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.     

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.     

Pharmacoepidemiology and the “Impact Factor”

The field of Pharmacoepidemiology/Drug Utilization research has been analysed by studying published research articles under the medical subject headings (MeSH terms) Pharmacoepidemiology, Drug Utilization and Drug Utilization Review. There were 1822 articles published, and stored in Medline, during the 32-month period between 1 January 2001 and 31 August 2003; these papers might represent a field of research, due to the similarity of MeSH terms used for coding and the set of journals in which the articles were published. A total of 457 articles, representing 25% of all articles in the field, were published in 14 different journals, and 50% of all articles (948) were collected in only 64 different journals. The two main journals publishing research in Pharmacoepidemiology/Drug Utilization are Pharmacoepidemiol Drug Saf and the Eur J Clin Pharmacol. These two publications are the official journals of the three main societies in the field and are at least partially focused on this subject, with 45.7% of all articles in Pharmacoepidemiol Drug Saf and 11.1% of all articles in Eur J Clin Pharmacol included under the studied MeSH terms; other journals only occasionally publish papers in this line of research. These two journals are the leaders in pharmacoepidemiology and drug utilization research, having impact factors (IFs) in 2002/2003 above (1.955/1.972 for EJCP) and a bit below (1.092/1.257 for PDS) the middle of the ranking of publications, according to the IF, in the Pharmacology and Pharmacy list of the Science Citation Index (SCI).     

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.     

lontophoretic Devices for Drug Delivery

Transdermal drug delivery of ionized drugs can be enhanced by iontophoresis. Drug in the ionic form, contained in some reservoir, can be phoresed through the skin with a small current across two electrodes, one above the reservoir and one at a distal skin location. Positive ions can be introduced from the positive pole, or negative ions from the negative pole. The design and development of iontophoretic devices are rather simple. Some of the principles of operation and the advantages/disadvantages and clinical implications associated with these devices are outlined in this review.     

Cocaine-induced cocaine craving

In nine experienced users of cocaine, we examined the urge to use cocaine or other drugs following a 40 mg dose of intravenous (IV) cocaine with and without oral pretreatment with 2.5 mg bromocriptine. The urge to use cocaine was assessed with a questionnaire constructed to assess both wanting and craving for cocaine or other drugs. Fifteen minutes after the administration of cocaine (but not after placebo), subjects' ratings for both drug wanting and drug craving were significantly increased. Our results provide a laboratory demonstration of cocaine-induced increases in the urge to use drugs in humans. The findings, stressing the role of internal stimuli associated with drug administration, suggest the possibility of distinguishing among related, but perhaps distinct, components of the fluctuating levels of motivation to reuse drugs.     

Cytochrome P450 2D6: overview and update on pharmacology,genetics, biochemistry

Of about one dozen human P450 s that catalyze biotransformations of xenobiotics, CYP2D6 is one of the more important ones based on the number of its drug substrates. It shows a very high degree of interindividual variability, which is primarily due to the extensive genetic polymorphism that influences expression and function. This so-called debrisoquine/sparteine oxidation polymorphism has been extensively studied in many different populations and over 80 alleles and allele variants have been described. CYP2D6 protein and enzymatic activity is completely absent in less than 1% of Asian people and in up to 10% of Caucasians with two null alleles, which do not encode a functional P450 protein product. The resulting poor metabolizer (PM) phenotype is characterized by the inability to use CYP2D6-dependent metabolic pathways for drug elimination, which affect up to 20% of all clinically used drugs. The consequences are increased risk of adverse drug reactions or lack of therapeutic response. Today, genetic testing predicts the PM phenotype with over 99% certainty. At the other extreme, the Ultrarapid Metabolizer (UM) phenotype can be caused by alleles carrying multiple gene copies. Intermediate Metabolizers (IM) are severely deficient in their metabolism capacity compared to normal Extensive Metabolizers (EM), but in contrast to PMs they express a low amount of residual activity due to the presence of at least one partially deficient allele. Whereas the intricate genetics of the CYP2D6 polymorphism is becoming apparent at ever greater detail, applications in clinical practice are still rare. More clinical studies are needed to show where patients benefit from drug dose adjustment based on their genotype. Computational approaches are used to predict and rationalize substrate specificity and enzymatic properties of CYP2D6. Pharmacophore modeling of ligands and protein homology modeling are two complementary approaches that have been applied with some success. CYP2D6 is not only expressed in liver but also in the gut and in brain neurons, where endogenous substrates with high-turnover have been found. Whether and how brain functions may be influenced by polymorphic expression are interesting questions for the future.     

A method to shorten the training phase of drug discrimination

Rats were trained to discriminate drug from no drug in a two-lever, food-reinforced task. One group was trained with cocaine (10 mg/kg) and a second group was trained with pentylenetetrazol (20 mg/kg). A method designed to shorten the time required for the training phase of drug discrimination experiments was assessed in subgroups for each drug. In one subgroup, single training sessions were conducted daily. In the other subgroup, a second session (either drug or saline) was conducted on days for which the first condition was saline. The training conditions were presented in an irregular sequence, with the same condition occurring in no more than two consecutive sessions. Rats trained by the accelerated method learned the discrimination in fewer days, with no decrement in acquisition per session, suggesting that drug discrimination training can be accomplished more rapidly by reducing inter-session interval.     

Pharmacoeconomics: where is the link with pharmacokinetics and biopharmaceutics?

Several, mainly macroeconomic factors are putting increasing pressure on health care budgets. These budget constraints lead to cost containment measures by all partners involved in health care. Pharmacotherapy, too, is facing an increasing involvement in health economics or outcomes research. This paper will first deal with some basic principles of pharmacoeconomics. The relationship with pharmacokinetics and biopharmaceutics has perhaps not yet been an issue as such, though it should be pointed out that they play a key role in the efficiency of drug use. Many of the basic R&D investments aimed at developing costeffective medicines should be founded on adequate pharmacokinetics. Also a rational use of drugs in practice can be achieved by adequate drug monitoring, resulting in a gain in costeffectiveness. Last but not least, pharmacokinetics and biopharmaceutics can offer opportunities for the rational use of new or existing pharmaceutical products and for the maintenance of a sufficient market share. Some of these more technical aspects are discussed in the second part of this presentation.     

Pharmaco-epidemiological perspectives

Parallel with increasing concerns about drug safety, the importance of drug surveillance and the application of epidemiologic techniques have grown rapidly during the past decades. The increasing use of computerized health care data facilitates the establishment of populations large enough (millions) to allow epidemiological studies. Such extensive studies are now being done routinely in North America. By the use of computerized pharmacy or billing records, drug exposure is linked to files which include diagnoses. These record-linkage systems provide objective drug histories for pharmaco-epidemiological cohort and case-control studies and these large data bases offer powerful tools for drug evaluation. A number of new drug-disease associations, many of potential importance for European populations, will be discovered through the increased use of large data bases in North America. The European community needs to develop a strategy to respond to these overseas findings to protect the society from either overreaction or underreaction to drug safety issues.This article is based on a paper presented in the session Drug utilization and ADR surveillance — new technology and methods, at the WHO Drug Utilization Research Group meeting in Oslo, Norway, 28–30 September 1987.     

Soft Drugs. XX. Design,Synthesis, and Evaluation of Ultra-Short Acting Beta-Blockers

A new type of ultra-short acting -blocker which might prove advantageous in treating acute arrhythmias was designed, synthesized and investigated. Based on the soft drug inactive metabolite approach, the inactive phenylacetic acid metabolite of both metoprolol and atenolol was reactivated by esterification with sulfur-containing aliphatic alcohols. Since the sulfur-containing moieties are labile to the ubiquitous esterases, the new compounds should be inactivated by a one step enzymatic cleavage back to the inactive phenylacetic acid derivative. Pharmacological and pharmacokinetic profiles of the new compounds were evaluated in rats and rabbits. Isoproterenol-induced tachycardia was inhibited with short-term infusion of each compound. This tachycardia blocking effect rapidly disappeared upon termination of infusion, while -blocking activity was 2–4-fold longer after comparable doses of the short-acting -blocker, esmolol. The rapid recovery from the -receptor blockade is believed due to fast hydrolysis of the soft drugs in the body. This is supported from in vitro results showing the t_l/2 of esmolol is about 10-fold longer than the new soft drugs in rat, rabbit, dog and human blood. Hydrolysis studies in phosphate buffered solutions indicated that the esters are labile to base-catalyzed hydrolysis. However, the relative t_1/2 values measured in biological media compared to phosphate buffered solution clearly support rapid enzymatic cleavage of the soft drugs. Interestingly, one of the soft -blockers, the sulfonyl ester derivative, showed a unique property of exhibiting good -receptor blocking activity without significant hypotensive action.     

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.     

Mechanisms of drug transfer across the human placenta.

In this review we summarized literature data on the mechanisms of human placental drug transport studied in the isolated perfused placental cotyledon, placental membrane vesicles or trophoblastic cell cultures. Overall human placental drug transport rarely exceeds the transfer of flowdependent and membranelimited marker compounds. Interestingly, relatively often placental drug transfer appeared to be much smaller, indicating impaired trans-placental transport, depending on the physico-chemical characteristics of the drug or placental factors such as tissue binding or metabolism. Although in perfusion studies overall human placental drug transport occurs by simple diffusion, at the membrane level several drug transport systems have been found, mainly for drugs structurally related to endogenous compounds.     

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.     

Emea and the new pharmaceutical procedures for Europe

The regulation of medicines throughout Europe has undergone significant change since the first pharmaceutical Directive in 1965. 1995 will bring the next major stage in this evolution with the introduction of the so-called Future System proposals. These will see the creation of the EMEA (the European Medicines Evaluation Agency), the introduction of a Centralized Procedure, applicable to a small number of innovative drugs, and a Decentralized Procedure, based on mutual recognition of licences granted by existing control authorities in other EC countries. The regulation of medicines in the United Kingdom has also changed considerably since the establishment of the Medicines Control Agency in 1989. This article looks at the new licensing arrangements for Europe and the development of medicines control in the UK over the last few years.     

The discriminative stimulus and subjective effects of d-amphetamine in humans

Seventeen normal, healthy adults were trained to discriminate between orally administered d-amphetamine (AMP; 10 mg) and placebo. Standardized subjective effects questionnaires were used to examine the relationship between the subjective and discriminative stimulus effects of AMP. Seven of the subjects were able to learn the discrimination reliably. These seven discriminators did not differ from the ten nondiscriminators in their subjective ratings of mood in the absence of drug. Discriminators were generally more sensitive than nondiscriminators to the subjective effects of AMP, although this difference in sensitivity reached statistical significance only for ratings of hungry. Stimulus substituion was tested in the discriminators with other doses of AMP (2.5 and 5 mg) and with 10 mg diazepam. The discriminative stimulus properties of AMP were dose-dependent, with 5 mg being the threshold dose. In five of the seven subjects the discriminative stimulus properties of diazepam did not substitute for those of AMP. The results demonstrate that the experimental paradigm can be used successfully to study the discriminative stimulus properties of drugs directly in humans.     

Phenylpropanolamine: reinforcing and subjective effects in normal human volunteers

The reinforcing and subjective effects of phenylpropanolamine (PPA, 25 and 75 mg, PO) were compared with those of d-amphetamine (AMP, 5 mg) in a group of normal, healthy adults (eight males, nine females) with no history of drug abuse. A discrete-trial choice procedure was used in which subjects first sampled placebo and a dose of one of the drugs. Subjects were then allowed to choose between self-administration of drug or placebo on three separate occasions. The relative frequency with which active drug was chosen over placebo was used as the primary index of the drug's reinforcing efficacy. Subjective effects were measured with the Profile of Mood States, a short version of the Addiction Research Center Inventory and a series of visual analog scales. Ratings of drug liking, drug labelling, general activity level and strength of drug preference were also obtained. As expected, AMP was chosen significantly more often than expected by chance (69% of occasions). AMP also increased ratings of drug liking, preference strength, and activity level, and produced a profile of subjective effects consistent with its well-established stimulant and euphorigenic properties. The low dose of PPA was without effect on most measures. PPA 75 mg was chosen significantly less often than expected by chance (39% of occasions). This dose of PPA was most frequently labelled as a stimulant, and produced significant increases on ratings of Anxiety and stimulated, and decreases on ratings of sedated and hungry. Unlike AMP, PPA did not affect ratings of drug liking or mood scales reflecting euphoria. In sum, these results indicate that PPA does not possess AMP-like dependence potential.     

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.     

Is there a need for more precise definitions of bioavailability?

Summary After evaluation of the present definitions in a set of particular cases, it was agreed that there was no need for more precise definitions and that the current ones were adequate in the majority of cases. However, it was felt that the present definitions might be improved, in particular in view of the existence of non-systemically acting drugs and future targeted drugs. Thus, the FDA definition might be modified as follows: Bioavailability means the rate and extent to which the active drug ingredient or therapeutic moiety from a drug product becomes available at the site of drug action or in a biological medium believed to reflect accessibility to a site of action.     

Current benzodiazepine issues

This article deals with some of the recent evidence bearing on the issues of the liability of benzodiazepines to lead to abuse, dependence, and adverse behavioral effects. Reviews of epidemiological, clinical and experimental literature indicated that the previous conclusion about abuse of these drugs still holds: the vast majority of the use of benzodiazepines is appropriate. Problems of nonmedical use arise nearly exclusively among people who abuse other drugs. Nevertheless, there are reasons for concern about patients who take benzodiazepines regularly for long periods of time. These drugs can produce physiological dependence when taken chronicaly, and although this does not appear to result in dose escalation or other evidence of psychological dependence, physiological dependence can result in patient discomfort if drug use is abruptly discontiniued. Also, physicians are currently prescribing shorter-acting benzodiazepines in preference to longer-acting benzodiazepines. The shorter-acting drugs can produce a more intense withdrawal syndrome following chronic administration. Furthermore, rates of use of benzodiazepines increase with age, and elderly patients are more likely than younger ones to take the drug chronically. The clearest adverse effect of benzodiazepines is impairment of memory. This, too, may be particular concern in older patients whose recall in the absence of drug is typically impaired relative to younger individuals, and who are more compromised following drug administration.This article was supported by USPHS Grant DA-00254 and by funding from Hoffmann-La Roche, Inc.