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Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance

Teh LK, Bertilsson L

Drug Metab. Pharmacokinet., 2012;27(1):55-67.
PMID: 22185816

CYP2D6 has received intense attention since the beginning of the pharmacogenetic era in the 1970s. This is because of its involvement in the metabolism of more than 25% of the marketed drugs, the large geographical and inter-ethnic differences in the genetic polymorphism and possible drug-induced toxicity. Many interesting reviews have been published on CYP2D6 and this review aims to reinstate the importance of the genetic polymorphism of CYP2D6 in different populations as well as some clinical implications and important drug interactions.
Fulltext Standardised extracts of Moringa Oleifera and Centella Asiatica enhanced the antioxidant activity, learning and memory effects by inhibiting acetylcholinesterase activity in D-galactose induced ageing rats

Hisyam Jamari, Mohd Salleh Rofiee, Richard James Johari, Mohd Zaki Salleh, Teh, Lay Kek

Pertanika Journal of Science & Technology, 2020;28(1):293-310.
MyJurnal

The potential of Moringa oleifera Lam. (Moringaceae) and Centella asiatica (L.) Urban (Apiaceae) extracts (TGT-PRIMAAGE) in slowing the decline of memory and learning activity was investigated using D-galactose-induced ageing rat model. The extracts were profiled and standardised based on markers identified using LC/MS-QTOF. Toxicity study of the extract was done, and the rat did not show any sign of toxicity. The extract was orally administered to the rat and dose dependent (100, 500 and 1000 mg/kg) efficacy were investigated. The rats were subjected to Morris Water Maze whereby 3 parameters were studied (number of entry to platform, latency and novel object recognition). Plasma was collected for the determination of catalase (CAT) activity and levels of malondialdehyde (MDA) and advanced glycation end products (AGEs). The activity of acetylcholinesterase (AChE), level of acetylcholine (ACh) and lipid peroxidation (LPO) were measured using the brain lysates. Significant improvement (p < 0.05) was seen in the memory and learning abilities in the aged rats that received medium and high dose of TGT-PRIMAAGE, and tocotrienol. Rats treated with TGT-PRIMAAGE had also shown improved CAT activity and resulted in reduced LPO. The level of ACh was found increased in parallel with the reduced AChE activity. The capabilities of learning and memory of the TGT-PRIMAAGE treated rats were enhanced via inhibition of AChE activity and subsequently increased level of ACh.
Fulltext Aqua zumba versus aqua jogging: comparative effects on health parameters among obese middle aged women

Sarina Md. Yusof, Maisarah Shari, Zulkifli Kadir, Aishah Adam, Teh, Lay Kek, Suhana Aiman, et al.

Movement Health & Exercise, 2018;7(2):11-21.
MyJurnal

Background: Obesity is major contributor to diseases and mortality. Constant weight loss significantly reverses diseases related to obesity and helps prolong human life expectancy. To date, there has been limited scientific evidence comparing the effectiveness of the Aqua Zumba® Fitness program and conventional aqua jog among obese women. Thus, the purpose of this study is to compare the effects between 12 weeks of Aqua Zumba® Fitness and aqua jog on health parameters among middle-age women. Methods: A total of sixty sedentary obese women (BMI >30 kg/m2), aged 40-59 years old were randomized to either Aqua Zumba® Fitness (AZ, n=20), aqua jog (AJ, n=20) or control group (C, n=20). Exercise groups were involved in different 12-week aqua exercise programs, 3 times per week, 60 minutes per session, with an intensity of 50-75% of maximum heart rate. Body mass (BM), skeletal muscle mass (SMM), body fat percentage (BF%), waist circumference (WC), upper and lower body strength (UBS and LBS), cardiorespiratory fitness (CRF), and flexibility were measured at baseline (week-0) and post-exercise intervention (week-13). Result: The AZ group demonstrated significant changes (p
Fulltext Technology advancement enabling the link of gut microbiota with obesity and metabolic disorder

Hartini Yusof, Mohamad Shafiq Aazmi, Teh Lay Kek, Mohd Zaki Salleh, Ili Ng Abdullah, Aminuddin Ahmad, et al.

Jurnal Sains Kesihatan Malaysia, 2015;13(1):77-91.
MyJurnal

Obesity is a growing epidemic due to an accelerated phase of industrialization and urbanization with the overfed people
now outnumbered the underfed. It is the major public health problem with a lot of research interest as it is associated
with many complicated chronic disorders such as type-2 diabetes, cardiovascular diseases (CVD) and cancers. A global
estimation of 2.8 million deaths per year is due to obesity and there are tremendous on-going efforts to identify hosts
and environmental factors that infl uence the cause and pathogenesis of obesity. Concerted efforts from different research
groups had successfully shown that obese subjects have altered composition of gut microbiota and transplantation of this
microbiota infl uences body weight in the germ-free recipient mice. The advancement of technology had made possible
the study of gut microbiota which was unculturable for better understanding of their impact to human health. Rapid
deep sequencing of DNA at reasonable cost through various options of platforms followed by data analysis using robust
bioinformatic tools are an important way of analysing the gut microbiome. Here we review the role of gut microbiota
which modulates host’s metabolic functions and gene expression, facilitating the extraction and storage of energy from the
ingested dietary substances and leading to body-weight gain. We will discuss on the different techniques used, focusing
on the high-defi nition technologies for the determination of the composition, function and ecology of gut microbiota. This
allows the appropriate selection of platform which becomes the key for success of subsequent research.
Fulltext Aqua Zumba versus Aqua Jogging: Comparative effects on health parameters among obese middle age women

Sarina Md. Yusof, Maisarah Shari, Zulkifli Kadir, Suhana Aiman, Norizzati Mohd Idris, Aishah Adam, et al.

Movement Health & Exercise, 2018;7(2):11-22.
MyJurnal

Background: Obesity is major contributor to diseases and mortality. Constant
weight loss significantly reverses diseases related to obesity and helps
prolong human life expectancy. To date, there has been limited scientific
evidence comparing the effectiveness of the Aqua Zumba® Fitness program
and conventional aqua jog among obese women. Thus, the purpose of this
study is to compare the effects between 12 weeks of Aqua Zumba® Fitness
and aqua jog on health parameters among middle-age women. Methods: A
total of sixty sedentary obese women (BMI >30 kg/m2), aged 40-59 years old
were randomized to either Aqua Zumba® Fitness (AZ, n=20), aqua jog (AJ,
n=20) or control group (C, n=20). Exercise groups were involved in different
12-week aqua exercise programs, 3 times per week, 60 minutes per session,
with an intensity of 50-75% of maximum heart rate. Body mass (BM),
skeletal muscle mass (SMM), body fat percentage (BF%), waist
circumference (WC), upper and lower body strength (UBS and LBS),
cardiorespiratory fitness (CRF), and flexibility were measured at baseline
(week-0) and post-exercise intervention (week-13). Result: The AZ group
demonstrated significant changes (p
Influence of DRD2 polymorphisms on the clinical outcomes of patients with schizophrenia

Zahari Z, Teh LK, Ismail R, Razali SM

Psychiatr Genet, 2011 Aug;21(4):183-9.
PMID: 21206399 DOI: 10.1097/YPG.0b013e3283437250

Variations in the gene for dopamine D2 receptor (DRD2) might have an influence on the outcome of antipsychotic treatment in schizophrenia. The objective of this study was to investigate the influence of DRD2 polymorphisms on treatment outcomes in patients with schizophrenia.
Fulltext Significant Decreased Expressions of CaN, VEGF, SLC39A6 and SFRP1 in MDA-MB-231 Xenograft Breast Tumor Mice Treated with Moringa oleifera Leaves and Seed Residue (MOLSr) Extracts

Lim WF, Mohamad Yusof MI, Teh LK, Salleh MZ

Nutrients, 2020 Sep 30;12(10).
PMID: 33007803 DOI: 10.3390/nu12102993

Moringa oleifera is a miracle plant with many nutritional and medicinal properties. Chemopreventive values of the combined mixture of moringa leaves and seed residue (MOLSr) at different ratios (M1S9, M1S1 and M9S1) were investigated. MOLSr extracts were subjected to phytochemical screening, antioxidant assays, metabolite profiling and cytotoxic activity on the primary mammary epithelial cells (PMECs), non-malignant Chang's liver cells and various human cancer cell lines (including breast, cervical, colon and liver cancer cell lines). The MOLSr ratio with the most potent cytotoxic activity was used in xenograft mice injected with MDA-MB-231 cells for in vivo tumorigenicity study as well as further protein and gene expression studies. M1S9, specifically composed of saponin and amino acid, retained the lowest antioxidant activity but the highest glucosinolate content as compared to other ratios. Cell viability decreased significantly in MCF-7 breast cancer cells and PMECs after treatment with M1S9. Solid tumor from MDA-MB-231 xenograft mice was inhibited by up to 64.5% at third week after treatment with high-dose M1S9. High-dose M1S9 significantly decreased the expression of calcineurin (CaN) and vascular endothelial cell growth factor (VEGF) proteins as well as the secreted frizzled-related protein 1 (SFRP1) and solute carrier family 39 member 6 (SLC39A6) genes. This study provides new scientific evidence for the chemoprevention potential of MOLSr extracts in a breast cancer model; however, the precise mechanism warrants further investigation.
Insight of the mitochondrial genomes of the Orang Asli and Malays: The heterogeneity and the disease-associated variants

Sukri A, Noorizhab MNF, Teh LK, Salleh MZ

Mitochondrion, 2022 01;62:74-84.
PMID: 34748985 DOI: 10.1016/j.mito.2021.10.010

Orang Asli are the oldest inhabitants in Peninsular Malaysia that forms as a national minority while the Malays are the majority. The study aimed to screen the mitochondrial genomes of the Orang Asli and the Malays to discover the disease-associated variants. A total of 99 Orang Asli from six tribes (Bateq, Cheq Wong, Orang Kanaq, Kensiu, Lanoh, and Semai) were recruited. Mitochondrial genome sequencing was conducted using a next-generation sequencing platform. Furthermore, we retrieved mitochondrial DNA sequences from the Malays for comparison. The clinical significance, pathogenicity prediction and frequency of variants were determined using online tools. Variants associated with mitochondrial diseases were detected in the 2 populations. A high frequency of variants associated with mitochondrial diseases, breast cancer, prostate cancer, and cervical cancer were detected in the Orang Asli and modern Malays. As medicine evolves to adopt prediction and prevention of diseases, this study highlights the need for intervention to adopt genomics medicine to strategise better healthcare management as a way forward for Precision Health.
Fulltext Influence of CYP2D6 polymorphisms on symptomatology and side-effects of patients with schizophrenia in Malaysia

Zahari Z, Salleh MR, Teh LK, Ismail R

Malays J Med Sci, 2009 Jul;16(3):12-20.
PMID: 22589660 MyJurnal

Our objective was to investigate the association of CYP2D6 polymorphisms with symptoms and side-effects of patients with schizophrenia.
Functional role of Ile264 in CYP2C8: mutations affect haem incorporation and catalytic activity

Singh R, Ting JG, Pan Y, Teh LK, Ismail R, Ong CE

Drug Metab. Pharmacokinet., 2008;23(3):165-74.
PMID: 18574320

The work described in this study aimed to express CYP2C8 wild-type and mutant proteins in bacterial expression system and to use the expressed proteins to investigate the structural and functional consequences of a reported allele CYP2C8(*)4 (carrying Ile264Met substitution) on protein activity. Ile264 was replaced by three different amino acids resulting in three mutant constructs, 2C8I264M, 2C8I264R and 2C8I264D. The presence of isoleucine at position 264 in CYP2C8 was found to be important for proper haem insertion and protein folding; whereas bulkier or charged residues were highly disruptive resulting in inactive proteins with minimum spectral and catalytic activities. This was evidenced from the low levels of Soret peak at 450 nm and negligible levels of tolbutamide methylhydroxylase activity. Kinetic study using paclitaxel indicated that all three mutants exhibited only 9.7 to 35.4% of the activity level observed in the wild-type. In addition, the mutants were more sensitive to proteinase K digestion, indicating a possible alteration of conformation. The combined effects of protein instability and compromised catalytic activity resulted in defective CYP2C8 protein which may have clinical implications in carriers of CYP2C8*4, particularly in terms of their capacity to clear potent drugs and their susceptibility to adverse drug reactions.
Fulltext The methanolic extract of Garcinia atroviridis (MeGa) reduces body weight and food intake, and improves lipid profiles by altering the lipid metabolism: a rat model

Lim WF, Nasir SM, Teh LK, James RJ, Izhar MHM, Salleh MZ

Turk J Biol, 2020;44(6):437-448.
PMID: 33402870 DOI: 10.3906/biy-2005-2

Garcinia species are widely used for their slimming effects via increased fat burning and suppression of satiety. However, scientific evidence for the biological effects of Garcinia atroviridis (GA) is lacking. We investigated the phytochemical composition, safety profiles, and antioxidant and antiobesity effects of methanolic extracts of Garcinia atroviridis (MeGa) in obese female rats. Repeated dose toxicity studies were conducted according to the OECD guidelines. Upon sacrifice, haematological, biochemical, lipid profile, and serum-based metabolomics analyses were performed to evaluate metabolic expression changes and their related pathways. MeGa contains several phytochemical groups and GA fruit acids. MeGa was found to be nontoxic in both male and female rats with an oral lethal dose (LD50) of 2000 mg/kg. After 9 weeks of treatment, MeGa-treated obese rats had lower weight gain and better lipid profiles (cholesterol and triglyceride), which correlated with the altered metabolic pathways involved in the metabolism of lipid (glycerophospholipid) and biosynthesis of unsaturated fatty acid. In addition, MeGa caused differential metabolism pathways of arachidonic acid and tryptophan that affect the inflammatory response and suppression of appetite. We concluded that MeGa is safe, and its slimming effects are due to the differential metabolism of lipids.
Pharmacogenotyping of CYP3A5 in predicting dose-adjusted trough levels of tacrolimus among Malaysian kidney-transplant patients

Hamzah S, Teh LK, Siew JS, Ahmad G, Wong HS, Zakaria ZA, et al.

Can J Physiol Pharmacol, 2014 Jan;92(1):50-7.
PMID: 24383873 DOI: 10.1139/cjpp-2013-0128

Tacrolimus (FK506) is a calcineurin inhibitor with a narrow therapeutic index that exhibits large interindividual variation. Seventy-eight kidney transplant patients treated with tacrolimus were recruited to study the correlation of dose adjusted trough level (level/dose; L/D) of tacrolimus with CYP3A5 and ABCB1 genotypes, as well as the mRNA copy number of ABCB1 in blood. Patients were genotyped for ABCB1 (C1236T, G2677T/A, and C3435T) and CYP3A5 (G6986A), while ABCB1 mRNA transcript copy number was determined by absolute quantification (real-time PCR) in 46 patients. CYP3A5*3 genotypes were found to be a good predictor of tacrolimus L/D in kidney-transplant patients. Significantly higher L/D was observed among non-expressors (2.85, 95%: 2.05-3.70 (ng·mL(-1))/(mg·kg(-1))) as compared with the expressors (1.15, 95%: 0.95-1.80 (ng·mL(-1))/(mg·kg(-1))) of CYP3A5 (Mann-Whitney U test; P < 0.001). No correlation was observed between L/D and the ABCB1 genotypes. A significant inverse correlation of blood ABCB1 mRNA level with L/D was demonstrated (Spearman's Rank Order correlation; P = 0.016, rs = -0.348). However, in multiple regression analysis, only CYP3A5*3 genotype groups were found to be significantly correlated with tacrolimus L/D (P < 0.001). These findings highlight the importance of CYP3A5*3 pharmacogenotyping among kidney-transplant patients treated with tacrolimus, and confirm the role of blood cell P-glycoprotein in influencing the L/D for tacrolimus.
Understanding the effects of Moringa oleifera in chronic unpredictable stressed zebrafish using metabolomics analysis

Rosdy MS, Rofiee MS, Samsulrizal N, Salleh MZ, Teh LK

J Ethnopharmacol, 2021 Oct 05;278:114290.
PMID: 34090909 DOI: 10.1016/j.jep.2021.114290

ETHNOPHARMACOLOGICAL RELEVANCE: Moringa leaves have been used for thousands of years to maintain skin health and mental fitness. People also use it to relieves pain and stress.
AIM OF THE STUDY: To determine the effects of Moringa oleifera leaves ethanol-aqueous (ratio 7:3) extract (MOLE) on the chronically stressed zebrafish.
METHOD: The changes in the stress-related behaviour and the metabolic pathways in response to MOLE treatment in zebrafish were studied. A chronic unpredictable stress model was adopted in which zebrafish were induced with different stressors for 14 days. Stress-related behaviour was assessed using a depth-preference test and a light and dark test. Three doses of MOLE (500, 1000, and 2000 mg/L) were administered to the zebrafish. Upon sacrifice, the brains were harvested and processed for LC-MS QTOF based, global metabolomics analysis.
RESULTS: We observed significant changes in the behavioural parameters, where the swimming time at the light phase and upper phase of the tank were increased in the chronically stressed zebrafish treated with MOLE compared to those zebrafish which were not treated. Further, distinctive metabolite profiles were observed in zebrafish with different treatments. Several pathways that shed light on effects of MOLE were identified. MOLE is believed to relieve stress by regulating pathways that are involved in the metabolism of purine, glutathione, arginine and proline, D-glutamine, and D-glutamate.
CONCLUSION: MOLE is potentially an effective stress reliever. However, its effects in human needs to be confirmed with a systematic randomised control trial.
Fulltext Transgenerational effects of paternal heroin addiction on anxiety and aggression behavior in male offspring

Farah Naquiah MZ, James RJ, Suratman S, Lee LS, Mohd Hafidz MI, Salleh MZ, et al.

Behav Brain Funct, 2016 Aug 31;12(1):23.
PMID: 27582026 DOI: 10.1186/s12993-016-0107-y

Heroin addiction is a growing concern, affecting the socioeconomic development of many countries. Little is known about transgenerational effects on phenotype changes due to heroin addiction. This study aims to investigate changes in level of anxiety and aggression up to four different generations of adult male rats due to paternal exposure to heroin.
Fulltext Aqueous Partition of Methanolic Extract of Dicranopteris linearis Leaves Protects against Liver Damage Induced by Paracetamol

Zakaria ZA, Kamisan FH, Mohd Nasir N, Teh LK, Salleh MZ

Nutrients, 2019 Dec 04;11(12).
PMID: 31817058 DOI: 10.3390/nu11122945

This study aimed to determine the antioxidant and hepatoprotective activities of semi-purified aqueous partition obtained from the methanol extract of Dicranopteris linearis (AQDL) leaves against paracetamol (PCM)-induced liver intoxication in rats. The test solutions, AQDL (50, 250, and 500 mg/kg), were administered orally to rats (n = 6) once daily for seven consecutive days followed by the hepatotoxicity induction using 3 g/kg PCM (p.o.). Blood was collected for serum biochemical parameters analysis while the liver was collected for histopathological examination and endogenous antioxidant enzymes analysis. AQDL was also subjected to antioxidant determination and phytochemical analysis. Results obtained show that AQDL possessed high total phenolic content (TPC) value and remarkable radical scavenging activities. AQDL also significantly (p < 0.05) reduced the liver weight/body weight (LW/BW) ratio or serum level of ALT, AST, and total bilirubin while significantly (p < 0.05) increase the level of superoxide dismutase (SOD) and catalase (CAT) without affecting the malondialdehyde (MDA) in the liver indicating its hepatoprotective effect. Phytoconstituents analyses showed only the presence of saponins and triterpenes, but lack of flavonoids. In conclusion, AQDL exerts hepatoprotective activity via its high antioxidant potential and ability to modulate the endogenous enzymatic antioxidant defense system possibly via the synergistic action of saponins and triterpenes.
Fulltext Inhibitory Effects of Raw-Extract Centella asiatica (RECA) on Acetylcholinesterase, Inflammations, and Oxidative Stress Activities via In Vitro and In Vivo

Hafiz ZZ, Amin M'M, Johari James RM, Teh LK, Salleh MZ, Adenan MI

Molecules, 2020 Feb 17;25(4).
PMID: 32079355 DOI: 10.3390/molecules25040892

Centella asiatica (C. asiatica) is one of the medicinal plants that has been reported to exert comprehensive neuroprotection in vitro and in vivo. In view of this, the present study was performed to investigate the effect of ethanolic extract of C. asiatica, designated as raw-extract of C. asiatica (RECA) in reducing the acetylcholinesterase (AChE), inflammations, and oxidative stress activities via both in vitro (SH-SY5Y and RAW 264.7 cells) and in vivo (Sprague Dawley rats). Quantitative high-performance liquid chromatography analysis reveals that RECA contains a significantly high proportion of glycosides than the aglycones with madecassoside as the highest component, followed by asiaticoside. Treatment of SH-SY5Y cells with RECA significantly reduced the AChE activity in a concentration-dependent manner with an IC50 value of 31.09 ± 10.07 µg/mL. Furthermore, the anti-inflammatory and antioxidant effects of RECA were evaluated by lipopolysaccharides (LPS)-stimulated RAW 264.7 cells. Our results elucidated that treatment with RECA significantly suppressed the level of pro-inflammatory cytokine/mediators and oxidative stress released in a concentration-dependent manner. Interestingly, these patterns of inhibition were consistent as observed in the LPS-induced neuroinflammation Sprague Dawley rats' model. The highest concentration used in the two models presented the most significant results. Herein, our findings strongly suggest that RECA may offer therapeutic potential for the treatment of Alzheimer's disease through inhibiting the AChE, inflammation, and oxidative stress activities.
Kratom (M. speciosa) exposure during adolescence caused long-lasting cognitive behavioural deficits associated with perturbated brain metabolism pathways in adult rats

Suhaimi FW, Zul Aznal AN, Mohamad Nor Hazalin NA, Teh LK, Hassan Z, Salleh MZ

Behav Brain Res, 2023 May 28;446:114411.
PMID: 36997094 DOI: 10.1016/j.bbr.2023.114411

Kratom (M. speciosa Korth) is an herbal plant native to Southeast Asia. The leaves have been widely used to alleviate pain and opioid withdrawal symptoms. However, the increasing trend of recreational use of kratom among youth is concerning because substance abuse may render the adolescent brain more susceptible to neuropathological processes, causing dramatic consequences that persist into adulthood. Therefore, the present study aimed to investigate the long-term effects of mitragynine, the main alkaloid and lyophilized kratom decoction (LKD) exposure during adolescence on cognitive behaviours and brain metabolite profiles in adult rats. Adolescent male Sprague-Dawley rats were given mitragynine (3, 10 or 30 mg/kg) or LKD orally for 15 consecutive days during postnatal days 31-45 (PND31-45). Behavioural testing was performed during adulthood (PND70-84) and the brains were subjected to metabolomic analysis. The results show that a high dose of mitragynine impaired long-term object recognition memory. Social behaviour and spatial learning were not affected, but both mitragynine and LKD impaired reference memory. Brain metabolomic study revealed several altered metabolic pathways that may be involved in the cognitive behavioural effects of LKD and mitragynine exposure. These pathways include arachidonic acid, taurine and hypotaurine, pantothenate and CoA biosynthesis, and tryptophan metabolism, while the N-isovalerylglycine was identified as the potential biomarker. In summary, adolescent kratom exposure can cause long-lasting cognitive behavioural deficits and alter brain metabolite profiles that are still evident in adulthood. This finding also indicates that the adolescent brain is vulnerable to the impact of early kratom use.
Fulltext Pathogenic nsSNPs that increase the risks of cancers among the Orang Asli and Malays

Khoruddin NA, Noorizhab MN, Teh LK, Mohd Yusof FZ, Salleh MZ

Sci Rep, 2021 Aug 09;11(1):16158.
PMID: 34373545 DOI: 10.1038/s41598-021-95618-y

Single-nucleotide polymorphisms (SNPs) are the most common genetic variations for various complex human diseases, including cancers. Genome-wide association studies (GWAS) have identified numerous SNPs that increase cancer risks, such as breast cancer, colorectal cancer, and leukemia. These SNPs were cataloged for scientific use. However, GWAS are often conducted on certain populations in which the Orang Asli and Malays were not included. Therefore, we have developed a bioinformatic pipeline to mine the whole-genome sequence databases of the Orang Asli and Malays to determine the presence of pathogenic SNPs that might increase the risks of cancers among them. Five different in silico tools, SIFT, PROVEAN, Poly-Phen-2, Condel, and PANTHER, were used to predict and assess the functional impacts of the SNPs. Out of the 80 cancer-related nsSNPs from the GWAS dataset, 52 nsSNPs were found among the Orang Asli and Malays. They were further analyzed using the bioinformatic pipeline to identify the pathogenic variants. Three nsSNPs; rs1126809 (TYR), rs10936600 (LRRC34), and rs757978 (FARP2), were found as the most damaging cancer pathogenic variants. These mutations alter the protein interface and change the allosteric sites of the respective proteins. As TYR, LRRC34, and FARP2 genes play important roles in numerous cellular processes such as cell proliferation, differentiation, growth, and cell survival; therefore, any impairment on the protein function could be involved in the development of cancer. rs1126809, rs10936600, and rs757978 are the important pathogenic variants that increase the risks of cancers among the Orang Asli and Malays. The roles and impacts of these variants in cancers will require further investigations using in vitro cancer models.
Fulltext Liquid Chromatography-Tandem Mass Spectrometry Method for the Determination of Vardenafil and Its Application of Bioequivalence

Gan KZ, Widodo RT, Chik Z, Teh LK, Rofiee MS, Mohamad Yusof MI

Int J Anal Chem, 2021;2021:5590594.
PMID: 33833807 DOI: 10.1155/2021/5590594

A simple, rapid, and sensitive method of liquid chromatography-tandem mass spectrometry (LC/MS/MS) method was developed and validated for the determination of vardenafil in rabbit plasma. A simple protein precipitation method with ice-cold acetonitrile was used for plasma extraction. The mass transitions m/z 489⟶151 and m/z 390⟶169 were used to measure vardenafil and tadalafil (internal standard), respectively, with a total assay run time of 6 min. The limit of detection was 0.2 ng/mL. The assay was reproducible with intra-assay and interassay precision ranging 1.17%-9.17% and 1.31%-5.86%, respectively. There was also good intra-assay and interassay accuracy between 89.3%-105.3% and 94%-102% of the expected value, respectively. The linearity range was 0.5-60 ng/mL in rabbit plasma (r 2 ≥ 0.99). The measured AUC from 0 to 24 h (AUC0 - 24t ) for the test and reference formulations were 174.38 ± 95.91 and 176.45 ± 76.88, respectively. For the test, C max and T max were 75.36 ± 59.53 ng/mL and 1.42 ± 0.19 h, whereas, for the reference, these were 58.22 ± 36.11 ng/mL and 2.04 ± 0.33 h, respectively. The test formulation achieved a slightly lower AUC0 - 24t value (p > 0.05), higher C max values (p > 0.05), faster T max (p
Fulltext Coupling Genotyping and Computational Modeling in Prediction of Anti-epileptic Drugs that cause Stevens Johnson Syndrome and Toxic Epidermal Necrolysis for Carrier of HLA-B*15:02

Teh LK, Selvaraj M, Bannur Z, Ismail MI, Rafia H, Law WC, et al.

J Pharm Pharm Sci, 2016;19(1):147-60.
PMID: 27096699 DOI: 10.18433/J38G7X

PURPOSE: The importance of HLA-B*15:02 genotyping to avoid carbamazepine induced SJS/TEN and molecular modeling to predict the role of HLA-B*15:0 and AEDs induced SJS/TEN are investigated.
METHODS: DNA was extracted from eighty-six patients. The patients were genotyped by AS-PCR. Computational modeling of the HLA-B*15:02 followed by docking studies were performed to screen 26 AEDs that may induce ADR among HLA-B*15:02 carriers.
RESULTS: Odd ratio for CBZ induced SJS/TEN and HLA-B*15:02 was 609.0 (95% CI: 23-15873; p=0.0002). Molecular modeling studies showed that acetazolamide, ethosuxiamide, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, primidone and sodium-valproate may induce ADR in HLA-B*15:02 carriers alike CBZ. Conclusion. We confirmed HLA-B*15:02 as a predictor of SJS/TEN and recommend pre-screening. Computational prediction of DIHR is useful in personalized medicine.

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