Context. The first asteroseismology results from CoRoT are presented, on a star showing Sun-like oscillations. We have analyzed a 60 day lightcurve of high-quality photometric data collected by CoRoT ...on the F5 V star HD 49933. The data reveal a rich spectrum of overtones of low-degree p modes. Aims. Our aim was to extract robust estimates of the key parameters of the p modes observed in the power spectrum of the lightcurve. Methods. Estimation of the mode parameters was performed using maximum likelihood estimation of the power spectrum. A global fitting strategy was adopted whereby 15 mode orders of the mode spectrum (45 modes) were fitted simultaneously. Results. The parameter estimates that we list include mode frequencies, peak linewidths, mode amplitudes, and a mean rotational frequency splitting. We find that the average large frequency (overtone) spacing derived from the fitted mode frequencies is 85.9 ± 0.15 μHz. The frequency of maximum amplitude of the radial modes is at 1760 μHz, where the observed rms mode amplitude is 3.75 ± 0.23 ppm. The mean rotational splitting of the non-radial modes appears to be in the range ≈2.7 μHz to ≈3.4 μHz. The angle of inclination offered by the star, as determined by fits to the amplitude ratios of the modes, appears to be in the range ≈50 degrees to ≈62 degrees.
Objective. The antimalarial agents chloroquine (CQ) and hydroxychloroquine (HCQ) are used in long-term treatment of connective tissue diseases (CTDs). A high incidence of heart conduction disorders, ...including bundle-branch block and incomplete or complete atrioventricular block, has been observed among patients treated with CQ. Since no data were available for HCQ, we studied electrocardiograms (ECGs) in 85 unselected patients with CTD treated with HCQ as the sole antimalarial.
Methods. Eighty-five unselected out-patients treated with HCQ for a minimum of 1 yr, and without established cardiac diseases had standard 12-lead ECGs.
Results. Two incomplete right bundle-branch blocks and one left bundle-branch block were observed. No atrioventricular block was observed. The mean PR interval was 137 ± 20 ms (range 99-188). The mean QTc interval was 410 ms (range 349-464). The mean heart rate was 73 beats/min (range 53-102).
Conclusion. PR interval, QTc interval and heart rate were not different from normal values. The rate of heart conduction disorders was similar to what is expected in the general population, and contrasted with prior results in CQ-treated patients. Our results add further evidence on the safety of HCQ compared with CQ.
Enoxaparin is frequently prescribed for pregnant women who are at high risk for thromboembolic complications. We conducted a population pharmacokinetics study with 75 pregnant women and 38 ...nonpregnant women as controls to evaluate enoxaparin pharmacokinetics during pregnancy and the postpartum period. Clearance of the drug was higher in the pregnant women throughout pregnancy when compared with nonpregnant women (0.78 ± 0.03 l/h vs. 0.52 ± 0.03 l/h, respectively P < 0.001) with the stage of the pregnancy having no influence. The volume of distribution was influenced by stage of the pregnancy, characterized by a two‐step increase, with an initial rise paralleling the woman's increase in body weight during the first two trimesters, followed by an additional increase of 41% during the last 2 months of pregnancy, independent of changes in weight. Using enoxaparin pharmacokinetic parameters to simulate anti‐Xa time profiles, we observed that the maintenance of the same doses throughout pregnancy resulted in a progressive reduction in mean and peak anti‐Xa activities. We recommend the administration of doses normalized for body weight changes so as to counteract enoxaparin pharmacokinetic changes that accompany various stages of pregnancy.
Clinical Pharmacology & Therapeutics (2008); 84, 3, 370–377 doi:10.1038/clpt.2008.73
Background: Poor adherence to treatment is difficult to diagnose accurately. Hydroxychloroquine (HCQ) has a long elimination half-life and its concentration in whole blood can be measured easily. ...Objective: To evaluate the utility of a very low blood HCQ concentration as a marker of poor compliance in patients with systemic lupus erythematosus (SLE). Methods: HCQ concentrations were determined on a blinded basis in 203 unselected patients with SLE. At the end of the study, the patients were informed of the results and retrospectively interviewed about their adherence to treatment. Results: 14 (7%) patients said that they had stopped taking HCQ (n = 8) or had taken it no more than once or twice a week (n = 6). Their mean (SD) HCQ concentration was 26 (46) ng/ml. range (0–129 ng/ml) By contrast, the other patients had a mean HCQ concentration of 1079 ng/ml range (205–2629 ng/ml). The principal barriers to adherence were related to HCQ treatment characteristics. Adherence subsequently improved in 10 of the 12 patients whose blood HCQ concentrations were remeasured. Conclusions: Very low whole-blood HCQ concentrations are an objective marker of prolonged poor compliance in patients with SLE. Regular drug assays might help doctors in detect non-compliance and serve as a basis for counselling and supporting these patients.
Context. CoRoT light curves have an unprecedented photometric quality, having simultaneously a high signal-to-noise ratio, a long time span and a nearly continuous duty-cycle. Aims. We analyse the ...light-curves of four bright targets observed in the seismology field and study short-lived small spots in solar-like stars. Methods. We present a simple spot modeling by iterative analysis. Its ability to extract relevant parameters is ensured by implementing relaxation steps to avoid convergence to local minima of the sum of the residuals between observations and modeling. The use of Monte-Carlo simulations allows us to estimate the performance of the fits. Results. Our starspot modeling gives a representation of the spots on these stars in agreement with other well tested methods. Within this framework, parameters such as rigid-body rotation and spot lifetimes seem to be precisely determined. Then, the lifetime/rotation period ratios are in the range 0.5-2, and there is clear evidence for differential rotation.
Objective
Blood concentrations of hydroxychloroquine (HCQ) vary widely among patients with systemic lupus erythematosus (SLE). A pharmacokinetic/pharmacodynamic relationship has been found in ...different situations, and a very low blood concentration of HCQ is a simple marker of nonadherence to treatment. Therefore, interest in blood HCQ concentration measurement has increased, but little is known about factors that influence blood HCQ concentration variability. This study was undertaken to analyze determinants of blood HCQ concentrations.
Methods
We conducted a retrospective analysis of patient data, including data from the Plaquenil Lupus Systemic (PLUS) study, to determine the association of epidemiologic, clinical, and biologic factors with blood HCQ concentrations. Data for nonadherent patients (blood HCQ concentration <200 ng/ml) were excluded.
Results
To examine homogeneous pharmacologic data, we restricted the analyses of the PLUS data to the 509 SLE patients receiving 400 mg/day. We found no association of ethnicity or smoking with blood HCQ concentrations and no pharmacokinetic drug–drug interaction with antacids or with inhibitors or inducers of cytochrome P450 enzymes. On multivariate analysis, high body mass index (P = 0.008), no treatment with corticosteroids (P = 0.04), increased time between the last tablet intake and measurement of blood HCQ concentrations (P = 0.017), low platelet count (P < 0.001), low neutrophil count (P < 0.001), and high estimated creatinine clearance (P < 0.001) were associated with low blood HCQ concentrations. In 22 SLE patients with chronic renal insufficiency (median serum creatinine clearance 52 ml/minute range 23–58 ml/minute) who received 400 mg/day HCQ, the median blood HCQ concentration was significantly higher than that in the 509 patients from the PLUS study (1,338 ng/ml range 504–2,229 ng/ml versus 917 ng/ml range 208–3316 ng/ml) (P < 0.001).
Conclusion
We provide a comprehensive analysis of determinants of blood HCQ concentrations. Because this measurement is increasingly being used, these data might be useful for clinicians.
Pharmacogenetics aims to identify the underlying genetic factors participating in the variability of drug response. Indeed, genetic variability at the DNA or RNA levels can directly or indirectly ...modify the pharmacokinetic or the pharmacodynamic parameters of a drug. The ultimate aim of pharmacogenetics is to move towards a personalised medicine by predicting responders and non-responders, adjusting the dose of the treatment, and identifying individuals at risk of adverse drug effects.
A literature research was performed in which we reviewed all pharmacogenetic studies in neurological disorders including neurodegenerative diseases, multiple sclerosis, stroke and epilepsy.
Several pharmacogenetic studies have been performed in neurology, bringing insights into the inter-individual drug response variability and in the pathophysiology of neurological diseases. The principal implications of these studies for the management of patients in clinical practice are discussed.
Although several genetic factors have been identified in the modification of drug response in neurological disorders, most of them have a marginal predictive effect at the single gene level, suggesting mutagenic interactions as well as other factors related to drug interaction and disease subtypes. Most pharmacogenetic studies deserve further replication in independent populations and, ideally, in pharmacogenetic clinical trials to demonstrate their relevance in clinical practice.
La pharmacogénétique vise à identifier des facteurs génétiques participant à la variabilité de la réponse au traitement avec pour objectif ultime d’aboutir à une médecine personnalisée. Les facteurs génétiques peuvent modifier le métabolisme ou la cible d’un médicament sur le plan individuel, avec la particularité en neurologie d’une relation non linéaire entre les concentrations périphériques du médicament et ses effets centraux.
Une recherche de la littérature a été effectuée pour passer en revue les études de pharmacogénétique réalisées dans les maladies neurologiques.
De nombreux gènes ont été identifiés, associés à la réponse au traitement en neurologie. Cependant, la plupart d’entre eux ont un effet prédictif faible au niveau individuel, suggérant des interactions multiples entre les facteurs génétiques et d’autres facteurs liés à la maladie et aux interactions médicamenteuses.
L’effort de recherche en pharmacogénétique dans les maladies neurologiques doit être poursuivi pour répliquer les résultats dans des populations indépendantes ou, idéalement, dans des épreuves cliniques de pharmacogénétique afin de démontrer leur pertinence pour la pratique clinique.
Cytochrome P450 (CYP)2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 loss‐of‐function alleles impair formation of active metabolites, resulting in reduced ...platelet inhibition. In addition, CYP2C19 loss‐of‐function alleles confer increased risks for serious adverse cardiovascular (CV) events among clopidogrel‐treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI). Guideline updates include emphasis on appropriate indication for CYP2C19 genotype–directed antiplatelet therapy, refined recommendations for specific CYP2C19 alleles, and additional evidence from an expanded literature review (updates at http://www.pharmgkb.org).
Clinical Pharmacology & Therapeutics (2013); 94 3, 317–323. doi:10.1038/clpt.2013.105
CYP2C19 is one of the principal enzymes involved in the bioactivation of the antiplatelet prodrug clopidogrel. A common loss‐of‐function allele, CYP2C19*2 (c.681G>A; rs4244285), is associated with ...increased risk for serious adverse cardiovascular events in both heterozygous and homozygous patients (~25–50% of the population) with acute coronary syndromes (ACSs) who are receiving clopidogrel, particularly among those undergoing percutaneous coronary intervention (PCI). We provide evidence from published literature and guidelines for CYPC19 genotype–directed antiplatelet therapy (periodically updated at http://www.pharmgkb.org).
Clinical Pharmacology & Therapeutics (2011) 90 2, 328–332. doi:10.1038/clpt.2011.132
Objectives
Benefits of hydroxychloroquine (HCQ) use on physician reported outcomes are well documented in systemic lupus erythematosus (SLE). We assess for the first time the association and ...predictive value of blood HCQ levels towards health-related quality of life (HRQOL) in SLE.
Methods
Data from the PLUS study (a randomized, double-blind, placebo-controlled, multicentre study) were utilized. Blood HCQ levels were quantified by high-performance liquid chromatography along with HRQOL assessments (Medical Outcomes Study-SF-36) at baseline (V1) and month 7 (V2).
Results
166 SLE patients’ data were analysed. Mean (SD) age and disease duration were 44.4 (10.7) and 9.3 (6.8) years. Eighty-seven per cent were women. Mean (SD, median, IQR) HCQ concentrations in the blood at V1 were 660 (314, 615, 424) ng/ml and increased to 1020 (632, 906, 781) ng/ml at V2 (mean difference 366 units, 95% confidence interval −472 to −260, p < 0.001). No significant correlations between HCQ concentrations with HRQOL domains at V1 or V2 were noted. There were no differences in HRQOL stratified by HCQ concentrations. HCQ concentrations at V1 or changes in HCQ concentration (V2-V1) were not predictive of HRQOL at V2 or changes in HRQOL (V2-V1).
Conclusions
No association of HCQ concentrations with current or longitudinal HRQOL were found in SLE.
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