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OBJECTIVE: To establish risk factors of unlicensed and off-label drug use by children outside the hospital. METHODS: A cross-sectional study based on 66 222 pharmacy dispensing records for the year 2000 was performed in the northern part of the Netherlands. All prescriptions were divided into the following categories: unlicensed (no product license), off-label (licensed drugs used outside the terms of the product license), and on-label (licensed drugs used according to the product license). For identifying possible problem areas, the proportions of unlicensed and off-label drug use were determined per age group (0-1, 2-5, 6-11, or 12-16 years) and per drug group. For all systemic drugs, a logistic regression was done that models the odds of receiving an unlicensed or off-label prescription as a function of several possible risk factors. RESULTS: Unlicensed drug use in Dutch children is the highest among 0 to 1-year-olds, and off-label drug use is the highest among 12- to 16-year-olds. Drug groups with highest percentages of unlicensed and off-label drug use were ophthalmologicals/otologicals (80.7% of all prescriptions in this group), blood and blood-forming organs (mainly vitamin K for breastfed newborns; 75.7%), cardiovascular drugs (74.7%), and dermatologicals (73.3%). Prescriptions by specialists (outpatient), prescriptions for new drugs, prescriptions for drugs with a low use in the pediatric population, and prescriptions for infants were risk factors for using a systemic drug unlicensed or off-label. CONCLUSION: Efforts to improve pediatric labeling are important and need full support. The present results can be used to focus these efforts. [ABSTRACT FROM AUTHOR]

Background: Even though unipolar depression is associated with considerably impaired social functioning, only a few studies so far have investigated Theory of Mind (ToM) abilities of unipolar depressed patients. Therefore, the main goal of this study is to examine whether depressed patients are impaired in their ToM as compared to healthy controls. Thereby, both aspects of ToM, i.e. decoding and reasoning, are examined separately., Methods: Acutely depressed patients with unipolar affective disorder (n=24) and healthy controls (n=20) were examined with the 'Reading the Mind in the Eyes Test' (RMET) and the 'Movie for the Assessment of Social Cognition' (MASC) to address the two aspects of ToM., Results: Patients compared to controls did not show impaired decoding ability in the RMET, but did show deficits in integrating contextual information about other people (reasoning) in the MASC. This impairment is independent of the mental state modality that had to be judged (emotional vs. cognitive)., Limitations: Possible differences between the diagnostic subgroups of depression, which play an important role in clarifying the opposing results concerning the association between ToM abilities and depression in the existing literature, have not been examined., Conclusions: It is possible that the low level of social functioning associated with depression can be ascribed partially to a ToM deficit and should be addressed in the treatment of depression., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Aims: To investigate the dosage and duration of inhaled steroids prescribed to children and to compare the prescribed doses with recommended doses for the treatment of asthma in children., Methods: For 2514 Dutch children aged 0-12 years who had used inhaled steroids in 2002, pharmacy dispensing data were obtained from the InterAction database, type of steroid (beclomethason, budesonide, fluticasone) and type of user (first time or existing) and the average prescribed doses according to age were determined and compared with the doses as recommended in the national Dutch Nederlands Huisartsen Genootschap (NHG) guideline. Furthermore, for all first-time users the duration of therapy with inhaled steroids was determined using a Kaplan-Meier analysis., Results: The major findings were that: (i) overall 43% of children starting inhaled steroids were prescribed doses that are half the recommended dose or less; (ii) overall 8% of the children starting inhaled steroids were prescribed doses that were twice the recommended dose or more, up to 50% in the 12-year-olds fluticasone group; and (iii) only 8% of the children who started with inhaled steroids used them continuously for a full year., Conclusions: Doses of inhaled steroids for many children deviate from those recommended, with lower doses more frequently occurring than higher doses. Less than 10% of the children receive prescriptions for a prolonged period of time.

Objective: We evaluated the adherence to national guidelines for the treatment of asthma in childhood., Methods: Prescriptions for anti-asthma medication for children (0-14 years of age) were retrieved from the InterAction DataBase (IABD) for the year 2002. These were compared with recommendations found in national guidelines., Results: Anti-asthma medication was prescribed for 3,612 children (5%) of the paediatric population. Inhaled medication was prescribed for 3,554 (98%) children. In 1,940 of 1,993 (97%) of the children under the age of 6 years pressurised metered dose inhalers (pMDIs) were given. Short-acting beta2-agonists had not been prescribed in the previous 2-year period in 559 children (15%), 543 children older than 8 years (36%) did not receive a prescription for a dry powder inhalator and 239 children (7%) had more than one type of inhalator. Long-acting beta2-agonists were prescribed in 396 children, but without concomitant inhaled corticosteroids (ICS) in 35 children (9%)., Conclusions: Inhalation therapy as the method of choice in asthma therapy and the use of pMDI in preschool children are widely accepted in the Netherlands. Not all children have been prescribed bronchodilators. Some children have more than one type of inhaler device and others use long-acting beta2-agonists not in combination with ICS. Although national and international guidelines about the treatment of asthma in children offer evidence-based advice, important principles are not followed. Effective interventions aimed at implementing existing guidelines into daily practice are urgently needed.

Study Objective: Despite the increasing attention for the role of paternal exposures around the period of conception, there is no factual information about drug utilisation of fathers. Therefore, the aim of this study was to describe the drugs dispensed to fathers around conception, using pharmacy dispensing data of community pharmacies in Denmark and The Netherlands., Design and Setting: Using pharmacy dispensing data from the Pharmaco-epidemiological Prescription Database of North Jutland in Denmark and the InterAction database in The Netherlands, we examined the prescriptions reimbursed in the half year before conception of 56,735 Danish fathers from 1991 to 2000, and 5859 Dutch fathers from 1995 to 2000., Main Results: One third of all fathers had taken up prescriptions for at least one drug in the half year before conception, both in Denmark and in The Netherlands. In the majority of fathers only one type of drug was dispensed, but in both countries at least 5% of all fathers had redeemed three or more types of drugs. The main drugs purchased by fathers in Denmark and The Netherlands were antibiotics (14.3 and 6.3% of all fathers, respectively), analgesics (6.1 and 7.6%), antihistamines (2.0 and 2.0%) and anti-ulcer drugs (1.6 and 2.5%)., Conclusion: A large proportion of fathers used drugs around the time of conception. This finding emphasises the importance of safety information on therapeutic drugs with respect to potential paternal teratogenicity.

Objective: This study aimed to develop and validate a method for retrospectively identifying parents in pharmacy data during pregnancy., Study Design and Setting: The principle of the method was to select all children 0-2 years in pharmacy records, and to consider men/women 15-50 years older with the same address as fathers/mothers., Results: Applying this method to the records of all 4 pharmacies in 1 town (33,000 inhabitants) resulted in identification of 807 fathers and 765 mothers, corresponding with 68.5% of all fathers, and 64.9% of all mothers from the town. Additionally, the method was applied to one selected pharmacy, resulting in 151 fathers and 170 mothers. Validation criterions, evaluated by pharmacy employees and GPs, disproved one of these fathers (0.7% of all identified fathers) and one mother (0.6%)., Conclusion: We conclude that automatic retrospective identification of parents in pharmacy data is feasible in a valid way. The main limitation is that not all parents were found, possibly resulting in selection bias.

Objective: To describe drug use in pregnancy, and compare drug use of pregnant women with non-pregnant women with respect to possible teratogenicity., Study Design: A cross-sectional study based on pharmacy records from 1997 to 2001 was performed. Pregnant women and matched non-pregnant women (same physician and age) were identified. Prescriptions were set against the Australian risk classification., Results: Thirty-five percent of all prescriptions for non-pregnant women were safe in pregnancy (Australian classification A), in 14% the risk was unknown (B1, B2), 49% were potentially harmful drugs (B3, C, D, X), and in 3% no classification was available. For pregnant women these figures were 86, 3, 10 and 2%, respectively. In non-pregnant women the highest percentages of prescriptions for unsafe drugs were for psycholeptics (99% not classified as safe), psychoanaleptics (100%), anti-inflammatory/antirheumetic products (100%), antihistamines (94%), antacids/anti-ulcer drugs (81%), antiepileptics (100%), beta-blockers (100%), systemic antimycotics (100%), antiprotozoals (97%), diuretics (100%) and immunosuppressives (100%). In pregnant women this pattern was comparable, except for antihistamines (22%) and antacids/anti-ulcer drugs (3%)., Conclusion: We conclude that many drugs used by non-pregnant women should be avoided in pregnancy, and that pregnant women indeed do so. However, for some drug groups the available safe alternatives are limited.

Purpose: Pharmacy-dispensing data are valuable sources of drug information, but the population that is covered by the pharmacies is often difficult to determine. We evaluated two methods using drug utilisation information to estimate the population size: a drug-use-based extrapolation of a known part of the population and a capture-recapture estimation without any prior knowledge of the population., Methods: Using pharmacy-dispensing data of three towns with known populations in the Netherlands, we estimated age-and-sex specific population sizes by extrapolating the proportion of drug-using inhabitants. In addition, we applied two-source and three-source capture-recapture models with all combinations of the following drug groups as different sources: anti-asthmatics, analgesics, antibiotics and anti-histamines., Results: Drug-use-based extrapolation resulted in the best estimates with the least variability. All capture-recapture models provided underestimations of the true population. Three-source capture-recapture resulted in better average estimates than two-source capture-recapture, but also had more variability., Conclusions: If a part of the population is known, and if there is reason to assume that drug utilisation patterns do not vary within the region, it is best to use drug-use-based extrapolation. In all other situations capture-recapture may be considered, with as main limitation that we found all models to underestimate the population considerably.

Purpose: The interpretation of the available studies on adverse drug reactions (ADRs) in children outside the hospital is hampered because none of these studies used a control group. The aim of this study was to describe ADRs in children outside the hospital, controlled for drug use in the paediatric background population., Methods: Using a case-control design, we compared drugs on which a suspected ADR was reported to the Netherlands Pharmacovigilance Centre LAREB, and drugs used in the general paediatric population from the InterAction pharmacy database, both in the year 2001, for children aged 0-16 years., Results: The main findings are that ADRs were disproportionately more often reported on systemic drugs (OR 3.0; [95%CI: 1.9-4.8]), new drugs (2.4; [1.6-2.7]), anti-infective drugs (1.7; [1.1-2.7]) and nervous system drugs (2.1; [1.3-3.5]), whereas unlicensed drugs (0.1; [0.0-0.4]), frequently used drugs (0.3; [0.2-0.5]) and dermatologicals (0.1; [0.0-0.4]) were less likely to be associated with a reported ADR. Overall, the proportion of off-label prescriptions did not differ between drugs suspected of an ADR and drugs used by children in a general population., Conclusions: The pattern of drugs associated with a reported ADR could not be solely explained on the basis of drug utilisation patterns in the general population.

Objective: To describe the choice of drugs as well as the dosage forms of anti-asthmatic drugs in children with regard to different age groups., Methods: Cross-sectional study based on computerized pharmacy dispensing records of 1999 for children aged 0-16 years in the north of the Netherlands. All children were selected and divided in the following age groups: 0-1, 2-5, 6-11 and 12-16-year-olds., Results: Inhaled beta 2-agonists and inhaled corticosteroids were the most widely used anti-asthmatic drugs in all age groups (respectively 59 and 58 users per 100 anti-asthmatic using 0-16 year-olds). Cromones were rarely used. Up to four years of age the use of treatment with aerosol inhalers increased simultaneously with a decrease of oral dosage forms. The use of dry powder inhalers started at the age of approximately 4 years old and increased to about 85% of the users at the age of 11, with the strongest increase around the age of 6 and 7., Conclusion: The choice of drugs and dosage forms corresponds with what might be expected based on guidelines for the treatment of asthma in children, except for the high use of deptropine in the youngest age group. Anti-asthmatic drugs for preventive treatment are used so frequently without beta 2-agonists that questions about possible overtreatment need to be raised.

Objective: To gather information on the adherence to the Dutch national neonatal vitamin K policy and on the administration of prescription medication during labor by community midwives., Methods: A telephone questionnaire under community midwives in the North of the Netherlands., Results: In the main, the vitamin K practices follow the guidelines with respect to who receives the first dose and maintenance therapy. There is possibly underdosing. Midwives use their license to administer medicines during labor in moderation: 91% report to never use tocolytics, oxytocics or analgesics., Conclusion: In general, the national vitamin K policy is followed. Information gathered prospectively is needed on the use of pharmacotherapy by community midwives in the perinatal period.

Objective: Although there is a global concern about the increased use of psychotropic agents in children, most research literature originates in the United States and is based on figures from the first half of the 1990s. Also, few studies document the use of various types of psychotropic agents. The objective of this study was to investigate the use of psychotropic medication in children in the Netherlands and to determine whether this corresponds with previously reported figures from the United States., Methods: A drug utilization study based on computerized pharmacy dispensing records was conducted from 1995 to 1999 for children aged 0 to 19 years in the north of the Netherlands., Results: Stimulants were the most widely used psychotropic agents among 0- to 19-year-olds (prevalence: 7.4/1000 in 1999), followed by hypnotics/anxiolytics (6.9/1000) and antidepressants (4.4/1000). Prevalence rates of stimulants increased from 1.5/1000 in 1995 to 7.4/1000 in 1999. Incidence rates, proportion of girls, and duration of stimulant treatment increased as well. Changes in prevalence rates of other psychotropic agents were much smaller than those of stimulants. Finally, the vast majority of children who were treated with psychotropic agents used only 1 agent at a time., Conclusion: The prevalence of stimulant use in the Netherlands is much lower than reported previously (28/1000 children in 1995) from the United States, and differences also existed with regard to the use of other psychotropic agents and combinations of psychotropic agents. However, the increase in Dutch stimulant use agrees with the previously reported 2.5-fold increase in the United States and shows that the increased use of stimulants is not limited to the United States.

Objective: To determine to what extent the negative reporting concerning deptropine and its removal from the professional guidelines for asthma in children was followed by changes in the prescription of deptropine to young children and to determine to what extent the alternatives to deptropine were prescribed in the same period., Design: Retrospective cross-sectional study in 5 calendar years., Methods: This study was performed using computerised pharmacy data from the InterAction database of public pharmacies in the northern part of the Netherlands. The percentage of 0-4-year-olds who were prescribed deptropine or one of its alternatives was determined per year from 1994-1999., Results: In 1994, 14.9% of the 0-4-year-olds used deptropine, and this proportion decreased to 4.8% in 1999. beta 2 adrenergic agonists and glucocorticosteroids, both by inhalation, were used by 2.4% and 1.8%, respectively, of the 0-4-year-olds in 1994, and these proportions were 6.8% and 7.0%, respectively, in 1999., Conclusion: Deptropine was still being prescribed frequently, although there has been a sharp decrease since 1994. beta 2 adrenergic agonists and glucocorticosteroids, both by inhalation, are being prescribed increasingly often.

Aims: : To determine the extent of drug use in children and the types of drugs that children use. METHODS Cross-sectional study and cohort study, using computerized pharmacy dispensing records for all children aged 0-16 years in the northern part of The Netherlands in 1998. The main outcome measures were proportion of children that used drugs (per sex and age group), mean number of drugs per child, 10 most widely used drug groups and cumulative proportions of drugs users (per drug group) during the first 2 years of life., Results: Drug use was the highest among infants, decreased till adolescence and increased from there. Overall, approximately 60% of all children used at least one drug in 1998. At younger ages, boys used more drugs than girls and at older ages girls used more drugs than boys. Systemic antibiotics were used by 21% of the children and were by far the most widely used drugs. Other frequently used drugs were analgesics (10%), corticosteroids for dermatologic use (9%), anthistamines (8%) and antiasthmatics (7%). Approximately 10% of the children had used at least one drug at the age of 1 month and at the age of 2 years this proportion was 81%., Conclusions: The majority of children was exposed to one or more drugs and this exposure started at very young age. This shows the importance of good guidelines for drug use in children and emphasizes the necessity of research of pharmacokinetic and pharmacodynamic properties in children to obtain safety, efficacy and quality evidence of these drugs.

The involvement of muscarinic autoreceptors in the regulation of hippocampal acetylcholine levels during acetylcholinesterase inhibition was examined by perfusing the acetylcholinesterase inhibitor neostigmine bromide (10, 100 or 1000 nM) alone and in the presence of the muscarinic receptor antagonist atropine methylnitrate (10 microM), in resting and behaviourally-activated animals. In resting animals, local perfusion of neostigmine caused a dose-dependent increase in acetylcholine levels. Coadministration of atropine did not affect basal levels in the presence of 10 nM neostigmine, but increased acetylcholine levels approximately four and 11-fold in the presence of 100 nM and 1000 nM neostigmine, respectively. In animals which were behaviourally activated by handling, acetylcholine levels increased two- to three-fold in the presence of all neostigmine concentrations. However, the handling-induced increase in acetylcholine levels was somewhat smaller with 1000 nM neostigmine as compared to 10 nM neostigmine. Atropine had no effect on handling-induced acetylcholine output in the presence of 10 nM neostigmine, but caused greater and longer increases in the presence of 100 nM and 1000 nM neostigmine. These data indicate that acetylcholine levels are greatly reduced by autoinhibition at higher levels of acetylcholine esterase inhibition. The handling-evoked increase in acetylcholine levels is only moderately affected by the level of acetylcholinesterase inhibition, despite the participation of autoreceptors in the handling effect at higher levels of acetylcholinesterase inhibition.