bluuebunny/crossref_metadata_2025 huggingface dataset:
The cigar as a drug delivery device: youth use of blunts
Authors: Soldz Stephen , Huyser Dana Joy , Dorsey Elizabeth
Published: October 2003

Aims  Blunts are hollowed‐out cigars used to smoke marijuana (and perhaps other substances) in the United States. We investigated rates of blunt use; whether cigar use reported in surveys may actually be blunt use; the relationship of blunt to cigar use; characteristics of blunt users; brands of cigars used to make blunts; and drugs added to blunts.

Design  A school‐based survey of youth, the Cigar Use Reasons Evaluation (CURE).

Setting  Eleven schools across Massachusetts.

Participants  A total of 5016 students in grades 7–12.

Measurements  CURE items assessing blunt, cigar and cigarette use, brands used to make blunts, drugs added to blunts and demographics were used.

Findings  Life‐time blunt use was reported by 20.0% of the sample, with use greater among high school (25.6%) than middle school (11.4%) students, and among males (23.7%) than females (16.6%). Self‐reported cigar use rates were not influenced strongly by blunt use being misreported as cigar use. In a multivariate model, blunt use was associated with male gender, higher grade in school, lower GPA, truancy, lower school attachment, not living in a two‐parent family, being of ‘other’ race/ethnicity and current use of both cigarettes and cigars. ‘Phillies’ was the most popular brand of cigar for making blunts, used by 59.$% of users. ‘Garcia y Vega’ (18.0%) was the second most popular. Twenty‐eight per cent of blunt users had added drugs other than marijuana to blunts.

Conclusions  The use of blunts as a drug delivery device is a serious problem. Efforts to address it will require the cooperation of the tobacco control and substance abuse prevention systems.
Longitudinal study on the prevalence of benzodiazepine (mis)use in a prison: importance of the analytical strategy
Authors: Borrey D. , Meyer E. , Duchateau L. , Lambert W. , Van Peteghem C. , Leenheer A. P. De
Published: October 2003

Aims  This study evaluates the suitability of gas chromatographic‐mass spectrometric (GC‐MS) analysis to follow‐up the extent of benzodiazepine (mis)use in a Belgian prison population and compares it to other analytical strategies (e.g. screening followed by confirmation of the positive samples).

Design and participants  From February to August 1998, 598 persons were jailed of which 188 (31.4% of the incoming detainees) volunteered to be screened. Urine samples (530 in total) were collected on the day of arrival and after 14, 30 and 90 days of imprisonment.

Measurements  All samples were screened by EMIT® for benzodiazepines and analysed subsequently by GC‐MS.

Findings  EMIT® screening yielded 117 (22.1%) positive samples, a number which increased to 174 (32.8%) after GC‐MS analysis. Of these 174 GC‐MS positive samples, 119 (68.4%) contained one benzodiazepine while for the remaining samples multiple benzodiazepine (mis)use could be demonstrated. A significant increase in benzodiazepine (mis)use was indicated only from day 0 to day 14 based on the GC‐MS results but not on the immunoassay results, even when the latter were complemented with GC‐MS analysis of the positively screened samples. The GC‐MS data also demonstrated that benzodiazepines are mainly (mis)used by subjects on benzodiazepine prescription as almost 50% of these subjects took additional non‐prescribed benzodiazepines. During GC‐MS analysis other drugs were co‐extracted unintentionally and chromatographed and 23.9% of the volunteers were positive for illegal drugs on the day of arrival.

Conclusion  Immunoassay results yield an underestimation of the problem of benzodiazepine (mis)use in prison due to the high false negative rate. GC‐MS analysis of all samples therefore is the recommended strategy for this type of longitudinal study as it yields more correct and detailed information than the immunoassay results.
Proguanil metabolism in relation to S‐mephenytoin oxidation in a Turkish population
Authors: BASCI N. E. , BOZKURT A. , KORTUNAY S. , ISIMER A. , SAYAL A. , KAYAALP S. O.
Published: October 2003

The oxidation of proguanil was studied in 89 unrelated healthy Turkish volunteers after administration of proguanil (single dose, 200 mg, orally). Based on the distribution of the ratio of proguanil to cycloguanil excreted in urine, and using an antimode value of 15, the prevalence of poor metabolizers in a Turkish population was estimated to be 5.6% (95% confidence interval 2.0%–17.3%) which was similar to that in the other Caucasian populations. The relationship between the oxidative capacities of CYP2C19 for the two substrates, proguanil and mephenytoin, was studied in 39 subjects (two poor and 37 extensive metabolizers of proguanil). The two poor metabolizers of proguanil were also identified as poor metabolizers of S‐mephenytoin and no misclassification by the two phenotyping methods was observed. The correlation between the metabolic ratio of proguanil to cycloguanil and the S/R‐mephenytoin ratio as assessed by Spearman's rank test, was statistically significant (rs=0.50, P<0.001).
Effects of picotamide, an antiplatelet agent, on cardiovascular events in 438 claudicant patients with diabetes: a retrospective analysis of the ADEP study
Authors: MILANI MASSIMO , LONGONI ALDO , MADERNA MICHELA
Published: October 2003

Picotamide is an antiplatelet drug which inhibits thromboxane A2 (TxA2) synthase and antagonizes TxA2 receptors. In the ADEP (Atherosclerotic Disease Evolution by Picotamide) trial, 2304 patients with peripheral obstructive arterial disease (POAD) were studied in a double‐blind, placebo‐controlled, 18‐month, multicentre trial. In this study, 151 events (13.1%) occurred on placebo and 122 (10.6%) on picotamide (900 mg day−1). The relative risk reduction was 19%, (P=0.056). This paper reports a post‐hoc analysis in a subgroup of 438 diabetic patients (picotamide=230; placebo=208). There were 32 vascular events on placebo (15%) and 18 on picotamide (8%) (relative risk reduction: 48%; 95% CI=26, 76; P=0.022). The results of this retrospective analysis suggest that a prospective study to investigate events in claudicant patients with diabetes mellitus is warranted.
Clinical drug monitoring by microdialysis: application to levodopa therapy in Parkinson's disease
Authors: O'CONNELL MARK T. , TISON FRANÇOIS , QUINN NIALL P. , PATSALOS PHILIP N.
Published: October 2003

1We describe the first application of microdialysis to monitor the pharmacokinetics of a drug in the blood of man.

2The aims of the study were to ascertain patient acceptability and tolerability of a new microdialysis probe and to assess its accuracy in determining the pharmacokinetics of levodopa and its principal plasma metabolite 3‐O‐methyldopa (3‐OMD).

3Eight patients with parkinsonism on chronic levodopa therapy were investigated.

4After an overnight fast, a flexible microdialysis probe, perfused with isotonic saline, was inserted into a forearm vein and a blood sampling cannula was inserted in a forearm vein of the other arm. After ingestion of a levodopa preparation (Madopar Dispersible}}rm), dialysate was collected over 5 or 10 min periods and blood samples were taken every 15 or 30 min for 2–6 h.

5Dialysate drug profiles were similar to those of plasma, and levodopa and 3‐OMD concentrations exhibited significant (P<0.001) correlation with those observed in the corresponding plasma samples.

6The mean (±s.d.) blood dialysate concentrations for levodopa and 3‐OMD were 36.1±9.2% and 43.4±8.4% respectively of the plasma content.

7The tolerability of the probe was excellent, and all eight patients found it preferable to conventional blood sampling.

8Microdialysis of blood is less invasive than frequent intermittent direct blood sampling, and can readily be used to continuously monitor levodopa pharmacokinetics. In a clinical setting, a combination of drug monitoring by this technique together with clinical evaluation of motor function can be used to optimize levodopa treatment in patients with Parkinson's disease.
A comparison of ciprofloxacin, norfloxacin, ofloxacin, azithromycin and cefixime examined by observational cohort studies
Authors: WILTON L. V. , PEARCE G. L. , MANN R. D.
Published: October 2003

1 The safety in everyday clinical usage of three 4‐quinolone antibiotics, (ciprofloxacin, norfloxacin and ofloxacin), was compared with similar data for azithromycin and cefixime, each agent being examined by Prescription‐Event Monitoring (PEM) during the early post‐marketing period.

2 In PEM the exposure data are derived from general practitioner prescriptions confidentially provided by the Prescription Pricing Authority. Outcome data are provided by questionnaires (green forms) on which the prescribing medical practitioner records event data. When necessary, further information is obtained from a number of sources which include follow‐up of all pregnancies and the patients' life‐time medical record.

3 The main outcome measures were demographic information, including the patient's date of birth and sex; the indication for prescribing the drug being monitored; the reason for stopping treatment; the start and stop dates of treatment and the events recorded during and after treatment.

4 The final cohort for each of the five antibiotics exceeded 11000 patients. The only event significantly related to the use of all five antibiotics was nausea/vomiting. This was also the most frequent adverse event causing treatment to be discontinued with norfloxacin, ofloxacin and azithromycin (relevant information was not requested in the studies of ciprofloxacin and cefixime). Vaginal candidiasis was significantly more frequently associated with the use of the three 4‐quinolones than with azithromycin and cefixime but it was frequently delayed until the week or two after the cessation of therapy. Within each event, as recorded in these studies, the highest event rates (the number of events per 1000 patients) in the week following the start of therapy were: 9.2 for diarrhoea with cefixime; 4.9 for nausea/vomiting with ofloxacin; 2.4 for rash with azithromycin; 2.2 for abdominal pain with norfloxacin; 1.5 for headache/migraine with ofloxacin; 1.4 for malaise/lassitude with ofloxacin; 1.2 for dizziness with norfloxacin. Uncommon events (reported in less than 1:1000 patients) included rare cases of allergic phenomena, convulsions and pseudomembranous colitis. There were no reports of tendinitis, tenosynovitis or tendon rupture in children but tendon disorders were reported in the two months following the start of treatment in 20 adults. A total of 307 pregnancies were reported. Thirty‐eight of the 55 women who received these drugs during the first trimester of pregnancy gave birth to healthy babies. No congenital abnormalities were reported. Apart from one case of unconfirmed pseudomembranous colitis, none of the other 2468 deaths that occurred in these studies was attributed to the antibiotics.

5 These five antibiotics are acceptably safe antimicrobial agents when used in general medical practice. PEM is an effective method for monitoring the safety of recently introduced antimicrobial agents.
The influence of the sparteine/debrisoquine genetic polymorphism on the disposition of dexfenfluramine
Authors: GROSS A. S. , PHILLIPS A. C. , RIEUTORD A. , SHENFIELD G. M.
Published: October 2003

1 To determine whether dexfenfluramine is a substrate of cytochrome P450 2D6 (CYP2D6), its disposition has been studied in nine extensive (EM) and eight poor metabolizers (PM) of debrisoquine.

2 Following a 30 mg dose of dexfenfluramine hydrochloride, urine was collected in all subjects for 96 h post‐dose and plasma samples were collected in 11 subjects (six EMs and five PMs). Dexfenfluramine and nordexfenfluramine were measured in urine by h.p.l.c. and in plasma by g.c.

3 Urinary recovery of dexfenfluramine was greater in PMs than EMs (4136±1509 μg vs 1986±792 μg; 95% CI of difference 926–3374; P<0.05) whereas that of nordexfenfluramine was similar in both phenotypes (PM: 1753±411 μg vs 1626±444 μg).

4 Dexfenfluramine AUC was higher in PMs (677±348 μg l−1 h) than EMs (359±250 μg l−1 h). The apparent oral clearance of dexfenfluramine was greater in EMs than PMs (93.6±42.4 l h−1vs 45.6±19.5 l h−1; 95% CI of difference 1.2–94.7; P<0.05). The renal clearance was similar in both phenotypes (EMs: 5.88±2.83 l h−1; PMs 6.60±2.01 l h−1), indicating that the higher urinary recovery of dexfenfluramine in PMs reflects higher plasma concentrations, rather than phenotype differences in the renal handling, of dexfenfluramine.

5 The apparent nonrenal clearance of dexfenfluramine was substantially lower (P<0.05; 95% CI of difference 3.0–94.1) in PMs (39.0±19.5 l h−1) than EMs (87.6±41.2 l h−1).

6 There was a significant inverse correlation (rs=−0.776 95% CI −0.31–−0.94; n=11; P=0.005) between the debrisoquine metabolic ratio and the apparent nonrenal clearance of dexfenfluramine.

7 PMs had a higher incidence of adverse effects (nausea and vomiting) than EMs.

8 In conclusion, the metabolism of dexfenfluramine is impaired in PMs. Thus CYP2D6, the isoenzyme deficient in poor metabolizers of debrisoquine, must catalyse at least one pathway of dexfenfluramine biotransformation.
Pre‐ and afterload reduction in chronic mitral regurgitation: a double‐blind randomized placebo‐controlled trial of the acute and 2 weeks' effect of nifedipine or isosorbide dinitrate treatment on left ventricular function and the severity of mitral regurgitation
Authors: KELBÆK HENNING , ALDERSHVILE JAN , SKAGEN KNUD , HILDEBRANDT PER , NIELSEN STEEN L.
Published: October 2003

1The acute effect and effect of 14 days' treatment with isosorbide dinitrate (ISDN) and nifedipine (NIF) was evaluated by radionuclide cardiography in patients with chronic mitral regurgitation and sinus rhythm.

2In 23 patients with clinically stable disease blood pressure was lowered by 15% and left ventricular volume was reduced by 16–20% after 20 mg sublingual ISDN causing combined pre‐and afterload reduction. Afterload reduction alone induced by 10 mg NIF resulted in an acute 9% decrease in left ventricular endsystolic volume, whereas forward stroke volume increased by 30%, and regurgitation fraction tended to decrease. No haemodynamic effects could be detected after 14 days' treatment with 20 mg ISDN orally twice daily (preload reduction), whereas 20 mg NIF twice daily (afterload reduction) caused an increase in forward stroke volume (18%) and a decrease in both regurgitant volume (20%) and regurgitation fraction (22%) without affecting blood pressure or heart rate.

3ISDN and NIF have beneficial acute haemodynamic effects in patients with chronic mitral regurgitation probably due to their pre‐ and afterload reducing properties. The reduction in regurgitation induced by NIF appears to be sustained after 14 days therapy.
Morphine, morphine‐6‐glucuronide and morphine‐3‐glucuronide pharmacokinetics in newborn infants receiving diamorphine infusions
Authors: BARRETT D. A. , BARKER D. P. , RUTTER N. , PAWULA M. , SHAW P. N.
Published: October 2003

1The pharmacokinetics of morphine, morphine‐6‐glucuronide (M6G) and morphine‐3‐glucuronide (M3G) were studied in 19 ventilated newborn infants(24–41 weeks gestation) who were given a loading dose of 50 μg kg−1 or 200 μg kg−1 of diamorphine followed by an intravenous infusion of 15 μg kg−1 h−1 of diamorphine. Plasma concentrations of morphine, M3G and M6G were measured during the accrual to steady‐state and at steady state of the diamorphine infusion.

2Following both the 50 μg kg−1 or 200 μg kg−1 loading doses the mean steady‐state plasma concentration (±s.d.) of morphine, M3G and M6G were 86±52 ng ml−1, 703±400 ng ml−1 and 48±28 ng ml−1 respectively and morphine clearance was found to be 4.6±3.2 ml min−1 kg−1.

3M3G formation clearance was estimated to be 2.5±1.8 ml min−1 kg−1, and the formation clearance of M6G was estimated to be 0.46±0.32 ml min−1 kg−1.

4M3G metabolite clearance was 0.46±0.60 ml min−1 kg−1, the elimination half‐life was 11.1±11.3 h and the volume of distribution was 0.55±1.13 l kg−1. M6G metabolite clearance was 0.71±0.36 ml min−1 kg−1, the elimination half‐life was 18.2±13.6 h and the volume of distribution was 1.03±0.88 l kg−1.

5No significant effect of the loading dose (50 μg kg−1 or 200 μg kg−1) on the plasma morphine or metabolite concentrations or their derived pharmacokinetic parameters was found.

6We were unable to identify correlations between gestational age of the infants and any of the determined pharmacokinetic parameters.

7M3G:morphine and M6G:morphine steady‐state plasma concentration ratios were 11.0±10.8 and 0.8±0.8, respectively.

8The metabolism of morphine in neonates, in terms of the respective contributions of each glucuronide pathway, was similar to that in adults.
Disposition of diazepam in young and elderly subjects after acute and chronic dosing
Authors: HERMAN ROBERT J. , WILKINSON GRANT R.
Published: October 2003

1The pharmacokinetics of diazepam were examined in seven young (20–30 years) and six elderly (60–75 years) males prior to and also after chronic oral dosing of diazepam.

2Following intravenous administration, the half‐life and volume of distribution of 14C‐labelled diazepam in the elderly were approximately twofold greater than corresponding estimates in younger subjects (mean ±s.d., 71.5±27.6 vs 44.5±16.5 h and 1.39±0.32 vs 0.88±0.30 1 kg−1, respectively). Clearance did not differ between the two groups (0.26±0.09 vs 0.29±0.09 ml min−1 kg−1).

3The accumulation of diazepam and its major metabolite, desmethyldiazepam, were extensive during chronic administration. A radioreceptor assay that measured total benzodiazepine activity, including diazepam and its active metabolites, indicated that the accumulation of ‘benzodiazepine equivalents’ was similar to the sum of the accumulated diazepam and desmethyldiazepam concentration levels. However, the level of ‘benzodiazepine equivalents’ on multiple‐dosing was about double that of the predicted steady‐state ‘equivalent’ concentration from single‐dose studies. This was due to the insensitivity of the radioreceptor assay for desmethyldiazepam following single‐dose diazepam administration.

4There were no age‐ or dosing‐related differences in diazepam clearance (0.37±0.22 vs 0.32±0.18 ml min−1 kg−1, young vs elderly, single‐dose; 0.37± 0.11 vs 0.27±0.12 ml min−1 kg−1, young vs elderly, multiple‐dose) and no age‐related differences in the levels of accumulated ‘benzodiazepine equivalents’ (243.7±60.1 vs 288.0±125.8 ng ml−1, young vs elderly).

5Thus, changes that occur in diazepam disposition with ageing after acute administration do not appear to be important during chronic dosing. On the other hand, accumulation of diazepam and desmethyldiazepam are considerable and would be expected to be clinically relevant.
A clinical pharmacologist's view of drug toxicity
Authors: BRECKENRIDGE ALASDAIR
Published: October 2003

1Our ability to understand the basis of adverse drug reactions has improved progressively, and with it, the ability to prevent their occurrence; one aim of the clinical pharmacologist is to identify patients at special risk.

2Four examples of clinical drug toxicity which illustrate how the subject has advanced over the past 20 years are described. These illustrate how a combination of clinical and laboratory medicine can be used to help our understanding of the basis of adverse drug reactions. With a fair degree of certainty one can also predict that advances in bioinformatics, genomics and combinatorial chemistry will progressively contribute to clinical toxicology in the future.
The clinical pharmacologist in drug regulation: a European perspective
Authors: RAWLINS MICHAEL D.
Published: October 2003

1The clinical pharmacologist in drug regulation has many roles to play. These include responsibilities for the premarketing assessment of a new product's efficacy and safety, for scrutiny of the summary of Product Characteristics, and for monitoring its performance after marketing. Furthermore, the clinical pharmacologist has a subsidiary responsibility in examining the results of preclinical pharmacological and toxicological studies.

2Clinical pharmacologists in regulatory authorities have one further, and crucial, responsibility—humility. From their training and experience they will (or should) know of their own scientific limitations and of the necessity for seeking help and advice from other disciplines.
New therapeutic agents for hypertension
Authors: REID JOHN L.
Published: October 2003

1Over the last 40 years a range of therapeutic strategies has been introduced for the long term treatment of hypertension.

2Although safe effective agents are available a significant number of patients are unable or unwilling to take these drugs as long term treatment.

3Both insufficient efficacy and adverse effects justify the search for new antihypertensive strategies.

4Recent developments include orally active angiotensin (AT1) receptor antagonists (ARA) which appear to offer the benefits of prevention of angiotensin II effects without the adverse effects of bradykinin potentiation, such as cough, which limit the usefulness of angiotensin converting enzyme (ACE) inhibitors.

5Imidazoline receptor agonists offer the potential of centrally active antihypertensives without the adverse effects of sedation and dry mouth. Further clinical experience is necessary to confirm whether the clinical efficacy and good tolerability are confirmed with long term use.

6Both ARA and imidazoline preferring substances offer the bonus of a desirable haemodynamic profile in patients with heart failure and may open new therapeutic avenues in the management of cardiac failure.
The influence of renal function on the pharmacokinetics of unchanged and acyl‐glucuroconjugated ketoprofen enantiomers after 50 and 100 mg racemic ketoprofen
Authors: SKEITH K.J. , DASGUPTA M. , LANGE R. , JAMALI F.
Published: October 2003

1To study the effect of renal dysfunction on the pharmacokinetics of ketoprofen (KT), and the possibility of saturation of clearance with elevation of dose, single 50 and 100 mg doses of racemic ketoprofen were administered in a cross‐over fashion to seven patients (creatinine clearance, CLCR, 6–72 ml min−1).

2The stereospecific disposition kinetics of KT enantiomers and their acyl‐glucuronide conjugates (KTconj ) were determined in plasma and urine for 24 h post‐dose.

3Decreased renal function was associated with a reduced KT oral clearance (CLO) and terminal elimination rate constant (λz). Renal clearance of KTconj (CLrconj) was reduced with diminished renal function.

4Following both 50 and 100 mg doses, there was significant stereoselectivity in the AUC of KT (mean S/R, 0.87 and 0.83, respectively), the AUC of KTconj (mean S/R, 3.4 and 5.2, respectively) and the cumulative urinary excretion of KTconj (mean S/R, 2.1 and 2.2, respectively). The stereoselectivity in renal dysfunction in contrast with the observations previously made in healthy subjects may suggest a disease‐related process.

5CLO remained constant after increasing the dose, indicating linearity in the pharmacokinetics of KT despite reduced CLCR. CLrconj, however, was significantly reduced after the 100 mg dose suggestive of saturation of the urinary clearance and existence of a compensatory pathway.

6Renal impairment reduces CLrconj and this appears to be the rate‐limiting step for clearance of KT due to the observed stronger correlations of CLO with CLrconj than with CLCR.

7Dose reduction of ketoprofen is indicated only for patients with CLCR< 20 ml min−1.
A prospective study of adverse drug reactions as a cause of admission to a paediatric hospital
Authors: MARTÍNEZ‐MIR I. , GARCÍA‐LÓPEZ M. , PALOP V. , FERRER J. M. , ESTAÑ L. , RUBIO E. , MORALES‐OLIVAS F. J.
Published: October 2003

1A total of 512 consecutive paediatric hospital admissions of children 2 years old or less were evaluated to assess the extent and pattern of admission caused by suspected adverse drug reactions (ADRs). The proportion of suspected ADRs related to hospital admissions was 4.3%.

2The organ‐systems most commonly implicated were the central nervous system (40.5%), digestive system (16.7%), and skin and appendages (14.3%). Together, they accounted for 71.5% of admissions attributed to ADRs. The most common clinical manifestations inducing admission were convulsions (4 cases), dizziness (4), vomiting (3), and tremor, fever, itching and apnoea (2 cases each).

3The four classes of drugs most frequently suspected in admissions due to ADRs were respiratory drugs (35%), anti‐infective agents (25%), drugs active on the central nervous system (15%) and drugs used in dermatology (10%). The most common drugs related to ADRs were a combination of chlorpheniramine, diphenhydramine, phenylephrine, guaiphenesin and salicylic acid (4 cases), followed by fenoterol, adrenaline, paracetamol, DTP vaccine and antipolio vaccine (2 cases each).

4There were no significant differences between children older and younger than 1 year (odds ratio 0.89; 95% CI 0.37–2.17) or between the sexes as regards hospital admittance due to suspected ADRs (odds ratio 1.94; 95% CI 0.72–5.42).

5The results of this kind of study may be influenced by patterns of drug utilization. Nevertheless, the lack of specific studies of drug effects in young children makes it desirable to carry out pharmacoepidemiological studies in this age group.
The effect of age on the pharmacokinetics of the opioid antagonist nalmefene
Authors: FRYE R. F. , MATZKE G. R. , JALLAD N. S. , WILHELM J. A. , BIKHAZI G. B.
Published: October 2003

1The disposition of nalmefene was evaluated in young and elderly normal healthy volunteers. Subjects received either a single 1 mg (n=18 young; n=11 elderly) or 2 mg (n=8 young; n=15 elderly) intravenous bolus dose of nalmefene.

2Following the administration of nalmefene, the initial plasma concentrations were significantly higher in elderly vs young subjects. The higher concentrations were the result of the 30 to 40% smaller central compartment apparent volume of distribution that was observed in the elderly subjects as compared with the young volunteers (2.8±1.1 vs 3.9±1.1 l kg−1 for 1 mg dose). The elderly volunteers also had a significantly shorter distributional half‐life (t1/2λ1) than young volunteers (0.7±0.7 vs 1.3±0.8 h for 1 mg dose). No significant differences between groups were observed for the elimination half‐life, clearance or steady‐state apparent volume of distribution.

3Although transiently higher nalmefene plasma concentrations were observed in the elderly immediately following drug administration, there was no association between this observation and adverse events. We conclude that no dosage alteration is warranted in elderly patients.
Inhibition of cytochrome P450 by nefazodone in vitro: studies of dextromethorphan O‐ and N‐demethylation
Authors: SCHMIDER JÜRGEN , GREENBLATT DAVID J. , VON MOLTKE LISA L. , HARMATZ JEROLD S. , SHADER RICHARD I.
Published: October 2003

Nefazodone (NEF), a 5‐HT2A/2C antagonist antidepressant, is extensively metabolized in the human body to hydroxy NEF (OH‐NEF), p‐hydroxy NEF (pOH‐NEF), a dione metabolite, and via cleavage of the molecule to m‐chlorophenyl‐piperazine (mCPP) and BMY‐33604. The latter is further metabolized to BMS‐183695‐01 (BMSa) and BMS‐183562‐01 (BMSb). To investigate the potential of NEF and its metabolites to interfere with the metabolism of other drugs, we tested these compounds for their ability to alter dextromethorphan (DMO) O‐demethylation to dextrorphan (DOP; an index reaction for CYP2D6) and N‐demethylation to 3‐methoxy morphinan (MEM, a recently proposed index reaction of CYP3A3/4). The assay was performed in an in vitro system with human liver microsomes from three different donors. NEF, OH‐NEF, pOH‐NEF, mCPP and BMSb were weak inhibitors of DMO O and N‐demethylation, with average Ki values ranging from 18 to 50 μm for DOP formation, and from 21 to >200 μm for MEM formation. The dione metabolite and BMSa did not produce detectable inhibition of either pathway. The findings for DMO O‐demethylation, well‐established as a CYP2D6‐mediated reaction, indicate that NEF and metabolites are weak inhibitors of this reaction, with Ki values at least 100 times higher than fluoxetine (Ki=0.1 μm±0.09). The implications of results on DMO N‐demethylation are not clear. In vivo data, as well as in vitro data based on ‘pure’ CYP3A3/4 substrates, provide evidence for clinically relevant CYP3A3/4 inhibition by NEF, OH‐NEF, and pOH‐NEF. Thus, formation of MEM by N‐demethylation of DMO may not constitute a suitable index reaction to probe CYP3A3/4 activity.
Lack of effect of chloroquine on the debrisoquine (CYP2D6) and S‐mephenytoin (CYP2C19) hydroxylation phenotypes
Authors: MASIMIREMBWA COLLEN M. , GUSTAFSSON LARS L. , DAHL MARJA‐LIISA , ABDI YAKOUB ADEN , HASLER JULIA A.
Published: October 2003

The effects of chloroquine (CHQ) on debrisoquine hydroxylase (CYP2D6) and S‐mephenytoin hydroxylase (CYP2C19) were assessed in 11 black Zimbabwean and 12 white Swedish healthy volunteers. The activity of CYP2D6 was measured as the urinary debrisoquine to 4‐hydroxydebrisoquine metabolic ratio and that of CYP2C19 as the urinary S‐ to R‐mephenytoin enantiomer ratio (S/R). There were no statistically significant differences in either metabolic ratio as a result of prophylactic or loading doses of CHQ. This indicates that CHQ does not inhibit CYP2D6 or CYP2C19 in vivo and is unlikely to compromise the metabolism of substrates for these two enzymes. It is, therefore, also unlikely that residual CHQ in populations under study will interfere with phenotyping of either CYP2D6 or CYP2C19.
The effects of co‐administration of benzhexol on the peripheral pharmacokinetics of oral levodopa in young volunteers
Authors: ROBERTS J. , WALLER D. G. , RENWICK A. G. , O'SHEA N. , MACKLIN B. S. , BULLING M.
Published: October 2003

1 The effects of benzhexol on the absorption and pharmacokinetics of an oral dose of levodopa have been studied in 10 young healthy volunteers. Subjects were given a suspension of levodopa (250 mg) 90 min after either benzhexol (5 mg) or placebo in a randomized cross over design with doses separated by at least 1 week; on each occasion carbidopa was given 1 h before and 5 h after the dose of levodopa. Soluble paracetamol and radiolabelled DTPA were given with the levodopa as markers of gastric emptying.

2 Most subjects showed two peaks in the levodopa plasma concentration–time curve on the placebo day, with the second minor peak occurring 1–2 h after the dose. After benzhexol administration all subjects showed two or more peak levodopa concentrations in plasma. Benzhexol administration caused a significant decrease in the maximum concentration (43%; P<0.05) of the initial peak and an increase (22%; P<0.1) in the maximum concentration of the second peak. This change in absorption profile caused by benzhexol significantly altered the ratios of the second peak compared with the initial peak for both the maximum concentrations (P<0.02) and for the AUC values (P<0.05). Benzhexol administration did not affect the total AUC of levodopa (7.30±1.09 vs 7.19±1.26 μg ml−1 h; means±s.d.).

3 The plasma concentration–time curves for paracetamol showed similar profiles to those for levodopa and the ratios of the peak concentrations and AUC values for the second peak compared with the initial peak were increased significantly by benzhexol administration (P<0.05). The total AUC of paracetamol was not affected by benzhexol administration (39.4±8.2 vs 40.0±8.9 μg ml−1 h; mean±s.d.)

4 Benzhexol altered the gastric emptying profile, shown by γ‐scintigraphy, with a reduced extent of initial emptying prior to the establishment of the plateau which is characteristic of levodopa administration in the fasting state. In consequence the ratio of the second to the initial phase of emptying was significantly higher (P<0.01) following benzhexol treatment.

5 Benzhexol reduces the initial phase of gastric emptying after a dose of levodopa so that there is a decrease in the initial peak and a greater proportion of the dose is absorbed subsequently following the second phase of gastric emptying which occurs approximately 1 h later. Theoretically, this altered concentration‐time profile could be an advantage for some patients with Parkinson's disease.
Clinical efficacy and pharmacokinetics of artemisinin monotherapy and in combination with mefloquine in patients with falciparum malaria
Authors: HASSAN ALIN M. , ASHTON M. , KIHAMIA C. M. , MTEY G. J. B. , BJÖRKMAN A.
Published: October 2003

1The aim of this study was to assess the pharmacokinetics, clinical efficacy and safety of artemisinin alone and in combination with mefloquine.

2Thirty‐eight adults with symptomatic Plasmodium falciparum malaria were randomly assigned to receive either artemisinin (500 mg single dose followed by another 500 mg on day 1 and then 250 mg twice daily for 4 days) or artemisinin (500 mg single dose followed by 750 mg on day 1 and then 250 mg three times daily for one more day) in co‐administration with mefloquine (250 mg three times daily for the first day). All drug administration was by the oral route. Patients were hospitalized at the Kibaha Designated District Hospital, Kibaha, Tanzania, for 6 days and a follow up for 3 weeks was performed.

3Treatment with the artemisinin/mefloquine combination resulted in a shorter parasite clearance time (PCT) of 24 (22, 27; 95% confidence interval) h vs 31 (27, 36) h and fever subsidence time (FST) of 14 (12, 16) h vs 20 (18, 23) h compared with artemisinin monotherapy. The 95% CI for the difference of the PCT and FST were 1.7, 12 and 3, 10, respectively. Parasites were detected in 7 out of 17 patients (41%) receiving artemisinin monotherapy at the 3rd and 4th week follow up visits. No parasites were detected after the combination therapy.

4The maximum plasma concentrations (Cmax) were similar after artemisinin monotherapy (615.4±387.0 ng ml−1) and in combination with mefloquine (851.8±523.6 ng ml−1). Elimination half‐lives (t1/2) were also identical at 2.2±0.6 h and 2.5±0.7 h, respectively. However, the AUC values were higher (P<0.05) after combination therapy (3252±1873 ng  ml−1 h) than after monotherapy (2234±1502 ng ml−1 h). The oral clearance values were lower (P<0.05) after combination therapy (195.4±86.9 l h−1) than after monotherapy (314.3±189.4 l h−1). PCT and FST normalized to initial parasitaemia correlated with AUC(0, t) (rs=0.56, P=0.02, rs=0.58, P=0.01, respectively) and with Cmax(rs=0.62, P=0.01, rs=0.68, P=0.005, respectively) in the artemisinin monotherapy only.

5One patient on the combination therapy developed a psychiatric condition and two patients on the monotherapy developed skin itch.
Bioavailability of the antiemetic metopimazine given as a microenema
Authors: HERRSTEDT JØRN , JØRGENSEN MORTEN , ANGELO HELLE RIIS , RASSING MARGRETHE RØMER , MØLLER‐SONNERGAARD JØRN , DOMBERNOWSKY PER
Published: October 2003

The absorption of the antiemetic metopimazine (MPZ) given as a single dose of (a) 40 mg microenema, (b) 40 mg orally and (c) 10 mg as a 60 min i.v. continuous infusion was investigated in six healthy volunteers. Blood samples were drawn and the serum concentrations of MPZ and its acid metabolite were measured. The bioavailability of MPZ given orally and as enemas was 22.3 and 19.5% respectively. Partial avoidance of hepatic first pass metabolism was seen with the enemas, which in contrast to suppositories, seems to represent a reliable form of rectal administration.
Clinical pharmacologists and drug regulation—future perspective in Japan
Authors: HIROKAWA K.
Published: October 2003

1The Japanese pharmaceutical administration system, and recommendations for the improvement of clinical trial methodology following the implementation of GCP guidelines in Japan are described with special reference to three recent developments in Japanese drug regulation.

2The implementation of GCP guidelines has not been fully satisfactory and clinical trials in Japan still run into problems. The Ministry of Health and Welfare has recently established a Committee on Safety of Medicines after serious trouble with a new drug was experienced. The Committee released an interim report on the reform of clinical trials supervision and the system for examination of New Drug Applications.

3ICH‐GCP guidelines will be implemented in Japan in the next few years. The principal differences between Japanese GCP and ICH‐GCP guidelines, and their effects on clinical trials in Japan with reference to the acceptability of ICH‐GCP, are discussed.

4The final proposals on the National Health Insurance drug pricing method and the appropriate use of drugs by the Central Social Insurance Medical Council are anticipated to have a significant impact on the drug market. The changes in pricing system, especially premiums for innovative drugs, and the implications for the drug market are considered.

5In these changed circumstances, the importance of the role of clinical pharmacologists in the framework of the new drug regulations in Japan is reviewed.
The regulation of pulmonary vascular tone
Authors: WILKINS MARTIN R. , LAN ZHAO  , AL‐TUBULY RIDA
Published: October 2003

1The ability to manipulate pharmacologically pulmonary vascular tone independent of effects on systemic blood vessels is a desirable objective. Elucidation of the biochemical mechanisms underlying hypoxia‐induced pulmonary vasoconstriction (HPV) may permit preferential targeting of the pulmonary circulation.

2Here we review our studies of the role of locally synthesized candidate vasoactive factors in HPV. In addition, we present data demonstrating an attenuated pressor response to hypoxia in the pulmonary circulation of Fischer 344 rats compared with the Wistar‐Kyoto (WKY) rat strain.

3We propose that a systematic genome‐wide search using the HPV phenotype and a panel of highly informative microsatellite markers will elucidate the genetic loci underlying the difference in susceptibility to HPV in these two rat strains and provide a valuable and novel insight into the factors that determine the HPV response.
Calcium supplementation and ototoxicity in patients receiving cisplatin
Authors: GRAU JUAN J. , ESTAPÉ JORGE , CUCHI MARÍA A. , FÍRVIDA JOSÉ L. , BLANCH JOSÉ L. , ASCASO CARLOS
Published: October 2003

We have studied the effect on ototoxicity of maintaining serum calcium concentration by calcium gluconate infusion in cancer patients receiving high‐dose cisplatin in a randomized study in two groups: 11 patients received calcium gluconate, 4 mg kg−1 i.v. infusion during cisplatin therapy; 11 other patients without any calcium supplementation served as controls. All of them received the first course of chemotherapy, based on cisplatin, 120 mg m2 with a hydration schedule. An audiogram was performed in each patient just before cisplatin and repeated after 1 day and 3 weeks. Mean total calcium concentration in control patients before and after chemotherapy was 2.2±0.14 (95% confidence interval 1.9–2.5) and 2.0±0.13 (95% CI 1.7–2.24) mmol l−1 respectively (P=0.0004) and for ionized calcium 1.22±0.52 (95% CI 0.21–2.23) and 1.11±0.07 (95% CI 0.97–1.25) mmol l−1 respectively (P=0.0005). Serum magnesium levels were maintained or increased by magnesium supplementation. Although there was no change in serum total or ionized calcium, or serum magnesium in the calcium infusion group, no differences in hearing loss between the groups were observed. High‐dose cisplatin chemotherapy for cancer patients induces an acute decrease of serum total calcium and serum ionized calcium and audiometric changes. Maintenance of calcium serum levels by calcium gluconate infusion did not protect against ototoxicity in those patients.
Pharmacokinetics of bismuth and ranitidine following multiple doses of ranitidine bismuth citrate
Authors: KOCH K. M. , KERR B. M. , GOODING A. E. , DAVIS I. M.
Published: October 2003

1The pharmacokinetics of bismuth and ranitidine derived from oral doses of ranitidine bismuth citrate 800 mg given twice daily for 28 days were examined in this double‐blind, placebo‐controlled, parallel‐group study in 27 healthy subjects.

2Bismuth accumulation in plasma reflected its multicompartmental disposition, achieving the majority of predicted steady state within 14–28 days. Bismuth absorption from ranitidine bismuth citrate is limited (<0.5% of the dose), and bismuth elimination is predominantly renal secretion. Peak plasma concentrations did not exceed 19 ng ml−1, remaining well below those associated with bismuth toxicity. Bismuth was measurable at low concentrations in plasma and urine for up to 5 months after the last dose. Plasma bismuth concentration‐time data and urinary excretion data were best described by separate multicompartmental models, with terminal half‐lives averaging 21 days and 45 days, respectively.

3The pharmacokinetics of ranitidine derived from ranitidine bismuth citrate were similar to those of ranitidine administered alone. Ranitidine did not appreciably accumulate in plasma.

4Ranitidine bismuth citrate was well‐tolerated during 28 days of repeated dosing.
Clonidine and or adrenaline decrease lignocaine plasma peak concentration after epidural injection
Authors: MAZOIT JEAN XAVIER , BENHAMOU DAN , VEILLETTE YVES , SAMII KAMRAN
Published: October 2003

Clonidine is an α2‐adrenoceptor agonist increasingly used in combination with lignocaine for spinal or epidural anaesthesia because of a prolonged analgesic effect. Like adrenaline, it may decrease lignocaine peak concentration (Cmax), thus leading to decreased toxicity. However, the effects of clonidine on resorption of lignocaine into the systemic circulation from the epidural space remain to be established. We studied the pharmacokinetics of lignocaine after epidural injection of lignocaine with or without clonidine, adrenaline and both drugs. Total body clearance and apparent volume of distribution were similar in the four groups, but the maximum observed concentration (Cmax) was markedly increased in the plain solution group as compared with the other groups: (plain lignocaine: 7.15±2.04 μg ml−1, lignocaine+adrenaline: 3.11±136 μg ml−1, lignocaine+clonidine: 4.48±1.26 μg ml−1, lignocaine+adrenaline+clonidine: 4.06±1.42 μg ml−1 [mean±s.d.]). Our results show that, clonidine decreases lignocaine Cmax to the same extent as adrenaline.
Effects of age on cardiovascular responses to adrenaline in man
Authors: White M. , Leenen F. H. H.
Published: October 2003

Aims Whereas the effects of ageing on β‐receptor mediated responses have been extensively studied in vitro and in vivo using the β‐adrenoceptor agonist isoprenaline, little is known regarding ageing induced changes in responses to endogenous catecholamines. In the present study, we assessed age‐related changes in cardiac responses to the endogenous β‐adrenoceptor agonist adrenaline and the influence of age‐related changes in arterial baroreflex function on these responses.

Methods Adrenaline alone was infused in 14 young subjects, age 30±2 years (eight males, six females), and 18 older subjects (six males, 12 females), age 60±2 years, and together with ganglionic blockade (trimetaphan) in seven young and 11 older subjects. Adrenaline was infused at 3–4 incremental rates, each rate for 8 min. Cardiac function was assessed by echocardiography.

Results Adrenaline alone, at infusion rates 20–160 ng kg−1 min−1 caused similar increases in heart rate in the two groups. In contrast, adrenaline caused larger increases in stroke volume, ejection fraction, cardiac index and systolic blood pressure and larger decreases in end‐systolic wall stress and diastolic blood pressure in the young compared with older subjects. Older females exhibited the smallest increases in stroke volume index and ejection fraction. With concomitant ganglionic blockade, all above cardiovascular responses to adrenaline were similar in the young and older group. Plasma adrenaline increased similarly in the two groups.

Conclusions We conclude that ganglionic blockade does not unmask an age‐related decrease in cardiovascular responses to adrenaline (in contrast to isoprenaline). A concomitant ageing induced decrease in neuronal uptake (which applies to adrenaline, but not isoprenaline) may explain such a differential effect..
Intra‐arterial substance P mediated vasodilatation in the human forearm: pharmacology, reproducibility and tolerability
Authors: Newby David E. , Sciberras David G. , Mendel Carl M. , Gertz Barry J. , Boon Nicholas A. , Webb David J.
Published: October 2003

Aims The current studies were designed to characterize the pharmacology, reproducibility and tolerability of the vasodilator response to intra‐arterial substance P infusion in the forearm of healthy man.

Methods On different occasions, eight healthy male volunteers received brachial artery infusions of substance P at doubling doses ranging from 0.5 to 128 pmol min−1. Blood flow was measured in both arms using venous occlusion plethysmography.

Results Substance P induced dose‐dependent vasodilatation in the human forearm which had a log‐linear relationship to dose. At doses of 1–8 pmol min−1, mean responses were highly reproducible both within and between days. There were no differences between responses to discontinuous doses and continuous doses of substance P. Substance P was generally well tolerated at doses of ≤64 pmol min−1 with no significant alteration in arterial blood pressure or heart rate. Skin oedema in the infused forearm and systemic vasodilatation, manifested by facial flushing and non‐infused forearm vasodilatation, occurred at doses of ≥16 pmol min−1.

Conclusions Forearm vasodilatation to substance P represents a reproducible and useful model in the assessment of peripheral endothelial cell NK1 receptor function.
Hospitalization for serious blood and skin disorders followinguse of co‐trimoxazole
Authors: Myers Marian Wald , Jick Hershel
Published: October 2003

Aims The objective of this study was to quantify the risk of serious blood and skin disorders associated with co‐trimoxazole.

Methods We conducted a population‐based cohort study of serious blood and skin disorders requiring hospitalization among otherwise healthy users of co‐trimoxazole at Group Health Cooperative and Puget Sound (GHC).

Results During the years 1987 to 1993 we found six cases of co‐trimoxazole‐associated blood disorders and three cases of co‐trimoxazole‐associated skin disorders yielding risks of 5.6/100 000 (95% CI 2.6–12.2) and 2.8/100 000 (95% CI 0.9–8.2) respectively. In all cases found there was prompt recovery after discontinuation of co‐trimoxazole. We found no cases of toxic epidermal necrolysis.

Conclusions We conclude that the risk of blood and skin disorders associated with the use of co‐trimoxazole leading to hospitalization is low.
Hospitalization for serious blood and skin disorders following co‐trimoxazole
Authors: Wald Myers Marian , Jick Hershel
Published: October 2003

Aims To quantify the risk of serious blood and skin disorders requiring hospitalization among otherwise healthy users of co‐trimoxazole

Methods We conducted a population‐based cohort study at Group Health Cooperative of Puget Sound (GHC).

Results During the years 1987 to 1993 we found six cases of co‐trimoxazole‐associated blood disorders and three cases of co‐trimoxazole‐associated skin disorders yielding risks of 5.6/100,000 (95% CI 2.6–12.2) and 2.8/100,000 (95% CI 0.9–8.2) respectively. In all cases found there was prompt recovery after discontinuation of co‐trimoxazole. We found no cases of toxic epidermal necrolysis.

Conclusions We conclude that the risk of blood and skin disorders associated with the use of co‐trimoxazole leading to hospitalization is low.