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Supersaturated drug delivery systems are commonly used to address the problems of poor aqueous solubility posed by most of the active pharmaceutical ingredients (APIs). However, the supersaturated systems are highly unstable due to their high free energy levels and demonstrate a tendency to precipitate. Understanding the crystallization tendency based on the mechanisms of crystallization, that is nucleation and crystal growth, is imperative to design formulation strategies and select appropriate precipitation inhibitors. This study aims to provide a classification system, based on both the nucleation and crystal growth tendency in the solution state of 60 APIs and nutraceuticals (in absence of polymer) from their desupersaturation profiles monitored by UV-Visible spectroscopy. The APIs and nutraceuticals are divided into four classes based on their induction time (t ind ) and crystal growth rate as fast nucleators-fast crystal growth (class I), fast nucleators-slow crystal growth (class II), slow nucleators-fast crystal growth (class III) and slow nucleators-slow crystal growth (class IV). Most of the molecules fall in the class I and class IV. An easy-to-use protocol for nucleation and crystal growth studies has been optimized. This protocol will find application to assess the crystallization tendency of the molecules in the preliminary screening stages, enabling appropriate formulation strategies to inhibit crystallization.

Purpose: Increased numbers of drugs and changes in pharmacokinetic and pharmacodynamic parameters among elderly people contribute to increased prevalence of adverse drug reactions. Drug-drug interactions (DDIs) are an important reason for admission to hospital and elderly people with dementia are particularly vulnerable. The aims of the present study were to assess the occurrence and characteristics of clinically relevant DDIs and to investigate potential risk factors associated with DDIs among elderly people with dementia., Methods: People ≥ 65 years with dementia, admitted to two hospitals in Northern Sweden, were included. The medical records of 458 patients were reviewed. Clinically relevant DDIs were identified using the Janusmed interactions database. Pharmacological classification was conducted using Stockley's classification system., Results: A total of 401 DDIs were identified among 43.2% of the study population, of which 98.5% had interactions that may require dose adjustment and 7.6% had drug combinations that should be avoided. Pharmacodynamic interactions were most common, of which furosemide-citalopram (n = 35) were most frequently observed. Omeprazol-citalopram (n = 25) was the most common drug combination among pharmacokinetic interactions. Citalopram and warfarin were the most commonly involved drug substances. An association was found between a higher number of medications being prescribed and having at least one DDI., Conclusion: Clinically relevant drug-drug interactions are prevalent among elderly people with dementia living in Northern Sweden. Drug-drug interactions should be identified in order to manage and prevent adverse outcomes. This is particularly important among this group of people especially when multiple medications are being prescribed.

Because of the growing healthcare market and the increasing health consciousness of the population, more and more food supplements are being placed on the market in addition to medicinal products. Concerning the demarcation of medicinal products to food supplements, not only is the intended purpose of the product critical, but the mode of action of the respective preparation also plays an important role. Following the legal definition, a drug has a pharmacological effect, without it being further defined. Therefore, many courts have already tried to interpret the term pharmacological effect, including the terms metabolic or immunologic effect, and try to describe this in more detail.It should be noted that the pharmacological effect, which means an interaction of the substance of a medicinal product with cellular constituent of the human body - unlike the effect of a foodstuff - must significantly affect the physiological functions and must therefore exert targeted effects on the human body and its functions, more than with the consumption of a conventional quantity of a food would be possible. These modifying physiological functions of the body must be addressed positively, which means beneficial to human health. Products which are consumed only for euphoria purposes, or even have a harmful effect, shall not be classified as medicinal products, despite their pharmacological mechanism of action.

Objective: The public accessibility of "big data" about the molecular targets of drugs and the biological functions of genes allows novel data science-based approaches to pharmacology that link drugs directly with their effects on pathophysiologic processes. This provides a phenotypic path to drug discovery and repurposing. This paper compares the performance of a functional genomics-based criterion to the traditional drug target-based classification., Methods: Knowledge discovery in the DrugBank and Gene Ontology databases allowed the construction of a "drug target versus biological process" matrix as a combination of "drug versus genes" and "genes versus biological processes" matrices. As a canonical example, such matrices were constructed for classical analgesic drugs. These matrices were projected onto a toroid grid of 50 × 82 artificial neurons using a self-organizing map (SOM). The distance, respectively, cluster structure of the high-dimensional feature space of the matrices was visualized on top of this SOM using a U-matrix., Results: The cluster structure emerging on the U-matrix provided a correct classification of the analgesics into two main classes of opioid and non-opioid analgesics. The classification was flawless with both the functional genomics and the traditional target-based criterion. The functional genomics approach inherently included the drugs' modulatory effects on biological processes. The main pharmacological actions known from pharmacological science were captures, e.g., actions on lipid signaling for non-opioid analgesics that comprised many NSAIDs and actions on neuronal signal transmission for opioid analgesics., Conclusions: Using machine-learned techniques for computational drug classification in a comparative assessment, a functional genomics-based criterion was found to be similarly suitable for drug classification as the traditional target-based criterion. This supports a utility of functional genomics-based approaches to computational system pharmacology for drug discovery and repurposing.

According to the EU Directive 2001/83 the European Pharmacopoeia is the official Pharmacopoeia of the European Union. Therefore the European Pharmacopoeia is one of the legal pharmacopoeial compendia in Germany. Any licensed medicinal product on the German market complies with the requirements of the compendial monographs, if applicable. Because the general monographs of the European Pharmacopoeia on Dosage Forms, Substances for Pharmaceutical Use and Pharmaceutical Preparations refer to the microbiological and biological methods of the Pharmacopoeia, the methods are relevant for medicinal products, too. This article presents a rough summary of the microbiological and biological methods of the European Pharmacopoeia and is intended to be a stimulus for the reader to better understand the original compendia. The short description of the methods mentioned, here, is a summary from the Pharmacopoeia and the non-official collection of comments on the texts of the European Pharmacopoeia.

Purpose: A medication error (ME) is an error that causes damage or poses a threat of harm to a patient. Several studies have shown that only a minority of MEs actually causes harm, and this might explain why medication reviews at hospital admission reduce the number of MEs without showing an effect on length of hospital stay, readmissions, or death. The purpose of this study was to define drugs that actually cause serious MEs. We conducted a literature search of medication reviews and other preventive efforts., Methods: A systematic search in PubMed, Embase, Cochrane Reviews, Psycinfo, and SweMed+ was performed. Danish databases containing published patient complaints, patient compensation, and reported medication errors were also searched. Articles and case reports were included if they contained information of an ME causing a serious adverse reaction (AR) in a patient. Information concerning AR seriousness, causality, and preventability was required for inclusion., Results: This systematic literature review revealed that 47 % of all serious MEs were caused by seven drugs or drug classes: methotrexate, warfarin, nonsteroidal anti-inflammatory drugs (NSAIDS), digoxin, opioids, acetylic salicylic acid, and beta-blockers; 30 drugs or drug classes caused 82 % of all serious MEs. The top ten drugs involved in fatal events accounted for 73 % of all drugs identified., Conclusion: Increasing focus on seven drugs/drug classes can potentially reduce hospitalizations, extended hospitalizations, disability, life-threatening conditions, and death by almost 50 %.

In this report, we refer to pharmaceuticals that are widespread in the urban aquatic environment and that mainly originate from wastewater treatment plants or non-point source sewage as "wastewater-marking pharmaceuticals" (WWMPs). To some extent, they reflect the condition or trend of water contamination and also contribute to aquatic environmental risk assessment. The method reported here for screening typical WWMPs was proposed based on academic concerns about them and their concentrations present in the urban aquatic environment, as well as their properties of accumulation, persistence, eco-toxicity and related environmental risks caused by them. The screening system consisted of an initial screening system and a further screening system. In the former, pharmaceuticals were categorised into different evaluation levels, and in the latter, each pharmaceutical was given a normalised final evaluation score, which was the sum of every score for its properties of accumulation, persistence, eco-toxicity and environmental risk in the aquatic environment. The system was applied to 126 pharmaceuticals frequently detected in the aquatic environment. In the initial screening procedure, five pharmaceuticals were classified into the "high" category, 16 pharmaceuticals into the "medium" category, 15 pharmaceuticals into the "low" category and 90 pharmaceuticals into the "very low" category. Subsequently, further screening were conducted on 36 pharmaceuticals considered as being of "high", "medium" and "low" categories in the former system. We identified 7 pharmaceuticals with final evaluation scores of 1-10, 10 pharmaceuticals with scores of 11-15, 15 pharmaceuticals with scores from 16 to 20 and 4 pharmaceuticals with scores above 21. The results showed that this screening system could contribute to the effective selection of target WWMPs, which would be important for spatial-temporal dynamics, transference and pollution control of pharmaceuticals in the urban aquatic environment. However, there remains a number of pharmaceutical parameters with measured data gaps, such as organic carbon adsorption coefficients and bioconcentration factors, which, if filled, would improve the accuracy of the screening system.

Background: Anticholinergic drugs are often involved in explicit criteria for inappropriate prescribing in older adults. Several scales were developed for screening of anticholinergic drugs and estimation of the anticholinergic burden. However, variation exists in scale development, in the selection of anticholinergic drugs, and the evaluation of their anticholinergic load. This study aims to systematically review existing anticholinergic risk scales, and to develop a uniform list of anticholinergic drugs differentiating for anticholinergic potency., Methods: We performed a systematic search in MEDLINE. Studies were included if provided (1) a finite list of anticholinergic drugs; (2) a grading score of anticholinergic potency and, (3) a validation in a clinical or experimental setting. We listed anticholinergic drugs for which there was agreement in the different scales. In case of discrepancies between scores we used a reputed reference source (Martindale: The Complete Drug Reference®) to take a final decision about the anticholinergic activity of the drug., Results: We included seven risk scales, and evaluated 225 different drugs. Hundred drugs were listed as having clinically relevant anticholinergic properties (47 high potency and 53 low potency), to be included in screening software for anticholinergic burden., Conclusion: Considerable variation exists among anticholinergic risk scales, in terms of selection of specific drugs, as well as of grading of anticholinergic potency. Our selection of 100 drugs with clinically relevant anticholinergic properties needs to be supplemented with validated information on dosing and route of administration for a full estimation of the anticholinergic burden in poly-medicated older adults.

Purpose: We aimed to demonstrate the suitability of the Anatomical Therapeutic Chemical Classification (ATC) to describe duplicate drugs and duplicate drug classes in prescription data and describe the pattern of duplicates from public and private primary care clinics of Kuala Lumpur, Malaysia., Methods: We analyzed prescription data year 2005 from all 14 public clinics in Kuala Lumpur with 12,157 prescriptions, and a sample of 188 private clinics with 25,612 prescriptions. As ATC Level 5 code represents the molecule and Level 4 represents the pharmacological subgroup, we used repetitions of codes in the same prescription to describe duplicate drugs or duplicate drug classes and compared them between the public and private clinics., Results: At Level 4 ATC, prescriptions with duplicates drug classes were 1.46% of all prescriptions in private and 0.04% in public clinics. At Level 5 ATC, prescriptions with duplicate drugs were 1.81% for private and 0.95% for public clinics. In private clinics at Level 5, 73.3% of prescriptions with duplicates involved systemic combination drugs; at Level 4, 40.3% involved systemic combination drugs. In the public sector at Level 5, 95.7% of prescriptions with duplicates involved topical products., Conclusions: Repetitions of the same ATC codes were mostly useful to describe duplicate medications; however, we recommend avoid using ATC codes for tropical products for this purpose due to ambiguity. Combination products were often involved in duplicate prescribing; redesign of these products might improve prescribing quality. Duplicates occurred more often in private clinics than public clinics in Malaysia.

Introduction: Black box warnings (BBWs) are the strongest medication-related safety warnings in a drug's labeling information and highlight major risks. Absence of a BBW or asynchronous addition of a BBW among same-class drugs could have major implications., Methods: We identified the 20 top-selling drugs in 2008 (10 with BBWs and 10 without BBWs on their label) that belonged to different drug classes. We collected labeling information on all drugs belonging in these 20 classes, and recorded differences in the presence and timing of acquisition of BBWs for same-class drugs., Results: Across the 20 evaluated drug classes, we identified 176 different agents, of which 7 had been withdrawn for safety reasons. The reasons for the withdrawals became BBWs in other same-class agents only in two of the seven cases. Differences were identified in 9 of the 20 classes corresponding to 15 BBWs that were not present in all drugs of the same class. The information for 10 of the 15 different BBWs were included in the labels of same-class drugs as simple warnings or text, while it was absent entirely in 5 BBWs. The median interval from the time the BBW had appeared in another drug of the same class was 66 months., Discussion: Differences in BBW labeling in same-class drugs are common and shape impressions about the safety of similar agents. BBW labeling needs to become more systematic.

Objective: The aim of this research was to describe the types of prescription medicines being imported into New Zealand., Setting: Imported medicines intercepted at the international mail centre in Auckland and referred to the New Zealand Medicines and Medical Devices Safety Authority (Medsafe) between July and December 2007 were studied., Method: During the study 3,918 prescription medicine imports were intercepted and entered into a database by Medsafe. These were categorised according to the country the medicines were posted from and medicine related details such as brand, active ingredient(s), route of administration, strength and quantity imported. Researchers systematically categorised medicines by therapeutic indications, dosage form, whether these medicines were available in New Zealand and if they were subsidised by the New Zealand government., Main Outcome Measure: Types of medicines imported into New Zealand and whether or not they were legally available and subsidised by the government., Results: Medicines were most commonly imported from India and China. Seventy eight percent of the total medicines imported were already available in New Zealand, and of these almost half were subsidised by the government. Antibiotics contributed to a significant proportion of the total subsidised medicines imported, the most common being amoxicillin. Four of the five most commonly imported medicines could be considered 'lifestyle' medicines (sildenafil, tadalafil, finasteride and sibutramine). 'High risk' medicines were identified--for example medicines used in the treatment of tuberculosis, malignant diseases and mental health disorders., Conclusion: This study is the first of its kind in New Zealand to explore the types of prescription medicines imported into the country. The majority of imported medicines were classified as 'lifestyle' medicines. The study findings also identified possible negative public health implications associated with some of the imported prescription medicines, for example resistance associated with the importation of antibiotics.

Background, Aim, and Scope: Aquatic microcontaminants (MCs) comprise diverse chemical classes, such as pesticides, biocides, pharmaceuticals, consumer products, and industrial chemicals. For water pollution control and the evaluation of water protection measures, it is crucial to screen for MCs. However, the selection and prioritization of which MCs to screen for is rather difficult and complex. Existing methods usually are strongly limited because of a lack of screening regulations or unavailability of required data. METHOD AND MODELS: Here, we present a simple exposure-based methodology that provides a systematic overview of a broad range of MCs according to their potential to occur in the water phase of surface waters. The method requires input of publicly available data only. Missing data are estimated with quantitative structure-property relationships. The presented substance categorization methodology is based on the chemicals' distribution behavior between different environmental media, degradation data, and input dynamics., Results: Seven different exposure categories are distinguished based on different compound properties and input dynamics. Ranking the defined exposure categories based on a chemical's potential to occur in the water phase of surface waters, exposure categories I and II contain chemicals with a very high potential, categories III and IV contain chemicals with a high potential, and categories V and VI contain chemicals with a moderate to low potential. Chemicals in category VII are not evaluated because of a lack of data. We illustrate and evaluate the methodology on the example of MCs in Swiss surface waters. Furthermore, a categorized list containing potentially water-relevant chemicals is provided., Discussion: Chemicals of categories I and III continuously enter surface waters and are thus likely to show relatively steady concentrations. Therefore, they are best suited for water monitoring programs requiring a relatively low sampling effort. Chemicals in categories II and IV have complex input dynamics. They are consequently more difficult to monitor. However, they should be considered if an overall picture is needed that includes contaminants from diffuse sources., Conclusions: The presented methodology supports compound selection for (a) water quality guidance, (b) monitoring programs, and (c) further research on the chemical's ecotoxicology. The results from the developed categorization procedure are supported by data on consumption and observed concentrations in Swiss surface waters. The presented methodology is a tool to preselect potential hazardous substances based on exposure-based criteria for policy guidance and monitoring programs and a first important step for a detailed risk assessment for potential microcontaminants.

Current systems for similarity-based virtual screening use similarity measures in which all the fragments in a fingerprint contribute equally to the calculation of structural similarity. This paper discusses the weighting of fragments on the basis of their frequencies of occurrence in molecules. Extensive experiments with sets of active molecules from the MDL Drug Data Report and the World of Molecular Bioactivity databases, using fingerprints encoding Tripos holograms, Pipeline Pilot ECFC_4 circular substructures and Sunset Molecular keys, demonstrate clearly that frequency-based screening is generally more effective than conventional, unweighted screening. The results suggest that standardising the raw occurrence frequencies by taking the square root of the frequencies will maximise the effectiveness of virtual screening. An upper-bound analysis shows the complex interactions that can take place between representations, weighting schemes and similarity coefficients when similarity measures are computed, and provides a rationalisation of the relative performance of the various weighting schemes.

Background: Medication use during pregnancy and lactation is prevalent. However, current knowledge of the risks and benefits of medication use during pregnancy and lactation is incomplete as the best available evidence has been obtained from cohort studies of inadvertent exposures and registries. This situation may partly explain health care providers' (HCP) risk perceptions and thus the increasing number of calls to Teratogen Information Services (TIS)., Objectives: The objectives of this study were (1) to identify the medication classes for which HCP are seeking counseling from the IMAGe center, a Quebec TIS; (2) to identify the medical conditions for which medication classes were used during pregnancy and lactation; (3) to identify and quantify predictors of medication information requests during pregnancy and lactation., Methods: A retrospective analysis of data was conducted within the population served by the IMAGe center, a TIS based at CHU Ste-Justine in Montreal, Quebec, Canada, that serves the French population of Canada. To be included, calls had to be received between January 1, 2004 and April 30, 2007, and the subject of the call had to be directly associated with the exposure, or not, of a pregnant or breastfeeding woman to medication. Multivariate generalized estimating equation (GEE) regression models were performed to identify the predictors of medication requests., Results: A total of 11, 076 requests regarding medication exposure during pregnancy, 12 055 requests regarding pregnant women before the exposure took place, and 13, 364 requests regarding lactation were included for analyses. Pregnant women were most frequently exposed to antidepressants (17.3), antibiotics (6.3%), and benzodiazepines (5.3%). Prior to drug exposure, the most frequent inquiries by HCP were on antibiotics (11.0%), anti-inflammatory drugs (6.0%), and antiemetics (5.1%). Inquiries concerning lactating women most frequently requested information on the drug classes of antidepressants (10.8%), antibiotics (9.1%), and anti-inflammatory drugs (7.8%). Depressive disorders were an indication of antidepressant, benzodiazepine and antipsychotic exposures reported to IMAGe. Associations were found between medication use and maternal age, previous pregnancies, trimester of pregnancy at the time of the call and lifestyle habits., Conclusions: The IMAGe received frequent inquiries on antidepressant, antibiotic, and benzodiazepine exposures, with depressive disorders being the most frequently declared indication. Predictors of medication requests were identified among exposed women during pregnancy, and breastfeeding women. These results emphasize the need for effective studies on drug use during pregnancy and lactation and for better knowledge transfer programs.

Background: Several publications indicate that the female gender experiences a higher incidence of adverse drug reactions (ADRs) than does the male gender. The reasons, however, remain unclear. Gender-specific differences in the pharmacokinetic and pharmacodynamic behaviour of drugs could not be identified as an explanation. The aim of this study was to analyse ADR risk with respect to gender, age and number of prescribed drugs., Methods: A prospective multicenter study based on intensive pharmacovigilance was conducted. Information on patient characteristics and evaluated ADRs was stored in a pharmacovigilance database--KLASSE., Results: In 2,371 patients (1,012 female subjects), 25,532 drugs were prescribed. In 782 patients, at least one ADR was found. A multivariate regression analysis adjusting for age, body mass index (BMI) and number of prescribed drugs showed a significant influence of female gender on the risk of encountering ADRs [odds ratio (OR) 1.596, confidence interval (CI) 1.31-1.94; p < 0.0001). Dose-related ADRs (51.8%) were the dominant type in female subjects. Comparing system organ classes of the World Health Organisation (SOC-WHO), cardiovascular (CV) ADRs were particularly frequent in female subjects (OR 1.92, CI 1.15-3.19; p = 0.012)., Conclusion: Our data confirm the higher risk of ADRs among female subjects compared with a male cohort. Several explanations were investigated. No single risk factor could be identified.

The concept of the Family of International Classifications has been created to have a common framework and language to report, compile, use, and compare health information at the national and international level. The family brings together different health classifications dealing with various dimensions of health and health care so as to present a more comprehensive picture of health care. The family of classifications in health consists of reference classifications, derived ones and related ones. The reference classifications cover the areas of death and disease, disability and health interventions. Other members cover fields like drugs, causes of injury and reasons for encounter. These classifications represent the building blocks of health information in order to be able to provide the best possible health to all people.

We investigate the classification performance of circular fingerprints in combination with the Naive Bayes Classifier (MP2D), Inductive Logic Programming (ILP) and Support Vector Inductive Logic Programming (SVILP) on a standard molecular benchmark dataset comprising 11 activity classes and about 102,000 structures. The Naive Bayes Classifier treats features independently while ILP combines structural fragments, and then creates new features with higher predictive power. SVILP is a very recently presented method which adds a support vector machine after common ILP procedures. The performance of the methods is evaluated via a number of statistical measures, namely recall, specificity, precision, F-measure, Matthews Correlation Coefficient, area under the Receiver Operating Characteristic (ROC) curve and enrichment factor (EF). According to the F-measure, which takes both recall and precision into account, SVILP is for seven out of the 11 classes the superior method. The results show that the Bayes Classifier gives the best recall performance for eight of the 11 targets, but has a much lower precision, specificity and F-measure. The SVILP model on the other hand has the highest recall for only three of the 11 classes, but generally far superior specificity and precision. To evaluate the statistical significance of the SVILP superiority, we employ McNemar's test which shows that SVILP performs significantly (p < 5%) better than both other methods for six out of 11 activity classes, while being superior with less significance for three of the remaining classes. While previously the Bayes Classifier was shown to perform very well in molecular classification studies, these results suggest that SVILP is able to extract additional knowledge from the data, thus improving classification results further.

Objective: To examine the prescription of drugs in Germany prior to, during and after pregnancy., Methods: For the first time, prescription data of a large cohort of pregnant women, from a German statutory sickness fund, were available for scientific analysis. For each woman who gave birth between June 2000 and May 2001 reimbursed prescriptions for two periods (90 days each) before pregnancy, three during and two after delivery were considered. The drugs were classified according to the ATC code., Results: Of the 41,293 women, 96.4% received at least one drug during pregnancy. A median of 7 drugs per women was prescribed. Excluding vitamins, minerals, iodide and iron, 85.2% received at least one drug and the median was 3. Magnesium, which was seldom prescribed outside of pregnancy, was by far the most frequently prescribed substance (20% of all prescriptions, 61% of the women). Iron (54% of the women) and iodide (31%) were also prescribed often. The prescription rates of gynaecological antiinfectives (maximum in third trimester: 23% of the women), antacids (max. in third trim.: 11%), as well as antiemetics and antinauseants (max. in first trim.: 8%) during pregnancy considerably increased. A decrease was seen for analgesics, antiinflammatory and antirheumatic drugs, muscle relaxants, ophtalmologicals and anti-acne preparations, for example. Potential teratogenic drugs were prescribed to 1.3% of the women., Conclusion: This analysis of a large nation-wide cohort of pregnant women showed that during pregnancy drugs were prescribed to most women, even when vitamins, minerals, iodide and iron were omitted. Magnesium and iron seemed to have been over-prescribed. On the other hand, the official recommendation for iodide substitution, to prevent thyroid diseases in mother and child, was insufficiently implemented. In our opinion, regular analysis of prescription data can identify potential harmful therapies and focal points where guidelines are needed and can check their implementation.

Introduction: There are scarce descriptions of hospital drug procurement in the primary literature. The aim of this study was to analyse the drug tender led by a clinical pharmacologist in a 1200-bed university hospital in Serbia, a developing country in socio-economic transition, and to give recommendations for future steps in hospital drug policy., Procedure and Outcomes: Drug tendering was conducted according to the public procurement law from January to April 2003. Analysis included the method of defined daily doses and anatomical therapeutic chemical classification, as well as minimal tender prices, free market prices, essential drugs and domestic and foreign manufacturers. The drug tender list consisted of 548 products, 1,315,501 pharmaceutical units and 312 drug entities, among which 164 were essential. For purchasing purposes, 479 drug formulations were selected, costing approximately 1.4 million Euros (approximately 10% of hospital budget). Three-quarters of the expenditure consisted of antimicrobials (29.1%), cytotoxics (28.8%) and intravenous infusions (17.7%). The top 20 drugs consumed 62.2% of the total drug expenditure. Competition for the most expensive and/or most used drugs was the key for financial success of applicants, even when they offered a limited number of drugs. The tender achieved 4.6% and 17.2% cost savings in comparison with minimal tender price and free-market price, respectively. The tender did not provide a fair balance between domestic and foreign manufacturers., Conclusion: The drug tender is resource-consuming, laborious, and risky job. Aggregation of individual tenders, on a national level and/or regional ones, is probably the best choice for hospitals in transition countries at this time.

Participation in road traffic/driving a motorized vehicle involves numerous skills capable of being influenced by medications. Common examples of the latter are psychoactive drugs, hypnotics and sedatives, antihistaminics, analgesics and psychostimulants. Both the therapeutic effect itself and potential side effects can pose a danger, for example, via the loss of psychomotoric coordination, or equilibrium or sensory disturbances. Every fourth accident can be traced back to the influence of some medication or other. In addition, the patient himself may be harboring a variety of major risks including age, physiological and mental status and previous illnesses.

Objective: The aim of this paper is to demonstrate the usefulness of the Bayesian Confidence Propagation Neural Network (BCPNN) in the detection of drug-specific and drug-group effects in the database of adverse drug reactions of the World Health Organization Programme for International Drug Monitoring., Methods: Examples of drug-adverse reaction combinations highlighted by the BCPNN as quantitative associations were selected. The anatomical therapeutic chemical (ATC) group to which the drug belonged was then identified, and the information component (IC) was calculated for this ATC group and the adverse drug reaction (ADR). The IC of the ATC group with the ADR was then compared with the IC of the drug-ADR by plotting the change in IC and its 95% confidence limit over time for both., Results: The chosen examples show that the BCPNN data-mining approach can identify drug-specific as well as group effects. In the known examples that served as test cases, beta-blocking agents other than practolol are not associated with sclerosing peritonitis, but all angiotensin-converting enzyme inhibitors are associated with coughing, as are antihistamines with heart-rhythm disorders and antipsychotics with myocarditis. The recently identified association between antipsychotics and myocarditis remains even after consideration of concomitant medication., Conclusion: The BCPNN can be used to improve the ability of a signal detection system to highlight group and drug-specific effects.

Objectives: The objectives were to determine the incidence of drug-related deaths in a university hospital and to find out which drugs are most commonly involved in these cases., Methods: The files of 1511 death cases (97.7% of all death cases in the Helsinki University Central Hospital during the year 2000) were scrutinised. In the cases of suspected drug-related deaths excluding suicides, the medication, its duration and indications, the route of drug administration, and the type of the adverse reactions were determined. The probability of a fatal adverse drug reaction was classified according to WHO's classification. In addition, the incidence of drug-related deaths was calculated from the death certificates., Results: Scrutiny of the patients' files showed that 75 of the death cases (5.0% of all deaths) were certainly or probably drug-related. This corresponds to about 0.05% of all hospital admissions. The most common adverse reactions were neutropenia caused by antineoplastic agents and gastrointestinal or intracranial haemorrhage due to anticoagulants or nonsteroidal anti-inflammatory drugs (NSAIDs). The incidence of drug-related deaths is only 0.5% when based on the International Classification of Diseases (ICD) codes in death certificates., Conclusions: Adverse drug reaction is a significant cause of death. Most of the deaths occurred in seriously ill patients with high-risk medication and they are seldom preventable. Incidence figures based on death certificates only may seriously underestimate the true incidence of fatal adverse reactions.

Objective: To investigate whether published drug utilisation studies contain satisfactory references to the ATC/DDD version applied and thus are usable for comparative purposes., Methods and Results: A literature survey of drug utilisation studies was made. Seventy-three articles were identified by two Medline searches, one in 1996 and another in 1998. The articles were classified into four different groups. Groups 1 and 2 give proper references to the defined daily doses (DDDs) used in the studies, either by full reference to the version of the ATC Index with DDDs or by listing the actual DDDs used. The articles in groups 1 and 2 represent 46% of the articles in the survey. The articles classified in groups 3 and 4 give references only to general articles about the anatomical therapeutic chemical classification (ATC)/DDD system or no references at all. Fifty-four percent of the articles in the survey were classified in these groups. In these articles it is not possible to identify which DDDs have been used in the presentation of drug consumption data., Conclusions: According to the results from our literature survey, it is not common practice to include the ATC codes and the DDD values used or to make reference to the versions of the ATC/DDD index used when results from drug utilisation studies are published. One possible reason for this might be little or no knowledge about the ATC/DDD system as a dynamic system in which alterations are made annually. The lack of references to the actual DDDs used in the studies make comparisons between different data sets difficult and misleading.

Objectives: Realising the limitations of spontaneous drug monitoring systems concerning the epidemiological aspects, a comprehensive program was founded. It was based on previous publications from the US, Canada and Northern Ireland, mainly those of the BCDSP (Boston Collaborative Drug Surveillance Programme)., Methods: Drug monitoring was carried out by a group of physicians which included the medical head of each of the divisions of internal medicine, a statistician and an informatician. Only probable or definite drug event relationships were included. A probable event is defined as one in which the drug interaction was more likely to be the cause than any non-drug-related cause. The same criteria were valid for the lethal reactions., Results: In the present evaluation, we found 26 probable lethal adverse drug reactions out of a total of 48,005 patients consecutively admitted to the divisions of internal medicine of three Swiss teaching hospitals during the years 1974-1993, an incidence of 0.054%. The median age of the cohort was 68 years (range 11-103 years), of which 49% were women. The median hospital stay was 14 days and the median number of drugs was eight per patient., Conclusion: The patients with a lethal outcome were presented under the eight pharmacologic-therapeutic classes of drugs and the classification proposed by NS Irey. This is based on long histopathologic experience and helps to identify preventable risks.

The process of compound selection and prioritization is crucial for both combinatorial chemistry (CBC) and high throughput screening (HTS). Compound libraries have to be screened for unwanted chemical structures, as well as for unwanted chemical properties. Property extrema can be eliminated by using property filters, in accordance with their actual distribution. Property distribution was examined in the following compound databases: MACCS-II Drug Data Report (MDDR), Current Patents Fast-alert, Comprehensive Medicinal Chemistry, Physician Desk Reference, New Chemical Entities, and the Available Chemical Directory (ACD). The ACDF and MDDRF subsets were created by removing reactive functionalities from the ACD and MDDR databases, respectively. The ACDF subset was further filtered by keeping only molecules with a 'drug-like' score [Ajay et al., J. Med. Chem., 41 (1998) 3314; Sadowski and Kubinyi, J. Med. Chem., 41 (1998) 3325] below 0.8. The following properties were examined: molecular weight (MW), the calculated octanol/water partition coefficient (CLOGP), the number of rotatable (RTB) and rigid bonds (RGB), the number of rings (RNG), and the number of hydrogen bond donors (HDO) and acceptors (HAC). Of these, MW and CLOGP follow a Gaussian distribution, whereas all other descriptors have an asymmetric (truncated Gaussian) distribution. Four out of five compounds in ACDF and MDDRF pass the 'rule of 5' test, a probability scheme that estimates oral absorption proposed by Lipinski et al. [Adv. Drug Deliv. Rev., 23 (1997) 3]. Because property distributions of HDO, HAC, MW and CLOGP (used in the 'rule of 5' test) do not differ significantly between these datasets, the 'rule of 5' does not distinguish 'drugs' from 'nondrugs'. Therefore, Pareto analyses were performed to examine skewed distributions in all compound collections. Seventy percent of the 'drug-like' compounds were found between the following limits: 0 < or = HDO < or = 2, 2 < or = HAC < or = 9, 2 < or = RTB < or = 8, and 1 < or = RNG < or = 4, respectively. The number of launched drugs in MDDR having 0 < or = HDO < or = 2 is 4.8 times higher than the number of drugs having 3 < or = HDO < or = 5. Skewed distributions can be exploited to focus on the 'drug-like space': 62.68% of ACDF ('nondrug-like') compounds have 0 < or = RNG < or = 2, and RGB < or = 17, while 28.88% of ACDF compounds have 3 < or = RNG < or = 13, and 18 < or = RGB < or = 56. By contrast, 61.22% of MDDRF compounds have RNG > or = 3, and RGB > or = 18, and only 24.73% of MDDRF compounds have 0 < or = RNG < or = 2 rings, and RGB < or = 17. The probability of identifying 'drug-like' structures increases with molecular complexity.

Design: Cross-sectional survey., Setting: The county of Malmöhus, with 817,000 inhabitants, in the far south of Sweden. All drugs handed in for destruction to the 65 pharmacies during one week in March 1996 were analysed., Results: 92% of the packages were prescription drugs for human use, 7% were over-the-counter drugs, and 1% were for veterinary use. Slightly less than half (48%) had expired when they were handed in for destruction. 36% were unbroken when returned and another 18% of the packages were nearly full. A comparison between the drugs sent in for destruction and the drugs sold in the county gave a ratio of 0.030. Antineoplastic and immunosuppressive drugs, drugs for the respiratory system, antiparasitic products, and cardiovascular drugs were returned to a greater extent than other types of drugs. Drugs for the genito-urinary tract, sex hormones, and drugs for the alimentary tract were returned to a lesser extent. Extrapolated to a whole year the value of caseated drugs was estimated to 60 SEK (5.83 Br,) per person. The value of unbroken packages was 20 SEK (1.94 Br,) per person per year., Conclusion: Although not all of the drugs handed in for destruction could have been unnecessarily prescribed or obtained by the patient, a more cautious approach to prescribing of drugs would likely yield significant savings.

As of 1 January 1994, the introduction of a new classification of the drugs to be reimbursed by the National Health Service was approved by the Italian parliament in order to limit expenditure on pharmaceutical agents. This has set off a 'cultural revolution', unprecedented in Italy. The criteria that inspired the expert group charged with attributing drugs to different classes (Class A: essential, free of charge drugs; Class B: drugs to be paid for 50% by the patient; Class C: drugs to be paid entirely by the patient) were principally scientific rather than merely economic or administrative. Expectedly, the creation of Class C (drugs not reimbursed by the National Health Service on account of their insufficiently proven clinical effectiveness, or their unfavourable cost/benefit ratio with respect to therapeutically equivalent agents) has provoked remarkable changes in general practitioners' prescription options, particularly given the fact that many of these drugs were among the most prescribed in Italy. A database including the prescriptions of about 940 general practitioners, dispensed through the 280 community pharmacies of the city of Turin, has been analysed for a comparative sample of time periods in 1993 and 1994, in order to quantify the changes that occurred and to qualify them with respect to more relevant therapeutic groups and sentinel drugs.

Wholesale data from Estonia covering all drug supplies during the period 1983-1989 have been studied using the defined daily dose (DDD) methodology. The use of all major pharmacological groups was compared with the corresponding statistics from the Nordic countries. The patterns of drug use showed large differences between the Nordic countries and Estonia. Many drugs were used in large quantities in Estonia although they are no longer considered to be first-line medications in the Nordic countries because of their high risk to benefit ratio. These included the pyrazolones (phenylbutazone, aminophenazone), chloramphenicol, aminoglycoside antibiotics, and Rauwolfia alkaloids. On the other hand, several groups of effective drugs were available in Estonia only in limited amounts, including the histamine (H2) receptor antagonists, hormonal contraceptives, beta-adrenoceptor antagonists, angiotensin converting enzyme inhibitors, and cephalosporins. There were also differences in the use of non-steroidal anti-inflammatory drugs, blood pressure lowering agents, and anti-asthmatic drugs. Amongst the factors influencing drug usage it appears that economic status, the ordering and invoicing routines of the pharmaceutical services, and therapeutic traditions were the main reasons for the differences found.

FARMAGUIDA, a databank of drugs marketed in Italy (2,596 pharmaceutical substances corresponding to 10,448 products), permits analysis of the nature and value of the drugs prescribed. It contains coded pharmaceutical and administrative information, an original classification, as well as indicators of the therapeutic status of each drug. The FARMAGUIDA classification was built hierarchically according to a three-level pattern: the first level (42 categories) corresponds to major pharmacological groups; the second level (157 groups) gathers drugs having similar clinical indications and/or pharmacological actions; and the third level (246 subgroups) classifies drugs according to chemical structure and/or the mechanism of action. Drugs not falling into well-established pharmacotherapeutic criteria (e.g. neurotropics or liver protectants) are classified into separate subgroups. Two larger groupings were also formulated: THER (11 headings), a utilization-oriented arrangement in which each heading also contained the corresponding placebo-like drugs, and PHARM (14 headings), a rational pharmacological arrangement, in which all placebo-like drugs were relegated into a separate set. The following quality indicators were created: DOC, which defines five degrees of documentation of clinical efficacy according to major textbooks of pharmacology and therapeutics; CLASS, which groups DOC values for a more simple evaluation of prescription data; PREP, which distinguishes monocomponent preparations from fixed-dose combinations, and also provides coded information about the rationale for the combination; HOSP, which hallmarks drugs that should be reserved for in-patients, e.g. anti-pseudomonal antibiotics. The composition of the list of reimbursable drugs, the Italian National Formulary (NF; 5782 products in 1990) was analyzed according to the FARMAGUIDA classification and indicators.(ABSTRACT TRUNCATED AT 250 WORDS)