Prediction of infant drug exposure through breastfeeding: population PK modeling and simulation of fluoxetine

BACKGROUND: Risks of significant infant drug exposurethrough breastmilk are poorly defined for many drugs, and largescalepopulation data are lacking. We used population pharmacokinetics(PK) modeling to predict fluoxetine exposure levels ofinfants via mother's milk in a simulated population of 1000 motherinfantpairs.METHODS: Using our original data on fluoxetine PK of 25breastfeeding women, a population PK model was developed withNONMEM and parameters, including milk concentrations, wereestimated. An exponential distribution model was used to account forindividual variation. Simulation random and distribution-constrainedassignment of doses, dosing time, feeding intervals and milk volumewas conducted to generate 1000 mother-infant pairs with characteristicssuch as the steady-state serum concentrations (Css) and infantdose relative to the maternal weight-adjusted dose (relative infantdose: RID). Full bioavailability and a conservative point estimate of1-month-old infant CYP2D6 activity to be 20% of the adult value(adjusted by weigth) according to a recent study, were assumed forinfant Css calculations.RESULTS: A linear 2-compartment model was selected as thebest model. Derived parameters, including milk-to-plasma ratios(mean: 0.66; SD: 0.34; range, 0 - 1.1) were consistent with the valuesreported in the literature. The estimated RID was below 10% in >95%of infants. The model predicted median infant-mother Css ratio was0.096 (range 0.035 - 0.25); literature reported mean was 0.07 (range0-0.59). Moreover, the predicted incidence of infant-mother Css ratioof >0.2 was less than 1%.CONCLUSION: Our in silico model prediction is consistent withclinical observations, suggesting that substantial systemic fluoxetineexposure in infants through human milk is rare, but further analysisshould include active metabolites. Our approach may be valid forother drugs. [supported by CIHR and Swiss National Science Foundation(SNSF)]

Population pharmacokinetic study of memantine: effects of clinical and genetic factors.

BACKGROUND AND OBJECTIVE: Memantine, a frequently prescribed anti-dementia drug, is mainly eliminated unchanged by the kidneys, partly via tubular secretion. Considerable inter-individual variability in plasma concentrations has been reported. We aimed to investigate clinical and genetic factors influencing memantine disposition. METHODS: A population pharmacokinetic study was performed including data from 108 patients recruited in a naturalistic setting. Patients were genotyped for common polymorphisms in renal cation transporters (SLC22A1/2/5, SLC47A1, ABCB1) and nuclear receptors (NR1I2, NR1I3, RXR, PPAR) involved in transporter expression. RESULTS: The average clearance was 5.2 L/h with a 27 % inter-individual variability (percentage coefficient of variation). Glomerular filtration rate (p = 0.007) and sex (p = 0.001) markedly influenced memantine clearance. NR1I2 rs1523130 was identified as the unique significant genetic covariate for memantine clearance (p = 0.006), with carriers of the NR1I2 rs1523130 CT/TT genotypes presenting a 16 % slower memantine elimination than carriers of the CC genotype. CONCLUSION: The better understanding of inter-individual variability of memantine disposition might be beneficial in the context of individual dose optimization.

Réduction de la consommation de sel: opportunité, impact et stratégies. [Population reduction of salt consumption: opportunities, impact and strategies].

A national survey showed that Swiss people eat high quantity of salt (9.1 g per day on average). The Swiss Federal Office of Public Health (FOPH) has launched a strategy to reduce salt intake in the population in order to decrease cardiovascular morbidity and mortality, mainly via blood pressure reduction. The most effective public health measures are to reduce the salt content of processed food rich in salt because they do not need to change consumers' eating behaviours. The FOPH has chosen to collaborate with the food industry on a voluntary basis. Regular population-based surveys will be needed to monitor the impact of current measures on salt consumption, hypertension prevalence as well as cardiovascular morbidity and mortality in the years to come.

Evaluation of Muscardinus avellanarius population density by nest box and by trap checking

Population densities of marked common dormice Muscardinus avellanarius are generally based on nest box checks. As dormice also use natural cavities and leaf nests, we tried to answer the question "what proportion of the population cannot be monitored by nest boy checks", using parallel trapping sessions. We selected a forest of 1.7ha where a 5-year nest box survey revealed an annual mean of 3.4 ± 1.4 dormice per check. The trap design (permanent grid of 77 hanging platforms) was developed in June. During July and August the traps were set every second week (4 sessions of two nights = 8 nights) resulting in a total of 75 captures with mean of 9.4 dormice per night and the presence of 16 different individuals. The grid of 60 nest boxes was checked weekly (8 times) which allowed the recapture of 19 dormice with a mean of 2.4 dormice, per control day and the presence of 6 different individuals. Population density estimated by calendar of capture and the minimal number of dormice alive methods gave for nest-box checks a value of 2.4 animals/ha and the trap checks 6.6 animals/ha with the conclusion that 63% of the population were not being monitored by nest box checks.

Eradication d'une population d'écrevisses de Louisiane, Procambarus clarkii, à l'étang de Vidy et situation des populations d'écrevisses à Lausanne, Suisse.

En juillet 2007, des écrevisses de Louisiane, Procambarus clarkii, ont été observées, pour la première fois en Suisse romande, dans l'étang artificiel de Vidy à Lausanne. Au printemps 2008, l'étang a été asséché pendant 2 mois pour tenter d'éradiquer les écrevisses. En juillet 2008, et au printemps 2009, des écrevisses de Louisiane furent à nouveau observées dans l'étang: des individus avaient survécu au traitement et/ou des écrevisses avaient à nouveau été introduites. En 2010, une nouvelle campagne d'éradication a été mise en place: l'étang fut asséché, son lit chaulé et les interstices entre les enrochements bétonnés. Lors du suivi 2011, plus aucune écrevisse ne fut capturée. L'opération semble donc finalement avoir été un succès. Les observations effectuées sur 20 plans d'eau dans un rayon de 4.5 km autour de l'étang de Vidy n'ont pas mis en évidence d'autres populations d'écrevisses de Louisiane. Plusieurs populations d'écrevisses américaines, orconectes limosus, et signal ̧ Pacifastacus lenuisculus, ont été localisées, ainsi qu'une population d'écrevisses à pattes rouges, Astacus astacus.

Adiponectin and C-reactive protein are positively associated with microalbuminuria in an adult Caucasian population

Objective: Microalbuminuria (MAU) is a marker of early kidney injury and cardiovascular risk. We assessed the association of MAU with plasma adiponectin, leptin, and hsCRP as inflammatory marker, accounting for hypertension, diabetes and obesity. Design and Methods: Population based, cross-sectional study in Caucasian subjects aged 35 to 75 years in Lausanne, Switzerland. MAU, measured by quantitative immunonephelometry on spot morning urine, was used either as a continuous (MAU) or dichotomized variable (MA defined as MAU > 2.5 and >3.5 mg/mmol creatinine in men and women, respectively). Results: The 2955 women (age 53.3_10.7, mean_SD years) had mean body mass index (BMI) 24.9_4.5 kg/m. The 2479 men (age 53.1_10.8 years) hadmean BMI 27.0_3.9 kg/m2.Median hsCRP was 1.3 and 1.3 mg/L, median adiponectin 6.2 and 10.6mg/mL in men and women, respectively. MA prevalence was 4.9% in women and 9.8% in men. In multivariate regression analysis adjusting for potential confounders (age, sex, hypertension, diabetes, eGFR, BMI, percent fat mass, insulin and smoking), logtransformed MAU was positively associated with hsCRP (P<0.001) and adiponectin (P¼0.002), but not with leptin. The association of adiponectin with MAU was stronger in subjects with low hsCRP, and vice versa (P interaction<0.001). Conclusion: Adiponectin and hsCRP are significant positive determinants of MAU, independently of diabetes, hypertension and fat mass. A negative interaction between hsCRP and adiponectin was found for their effect on MAU. Whether hyperadiponectinemia represents an adequate protective response to vascular stress or has negative causal impact on the development of MAU should be assessed in further studies.

High genetic variability and low local diversity in a population of arbuscular mycorrhizal fungi.

Arbuscular mycorrhizal fungi (AMF) are ecologically important root symbionts of most terrestrial plants. Ecological studies of AMF have concentrated on differences between species; largely assuming little variability within AMF species. Although AMF are clonal, they have evolved to contain a surprisingly high within-species genetic variability, and genetically different nuclei can coexist within individual spores. These traits could potentially lead to within-population genetic variation, causing differences in physiology and symbiotic function in AMF populations, a consequence that has been largely neglected. We found highly significant genetic and phenotypic variation among isolates of a population of Glomus intraradices but relatively low total observed genetic diversity. Because we maintained the isolated population in a constant environment, phenotypic variation can be considered as variation in quantitative genetic traits. In view of the large genetic differences among isolates by randomly sampling two individual spores, <50% of the total observed population genetic diversity is represented. Adding an isolate from a distant population did not increase total observed genetic diversity. Genetic variation exceeded variation in quantitative genetic traits, indicating that selection acted on the population to retain similar traits, which might be because of the multigenomic nature of AMF, where considerable genetic redundancy could buffer the effects of changes in the genetic content of phenotypic traits. These results have direct implications for ecological research and for studying AMF genes, improving commercial AMF inoculum, and understanding evolutionary mechanisms in multigenomic organisms.

Communication, Coordination, and Efficiency in Evolutionary One-population Models

We analyze the role of commitment in pre-play communication for ensuring efficient evolutionarily stable outcomes in coordination games. All players are a priori identical as they are drawn from the same population. In games where efficient outcomes can be reached by players coordinating on the same action we find commitment to be necessary to enforce efficiency. In games where efficienct outcomes only result from play of different actions, communication without commitment is most effective although efficiency can no longer be guaranteed. Only when there are many messages then inefficient outcomes are negligible as their basins of attraction become very small.