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P450 (Cytochrome) Oxidoreductase Gene (POR) Common Variant (POR*28) Significantly Alters CYP2C9 Activity in Swedish, But Not in Korean Healthy Subjects

Hatta FH, Aklillu E

OMICS, 2015 Dec;19(12):777-81.
PMID: 26669712 DOI: 10.1089/omi.2015.0159

CYP2C9 enzyme contributes to the metabolism of several pharmaceuticals and xenobiotics and yet displays large person-to-person and interethnic variation. Understanding the mechanisms of CYP2C9 variation is thus of immense importance for personalized medicine and rational therapeutics. A genetic variant of P450 (cytochrome) oxidoreductase (POR), a CYP450 redox partner, is reported to influence CYP2C9 metabolic activity in vitro. We investigated the impact of a common variant, POR*28, on CYP2C9 metabolic activity in humans. 148 healthy Swedish and 146 healthy Korean volunteers were genotyped for known CYP2C9 defective variant alleles (CYP2C9*2, *3). The CYP2C9 phenotype was determined using a single oral dose of 50 mg losartan. Excluding oral contraceptive (OC) users and carriers of 2C9*2 and *3 alleles, 117 Korean and 65 Swedish were genotyped for POR*5, *13 and *28 using Taqman assays. The urinary losartan to its metabolite E-3174 metabolic ratio (MR) was used as an index of CYP2C9 metabolic activity. The allele frequency of the POR*28 variant allele in Swedes and Koreans was 29% and 44%, respectively. POR*5 and *13 were absent in both study populations. Considering the CYP2C9*1/*1 genotypes only, the CYP2C9 metabolic activity was 1.40-fold higher in carriers of POR*28 allele than non-carriers among Swedes (p = 0.02). By contrast, no influence of the POR*28 on CYP2C9 activity was found in Koreans (p = 0.68). The multivariate analysis showed that ethnicity, POR genotype, and smoking were strong predictors of CYP2C9 MR (p < 0.05). This is the first report to implicate the importance of POR*28 genetic variation for CYP2C9 metabolic activity in humans. These findings contribute to current efforts for global personalized medicine and using medicines by taking into account pharmacogenetic and phenotypic variations.
Fulltext Development and Validation of Questionnaires to Assess Workplace Violence Risk Factors (QAWRF): A Tripartite Perspective of Worksite-Specific Determinants in Healthcare Settings

Mohd Hatta FH, Samsudin EZ, Aimran N, Ismail Z

Risk Manag Healthc Policy, 2023;16:1229-1240.
PMID: 37431510 DOI: 10.2147/RMHP.S411335

INTRODUCTION: Workplace violence (WPV) incidences are prevalent in healthcare, and existing WPV interventions have only moderate evidence for effectiveness. This study aimed to develop and validate an instrument to assess worksite-specific WPV risk factors in healthcare settings based on a tripartite perspective of key stakeholders to facilitate improved interventions.
METHODS: Three questionnaires were developed to get the responses from healthcare administrators, workers, and clients, representing the three components of Questionnaires to Assess Workplace Violence Risk Factors (QAWRF). The domains of the questionnaires were developed based on The Chappell and Di Martino's Interactive Model of Workplace Violence, and the items were generated from 28 studies identified from a systematic review of the literature. Six experts, 36 raters, and 90 respondents were recruited to assess the content validity, face validity, and usability and reliability of the QAWRF respectively. Item and Scale Level Content Validity Index, Item and Scale Level Face Validity Index, and Cronbach's alpha values were determined for QAWRF-administrator, QAWRF-worker, and QAWRF-client.
RESULTS: The psychometric indices for QAWRF are satisfactory.
CONCLUSION: QAWRF holds good content validity, face validity, and reliability, and findings from QAWRF can contribute towards worksite-specific interventions that are expected to be resource efficient and more effective than general WPV interventions.
Differences in CYP2C9 Genotype and Enzyme Activity Between Swedes and Koreans of Relevance for Personalized Medicine: Role of Ethnicity, Genotype, Smoking, Age, and Sex

Hatta FH, Lundblad M, Ramsjo M, Kang JH, Roh HK, Bertilsson L, et al.

OMICS, 2015 Jun;19(6):346-53.
PMID: 25977991 DOI: 10.1089/omi.2015.0022

Global personalized medicine demands the characterization of person-to-person and between-population differences in drug pharmacokinetics and pharmacodynamics. CYP2C9 pharmacokinetic pathway is subject to modulation by both genetic and environmental factors. CYP2C9 genotype-based dose recommendations (e.g., for warfarin) is advocated. However, the overall contribution of genotype for variation in enzyme activity may differ between populations. We evaluated the importance of ethnicity, genotype, smoking, body weight, age, and sex for CYP2C9 enzyme activity. CYP2C9 genotype and phenotype was determined in 148 Swedes and 146 Koreans using losartan as a probe. CYP2C9 enzyme activity was assessed using urinary losartan/metabolite E-3174 ratio. The frequency of CYP2C9 defective variant alleles (*2 and *3) was significantly higher in Swedes (10.8% and 12.5%) than in Koreans (0% and 5.8%). In matched genotypes, CYP2C9 enzyme activity was significantly lower in Swedes compared to Koreans (p<0.0001). In a univariate analysis, age, weight, ethnicity, genotype, and smoking were significant predictors of CYP2C9 phenotype. A stepwise multivariate analysis indicated ethnicity, genotype, and smoking remained as significant predictors of CYP2C9 enzyme activity, accounting for 50% of the total variance. In both study populations, CYP2C9 genotype was a significant predictor of CYP2C9 enzyme activity, but its contribution in explaining the total variance was lower in Koreans (26.6%) than Swedes (40%). In conclusion, we report significantly lower CYP2C9 enzyme activity in Swedes compared to Koreans, partly but not exclusively due to CYP2C9 pharmacogenetic variations. Ethnicity and environment factors need to be considered together with genotype for population-specific dose optimization and global personalized medicine.
Fulltext Therapeutic potentials of iridoids derived from Rubiaceae against in vitro and in vivo inflammation: A scoping review

Jaafar A, Zulkipli MA, Mohd Hatta FH, Jahidin AH, Abdul Nasir NA, Hazizul Hasan M

Saudi Pharm J, 2024 Jan;32(1):101876.
PMID: 38226349 DOI: 10.1016/j.jsps.2023.101876

Acute inflammation may develop into chronic, life-threatening inflammation-related diseases if left untreated or if there are persistent triggering factors. Cancer, diabetes mellitus, stroke, cardiovascular diseases, and neurodegenerative disorders are some of the inflammation-related diseases affecting millions of people worldwide. Despite that, conventional medical therapy such as non-steroidal anti-inflammatory drugs (NSAIDs) is associated with serious adverse effects; hence, there is an urgent need for a newer and safer therapeutic alternative from natural sources. Iridoids are naturally occurring heterocyclic monoterpenoids commonly found in Rubiaceae plants. Plant extracts from the Rubiaceae family were demonstrated to have medicinal benefits against neurodegeneration, inflammation, oxidative stress, hyperglycaemia, and cancer. However, the therapeutic effects of natural iridoids derived from Rubiaceae as well as their prospective impacts on inflammation in vitro and in vivo have not been thoroughly explored. The databases of PubMed, Scopus, and Web of Science were searched for pertinent articles in accordance with PRISMA-ScR guidelines. A total of 31 pertinent articles from in vitro and in vivo studies on the anti-inflammatory potentials of iridoids from Rubiaceae were identified. According to current research, genipin, geniposide, and monotropein are the most researched iridoids from Rubiaceae that reduce inflammation. These iridoids primarily act by attenuating inflammatory cytokines and mediators via inhibition of the NF-κB signalling pathway in various disease models. A comprehensive overview of the current research on the anti-inflammatory properties of iridoids from the Rubiaceae family is presented in this review, highlighting the characteristics of the experimental models used as well as the mechanisms of action of these iridoids. To develop an alternative therapeutic agent from iridoids, more studies are needed to elucidate the effects and mechanism of action of iridoids in a wide variety of experimental models as well as in clinical studies pertaining to inflammation-related diseases.
Fulltext Construct Validity and Test-Retest Reliability of Questionnaires to Assess Workplace Violence Risk Factors (QAWRF): A Tripartite Perspective of Worksite-Specific Determinants in Healthcare Settings

Mohd Hatta FH, Samsudin EZ, Aimran N, Ismail Z, Sapian NAM

Risk Manag Healthc Policy, 2024;17:455-471.
PMID: 38481392 DOI: 10.2147/RMHP.S439914

INTRODUCTION: Among available workplace violence (WPV) interventions, only data-driven, worksite-based, and risk-based approach WPV interventions had moderate evidence for effectiveness in decreasing the risk of WPV. The Questionnaires to Assess Workplace Violence Risk Factors (QAWRF) had been previously developed to determine the level of WPV risk factors in each healthcare setting based on the tripartite perspective of key stakeholders to enable effective WPV interventions. This study aimed to determine the construct validity and test-retest validity of QAWRF.
METHODS: QAWRF, a three-component instrument consisting of QAWRF-Administrators, QAWRF-Workers, and QAWRF-Clients, had previously undergone content validation, face validation, and internal consistency reliability testing. 965 respondents were recruited to examine the construct validity of QAWRF, and a subset of these (n = 90) were retested again at an interval of three weeks to assess its test-retest reliability. Confirmatory factor analysis (CFA) was performed, and fitness indices, average variance extracted, correlation coefficient, composite reliability, and intraclass correlation coefficient were determined.
RESULTS: QAWRF-Administrator, QAWRF-Worker, and QAWRF-Client had acceptable factor loadings (≥0.6), absolute fit (Root Mean Square Error of Approximation > 0.1), incremental fit (Confirmatory Fit Index and Tucker Lewis Index > 0.9), parsimonious fit (Chi-square/degree of freedom < 5), correlation coefficient between construct (≤0.85), discriminant validity index, and construct reliability (≥0.6). CFA supported a four-factor model for QAWRF-Administrator and QAWRF-Worker, and a two-factor model for QAWRF-Client.
CONCLUSION: QAWRF holds good construct validity and test-retest reliability. By using QAWRF, healthcare managers can identify specific WPV risk factors that are perceived by stakeholders as prevalent at a particular workplace, and these findings can contribute towards data-driven, worksite-specific, and targeted WPV interventions in healthcare settings that are expected to be resource-efficient and more effective than general WPV interventions.
Applications of CRISPR in Parasitology

Tee PYE, Chu SYC, Kok CCY, Foo M, Tan CZJ, Foo JB, et al.

Curr Pharm Biotechnol, 2024 Jul 12.
PMID: 39005116 DOI: 10.2174/0113892010316710240626042205

Clustered Regions of Interspersed Palindromic Repeat (CRISPR)-based techniques have been utilized in various research areas, including agriculture, biotechnology, and medicine. With the use of a short sequence guide RNA and CRISPR-associated (Cas) protein, this technique allows for robust, site-specific manipulation of the genome, aiding researchers in making important biomedical discoveries and scientific advancements. In this review, we explored the applications of CRISPR/Cas systems in the field of parasitology for the identification and validation of novel functional genes, diagnosis of parasitic infections, reduction of parasite virulence, and the disruption of disease transmission. We also discussed how CRISPR can be used for the development of therapeutics, vaccines, and drug discovery. Furthermore, the challenges and future perspectives of this technology are also highlighted.
Fulltext Systematic pharmacogenomics analysis of a Malay whole genome: proof of concept for personalized medicine

Salleh MZ, Teh LK, Lee LS, Ismet RI, Patowary A, Joshi K, et al.

PLoS One, 2013;8(8):e71554.
PMID: 24009664 DOI: 10.1371/journal.pone.0071554

BACKGROUND: With a higher throughput and lower cost in sequencing, second generation sequencing technology has immense potential for translation into clinical practice and in the realization of pharmacogenomics based patient care. The systematic analysis of whole genome sequences to assess patient to patient variability in pharmacokinetics and pharmacodynamics responses towards drugs would be the next step in future medicine in line with the vision of personalizing medicine.
METHODS: Genomic DNA obtained from a 55 years old, self-declared healthy, anonymous male of Malay descent was sequenced. The subject's mother died of lung cancer and the father had a history of schizophrenia and deceased at the age of 65 years old. A systematic, intuitive computational workflow/pipeline integrating custom algorithm in tandem with large datasets of variant annotations and gene functions for genetic variations with pharmacogenomics impact was developed. A comprehensive pathway map of drug transport, metabolism and action was used as a template to map non-synonymous variations with potential functional consequences.
PRINCIPAL FINDINGS: Over 3 million known variations and 100,898 novel variations in the Malay genome were identified. Further in-depth pharmacogenetics analysis revealed a total of 607 unique variants in 563 proteins, with the eventual identification of 4 drug transport genes, 2 drug metabolizing enzyme genes and 33 target genes harboring deleterious SNVs involved in pharmacological pathways, which could have a potential role in clinical settings.
CONCLUSIONS: The current study successfully unravels the potential of personal genome sequencing in understanding the functionally relevant variations with potential influence on drug transport, metabolism and differential therapeutic outcomes. These will be essential for realizing personalized medicine through the use of comprehensive computational pipeline for systematic data mining and analysis.