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.     

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.     

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.     

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.     

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.     

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 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.     

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.     

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.     

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.     

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.     

Nursing and residential care for the elderly in Northern Ireland: the contribution of the pharmacist

Aim of the study: To gain more detailed information on the current pharmaceutical service provision in nursing and residential homes in Northern Ireland and to assess the views of care staff on future pharmacy services. Method: A structured questionnaire was developed and mailed to all nursing and residential homes (n=586) in Northern Ireland on two occasions. Results: A response rate of 68% (n=396) was obtained. The most frequent services currently provided by community pharmacists were the supply of medication and the collection of unwanted, discontinued or outofdate medicines. The majority of respondents also reported receiving advice on safekeeping, correct administration of medicines, advice on more appropriate formulations and advice on patient medication records from the community pharmacist. Over a third of all the respondents received advice on compliance devices. A similar proportion stated that their care staff were trained by the pharmacist on broad medication management issues.Over 90% of all homes strongly supported staff training by pharmacists on the recognition of medicationrelated problems as a future service. Over 70% of all respondents thought additional guidelines and advice for missed dosages and the use of home remedies would be beneficial. A review of patient medication records to assess drugdrug interactions and possible adverse drug reactions by pharmacists was supported by over 65% of all respondents. Conclusions: This work has demonstrated that those responsible for care in nursing and residential facilities strongly support further involvement by the pharmacist in these care facilities; pharmacy policy makers must ensure that such services are developed to meet the needs of these vulnerable elderly residents.     

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.     

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.     

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.     

Stability of dithranol in creams

The stability of the anthrachinone derivative dithranol in creams was studied during storage at temperatures of 4°C and 20°C. Aluminumcoated tubes with 0.1, 0.3 and 0.5% dithranol were stored and samples were analysed immediately and after 3, 6 and 12 months of storage. The 0.3% dithranol cream was also stored in polypropylene tubes. Drug concentration was analysed by highperformance liquid chromatography. All concentrations tested were stable for 12 months of storage at 4°C in aluminumcoated tubes. This means that these low concentrations are sufficiently stable to be prepared in advance for at least 12 months if prepared as described and kept refrigerated. Polypropylene tubes should not be used.     

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.     

Prevention of heterotopic ossification after total hip replacement with NSAIDs

Introduction: non steroidal antiinflammatory drugs ((NSAIDs) and prophylactic radiotherapy can prevent ectopic bone formation around the hip after total hip arthroplasty. Methods: We retrieved from Medline, Embase and the Cochrane Register (clinical)) trials and other relevant literature on the prevention of heterotopic ossification (HO) from 19902002 for further review.Results: Review of these clinical trials shows that HO is effectively prevented by a postoperative NSAID treatment with indomethacin for at least seven days. The best evidence is available for indomethacin, although naproxen, diclofenac and ibuprofen are also well documented. Short term use of ibuprofen is not effective. If NSAIDs are contraindicated, preoperative or postoperative radiotherapy is a very effective therapeutic option to prevent HO. Discussion and conclusion: Because of the potential of serious gastrointestinal side effects of NSAIDs and their interaction with anticoagulant drugs, rofecoxib and other COX2 specific NSAIDs may be a safer option for the treatment of HO. However, randomised controlled studies are needed to confirm the results of the rofecoxib study.     

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.