discussion  The multiple‐dose pharmacokinetics of bosentan are consistent with the phenomenon of auto‐induction. In the presence of CYP3A4 inhibitors, bosentan concentrations may be increased 2‐fold.
Pharmacokinetics and pharmacodynamics of low‐dose methotrexate in the treatment of psoriasis
Authors: Chládek Jaroslav , Grim Jiøı´ , Martínková Jiøina , Šimková Marie , Vanı`èková Jaroslava , Koudelková Vı`ra , Noièková Marie
Published: March 2003

Aims  The aim of this 13 week, randomized, parallel‐group study was to evaluate the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD) of low‐dose intermittent oral methotrexate (LDMTX) in patients with psoriasis.

Methods  Twenty‐four psoriatic patients (15 male and 9 female, aged 31–73 years) were given weekly doses of MTX doses of either 7.5 mg or 15 mg with each dose divided into three aliquots given at 12 h intervals. The pharmacokinetics of MTX were evaluated at weeks 1 and 13. Skin impairment was assessed using the PASI‐scoring system (The Psoriasis Area and Severity Index) at baseline and at weeks 5, 9 and 13 of therapy. Haematological and biochemistry tests were also performed at these times.

Results  The comparison of the areas under the plasma concentration‐time curve (AUCMTX) after the first and third weekly doses showed that the extent of MTX accumulation in plasma was only about 12%. Two‐way anova (factors: subject and the week of therapy) on the log‐transformed AUCMTX showed no effect of the week of therapy (P>0.8). Moreover, the intraindividual variability in the AUCMTX was at least 4‐fold less than the interindividual variability (F‐test; P<0.01). The steady‐state total plasma clearance of MTX ranged from 5.0 to 18.2 l h−1 and was proportional to the renal clearance (r2=0.45, P<0.001) which accounted for 65±20% of the former. The renal clearance of 7‐OHMTX was approximately 4–8% of that of the parent compound. PK/PD analysis revealed a highly significant inverse relationship between PASI (expressed as a percent of the initial value) and a steady‐state AUCMTX (rs=−0.65, P<0.001). Seventeen subjects (8 from the 7.5 mg group and 9 from the 15 mg group MTX, P=0.67) achieved a greater than 50% decrease in the initial PASI score and were classified as responders. Thirteen of 14 subjects with AUC(24,36 h)≥700 nmol l−1 h responded to pharmacotherapy. Conversely, only 4 out of 10 subjects with AUC(24,36 h)<700 nmol l−1 h were responders (P<0.01, Fisher's exact test).

Conclusions  A strong correlation was observed between the pharmacokinetics (AUCMTX at the steady state) and antipsoriatic effect (PASI‐score) of LDMTX. The considerable interindividual variability and low intraindividual variability in MTX pharmacokinetics support a role for therapeutic monitoring and dose individualization at the start of pharmacotherapy. The results of this study suggest that a steady state AUCMTX values of 700 nmol l−1h and higher are associated with a significantly better success rate of antipsoriatic therapy than lower values.
Interaction between saquinavir soft‐gel and rifabutin in patients infected with HIV
Authors: Moyle G. J. , Buss N. E. , Goggin T. , Snell P. , Higgs C. , Hawkins D. A.
Published: March 2003

Aims  To evaluate the potential pharmacokinetic interaction between the HIV protease inhibitor saquinavir and rifabutin.

Methods  Fourteen HIV‐infected patients provided full steady‐state pharmacokinetic profiles following administration of rifabutin alone (300 mg once daily) or saquinavir soft‐gel formulation (1200 mg three times daily) plus rifabutin (300 mg once daily) in this open label, partially randomized study.

Results  Coadministration of saquinavir and rifabutin resulted in a reduction in saquinavir AUC(0,8 h) and Cmax(0,8 h) of 47% (95% CI 30, 60%) and 39% (95% CI 11, 59%), respectively. Rifabutin AUC(0,24 h) and Cmax(0,24 h) was increased by an average of 44% (95% CI 17, 78%) and 45% (95% CI 14, 85%), respectively. Saquinavir in combination with rifabutin was well tolerated. Gastrointestinal intolerance and asymptomatic increases in liver enzymes were the only adverse events of note.

Conclusions  Administration of rifabutin with saquinavir may decrease the efficacy of this HIV protease inhibitor.
Enantioselective distribution of albendazole metabolites in cerebrospinal fluid of patients with neurocysticercosis
Authors: Takayanagui O. M. , Bonato P. S. , Dreossi S. A. C. , Lanchote V. L.
Published: March 2003

Aims Albendazole (ABZ) is effective in the treatment of neurocysticercosis. ABZ undergoes extensive metabolism to (+) and (−)‐albendazole sulphoxide (ASOX), which are further metabolized to albendazole sulphone (ASON). We have investigated the distribution of (+)‐ASOX (−)‐ASOX, and ASON in cerebrospinal fluid (CSF) of patients with neurocysticercosis.

Methods Twelve patients with a diagnosis of active brain parenchymal neurocysticercosis treated with albendazole for 8 days (15 mg kg−1 day−1) were investigated. On day 8, serial blood samples were collected during the dose interval (0–12 h) and one CSF sample was taken from each patient by lumbar puncture at different time points up to 12 h after the last albendazole dose. Albendazole metabolites were determined in CSF and plasma samples by h.p.l.c. using a Chiralpak AD column and fluorescence detection. Population curves for CSF albendazole metabolite concentrationvstime were constructed.

Results The mean plasma/CSF ratios were 2.6 (95% CI: 1.9, 3.3) for (+)‐ASOX and 2.7 (95% CI: 1.8, 3.7) for (−)‐ASOX, with the two‐tailedP value of 0.9873 being non‐significant. These data indicate that the transport of ASOX through the blood–brain barrier is not enantioselective, but rather depends on passive diffusion. The present results suggest the accumulation of the (+)‐ASOX metabolite in the CSF of patients with neurocysticercosis. The CSF AUC(+)/AUC(−)ratio was 3.4 for patients receiving albendazole every 12 h. The elimination half‐life of both ASOX enantiomers in CSF was 2.5 h. ASOX was the predominant metabolite in the CSF compared with ASON; the CSF AUCASOX/AUCASONratio was approximately 20 and the elimination half‐life of ASON in CSF was 2.6 h.

Conclusions We have demonstrated accumulation of the (+)‐ASOX metabolite in CSF, which was about three times greater than the (−) antipode. ASOX concentrations were approximately 20 times higher than those observed for the ASON metabolite.
Use of nonsteroidal anti‐inflammatory drugs and the risk of first‐time acute myocardial infarction
Authors: Schlienger Raymond G. , Jick Hershel , Meier Christoph R.
Published: March 2003

Aims
Aspirin decreases the risk of clinical manifestations of atherothrombosis. This effect is mainly due to inhibition of platelet aggregation and potentially due to anti‐inflammatory properties of aspirin. To evaluate whether use of non‐aspirin non‐steroidal anti‐inflammatory drugs (NSAIDs) may also be associated with a decreased risk of first‐time acute myocardial infarction (AMI), we performed a population‐based case‐control analysis using the United Kingdom‐based General Practice Research Database (GPRD)

Methods
We identified first‐time AMI‐patients free of preexisting diagnosed cardiovascular or metabolic diseases. We compared use of NSAIDs prior to the index date between cases and control patients who were matched to cases on age, gender, practice and calendar time.

Results
A total of 3319 cases (≤75 years) with a diagnosis of first‐time AMI between 1992 and 1997 and 13139 controls (matched to cases on age, sex, general practice attended, calendar time, years of prior history in the GPRD) were included. Overall, the relative risk estimate of AMI (adjusted for smoking, body mass index, hormone replacement therapy and aspirin) in current NSAID users was 1.17 (95% CI 0.99, 1.37). Long‐term current NSAID use (≥30 prescriptions) yielded an adjusted odds ratio (OR) of 1.20 (95% CI 0.94, 1.55). Stratification by age (<65 years vs≥65 years) and sex did not materially change the results.

Conclusions
Our findings indicate that current NSAID exposure in patients free of diagnosed cardiovascular or metabolic conditions predisposing to cardiovascular diseases does not decrease the risk of AMI.
Direct in vivo evidence of a vascular statin: a single dose of cerivastatin rapidly increases vascular endothelial responsiveness in healthy normocholesterolaemic subjects
Authors: Omori Hisako , Nagashima Hirotaka , Tsurumi Yukio , Takagi Atsushi , Ishizuka Naoko , Hagiwara Nobuhisa , Kawana Masatoshi , Kasanuki Hiroshi
Published: March 2003

Aims
HMG‐CoA reductase inhibitors (statins) have been demonstrated to have in vitro vascular effects. The aim of this study was to determine whether statins actually have in vivo vascular effects independent of their cholesterol‐lowering effect.

Methods
We investigated the effect of a single dose of cerivastatin on vascular endothelial function by measuring flow‐mediated dilatation of the brachial artery on ultrasound in 30 healthy volunteers with normal serum cholesterol concentrations. They were randomized to either placebo group (n = 15) or cerivastatin group (n = 15), and flow‐mediated dilatation and endothelium‐dependent dilatation were evaluated at before and 1 h, 3 h, 6 h, and 12 h after administration of placebo or cerivastatin.

Results
There were no differences in total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, malondialdehyde‐LDL, and high‐sensitivity C‐reactive protein before and after administration of placebo or cerivastatin. Cerivastatin significantly increased flow‐mediated dilatation at 3 h (P < 0.001), and this increase rapidly returned to the baseline level 6 h after administration. Endothelium‐­independent dilatation of brachial artery was not altered.

Conclusions
A single dose of cerivastatin increased vascular endothelial responsiveness. Our data suggest that cerivastatin has a direct effect on the blood vessels that is independent of its lipid‐lowering effect, and thus can be considered as a vascular statin.
Inducibility of CYP1A2 by omeprazole in vivo related to the genetic polymorphism of CYP1A2
Authors: Han Xing‐Mei , Ouyang Dong‐Sheng , Chen Xiao‐Ping , Shu Yan , Jiang Chang‐Hong , Tan Zhi‐Rong , Zhou Hong‐Hao
Published: March 2003

Aims  To evaluate the effect of the CYP1A2*1C and CYP1A2*1F polymorphisms on the inducibility of CYP1A2 by omeprazole in healthy subjects.

Methods  Mutations of CYP2C19 and CYP1A2 were identified by PCR‐RFLP. Omeprazole, 120 mg day−1, was given to 12 extensive metabolizers (EM) with respect to CYP2C19 (six CYP1A2*1F/CYP1A2*1F and six CYP1A2*1C/CYP1A2*1F of CYP1A2) for 7 days. CYP1A2 activity was determined on three occasions, namely on day 1, day 9 and day 16 using the caffeine plasma index (the ratio of the concentrations of paraxanthine to caffeine), 6 h after oral administration of 200 mg caffeine.

Results  There was a significant difference (P = 0.002) between the caffeine ratios for CYP1A2*1F/CYP1A2*1F and CYP1A2*1C/CYP1A2*1F genotypes on day 9, but not on day 1 or day 16 (P > 0.05). The changes in the ratios from day 9 to day 1 (48% ± 20%vs 19% ± 20%) and from day 9 to day 16 (50% ± 31%vs 15% ± 22%) were significantly different (P < 0.05) between the CYP1A2*1F/CYP1A2*1F and CYP1A2*1C/CYP1A2*1F genotypes.

Conclusion  The CYP1A2*1C and CYP1A2*1F genetic polymorphisms influenced the induction of CYP1A2 activity in vivo by omeprazole.
Population pharmacokinetics and pharmacokinetic‐pharmacodynamic relationships of the novel anticancer agent E7070 in four phase I studies
Authors: Van Kesteren CH. , Mathôt R. A. A. , Raymond E. , Armand J. P. , Dittrich CH. , Dumez H. , Roché H. , Droz J. P. , Punt C. , Ravic M. , Wanders J. , Beijnen J. H. , Fumoleau P. , Schellens J. H. M.
Published: March 2003

E7070 is a novel chloroindolyl sulphonamide being developed as an anti‐cancer agent for the treatment of solid tumours. E7070 arrests cell cycle progression in the G1 phase and induces apoptosis. In various in vitro and in vivo models, E7070 appeared to be highly active. Four phase I dose‐escalation studies have been conducted to identify the dose‐limiting toxicities (DLTs) and the maximum tolerated dose. Adult patients with advanced solid tumours resistant or not amenable to conventional therapy received E7070 at four different treatment schedules: 1) 1 h i.v. infusion (doses 50–1000 mg m−2), 2) daily times five 1 h i.v. infusion (d×5) (10–200 mg m−2 day−1), 3) weekly times four 1 h infusion (40–500 mg m−2 week−1), 4) 120 h continuous i.v. infusion (civ) (6–200 mg m−2 day−1). DLTs were haematological in all studies. Pharmacokinetic (PK) sampling was performed in 143 patients (corresponding numbers of patients were 40, 35, 43 and 25) during the first cycle. In this study we investigated the PK and its relationship with the pharmacodynamics for all studies. A population PK model was developed to describe the combined data of the four studies. E7070 showed non‐linear PK at higher dose levels. Therefore, a basic 3‐compartmental model was extended with saturable transport to one of the peripheral compartments and parallel linear and a non‐linear pathways of elimination from the central compartment. The model adequately described the data. A validation using a bootstrap procedure indicated that the model was robust. Total clearance (CL) of E7070 was highly dependent on the plasma concentration; shortly after infusion, at the higher concentrations (i.e. 10–200 mg l−1), CL was 0.5 l h−1 and gradually increased to 5.5 l h−1 at the lower concentrations (0.1–0.01 mg l−1). For each individual, Bayesian estimates of AUC (area under the plasma concentration time curve) were obtained using the PK model. The percentage decreases in neutrophils (ANC) and thrombocytes (THR) were plotted against dose, dose level and AUC for each study. In general, AUC was a better predictor for haematological toxicity than dose and dose level, as variability was reduced when related to AUC. The relationship between % decrease in ANC and THR and AUC could be described using a maximum effect (Emax) model. A maximum % decrease in ANC and THR of approximately 95% was reached with all four schedules.

In conclusion, the non‐linear PK of E7070 in all treatment schedules was adequately described using the population PK model. The dose‐limiting, haematological toxicity of E7070 is related to the total exposure, expressed as AUC.
Rectal ropivacaine is absorbed proportionally to the dose, with low intraindividual variability
Authors: Arlander Eva , Sjövall Jan , Sörstad Jörgen , Norsten‐Höög Carina , Gustafsson Lars L.
Published: March 2003

Aims  This study investigated the absorption characteristics and the tolerability of rectally administered ropivacaine, a local anaesthetic, intended as a new local therapy for ulcerative colitis.

Methods  Thirty‐two healthy volunteers participated in a randomized, placebo‐controlled study. In study phase 1 (n = 16, double‐blind, crossover) single rectal doses of ropivacaine corresponding to 50, 100 and 200 mg base were given as 20‐ml gel enemas. Eight of these subjects also received an i.v. infusion corresponding to 20 mg (2H3)ropivacaine base given with the last rectal dose. In study phase 2 (n = 16, single‐blind, crossover) the same rectal doses were given but formulated in 20, 40 and 80 ml gel, respectively. Peripheral venous plasma samples and urine were collected over 12 h after dosing and analysed for ropivacaine base by gas chromatography and (2H3)ropivacaine by gas chromatography‐mass spectrometry. Ropivacaine and metabolites were analysed in urine by reversed phase liquid chromatography.

Results  AUC was proportional to the dose with a point estimate [95% confidence interval (CI)] for the increase, after doubling the dose, of 1.91 (1.66–2.20) and 1.95 (1.78–2.13) in study phases 1 and 2, respectively. The increase in Cmax was also proportional to the dose with corresponding results of 1.76 (1.52–2.04) and 1.84 (1.70–1.99). The volume of the rectal formulation had no influence on either the extent or the time course of absorption. The mean (s.d.) absolute bioavailability (%F) was 56 (18)%. AUC and Cmax showed a two‐ to three‐fold lower intra‐ than interindividual variability. Zero‐order kinetics dominated the first 4 h of the absorption phase. Thereafter first‐order kinetics were observed. The terminal half‐lives were similar between the rectal doses and were longer than that after the i.v. administration, indicating an absorption‐dependent half‐life. The main urinary metabolite was 3‐hydroxyropivacaine corresponding to about 23% of the dose. The subjects had no difficulties in retaining the doses and rectal administration of ropivacaine was well tolerated, both locally and systemically.

Conclusions  Plasma drug concentrations were proportional to the dose after rectally administered doses corresponding to 50–200 mg ropivacaine base in a gel formulation. The drug was well‐tolerated. Mean bioavailability was about 60% and not influenced by variations in the enema volume. Initial absorption seemed to follow zero‐order kinetics and then first‐order kinetics after about 4 h. Cmax and AUC showed considerably less intra‐ compared with inter‐individual variability, resulting in more consistent plasma concentrations within subjects.
Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients
Authors: Bauer Steffen , Störmer Elke , Johne Andreas , Krüger Hagen , Budde Klemens , Neumayer Hans‐Hellmut , Roots Ivar , Mai Ingrid
Published: March 2003

Aim This study investigated the effects of St John's wort extract (SJW) on the pharmacokinetics and metabolism of the immunosuppressant cyclosporin A (CSA).

Methods In an open‐label study, 11 renal transplant patients received 600 mg SJW extract daily for 14 days in addition to their regular regimen of CSA. Blood concentrations of CSA and its metabolites AM1, AM1C, AM9, AM19, and AM4N were measured by HPLC.

Results After 2 weeks of SJW coadministration, dose‐corrected AUC0−12, Cmax and Ctrough values for CSA decreased significantly by 46%[geometric mean ratio baseline/SJW (95% CI): 1.83 (1.63–2.05)], 42%[1.72 (1.42–2.08)], and 41%[1.70 (1.17–2.47)], respectively. CSA doses were increased from a median of 2.7 mg day−1 kg−1 at baseline to 4.2 mg day−1 kg−1 at day 15, with the first dose adjustment required only 3 days after initiation of SJW treatment. Additionally, the metabolite pattern of CSA was substantially altered during SJW treatment. Whereas dose‐corrected AUC values for AM1, AM1c and AM4N significantly decreased by 59%, 61%, and 23% compared with baseline, AUC values for AM9 and AM19 were unchanged. Following the increase in CSA dose, observed AUC and Cmax values for AM9, AM19, and AM4N increased by 20–51% and 43–90%, respectively.

Conclusion Administration of SJW extract to patients receiving CSA treatment resulted in a rapid and significant reduction of plasma CSA concentrations. Additionally, the substantial alterations in CSA metabolite kinetics observed may affect the toxicity profile of the drug.