Showing papers in "British Journal of Clinical Pharmacology in 2004"

What is a clinical trial

Abstract: Editorial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Research: Eat your way to health . . . . . . . . . . . . . . . . . . . . . .2 Focus: Clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 Spotlight: Patient’s Friends Society . . . . . . . . . . . . . . . . . . . . .3 Spotlight: Taichung Kaihuai Association . . . . . . . . . . . . . . . . .4 Advocacy: Let’s help women everywhere fight cancer . . . . . .4 Feature: East meets West in patient care . . . . . . . . . . . . . . . . .5 Pink October 2004: News from around the world . . . . . . .6-12 Conference outcome: Patients demand more say . . . . . . . . .12 Personal account: Why me? . . . . . . . . . . . . . . . . . . . . . . . . .13 Personal account: On top of the world . . . . . . . . . . . . . . . . .14 Book: Enter Sandman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15 Conference announcements . . . . . . . . . . . . . . . . . . . . . .15-16 Editor-in-Chief: Ranjit Kaur Editorial Board: Jeff Dunn Tom Hudson Isabel Mortara Lohes Rajeswaran Páraic Réamonn Ann Steyn bloom

The revision of the Declaration of Helsinki: past, present and future

Abstract: The World Medical Association's Declaration of Helsinki was first adopted in 1964. In its 40-year lifetime the Declaration has been revised five times and has risen to a position of prominence as a guiding statement of ethical principles for doctors involved in medical research. The most recent revision, however, has resulted in considerable controversy, particularly in the area of the ethical requirements surrounding placebo-controlled trials and the question of responsibilities to research participants at the end of a study. This review considers the past versions of the Declaration of Helsinki and asks the question: How exactly has the text of the Declaration changed throughout its lifetime? Regarding the present form of the Declaration of Helsinki we ask: What are the major changes in the most recent revision and what are the controversies surrounding them? Finally, building on the detailed review of the past and present versions of the Declaration of Helsinki, we give consideration to some of the possible future trajectories for the Declaration in the light of its history and standing in the world of the ethics of medical research.

Acute and clinically relevant drug-induced liver injury: a population based case-control study.

Abstract: Aims To provide quantitative information about the absolute and relative risks of acute and clinically relevant drug-induced liver injury. Methods We performed a population-based case-control study using the UK-based General Practice Research Database as the source of information. A total of 1636792 persons subjects aged 5–75 years old registered in the database from 1 January, 1994 to 31 December, 1999 were followed-up for a total of 5404705 person-years. Cases were identified by an exhaustive computer search, then reviewed manually and finally validated against the clinical records. Only idiopathic cases serious enough to be referred to hospital or a consultant were selected. A total of 5000 controls were randomly sampled from the person-time of study cohort. Current users were defined if a prescription ended within 15 days of the index date, and nonusers if there was no prescription before the index date. Results One hundred and twenty-eight patients were considered as valid cases, being the crude incidence rate of 2.4 (95% confidence interval: 2.0, 2.8) per 100 000 person-years. The strongest associations were found with chlorpromazine (adjusted odds ratio (AOR); 95% CI = 416; 45, 3840), amoxicillin/clavulanic acid (AOR = 94.8; 27.8, 323), flucloxacillin (AOR = 17.7; 4.4, 71.0), macrolides (AOR = 6.9; 2.3, 21.0), tetracyclines (AOR = 6.2; 2.4, 15.8); metoclopramide (AOR = 6.2; 1.8, 21.3); chlorpheniramine (AOR = 9.6; 1.9, 49.7); betahistine (AOR = 15.3; 2.9, 80.7); sulphasalazine (AOR = 25.5; 6.0, 109); azathioprine (AOR = 10.5; 1.4, 76.4), diclofenac (AOR = 4.1; 1.9, 8.8) and antiepileptics (AOR = 5.1; 1.9, 13.7). A dose-effect was apparent for diclofenac, amoxicillin/clavulanic acid and flucloxacillin. The combination of two or more hepatotoxic drugs increased the risk by a factor of 6. The highest crude incidence rates were found for chlorpromazine, azathioprine, and sulfasalazine (about 1 per 1000 users). Conclusions Idiopathic, acute and clinically relevant liver injury, which has the use of drugs as the most probable aetiology, is a rare event in the general population. The relative risks of 40 drugs/therapeutic classes are provided, along with the crude incidence rates for 15 of them where a statistical association was found.

What is the best size descriptor to use for pharmacokinetic studies in the obese

Abstract: The prevalence of obesity in the western world is dramatically rising, with many of these individuals requiring therapeutic intervention for a variety of disease states. Despite the growing prevalence of obesity there is a paucity of information describing how doses should be adjusted, or indeed whether they need to be adjusted, in the clinical setting. This review is aimed at identifying which descriptors of body size provide the most information about the relationship between dose and concentration in the obese. The size descriptors, weight, lean body weight, ideal body weight, body surface area, body mass index, fat-free mass, percent ideal body weight, adjusted body weight and predicted normal body weight were considered as potential size descriptors. We conducted an extensive review of the literature to identify studies that have assessed the quantitative relationship between the parameters clearance (CL) and volume of distribution (V) and these descriptors of body size. Surprisingly few studies have addressed the relationship between obesity and CL or V in a quantitative manner. Despite the lack of studies there were consistent findings: (i) most studies found total body weight to be the best descriptor of V. A further analysis of the studies that have addressed V found that total body weight or another descriptor that incorporated fat mass was the preferred descriptor for drugs that have high lipophilicity; (ii) in contrast, CL was best described by lean body mass and no apparent relationship between lipophilicity or clearance mechanism and preference for body size descriptor was found. In conclusion, no single descriptor described the influence of body size on both CL and V equally well. For drugs that are dosed chronically, and therefore CL is of primary concern, dosing for obese patients should not be based on their total weight. If a weight-based dose individualization is required then we would suggest that chronic drug dosing in the obese subject should be based on lean body weight, at least until a more robust size descriptor becomes available.

Meta‐analysis of large randomized controlled trials to evaluate the impact of statins on cardiovascular outcomes

Abstract: Aims Since 2002, there have been five major outcome trials of statins reporting findings from more than 47 000 subjects. As individual trial results differed, we performed a meta-analysis to ascertain the effectiveness and safety of statins overall and in subgroups. The aim of the study was to estimate the effect of statins on major coronary events and strokes, all-cause mortality and noncardiovascular mortality, and in different subgroups. Methods PubMed was searched for trials published in English. Randomized placebo-controlled statin trials with an average follow up of at least 3 years and at least 100 major coronary events were included. For each trial, the statin used, number and type of subjects, proportion of women, mean age and follow up, baseline and change in lipid profile, cardiovascular and non-cardiovascular outcomes were recorded. Results Ten trials involving 79 494 subjects were included in the meta-analysis. Due to heterogeneity, ALLHAT-LLT was excluded from some analyses. Statin therapy reduced major coronary events by 27% (95%CI 23, 30%), stroke by 18% (95%CI 10, 25%) and all-cause mortality by 15% (95%CI 8, 21%). There was a 4% (95%CI −10, 3%) nonsignificant reduction in noncardiovascular mortality. The reduction in major coronary events is independent of gender and presence of hypertension or diabetes. The risk reduction was greater in smokers (P < 0.05). Coronary events were reduced by 23% (95%CI 18, 29%) in pravastatin trials and 29% (95%CI 25, 33%) in five trials using other statins. Pravastatin reduced strokes by 12% (95%CI 1, 21%) whilst other statins reduced strokes by 24% (95%CI 16, 32%) (P = 0.04). Conclusions Statins reduce coronary events, strokes and all-cause mortality without increasing noncoronary mortality. The benefits accrue in men and women, hypertensives and normotensives, diabetics and nondiabetics, and particularly in smokers. Pravastatin appears to have less impact on strokes.

A prospective multicentre study of pharmacist initiated changes to drug therapy and patient management in acute care government funded hospitals

Abstract: Aims To determine the cost savings of pharmacist initiated changes to hospitalized patients' drug therapy or management in eight major acute care government funded teaching hospitals in Australia. Methods This was a prospective study performed in eight hospitals examining resource implications of pharmacists' interventions assessed by an independent clinical panel. Pharmacists providing clinical services to inpatients recorded details of interventions, defined as any action that directly resulted in a change to patient management or therapy. An independent clinical review panel, convened at each participating centre, confirmed or rejected the clinical pharmacist's assessment of the impact on length of stay (LOS), readmission probability, medical procedures and laboratory monitoring and quantified the resultant changes, which were then costed. Results A total of 1399 interventions were documented. Eight hundred and thirty-five interventions impacted on drug costs alone. Five hundred and eleven interventions were evaluated by the independent panels with three quarters of these confirmed as having an impact on one or more of: length of stay, readmission probability, medical procedures or laboratory monitoring. There were 96 interventions deemed by the independent panels to have reduced LOS and 156 reduced the potential for readmission. The calculated savings was $263 221 for the eight hospitals during the period of the study. This included $150 307 for length of stay reduction, $111 848 for readmission reduction. Conclusions The annualized cost savings relating to length of stay, readmission, drugs, medical procedures and laboratory monitoring as a result of clinical pharmacist initiated changes to hospitalized patient management or therapy was $4 444 794 for eight major acute care government funded teaching hospitals in Australia.

Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

Abstract: Aim The aim of this study was to investigate the effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin.

Database analyses for the prediction of in vivo drug–drug interactions from in vitro data

Abstract: Aims In theory, the magnitude of an in vivo drug–drug interaction arising from the inhibition of metabolic clearance can be predicted using the ratio of inhibitor concentration ([I]) to inhibition constant (Ki). The aim of this study was to construct a database for the prediction of drug–drug interactions from in vitro data and to evaluate the use of the various estimates for the inhibitor concentrations in the term [I]/Ki.

Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems

Abstract: Aims Muscular problems are the major group of side-effects during statin treatment. They are known to occur much more frequently during and after exercise.

Drug metabolism and ageing

Abstract: Important changes in drug metabolism occur with ageing Age-associated reductions in function of some but not all cytochrome P450 enzymes (CYPs) have been described Induction and inhibition of CYPs needs to be revisited in light of recent advances The function and pharmacology of transporters have not yet been examined for an age-related effect Finally, the concept of frailty is being underpinned by studies documenting a decline in drug metabolism and changes in disposition in frail older people compared with either healthy elderly or the young

Medication reviews in the community: results of a randomized, controlled effectiveness trial.

Abstract: Aims To examine the effectiveness of a multidisciplinary service model delivering medication review to patients at risk of medication misadventure in the community. Methods The study was carried out in three Australian states; Queensland, New South Wales and Western Australia, and conducted as a randomized, controlled effectiveness trial with the general practitioner (GP) as the unit of randomization. In total, 92 GPs, 53 pharmacists and 400 patients enrolled in the study. The multidisciplinary service model consisted of GP education, patient home visits, pharmacist medication reviews, primary healthcare team conferences, GP implementation of action plans in consultation with patients, and follow-up surgery visits for monitoring. Effectiveness was assessed using the four clinical value compass domains of (i) functional status, (ii) clinical outcomes, (iii) satisfaction and (iv) costs. The domains of functional status (assessed by the health-related quality of life measure SF-36 subscales) and clinical outcomes (as assessed by adverse drug events (ADEs), number of GP visits, hospital services and severity of illness) were measured at baseline and endpoint. Satisfaction was measured by success in implementation and by participant satisfaction at endpoint, and costs (as assessed using medication and healthcare service costs, less intervention costs) were measured preintervention and during the trial. In addition, process evaluation was conducted for intervention patients, in which problems and recommendations from the medication reviews were described. Results The model was successfully implemented with 92% of intervention GPs suggesting that the model had improved the care of participating patients, a view shared by 94% of pharmacists. In addition, positive trends in clinical outcomes (ADEs and severity of illness) and costs (an ongoing trend towards reduction in healthcare service costs) were evident, although the trial was limited to a 6-month intervention time. No differences between intervention and control groups were identified for the health-related quality of life domain. The cost–effectiveness ratio for the intervention based on cost savings, reduced adverse events and improved health outcomes was small. The most common problems identified in the medication reviews were potential adverse drug reactions, suboptimal monitoring and adherence/lack of concordance issues. In total, 54.4% of recommendations were enacted, and 23.9% were implemented precisely as recommended in the medication review. Follow-up evaluation showed that 70.9% of actions had a positive outcome, 15.7% no effect and 3.7% had a negative outcome. Conclusions Most studies emphasize efficacy and the best achievable clinical outcomes rather than whether an intervention will be effective in practice. The current trial showed that three of the four domains in the clinical value compass showed trends of improvement or were indeed improved in the relatively short follow-up period of the trial, suggesting that a service based on this model could achieve similar benefits in practice. A domiciliary medication review programme similar to this model has now been implemented into national Australian practice, where GPs and pharmacists are reimbursed by the Australian government for the provision of these services.

Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin

Abstract: Aims Simvastatin, a substrate for CYP3A4, is extensively metabolized during the first pass. Our aim was to investigate the effect of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin.

Pharmacokinetics of oral fumarates in healthy subjects.

Abstract: Aims To characterize the pharmacokinetics of fumarates in healthy subjects. Methods Ten subjects received a single fumarate tablet (containing 120 mg of dimethylfumarate and 95 mg of calcium-monoethylfumarate) in the fasted state and after a standardized breakfast in randomized order. Prior to and at fixed intervals after the dose, blood samples were drawn and the concentrations of monomethylfumarate, the biologically active metabolite, as well as dimethylfumarate and fumaric acid were measured using high-performance liquid chromatography. Results After a lag time, a transient increase in serum monomethylfumarate concentrations in the blood was observed, whereas dimethylfumarate and fumaric acid concentrations remained below the detection limit. The tlag was 240 min [range 60–603 min; 95% confidence interval (CI) 139, 471] shorter when the tablet was taken after an overnight fast (90 min; range 60–120 min; 95% CI 66, 107) than when taken with breakfast (300 min; range 180–723 min; 95% CI 0, 1002). The tmax was 241 min (range 60–1189 min, 95% CI 53, 781) shorter when the tablet was taken after an overnight fast (182 min; range 120–240 min; 95% CI 146, 211) than when taken with breakfast (361 min; range 240–1429 min; 95% CI 0, 1062). The mean Cmax for monomethylfumarate in the blood of fasting subjects was to 0.84 mg l−1 (range 0.37–1.29 mg l−1; 95% CI 0.52, 1.07) and did not differ from that in fed subjects (0.48 mg l−1; range 0–1.22 mg l−1; 95% CI 0, 5.55). Conclusions The pharmacokinetics of monomethylfumarate in healthy subjects after a single tablet of fumarate are highly variable, particularly after food intake. Further experiments exploring the pharmacokinetics of oral fumarates are warranted in order to elucidate the mechanisms underlying variability in reponse in patients.

Antipsychotic polypharmacy in patients with schizophrenia: a multicentre comparative study in East Asia.

Abstract: Antipsychotic polypharmacy was found in 457% ( n = 1097) of the patients with wide intercountry variations Polypharmacy was associated with male gender [odds ratio (OR) 124, 95% confidence interval (CI) 106, 146, P < 001], advanced age ( t = - 7 81, df = 2396, P < 0001), psychiatric hospital setting (OR 134, 95% CI 111, 162) as well as higher daily CPZeq doses (41147 vs 98310 CPZeq day - 1 , z = - 2594, P < 0001), anticholinergic use (OR 317, 95% CI 265, 379, P < 0001) and less use of an atypical antipsychotic drug (OR 083, 95% CI 071, 098, P < 005) On multivariate analysis, country, age and duration of illness were significantly associated with antipsychotic polypharmacy

European surveillance of antimicrobial consumption (ESAC): data collection performance and methodological approach.

Abstract: Background Europe is a continent with strong public healthcare systems, but diverging antibiotic policies and resistance patterns. Aims To describe the performance and methodological approach in a retrospective data collection effort (1997–2001), through an international network of surveillance systems, aiming to collect publicly available, comparable and reliable data on antibiotic use in Europe. Methods A central multidisciplinary management team co-ordinated a network of national representatives, liasing with national data providers and bodies responsible for antibiotic policy. The data collected were screened for bias, using a checklist. We focused on detection bias in sample and census data; errors in assigning medicinal product packages to the Anatomical Therapeutic Chemical Classification (ATC); errors in calculations of defined daily doses (DDD) per package; bias by over-the-counter sales and parallel trade; and bias in ambulatory care (AC)/hospital care (HC) mix. Datasets were corrected after national feedback, and classified as valid; valid but with minor bias; not valid. Results Of the 31 participating countries, 21 countries delivered AC data suitable for cross-national comparison (14 for all 5 years). Of these, 17 countries provided data on a quarterly basis for at least 1 year. For HC, 14 countries were able to deliver valid data (nine for all 5 years). A valid estimate of the total exposure of national populations to human antibiotic consumption could be made in 17 countries. Conclusion In cross-national comparisons of antibiotic consumption in Europe, methodological rigour in correcting for various sources of bias and checking the validity of ATC/DDD assignment is needed.

Current approaches to prevent NSAID-induced gastropathy--COX selectivity and beyond.

Abstract: Gastrointestinal (GI) toxicity associated with nonsteroidal anti-inflammatory drugs (NSAIDs) is still an important medical and socio-economic problem – despite recent pharmaceutical advances. To prevent NSAID-induced gastropathy, three strategies are followed in clinical routine: (i) coprescription of a gastroprotective drug, (ii) use of selective COX-2 inhibitors, and (iii) eradication of Helicobacter pylori. Proton pump inhibitors are the comedication of choice as they effectively reduce gastrointestinal adverse events of NSAIDs and are safe even in long-term use. Co-medication with vitamin C has only been little studied in the prevention of NSAID-induced gastropathy. Apart from scavenging free radicals it is able to induce haeme-oxgenase 1 in gastric cells, a protective enzyme with antioxidant and vasodilative properties. Final results of the celecoxib outcome study (CLASS study) attenuated the initial enthusiasm about the GI safety of selective COX-2 inhibitors, especially in patients concomitantly taking aspirin for cardiovascular prophylaxis. Helicobacter pylori increases the risk for ulcers particularly in NSAID-naive patients and therefore eradication is recommended prior to long-term NSAID therapy at least in patients at high risk. New classes of COX-inhibitors are currently evaluated in clinical studies with very promising results: NSAIDs combined with a nitric oxide releasing moiety (NO-NSAID) and dual inhibitors of COX and 5-LOX. These drugs offer extended anti-inflammatory potency while sparing gastric mucosa.

Population pharmacokinetics of total and unbound plasma cisplatin in adult patients

Abstract: Aims To investigate the pharmacokinetics of unbound (ultrafilterable) and total plasma platinum using a population approach and to identify patient characteristics that may influence the disposition of the drug. Methods Pharmacokinetic and demographic data were collected from adult patients treated with 30-min daily infusions of cisplatin for various malignancies. Unbound and total platinum concentration-time data were analysed using a nonlinear mixed effects model. Results Data from 43 patients were available for analysis. A linear two-compartment model best described total and unbound platinum plasma concentration-time data. The mean population estimates for total and unbound drug were, respectively, 0.68 and 35.5 l h−1 for clearance and 21.1 and 23.4 l for central distribution volume (V1). Unbound clearance (CL) was dependent on body surface area (BSA) and creatinine clearance, and V1 was dependent on BSA. The elimination rate constant for plasma-bound platinum (modelled as metabolite formation) was 0.014 h−1. The pharmacokinetic parameter, fm/Vm, a measure of the clearance of unbound platinum due to irreversible plasma binding, was related to serum protein concentration and to the inverse of dose per m2. The covariate modelling of CL, V1 and fm/Vm improved the intersubject variabilities associated with these parameters. The final pharmacokinetic models were validated using 200 bootstrap samples from the original datasets. Conclusions The results support the conventional dose adjustment of cisplatin based on BSA. They also support the need for a dose reduction in case of renal insufficiency.

Toxicity of nitrazepam in the elderly: A report from the Boston collaborative drug surveillance program. Commentary. Author's reply

Abstract: 1 To assess the potential hazards of nitrazepam therapy of insomnia in the elderly, adverse reactions to nitrazepam were studied in 2111 hospitalized medical patients who received the drug. 2 Manifestations of unwanted central nervous system (CNS) depression (such as drowsiness or 'hangover') were reported in 49 nitrazepam recipients (2.3%), and signs of unwanted CNS stimulation (such as nightmares, insomnia, agitation, etc.) in 15 (0.7%). None of the adverse reactions were considered serious. 3 Physician-rated clinical efficacy of nitrazepam was not related to dose, but the frequency of both types of adverse reactions increased significantly at higher daily doses. CNS depression also was significantly more frequent in the elderly, being reported in 11% of those aged 80 years or older, whereas the frequency of CNS stimulation was not correlated with age. 4 The effect of age on the reported rate of unwanted CNS depression was most striking at high doses. Among patients aged 80 years or over whose daily dose averaged 10 mg or more, 55% experienced unwanted CNS depression attributed to nitrazepam. 5 Low doses of nitrazepam are safe for elderly individuals, but the elderly are readily susceptible to excessive CNS depression at high doses. The findings suggest that there is little reason to exceed 5 mg doses of nitrazepam for most patients, particularly those who are elderly.

Vancomycin pharmacokinetics in critically ill patients receiving continuous venovenous haemodiafiltration

Abstract: Aims To investigate the pharmacokinetics of vancomycin in critically ill patients on continuous venovenous haemodiafiltration (CVVHDF), a continuous renal replacement therapy (CRRT) and to see if routine measures approximate vancomycin clearance.

Quantitative justification for target concentration intervention – parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides

Abstract: Aims [1] To quantify the random and predictable components of variability for aminoglycoside clearance and volume of distribution [2] To investigate models for predicting aminoglycoside clearance in patients with low serum creatinine concentrations [3] To evaluate the predictive performance of initial dosing strategies for achieving an aminoglycoside target concentration. Methods Aminoglycoside demographic, dosing and concentration data were collected from 697 adult patients (>=20 years old) as part of standard clinical care using a target concentration intervention approach for dose individualization. It was assumed that aminoglycoside clearance had a renal and a nonrenal component, with the renal component being linearly related to predicted creatinine clearance. Results A two compartment pharmacokinetic model best described the aminoglycoside data. The addition of weight, age, sex and serum creatinine as covariates reduced the random component of between subject variability (BSVR) in clearance (CL) from 94% to 36% of population parameter variability (PPV). The final pharmacokinetic parameter estimates for the model with the best predictive performance were: CL, 4.7 l h(-1) 70 kg(-1); intercompartmental clearance (CLic), 1 l h(-1) 70 kg(-1); volume of central compartment (V-1), 19.5 l 70 kg(-1); volume of peripheral compartment (V-2) 11.2 l 70 kg(-1). Conclusions Using a fixed dose of aminoglycoside will achieve 35% of typical patients within 80-125% of a required dose. Covariate guided predictions increase this up to 61%. However, because we have shown that random within subject variability (WSVR) in clearance is less than safe and effective variability (SEV), target concentration intervention can potentially achieve safe and effective doses in 90% of patients.

Stroke prevention and atrial fibrillation: reasons leading to an inappropriate management. Main results of the SAFE II study

Abstract: Aims The aim of the Stroke and Atrial Fibrillation Ensemble (SAFE) II study was to identify the reasons underlying the under-utilization of oral anticoagulation (OAC) in patients with nonvalvular atrial fibrillation (NVAF). Methods We investigated from all available sources the reasons why patients hospitalized for a stroke, who had a previously known NVAF, were not receiving OAC beforehand. We interviewed general practitioners (GPs) and cardiologists with a structured questionnaire, to identify the reasons for their therapeutic choice. Results Of 370 patients, 257 were theoretically eligible for OAC according to guidelines and the presence of contra-indications, but only 82 (22.2%) of them had actually received OAC before. We found that factors independently associated with the prescription of OAC were being followed-up by a cardiologist and having a younger GP. The leading reason evoked by GPs or cardiologists to explain why patients were not treated with OAC was the presence of a ‘potential contra-indication’, which was often inappropriate, followed by ‘there was no indication’, ‘low compliance’ and ‘fear of bleeding’. Conclusions An important reason for not prescribing OAC was the lack of knowledge about trials and guidelines. Medical education about OAC in NVAF should therefore be improved.

The safety and tolerability of donepezil in patients with Alzheimer's disease

Abstract: Cholinesterase (ChE) inhibitors, which prevent the hydrolysis of acetylcholine, have been approved for the symptomatic treatment of Alzheimer's disease (AD) for over a decade. However, the first ChE inhibitors were associated with a high incidence of side-effects and general tolerability concerns, including hepatotoxicity. Side-effects associated with increased cholinergic activity, particularly in the gastrointestinal (GI) system, can prevent patients from achieving effective doses of drug. In addition, the advanced age and frail nature of patients with AD mean that poor tolerability is a serious concern. The potential for drug–drug interactions is also an important consideration, due to the high prevalence of comorbid disease in these patients. Data both from clinical trials and studies in routine clinical practice have shown that donepezil is associated with a low incidence of GI adverse events (AEs) that is comparable with placebo. Donepezil is a potent, selective inhibitor of acetylcholinesterase, and selective inhibition of central as opposed to peripheral ChEs might be expected to reduce the incidence of AEs, thus this may explain the lower incidence of cholinergic AEs observed following treatment with donepezil, compared with nonselective ChE inhibitors. There are no differences in cardiovascular AEs, including bradycardia, between placebo and donepezil groups in the clinical trials published to date, even in a very sick vascular dementia population with high rates of comorbidity and concomitant medication use. Data from single- and multiple-dose studies of donepezil in patients with hepatic impairment and with moderately to severely impaired renal function indicate that donepezil is safe and well tolerated in these groups. Furthermore, both in vitro and clinical studies have shown that donepezil is not associated with drug–drug interactions. The incidence of weight loss is very similar between donepezil- and placebo-treated patients. Although insomnia and other sleep disorders have been reported following administration of donepezil, lengthening the time period before increasing the dose of donepezil from 5 to 10 mg day−1 or switching to morning dosing can reduce these events to the levels of placebo-treated patients. Over 770 million days of patient use and an extensive publication database demonstrate that donepezil has a good tolerability and safety profile.

Alprazolam is relatively more toxic than other benzodiazepines in overdose.

Abstract: Aims To describe alprazolam poisoning and the relative toxicity of alprazolam compared with other benzodiazepines.

The effect of quinidine, used as a probe for the involvement of P-glycoprotein, on the intestinal absorption and pharmacodynamics of methadone

Abstract: Correspondence Evan D. Kharasch , Department of Anaesthesiology, Box 356540, University of Washington, 1959 NE Pacific Street RR-442, Seattle, WA 98195, USA. Tel: + 1 20654 32039 Fax: namics of oral and intravenous methadone are greater after inhibition of intestinal + 1 20668 53079 E-mail: and brain P-gp, using the P-gp inhibitor quinidine as an kharasch@u.washington.eduThis study was presented in preliminary form at the annual meetings of the International Society for Anaesthetic Pharmacology (Orlando, FL 2002) and the American Society for Clinical Pharmacology and Therapeutics (Washington DC, 2003). Keywords blood–brain barrier, intestinal absorption, methadone, miosis, P-glycoprotein, pharmacodynamics, quinidine Received 6 August 2003 Accepted 16 October 2003

Tizanidine is mainly metabolized by cytochrome P450 1A2 in vitro

Abstract: Aims To identify the cytochrome P450 (CYP) enzyme(s) that catalyze the metabolism of tizanidine in vitro. Methods The effect of CYP isoform inhibitors on the elimination of tizanidine was studied using pooled human liver microsomes. The metabolism of the drug by a range of human recombinant CYP isoforms was then investigated. Results Incubation of tizanidine (80 nm) with human liver microsomes resulted in time- and NADPH-dependent substrate consumption with a half-life of 50 min, initial reaction velocity of 1.1 pmol min−1 mg−1 protein and intrinsic clearance of 17 ml min−1 kg−1. The predicted in vivo hepatic clearance (CLh) of tizanidine using the well-stirred and parallel-tube model was close (68% and 82%, respectively) to its estimated in vivo CLh. Fluvoxamine and furafylline strongly inhibited tizanidine metabolism. Inhibitors specific to isoforms other than CYP1A2 had no substantial effect. Recombinant CYP1A2 metabolized tizanidine to a substantial degree (35% in 45 min), but other recombinant CYPs had little metabolic capacity for the drug. Conclusions CYP1A2 is primarily responsible for the metabolism of tizanidine. CYP1A2 inhibitors may inhibit its metabolism also in vivo.

The use of pharmacokinetic and pharmacodynamic data in the assessment of drug safety in early drug development.

Abstract: The pharmaceutical industry continues to look for ways to reduce drug candidate attrition throughout the drug discovery and development process. A significant cause of attrition is due to safety issues arising either as a result of animal toxicity testing or in the clinical programme itself. A factor in the assessment of safety during early drug development is the pharmacokinetic profile of the compound. This allows safety data to be considered in the light of systemic drug exposure and therefore permits a quantitative assessment. This is particularly applicable when assessing the risk of a new chemical entity (NCE) in relation to safety parameters such as QT interval prolongation, where free plasma concentrations have been shown to be predictive of this property in relation to potency in preclinical testing. Prior to actual human exposure it is therefore important to be able to predict reliably the pharmacokinetic behaviour of an NCE in order to place such safety findings into a quantitative risk context. The emerging science of pharmacogenetics is likely to further our ability to assess the risk of NCEs to populations and individuals due to genetic variance. The drug metabolizing enzyme CYP2D6 has been recognized as providing the potential to result in widely differing systemic drug exposure in the patient population due to polymorphic expression. Further knowledge is likely to add to our understanding of population differences in exposure and response and aid in the identification of risk factors. One potential strategy for improving the effectiveness of the drug discovery process is to obtain clinical pharmacokinetic data more rapidly in order to assess more accurately the potential for both efficacy and safety of an NCE. Whilst procedures and technologies are available that allow this on the microdose scale, it is important that we recognize potential limitations of these approaches in order that they can be applied beneficially.

Blood–brain barrier transport of morphine in patients with severe brain trauma

Abstract: Results The area under the concentration-time curve (AUC) ratio of unbound morphine in brain tissue to plasma was 0.64 (95% confidence interval 0.40, 0.87) in 'better' brain tissue ( P < 0.05 vs. the subcutaneous fat/plasma ratio), 0.78 (0.49, 1.07) in 'worse' brain tissue and 1.00 (0.86, 1.13) in subcutaneous fat. The terminal half-life and T max were longer in the brain vs. plasma and fat, respectively. The relative recovery for morphine was higher in 'better' than in 'worse' brain tissue. The T max value tended to be shorter in 'worse' brain tissue.

Evaluation of the clinical value of pharmacists’ modifications of prescription errors

Abstract: Aims Our objective was to examine the clinical value of pharmacists’ interventions to correct prescription errors. Methods In this study, we reviewed a random sample of prescriptions that had been modified in pharmacies. These prescriptions were collected on one predetermined day between 25th February and 12th March 1999 from 141 Dutch community pharmacies. Each prescription modification was evaluated by a panel of reviewers, including representatives of five groups of health care professionals. After generally rating each modification as positive, negative, or neutral, the reviewers assessed its outcome (in terms of prevention of an adverse drug reaction [ADR], an improvement in effectiveness, both, or other), the probability and importance of improvements in effectiveness and/or the probability and seriousness of an ADR in the case of a nonintervention. Our analyses included 144 interventions from the first general assessment and a selection of 90 consistently rated ‘positive’ interventions (from all assessments). Results On average, one in 200 prescriptions (0.49%) was found to have been positively modified by Dutch community pharmacists. About half of these interventions (49.8%) were aimed at preventing ADRs; 29.2% were rated as a positive modification in the effectiveness of pharmacotherapy and 8.6% affected both effectiveness and ADR. Reviewers’ ratings varied widely between different categories of drug-related problems (DRPs). The impact of individual interventions (n = 83) varied, and for 53% of these interventions it was estimated to be relatively high. Conclusions Pharmacists’ interventions led to modification of prescriptions for an array of DRPs. Such interventions can contribute positively to the quality of pharmacotherapy. By extrapolating our data, we estimated a daily occurrence of approximately 2700 positive interventions in all Dutch pharmacies (1.6 per pharmacy per day). Reviewers rated the impact of interventions on a patient's health as significant in a substantial number of cases.