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Background: Filarial nematodes cause severe illnesses in humans and canines including limb deformities and disfigurement, heart failure, blindness, and death, among others. There are no vaccines, and current drugs against filarial nematodes infections have only modest effects and are prone to complications. Methodology/principal findings: We identified a gene (herein called DiMT) encoding an S-adenosyl-L-methionine (SAM)-dependent methyltransferase with orthologs in parasite filarial worms but not in mammals. By in silico analysis, DiMT possesses catalytic sites for binding SAM and catecholamines with high affinity. We expressed and purified recombinant DiMT protein and used it as an enzyme in a series of SAM-dependent methylation assays. DiMT acted specifically as a catechol-O-methyltransferase (COMT), catalyzing catabolic methylation of dopamine, and depicted Michaelis Menten kinetics on substrate and co-substrate. Among a set of SAM-dependent methyltransferase inhibitors, we identified compounds that bound with high affinity to DiMT's catalytic sites and inhibited its enzymatic activity. By testing the efficacy of DiMT inhibitors against microfilariae of Dirofilaria immitis in culture, we identified three inhibitors with concentration- and time-dependent effect of killing D. immitis microfilariae. Importantly, RNAi silencing of a DiMT ortholog in Caenorhabditis elegans has been shown to be lethal, likely as a result of excessive accumulation of active catecholamines that inhibit worm locomotion, pharyngeal pumping and fecundity. Conclusions/significance: Together, we have unveiled DiMT as an essential COMT that is conserved in parasitic filarial nematodes, but is significantly different from mammalian COMTs and, therefore, is a viable target for development of novel drugs against filarial nematode infections. Author summary: Parasitic filarial nematodes cause serious illnesses in humans and canines including limb deformities and disfigurement, blindness, heart failure, and death, among others. There are no vaccines, and current drugs in use against filarial nematodes infections have only modest effects and are prone to complications. In this study, we explored a unique enzyme (DiMT), conserved in all parasitic filarial nematodes but not in mammalian species. Using computation, biochemistry and molecular biology approaches, we validated DiMT as a catechol-O-methyltransferase that functions to inactivate catecholamines to prevent their accumulation and hence block their deleterious effects in filarial nematodes, including loss of worm viability, reproduction and survival. Subsequently, we identified DiMT's chemical inhibitors and demonstrated that they possess anti-filarial nematode efficacy through blocking the inactivation of catecholamines. Together, we have unveiled DiMT as a viable molecular target for the development of new drugs for treating filarial nematode infections. [ABSTRACT FROM AUTHOR]

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The mapping and sequencing of the human genome at the turn of the new millennium marks a pivotal reassessment of genomic science in its potential to replace traditional "one-size-fits-all" medicine with a personalised approach. The use of racial proxies in the development of pharmacogenomic products risks conflating genetics with race under the guise of alleviating health disparities. This article argues that the current genomic approaches to realising personalised medicine do not deliver on the promise for optimised health for all and may result in irreversible harm, including psychological, social and medical harm, to racial minority groups. In light of recent epigenetic findings, the article provides a reconceptualisation of the genome and race, which is necessary to understand enduring racial disparities and the cumulative effects of racial discrimination. It then addresses the need for regulatory oversight of the approval of race-based pharmacogenomic products. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Educational & Psychological Sciences is the property of Arab Journal of Sciences & Research Publishing (AJSRP) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The article offers the issue information of the publication "Clinical Pharmacology & Therapeutics" including the members of the editorial boards such as Scott A. Waldman and Andre Terzic, and notes the copyright information of the issue.

Advances in pharmacogenomics (PGx) have the potential to transform healthcare by allowing precision medicine to become a reality. However, PGx knowledge is new, complex, and evolving, and relying on the cognition of clinicians alone is insufficient for clinical implementation. Integrating clinical decision support (CDS) tools in the electronic health record (EHR) is critical for translating PGx into clinical practice. Herein, we review current strategies to implement PGx using EHR-CDS functionalities. [ABSTRACT FROM AUTHOR]

N-Acetyletransferase-1 (NATI) is the phase II metabolizing enzyme, renders for the detoxification of many drugs and arylamines present in foods. NATI is polymorphic in nature, varies in different ethnic groups. The present study was designed to evaluate the acetylation capacity of NATI using 5-aminosalicyclic acid in the healthy Pakistani population. The blood samples were collected at 3 hour from each volunteer for acetyl metabolites. The concentrations of acetyl metabolite and parent drug were determined in plasma samples by HPLC. The concentrations of 5-aminosalicyclic acid (5-ASA), acetyl 5-aminosalicyclic acid (Ac5-ASA), ratio of Ac5-ASA/5-ASA were determined to assign the population into slow or fast acetylators by using the statistical model probit plot. NATI acetylation activity by 5-ASA showed bimodal frequency distribution in the population. Almost 71% of the population was fast acetylator and 29% was slow acetylator. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a common psychiatric disease. Selective serotonin reuptake inhibitors (SSRIs) are an important class of drugs used in the treatment of MDD. However, many patients do not respond adequately to SSRI therapy. We used a pharmacometabolomics-informed pharmacogenomic research strategy to identify citalopram/escitalopram treatment outcome biomarkers. Metabolomic assay of plasma samples from 20 escitalopram remitters and 20 nonremitters showed that glycine was negatively associated with treatment outcome (P = 0.0054). This observation was pursued by genotyping tag single-nucleotide polymorphisms (SNPs) for genes encoding glycine synthesis and degradation enzymes, using 529 DNA samples from SSRI-treated MDD patients. The rs10975641 SNP in the glycine dehydrogenase (GLDC) gene was associated with treatment outcome phenotypes. Genotyping for rs10975641 was carried out in 1,245 MDD patients in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, and its presence was significant (P = 0.02) in DNA taken from these patients. These results highlight a possible role for glycine in SSRI response and illustrate the use of pharmacometabolomics to 'inform' pharmacogenomics. [ABSTRACT FROM AUTHOR]

Sulfotransferases (SULTs) play a significant role in the biotransformation of a variety of xenobiotics and endogenous compounds. SULTs are genetically polymorphic enzymes; to date, 12 human cytosolic SULT isoforms have been identified. This study investigated SULT1A1 and SULT1A2 gene polymorphism using a PCR-RFLP method ( n = 303). The frequency of the SULT1A1*1 allele was 76.2% and SULT1A1*2 was 23.8%. The SULT1A1*3 allele could not be identified. The SULT1A2 frequencies were 69.2% ( SULT1A2*1), 18.3% ( SULT1A2*2), and 12.5% ( SULT1A2*3). The SULT1A1 and SULT1A2 loci were in Hardy-Weinberg equilibrium ( SULT1A1 χ = 0.58, P = 0.44; SULT1A2 χ = 7.28, P = 0.06). Linkage analysis indicated a close linkage between these two genes (χ = 5.31, P < 0.01); therefore, the statistical hypothesis that SULT1A1 and SULT1A2 alleles are independently distributed was rejected. Additionally, a strongly positive linkage was detected between SULT1A1*2 and SULT1A2*2 alleles in this population ( D′ = 0.79, χ = 33.33). [ABSTRACT FROM AUTHOR]

A table of contents for the issue is presented.

Discusses the genetic polymorphisms for cathecol oxygen-methyltransferase, thiopurine methyltransferase and histamine nitrogen-methyltransferase. Role of inheritance in the regulation of gene expression; Pharmacogenetics of methyltransferase enzymes; Physiological significance of sulphur-methylation pathway.

Catechol-O-methyltransferase (COMT) catalyzes the O-methylation of catechol hormones, neurotransmitters and certain drugs. It is subject to genetic polymorphism and ethnic differences. High red blood cell (RBC) COMT activity has been correlated with a poor response to levodopa treatment in Parkinson's disease. RBC COMT was determined in a Norwegian population ( n=213) of whom 115 were Saami (Lapps). The Saami had 16.5% lower RBC COMT activity compared to a non-Saami population sample from the northern part of Norway ( n=50), 13.9 vs. 16.4 units/ml RBC (U) ( P=0.04). This is the first report of any population with lower RBC COMT activity than a Caucasian population. A wide range of RBC COMT activities was found in the entire population examined (1.3-38.3 U). [ABSTRACT FROM AUTHOR]

(−)-Deprenyl has been increasingly used in recent years as an adjuvant with levodopa and a decarboxylase inhibitor in the treatment of Parkinson's disease. The inhibition of dopa decarboxylase and monoamine oxidase B resulting from this combination suggests that there may be a counter-regulatory increase in the activity of the third main enzyme in the catabolism of levodopa, i.e. catecholamine-O-methyl transferase (COMT). The current study on 36 patients with Parkinson's disease under long-term treatment with levodopa/dopadecarboxylase inhibitor showed, however, that the erythrocyte-COMT was unaffected by additional (−)-deprenyl medication. The patients in this study received levodopa and benserazide either with (−)-deprenyl (n=21) or without (−)-deprenyl (n=15). When allowance was made for the different genotypes, COMT, COMT, and COMT, there were no differences in the enzyme activities between the two treatment groups and the untreated controls (n=26). On the basis of these results, consideration is given to the conditions in which COMT inhibitors are likely to be of value in the treatment of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Catechol-O-methyltransferase (COMT) plays an important role in the inactivation of catecholamines. It has been demonstrated that erythrocyte COMT activity is genetically determined and controlled by a major autosomal locus with two alleles. The recent development of a method which allows the detection of COMT isozymes directly in autoradiozymograms has provided the means to investigate the chromosome location of the gene by using somatic cell hybrids. We have found that a single form of the COMT enzyme is expressed in several mouse-human fibroblast cell lines. The data obtained from the segregation analysis of the COMT enzyme in these hybrids and their subclones have provided evidence for the location of a major gene for COMT activity on human chromosome 22. [ABSTRACT FROM AUTHOR]

The Mayo Clinic Center for Individualized Medicine (CIM) is designed to discover and integrate the latest in genomic, molecular, and clinical science into personalized care for patients across a multiple‐site academic medical center. Despite a highly integrated structure, fully electronic medical record, and strong administrative support, achievement of this goal has had challenges. This article will describe the activities of the CIM, with emphasis on the strategy being used to clinically implement genomics. Clinical Pharmacology & Therapeutics (2013); 94 2, 204–206. doi:10.1038/clpt.2013.52 [ABSTRACT FROM AUTHOR]