Population pharmacokinetic approach to evaluate the effect of CYP2D6, CYP3A, ABCB1, POR and NR1I2 genotypes on donepezil clearance.

AIMS: A large interindividual variability in plasma concentrations has been reported in patients treated with donepezil, the most frequently prescribed antidementia drug. We aimed to evaluate clinical and genetic factors influencing donepezil disposition in a patient population recruited from a naturalistic setting. METHODS: A population pharmacokinetic study was performed including data from 129 older patients treated with donepezil. The patients were genotyped for common polymorphisms in the metabolic enzymes CYP2D6 and CYP3A, in the electron transferring protein POR and the nuclear factor NR1I2 involved in CYP activity and expression, and in the drug transporter ABCB1. RESULTS: The average donepezil clearance was 7.3 l h(-1) with a 30% interindividual variability. Gender markedly influenced donepezil clearance (P < 0.01). Functional alleles of CYP2D6 were identified as unique significant genetic covariate for donepezil clearance (P < 0.01), with poor metabolizers and ultrarapid metabolizers demonstrating, respectively, a 32% slower and a 67% faster donepezil elimination compared with extensive metabolizers. CONCLUSION: The pharmacokinetic parameters of donepezil were well described by the developed population model. Functional alleles of CYP2D6 significantly contributed to the variability in donepezil disposition in the patient population and should be further investigated in the context of individual dose optimization to improve clinical outcome and tolerability of the treatment.

Salting kinetics and salt diffusivities in farmed Pantanal caiman muscle

The legal Pantanal caiman (Caiman crocodilus yacare) farming, in Brazil, has been stimulated and among meat preservation techniques the salting process is a relatively simple and low-cost method. The objective of this work was to study the sodium chloride diffusion kinetics in farmed caiman muscle during salting. Limited volumes of brine were employed, with salting essays carried at 3, 4 and 5 brine/muscle ratios, at 15%, 20% and 25% w/w brine concentrations, and brine temperatures of 10, 15 and 20ºC. The analytical solution of second Fick's law considering one-dimensional diffusion through an infinite slab in contact with a well-stirred solution of limited volume was used to calculate effective salt diffusion coefficients and to predict the sodium chloride content in the fillets. A good agreement was obtained between the considered analytical model and experimental data. Salt diffusivities in fillets were found to be in the range of 0.47x10-10 to 9.62x10-10 m²/s.

Determination of the Enantiomers of Mianserin and its Metabolites in Plasma by Capillary Electrophoresis After Liquid-Liquid Extraction and On-Column Sample Preconcentration

Capillary electrophoresis has drawn considerable attention in the past few years, particularly in the field of chiral separations because of its high separation efficiency. However, its routine use in therapeutic drug monitoring is hampered by its low sensitivity due to a short optical path. We have developed a capillary zone electrophoresis (CZE) method using 2mM of hydroxypropyl-β-cyclodextrin as a chiral selector, which allows base-to-base separation of the enantiomers of mianserin (MIA), desmethylmianserin (DMIA), and 8-hydroxymianserin (OHMIA). Through the use of an on-column sample concentration step after liquid-liquid extraction from plasma and through the presence of an internal standard, the quantitation limits were found to be 5 ng/mL for each enantiomer of MIA and DMIA and 15 ng/mL for each enantiomer of OHMIA. To our knowledge, this is the first published CE method that allows its use for therapeutic monitoring of antidepressants due to its sensitivity down to the low nanogram range. The variability of the assays, as assessed by the coefficients of variation (CV) measured at two concentrations for each substance, ranged from 2 to 14% for the intraday (eight replicates) and from 5 to 14% for the interday (eight replicates) experiments. The deviations from the theoretical concentrations, which represent the accuracy of the method, were all within 12.5%. A linear response was obtained for all compounds within the range of concentrations used for the calibration curves (10-150 ng/mL for each enantiomer of MIA and DMIA and 20-300 ng/mL for each enantiomer of OHMIA). Good correlations were calculated between [(R) + (S)]-MIA and DMIA concentrations measured in plasma samples of 20 patients by a nonchiral gas chromatography method and CZE, and between the (R)- and (S)-concentrations of MIA and DMIA measured in plasma samples of 37 patients by a previously described chiral high-performance liquid chromatography method and CZE. Finally, no interference was noted from more than 20 other psychotropic drugs. Thus, this method, which is both sensitive and selective, can be routinely used for therapeutic monitoring of the enantiomers of MIA and its metabolites. It could be very useful due to the demonstrated interindividual variability of the stereoselective metabolism of MIA.

Death following acute poisoning by moclobemide

A fatality due to ingestion of a reversible inhibitor of monoamine-oxidase A (MAO-A) is reported. Moclobemide is generally considered as a safe drug far less toxic than tricyclic anti-depressants. However, severe intoxications may result from interactions with other drugs and food such as selective serotonin reuptake inhibitors (SSRIs), anti-Parkinsonians of the MAOI-type (e.g. selegiline) or tyramine from ripe cheese or other sources. In the present case, high levels of moclobemide were measured in peripheral blood exceeding toxic values reported so far in the scientific literature. The body fluid concentrations of moclobemide were of 498 mg/l in peripheral whole blood, 96.3 mg/l in urine while an amount of approximately 33 g could be recovered from gastric contents. The other xenobiotics were considered of little toxicological relevance. The victim (male, 48-year-old) had a past history of depression and committed one suicide attempt 2 years before death. Autopsy revealed no evidence of significant natural disease or injury. It was concluded that the manner of death was suicide and that the unique cause of death was massive ingestion of moclobemide.

Leopold Center for Sustainable Agriculture, Annual Report 1997-1998

The Leopold Center was established by the Iowa Legislature as part of the Iowa Groundwater Protection Act of 1987. Its mandated missions are to identify impacts of agricultural practices, contribute to the development of profitable farming systems that conserve natural resources, and cooperate with Iowa State University Extension to inform the public of new findings.Information for this report was compiled by Leopold Center staff with the help of its researchers and educators who are committed to improving Iowa agriculture and the lives of Iowans.

Therapeutic drug monitoring and pharmacogenetic tests as tools in pharmacovigilance.

Therapeutic drug monitoring (TDM) and pharmacogenetic tests play a major role in minimising adverse drug reactions and enhancing optimal therapeutic response. The response to medication varies greatly between individuals, according to genetic constitution, age, sex, co-morbidities, environmental factors including diet and lifestyle (e.g. smoking and alcohol intake), and drug-related factors such as pharmacokinetic or pharmacodynamic drug-drug interactions. Most adverse drug reactions are type A reactions, i.e. plasma-level dependent, and represent one of the major causes of hospitalisation, in some cases leading to death. However, they may be avoidable to some extent if pharmacokinetic and pharmacogenetic factors are taken into consideration. This article provides a review of the literature and describes how to apply and interpret TDM and certain pharmacogenetic tests and is illustrated by case reports. An algorithm on the use of TDM and pharmacogenetic tests to help characterise adverse drug reactions is also presented. Although, in the scientific community, differences in drug response are increasingly recognised, there is an urgent need to translate this knowledge into clinical recommendations. Databases on drug-drug interactions and the impact of pharmacogenetic polymorphisms and adverse drug reaction information systems will be helpful to guide clinicians in individualised treatment choices.

Sessió clínica: Internet, salut i e-pacients. Eines i recursos a l'abast per a una informació de qualitat

Sessió clínica a un EAP amb dos objectius: proporcionar als professionals sanitaris de l'EAP orientacions bàsiques per ajudar els pacients a avaluar la informació sobre temes de salut localitzada a Internet, i promoure entre els professionals sanitaris l'ús de la prescripció web per formentar l'autonomia dels pacients. El contingut de la sessió va ser: breu introducció a Internet, tendències actuals en e-salut, criteris d'avaluació de pàgines web, segells de qualitat i prescripció web.

Leopold Center for Sustainable Agriculture Annual Report, 1998-1999

The Leopold Center was established by the Iowa Legislature as part of the Iowa Groundwater Protection Act of 1987. Its mandated missions are to identify impacts of agricultural practices, contribute to the development of profitable farming systems that conserve natural resources, and cooperate with Iowa State University Extension to inform the public of new findings.Information for this report was compiled by Leopold Center staff with the help of its researchers and educators who are committed to improving Iowa agriculture and the lives of Iowans.

Leopold Center for Sustainable Agriculture Annual Report, 1999-2000

The Leopold Center was established by the Iowa Legislature as part of the Iowa Groundwater Protection Act of 1987. Its mandated missions are to identify impacts of agricultural practices, contribute to the development of profitable farming systems that conserve natural resources, and cooperate with Iowa State University Extension to inform the public of new findings.Information for this report was compiled by Leopold Center staff with the help of its researchers and educators who are committed to improving Iowa agriculture and the lives of Iowans.

Leopold Center for Sustainable Agriculture Annual Report, 2000-2001

The Leopold Center was established by the Iowa Legislature as part of the Iowa Groundwater Protection Act of 1987. Its mandated missions are to identify impacts of agricultural practices, contribute to the development of profitable farming systems that conserve natural resources, and cooperate with Iowa State University Extension to inform the public of new findings.Information for this report was compiled by Leopold Center staff with the help of its researchers and educators who are committed to improving Iowa agriculture and the lives of Iowans.

Leopold Center for Sustainable Agriculture Annual Report, 2001-2002

The Leopold Center was established by the Iowa Legislature as part of the Iowa Groundwater Protection Act of 1987. Its mandated missions are to identify impacts of agricultural practices, contribute to the development of profitable farming systems that conserve natural resources, and cooperate with Iowa State University Extension to inform the public of new findings.Information for this report was compiled by Leopold Center staff with the help of its researchers and educators who are committed to improving Iowa agriculture and the lives of Iowans.

Leopold Center for Sustainable Agriculture Annual Report, 2002-2003

The Leopold Center was established by the Iowa Legislature as part of the Iowa Groundwater Protection Act of 1987. Its mandated missions are to identify impacts of agricultural practices, contribute to the development of profitable farming systems that conserve natural resources, and cooperate with Iowa State University Extension to inform the public of new findings.Information for this report was compiled by Leopold Center staff with the help of its researchers and educators who are committed to improving Iowa agriculture and the lives of Iowans.

Leopold Center for Sustainable Agriculture Annual Report, 2003-2004

The Leopold Center was established by the Iowa Legislature as part of the Iowa Groundwater Protection Act of 1987. Its mandated missions are to identify impacts of agricultural practices, contribute to the development of profitable farming systems that conserve natural resources, and cooperate with Iowa State University Extension to inform the public of new findings.Information for this report was compiled by Leopold Center staff with the help of its researchers and educators who are committed to improving Iowa agriculture and the lives of Iowans.

Leopold Center for Sustainable Agriculture Annual Report, 2004-2005

The Leopold Center was established by the Iowa Legislature as part of the Iowa Groundwater Protection Act of 1987. Its mandated missions are to identify impacts of agricultural practices, contribute to the development of profitable farming systems that conserve natural resources, and cooperate with Iowa State University Extension to inform the public of new findings.Information for this report was compiled by Leopold Center staff with the help of its researchers and educators who are committed to improving Iowa agriculture and the lives of Iowans.

Leopold Center for Sustainable Agriculture Annual Report, 2005-2006

The Leopold Center was established by the Iowa Legislature as part of the Iowa Groundwater Protection Act of 1987. Its mandated missions are to identify impacts of agricultural practices, contribute to the development of profitable farming systems that conserve natural resources, and cooperate with Iowa State University Extension to inform the public of new findings.Information for this report was compiled by Leopold Center staff with the help of its researchers and educators who are committed to improving Iowa agriculture and the lives of Iowans.