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Fulltext Relationship between serum methadone concentration and cold pressor pain sensitivity in patients undergoing methadone maintenance therapy

Zahari Z, Lee CS, Ibrahim MA, Musa N, Mohd Yasin MA, Lee YY, et al.

Iran J Pharm Res, 2018;17(Suppl):8-16.
PMID: 29796025

Hyperalgesia is a common clinical phenomenon among opioid dependent patients on methadone maintenance therapy (MMT) and it may be associated with undertreated pain and/or therapeutic failure. This study aimed to investigate association between serum methadone concentration (SMC) and cold pressor pain responses. Cold pressor pain responses in 147 opioid dependent patients on MMT were assessed using cold pressor test (CPT) at 0 h and at 2, 4, 8, 12, and 24 h after the dose intake. Blood samples were collected at 24 h after the dose. Serum methadone concentrations were measured using the Methadone ELISA kit and classified into two categories: < 400 ng/mL and ≥ 400 ng/mL. Eighty-eight patients (59.9%) had trough concentrations of < 400 ng/mL and 40.1% had trough concentrations of ≥ 400 ng/mL. There were significant effects of SMC on the cold pressor pain threshold (p = 0.019). Patients with concentrations < 400 ng/mL had significantly higher (almost 60% higher) cold pressor pain threshold (adjusted mean (95% CI) = 30.15 (24.29, 36.01) s) compared to those with concentrations of ≥ 400 ng/mL (18.93 (11.77, 26.08) seconds). There was also a 20% difference in pain tolerance, and 6% difference in cold pressor pain intensity score, neither of which were significant statistically (p > 0.05). Our results suggest an association of trough methadone concentration with the cold pressor pain threshold among opioid dependent patients on MMT. It would be useful to study the mechanisms underlying this association to help managing pain in such a population.
Study site: Psychiatric Clinic, Hospital Universiti Sains Malaysia (HUSM); Psychiatric Clinic, Hospital Raja Perempuan Zainab II; and eight other government MMT clinics in Kelantan, Malaysia
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.
Fulltext A Nested Allele-Specific Multiplex Polymerase Chain Reaction Method for the Detection of DRD2 Polymorphisms

Zahari Z, Salleh MR, Zahri Johari MK, Musa N, Ismail R

Malays J Med Sci, 2011 Oct;18(4):44-57.
PMID: 22589672 MyJurnal

The dopamine D2 receptor gene (DRD2) plays a role in many diseases such as schizophrenia, Parkinson's disease, and addictive behaviour. Methods currently available for the detection of DRD2 polymorphisms are costly and cannot detect all 8 polymorphisms of our research interest simultaneously (Val96Ala, Leu141Leu, Val154Ile, Pro310Ser, Ser311Cys, TaqI A, A-241G, and -141C Ins/Del). Therefore, we developed a nested multiplex polymerase chain reaction (PCR) for simultaneous detection of these polymorphisms.
Synthesis and evaluation of antimycobacterial activity of new benzimidazole aminoesters

Yoon YK, Ali MA, Wei AC, Choon TS, Ismail R

Eur J Med Chem, 2015 Mar 26;93:614-24.
PMID: 24996257 DOI: 10.1016/j.ejmech.2013.06.025

A total of 51 novel benzimidazoles were synthesized by a 4-step reaction starting from basic compound 4-fluoro-3-nitrobenzoic acid under relatively mild reaction conditions. The structure of the novel benzimidazoles was confirmed by mass spectra as well as (1)H NMR spectroscopic data. Out of the 51 novel synthesized compounds, 42 of them were screened for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain using BacTiter-Glo™ Microbial Cell Viability (BTG) method. Results of activity screened using Alamar Blue method was also provided for comparison purposes. Two of the novel benzimidazoles synthesized showed moderately good activity with IC50 of less than 15 μM. Compound 5g, ethyl 2-(4-(trifluoromethyl)phenyl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole-5-carboxylate, was found to be the most active with IC50 of 11.52 μM.
Fulltext Neuropsychiatric Presentation in Indirect Carotid-Cavernous Fistula: A Case Report

Ying Sze C, Bakin S, Ismail R

Cureus, 2023 Apr;15(4):e37523.
PMID: 37193417 DOI: 10.7759/cureus.37523

Carotid-cavernous fistula (CCF) is a rare sight and potentially life-threatening disorder arising from an abnormal connection between the carotid artery and the cavernous sinus. It can be classified into direct or indirect according to different arteriovenous shunts. Direct CCF usually has dramatic ocular presentations, whereas indirect CCF has a more insidious course and may be associated with neurologic symptoms in posteriorly draining fistulas. A 61-year-old gentleman presented with five days history of altered behavior and double vision preceding a bulging left eye. Ocular examination showed left eye proptosis, generalized chemosis, total ophthalmoplegia, and raised intra-ocular pressure. Computed tomography angiography (CTA) brain and orbit demonstrated dilated superior ophthalmic vein (SOV) with communication to a tortuous cavernous sinus suggestive of carotid-cavernous fistula (CCF). Digital subtraction angiography (DSA) eventually confirmed the presence of indirect communication between branches of the bilateral external carotid artery (ECA) and left cavernous sinus, which is a type C indirect CCF according to the Barrow classification. Total embolization of left CCF was successfully achieved via transvenous access. A marked reduction of proptosis and intra-ocular pressure was noted following the procedure. Although rare, neuropsychiatric presentation could be a possible presentation of CCF, and treating physicians should be aware of it. A high index of suspicion and prompt diagnosis is crucial in managing this sight and life-threatening condition. Early intervention can improve the prognosis of patients.
Fulltext TVET programme and health-related quality of life among low-income populations during the COVID-19 pandemic in Malaysia

Yasin RM, Tan MP, Said MA, Rasul MS, Thangiah N, Rizal H, et al.

Front Public Health, 2024;12:1164056.
PMID: 38504686 DOI: 10.3389/fpubh.2024.1164056

INTRODUCTION: Education improves the economy and quality of life. The availability of skilled education in Malaysia is not restricted to the younger generation but is available to people of all ages, including those with low incomes.
METHODS: This study used the EuroQol 5-Dimension 5-Level (EQ- 5D-5L) tool during the COVID-19 pandemic to examine relationships between socio-demographics, knowledge, and attitudes towards education and outcomes of health-related quality of life (HRQOL). Between September and October 2020 and January and February 2021, a cross-sectional study using a multi-stage sampling technique was carried out.
RESULTS: A total of 1,997 adults participated, with a mean age of 45.17 (SD 14.113). In total, 74.9% had good knowledge, while 59.8% had a positive attitude towards skill education. In univariate analyses, the EQ-5D-5L score was related to age, income, education level, marital status, employment status, financial strain level, and knowledge and attitude towards skilled education. Generalised linear model analyses demonstrated that lower EQ-5D-5L scores were associated with older age, financial constraints, and a negative attitude towards skills education. However, additional adjustments for knowledge and attitude towards skills education show only an increase in age and financial strain was significant.
CONCLUSION: The findings suggest that appropriate strategies be implemented to increase low-income populations' knowledge and attitude towards skill education. Improving education may improve the quality of life for this vulnerable group. Additionally, a qualitative study can be conducted to determine the barriers to low-income households participating in skilled education to fill in the knowledge gap.
Fulltext Tualang honey supplementation as cognitive enhancer in patients with schizophrenia

Yahaya R, Zahary MN, Othman Z, Ismail R, Nik Him NAS, Abd Aziz A, et al.

Heliyon, 2020 May;6(5):e03948.
PMID: 32426546 DOI: 10.1016/j.heliyon.2020.e03948

Introduction: Schizophrenia is a chronic mental illness with clusters of symptoms, including cognitive impairment. This study aimed to explore the effect of Tualang Honey (TH) on cognitive domains, especially as it pertained to the verbal memory of schizophrenia patients.
Method: This was a cross-sectional study involved 80 individuals, diagnosed with schizophrenia. The Malay Version Auditory Verbal Learning Test (MVAVLT) was used. Data were analysed using SPSS 20.0 software. Intention to treat analysis was applied.
Result: A comparison of the total learning score at eight weeks between the two groups based on time effect and time-treatment interaction favoured TH group.
Conclusion: This study concludes that by supplementing schizophrenia patients with 8-week of TH did improve total learning performance across domains in the immediate memory among patients with schizophrenia.
Fulltext Prevalence of asymptomatic atrial fibrillation in Malaysian patients with hypertension

Wong JS, Bau R, Ahmad F, Ismail R, Yip AFY

Med J Malaysia, 2013 Apr;68(2):141-3.
PMID: 23629560 MyJurnal

Atrial fibrillation (AF) is usually asymptomatic and often associated with established cardiovascular risk factors such as hypertension. The prevalence atrial fibrillation in patients admitted to Malaysian hospitals has been determined, but asymptomatic atrial fibrillation (AAF) in hypertensive patients in the primary care setting is not established. This study reports the prevalence of AAF in hypertensive patients in Malaysia, in a primary care setting. The overall prevalence of AAF was 0.75% with no differences between the gender. The prevalence of AAF increases with age - in the age groups of 30-39, >40-49, >50-59, >60-69, 70-79 and >80 years old were 0%, 0.17%, 0.35%, 2.32%, 2.59%, and 0% respectively. Hypertensive patients with age of ≥ 61 year old were associated with a probability of 10.6 times higher for AAF. We suggest the age threshold to screen for AAF to be age of 60. It is estimated that there are 49,029 Malaysians with AAF in 2010. A large population is at risk of AAF-related complications. There is justification for an even greater emphasis on diagnostic, primary and secondary prevention strategies.
Study site: Klinik Kesihatan Bintulu, Sarawak, Malaysia
A facile three-component [3+2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines acting as antimycobacterial agents

Wei AC, Ali MA, Yoon YK, Ismail R, Choon TS, Kumar RS

Bioorg Med Chem Lett, 2013 Mar 1;23(5):1383-6.
PMID: 23352268 DOI: 10.1016/j.bmcl.2012.12.069

A series of fourteen dispiropyrrolidines were synthesized using [3+2]-cycloaddition reactions and were screened for their antimycobacterial activity against Mycobacterium tuberculosis H(37)Rv in HTS (High Throughput Screen). Most of the compounds showed moderate to good activity with MIC of less than 20 μM. Compound 4'-(4-bromophenyl)-1'-methyldispiro[acenaphthylene-1,2'-pyrrolidine-3',2″-indane]-2,1″(1H)-dione (4c) was found to be the most active with MIC of 12.50 μM.
Antimycobacterial activity: a facile three-component [3+2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines

Wei AC, Ali MA, Yoon YK, Ismail R, Choon TS, Kumar RS, et al.

Bioorg Med Chem Lett, 2012 Aug 1;22(15):4930-3.
PMID: 22749825 DOI: 10.1016/j.bmcl.2012.06.047

A series of twelve dispiropyrrolidines were synthesized using [3+2]-cycloaddition reactions. The synthesized compounds were screened for their antimycobacterial activity against M. tuberculosis H(37)Rv and INH resistant M. tuberculosis strains using agar dilution method, four of them showed good activity with MIC of less than 1 μM. Compound 4'-[5-(4-fluorophenyl)pyridin-3-yl]-1'-methyldispiro[indan-2,2' pyrrolidine-3',2″-indan]-1,3,1″-trione (4b) was found to be the most active with MIC of 0.1215 and 5.121 μM, respectively.
Fulltext Patients' willingness to pay for their drugs in primary care clinics in an urbanized setting in Malaysia: a guide on drug charges implementation

Wan Puteh SE, Ahmad SNA, Aizuddin AN, Zainal R, Ismail R

Asia Pac Fam Med, 2017;16:5.
PMID: 28392749 DOI: 10.1186/s12930-017-0035-5

BACKGROUND: Malaysia is an upper middle income country that provides subsidized healthcare to ensure universal coverage to its citizens. The challenge of escalating health care cost occurs in most countries, including Malaysia due to increase in disease prevalence, which induced an escalation in drug expenditure. In 2009, the Ministry of Health has allocated up to Malaysian Ringgit (MYR) 1.402 billion (approximately USD 390 million) on subsidised drugs. This study was conducted to measure patients' willingness to pay (WTP) for treatment of chronic condition or acute illnesses, in an urbanized population.
METHODS: A cross-sectional study, through face-to-face interview was conducted in an urban state in 2012-2013. Systematic random sampling of 324 patients was selected from a list of patients attending ten public primary cares with Family Medicine Specialist service. Patients were asked using a bidding technique of maximum amount (in MYR) if they are WTP for chronic or acute illnesses.
RESULTS: Patients are mostly young, female, of lower education and lower income. A total of 234 respondents (72.2%) were not willing to pay for drug charges. WTP for drugs either for chronic or acute illness were at low at median of MYR10 per visit (USD 3.8). Bivariate analysis showed that lower numbers of dependent children (≤3), higher personal and household income are associated with WTP. Multivariate analysis showed only number of dependent children (≤3) as significant (p = 0.009; 95% CI 1.27-5.44) predictor to drugs' WTP.
CONCLUSION: The result indicates that primary care patients have low WTP for drugs, either for chronic condition or acute illness. Citizens are comfortable in the comfort zone whereby health services are highly subsidized through universal coverage. Hence, there is a resistance to pay for drugs.
Effect of natural antibacterial clays against single biofilm formation by Staphylococcus aureus and Salmonella Typhimurium bacteria on a stainless-steel surface

Wan Omar WH, Mahyudin NA, Azmi NN, Mahmud Ab Rashid NK, Ismail R, Mohd Yusoff MHY, et al.

Int J Food Microbiol, 2023 Jun 02;394:110184.
PMID: 36996693 DOI: 10.1016/j.ijfoodmicro.2023.110184

Staphylococcus aureus and Salmonella Typhimurium have a propensity to develop biofilms on food contact surfaces, such as stainless-steel, that persist despite rigorous cleaning and sanitizing procedures. Since both bacterial species pose a significant public health risk within the food chain, improved anti-biofilm measures are needed. This study examined the potential of clays as antibacterial and anti-biofilm agents against these two pathogens on appropriate contact surfaces. Natural soil was processed to yield leachates and suspensions of both untreated and treated clays. Soil particle size, pH, cation-exchange capacity, and metal ions were characterized to assess their importance in bacterial killing. Initial antibacterial screening was performed on nine distinct types of natural Malaysian soil using a disk diffusion assay. Untreated leachate from Kuala Gula and Kuala Kangsar clays were found to inhibit S. aureus (7.75 ± 0.25 mm) and Salmonella Typhimurium (11.85 ± 1.63 mm), respectively. The treated Kuala Gula suspension (50.0 and 25.0 %) reduced S. aureus biofilms by 4.4 and 4.2 log at 24 and 6 h, respectively, while treated Kuala Kangsar suspension (12.5 %) by a 4.16 log reduction at 6 h. Although less effective, the treated Kuala Gula leachate (50.0 %) was effective in removing Salmonella Typhimurium biofilm with a decrease of >3 log in 24 h. In contrast to Kuala Kangsar clays, the treated Kuala Gula clays contained a much higher soluble metal content, especially Al (301.05 ± 0.45 ppm), Fe (691.83 ± 4.80 ppm) and Mg (88.44 ± 0.47 ppm). Elimination of S. aureus biofilms correlated with the presence of Fe, Cu, Pb, Ni, Mn and Zn irrespective of the pH of the leachate. Our findings demonstrate that a treated suspension is the most effective for eradication of S. aureus biofilms with a potential as a sanitizer-tolerant, natural antibacterial against biofilms for applications in the food industry.
Efficacy and safety of single versus multiple daily doses of glibenclamide in type 2 diabetes mellitus

Wan Mohamad WB, Tun Fizi A, Ismail RB, Mafauzy M

Diabetes Res Clin Pract, 2000 Aug;49(2-3):93-9.
PMID: 10963819 DOI: 10.1016/s0168-8227(00)00138-8

Although long acting, glibenclamide is frequently given in split doses for type 2 diabetes mellitus. This may discourage compliance. It is thus appropriate to consider dosing it less frequently. We therefore studied glibenclamide effects when used once daily and when used in split doses. Our objective was to assess the feasibility of using once daily dosing as a regimen of choice. We measured plasma glucose, insulin, glibenclamide, lipids, HbAl and body mass index associated with the regimens. We also compared the number of hypoglycemic episodes occurring with them. Thirty type 2 diabetics on multiple daily glibenclamide were enrolled. Their regimens were changed over to once daily. Blood for glucose, insulin, lipids, HbAl and glibenclamide and body weight measurements were determined before and after the crossover period. We found no major difference in the sugar and insulin profiles with the two regimens. Fasting total cholesterol and triglyceride were also similar and so were plasma glibenclamide. The HbAl levels and body mass index and number of minor and major hypoglycemic episodes and hospital admissions for hypoglycemia also did not differ. We conclude that single daily dosing of glibenclamide was equivalent to multiple daily dose regimens. It can be used to an advantage to improve patient's compliance.
Variations between women and men in risk factors, treatments, cardiovascular disease incidence, and death in 27 high-income, middle-income, and low-income countries (PURE): a prospective cohort study

Walli-Attaei M, Joseph P, Rosengren A, Chow CK, Rangarajan S, Lear SA, et al.

Lancet, 2020 07 11;396(10244):97-109.
PMID: 32445693 DOI: 10.1016/S0140-6736(20)30543-2

BACKGROUND: Some studies, mainly from high-income countries (HICs), report that women receive less care (investigations and treatments) for cardiovascular disease than do men and might have a higher risk of death. However, very few studies systematically report risk factors, use of primary or secondary prevention medications, incidence of cardiovascular disease, or death in populations drawn from the community. Given that most cardiovascular disease occurs in low-income and middle-income countries (LMICs), there is a need for comprehensive information comparing treatments and outcomes between women and men in HICs, middle-income countries, and low-income countries from community-based population studies.
METHODS: In the Prospective Urban Rural Epidemiological study (PURE), individuals aged 35-70 years from urban and rural communities in 27 countries were considered for inclusion. We recorded information on participants' sociodemographic characteristics, risk factors, medication use, cardiac investigations, and interventions. 168 490 participants who enrolled in the first two of the three phases of PURE were followed up prospectively for incident cardiovascular disease and death.
FINDINGS: From Jan 6, 2005 to May 6, 2019, 202 072 individuals were recruited to the study. The mean age of women included in the study was 50·8 (SD 9·9) years compared with 51·7 (10) years for men. Participants were followed up for a median of 9·5 (IQR 8·5-10·9) years. Women had a lower cardiovascular disease risk factor burden using two different risk scores (INTERHEART and Framingham). Primary prevention strategies, such as adoption of several healthy lifestyle behaviours and use of proven medicines, were more frequent in women than men. Incidence of cardiovascular disease (4·1 [95% CI 4·0-4·2] for women vs 6·4 [6·2-6·6] for men per 1000 person-years; adjusted hazard ratio [aHR] 0·75 [95% CI 0·72-0·79]) and all-cause death (4·5 [95% CI 4·4-4·7] for women vs 7·4 [7·2-7·7] for men per 1000 person-years; aHR 0·62 [95% CI 0·60-0·65]) were also lower in women. By contrast, secondary prevention treatments, cardiac investigations, and coronary revascularisation were less frequent in women than men with coronary artery disease in all groups of countries. Despite this, women had lower risk of recurrent cardiovascular disease events (20·0 [95% CI 18·2-21·7] versus 27·7 [95% CI 25·6-29·8] per 1000 person-years in men, adjusted hazard ratio 0·73 [95% CI 0·64-0·83]) and women had lower 30-day mortality after a new cardiovascular disease event compared with men (22% in women versus 28% in men; p<0·0001). Differences between women and men in treatments and outcomes were more marked in LMICs with little differences in HICs in those with or without previous cardiovascular disease.
INTERPRETATION: Treatments for cardiovascular disease are more common in women than men in primary prevention, but the reverse is seen in secondary prevention. However, consistently better outcomes are observed in women than in men, both in those with and without previous cardiovascular disease. Improving cardiovascular disease prevention and treatment, especially in LMICs, should be vigorously pursued in both women and men.
FUNDING: Full funding sources are listed at the end of the paper (see Acknowledgments).
Fulltext Post-traumatic Stress Symptoms in Adolescents Exposed to the Earthquake in Lombok, Indonesia: Prevalence and Association With Maladaptive Trauma-Related Cognition and Resilience

Wahab S, Yong LL, Chieng WK, Yamil M, Sawal NA, Abdullah NQ, et al.

Front Psychiatry, 2021;12:680393.
PMID: 34819880 DOI: 10.3389/fpsyt.2021.680393

Background: Natural disasters may physically and psychologically affect individuals and their surrounding community. This study determines the prevalence of post-traumatic stress (PTS) symptoms and its association with maladaptive trauma-related cognition and resilience among adolescents post-earthquake. Materials and Methods: Data were collected, in this cross-sectional study, during an intervention program post-earthquake held in a state high school located at Lombok, Indonesia. The study sample engaged students 14-19 years of age using the purposive sampling method. The questionnaires used to measure PTS symptoms, maladaptive trauma-related cognition, and resilience were Children's Revised Impact of Event Scale-13 (CRIES-13), Child Post-Traumatic Cognitions Inventory (CPTCI), and Child and Youth Resilience Measure-Revised (CYRM-R), respectively. Results: The prevalence of PTS symptoms was 69.9%. Among the respondents, 61.37% were female and 56.48% had mothers with lower educational levels. Using multiple linear regression, the final predictors of PTS symptoms were excessive reactions (e.g., wailing loudly, miserable shrieking) of proxy during earthquake (β = 3.283, p = 0.005), maladaptive trauma-related cognition (β = 0.224, p = 0.002), and resilience (β = 0.192, p < 0.001) with female gender (β = 7.350, p < 0.001) as a control variable. Through simple linear regression, victims who witnessed injury or death during the earthquake (p = 0.003), had a proxy died during the earthquake (p = 0.01), and trapped victims or those who had difficulty escaping (p = 0.01) were identified to potentially predict the occurrence of PTS symptoms, warranting further study. Conclusion: The presence of excessive proxy reactions during the earthquake, maladaptive trauma-related cognition, and resilience in adolescents exposed to a natural disaster are worth targeting and prioritizing in future post-disaster interventions.
Fulltext Inhibitory potency of 8-methoxypsoralen on cytochrome P450 2A6 (CYP2A6) allelic variants CYP2A6 15, CYP2A6 16, CYP2A6 21 and CYP2A6 22: differential susceptibility due to different sequence locations of the mutations

Tiong KH, Mohammed Yunus NA, Yiap BC, Tan EL, Ismail R, Ong CE

PLoS One, 2014;9(1):e86230.
PMID: 24475091 DOI: 10.1371/journal.pone.0086230

Human cytochrome P450 2A6 (CYP2A6) is a highly polymorphic isoform of CYP2A subfamily. Our previous kinetic study on four CYP2A6 allelic variants (CYP2A6 15, CYP2A6 16, CYP2A6 21 and CYP2A6 22) have unveiled the functional significance of sequence mutations in these variants on coumarin 7-hydroxylation activity. In the present study, we further explored the ability of a typical CYP2A6 inhibitor, 8-methoxypsoralen (8-MOP), in inhibition of these alleles and we hypothesized that translational mutations in these variants are likely to give impact on 8-MOP inhibitory potency. The CYP2A6 variant and the wild type proteins were subjected to 8-MOP inhibition to yield IC50 values. In general, a similar trend of change in the IC50 and Km values was noted among the four mutants towards coumarin oxidation. With the exception of CYP2A6 16, differences in IC50 values were highly significant which implied compromised interaction of the mutants with 8-MOP. Molecular models of CYP2A6 were subsequently constructed and ligand-docking experiments were performed to rationalize experimental data. Our docking study has shown that mutations have induced enlargement of the active site volume in all mutants with the exception of CYP2A6 16. Furthermore, loss of hydrogen bond between 8-MOP and active site residue Asn297 was evidenced in all mutants. Our data indicate that the structural changes elicited by the sequence mutations could affect 8-MOP binding to yield differential enzymatic activities in the mutant CYP2A6 proteins.
In vitro modulation of naturally occurring flavonoids on cytochrome P450 2A6 (CYP2A6) activity

Tiong KH, Yiap BC, Tan EL, Ismail R, Ong CE

Xenobiotica, 2010 Jul;40(7):458-66.
PMID: 20402563 DOI: 10.3109/00498251003786749

1. The effect of flavonoids on coumarin 7-hydroxylation, an activity marker of an important human liver cytochrome P450 isoform, cytochrome P450 2A6 (CYP2A6), was investigated in this study. 2. Coumarin 7-hydroxylase activity was measured fluorometrically in reaction mixtures containing cDNA-expressed CYP2A6, nicotinamide adenine dinucleotide phosphate generating system and 10 uM coumarin, at various concentrations of flavonoids. 3. Among the 23 compounds tested, most of the active members were from flavonol group of hydroxylated flavonoids, with myricetin being the most potent inhibitor followed by quercetin, galangin, and kaempferol. 4. Further exploration of the inhibition mechanism of these compounds revealed that myricetin, galangin, and kaempferol exhibited mixed-type of inhibition pattern while quercetin was observed to exhibit competitive mode of inhibition. 5. Structure-function analyses revealed that degree of inhibition was closely related to the number and location of hydroxyl groups, glycosylation of the free hydroxyl groups, degree of saturation of the flavane nucleus as well as the presence of the alkoxylated function.
Fulltext Functional characterization of cytochrome P450 2A6 allelic variants CYP2A6*15, CYP2A6*16, CYP2A6*21, and CYP2A6*22

Tiong KH, Yiap BC, Tan EL, Ismail R, Ong CE

Drug Metab. Dispos., 2010 May;38(5):745-51.
PMID: 20139165 DOI: 10.1124/dmd.109.031054

Variation in CYP2A6 levels and activity can be attributed to genetic polymorphism and, thus, functional characterization of allelic variants is necessary to define the importance of CYP2A6 polymorphism in humans. The aim of the present study was to investigate the reported alleles CYP2A6*15, CYP2A6*16, CYP2A6*21, and CYP2A6*22, in terms of the functional consequences of their mutations on the enzyme catalytic activity. With use of the wild-type CYP2A6 cDNA as template, site-directed mutagenesis was performed to introduce nucleotide changes encoding K194E substitution in CYP2A6*15, R203S substitution in CYP2A6*16, K476R substitution in CYP2A6*21, and concurrent D158E and L160I substitutions in CYP2A6*22. Upon sequence verification, the CYP2A6 wild-type and mutant constructs were individually coexpressed with NADPH-cytochrome P450 reductase in Escherichia coli. A kinetic study using a coumarin 7-hydroxylase assay indicated that CYP2A6*15 exhibited higher V(max) than the wild type, whereas all mutant constructs, except for variant CYP2A6*16, exhibited higher K(m) values. Analysis of the V(max)/K(m) ratio revealed that all mutants demonstrated 0.85- to 1.05-fold differences from the wild type, with the exception of variant CYP2A6*22, which only portrayed 39% of the wild-type intrinsic clearance. These data suggested that individuals carrying the CYP2A6*22 allele are likely to have lower metabolism of CYP2A6 substrate than individuals expressing CYP2A6*15, CYP2A6*16, CYP2A6*21, and the wild type.
Fulltext Diabetes Treatment and Mental Illness: A Call for an Integrated Health Care System in Underserved Semi-Rural Malaysia

Thangiah G, Johar H, Ismail R, Reininghaus U, Bärnighausen T, Thurairajasingam S, et al.

Int J Environ Res Public Health, 2022 Aug 14;19(16).
PMID: 36011650 DOI: 10.3390/ijerph191610015

Diabetes mellitus (DM) management imposes a tremendous psychological burden on patients. The study investigates the association between DM treatment with blood glucose (BG) control and common mental health conditions. A cross-sectional study was conducted among 1821 individuals with DM in a community-based survey conducted in 2013. Information on respondents’ sociodemographic, mental health, DM treatment, and BG levels was collected. Multinomial logistic regression was employed to examine the association of diabetes treatment with controlled BG levels (<11.1 mmol/L) (42.5%, n = 774) or uncontrolled BG levels (34.3%, n = 625) compared with those not undergoing treatment (23.2%, n = 422) on depression anxiety, and stress. Having DM treatment and controlled BG was associated with high depressive symptoms (Relative Risk Ratio, RRR: 2.42; 95% CI 1.33−4.41) and high anxiety symptoms (1.66; 1.08−2.56) but not with perceived stress. However, treated DM with uncontrolled BG was associated with anxiety (high: 1.64; 1.05−2.56; low: 2.59; 1.10−6.09) but not depression or perceived stress. Our results suggest that being treated for DM, regardless of glucose control status, was associated with anxiety symptoms, whereas being treated with controlled BG was associated with high depressive symptoms. This situation highlights the need for integrative, multidisciplinary care for DM patients with mental health comorbidities.
Mutational analysis of CYP2C8 in hypertensive patients using denaturing high performance liquid chromatography

Teh LK, Zahri MK, Zakaria ZA, Ismail R, Salleh MZ

J Clin Pharm Ther, 2010 Dec;35(6):723-8.
PMID: 21054465 DOI: 10.1111/j.1365-2710.2009.01146.x

CYP2C8 is involved in the cytochrome P450 (CYP) epoxygenase pathway. Arachidonic acid metabolites such as epoxyeicosatrienenoic acids and hydroxyeicosatetrenoic acids, produced may have a role in hypertension. We aimed to develop a medium through-put method for screening samples of known and new mutations of CYP2C8 using denaturing high performance liquid chromatography (DHPLC).

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