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.     

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.     

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.     

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.     

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.     

Design and implementation of a common drug information database for a university hospital

Background: Providing high quality problem oriented drug information relies on the ability to easily collect appropriate background information on clinical cases, to access relevant information from published sources by defined search strategies and to store and retrieve previously answered questions. To do this efficiently, an easy to use, flexible and reliable drug information database is necessary. Methods: We designed and implemented an Intranet based drug information database for a major university hospital in Germany. The overall design and the technical details of its design are discussed. We developed a generic, XML based data model for pharmaceutical inquiries including a MeSH oriented system of 99 pharmaceutical qualifiers to enable efficient indexing of questions and the searching of indexed questions.Results: The system provides query statistics and various search algorithms. The software implementation takes into account recent FDA recommendations for software used in clinical trials; internal review for quality control is supported. The database currently consists of 4224 records after 3.5 years of operation. Each inquiry consists of 50 items, 18 of 50 are categorized; 135 text elements support data entry. Our evaluation is focused on technical feasibility, user acceptance and query patterns.Conclusion: The intensive use and widespread acceptance of the database indicates a need for a computerized drug information system and suggests that Intranet technology can perform this task.     

The quality of Dutch hospital drug formularies: Evaluation of technical features and organisational information

Introduction: Hospital drug formularies (HDFs) are widely used tools to help influence clinicians' prescribing behaviour. Besides the therapeutic quality of HDFs, the available information and the way in which this is presented are key factors in HDFs' success or failure to influence prescribing behaviour and enhance prescribing quality. This research evaluates the technical features and organisational information of Dutch HDFs. Methods: Seventytwo (75%) of all Dutch HDFs were evaluated based on criteria retrieved from international literature and additional criteria drafted by occupational groups working with HDFs. Aspects that were studied were physical appearance and layout, practicability with respect to the available information and how easily this could be retrieved from the HDFs, information regarding drug choice policies such as seamless care, and the available type of therapeutic and pharmaceutical information. Results: Thirtythree (46%) of the HDFs were less than 3 years old. Physical appearance of all HDFs was very well looked after. Two (3%) HDFs were diseaseoriented rather than drugoriented. Changes from preadmission therapy were addressed in 30 (42%) of the HDFs, but other seamless care policies were addressed in less than 20% of the HDFs. Finally, less than 50% provided therapeutic information that clinicians indicated as important. Discussion: Although Dutch HDFs are technically practicable with respect to userconvenience, practiceoriented features are capable of improvements. Furthermore, Dutch HDFs lack important clinical information for daily practice. To enhance seamless care across healthcare, generic prescribing and prescribing on admission from and discharge to any other sectors should be addressed more specifically.     

Elevated plasma levels of clozapine after concomitant use of fluvoxamine

Selective serotonin reuptake inhibitors can be added to clozapine therapy in order to treat remaining negative symptoms and obsessive compulsive symptoms. The present case report describes a 44yearold man exhibiting extremely elevated plasma levels of clozapine after the addition of fluvoxamine, up to 4160 mcg/l. The elevated plasma levels of clozapine, which were discovered 6 months after the SSRI was added, is likely to be caused by a drugdrug interaction. Clozapine is a substrate of CYP 1A2 and is predominantly metabolised in the liver. Of the SSRIs, fluvoxamine is one of the most potent inhibitors of the isoenzyme CYP 1A2. This case serves to emphasise the need for continuous attention to drugdrug interactions, especially when they might be easily overlooked due to the lack of clear symptoms.     

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.     

Desire for information about drugs A multi‐method study in general medical inpatients

The purpose of this paper is to investigate patients' drug information preferences using a combination of quantitative and qualitative methods. Patient interviews (n=299) were conducted on general medical wards in three London teaching hospitals. The purpose was to refine and validate a quantitative 12item scale, the Intrinsic Desire for Information (IDI), by interfacing quantitative and qualitative data, and to explore the relationship between this scale score and patient demographics. The IDIscale was subjected to factor analysis. Two secondary factors were found in the IDI scale; a 5item factor describing the extent of information desired and a weaker 3item factor describing an inhibited desire for knowledge about illness/drugs. Reliability analysis and multiple regression analysis were undertaken. Responses to open answer questions during the qualitative interviews were transcribed at the bedside and imported into QSR NUD*IST software program for coding and analysis. The methodology employed in this study involved importing quantitative, summative data into a qualitative data base and reanalysing both the quantitative and qualitative data to validate the scale. Age was a predominant factor associated with patient desire for information, although the data suggest that educational and socioeconomic status are also influential. Factor 1, the extent of information desired, may have value in targeting receptive patients, or in identifying those who may be refractory to drug information. The refined tool could help health services to effectively target information provision based on evidence, rather than supposition.     

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.     

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.     

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.     

Evaluation of physicochemical incompatibilities during parenteral drug administration in a paediatric intensive care unit

Patients in paediatric intensive care units (PICU) often receive numerous medications by the parenteral route. Frequently two or more drugs are delivered simultaneously through the same line and the risk of physicochemical incompatibilities is thus important. The objectives of this study were 1) to identify prospectively the combinations of injectable drugs administered in the PICU of our university hospital and 2) to analyze them according to information found in the literature. The data were collected by a pharmacist over a 30day period and classified in three categories: compatible, incompatible and undocumented. Nineteen patients were included in the study with a median age of 3.2 years. The mean number (± SD) of injectable drugs per patient and per day was 6.5 (± 2.8), for a total of 26 drugs and 7 solutes. 64 combinations of drugs were observed with 2 (31.3%), 3(45.3%), 4 (10.9%) or 5 (12.5%) drugs. 81 drug drug and 94 drug solute combinations were recorded. Among these, 151 (86.3%) were compatible, 6 (3.4%) incompatible and 18 (10.3%) undocumented. The incompatibilities included furosemide (Lasix®), a drug in alkaline solution and VaminaGlucose®, a total parenteral nutrition solution. No clinical consequences resulting from drug incompatibilities were shown in this study. We suggest that in vitro compatibility tests on standard drug combinations, as well as a training program for nurses on drug incompatibility problems would sensitively increase the security of parenteral drug administration.     

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.     

Physico‐chemical stability of docetaxel premix solution and docetaxel infusion solutions in PVC bags and polyolefine containers

We assessed the physical and chemical stability of docetaxel infusion solutions. Stability of the antineoplastic drug was determined 1.) after reconstitution of the injection concentrate and 2.) after further dilution in two commonly used vehiclesolutions, 0.9% sodium chloride and 5% dextrose, in PVC bags and polyolefine containers. Chemical stability was measured by using a stabilityindicating HPLC assay with ultraviolet detection. Physical stability was determined by visual inspection. The stability tests revealed that reconstituted docetaxel solutions (= premix solutions) are physicochemically stable (at a level 95% docetaxel) for a minimum of four weeks, independent of the storage temperature (refrigerated, room temperature). Diluted infusion solutions (docetaxel concentration 0.3 mg/ml and 0.9 mg/ml), with either vehiclesolution, proved physicochemically stable (at a level 95% docetaxel) for a minimum of four weeks, when prepared in polyolefine containers and stored at room temperature. However, diluted infusion solutions exhibited limited physical stability in PVC bags, because docetaxel precipitation occured irregularly, though not before day 5 of storage. In addition, timedependent DEHPleaching from PVC infusion bags by docetaxel infusion solutions must be considered.     

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.     

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.     

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.