Publications by authors named "Rusli Ismail"

64 Publications

Influence of Polymorphisms on the Clinical Outcomes of Opioiddependent Patients on Methadone Maintenance Therapy.

J Pharm Bioallied Sci 2020 Nov 5;12(Suppl 2):S787-S803. Epub 2020 Nov 5.

Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia (USM), Kelantan, Malaysia.

Introduction: Dopamine receptor D2 (DRD2) is one of the dopamine receptors that have been studied in relation to opioid dependence. It is possible, therefore, that gene () polymorphisms influence treatment outcomes of patients with opioid dependence. The objective of this study was to investigate the influence of polymorphisms on the clinical outcomes of opioid-dependent patients on methadone maintenance therapy (MMT).

Materials And Methods: Patients with opioid dependence ( = 148) were recruited from MMT clinics. Pain sensitivity, severity of the opiate withdrawal syndrome, and sleep quality were assessed using cold pressor test (CPT), Subjective Opiate Withdrawal Scale (SOWS-M), and Pittsburgh Sleep Quality Index (PSQI)-Malay, respectively. Deoxyribonucleic acid (DNA) was extracted from whole blood, and then was used for genotyping of Val96Ala, Leu141Leu, Val154Ile, Pro310Ser, Ser311Cys, A, -141C , and -241 polymorphisms.

Results: Among 148 patients, 8.1% ( = 12), 60.8% ( = 90), 27.7% ( = 41), and 29.1% ( = 43) had at least one risk allele for Ser311Cys, A, -141C and polymorphisms, respectively. There were no significant differences in pain responses (pain threshold, tolerance, and intensity), SOWS, and PSQI scores between polymorphisms.

Conclusion: The common polymorphisms are not associated with pain sensitivity, severity of the opiate withdrawal syndrome, and sleep quality in patients with opioid dependence on MMT. However, this may be unique for Malays. Additional research should focus on investigating these findings in larger samples and different ethnicity.
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http://dx.doi.org/10.4103/jpbs.JPBS_248_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021064PMC
November 2020

Thymoquinone: From to a protective pharmacological compound in managing opioid dependence and amphetamine type stimulant issues.

Iran J Basic Med Sci 2020 Jul;23(7):849-852

Faculty of Medicine, University Sultan Zainal Abidin, City Campus, 20400 Kuala Terengganu, Malaysia.

Opioids, amphetamines, and other types of substances have been widely abused around the world. Opioid dependence and tolerance are two distinct phenomena that have been associated with substance abuse issues. The management of its adverse consequences is becoming more challenging. More and more people are treated in Methadone Maintenance Therapy (MMT) program yet the issues are still unresolved. Researchers are continuing to study the best formulation in treating opioid dependent people starting with modern and alternative drug therapies. Since 2008 , thymoquinone (TQ) has been extensively studied by researchers around the world and has emerged to be a new potential drug candidate in managing substance abuse issues. Thus, the aim of this article is to review the effects that TQ may have on opioid dependent subjects and other abused substances such as amphetamine may have been studied. All of the articles from 2008 until 2019 involving the effects of TQ on substance abuse from Google Scholar®, Scopus®, and Pubmed® databases have been searched and reviewed. The keywords used were thymoquinone, opioid dependence, amphetamine, and Nigella sativa. The research results also have been discussed in this article. Based on the research conducted, TQ was effective in reducing the adverse health consequences associated with substance abuse such as withdrawal symptoms, tolerance, and cell damages. It is concluded that TQ could be a potential drug that can be complemented with the currently available drugs in substance abuse therapies.
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http://dx.doi.org/10.22038/ijbms.2020.41678.9841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395189PMC
July 2020

Tualang honey supplementation as cognitive enhancer in patients with schizophrenia.

Heliyon 2020 May 12;6(5):e03948. Epub 2020 May 12.

Faculty of Medicine, Medical Campus, Universiti Sultan Zainal Abidin, Jalan Sultan Mahmud, 20400 Kuala Terengganu, Terengganu, Malaysia.

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.
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http://dx.doi.org/10.1016/j.heliyon.2020.e03948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226648PMC
May 2020

Relationship between Serum Methadone Concentration and Cold Pressor Pain Sensitivity in Patients Undergoing Methadone Maintenance Therapy.

Iran J Pharm Res 2018 ;17(Suppl):8-16

Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia (USM), Kelantan, Malaysia.

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 ( = 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 ( > 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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958320PMC
January 2018

ABCB1 Polymorphisms and Cold Pressor Pain Responses: Opioid-Dependent Patients on Methadone Maintenance Therapy.

Nurs Res 2017 Mar/Apr;66(2):134-144

Zalina Zahari, MSc, is Pharmacist, Department of Pharmacy, Hospital Universiti Sains Malaysia, and Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. Chee Siong Lee, MMed, is Emergency Medicine Specialist, Department of Emergency Medicine, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. Muslih Abdulkarim Ibrahim, PhD, is Senior Lecturer, Department of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University, Hawler, Iraq. Nurfadhlina Musa, MSc, is Senior Research Officer, Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. Mohd Azhar Mohd Yasin, MMed, is Psychiatrist, Department of Psychiatry, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. Mohd Azhar Mohd Yasin, MMed, is Psychiatrist, Department of Psychiatry, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. Yeong Yeh Lee, PhD, is Professor, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. Soo Choon Tan, PhD, is Professor, Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. Nasir Mohamad, PhD, is Professor, Faculty of Medicine and Health Sciences, Universiti Sultan Zainal Abidin, Kuala Terengganu, Terengganu, Malaysia. Rusli Ismail, PhD, is Professor, Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia.

Background: Methadone is a substrate of the P-glycoprotein efflux transporter, which is encoded by ABCB1 (MDR1), and thus, ABCB1 polymorphisms may influence the transport of methadone at the blood-brain barrier, affecting its adverse effects.

Objectives: This study investigated the association between ABCB1 polymorphisms and cold pressor pain responses among opioid-dependent patients on methadone maintenance therapy (MMT).

Methods: Malay male opioid-dependent patients receiving MMT (n = 148) were recruited. Cold pressor pain responses (pain threshold, pain tolerance, and pain intensity) were measured at 0, 2, 4, 8, 12, and 24 hours post-methadone dose. DNA was extracted from whole blood and genotyped for ABCB1 polymorphisms including 1236C>T (rs1128503), 2677G>T/A (rs2032582), and 3435C>T (rs1045642) using the allelic discrimination real-time polymerase chain reaction. Repeated-measure analysis of variance between-group analysis was used to compare the three cold pressor pain responses and ABCB1 polymorphisms (1236C>T, 2677G>T/A, and 3435C>T) according to genotypes and allelic additive models, genotype dominant and recessive models, haplotypes, and diplotypes.

Results: Patients with 2677 GG or 2677G allele had the lowest pain threshold compared with 2677G>T/A genotypes or alleles (p = .007 and .002, respectively). Haplotype analysis showed a significant association between ABCB1 haplotypes and pain threshold (p = .02). Patients with 2677G allele had the lowest pain tolerance compared to those with 2677T and 2677A alleles (2677G < 2677T < 2677A allele carriers; p = .05). In terms of pain intensity scores, patients with 2677 GG or 2677G allele had the highest scores compared to other 2677G>T/A genotypes or alleles (p = .04 and .008, respectively). Haplotype analysis revealed a significant difference between patients with CGC haplotype and those without this haplotype (p = .02).

Discussion: To the best of our knowledge, this study provides the first evidence that ABCB1 polymorphisms are associated with cold pressor pain responses among Malay male patients with opioid dependence on MMT. The results may provide an initial prediction on heightened pain sensitivity or hyperalgesia for individuals who are carriers of the ABCB1 polymorphisms.
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http://dx.doi.org/10.1097/NNR.0000000000000204DOI Listing
May 2017

Sleep quality in opioid-naive and opioid-dependent patientson methadone maintenance therapy in Malaysia.

Turk J Med Sci 2016 Dec 20;46(6):1743-1748. Epub 2016 Dec 20.

Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

Background/aim: Sleep disturbances may contribute to poor treatment outcomes in opioid-dependent patients. The extent to which the sleep profiles of opioid-dependent patients differ from those of the general Malaysian population is not documented. This study compared opioid-naive subjects and opioid-dependent patients on methadone maintenance therapy (MMT) in terms of their sleep quality.

Materials And Methods: Participants comprised Malay male opioid-naive subjects (n = 159) and opioid-dependent patients (n = 160) from MMT clinics in Kelantan, Malaysia, between March and October 2013. Sleep quality was evaluated using the translated and validated Malay version of the Pittsburgh Sleep Quality Index (PSQI).

Results: The opioid-dependent patients exhibited higher global PSQI scores [adjusted mean (95% CI) = 5.46 (5.02, 5.90)] than the opioid-naive group [4.71 (4.26, 5.15)] [F (1, 313) = 4.77, P = 0.030].

Conclusion: This study confirmed the poorer sleep quality among opioid-dependent patients on MMT, as manifested by their higher global PSQI scores. The sleep complaints in this patient population are a factor to consider and, when necessary, sleep evaluation and treatment should be undertaken to improve MMT patients' quality of sleep and overall treatment outcome.
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http://dx.doi.org/10.3906/sag-1507-132DOI Listing
December 2016

Relationship Between ABCB1 Polymorphisms and Cold Pain Sensitivity Among Healthy Opioid-naive Malay Males.

Pain Pract 2017 09 22;17(7):930-940. Epub 2017 Feb 22.

Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Kelantan, Malaysia.

Background: Endogenous and exogenous opioids are substrates of the permeability glycoprotein (P-gp) efflux transporter, which is encoded by the ABCB1 (MDR1) gene. Genetic polymorphisms of ABCB1 may contribute to interindividual differences in pain modulation and analgesic responses. We investigated the relationship between ABCB1 polymorphisms and cold pain sensitivity among healthy males.

Methods: Cold pain responses, including pain threshold and pain tolerance, were measured using the cold-pressor test (CPT). DNA was extracted from whole blood and genotyped for ABCB1 polymorphisms, including c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), and c.3435C>T (rs1045642), using the allelic discrimination real-time polymerase chain reaction.

Results: A total of 152 participants were recruited in this observational study. Frequencies of mutated allele for c.1236C>T, c.2677G>T/A, and c.3435C>T polymorphisms were 56.6%, 49.7%, and 43.4%, respectively. Our results revealed an association of the CGC/CGC diplotype (c.1236C>T, c.2677G>T/A, and c.3435C>T) with cold pain sensitivity. Participants with the CGC/CGC diplotype had 90% and 72% higher cold pain thresholds (87.62 seconds vs. 46.19 seconds, P = 0.010) and cold pain tolerances (97.24 seconds vs. 56.54 seconds, P = 0.021), respectively, when compared with those without the diplotype.

Conclusion: The CGC/CGC diplotype of ABCB1 polymorphisms was associated with variability in cold pain threshold and pain tolerance in healthy males.
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http://dx.doi.org/10.1111/papr.12546DOI Listing
September 2017

Inhibition of Human Cytochrome P450 2c8-catalyzed Amodiaquine N-desethylation: Effect of Five Traditionally and Commonly Used Herbs.

Pharmacognosy Res 2016 Oct-Dec;8(4):292-297

Centre of Excellence for Research in AIDS, Universiti Malaya, 59990 Kuala Lumpur, Malaysia.

Background: In Southeast Asia and many parts of the world, herbal products are increasingly used in parallel with modern medicine.

Objective: This study aimed to investigate the effects of herbs commonly used in Southeast Asia on activity of cytochrome P450 2C8 (CYP2C8), an important human hepatic enzyme in drug metabolism.

Materials And Methods: The selected herbs, such as Jack (ELJ), (LP), (EP), (AP), and (GB), were subjected to inhibition studies using an CYP2C8 activity marker, amodiaquine N-desethylase assay. Inhibition parameters, inhibitory concentration 50% (IC), and K values were determined to study the potency and mode of inhibition.

Results: All herbs inhibited CYP2C8 with the following order of potency: LP > ELJ > GB > AP > EP. LP and ELJ inhibited potently at K's of 2 and 4 times the K of quercetin, the positive control. The inhibition by LP was uncompetitive in nature as compared to competitive or mixed type inhibition observed with other herbs. GB exhibited moderate inhibitory effect at a K6 times larger than quercetin K. AP and EP, on the other hand, showed only weak inhibition.

Conclusion: The herbs we chose represented the more commonly used herbs in Southeast Asia where collision of tradition and modernization in healthcare, if not properly managed, may lead to therapeutic misadventures. We conclude that concurrent consumption of some herbs, in particular, LP and ELJ, may have relevance in drug-herb interactions via CYP2C8 inhibition .

Summary: Herbs are increasingly used in parallel with modern medicines nowadays. In this study five commonly used herbs in Southeast Asia region, ELJ, LP, EP, AP and GB, were investigated for their inhibitory potency on CYP2C8, an important drug-metaboliz-ing human hepatic enzyme. All herbs inhibited CYP2C8 activity marker, amodiaquine N-desethylation, with potency order of LP > ELJ > GB >AP > EP. LP, ELJ and GB exhibited K values of 2, 4 and 6 times the K of quercetin, the positive control, indicating potent to moderate degree of enzyme inhibition. AP and EP, on the other hand, showed only weak inhibition. In summary, concurrent consumption of some herbs especially LP and ELJ may have relevance in drug-herb interactions via CYP2C8 inhibition . : AQ: Amodiaquine, AP: , CYP: Cytochrome P450, DEAQ: Desethylamodiaquine, EP: , ELJ: , GB: , K: Inhibition constant, LP: , Vmax: Maximal velocity, K: Michaelis-Menten constant.
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http://dx.doi.org/10.4103/0974-8490.188886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004522PMC
October 2016

CYP2B6 and OPRM1 Receptor Polymorphisms at Methadone Clinics And Novel OPRM1 Haplotypes: A Cross-Sectional Study.

Drug Metab Lett 2016 ;10(3):213-218

College of Medicine, Qassim University, Kingdom of Saudi Arabia, P.O. BOX 54, Post-Code 51911, Saudi Arabia.

Introduction: Methadone is accepted as an alternative therapy in opioid use disorders worldwide. Methadone responsiveness, however, is affected by a range of CYP450 enzymes and OPRM1 polymorphisms.

Objective: This study sought to detect CYP2B6 and OPRM1 variants and their genotypes, as major contributors to inter-variability in methadone responsiveness and methadone dose requirements.

Methods: We carried out a prospective experimental one-phase pharmacogenetic study in four addiction clinics in Malaysia. Patients on stable methadone maintenance therapy were recruited. The prevalence of the CYP2B6 and OPRM1 polymorphisms was determined using a nested polymerase chain reaction (PCR), followed by genotyping. A two-step multiplex PCR method was developed to simultaneously detect the 26 SNPs in these two genes.

Results: 120 males were recruited for this study. The patients were between 21and 59 years old, although the majority of the patients were in their 30s. C64T and G15631T in CYP2B6and G31A, G691C, and A118G in OPRM1 were found to be polymorphic, and the allelic frequencies of each were calculated. We further detected eight new haplotypes.

Conclusion: C64T and G15631T in CYP2B6and G31A, G691C, and A118G in OPRM1were found to be polymorphic. The new haplotypes may give a new insight on methadone clinics.
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http://dx.doi.org/10.2174/1872312810666160810104040DOI Listing
October 2017

Relationship between CYP2B6*6 and cold pressor pain sensitivity in opioid dependent patients on methadone maintenance therapy (MMT).

Drug Alcohol Depend 2016 Aug 6;165:143-50. Epub 2016 Jun 6.

Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia (USM), Kelantan, Malaysia; Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia.

Background: CYP2B6 polymorphisms contribute to inter-individual variations in pharmacokinetics of methadone. Increased pain sensitivity is frequently reported by opioid dependent patients on methadone maintenance therapy (MMT). It is possible, therefore, that genetic polymorphisms in CYP2B6, which affects the metabolism of methadone, influence pain sensitivity among patients on MMT. This study investigated CYP2B6 polymorphisms and pain sensitivity in this group.

Methods: The cold pressor pain responses of 148 opioid dependent patients receiving MMT were evaluated using the cold pressor test (CPT). DNA was extracted from whole blood and subjected to polymerase chain reaction (PCR)-genotyping.

Results: Of the 148 subjects, 77 (52.0%) were carriers of CYP2B6*6 allele. CYP2B6*6 allele carriers had shorter cold pain threshold and pain tolerance times than non-carriers of CYP2B6*6 allele (21.05s vs 33.69s, p=0.036 and 27.15s vs 44.51s, p=0.020, respectively). Pain intensity scores of the CYP2B6*6 allele carriers was 67.55, whereas that of the CYP2B6*6 allele non-carriers was 64.86 (p=0.352).

Conclusion: Our study indicates that the CYP2B6*6 allele is associated with a lower pain threshold and lower pain tolerance among males with opioid dependence on MMT. The CYP2B6*6 allele may provide a mechanistic explanation for clinical observations of heightened pain sensitivity among opioid dependent patients receiving MMT.
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http://dx.doi.org/10.1016/j.drugalcdep.2016.05.028DOI Listing
August 2016

Relationship between ABCB1 polymorphisms and serum methadone concentration in patients undergoing methadone maintenance therapy (MMT).

Am J Drug Alcohol Abuse 2016 09 10;42(5):587-596. Epub 2016 Jun 10.

b Pharmacogenetics and Novel Therapeutics Cluster , Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia (USM) , Kelantan , Malaysia.

Background: Methadone is a substrate of the permeability glycoprotein (P-gp) efflux transporter, which is encoded by the ABCB1 (MDR1) gene. Large interindividual variability in serum methadone levels for therapeutic response has been reported. Genetic variations in ABCB1 gene may be responsible for the variability in observed methadone concentrations.

Objective: This study investigated the associations of ABCB1 polymorphisms and serum methadone concentration over the 24-hour dosing interval in opioid-dependent patients on methadone maintenance therapy (MMT).

Methods: One hundred and forty-eight male opioid-dependent patients receiving MMT were recruited. Genomic deoxyribonucleic acid (DNA) was extracted from whole blood and genotyped for ABCB1 polymorphisms [i.e. 1236C>T (dbSNP rs1128503), 2677G>T/A (dbSNP rs2032582), and 3435C>T (dbSNP rs1045642)] using the allelic discrimination real-time polymerase chain reaction (PCR). Blood samples were collected at 0, 0.5, 1, 2, 4, 8, 12, and 24 hours after the dose. Serum methadone concentrations were measured using the Methadone ELISA Kit.

Results: Our results revealed an association of CGC/TTT diplotype (1236C>T, 2677G>T/A, and 3435C>T) with dose-adjusted serum methadone concentration over the 24-hour dosing interval. Patients with CGC/TTT diplotype had 32.9% higher dose-adjusted serum methadone concentration over the 24-hour dosing interval when compared with those without the diplotype [mean (SD) = 8.12 (0.84) and 6.11 (0.41) ng ml mg, respectively; p = 0.033].

Conclusion: There was an association between the CGC/TTT diplotype of ABCB1 polymorphisms and serum methadone concentration over the 24-hour dosing interval among patients on MMT. Genotyping of ABCB1 among opioid-dependent patients on MMT may help individualize and optimize methadone substitution treatment.
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http://dx.doi.org/10.3109/00952990.2016.1172078DOI Listing
September 2016

Comparison of Pain Tolerance between Opioid Dependent Patients on Methadone Maintenance Therapy (MMT) and Opioid Naive Individuals.

J Pharm Pharm Sci 2016 ;19(1):127-36

Department of Pharmacy, Hospital Universiti Sains Malaysia, Kelantan, Malaysia. Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia (USM), Kelantan, Malaysia.

Purpose: This study compared pain sensitivity among opioid dependent patients on methadone maintenance therapy (MMT) and opioid naive subjects.

Methods: The three hundred participants comprised 152 opioid naive subjects and 148 opioid dependent patients. Opioid naive subjects had not taken any opioids including morphine and methadone to their best knowledge and were presumed so after two consecutive negative urine screenings for drugs. All opioid dependent patients were stabilized in treatment, defined as having been enrolled in the program for more than one month with no change of methadone dosage over the past one month. Excluded from the study were individuals with chronic or ongoing acute pain and individuals with a history of analgesics ingestion within 3 d before the cold pressor test (CPT). Pain tolerance to CPT was evaluated at 0 h, and at 2, 4, 8, 12, and 24 h post-methadone dose.

Results: Patients exhibited a significantly shorter mean pain tolerance time of 34.17 s (95% CI 24.86, 43.49) versus 61.36 (52.23, 70.48) [p < 0.001] compared with opioid naive subjects. Time-dependent mean pain tolerance was also significantly different when naive subjects were compared to patients (p = 0.016).

Conclusions: This study revealed hyperalgesia amongst patients on MMT, as manifested by their quicker hand withdrawal. The complaints of pain in this population should not be underestimated and the pain should be evaluated seriously and managed aggressively.
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http://dx.doi.org/10.18433/J3NS49DOI Listing
February 2017

Report: Demographic profiles and sleep quality among patients on methadone maintenance therapy (MMT) in Malaysia.

Pak J Pharm Sci 2016 Jan;29(1):239-46

Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM), University Sains Malaysia, KubangKerian, Kelantan, Malaysia / Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia.

Poor sleep quality was frequently reported by opioid dependence patients during methadone maintenance therapy (MMT). The study investigated a sample of patients on MMT to investigate the severity and prevalence of sleep problems in MMT patients. We evaluated sleep quality and disturbances of 119 Malay male patients from MMT clinics in Kelantan, Malaysia between March and July 2013 using the Pittsburgh Sleep Quality Index (PSQI)-Malay version. Patients' demographic, clinical data, past drug history and methadone treatment variables were recorded. Patients averaged 37.5 years of age (SD 6.79) and their mean age of first time illicit drug use was 19.3 years (SD 4.48). Their mean age of entering MMT was 34.7 years (SD 6.92) and the mean duration in MMT was 2.8 years (SD 2.13). The mean current daily dosage of methadone was 77.8 mg (SD 39.47) and ranged from 20 to 360 mg. The mean global PSQI score was 5.6 (SD 2.79) and 43.7% patients were identified as 'poor sleepers' (global PSQI scores >5). This study confirms the poor overall sleep quality among patients on MMT. The prevalence and severity of sleep problems in MMT patients should not be underestimated.
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January 2016

The AC/AG Diplotype for the 118A>G and IVS2 + 691G>C Polymorphisms of OPRM1 Gene is Associated with Sleep Quality Among Opioid-Dependent Patients on Methadone Maintenance Therapy.

Pain Ther 2016 Jun 20;5(1):43-54. Epub 2016 Jan 20.

Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia (USM), Kota Bharu, Kelantan, Malaysia.

Introduction: Methadone is a full agonist of the opioid receptor mu 1 which is encoded by the OPRM1 gene. Sleep disorders were frequently reported by opioid-dependent patients during methadone maintenance therapy (MMT). It is possible, therefore, that genetic polymorphisms in OPRM1 influence sleep quality among patients on MMT. This study investigated the association of OPRM1 polymorphisms with sleep quality among opioid-dependent patients on MMT.

Methods: The sleep quality of 165 male opioid-dependent patients receiving MMT was evaluated using the Pittsburgh Sleep Quality Index (PSQI). DNA was extracted from whole blood and subjected to polymerase chain reaction (PCR) genotyping.

Results: Patients with IVS2 + 691 CC genotype had higher PSQI scores [mean (SD) = 5.73 (2.89)] compared to those without the IVS2 + 691 CC genotype (IVS2 + 691 GG/GC genotype) [4.92 (2.31)], but the difference did not reach statistical significance (p = 0.081). Patients with combined 118 AA genotype and IVS2 + 691 GC genotype (AC/AG diplotype) had significantly lower PSQI scores [mean (SD) = 4.25 (2.27)] compared to those without the diplotype [5.68 (2.77)] (p = 0.018).

Conclusion: Our study indicates that the AC/AG diplotype for the 118A>G and IVS2 + 691G>C polymorphisms of OPRM1 gene is associated with better sleep quality among males with opioid dependence on MMT.
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http://dx.doi.org/10.1007/s40122-016-0044-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912965PMC
June 2016

The Opposing Roles of IVS2+691 CC Genotype and AC/AG Diplotype of 118A>G and IVS2+691G>C of OPRM1 Polymorphisms in Cold Pain Tolerance Among Opioid-Dependent Malay Males on Methadone Therapy.

Pain Ther 2015 Dec 18;4(2):179-96. Epub 2015 Nov 18.

Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia (USM), Kota Bharu, Kelantan, Malaysia.

Introduction: We recently reported that a majority of opioid-dependent Malay males on methadone therapy are cold pain sensitive. It is postulated that common OPRM1 polymorphisms may be responsible. This study investigated the association between 118A>G (dbSNP rs1799971) and IVS2+691G>C (dbSNP rs2075572) variants on cold pain responses among opioid-dependent Malay males on methadone maintenance therapy.

Methods: Cold pain responses including pain threshold, pain tolerance, and pain intensity were measured using the cold pressor test. DNA was extracted from the venous blood before polymerase chain reaction genotyping. Repeated measures analysis of variance was used to compare the cold pain responses and OPRM1 polymorphisms (118A>G and IVS2+691G>C) using models including genotype dominant and recessive models, allelic additive models, and analysis of haplotypes and diplotypes.

Results: A total of 148 participants were recruited. With the recessive model, those with IVS2+691 homozygous CC genotype had a shorter cold pain tolerance time than those without CC genotype (i.e., GG/GC genotype; 29.81 vs. 43.08 s, respectively, P = 0.048). On the other hand, with diplotype analysis, participants with combined homozygous 118 AA genotype and heterozygous IVS2+691 GC genotype (i.e., AC/AG diplotype) had a longer cold pain tolerance time than those without this diplotype (49.34 vs. 31.48 s, respectively, P = 0.043). Cold pain threshold was not associated with any of the 118A>G and IVS2+691G>C variations despite being analyzed using various models (all P > 0.05).

Conclusion: The IVS2+691 CC genotype and AC/AG diplotype of 118A>G and IVS2+691G>C seem to have opposing roles in pain tolerance among opioid-dependent Malay males on methadone therapy. Haplotypes of OPRM1 may be associated with altered binding affinity.
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http://dx.doi.org/10.1007/s40122-015-0041-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676768PMC
December 2015

High allele frequency of CYP2C9*3 (rs1057910) in a Negrito's subtribe population in Malaysia; Aboriginal people of Jahai.

Ann Hum Biol 2016 Sep 24;43(5):445-50. Epub 2015 Sep 24.

a Department of Paediatrics , School of Medical Sciences, Universiti Sains Malaysia , Health Campus, Kubang Kerian , Kelantan , Malaysia .

Background: CYP2C9 gene polymorphisms modulate inter-individual variations in the human body's responses to various endogenous and exogenous drug substrates. To date, little is known about the CYP2C9 gene polymorphisms among the aboriginal populations of the world, including those in Malaysia.

Aim: To characterise and compare the CYP2C9 polymorphisms (CYP2C9*2, CYP2C9*3, CYP2C9*4 and CYP2C9*5) between one of Malaysia's aboriginal populations, Jahai, with the national major ethnic, Malay. To also compare the allele frequencies from these two populations with available data of other aboriginal populations around the world.

Subjects And Methods: The extracted DNA of 155 Jahais and 183 Malays was genotyped for CYP2C9 polymorphisms using a nested multiplex allele-specific polymerase chain reaction technique. The results were confirmed by DNA direct sequencing.

Results: Genotyping results revealed that CYP2C9*2, CYP2C9*4 and CYP2C9*5 were absent in Jahais, while only the latter two were absent in Malays. The CYP2C9*3 allelic frequency in Jahais was 36.2%, making them the most frequent carriers of the allele thus far reported in any ethnic group from Southeast Asia.

Conclusions: The high frequency of CYP2C9*3 and the absence of CYP2C9*2 in Jahais suggest that genetic drift may be occurring in this ethnic group. This is the first study to determine the CYP2C9 polymorphisms in an aboriginal population in Malaysia.
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http://dx.doi.org/10.3109/03014460.2015.1068372DOI Listing
September 2016

Prevalence and Correlates of HIV and Hepatitis C Virus Infections and Risk Behaviors among Malaysian Fishermen.

PLoS One 2015 5;10(8):e0118422. Epub 2015 Aug 5.

Centre of Excellence for Research in AIDS (CERiA), Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

Fishermen in Southeast Asia have been found to be highly vulnerable to HIV, with research evidence highlighting the role of sexual risk behaviors. This study aims to estimate the rate of HIV as well as hepatitis C virus (HCV) infections among Malaysian fishermen, and the risky sexual and injection drug use behaviors that may contribute to these infections. The study also includes an assessment of socio-demographic, occupational and behavioral correlates of testing positive for HIV or HCV, and socio-demographic and occupational correlates of risk behaviors. The study had a cross-sectional design and recruited 406 fishermen through respondent-driven sampling (RDS). Participants self-completed a questionnaire and provided biological specimens for HIV and HCV testing. We conducted and compared results of analyses of both unweighted data and data weighted with the Respondent-Driven Sampling Analysis Tool (RDSAT). Of the participating fishermen, 12.4% were HIV positive and 48.6% had HCV infection. Contrary to expectations and findings from previous research, most fishermen (77.1%) were not sexually active. More than a third had a history of injection drug use, which often occurred during fishing trips on commercial vessels and during longer stays at sea. Of the fishermen who injected drugs, 42.5% reported unsafe injection practices in the past month. Reporting a history of injection drug use increased the odds of testing HIV positive by more than 6 times (AOR = 6.22, 95% CIs [2.74, 14.13]). Most fishermen who injected drugs tested positive for HCV. HCV infection was significantly associated with injection drug use, being older than 25 years, working on a commercial vessel and spending four or more days at sea per fishing trip. There is an urgent need to strengthen current harm reduction and drug treatment programs for Malaysian fishermen who inject drugs, especially among fishermen who work on commercial vessels and engage in deep-sea fishing.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118422PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526636PMC
May 2016

Relationship between cold pressor pain-sensitivity and sleep quality in opioid-dependent males on methadone treatment.

PeerJ 2015 9;3:e839. Epub 2015 Apr 9.

Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia , Kubang Kerian, Kelantan , Malaysia ; Centre of Excellence for Research in AIDS (CERiA), University of Malaya , Kuala Lumpur , Malaysia.

Aim. Poor sleep quality due to pain has been reported among opioid-dependent male patients on methadone maintenance therapy (MMT) but objective pain data are lacking. This study aimed to investigate the rate of pain-sensitivity using cold pressor test (CPT) and the relationship between pain-sensitivity and sleep quality in this population. Methods. A total of 168 male participants were included into the study. Objective pain-tolerance was evaluated at 0 h and at 24 h after the first CPT. Malay version of the Pittsburgh Sleep Quality Index (PSQI) and the subjective opiate withdrawal scale (SOWS) questionnaires were administered to evaluate the quality of sleep and withdrawal symptoms, respectively. Results. The mean age of study participants was 37.22 (SD 6.20) years old. Mean daily methadone dose was 76.64 (SD 37.63) mg/day, mean global PSQI score was 5.47 (SD 2.74) and mean averaged SOWS score was 5.43 (SD 6.91). The averaged pain-tolerance time ranged from 7 to 300 s with a mean time of 32.16 (SE 2.72) s, slightly below the cut-off score of 37.53 s. More specifically, 78.6% (n = 132) of participants were identified as pain-sensitive (averaged pain-tolerance time ≤37.53 s), and 36 (21.4%) participants were pain-tolerant (averaged pain-tolerance time >37.53 s). The pain-sensitive group reported poorer sleep quality with mean (SD) PSQI of 5.78 (2.80) compared with the pain-tolerant group with mean (SD) PSQI of 4.31 (2.18) (p = 0.005). With analysis of covariance, pain-sensitive group was found to have higher global PSQI scores (adjusted mean 5.76, 95% CI 5.29; 6.22) than pain-tolerant participants (adjusted mean 4.42, 95% CI 3.52; 5.32) (p = 0.010). Conclusions. Majority of opioid-dependent male patients on methadone treatment are pain-sensitive with CPT. Poor sleep quality is associated with cold pressor pain-sensitivity. Pain and sleep complaints in this male population should not be overlooked.
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http://dx.doi.org/10.7717/peerj.839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393806PMC
April 2015

In vitro effect of important herbal active constituents on human cytochrome P450 1A2 (CYP1A2) activity.

Phytomedicine 2014 Oct 16;21(12):1645-50. Epub 2014 Sep 16.

School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia. Electronic address:

This study was designed to investigate eight herbal active constituents (andrographolide, asiaticoside, asiatic acid, madecassic acid, eupatorin, sinensetin, caffeic acid, and rosmarinic acid) on their potential inhibitory effects on human cytochrome P450 1A2 (CYP1A2) activity. A fluorescence-based enzyme assay was performed by co-incubating human cDNA-expressed CYP1A2 with its selective probe substrate, 3-cyano-7-ethoxycoumarin (CEC), in the absence or presence of various concentrations of herbal active constituents. The metabolite (cyano-hydroxycoumarin) formed was subsequently measured in order to obtain IC50 values. The results indicated that only eupatorin and sinensetin moderately inhibited CYP1A2 with IC50 values of 50.8 and 40.2 μM, while the other active compounds did not significantly affect CYP1A2 activity with IC50 values more than 100 μM. Ki values further determined for eupatorin and sinensetin were 46.4 and 35.2 μM, respectively. Our data indicated that most of the investigated herbal constituents have negligible CYP1A2 inhibitory effect. In vivo studies however may be warranted to ascertain the inhibitory effect of eupatorin and sinensetin on CYP1A2 activity in clinical situations.
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http://dx.doi.org/10.1016/j.phymed.2014.08.003DOI Listing
October 2014

Facile, regio- and diastereoselective synthesis of spiro-pyrrolidine and pyrrolizine derivatives and evaluation of their antiproliferative activities.

Molecules 2014 Jul 10;19(7):10033-55. Epub 2014 Jul 10.

New Drug Discovery Research, Department of Medicinal Chemistry, Sunrise University, Alwar, Rajasthan-301030, India.

A number of novel spiro-pyrrolidines/pyrrolizines derivatives were synthesized through [3+2]-cycloaddition of azomethine ylides with 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones 2a-n. Azomethine ylides were generated in situ from the reaction of 1H-indole-2,3-dione (isatin, 3) with N-methylglycine (sarcosine), phenylglycine, or proline. All compounds (50 μM) were evaluated for their antiproliferative activity against human breast carcinoma (MDA-MB-231), leukemia lymphoblastic (CCRF-CEM), and ovarian carcinoma (SK-OV-3) cells. N-α-Phenyl substituted spiro-pyrrolidine derivatives (5a-n) showed higher antiproliferative activity in MDA-MB-231 than other cancer cell lines. Among spiro-pyrrolizines 6a-n, a number of derivatives including 6a-c and 6i-m showed a comparable activity with doxorubicin in all three cell lines. Among all compounds in three classes, 6a, 6b, and 6m, were found to be the most potent derivatives showing 64%, 87%, and 74% antiproliferative activity in MDA-MB-231, SK-OV-3, and CCRF-CEM cells, respectively. Compound 6b showed an IC50 value of 3.6 mM in CCRF-CEM cells. These data suggest the potential antiproliferative activity of spiro-pyrrolidines/pyrrolizines.
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http://dx.doi.org/10.3390/molecules190710033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6271256PMC
July 2014

Synthesis and evaluation of antimycobacterial activity of new benzimidazole aminoesters.

Eur J Med Chem 2015 Mar 22;93:614-24. Epub 2013 Jun 22.

Centre of Excellence for Research in AIDS (CERiA), University Malaya, Minden 59990, Kuala Lumpur, Malaysia.

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.
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http://dx.doi.org/10.1016/j.ejmech.2013.06.025DOI Listing
March 2015

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.

PLoS One 2014 27;9(1):e86230. Epub 2014 Jan 27.

Discipline of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086230PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903516PMC
November 2014

Antituberculosis: synthesis and antimycobacterial activity of novel benzimidazole derivatives.

Biomed Res Int 2013 5;2013:926309. Epub 2013 Dec 5.

New Drug Discovery Research, Department of Medicinal Chemistry, Sunrise University, Alwar, Rajasthan 301030, India.

A total of seven novel benzimidazoles were synthesized by a 4-step reaction starting from 4-fluoro-3-nitrobenzoic acid under relatively mild reaction conditions. The synthesized compounds were screened for their antimycobacterial activity against M. tuberculosis H₃₇Rv (MTB-H₃₇Rv) and INH-resistant M. tuberculosis (INHR-MTB) strains using agar dilution method. Three of them displayed good activity with MIC of less than 0.2 μM. Compound ethyl 1-(2-(4-(4-(ethoxycarbonyl)-2-aminophenyl)piperazin-1-yl)ethyl)-2-(4-(5-(4-fluorophenyl)pyridin-3-ylphenyl-1H-benzo[d]imidazole-5-carboxylate (5 g) was found to be the most active with MIC of 0.112 μM against MTB-H₃₇Rv and 6.12 μM against INHR-MTB, respectively.
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http://dx.doi.org/10.1155/2013/926309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870127PMC
July 2014

Effect of eurycomanone on cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 in vitro.

J Nat Med 2014 Apr 24;68(2):402-6. Epub 2013 Jul 24.

School of Medical Sciences, International Medical University, 126 Jalan 19/155B, Bukit Jalil, 57000, Kuala Lumpur, Malaysia.

Eurycomanone, an active constituent isolated from Eurycoma longifolia Jack, was examined for modulatory effects on cytochrome P450 (CYP) isoforms CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 using in vitro assays. The IC50 value was determined to assess the potencies of modulation for each CYP isoform. Our results indicated that eurycomanone did not potently inhibit any of the CYP isoforms investigated, with IC50 values greater than 250 μg/ml. Hence there appears to be little likelihood of drug-herb interaction between eurycomanone or herbal products with high content of this compound and CYP drug substrates via CYP inhibition.
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http://dx.doi.org/10.1007/s11418-013-0794-8DOI Listing
April 2014

Influence of Cytochrome P450, Family 2, Subfamily D, Polypeptide 6 (CYP2D6) polymorphisms on pain sensitivity and clinical response to weak opioid analgesics.

Drug Metab Pharmacokinet 2014 11;29(1):29-43. Epub 2013 Jun 11.

Department of Pharmacy, Hospital Universiti Sains Malaysia.

  CYP2D6 polymorphisms show large geographical and interethnic differences. Variations in CYP2D6 activity may impact upon a patient's pain level and may contribute to interindividual variations in the response to opioids. This paper reviews the evidence on how CYP2D6 polymorphisms might influence pain sensitivity and clinical response to codeine and tramadol. For example, it is shown that (1) CYP2D6 poor metabolizers (PMs) may be less efficient at synthesizing endogenous morphine compared with other metabolizers. In contrast, ultra-rapid metabolizers (UMs) may be more efficient than other metabolizers at synthesizing endogenous morphine, thus strengthening endogenous pain modulation. Additionally, for codeine and tramadol that are bioactivated by CYP2D6, PMs may undergo no metabolite formation, leading to inadequate analgesia. Conversely, UMs may experience quicker analgesic effects but be prone to higher mu-opioid-related toxicity. The literature suggested the potential usefulness of the determination of CYP2D6 polymorphisms in elucidating serious adverse events and in preventing subsequent inappropriate selection or doses of codeine and tramadol. Notably, even though many studies investigated a possible role of the CYP2D6 polymorphisms on pain sensitivity, pharmacokinetics and pharmacodynamics of these drugs, the results of analgesia and adverse effects are conflicting. More studies are required to demonstrate genetically determined unresponsiveness and risk of developing serious adverse events for patients with pain and these should involve larger numbers of patients in different population types.
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http://dx.doi.org/10.2133/dmpk.dmpk-13-rv-032DOI Listing
October 2014

In vitro approaches to investigate cytochrome P450 activities: update on current status and their applicability.

Expert Opin Drug Metab Toxicol 2013 Sep 17;9(9):1097-113. Epub 2013 May 17.

Monash University Sunway Campus, Jeffrey Cheah School of Medicine and Health Sciences, Jalan Lagoon Selatan, 46150 Bandar Sunway, Selangor, Malaysia.

Introduction: Cytochromes P450 (CYPs) play a central role in the Phase I metabolism of drugs and other xenobiotics. It is estimated that CYPs can metabolize up to two-thirds of drugs present in humans. Over the past two decades, there have been numerous advances in in vitro methodologies to characterize drug metabolism and interaction involving CYPs.

Areas Covered: This review focuses on the use of in vitro methodologies to examine CYPs' role in drug metabolism and interaction. There is an emphasis on their current development, applicability, advantages and limitations as well as the use of in silico approaches in complementing and supporting in vitro data. The article also highlights the challenges in extrapolating in vitro data to in vivo situations.

Expert Opinion: Advances in in vitro methodologies have been made such that data can be used for in vivo prediction with comfortable degree of confidence. Improved assay designs and analytical techniques have permitted development of miniaturized assay format and automated system with improved sensitivity and throughput capacity. High-quality experimental designs and scientifically rigorous assessment/validation protocols remain crucial in developing reliable and robust in vitro models. With continued progress made in the field, in vitro methodologies will continually be employed in evaluating CYP activities in pharmaceutical industries and laboratories.
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http://dx.doi.org/10.1517/17425255.2013.800482DOI Listing
September 2013

A facile three-component [3+2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines acting as antimycobacterial agents.

Bioorg Med Chem Lett 2013 Mar 4;23(5):1383-6. Epub 2013 Jan 4.

Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.

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.
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http://dx.doi.org/10.1016/j.bmcl.2012.12.069DOI Listing
March 2013

In-vitro inhibitory effect of Tualang honey on cytochrome P450 2C8 activity.

J Pharm Pharmacol 2012 Dec 8;64(12):1761-9. Epub 2012 Jun 8.

Pharmacogenetics & Novel Therapeutics Cluster, Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Penang, Malaysia.

Objectives: To investigate the effect of Tualang honey on cytochrome P450 2C8 (CYP2C8) activity in vitro using an amodiaquine N-desethylase assay.

Methods: CYP2C8 and NADPH cytochrome P450 reductase was cotransformed, expressed and harvested. The incubation assay contained expressed proteins, MgCl(2), NADP, glucose 6-phosphate, glucose-6-phosphate dehydrogenase, potassium phosphate buffer, and amodiaquine. The rate of conversion of amodiaquine to desethylamodiaquine, the metabolite, was determined using a high performance liquid chromatography (HPLC) method. The inhibition parameters, IC50 (concentration of inhibitor causing 50% inhibition of original enzyme activity) and apparent inhibition constant (K(i) ) values were determined.

Key Findings: The recombinant proteins were successfully expressed and used to investigate the effect of Tualang honey on CYP2C8 activity. The activity was measured by the rate of metabolism of amodiaquine to desethylamodiaquine determined using a successfully developed HPLC method. Kinetic parameters as determined by nonlinear least-squares regression and evaluated with Aikeike's goodness of fit criteria revealed that Tualang honey competitively inhibited CYP2C8 activity in a dose-dependent manner. Maximum inhibition of 80% occurred at 0.01% honey. The IC50 and K(i) values were (10.0 ± 3.0) × 10(-3) % and (5.1 ± 0.5) × 10(-3) % w/v, respectively.

Conclusions: This study has provided evidence for the in vitro inhibition of CYP2C8-mediated amodiaquine N-desethylase activity by Tualang honey. It revealed that honey, through this inhibition, may have the potential to cause in-vivo drug-food interaction with drugs metabolized by CYP2C8.
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http://dx.doi.org/10.1111/j.2042-7158.2012.01551.xDOI Listing
December 2012

A regio- and stereoselective 1,3-dipolar cycloaddition for the synthesis of new-fangled dispiropyrrolothiazoles as antimycobacterial agents.

Bioorg Med Chem Lett 2012 Dec 22;22(24):7418-21. Epub 2012 Oct 22.

Department of Chemistry, College of Sciences, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia.

A series of dispiropyrrolothiazoles compounds were synthesized using 1,3-dipolar cycloaddition and were screened for antimycobacterial activity against Mycobacterium tuberculosis H(37)Rv and INH resistant M. tuberculosis strains. Two of them were showing good activity with MIC of less than 1 μM. Compound (5f) was found to be the most active with MIC of 0.210 and 8.312 μM respectively.
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http://dx.doi.org/10.1016/j.bmcl.2012.10.059DOI Listing
December 2012

Inhibitory effects of cytochrome P450 enzymes CYP2C8, CYP2C9, CYP2C19 and CYP3A4 by Labisia pumila extracts.

J Ethnopharmacol 2012 Sep 31;143(2):586-91. Epub 2012 Jul 31.

School of Pharmacy and Health Sciences, International Medical University, 126, Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.

Ethnopharmacological Relevance: Labisa pumila (LP), popularly known with its local name, Kacip Fatimah, is a well known herb grown in Indochina and Southeast Asia and is traditionally used to regain energy after giving birth in women. The propensity of LP to cause drug-herb interaction via cytochrome P450 (CYP) enzyme system has not been investigated.

Aim Of The Study: To evaluate the in vitro inhibitory effects of various LP extracts (aqueous, ethanol, dichloromethane (DCM) and hexane) on cytochrome P450 2C8 (CYP2C8), CYP2C9, CYP2C19 and CYP3A4 activities.

Materials And Methods: Probe substrate-based high performance liquid chromatography (HPLC) methods were established for CYP2C9, CYP2C19 and CYP3A4 whereas a fluorescence-based enzyme assay was established for CYP2C8. The metabolite formations were examined after incubation of probe substrate with respective CYP isoform in the present or absent of LP extracts. The inhibitory effect of LP was characterized with kinetic parameters IC(50) and K(i) values.

Results: LP extracts showed differential effect of CYP activities with the order of inhibitory potency as follows: dichloromethane>hexane>ethanol>aqueous. This differential effect was only observed in CYP2C isoforms but not CYP3A4. Both the hexane and DCM extracts exhibited moderate to potent inhibition towards CYP2C activities in different modes including non-competitive, competive and mixed-type. The DCM effect was notably strong for CYP2C8 and CYP2C9 showing K(i) values of below 1 μg/ml. The selectivity of LP for CYP2C isoforms rather than CYP3A4 may be attributed to the presence of relatively small, lipophilic yet slightly polar compounds within the LP extracts.

Conclusions: The results of our study revealed that phytoconstituents contained in LP, particularly in hexane and dichloromethane extracts, were able to selectively inhibit CYP2C isoforms. The inactivation was characterized by low K(i) values, in particular, in CYP2C8 and CYP2C9. These in vitro data indicate that LB preparations contain constituents that can potently inhibit CYP2C activities and suggest that this herb should be examined for potential pharmacokinetic drug interactions in vivo.
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http://dx.doi.org/10.1016/j.jep.2012.07.024DOI Listing
September 2012