K.L.L. Movig

Psychoactive substance use and the risk of motor vehicle accidents

The driving performance is easily impaired as a consequence of the use of alcohol and/or licit and illicit drugs. However, the role of drugs other than alcohol in motor vehicle accidents has not been well established. The objective of this study was to estimate the association between psychoactive drug use and motor vehicle accidents requiring hospitalisation. A prospective observational case-control study was conducted in the Tilburg region of The Netherlands from May 2000 to August 2001. Cases were car or van drivers involved in road crashes needing hospitalisation. Demographic and trauma related data was collected from hospital and ambulance records. Urine and/or blood samples were collected on admission. Controls were drivers recruited at random while driving on public roads. Sampling was conducted by researchers, in close collaboration with the Tilburg police, covering different days of the week and times of the day. Respondents were interviewed and asked for a urine sample. If no urine sample could be collected, a blood sample was requested. All blood and urine samples were tested for alcohol and a number of licit and illicit drugs. The main outcome measures were odds ratios (OR) for injury crash associated with single or multiple use of several drugs by drivers. The risk for road trauma was increased for single use of benzodiazepines (adjusted OR 5.1 (95% Cl: 1.8-14.0)) and alcohol (blood alcohol concentrations of 0.50-0.79 g/l, adjusted OR 5.5 (95% Cl: 1.3-23.2) and >or=0.8 g/l, adjusted OR 15.5 (95% Cl: 7.1-33.9)). High relative risks were estimated for drivers using combinations of drugs (adjusted OR 6.1 (95% Cl: 2.6-14.1)) and those using a combination of drugs and alcohol (OR 112.2 (95% Cl: 14.1-892)). Increased risks, although not statistically significantly, were assessed for drivers using amphetamines, cocaine, or opiates. No increased risk for road trauma was found for drivers exposed to cannabis. The study concludes that drug use, especially alcohol, benzodiazepines and multiple drug use and drug-alcohol combinations, among vehicle drivers increases the risk for a road trauma accident requiring hospitalisation.

Validity of hospital discharge International Classification of Diseases (ICD) codes for identifying patients with hyponatremia

Medical diagnosis can be studied using various sources of information, such as medical and hospital discharge records and laboratory measurements. These sources do not always concur. The objective of the present study was to assess the sensitivity, specificity, and positive and negative predictive values of hospital discharge diagnosis compared with clinical laboratory data for the identification of hyponatremia. Patients with hyponatremia were selected from a hospital information system determined by the International Classification of Diseases, 9th edition (ICD-9). The validity parameters for hyponatremia (ICD code 276.1) were estimated by comparison with accurate serum sodium (Na+) levels. A total of 2632 cases of hyponatremia were identified using laboratory measurements (Na+ < or =135 mmol/L). The sensitivity of ICD coding for hyponatremia was maximally about 30% for patients with very severe hyponatremia (Na+ < or =115 mmol/L). Corresponding specificities were high (>99%). In 87% of the cases with severe hyponatremia (Na+ < or =125 mmol/L), other discharge ICD codes reflecting severe morbidity were found. This study suggests that ICD codes for hyponatremia represent only one third of the patients admitted to the hospital and experiencing hyponatremia. About two thirds of the patients with hyponatremia were classified as hospitalized for other reasons. To assess the validity of case finding of patients with hyponatremia, the use of analytical techniques, such as certain laboratory measurements, is advisable.

Glycopyrrolate for sialorrhea in Parkinson disease: a randomized, double-blind, crossover trial.

Background: Sialorrhea affects approximately 75% of patients with Parkinson disease (PD). Sialorrhea is often treated with anticholinergics, but central side effects limit their usefulness. Glycopyrrolate (glycopyrronium bromide) is an anticholinergic drug with a quaternary ammonium structure not able to cross the blood-brain barrier in considerable amounts. Therefore, glycopyrrolate exhibits minimal central side effects, which may be an advantage in patients with PD, of whom a significant portion already experience cognitive deficits. Objective: To determine the efficacy and safety of glycopyrrolate in the treatment of sialorrhea in patients with PD. Methods: We conducted a 4-week, randomized, double-blind, placebo-controlled, crossover trial with oral glycopyrrolate 1 mg 3 times daily in 23 patients with PD. The severity of the sialorrhea was scored on a daily basis by the patients or a caregiver with a sialorrhea scoring scale ranging from 1 (no sialorrhea) to 9 (profuse sialorrhea). Results: The mean (SD) sialorrhea score improved from 4.6 (1.7) with placebo to 3.8 (1.6) with glycopyrrolate (p = 0.011). Nine patients (39.1%) with glycopyrrolate had a clinically relevant improvement of at least 30% vs 1 patient (4.3%) with placebo (p = 0.021). There were no significant differences in adverse events between glycopyrrolate and placebo treatment. Conclusions: Oral glycopyrrolate 1 mg 3 times daily is an effective and safe therapy for sialorrhea in Parkinson disease. Classification of evidence: This study provides Class I evidence that glycopyrrolate 1 mg 3 times daily is more effective than placebo in reducing sialorrhea in patients with Parkinson disease during a 4-week study.

Serotonergic antidepressants associated with an increased risk for hyponatraemia in the elderly

AbstractBackground. Hyponatraemia may have serious clinical consequences. Several reports of hyponatraemia associated with the use of antidepressants have been published. However, it remains unclear whether a specific class or individual antidepressants are associated with an increased risk for hyponatraemia.n Objectives. To investigate the association between the use of serotonergic antidepressant drugs and the occurrence of hyponatraemia compared with non-users of these agents and to determine the time-to-admission rate after initiation of these drugs.n Methods. A matched case-control study was conducted. Data were obtained from the PHARMO database including information on drug dispensing and hospital admission indications for 320,000 inhabitants of eight Dutch cities. Data from 1990 to 1998 were used. Case patients (n=203) were all patients who were admitted to a hospital for hyponatraemia. Community controls (n=608), matched by age and gender, were sampled within the same living area and calendar (index) date as the case patients. All patients were 18xa0years of age or older. Exposure to antidepressant drugs, classified as serotonergic versus non-serotonergic agents, and potential confounding factors were determined on the index date. Time-to-admission was defined as the period between start of the antidepressant drug and hospital admission. Conditional logistic regression model was used to estimate odds ratios (ORs) and to adjust for potential confounding factors.n Results. Ten (5%) case patients used serotonergic antidepressants compared with eight (1%) in the control group; compared with non-use, the risk for hyponatraemia was fourfold higher [OR 3.96; 95% confidence interval (CI) 1.33, 11.83] due to serotonergic antidepressant drug use. Risk for developing hyponatraemia was greatest in the first 2xa0weeks of serotonergic drug therapy.n Conclusion. Use of serotonergic antidepressants is associated with the development of hyponatraemia. Hyponatraemia occurred during the first 2xa0weeks of treatment, which justifies blood-sodium monitoring during the first weeks after initial treatment with a serotonergic antidepressant.

Interference of NSAIDs with the thrombocyte inhibitory effect of aspirin: A placebo-controlled, ex vivo, serial placebo-controlled serial crossover study

PurposeNonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid (ASA) are often prescribed concurrently in patients with nociceptive pain and cardiovascular comorbidity. NSAIDs and ASA inhibit the same COX-enzymes, and thus may interact. ASA’s cardioprotective antiplatelet effect is entirely COX-1 dependent. NSAIDs can be either non-COX-1 and COX-2 selective or COX-2 selective. The aim of this study was to examine the interaction between ASA and different selective and nonselective NSAIDs on thrombocyte function.MethodsSingle-blind, prospective, placebo-controlled, ex vivo, serial crossover trial of 3-day cycles separated by washout periods of at least 12xa0days in 30 healthy volunteers, evaluating interaction on ASA’s antithrombocyte effect by naproxen, ibuprofen, meloxicam, or etoricoxib taken 2xa0h before ASA. Ex vivo thrombocyte function, closure time (CT) in seconds, was measured using the Platelet Function Analyzer 100 (PFA-100). CT prolongation during a cycle reflects thrombocyte inhibitory effect. ASA nonresponse was defined as CT prolongation <40xa0% in the placebo cycle. ASA nonresponders were excluded. Wilcoxon signed-rank was used to evaluate NSAID effect on ASA-induced CT prolongation.ResultsIbuprofen and naproxen inhibit ASA’s antithrombocyte effect below the nonresponse threshold. Etoricoxib and meloxicam do not cause relevant change in ASA thrombocyte inhibition. Naproxen has an inherent weak thrombocyte inhibitory action below the ASA response threshold.ConclusionsCOX-1 affinity determines the interaction between NSAIDs and ASA on thrombocyte adhesion and aggregation. Ibuprofen and naproxen, but not etoricoxib or meloxicam, taken 2xa0h before ASA, significantly inhibit ASA’s antithrombocyte effect.

Dopaminergic drugs and the risk of hip or femur fracture: a population-based case–control study

SummaryThe effect of dopaminergic medication on the risk of hip/femur fractures is not clear. Our results showed a nearly twofold increased risk of hip/femur fractures in current dopaminergic drug users. Concomitant use of antidepressants further increased this risk. Fracture risk assessment may be warranted in elderly users of dopaminergic drugs.IntroductionDopaminergic drugs, often used in the treatment of Parkinson’s disease, have several pharmacological effects that may increase or decrease the risk of falling and fractures. Thus, the effect of dopaminergic medication on the risk of hip/femur fractures is not clear. The objective of the study was to examine the effect of dopaminergic medication and concomitant use of psychotropics on the risk of hip/femur fractures taking into account the timing of dopaminergic drug use.MethodsA population-based case–control study in the PHARMO database was conducted for the period 1991 to 2002. Cases were patients aged 18xa0years and older with a first hip or femur fracture and matched to four control patients by year of birth, sex and geographical region.ResultsThe study population included 6,763 cases and 26,341 controls. Current use of dopaminergic drugs (1–30xa0days before the index date) was associated with an increased risk of hip/femur fractures compared to never use (ORadj 1.76, 95% CIu2009=u20091.39–2.22), but this excess risk rapidly dropped to baseline levels when treatment had been discontinued >1xa0year ago. Concomitant use of antidepressants among current dopaminergic drug users further increased the risk of hip/femur fractures (ORadj 3.51, 95% CIu2009=u20092.10–5.87) while there was no additional risk with concomitant use of other psychotropics.ConclusionsAlthough the observed association between dopaminergic drugs and fracture risk may not be entirely causal, due to absence of information on the (severity of the) underlying disease, fracture risk assessment may be warranted in elderly users of dopaminergic drugs.

Analysis of low concentration sufentanil citrate/bupivacaine hydrochloride admixtures, using solid phase extraction followed by high-performance liquid chromatography

A method has been developed for the quantitative determination of low concentrations of sufentanil citrate (1.0 microg/ml), in the presence of bupivacaine hydrochloride (0.125%), in the quality control of pharmaceutical preparations. The main problem in analysis of this combination is the low concentration of sufentanil citrate in the presence of relatively high concentrations of bupivacaine hydrochloride. This paper describes the validation of a HPLC method of sufentanil citrate in an admixture with bupivacaine hydrochloride using solid phase extraction (SPE). The optimized method shows good linearity, precision and accuracy. The limits of detection (0.09 microg/l) and quantification (0.29 microg/l) for sufentanil citrate are lower than the maximal accepted limits. This method is currently used in stability studies.

The impact of hospitalisation on the initiation and long-term use of benzodiazepines

BackgroundInappropriate (long-term) use of benzodiazepines (BZDs) is a reason for concern. Several studies have suggested that hospitalisation may be a determinant for initiation of BZD use as well as for long-term use. However, the available evidence is conflicting.ObjectiveTo determine whether hospitalisation induces initiation of BZD use and subsequent long-term use.MethodsA retrospective follow-up study was conducted. Randomly, 10,000 patients who had been hospitalised were selected (index date). Non-hospitalised patients, matched on age and gender, were sampled from the same living region and assigned the same index date as the corresponding hospitalised patient. Patients were included if adequate medication data were available from 18xa0months before to 18xa0months after the index date. Initiation of BZD use was defined as a prescription for a BZD or BZD-related hypnotic without a prescription for any of these drugs during the prior 6xa0months. Long-term use was defined as a period of consecutive use for at least 6xa0months following initiation.ResultsIn this study, 8,681 hospitalised patients and an equal number of non-hospitalised patients were finally included. Overall, the relative risk for initiation of BZD use was almost twice as high [IDR 1.97 (95%CI 1.84–2.10)] among hospitalised patients as in non-hospitalised patients. This relative risk was most clearly elevated during the time window from 3xa0months before to 3xa0months after hospitalisation [IDR 4.81 (95%CI 4.08–5.67)]. The relative risk for long-term use during the entire 36-month observation period was not higher [IDR 1.04 (95%CI 0.95–1.13)] among hospitalised patients than among non-hospitalised patients. Within the time window of 3xa0months before and after hospitalisation, the relative risk for long-term use was significantly lower for the hospitalised group [RR 0.82 (CI 0.69–0.98)].ConclusionOur results confirm that hospitalisation is associated with an increased risk for initiation of BZD use; the risk is highest during the 3xa0months just before and after hospitalisation. However, hospitalisation appeared not to be a determinant for long-term use of BZDs.

Therapeutic drug monitoring of monoclonal antibodies in inflammatory and malignant disease: Translating TNF‐α experience to oncology

Lack of response to monoclonal antibodies (mAbs) has been associated with inadequate mAb serum concentrations. Therapeutic drug monitoring (TDM) of mAbs has the potential to guide to more effective dosing in individual patients. This review discusses the mechanisms responsible for interpatient variability of mAb pharmacokinetics, summarizes exposure‐response data of mAbs used in inflammatory and malignant disease, presents current evidence of mAb‐TDM in inflammatory disease, and provides hurdles and required future steps for further implementing mAb‐TDM.

Clinical and pharmacogenetic determinants for the discontinuation of non-ergoline dopamine agonists in Parkinson’s disease

ObjectiveTo identify determinants for the discontinuation of non-ergoline dopamine agonist (DA) treatment in patients with Parkinson’s disease (PD) and to identify genetic determinants in genes encoding dopamine receptor (DR)D2 and DRD3 in a exploratory analysis.MethodsPatients included were first-time users of the non-ergoline DA ropinirole or pramipexole who had been diagnosed with PD before 2005. Treatment discontinuation was defined as a gap of 180xa0days or more between two refills of the DA. Non-genetic determinants for discontinuation were studied in the overall population, and genetic determinants [DRD2 141C Ins/Del, DRD2 (CA)n STR, DRD2 TaqIA, DRD3 MscI single nucleotide polymorphism (SNP) and DRD3 MspI SNP] were studied in a subgroup. Cox proportional hazard analysis was used to estimate the hazard ratios (HR) for the discontinuation of non-ergoline DA treatment.ResultsThe study population comprised 90 patients. Apomorphine use was associated with non-ergoline DA discontinuation, although the apomorphine group consisted only of three patients [HR 6.26; 95% confidence interval (CI) 1.85–21.2]. Daily levodopa dosages between 500 and 1000xa0mg were positively associated with discontinuation (HR 2.31; 95% CI 1.08–4.93). Included in the exploratory pharmacogenetic analysis were 38 patients. The absence of a 15× DRD2 CA repeat allele was significantly related with a decreased discontinuation of non-ergoline treatment (HR 0.23; 95% CI 0.07–0.81). The DRD3 MspI polymorphism showed a non-significant allele dose effect, suggestive of a causal relationship.ConclusionThis study identified apomorphine use and levodopa dosages between 500 and 1000xa0mg as non-genetic and the 15× DRD2 CA repeat allele as genetic determinants for the discontinuation of non-ergoline DA treatment in patients with PD. More research is needed to replicate these findings.