The metabolization of drugs as a factor in the development of adverse drug reactions

When medicines cause side effects, we often assume that the original active substance is responsible for this. However, after ingestion, the active substance is processed (metabolized) by enzymes or attached to polar compounds in order to accelerate its excretion from the body. The original active substance undergoes chemical changes and drug metabolites are formed. These drug metabolites have their own characteristics and can also cause side effects. Recognizing, predicting and preventing these side effects requires knowledge of the metabolism of the parent drug, the formation of metabolites and their effects in the body.In this thesis we investigated the knowledge about the role of drug metabolization and metabolites on side effects. Various data sources have been explored and used for this purpose. Phenoconversion has also been investigated as a method to intervene in drug metabolization and prevent the formation of unwanted metabolites.It appears that the role of drug metabolism and the formation of drug metabolites in side effects is well recognized, but the available information is not yet fully exploited. For example, knowledge about certain chemical structures in medicines can be included more often in the recognition and prediction of known and unknown side effects.Once the role of drug metabolism and the formation of the drug metabolites in the development of the side effect is recognized, action can be taken to prevent side effects. Phenoconversion appears to be a suitable method to prevent the formation of unwanted metabolites and could be investigated and possibly be applied more often

Inhibition of CYP2D6 with low dose (5 mg) paroxetine in patients with high 10-hydroxynortriptyline serum levels-A prospective pharmacokinetic study

The antidepressant nortriptyline is metabolized by cytochrome P450 2D6 (CYP2D6) to the less active and more cardiotoxic drug metabolite, 10-hydroxynortriptyline. High serum levels of this metabolite (>200 μg/L) may lead to withdrawal of nortriptyline therapy. Adding CYP2D6 inhibitors reduce the metabolic activity of CYP2D6 (phenoconversion) and so decrease the forming of hydroxynortriptyline. In this study, 5 mg paroxetine is administered to patients with high hydroxynortriptyline concentrations (>200 μg/L). The shift in number of patients to therapeutic nortriptyline (50-150 μg/L) and safe hydroxynortriptyline (<200 μg/L) concentrations, and the degree of phenoconversion, expressed as the change in ratio nortriptyline/hydroxynortriptyline concentrations before and after paroxetine addition, are prospectively observed and described. After paroxetine addition, 12 patients (80%) had therapeutic nortriptyline and safe hydroxynortriptyline concentrations. Hydroxynortriptyline concentrations decreased in all patients. The average nortriptyline/hydroxynortriptyline concentrations ratio increased from 0.32 to 0.59. This study shows that 5 mg paroxetine addition is able to lower high hydroxynortriptyline serum levels to safe ranges

Spanish, Portuguese, and Neo-Latin Poetry Written and/or Published by Seventeenth-and Eighteenth-Century Sephardim from Hamburg and Frankfurt (1)

This is the first of a two-part study the intention of which is to reproduce and evaluate Spanish, Portuguese, and Neo-Latin poetry written by 17th and 18th- century Hamburg-based Sephardim. The general conclusion is that considered in isolation these poems are, at best, circumstancial and of limited creative significance, but when considered as part of a pan-European literary phenomenon they represent an attempt to create a new literary discourse.El presente artículo es la primera entrega de un trabajo, cuya segunda parte aparecerá también en Sefarad. Incluye una introducción histórica y evaluativa, y textos de poemas en español, portugués y neolatín escritos en los siglos XVII y XVIII por sefardíes de Hamburgo. Examinados aisladamente, los poemas que componen este poemario muestran poca creatividad; pero si se consideran como la aportación de los sefardíes diaspóricos a un fenómeno pan-europeo, se observa que nos encontramos ante un intento de recrear y desde luego crear un nuevo discurso literario

Would those who need ISA, use it? Investigating the relationship between drivers' speed choice and their use of a voluntary ISA system

Intelligent Speed Adaptation (ISA) is one of the most promising new technologies for reducing the prevalence and severity of speed-related accidents. Such a system could be implemented in a number of ways, representing various "levels of control" over the driver. An ISA system could be purely advisory or could actually control the maximum speed of a vehicle. A compromise would be to introduce a system that allows a driver to choose when to engage ISA, thus creating a “voluntary” system. Whilst these voluntary systems are considered more acceptable by drivers, they will not offer safety benefits if they are not used by the driver. Two studies were carried out that examined the relationship between drivers’ reported and actual speeding behaviour, their propensity to engage a voluntary ISA system and their attitudes towards such a system. These studies were carried out in a driving simulator and in an instrumented vehicle. In both the studies, drivers’ propensity to exceed the speed limit was lowered when ISA was available but this effect was confined to the lower speed limits. In general, drivers engaged ISA for approximately half of their driving time, depending on the speed limit of the road and indeed, on the nature of the road and the surrounding traffic. This was particularly true in the field study where drivers were more inclined to “keep up with” the surrounding traffic. The results from the on-road study indicated that those drivers who considered ISA to be both a useful and pleasant system, were overall more likely to engage it. However, those drivers who confessed to enjoying exceeding the speed limit were less likely to use ISA. This is an important finding when considering the mechanisms for implementing ISA: those drivers who would benefit most would be less likely to use a voluntary system

Cost-effectiveness of central automated unit dose dispensing with barcode-assisted medication administration in a hospital setting

Background : Central automated unit dose dispensing (cADD) with barcode-assisted medication administration (BCMA) has been shown to reduce medication administration errors (MAEs). Little is known about the cost-effectiveness of this intervention. Objective : To estimate the cost-effectiveness of cADD with BCMA compared to usual care. Methods : An economic evaluation was conducted alongside a prospective before-and-after effectiveness study in a Dutch university hospital. The primary effect measure was the difference between the rate of MAEs before and after implementation of cADD with BCMA, obtained by disguised observation in six clinical wards and subsequent extrapolation to the entire hospital. The cost-analysis was conducted from a hospital perspective with a 12-month incremental costing approach. The total costs covered the pharmaceutical service, nurse medication handling, wastage, and materials related to cADD. The primary outcome was the cost-effectiveness ratio expressed as costs per avoided MAE, obtained by dividing the annual incremental costs by the number of avoided MAEs. The secondary outcome was the cost-effectiveness ratio expressed as costs per avoided potentially harmful MAE (i.e. MAEs with the potential to cause harm). Results : The intervention was associated with an absolute MAE reduction of 4.5% and a reduction of 2.7% for potentially harmful MAEs. Based on 2,260,870 administered medications in the entire hospital annually, a total of 102,210 MAEs and 59,830 potentially harmful MAEs were estimated to be avoided. The intervention was associated with an increased incremental cost of €1,808,600 annually. The cost-effectiveness ratio was €17.69 per avoided MAE and €30.23 per avoided potentially harmful MAE. Conclusions : The implementation of cADD with BCMA was associated with a reduced rate of medication errors, including harmful ones, at higher overall costs. The costs per avoided error are relatively low, and therefore, this intervention could be an important strategy to improve patient safety in hospitals

Patients' perspectives on a drug safety monitoring system for immune-mediated inflammatory diseases based on patient-reported outcomes

Patient-reported outcomes (PROs) on adverse drug reactions (ADRs) are increasingly used in cohort event monitoring (CEM) to obtain a better understanding of patients’ real-world experience with drugs. Despite the leading role for patients, little is known about their perspectives on CEM systems. In a cross-sectional open survey following the rationale of the Technology Acceptance Model, we aimed to obtain insight in patients’ perspectives on the perceived usefulness, ease of use and attitude toward using a PRO-based drug safety monitoring system for ADRs attributed to biologics. Patients considered structural reporting of ADRs in web-based questionnaires as useful and not burdensome. It was preferred to link the questionnaire frequency to regular hospital consultations or the biologic administration schedule. Various respondents were interested in sharing questionnaires with their medical specialist (49.0%) or pharmacist (34.2%), and suggested to minimize the questionnaire frequency in case of an unaltered situation or absence of ADRs. Patients’ perspectives should be considered in the setup of PRO-based CEM studies, as this contributes to data quality and patient centeredness. Since incorporation of patients’ perspectives in CEM studies is indispensable, a delicate balance should be found between user-friendliness and study aims.</p