Evaluation of the activity of CYP2C19 in Gujrati and Marwadi subjects living in Mumbai (Bombay)

BACKGROUND: Inherited differences in the metabolism and disposition of drugs, and genetic polymorphisms in the targets of drug therapy (e.g., receptors), can greatly influence efficacy and toxicity of medications. Marked interethnic differences in CYP2C19 (a member of the cytochrome P-450 enzyme superfamily catalyzing phase I drug metabolism) which affects the metabolism of a number of clinically important drugs have been documented. The present study evaluated the activity of CYP2C19 in normal, healthy Gujrati and Marwadi subjects by phenotyping (a western Indian population). METHODS: All subjects received 20 mg of omeprazole, which was followed by blood collection at 3 hrs to estimate the metabolic ratio of omeprazole to 5-hydroxyomeprazole. The analysis was done by HPLC. RESULTS: It was seen that 10.36% of this population were poor metabolizers(PM) whereas 89.63% were extensive metabolizers(EM). CONCLUSION: A genotyping evaluation would better help in identifying population specific genotypes and thus help individualize drug therapy

An integrated network visualization framework towards metabolic engineering applications

Background Over the last years, several methods for the phenotype simulation of microorganisms, under specified genetic and environmental conditions have been proposed, in the context of Metabolic Engineering (ME). These methods provided insight on the functioning of microbial metabolism and played a key role in the design of genetic modifications that can lead to strains of industrial interest. On the other hand, in the context of Systems Biology research, biological network visualization has reinforced its role as a core tool in understanding biological processes. However, it has been scarcely used to foster ME related methods, in spite of the acknowledged potential. Results In this work, an open-source software that aims to fill the gap between ME and metabolic network visualization is proposed, in the form of a plugin to the OptFlux ME platform. The framework is based on an abstract layer, where the network is represented as a bipartite graph containing minimal information about the underlying entities and their desired relative placement. The framework provides input/output support for networks specified in standard formats, such as XGMML, SBGN or SBML, providing a connection to genome-scale metabolic models. An user-interface makes it possible to edit, manipulate and query nodes in the network, providing tools to visualize diverse effects, including visual filters and aspect changing (e.g. colors, shapes and sizes). These tools are particularly interesting for ME, since they allow overlaying phenotype simulation results or elementary flux modes over the networks. Conclusions The framework and its source code are freely available, together with documentation and other resources, being illustrated with well documented case studies.This work is partially funded by ERDF - European Regional Development Fund through the COMPETE Programme (operational programme for competitiveness) and by National Funds through the FCT (Portuguese Foundation for Science and Technology) within project ref. COMPETE FCOMP-01-0124-FEDER-015079 and the FCT Strategic Project PEst-OE/EQB/LA0023/2013. The work of PV is funded by PhD grant ref. SFRH/BDE/51442/2011

Demographic and spatial predictors of anemia in women of reproductive age in Timor-Leste: Implications for health program prioritization

10.1371/journal.pone.0091252PLoS ONE93-POLN

The guinea pig ileum lacks the direct, high-potency, M2-muscarinic, contractile mechanism characteristic of the mouse ileum

We explored whether the M2 muscarinic receptor in the guinea pig ileum elicits a highly potent, direct-contractile response, like that from the M3 muscarinic receptor knockout mouse. First, we characterized the irreversible receptor-blocking activity of 4-DAMP mustard in ileum from muscarinic receptor knockout mice to verify its M3 selectivity. Then, we used 4-DAMP mustard to inactivate M3 responses in the guinea pig ileum to attempt to reveal direct, M2 receptor-mediated contractions. The muscarinic agonist, oxotremorine-M, elicited potent contractions in ileum from wild-type, M2 receptor knockout, and M3 receptor knockout mice characterized by negative log EC50 (pEC50) values ± SEM of 6.75 ± 0.03, 6.26 ± 0.05, and 6.99 ± 0.08, respectively. The corresponding Emax values in wild-type and M2 receptor knockout mice were approximately the same, but that in the M3 receptor knockout mouse was only 36% of wild type. Following 4-DAMP mustard treatment, the concentration–response curve of oxotremorine-M in wild-type ileum resembled that of the M3 knockout mouse in terms of its pEC50, Emax, and inhibition by selective muscarinic antagonists. Thus, 4-DAMP mustard treatment appears to inactivate M3 responses selectively and renders the muscarinic contractile behavior of the wild-type ileum similar to that of the M3 knockout mouse. Following 4-DAMP mustard treatment, the contractile response of the guinea pig ileum to oxotremorine-M exhibited low potency and a competitive-antagonism profile consistent with an M3 response. The guinea pig ileum, therefore, lacks a direct, highly potent, M2-contractile component but may have a direct, lower potency M2 component

Mefloquine pharmacokinetics and mefloquine-artesunate effectiveness in Peruvian patients with uncomplicated Plasmodium falciparum malaria

<p>Abstract</p> <p>Background</p> <p>Artemisinin-based combination therapy (ACT) is recommended as a means of prolonging the effectiveness of first-line malaria treatment regimens. Different brands of mefloquine (MQ) have been reported to be non-bioequivalent; this could result in sub-therapeutic levels of mefloquine with decreased efficacy. In 2002, mefloquine-artesunate (MQ-AS) combination therapy was adopted as the first-line treatment for uncomplicated <it>Plasmodium falciparum </it>malaria in the Amazon region of Peru. Although MQ resistance has yet to be reported from the Peruvian Amazon, it has been reported from other countries in the Amazon Region. Therefore, continuous monitoring is warranted to ensure that the first-line therapy remains efficacious. This study examines the <it>in vivo </it>efficacy and pharmacokinetic parameters through Day 56 of three commercial formulations of MQ (Lariam^®, Mephaquin^®, and Mefloquina-AC^®Farma) given in combination with artesunate.</p> <p>Methods</p> <p>Thirty-nine non-pregnant adults with <it>P. falciparum </it>mono-infection were randomly assigned to receive artesunate in combination with either (1) Lariam, (2) Mephaquin, or (3) Mefloquina AC. Patients were assessed on Day 0 (with blood samples for pharmacokinetics at 0, 2, 4, and 8 hours), 1, 2, 3, 7, and then weekly until day 56. Clinical and parasitological outcomes were based on the standardized WHO protocol.</p> <p>Whole blood mefloquine concentrations were determined by high-performance liquid chromatography and pharmacokinetic parameters were determined using non-compartmental analysis of concentration versus time data.</p> <p>Results</p> <p>By day 3, all patients had cleared parasitaemia except for one patient in the AC Farma arm; this patient cleared by day 4. No recurrences of parasitaemia were seen in any of the 34 patients. All three MQ formulations had a terminal half-life of 14–15 days and time to maximum plasma concentration of 45–52 hours. The maximal concentration (C_max) and interquartile range was 2,820 ng/ml (2,614–3,108) for Lariam, 2,500 ng/ml (2,363–2,713) for Mephaquin, and 2,750 ng/ml (2,550–3,000) for Mefloquina AC Farma. The pharmacokinetics of the three formulations were generally similar, with the exception of the C_maxof Mephaquin which was significantly different to that of Lariam (<it>p </it>= 0.04).</p> <p>Conclusion</p> <p>All three formulations had similar pharmacokinetics; in addition, the pharmacokinetics seen in this Peruvian population were similar to reports from other ethnic groups. All patients rapidly cleared their parasitaemia with no evidence of recrudescence by Day 56. Continued surveillance is needed to ensure that patients continue to receive optimal therapy.</p

A cluster randomized trial of standard quality improvement versus patient-centered interventions to enhance depression care for African Americans in the primary care setting: study protocol NCT00243425

<p>Abstract</p> <p>Background</p> <p>Several studies document disparities in access to care and quality of care for depression for African Americans. Research suggests that patient attitudes and clinician communication behaviors may contribute to these disparities. Evidence links patient-centered care to improvements in mental health outcomes; therefore, quality improvement interventions that enhance this dimension of care are promising strategies to improve treatment and outcomes of depression among African Americans. This paper describes the design of the BRIDGE (Blacks Receiving Interventions for Depression and Gaining Empowerment) Study. The goal of the study is to compare the effectiveness of two interventions for African-American patients with depression--a standard quality improvement program and a patient-centered quality improvement program. The main hypothesis is that patients in the patient-centered group will have a greater reduction in their depression symptoms, higher rates of depression remission, and greater improvements in mental health functioning at six, twelve, and eighteen months than patients in the standard group. The study also examines patient ratings of care and receipt of guideline-concordant treatment for depression.</p> <p>Methods/Design</p> <p>A total of 36 primary care clinicians and 132 of their African-American patients with major depressive disorder were recruited into a cluster randomized trial. The study uses intent-to-treat analyses to compare the effectiveness of standard quality improvement interventions (academic detailing about depression guidelines for clinicians and disease-oriented care management for their patients) and patient-centered quality improvement interventions (communication skills training to enhance participatory decision-making for clinicians and care management focused on explanatory models, socio-cultural barriers, and treatment preferences for their patients) for improving outcomes over 12 months of follow-up.</p> <p>Discussion</p> <p>The BRIDGE Study includes clinicians and African-American patients in under-resourced community-based practices who have not been well-represented in clinical trials to improve depression care. The patient-centered and culturally targeted approach to depression care is a relatively new one that has not been tested in most previous studies. The study will provide evidence about whether patient-centered accommodations improve quality of care and outcomes to a greater extent than standard quality improvement strategies for African Americans with depression.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00243425</p