Association of Oseltamivir Activation with Gender and Carboxylesterase 1 Genetic Polymorphisms

Oseltamivir, an inactive antiâ influenza virus prodrug, is activated (hydrolysed) in vivo by carboxylesterase 1 (CES1) to its active metabolite oseltamivir carboxylate. CES1 functions are significantly associated with certain CES1 genetic variants and some nonâ genetic factors. The purpose of this study was to investigate the effect of gender and several CES1 genetic polymorphisms on oseltamivir activation using a large set of individual human liver samples. CES1â mediated oseltamivir hydrolysis and CES1 genotypes, including the G143E (rs71647871), rs2244613, rs8192935, the â 816A>C (rs3785161) and the CES1P1/CES1P1VAR, were determined in 104 individual human livers. The results showed that hepatic CES1 protein expression in females was 17.3% higher than that in males (p = 0.039), while oseltamivir activation rate in the livers from female donors was 27.8% higher than that from males (p = 0.076). As for CES1 genetic polymorphisms, neither CES1 protein expression nor CES1 activity on oseltamivir activation was significantly associated with the rs2244613, rs8192935, â 816A>C or CES1P1/CES1P1VAR genotypes. However, oseltamivir hydrolysis in the livers with the genotype 143G/E was approximately 40% of that with the 143G/G genotype (0.7 ± 0.2 versus 1.8 ± 1.1 nmole/mg protein/min, p = 0.005). In summary, the results suggest that hepatic oseltamivir activation appears to be more efficient in females than that in males, and the activation can be impaired by functional CES1 variants, such as the G143E. However, clinical implication of CES1 gender differences and pharmacogenetics in oseltamivir pharmacotherapy warrants further investigations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134982/1/bcpt12625.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134982/2/bcpt12625_am.pd

Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in Critically I ll Patients Receiving Continuous Venovenous Hemodialysis and/or Extracorporeal Membrane Oxygenation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94511/1/phar1151.pd

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

Use of feedback to improve mental number line representations in primary care clinics

Abstract Background As patients become more engaged in decisions regarding their medical care, they must weigh the potential benefits and harms of different treatments. Patients who are low in numeracy may be at a disadvantage when making these decisions, as low numeracy is correlated with less precise representations of numerical magnitude. The current study looks at the feasibility of improving number representations. The aim of this study was to evaluate whether providing a small amount of feedback to adult subjects could improve performance on a number line placement task and to determine characteristics of those individuals who respond best to this feedback. Methods Subjects from two outpatient clinic waiting rooms participated in a three phase number line task. Participants were asked to place numbers on a computerized number line ranging from 0 to 1000 in pre-test, feedback, and post-test phases. Generalized estimating equations were used to model log-transformed scores and to test whether 1) performance improved after feedback, and 2) the degree of improvement was associated with age, education level or subjective numeracy. Results There was an overall improvement in task performance following the feedback. The average percent absolute error was 7.32% (SD: 6.00) for the pre-test and 5.63% (SD: 3.71) for the post-test. There was a significant interaction between college education and post-test improvement. Only subjects without some college education improved with feedback. Conclusions Adults who do not have higher levels of education improve significantly on a number line task when given feedback

Single dose oral ranolazine pharmacokinetics in patients receiving maintenance hemodialysis

Purpose: Ranolazine is a novel anti-angina treatment approved in the United States for chronic stable angina. Ranolazine pharmacokinetics have not been studied previously in patients who receive maintenance hemodialysis. This study describes the pharmacokinetics of ranolazine and three major metabolites (CVT-2738, CVT-2512, CVT-2514) in patients receiving thrice weekly hemodialysis. Methods: Eight participants receiving maintenance hemodialysis completed this prospective, open-label study (study identifier NCT01435174 at Clinicaltrials.gov). Three participants received a single tablet of ranolazine 500 mg (followed by an interim analysis), and five received 2 tablets of ranolazine 500 mg. Blood samples were collected over 65 h to determine the pharmacokinetic characteristics during and between hemodialysis sessions. Non-compartmental analysis was used to determine the individual pharmacokinetic parameters. Results: Ranolazine off-hemodialysis elimination phase half-lives were 3.6 and 3.9 h for 500 mg and 1000 mg doses, respectively. The time to maximum concentration ranged from 2 to 18 hours and the average maximum concentration was 0.65 ± 0.27 mcg/mL and 1.18 ± 0.48 mcg/mL for ranolazine 500 mg and 1000 mg dose, respectively. The mean hemodialysis percent reduction ratio for the ranolazine 500 mg dose was 52.3 ± 8.1% and for the ranolazine 1000 mg dose was 69.2 ± 37.6%. Conclusions: Data on ranolazine dosing in patients receiving maintenance hemodialysis is almost non-existent. Given the extent of pharmacokinetic variability observed with the 500 mg and 1000 mg oral doses of ranolazine, neither can be recommended as a starting dose in patients receiving maintenance hemodialysis. Guided by the information gained form this study about the extent of hemodialytic drug clearance, further multi-dose clinical trials of ranolazine are needed to optimize therapeutic outcomes in this patient population

Pharmacokinetics of ertapenem in critically ill patients receiving continuous venovenous hemodialysis or hemodiafiltration

This study characterizes the pharmacokinetics of ertapenem, a carbapenem antibiotic, in critically ill adult subjects receiving continuous renal replacement therapy (CRRT). Eight critically ill patients with suspected/known Gram-negative infections receiving continuous venovenous hemodialysis (CVVHD) or continuous venovenous hemodiafiltration (CVVHDF) and ertapenem were enrolled. One gram of ertapenem was infused over 30 min. Predialyzer blood samples were drawn with the first dose of ertapenem from the hemodialysis tubing at time zero, 30 min, and 1, 2, 4, 8, 12, 18, and 24 h after the start of the ertapenem infusion. Effluent was collected at the same time points. Ertapenem total serum, unbound serum, and effluent concentrations from all eight subjects were used simultaneously to perform a population compartmental pharmacokinetic modeling procedure using NONMEM. Monte Carlo simulations were performed to evaluate the ability of several ertapenem dosing regimens (500 mg once daily, 750 mg once daily, 500 mg twice daily, and 1,000 mg once daily) to obtain effective unbound serum concentrations above 0.5, 1, and 2 ?g/ml. For our simulated patients, all regimens produced unbound ertapenem concentrations above 2 ?g/ml for 40% of the dosing interval for at least 96% of simulated patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00877370.)Merck & Co. provided funding for this investigator-initiated study.Scopu