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.     

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.     

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.     

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.     

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.     

Clinical pharmacokinetics of camptothecin topoisomerase I inhibitors.

In this review the clinical pharmacokinetics of camptothecin topoisomerase I inhibitors, an important new class of anticancer drugs, is discussed. Two prototypes, topotecan and irinotecan, are currently marketed in many European countries and the USA for the treatment of patients with ovarian and colorectal cancer, respectively. Other camptothecin derivatives, including lurtotecan, 9aminocamptothecin (9AC) and 9nitrocamptothecin (9NC), are at different stages of clinical development. The common property of camptothecin analogues is their action against DNA topoisomerase I, but beyond this similarity the compounds differ widely in terms of antitumour efficacy, pharmacology, pharmacokinetics and metabolism. We review chemistry, mechanism of action, stability and bioanalysis of the camptothecins. Dosage and administration, status of clinical application, pharmacokinetics, pharmacodynamics and drug interactions are discussed.     

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.     

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.     

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.     

Number of non‐diabetic drugs: a simple comorbidity indicator for diabetes?

Introduction: The number of nondiabetic drugs, taken by a patient with diabetes at any one point in time, has been validated in previous studies as a comorbidity indicator.Aim: The aim of the paper is to examine the relationship between this comorbidity indicator and health status in people with Type 2 diabetes.Method: The analysis presented is from a prospective cohort study of people with Type 2 diabetes before and after commencing insulin therapy, with simultaneous collection of health status, clinical and other comparative data. Results: Of the 48 people for whom both health status and drug data were available, 26 (54%) were taking at least one nondiabetic drug and 16 (33%) were taking 3 or more nondiabetic drugs, at the baseline assessment. There were no significant relationships between the number of nondiabetic drugs taken, and age, duration of diabetes or baseline HbA₁c measurements. However, there were statistically significant relationships between the number of nondiabetic drugs and health status, in terms of depression and physical function.Conclusion: Drug data are routinely recorded in primary care and therefore the number of nondiabetic drugs is a potentially widely available indicator. This indicator could be a useful, simple addition to datasets that not only proxies comorbidity but also relates to patients' physical function and depression status.     

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.     

Recent developments in the management of psychosis.

Antipsychotic drugs are effective in psychoses, whatever the aetiology of the disorder. The positive symptoms tend to respond more readily. The need for developing new drugs arises from the refractoriness of the negative symptoms, the 1025% of the patients that are treatmentresistant and the problems of short, and longterm extrapyramidal sideeffects. Thus far, five drugs differing from the classical antipsychotics have been licensed for use: clozapine, olanzepine, risperidone, sertindole and sulpiride, and in at least some European countries quetiapine is now in the final phase of clinical research. This review starts with a brief introduction to symptomatology, is limited to the registered drugs and addresses differences with the classical drugs in pharmacology, pharmacokinetics, clinical aspects and sideeffects. Clozapine, risperidone and sulpiride can be considered for clinical use in refractory patients, and these three together with olanzapine and sertindole are candidates when extrapyramidal sideeffects cause a clinical problem.     

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.     

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.     

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.     

Distribution of pharmaceuticals ? a Norwegian logistic perspective

There is a general concern about rising costs of pharmaceutical expences. One political measure is a more efficient distribution system, which can take the form of new channels for retailing. In Norway mailorder pharmacy (MOP) has been brought to the agenda due to the recently proposed law regulating pharmacies (Apoteklov), market developments abroad, demand for selfmedication, the increase in OTCproducts and advances in information technology. Mailorder pharmacy involves direct delivery of medications through postal mail to patients or those responsible for dispensing medication. With reference to the USA, mailorder pharmacy has filled a niche in the market and several other countries are following. We are convinced that it is possible to maintain a high level of service quality in the sense of safety, councelling and compliance, and that there is a potential to develop a model for this distribution form in Norway. We believe that the actors in the Norwegian pharmaceutical market are better served in taking a more active role in this area and where possible initiating pilot projects in mailorder distribution. The pharmacists will continue to play an important role as a retail outlet and should, with their influence over patients, their knowledge and experience, contribute towards developing MOP to be a safe and complementary sales outlet. Developing such a solution demands the right balance between performance and quality on the one hand and efficiency on the other; two criteria, which we believe, do not contradict each other.     

Genotyping of the arylamine N‐acetyltransferase polymorphism in the prediction of idiosyncratic reactions to trimethoprim‐sulfamethoxazole in infants.

The pathogenesis of hypersensitivity to trimethoprimsulfamethoxazole (TMPSMX) is supposed to be associated with the slow acetylation phenotype. This pharmacogenetic defect is associated with the mutations of the arylamine Nacetyltransferase (NAT2) encoding gene. The aim of the study was to compare the usefulness of the acetylation phenotype and NAT2 coding genotype in the prediction of idiosyncratic reaction to Cotrimoxazole in infants. The study was carried out in the group of 20 infants, aged 212 months (mean age 6.3 months) treated with Cotrimoxazole, administered at 100 mg/kg b.w./24 h doses. In seven children (35%) no adverse effects of the treatment have been observed, whereas in 13 (65%) children various adverse effects occurred as a result of the therapy, such as rash (4 children), granulocytopenia with anemization (5 children) or liver impairment (4 children). The acetylation phenotype of each child was determined on the basis of urine of Nacetyl isoniazid/isoniazid ratio, after ingestion of isoniazid as a model drug. Furthermore we used polymerase chain reaction (PCR) followed by the analysis of restriction fragments length polymorphism (RFLP) technique to identify the known mutant alleles of the NAT2 gene. It has been presumed that the genotype determining fast acetylation contains at least one of wildtype allele. No correlation has been found between the observed adverse effects of Cotrimoxazole and age, gender and acetylation phenotype. However, it has been demonstrated that the risk of adverse effects of Cotrimoxazole is considerably higher in children with mutations of the NAT2 encoding gene. The comparison of the results from PCRRFLP genotyping with phenotyping suggested that in infants, the NAT2 genotype rather than phenotype provides the basis for the detection of hypersensitivity to TMPSMX.     

Therapy related hospital admission in patients on polypharmacy in Singapore: a pilot study

Objective: To estimate the incidence of drug-related problems (DRPs)associated hospital admission, and its correlation to polypharmacy and age.Method: A retrospective, crosssectional study in in-patients on polypharmacy in Singapore. Significant differences (p < 0.05) between number of medications taken and age of patients were tested with the chisquare test.Results: The study population consisted of 347 patients (aged 16–97) on a mean of 7.4 ± 2.1 medications. 10.8% of the study population had DRPs on admission: 71.9% of which were dominant reasons for admission, and DRPs contributed partly in the remaining cases. These DRPs were mostly avoidable, and can be broadly classified into noncompliance, adverse drug reactions, require synergistic therapy, inappropriate dose and untreated condition. 52% of these cases were made up of geriatric patients. No statistical difference was found between patients on polypharmacy and those on major polypharmacy (10 and more drugs) in having a DRP.Conclusion: In this study, DRPs contributing to hospital admission appeared to be avoidable. Geriatrics were more susceptible to DRPs and future efforts are required in managing medications prescribed for these patients to reduce such incidences.     

Leading ordinary lives: a qualitative study of younger women''s perceived functions of antidepressants

Background: While the overall consumption of psychotropic medicines such as tranquillisers and hypnotics has declined, the consumption of the newer antidepressants – selective serotonin reuptake inhibitors (SSRIs) has increased drastically since their introduction. In order to understand the mechanisms underlying the use, it is important to gain insight into the users' perceptions about their medicine and use.Objective: To analyse younger women's perceived functions of SSRIs in their everyday lives. Methods: 12 in depth interviews and 6 re interviews were conducted with a community based sample of 21 to 34 year old women taking SSRIs. The women were recruited through Danish pharmacies.Results: Prior to taking SSRIs the women struggled with their emotional problems, often in great frustration and distress. While taking SSRIs the women experienced that the medicine functioned both at a psychological and a social level. They believed that the medicine gave them resources to behave actively in a way that was not previously possible. They felt that the medicine use enabled them to concentrate on daily life activities other than dealing solely with their emotional problems. The women found that the medicine gave them back a sense of 'normality'.Conclusion: The main finding in this paper is that the perceived functions of SSRIs were related to social meanings and goals in everyday life.