Failure to weigh patients in hospital: a medication safety risk.

Often patients are not weighed in hospital. Failure to weigh patients prescribed renally excreted drugs may correlate to adverse drug events. We carried out a cross-sectional study of patients prescribed common renally excreted drugs (heparin, enoxaparin and gentamicin), admitted to two wards at Royal North Shore Hospital, Sydney over 3 months. Of all patients surveyed, 28% (22/78) in the orthopaedic ward and 22% (27/124) in the medical ward were weighed. Among those prescribed therapeutic doses of the study drugs, 25% (3/12) in the orthopaedic ward and 27% (7/26) in the medical ward were weighed. Patients prescribed therapeutic anticoagulation who were not weighed experienced more haemorrhagic complications than patients who were weighed (P = 0.03). Patients prescribed renally excreted drugs in hospital are frequently not weighed. This is associated with reduced medication safety.

The many essential interfaces of clinical pharmacology.

1. Clinical pharmacology requires numerous skills and most activities involve interactions with other specialities, both clinical and experimental. 2. A range of experts has had a major influence on the nature and design of my research, which is illustrated by the evolution of my knowledge of adverse drug reactions and how to prevent them. 3. Clinical pharmacologists are uniquely placed to coordinate programmes to achieve quality use of medicines. but we will only achieve our aims if multiple interactions with other experts are encouraged and developed.

Recording previous adverse drug reactions--a gap in the system.

AIMS: To measure the accuracy of recording of previous adverse drug reaction (ADR) history in patients admitted to a teaching hospital before and after an education programme. METHODS: One month survey of patients on one medical and one surgical ward, repeated after a 1 month education programme. Patients answered a questionnaire about previous ADRs and this information was compared with that in all relevant sections of their medical records and medication charts. RESULTS: Of 117 patients at baseline, 50 had a total of 81 previous ADRs. Only 75% were recorded on medication charts and 57% and 64%, respectively, in medical and nursing notes. In the post education survey of 124 patients, 56 had 105 previous ADRs, 85% were recorded on medication charts and 64% and 70% in medical and nursing records. These differences were not significant. Serious ADRs were also poorly recorded at baseline but, due to intervention by ward pharmacists, their recording on medication charts improved significantly after education. Pharmacists also significantly improved the quality of description of previous ADRs in both parts of the study. CONCLUSIONS: Previous ADR history obtainable from hospital patients is poorly recorded in medical records and an intensive education programme only produced a significant change in recording by ward pharmacists. Better strategies are needed to improve this essential aspect of history taking.

High-performance liquid chromatography-electrospray ionization mass spectrometry method for the measurement of moclobemide and two metabolites in plasma.

A rapid and sensitive liquid chromatography-electrospray ionisation mass spectrometry (HPLC-ESI-MS) assay has been developed for the measurement of moclobemide and metabolites, Ro12-5637 and Ro12-8095, in human plasma. Sample preparation (0.5 ml plasma) involves solid-phase extraction using C18 cartridges. A Nova-Pak phenyl column (Waters, 4 microm, 150x2 mm I.D.) was employed for analyte separation with a mixture of 0.2 M ammonium formate buffer, pH 3.57 and acetonitrile as the mobile phase. The within- and between-day precisions of the assay were <18% and the limit of quantification for all analytes was 0.01 microg/ml. The total run-time was 6 min. The method described was used to measure moclobemide, Ro12-5637 and Ro12-8095 in human plasma following an oral 300 mg dose.

Urine drug screens in overdose patients do not contribute to immediate clinical management.

A prospective study assessed whether routine urine drug screens might alter the management of overdose patients. Urine was collected from 107 patients with a diagnosis of deliberate self-poisoning seen in the emergency department (ED) of a teaching hospital. The mean age of patients was 36 years (range 13-86 years) and 64% were female. All patients recovered after standard investigations and management, which did not include knowledge of urinary drug screen results. Two hundred ninety-seven compounds were detected in the 107 urine samples. Twenty percent were drugs administered in the ED. Sixty-five percent of patients were found to have taken more than one drug. Benzodiazepines were detected in 18% of samples, paracetamol in 10%, and alcohol in 8%. Sixty-one drugs, in 35 people, were identified that the patients did not report taking. Of these, paracetamol (10), benzodiazepines (9), and tetrahydrocannabinol (8) were the most common. All patients in whom paracetamol was found had already had paracetamol detected in blood and appropriate management instituted. If the results of urine screening had been immediately available this would not have affected the management or outcome of any patient.

Intern Prescribing for Common Clinical Conditions.

To examine the ability of interns to prescribe appropriately for common clinical conditions at the commencement and completion of the intern year. Interns' perceptions of their ability to prescribe and the perceived influences on their practices were also assessed. The study was conducted at a teaching hospital in urban New South Wales, Australia. A self-complete questionnaire was administered to 56 interns at the beginning and end of internship. At the beginning of the year respondents were asked to identify how equipped they felt they were to perform specific functions related to prescribing practice. Interns were also asked to write hospital prescriptions for four common clinical cases scenarios: post-operative pain, urinary tract infection, asthma, and community-acquired pneumonia. At the end of the year interns were asked to prescribe for the same clinical scenarios and also asked to identify the main influences on their practice. At the beginning of the year 54% of interns felt equipped to choose an appropriate drug for common clinical conditions, however, few felt they were able to determine the appropriate dose (23% of respondents) or dose frequency (25%). A previously validated four-point rating scale was used by two assessors to judge appropriateness of prescribing [Kappa = 0.6]. At the beginning of the year at least two-thirds of interns were prescribing 'inappropriately' for all clinical conditions. By the end of the year 75% were prescribing 'appropriately' for all conditions. The main perceived influences on prescribing practices were registrars, consultants, books and pharmacists.The use of hypothetical clinical cases to explore prescribing ability has shown that doctors are ill-equipped to perform various aspects of prescribing on graduating from medical school. Although our findings may not translate into practice directly they highlight the existence of a potential problem that warrants further study, especially in the areas of actual practice and the influences on it in the early postgraduate years.

Amelioration of experimental cisplatin and paclitaxel neuropathy with glutamate.

A major toxic effect of the chemotherapeutic agents paclitaxel and cisplatin is peripheral neuropathy. We report the use of a rat model of cytotoxic neuropathy to evaluate the role of glutamate as a possible neuroprotectant for these two drugs. Neuropathy was manifest as gait disturbance in 100% of paclitaxel treated animals after 2 weeks and 100% of cisplatin treated animals after 8 weeks. Significant elevations of mean tail-flick threshold, a measure of sensory impairment, were observed in animals treated with both cytotoxics. Impaired rota-rod performance was observed in both light and dark with paclitaxel, indicating motor neuropathy. There was a trend towards impairment in the dark for cisplatin, suggesting proprioceptive loss. In cytotoxic treated animals supplemented with oral sodium glutamate (approx. 500 mg/kg/day in drinking water) from 24 h before chemotherapy, there was a significant delay in time to onset of gait disturbance allowing significantly higher mean doses to be tolerated. Mean tail-flick and rota-rod scores were unchanged from baseline for both drugs. Glutamate therefore protected against both sensory and motor neuropathy. Similar doses of glutamate did not impair the cytotoxic efficacy of paclitaxel or cisplatin against a transplantable rat mammary adenocarcinoma grown subcutaneously in rats. Our findings suggest that glutamate warrants clinical trial as a neuroprotectant in patients receiving paclitaxel or cisplatin.

Influence of grapefruit juice on cisapride pharmacokinetics.

OBJECTIVE: Grapefruit juice increases the oral bioavailability of several drugs metabolized by cytochrome P450 3A4. This study investigated the influence of grapefruit juice on the pharmacokinetics of oral cisapride, a substrate of CYP3A4. METHODS: Fourteen healthy volunteers received in random order 10 mg cisapride (Prepulsid) with 250 mL water or grapefruit juice after an overnight fast. Blood samples were taken for 25 hours and urine was collected for 36 hours after dosing. Plasma concentrations of cisapride and urinary norcisapride were measured by HPLC. The influence of grapefruit juice on pharmacokinetic parameters (mean +/- SD) was assessed with the Wilcoxon matched pairs test for 13 subjects (1 subject did not fast as instructed). RESULTS: Grapefruit juice increased cisapride maximum measured plasma concentration (Cmax; water, 65+/-398 ng/mL; grapefruit juice, 87+/-40 ng/mL; P = .009) and area under the plasma concentration-time curve from 0 to 25 hours [AUC(0-25); water, 418+/-280 h x ng/mL; grapefruit juice, 580+/-289 h x ng/mL; P = .005] and prolonged the time to reach Cmax (water, 1.26+/-0.36 hours; grapefruit juice, 1.72+/-0.55 hours; P = .02). Half-life was not affected. Urinary norcisapride recovery was similar and thus the partial apparent metabolic clearance to norcisapride was lower (P = .046) after grapefruit juice (89.5+/-41.2 mL/min) than after water (121.5+/-54.7 mL/min). There was considerable interindividual variation in the grapefruit juice effect [range of AUC(0-25) grapefruit juice/water ratio, 0.90 to 2.65). CONCLUSIONS: Grapefruit juice increases the oral bioavailability of cisapride, with large interindividual variation in the change in Cmax and AUC. Because cisapride has a wide therapeutic index, the interaction may not be of major clinical significance for efficacy, but further studies are necessary at steady state to rule out the possibility of side effects in susceptible individuals.

Pharmacokinetics of tolbutamide in ethnic Chinese.

AIMS: Ethnic differences in drug disposition have been described for many drugs. Despite the widespread use of tolbutamide in Asian populations, the pharmacokinetics of tolbutamide, a CYP2C9 substrate, have not been described in ethnic Chinese. METHODS: The pharmacokinetics of tolbutamide (500 mg orally) were studied in 10 young, healthy volunteers (seven male/three female; age 21-29 years), each of whom had four ethnic Chinese grandparents. Plasma concentrations of tolbutamide were measured for 32 h post-dose by high performance liquid chromatography. The concentrations of hydroxytolbutamide and carboxytolbutamide were also measured in urine for 32 h post-dose. Noncompartmental pharmacokinetic parameters were calculated using standard equations and compared with those previously reported in Caucasian subjects using the Mann-Whitney U test. RESULTS: Pharmacokinetic parameters in Chinese (mean+/-s.d.) including Cmax (63+/-11 microg ml(-1)), tmax (median 3.3 h; range 1.6-6.0 h), V/F (9.1+/-1.7 l) and t1/2, (9.1 h; harmonic mean) were similar to the values in Caucasians. CL/F (637+/-88 ml h(-1)) was higher in Chinese than Caucasians. The urinary recoveries of hydroxytolbutamide (13+/-1% of dose) and carboxytolbutamide (68+/-5% of dose) and the partial apparent metabolic clearance (0.15+/-0.02 ml min(-1) kg(-1)) in Chinese were comparable with Caucasians. CONCLUSIONS: The pharmacokinetics of tolbutamide have been described in ethnic Chinese and the disposition is similar to that reported in Caucasians. This study suggests that there is no substantial ethnic difference in the tolbutamide hydroxylase activity of CYP2C9.

Relationship between proguanil metabolic ratio and CYP2C19 genotype in a Caucasian population.

AIMS: To investigate the relationship between proguanil metabolic ratio (MR, proguanil/cycloguanil) and CYP2C19 genotype in a Caucasian population. METHODS: Ninety-nine Caucasians (age range: 18-55 years, 54 female, 45 male) were genotyped for CYP2C19 and phenotyped for proguanil oxidation by collecting urine for 8 h after taking 100 mg proguanil hydrochloride. Proguanil and cycloguanil concentrations were measured by h.p.l.c. PCR was employed for CYP2C19 genotyping. RESULTS: The three (3%) individuals who were homozygous for CYP2C19*2 (*2/*2) had the highest proguanil MRs (range: 8.0-134.6). Seventy-three (74%) individuals were homozygous for the wild-type allele (*1/*1) and 23 (23%) were heterozygous (*1/*2). The *1/*1 individuals had lower MRs (median=1.4, range: 0.23-5.9, P=0.003, Mann-Whitney U-test) than the *1/*2 subjects (median=2.5, range: 0.88-7.3). CONCLUSIONS: A CYP2C19 gene-dose effect for proguanil oxidation to cycloguanil was observed, confirming a role for CYP2C19 in cycloguanil formation in vivo. However, there was substantial overlap of proguanil MRs in subjects of different CYP2C19 genotypes, due possibly to variability in the activity of other enzymes contributing to the formation of cycloguanil.

The influence of information provided by patients on the accuracy of medication records.

OBJECTIVE: To assess two interventions for improving the accuracy of doctors' information about their patients' medication. DESIGN AND SETTING: A 12-month two-armed (parallel designed) prospective study among elderly patients of four general practitioners (GPs) in two local government areas of Sydney's North Shore. PATIENTS: 206 elderly, ambulant, self-caring patients (69 men, 137 women; median age, 75 year; range, 60-94 years). INTERVENTION: Patients were issued with a medication record card (MRC), filled in by their GPs with what they believed to be the patient's current medications, and were asked to produce it at all subsequent consultations. Patients of two of the GPs were additionally asked to bring their currently used medications to all scheduled appointments. MAIN OUTCOME MEASURE: Accuracy of the MRC, determined by confirmatory home visits and inspection of medications by a pharmacist. RESULTS: The proportion of patients with regimens recorded accurately on their MRCs improved significantly (from 25.9% to 42.0%) only in the group asked to bring their medications to consultations (P = 0.03). Most errors of recording were of omission, with patients taking a median of two medications (range, 0-10) of which their GPs were not aware. CONCLUSION: Requesting that patients bring their medications to consultations, in conjunction with the use of medication record cards, can improve information for doctors about their patients' medications.

Integrating clinical pharmacology teaching with general practice.

AIMS: To make Clinical Pharmacology teaching relevant and introduce students to therapeutic problems relevant to general practice. METHODS: Six topics in the 'core curriculum' for Clinical Pharmacology were taught jointly by a Clinical Pharmacologist and General Practitioners (GPs). Formal teaching was reduced by issuing handouts containing copies of the overheads used. At least half the time was spent on interactive discussion of case histories. RESULTS: Students rated the sessions more highly than other Clinical Pharmacology teaching and were not disadvantaged in examinations. All participants enjoyed and learnt from the experience and the GPs gained confidence in their ability to teach. CONCLUSIONS: This simple method is ideal for teaching Clinical Pharmacology and Therapeutics.

Modified high-performance liquid chromatographic method to measure both dextromethorphan and proguanil for oxidative phenotyping.

The activities of the polymorphic enzymes cytochromes P450 2D6 and 2C19 can be assessed by administering the probe drugs, dextromethorphan and proguanil, respectively. An existing high-performance liquid chromatographic technique, which measures dextromethorphan and its metabolites, has been modified to also measure proguanil and its polymorphic metabolite, cycloguanil in urine. Proguanil and cycloguanil are assayed in separate aliquots of urine to that used for dextromethorphan/dextrorphan as pretreatment with beta-glucuronidase is required for the analysis of dextrorphan. To assay all four compounds a common extraction procedure is used and a single reversed-phase column and isocratic mobile phase with UV and fluorescence detectors connected in series are required. This technique is specific and sensitive for each analyte (limits of detection, dextrorphan/dextromethorphan/proguanil: 0.1 microgram/ml, cycloguanil: 0.2 microgram/ml). All assays are linear over the concentration ranges investigated (dextromethorphan/dextrorphan: 0.5-10 micrograms/ml, proguanil/cycloguanil: 1-20 micrograms/ml). The method described therefore uses laboratory resources very efficiently for all the assays required for hydroxylation phenotyping using proguanil and dextromethorphan.