Can two, four or eight‐hour urine collections after voluntary voiding be used instead of twenty ‐four hour collections for the estimation of creatinine clearance in healthy subjects

The accuracy of creatinine clearance estimations obtained from 4hour (16:0020:00, 20:0024:00, 08:0012:00, 12:0016:00) and 8hour (16:0024:00, 24:0008:00 and 08:0016:00) urine collections and the Cockcroft Gault formula compared with the standard 24hour collection, as well as the cyclical variation in creatinine excretion were studied in a group of 22 healthy subjects (Serum creatinine < 1.5mg/dl, Blood Urea Nitrogen < 50mg/dl) after voluntary voiding. The mean 4hour and 8hour creatinine clearances were not significantly different from the 24hour values. Clearance values from 8hour collections between 24:0008:00 and 16:0024:00 were found to be the most accurate and gave the best correlations. Furthermore only the mean absolute percentage deviations of the 8hour from the 24hour clearance values were significantly less than 20%. Significant cyclical variations in creatinine clearance over 24 hours were not observed. Time intervals between 23:0007:00 and 07:0009:00 were chosen for the comparisons between 8hour, 2hour, Cockcroft Gault creatinine clearance estimations and the 24hour values in 21 healthy subjects. The mean 2hour and 8hour creatinine clearances were not significantly different from the 24hour values. However, once again only the 8hour clearance values differed by less than 20% from the 24hour values and they were more accurate and better correlated than the 2hour values. As expected, in both groups of subjects, the percentage of clearance values that deviated by more than 20% from the 24hour values decreased as the length of the collection times increased. The Cockcroft Gault formula in both groups of volunteers gave less accurate clearance estimations, smaller correlation coefficients (not statistically significant in Group I subjects) and percentage deviations from the 24hour values greater than 20%. Undetected early stage renal insufficiency in three volunteers and the use of actual instead of normalized Scr values may have been the cause of these poor clearance estimations. In healthy subjects (Scr < 1.5mg/dl) 24hour creatinine clearance may be estimated from an 8hour urine collection with voluntary voiding if a 20% deviation from the 24hour value is considered clinically acceptable.     

Factors associated with non-response in proton pump inhibitor users: a study of lansoprazole therapy

Background: Proton pump inhibitors (PPI) demonstrate high healing rates of 8598% in clinical trials. Due to the limited knowledge regarding response and nonresponse to lansoprazole in daily practice and for the reason that resistance to PPIs is scarce, we investigated factors possibly associated with nonresponse. Methods: Data were used from a prospective, open label, observational followup study in which 10,008 lansoprazole users were followed over time. The study was designed according to the SAMM guidelines. A matched nested casecontrol design was used to compare nonresponding (cases) and responding (controls) lansoprazole users. Nonresponse was defined as worsening or nonimprovement of symptoms at the first evaluation after at least 8 weeks of use, response as disappearance or improvement of symptoms within 8 weeks of use. Controls were matched for the evaluating physician.Results: A total of 186 nonresponders and 372 responders to PPI treatment were identified as cases and controls. Age of over 60 years, heavy smoking and previous use of PPIs were significantly more common in nonresponding patients compared with responding patients. There were no differences found between the reported diagnosis regarding response. Conclusion: In daily clinical practice, previous use of PPIs, heavy smoking and an age > 60 years were significantly associated with nonresponse to treatment with lansoprazole. Previous use of PPIs in nonresponding patients might suggest resistance to PPIs. The knowledge that nonresponse drives nonresponse may encourage physicians to follow PPI users with previous PPI use more closely.     

Quantification of communication processes, is it possible?

The PAS^® system (ProblemAnalysisSolutionsystem) is developed to quantify oral communication processes during counselling in pharmacy practice. The pharmacist translates the patients' drugrelated questions into a Pcode, the analysis of the question into an Acode and finally the given solution upon the question into a Scode. The PAS^® system has been developed for two goals. First, for the registation of drugrelated questions from patients which gives the pharmacist insight in the most common issues addressed by patients. Second, it might help the pharmacist to structure the communication with the patient during the consultation. Fortyone pharmacists participated in the evaluation of the PAS^® system. The validation of the PAS^® system consisted of two phases: the external validation and the internal validation. Kappa values were calculated as a measure of agreement in the coding by the pharmacists. The kappavalue of the external validation for the P , A and Scodes for the total set of questions indicate a moderate to poor agreement. This means that pharmacists categorize drugrelated questions from patients in a different way. Therefore we conclude that the PAS system is less reliable for research purpose. The kappavalue of the internal validation for the Pcode varies from 0.42 to 0.91. For the Acode it varies from 0.07 to 0.35 and for the Scode from zero to 0.68. Internal reproducibility is good for Pcode but not for the Acode and Scode This implies that the pharmacist can use the Pcodes for registration of patients' questions in his own pharmacy. Moreover, the usage of the PAS^® system during counselling in pharmacy practice can structure the consultation.     

An accelerated stability study of 5‐flucytosine in intravenous solution

The stability of the antimycotic drug flucytosine (5FC) and the extent of 5fluorouracil (5FU) formation in 5FC intravenous solution was studied in an accelerated stability experiment. 5FC intravenous solution (10 mg/ml) was heated at 40, 60, 70, 80 and 90 C for a maximum of 131 days. At appropriate time intervals samples were taken and the concentrations of 5FC and 5FU were determined using a newly developed, stability indicating HPLCUV method. Heating the 5FC intravenous solution at 40, 60, 70, 80 and 90 C lead to 5FC decomposition of respectively 0, 8.9, 14.4, 52.5 and 61.6%. The Arrhenius plot of the 5FC decomposition is described by: Lnk5-FC decomposition = 80.1892 * 1/T 0.2396 and the 5FU formation is described by Lnk5FU formation = 13087 * 1/T + 34.4028. It is concluded that 5FC is very stable in intravenous solution at regular storing temperatures and can therefore be stored at ambient temperatures for several years before the critical limit of 95% 5FC is reached. However, the toxic and teratogen degradation product 5FU may be present in considerable amounts in the product, due to both impurities in the raw material and the formation from 5FC upon sterilisation and storage.     

Risk factors for the development of adverse drug events in hospitalized patients

Adverse drug events in hospitalized patients lead to increased morbidity, mortality and costs. Early detection of adverse drug events could aid in the prevention of these adverse outcomes. A costeffective system for the early detection of adverse drug events should focus on high risk patients. A study was set up with the primary aim to identify characteristics that are associated with the development of adverse drug events (ADEs) in hospitalized patients.ADE reports were gathered from physicians and nurses (spontaneous reports) and from patients after intensive ward interviews by hospital pharmacists. All patients admitted to the internal medicine wards of two Dutch hospitals, during a two month period, were included.The following characteristics were analyzed for their potential relationship to the occurence of ADEs: age (categorized), gender, number of drugs prescribed during hospital stay, types of drugs used and changes in drug use on admission.Age was found to be inversely associated with the development of ADEs (OR 0.36, CI 0.210.61 for age category > 80 years; OR 0.56; CI 0.311.02 for age category 7580 years and OR 0.69; CI 0.421.11 for age category 6074 years). Furthermore, statistically significant associations were found for the number of drugs prescribed per hospitalized patient (for the class of 46 drugs per patient OR 2.61, CI 1.325.18), for newly prescribed drugs (OR 6.65, CI 2.6316.81) and for the cessation of drugs on hospital admission (OR 1.50, CI 1.022.20). The use of gastrointestinal drugs (OR 2.13, CI 1.323.45), central nervous system drugs (OR 1.66, CI 1.072.57) and antibiotics (OR 2.44, CI 1.653.60) were associated with the development of ADEs, when compared to all other drugs taken by the patients.In this study, the most important risk factors are the number of drugs used per patient and the starting of a new drug during hospitalization. As most hospitalized patients start new drug therapies while in hospital, this seems an inappropriate focus. However, careful monitoring of patients using more than 7 drugs at a time may be possible in a costeffective system for the early detection of ADEs.     

European drug information centres ‐ survey of activities

A questionnaire survey of European drug information centres (DICs) was conducted. DICs mentioned in the ESCP directories and other sources were identified and contacted. Information on basic characteristics was obtained: affiliation, the scope of activities, employees, questionanswer service characteristics, information sources and the economic aspects of the DICs' work. Information from 84 DICs was analysed (return rate = 71.3%). DICs are mainly affiliated to hospitals (68%), rather rarely with faculties of pharmacy (6%) or with faculties of medicine (8.3%). Activities of DICs mainly include: questionanswer service (98%), issue of bulletins (68%), participation in P&T committees (63%), tuition (61%) and druguse evaluation (52%). Pharmacists, 12 full or parttime, are the most frequent employees working in the DICs. When the questionanswer service was analysed, it was found that 56% of the DICs are open only to the healthcare professionals and 43% provide a service to the lay public. Questions are mainly concerned with the side effects, indication/therapeutic use and the dosage of the drugs. The majority of DICs (91%) document their activities, very often on a computer database. Quality assurance is provided by almost 75% of DICs, usually by a review (58 %) or a feedback questionnaire (32%). Information sources listed as most frequently used include Martindale The Extrapharmacopeia, journals such as Lancet, Medline and Micromedex databases. DICs are usually financially supported by the organizations to whom they are affiliated. Fees are charged, for special activities, by 9.5% of DICs.     

Sex differences in the medication choice for hypertension in general practice. A study with written case simulations

The objective of this study was to explore explanations for the preference of physicians to prescribe blockers to hypertensive men and diuretics to hypertensive women.A qualitative study among 12 family physicians was conducted with a combination of written case simulations, semistructured interviews and statements on attitudes of physicians towards antihypertensive drug choice.Among the male hypertensive cases the most frequently prescribed drugs were blockers, whereas among the female hypertensive cases diuretics were more often prescribed. Physician characteristics associated with a preferred prescribing of blockers to hypertensive men and diuretics to hypertensive women were: older age (no residency in family medicine), the believe that blockers are more effective in men with regard to lowering blood pressure and that diuretics are more effective in women, a nonevidence based attitude and a sexrelated attitude towards the choice of blockers and diuretics in general, and in particular towards the prescribing of blockers to hypertensive men because men have a higher absolute risk of coronary heart disease than women. An additional explanation for these findings may be the higher prevalence of ankle oedema among women. Patient characteristics associated with more prescribing of blockers to hypertensive men and diuretics to hypertensive women were: current employment and a "highrisk" profile in terms of blood pressure level and additional cardiovascular risk factors.Although, most considerations underlying a preferred prescribing of blockers to hypertensive men and diuretics to hypertensive women were not evidencebased, the actual choice of antihypertensive drug (diuretic or blocker) was evidencebased. These considerations may also play a role in the sex difference in the choice of calcium antagonists and angiotensin converting enzyme inhibitors and require further investigation.     

New therapeutic targets for rheumatoid arthritis

New insights into the pathogenesis of rheumatoid arthritis (RA) and consequently new targets of therapy are covered in a broad overview fashion. Shortterm significant beneficial effect on RA disease activity has been established in a small but rapidly growing number of doubleblind placebocontrolled trials now including recombinant human IL1 receptor antagonist, chimeric (mouse/human) monoclonal antibodies (mAb) against TNFa (cA2), humanised (human/mouse) antiTNFa mAb (CDP571) and recombinant human TNFreceptorFc fusion protein (TNFR : Fc). Placebocontrolled trials of antiT cells agents such as chimeric antiCD4 mAb (cMT412) and antiCD5 immunoconjugate, did not demonstrate clinical benefit. A placebocontrolled study of the antiT cell derived cytokine IL2 (DAB486IL2) showed only modes clinical improvement. Other antiT cell approaches such as autologous T cell vaccination and induction of tolerance by oral type II collagen have been unsuccessful. The one controlled trial with an antiinflammatory cytokine, recombinant human IFNg, showed modest clinical benefits. Controlled trials with IL4 and IL10 and with antiadhesion molecules are awaited.     

Part 2: Pharmacology of neuromuscular blocking agents

Clinically, neuromuscular blockade is induced with either depolarizing or nondepolarizing relaxants. Suxamethonium is the only depolarizing relaxant still in use. It is hydrolysed in the plasma by pseudocholinesterase (plasma cholinesterase). In some patients and in particular diseases the plasma cholinesterase activity is low and hence the effect of suxamethonium prolonged. Suxamethonium is characterized by sideeffects such as myalgia, fasciculations and increase in intraocular, intracranial and intragastric pressure. More serious adverse reactions are masseter muscle spasm and potassium release, in patients with some neuromuscular diseases and increase in extrajunctional acetylcholine receptors. As nondepolarizing muscle relaxants benzylisoquinolines and steroidal compounds are mainly used. Each relaxant has its own pharmacological characteristics. The effect of most relaxants depends on liver and renal function because the pharmacokinetic behaviour is strongly dependent on these organs. Also, acidbase balance disturbances, change in temperature, and neurological diseases have an effect on the profile of the relaxants. A number of drugs (anaesthetics, antibiotics, antiepileptics, etc.) have an effect on neuromuscular transmission, and thus interact with the relaxants. Some non-depolarizing relaxants cause histamine release and cardiovascular effects.     

Peri‐marketing surveillance of lamotrigine in the Netherlands: Doctors'' and patients'' viewpoints

Purpose: Evaluation of daily clinical practice in prescribing lamotrigine in refractory epilepsy patients.Methods: A collaborative, retrospective, perimarketing study was performed in in and outpatients attending one of the three Dutch epilepsy centres. Analysis of both patients' and doctors' information was performed in 520 patients using questionnaires and medical files.Results:After one year of treatment 76% of patients maintained LTG treatment, an intentiontotreat analysis showed >= 50% seizure reduction in 23% of patients; 2050% seizure reduction in 23% of patients. Six percent of patients became at least three months seizure free. In about 20% of patients seizures became less severe and shorter of duration, while in 6% an increase was found.After three months a significant decrease in number of concomitant antiepileptic drugs was found (change from mean 1,8 to 1,5 AEDs) (p=< 0.01). After twelve months the mean number of AEDs was 1,4 per patient. Overall percentage of side effects appeared to be significantly higher if patients' questionnaire data were used. Epilepsy patients considered side effects as an important factor in the choice of medication and in withdrawal of medication. Future developments of new AEDs should take this into account. Conclusion: This perimarketing study gives insight information about longterm daily use of lamotrigine, with emphasis on effectiveness. Patients complained in the questionnaires much more about sideeffects, than was known according to the medical file. Therefore, it seems necessary to perform perimarketing studies more systematically.     

Comparative trials in registration files of cardiovascular drugs: Comparator drugs and dosing schemes.

Registration files of 13 cardiovascular drugs were analysed with respect to the number of doubleblind phaseIII clinical trials, the use of placebo and active comparator drugs and their dosing schemes. Half of the 146 doubleblind trials used active comparator drugs. The majority of files included firstchoice reference drugs, but we also found trials in three files with lower dosing schemes of comparator drugs and four files which included only placebo or active controlled doubleblind trials. To allow a better interpretation of the information provided in European Public Assessment Reports, which are published for every product approved for marketing in the European Union, uniform reporting is recommended on basic details of trial design, such as comparator drugs used and dosing schemes.     

Evaluation of the impact of pharmacist''s advice giving on the outcomes of self‐medication in patients suffering from dyspepsia

The aim of this study was to investigate the outcomes of selfmedication in patients suffering from dyspepsia by comparing changes in the Health related Quality of Life before and after selfmedication of dyspeptic disorders. Another study objective was the quantitative and qualitative analysis of the pharmacist's advicegiving to patients with dyspepsia. Therefore the impact of the counselling by the pharmacist on the patient's health outcomes was surveyed and compared between study and control pharmacies. Moreover, the study analysed the influence of a special training on the services provided by the pharmacies with regard to selfmedication.A beneficial effect of selfmedication on the HRQoL of patients with dyspepsia on a weekly basis has been detected in the study. There is evidence that advicegiving and counselling by the pharmacists in selfmedication have a measurable impact on selfmedication outcomes. Moreover, the study reveals that patients value the information provided by the pharmacist. Pharmacists gathered the relevant and comprehensive information from the patients having dyspeptic symptoms and provided advice concerning OTCdrugs. Moreover, pharmacists frequently discussed the relevance of factors aggravating dyspeptic disorders such as lifestyle, drinking, smoking, and manner of nutrition with the patient. Training programs and treatment guidelines for the pharmacist seem to obtain a positive effect on his performance. The findings of the study substantiate the value of a pharmacistcontrolled selfmedication. The study results suggest that the quality of primary health care in selfmedication would improve if pharmacists' involvement were even more intense.     

Cost‐effectiveness analysis of tropisetron vs. chlorpromazine‐dexamethasone in the control of acute emesis induced by highly emetogenic chemotherapy in children

Objective. To perform a costeffectiveness analysis (CEA) between a standard antiemetic regimen chlorpromazine + dexamethasone (CPMDEX) and a 5HT3 receptor antagonist tropisetron (TROP) in the control of acute emesis induced by highly emetogenic chemotherapy in children, considering two analytic perspectives: hospital and patients. Methods. The CEA was performed by constructing a decision tree, for both analytic perspectives, of the possible outcomes of treatment with TROP (single 0.2 mg/kg i.v.) or CPM (515 mg i.v. infusion for 3 doses) plus DEX (2 mg/m2 i.v. bolus i.v. × 2). The patients were stratified by age in two groups (212 and 1317). To estimate the probability of each endpoint at the decision tree we have taken as a base a trial developed in the Department of Pediatrics. Direct medical cost of primary therapy, failure, complications and side effects were included in the cost calculations. Results. From patients' analytic perspective, TROP was more costeffective than CPMDEX for both groups of patients. Discrepancy between both analytic perspectives in 1317 yearold patient's group was resolved in favour of the option chosen from the patients' analytic perspective (TROP). Sensitivity analysis showed the reliability of the results. Conclusions. 1. TROP was more costeffective than CPMDEX. 2. Taking into account the patients' analytic perspective is essential when we compare antiemetics pharmacoeconomically. 3. It seems necessary to increase the effectiveness of TROP in pediatric patients receiving highly emetogenic chemotherapy with strategies such as the addition of a steroid.     

Measurement of patient compliance.

Recent developments in our knowledge of the reninangiotensin system (RAS) necessitate an update of the classical view on this system. These developments pertain to the pathways leading to formation of angiotensin II and other active metabolites, their receptors, biological functions and the presence of reninangiotensin systems in tissues. The implications of the above new developments for the current interest in tissue reninangiotensin systems as potential targets for drug therapy in cardiovascular disease are discussed in this review.     

Agreement between self‐reported antihypertensive drug use and pharmacy records in a population‐based study in The Netherlands

From 1987 to 1991, over 36,000 men and women aged 2059 years have been examined in the Monitoring Project on Cardiovascular Disease Risk Factors in The Netherlands. Classification of the treatment status of hypertensives in this populationbased study was based on selfadministered questionnaires. In order to assess the accuracy of selfreported antihypertensive drug use we compared the questionnaire information with computerized pharmacy records from a sample of 372 hypertensive subjects. Most antihypertensive drugs that were mentioned in the questionnaire were present in the pharmacy medication history (93%). However, this percentage was less (76%) when a comparison was made with the calculated duration of use based on the number of units prescribed and the directions for use in the pharmacy records. About 94% of the hypertensive subjects who were using an antihypertensive drug according to the pharmacy records, also mentioned at least one antihypertensive drug in the questionnaire. Agreement between selfreported antihypertensive drug use and pharmacy records was consistently high for all classes of antihypertensive drugs. Among 321 (86%) subjects, the number and types of selfreported antihypertensive drugs were exactly the same as in the pharmacy records. In conclusion, the agreement between selfreported antihypertensive drug use and pharmacy records was high, and the selfreported questionnaire information on antihypertensive drug use can be reliably used for the classification of treatment status of hypertensive subjects in this populationbased study.     

Patients'' opinions of CFC‐free inhaler changeover in primary care

Objective: To determine patient's opinions regarding the changeover from CFC containing to CFCfree salbutamol. Design: Patients receiving metered dose salbutamol inhaler therapy were identified and verbal consent was obtained before a semistructured interview was performed.Setting An outpatient respiratory clinic within a busy teaching hospita. Main outcome measures: Knowledge of CFCfree inhaler therapy and acceptance of change. Results: A total of 28 patients were identified of whom only eight (29%) had been changed to a CFCfree product. Six of these (75%) had received counselling from their GP or pharmacist regarding the change. Differences were reported by all of the patients who had been changed to a CFCfree inhaler with comments including difference in taste (6 patients), difference in feel (6), less effective (1) and more effective (1). Three patients preferred the CFCfree inhaler to their previous therapy. Although 13 out of the 20 patients who had not received a CFCfree inhaler stated they were happy with the potential changeover, 10 (80%) has concerns relating to effectiveness. Conclusion: The majority of patients still receiving CFC inhalers were aware that the production of CFCcontaining products had been restricted although they were unaware of the imminent changes that would take place regarding their inhaler therapy. However, the small sample size recruited in this study may mean that the results are unrepresentative of the CFCfree implementation process in the Grampian Health Board area as a whole. Nonetheless, in view of the differences experienced by patients who received CFCfree inhalers and the concerns stated about potential lack of efficacy by patients about to be changed over, it is essential that healthcare professionals provide advice on CFCfree inhalers to all patients.     

Determination and pharmacokinetics of dextromoramide in methadone maintenance therapy.

To study the pharmacokinetics of dextromoramide in longterm opiate addicts on methadone maintenance therapy (MMT) a reversephase HPLC technique was developed to monitor dextromoramide and methadone concentrations in plasma simultaneously. After liquidliquid extraction from plasma, dextromoramide and methadone were determined using a Supelcosil LCABZ column and a mobile phase of KH2phosphate buffer (25 mM, pH 2.5) mixed with acetonitrile (80:20, v/v) and UV detection at 206 nm. The method was found to be sufficiently sensitive, specific and reproducible to apply in six subjects on MMT for many years, receiving orally administered dextromoramide as adjuvant. Pharmacokinetic data sets for dextromoramide in each subject were conducted and analysed further, indicating short elimination halflife values (71 min, range 31152 min). Contrary to previous studies, in all subjects tested the pharmacokinetics of dextromoramide are best described using an onecompartment model.     

Changing doctor prescribing behaviour

The aim of this overview was to identify interventions that change doctor prescribing behaviour and to derive conclusions for practice and further research. Relevant studies (indicating prescribing as a behaviour change) were located from a database of studies maintained by the Cochrane Collaboration on Effective Professional Practice. This register is kept up to date by searching the following databases for reports of relevant research: DHSSDATA; EMBASE; MEDLINE; SIGLE; Resource Database in Continuing Medical Education (19751994), along with bibliographies of related topics, hand searching of key journals and personal contact with content area experts. Randomised controlled trials and nonequivalent group designs with pre and postintervention measures were included. Outcome measures were those used by the study authors. For each study we determined whether these were positive, negative or inconclusive. Positive studies (+) were those that demonstrated a statistically significant change in the majority of outcomes measured at level of p 0.05 between the intervention and control groups. Negative studies () showed a significant change in the opposite direction and inconclusive studies () showed no significant change compared to control or no overall positive findings. We identified 79eligible studies which described 96 separate interventions to change prescribing behaviour. Of these interventions, 49 (51%, 41%61%) showed a positive significant change compared to the control group but interpretation of specific interventions is limited due to wide and overlapping confidence intervals.     

Para‐methylthioamphetamine, a new amphetamine designer drug of abuse

A case study is described of a patient who was intoxicated after the intake of socalled herbal stimulants. A visit to a physician after the intoxication prompted to this investigation and the case was examined for its direct cause. An interview with the patient revealed that the source of the herbal stimulants was a socalled 'S5 tablet'. Information provided on the packings of the tablet only indicated the presence of natural alkaloids and vitamines. Toxicological analysis however proved that the 'S5 tablet' contained paramethylthioamphetamine (MTA), mainly. MTA is a relative unknown amphetamine designer drug, which has only been studied as a model compound in some structureactivity relationship studies. The fact that MTA appeared in tablets was therefore completely unexpected. Not only the potential abuse of this new amphetamine designer drug is a serious matter of concern, but also the misleading information provided with the tablet.