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Correlation of tramadol pharmacokinetics and CYP2D6*10 genotype in Malaysian subjects

Gan SH, Ismail R, Wan Adnan WA, Wan Z

J Pharm Biomed Anal, 2002 Sep 05;30(2):189-195.
PMID: 12191703

The aim of the present study is to investigate the influence of the CYP2D6*10 allele on the disposition of tramadol hydrochloride in Malaysian subjects. A single dose of 100 mg tramadol was given intravenously to 30 healthy orthopaedic patients undergoing various elective surgeries. After having obtained written informed consents, patients were genotyped for CYP2D6*10: the most common CYP2D6 allele among Asians by means of allele-specific polymerase chain reaction. The presence of other mutations (CYP2D6*1, *3, *4, *5, *9 and *17) was also investigated. Tramadol was extracted from 1 ml serum with an n-hexane: ethylacetate combination (4:1) after alkalinisation with ammonia (pH 10.6). Serum concentrations were measured by means of high-performance liquid chromatography. The pharmacokinetics of tramadol was studied during the 24 h after the dose. As among other Asians, the allele frequency for CYP2D6*10 among Malaysians was high (0.43). Subjects who were homozygous for CYP2D6*10 had significantly (P=0.046) longer mean serum half-life of tramadol than subjects of the normal or the heterozygous group (Kruskal-Wallis test). When patients were screened for the presence of other alleles, the pharmacokinetic parameter values were better explained. CYP2D6 activity may play a main role in determining tramadol pharmacokinetics. The CYP2D6*10 allele particularly was associated with higher serum levels of tramadol compared with the CYP2D6*1 allele. However, genotyping for CYP2D6*10 alone is not sufficient to explain tramadol disposition.
Fulltext Clinical pharmacists' intervention on pain management in cancer patients (PharmaCAP trial): study protocol for a randomized controlled trial

Shrestha S, Blebil AQ, Teoh SL, Sapkota S, Kc B, Paudyal V, et al.

J Pharm Policy Pract, 2023 Jan 24;16(1):14.
PMID: 36694232 DOI: 10.1186/s40545-022-00505-0

INTRODUCTION: Evidence-based services to support cancer patients with pain via clinical pharmacy services are currently lacking. Therefore, there is a need to undertake a randomized controlled trial (RCT) to explore the effectiveness of clinical pharmacists (CPs)' input into the multidisciplinary team (MDT) in providing better therapeutic outcomes for cancer pain management.
OBJECTIVES: The main aim of this pilot RCT is to determine the feasibility and preliminary efficacy of integrating CPs into the MDT for cancer pain management on the clinical outcomes of cancer patients experiencing pain.
METHODS: This study protocol outlines two-armed multicenter pilot RCT. Cancer patients suffering from pain will be randomly allocated to receive either clinical pharmacy services, i.e., PharmaCAP trial intervention from the CP, or the usual standard care (i.e., control group). Patients will be recruited consecutively from two hospitals in Kathmandu valley, Nepal. The outcomes will be assessed at baseline (pre-intervention) and 4 weeks post-intervention. The primary feasibility outcomes will include eligibility rate, recruitment rate, willingness to participate, acceptability of screening procedures and random allocation, possible contamination between the groups, intervention fidelity and compliance, treatment satisfaction, and patient understanding of the provided interventions. Subsequently, the primary clinical outcome, i.e., pain intensity of cancer patients, will be assessed. The secondary clinical outcomes will include health-related quality of life (HRQoL), anxiety, depression, adverse drug reactions, and patient medication compliance following the integration of CP into the healthcare team.
DISCUSSION: The feasibility and potential for integrating CP involvement in MDT to improve clinical outcomes of cancer patients with pain will be evaluated through the PharmaCAP trial.
TRIAL REGISTRATION: ClinicalTrials.gov NCT05021393. Registered on 25th August 2022.
Clinical Relevance of MTHFR, eNOS, ACE, and ApoE Gene Polymorphisms and Serum Vitamin Profile among Malay Patients with Ischemic Stroke

Wei LK, Au A, Menon S, Gan SH, Griffiths LR

J Stroke Cerebrovasc Dis, 2015 Sep;24(9):2017-25.
PMID: 26187788 DOI: 10.1016/j.jstrokecerebrovasdis.2015.04.011

The purpose of this study was threefold. First, it was to determine the relationship between serum vitamin profiles and ischemic stroke. The second purpose was to investigate the association of methylenetetrahydrofolate reductase (MTHFR), endothelial nitric oxide synthase (eNOS), angiotensin converting enzyme (ACE), and apolipoprotein-E (ApoE) gene polymorphisms with ischemic stroke and further correlate with serum vitamin profiles among ischemic stroke patients. The third purpose of the study was to highlight the interaction of MTHFR and eNOS haplotypes with serum vitamin profiles and ischemic stroke risks.
Antioxidant Potential, Subacute Toxicity, and Beneficiary Effects of Methanolic Extract of Pomelo (Citrus grandis L. Osbeck) in Long Evan Rats

Ali MY, Rumpa NN, Paul S, Hossen MS, Tanvir EM, Hossan T, et al.

J Toxicol, 2019;2019:2529569.
PMID: 31281355 DOI: 10.1155/2019/2529569

The aim of this study was to investigate the antioxidant potentials, subacute toxicity, and beneficiary effects of methanolic extract of pomelo (Citrus grandis L. Osbeck) in rats. Long Evans rats were divided into four groups of eight animals each. The rats were orally treated with three doses of pomelo (250, 500, and 1000 mg/kg) once daily for 21 days. Pomelo extract contained high concentrations of polyphenols, flavonoids, and ascorbic acid while exhibiting high 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity and ferric reducing antioxidant power values. There was no significant change in the body weight, percentage water content, and relative organ weight at any administered doses. In addition, no significant alterations in the hematological parameters were also observed. However, rats which received 1000 mg/kg dose had a significant reduction in some serum parameters, including alanine transaminase (15.29%), alkaline phosphatase (2.5%), lactate dehydrogenase (15.5%), γ-glutamyltransferase (20%), creatinine (14.47%), urea (18.50%), uric acid (27.14%), total cholesterol (5.78%), triglyceride (21.44%), low-density lipoprotein cholesterol (40.74%), glucose (2.48%), and all atherogenic indices including cardiac risk ratio (24.30%), Castelli's risk index-2 (45.71%), atherogenic coefficient (42%), and atherogenic index of plasma (25%) compared to control. In addition, the highest dose (1000 mg/kg) caused a significant increase in iron (12.07%) and high-density lipoprotein cholesterol (8.87%) levels. Histopathological findings of the vital organs did not indicate any pathological changes indicating that pomelo is nontoxic, safe, and serves as an important source of natural antioxidants. In addition, the fruit extract has the potential to ameliorate hepato- and nephrotoxicities and cardiovascular diseases as well as iron deficiency anemia.
Fulltext Tualang honey ameliorates viral load, CD4 counts and improves quality of life in asymptomatic human immunodeficiency virus infected patients

Wan Yusuf WN, Wan Mohammad WMZ, Gan SH, Mustafa M, Abd Aziz CB, Sulaiman SA

J Tradit Complement Med, 2019 Oct;9(4):249-256.
PMID: 31453119 DOI: 10.1016/j.jtcme.2018.05.003

This is the first study to report on the effects of honey in asymptomatic HIV positive subjects in ameliorating CD4 count, viral load (VL) and quality of life (QOL). It is a randomized, controlled, open labelled study, comparing the effects of Tualang honey (TH) administration for six months at three different doses: 20 g (THL), 40 g (THI) or 60 g (THH) daily compared with control (no administered treatment, THC). Only asymptomatic HIV positive subjects (n=95) having CD4 count 250-600 cell/ml, not on antiretrovirals were enrolled. Blood, (together with QOL questionnaires administration) were investigated at baseline, three and six months (CD4 cell count) while VL was determined only at baseline and six months. Significant reductions in CD4 counts in THL and THC groups (p= 0.003 for both) were seen with no significant reductions in the CD4 counts in THI and THH groups (p=0.447 and 0.053 respectively). There was improvement in VL in THC and THI (130% and 32% respectively) and reductions in THL and THH (26% and 8% respectively). Within and between group analyses for VL indicated significant differences between THL and THH compared to THC. In addition, significant improvement in QOL of groups which received TH was noted. TH has the potential to improve the QOL (physical and psychological) and CD4 counts. There was a trend of lower VL in asymptomatic HIV subjects following TH administration thus supporting the possible role of TH in boosting the immune system by improving CD4 counts, causing VL reductions in HIV positive subjects.
Fulltext Prevalence and risk factors of prehypertension in university students in Sabah, Borneo Island of East Malaysia

Qaiser S, Daud MNM, Ibrahim MY, Gan SH, Rahman MS, Sani MHM, et al.

Medicine (Baltimore), 2020 May 22;99(21):e20287.
PMID: 32481309 DOI: 10.1097/MD.0000000000020287

Unhealthy lifestyle contributes mainly to an increased prevalence of non-communicable diseases including hypertension and cardiovascular diseases tend to increase in Malaysia. These diseases lead to an increased risk of end organ damage and cardiovascular complications. In this study, the prevalence of prehypertension and its associated risk factors among a cohort of university students in Sabah was determined.This is a prospective, cross-sectional study conducted among 365 undergraduate students irrespective of faculties at Universiti Malaysia Sabah (UMS). Standardized and validated World Health Organization (WHO) STEPS questionnaires were used to collect sociodemographic data. Additionally, clinical and anthropometric data were measured and recorded by a trained staff, followed by descriptive and logistic regression analyses.A total of 365 UMS undergraduate students aged 18 years and above participated in the study. The prevalence of prehypertension among university students was high (31%) (95% CI [29.1%, 34.3%]). Well-known risk factors for hypertension including family history of hypertension, reduced sleep duration, reduced physical activity, smoking, being overweight or obese were significantly associated with the risk of developing prehypertension (P
Hyperthermic effects of Durio zibethinus and its interaction with paracetamol

Chua YA, Nurhaslina H, Gan SH

Methods Find Exp Clin Pharmacol, 2008 Dec;30(10):739-43.
PMID: 19271022 DOI: 10.1358/mf.2008.30.10.1316830

Because durian (Durio zibethinus), which is known in Southeast Asia as "the king of fruits", is thought to have special body-warming properties, it should not be consumed with paracetamol due to a risk of toxic effects. The claim of warming properties, however, has not been scientifically proven. This study was conducted to investigate durian's hyperthermic effect and its toxicity when consumed together with paracetamol in rats. Five groups of rats (n=6) were fed with: 1) distilled water (4 ml/250 g), 2) homogenized durian (4 g/250 g), 3) paracetamol solution (2400 mg/kg), 4) durian (4 g/250 g) followed by paracetamol solution (2400 mg/kg), or 5) prazosin solution (15 mg/kg, pregavaged) followed 1 h later by durian (4 g/250 g) and paracetamol solution (2400 mg/kg). Rectal temperature, systolic blood pressure and serum alanine aminotransferase (ALT) levels were taken from each rat at baseline and after the various administrations at 1, 2 and 5 h. Our results showed that the body temperature of rats in the durian-treated group was not significantly elevated when compared to the control. However, there was a significant decrease in body temperature over time in animals from groups 4 and 5. We did not, however, observe a consistent pattern of blood pressure change. Serum chemical analysis for ALT also did not show any significant change in any of the groups. In conclusion, contrary to what some believe, even though durian was found to increase body temperature in some rats, this increment was not significant. Rats receiving the durian-paracetamol combination showed a significant drop in body temperature, which may explain the belief that the two mixtures are toxic. However, the exact mechanism of toxicity is still unknown.
Computational epigenetic profiling of CpG islets in MTHFR

Wei K, Sutherland H, Camilleri E, Haupt LM, Griffiths LR, Gan SH

Mol Biol Rep, 2014 Dec;41(12):8285-92.
PMID: 25213548 DOI: 10.1007/s11033-014-3729-x

Computational epigenetics is a new area of research focused on exploring how DNA methylation patterns affect transcription factor binding that affect gene expression patterns. The aim of this study was to produce a new protocol for the detection of DNA methylation patterns using computational analysis which can be further confirmed by bisulfite PCR with serial pyrosequencing. The upstream regulatory element and pre-initiation complex relative to CpG islets within the methylenetetrahydrofolate reductase gene were determined via computational analysis and online databases. The 1,104 bp long CpG island located near to or at the alternative promoter site of methylenetetrahydrofolate reductase gene was identified. The CpG plot indicated that CpG islets A and B, within the island, contained 62 and 75 % GC content CpG ratios of 0.70 and 0.80-0.95, respectively. Further exploration of the CpG islets A and B indicates that the transcription start sites were GGC which were absent from the TATA boxes. In addition, although six PROSITE motifs were identified in CpG B, no motifs were detected in CpG A. A number of cis-regulatory elements were found in different regions within the CpGs A and B. Transcription factors were predicted to bind to CpGs A and B with varying affinities depending on the DNA methylation status. In addition, transcription factor binding may influence the expression patterns of the methylenetetrahydrofolate reductase gene by recruiting chromatin condensation inducing factors. These results have significant implications for the understanding of the architecture of transcription factor binding at CpG islets as well as DNA methylation patterns that affect chromatin structure.
Impact of CYP2D6 genetic polymorphism on tramadol pharmacokinetics and pharmacodynamics

Gan SH, Ismail R, Wan Adnan WA, Zulmi W

Mol Diagn Ther, 2007;11(3):171-81.
PMID: 17570739

Tramadol is metabolized by the highly polymorphic enzyme cytochrome P450 (CYP)2D6. Patients with different CYP2D6 genotypes may respond differently to tramadol in terms of pain relief and adverse events. In this study, we compare the pharmacokinetics and effects of tramadol in Malaysian patients with different genotypes to establish the pharmacokinetic-pharmacodynamic relationship of tramadol.
Fulltext Two-year variations of phenolics, flavonoids and antioxidant contents in acacia honey

Moniruzzaman M, Sulaiman SA, Azlan SA, Gan SH

Molecules, 2013;18(12):14694-710.
PMID: 24287998 DOI: 10.3390/molecules181214694

Honey is a good source of several important chemical compounds and antioxidants and is harvested throughout the year. However, no study has determined how their contents change over the years. The aim of the present research was to investigate the changes in the phenolics, flavonoids and antioxidant properties, as well as other physicochemical properties, of Malaysian acacia honey collected during different months during a two year period. The DPPH (1,1-diphenyl-2-picrylhydrazyl) and FRAP (ferric reducing antioxidant power) methods were used to determine the total antioxidant activity of the honey samples. Generally, honey samples collected in the beginning and the middle of the year tended to have higher sugar content, which may be attributed to its high acidic nature and low moisture content. There was a gradual increase in the phenolic content of the acacia honey samples collected between September 2010 and December 2010. The honey sample collected at the beginning of the year (January) showed the highest color intensity and was dark amber in color. It also contained the highest concentration of phenolic compounds (341.67 ± 2.94 mg(gallic acid)/kg), the highest flavonoid content (113.06 ± 6.18 mg(catechin)/kg) and the highest percentage of DPPH inhibition and the highest FRAP value, confirming its high antioxidant potential. There was a positive correlation between DPPH and total phenolic content, suggesting that phenolic compounds are the strongest contributing factor to the radical scavenging activity of Malaysian acacia honeys. Overall, our results indicated that there were significant seasonal variations in the antioxidant potentials of honey over the two year period and the time of honey collection affects its physicochemical properties. Therefore, acacia honey from Malaysia should ideally be collected during the dry season, particularly in the months of January, May and June.
Physicochemical and antioxidant properties of Algerian honey

Khalil I, Moniruzzaman M, Boukraâ L, Benhanifia M, Islam A, Islam N, et al.

Molecules, 2012 Sep 20;17(9):11199-215.
PMID: 22996344

The aim of the present study was to characterize the physical, biochemical and antioxidant properties of Algerian honey samples (n = 4). Physical parameters, such as pH, moisture content, electrical conductivity (EC), total dissolved solids (TDS), color intensity, total sugar and sucrose content were measured. Several biochemical and antioxidant tests were performed to determine the antioxidant properties of the honey samples. The mean pH was 3.84 ± 0.01, and moisture the content was 13.21 ± 0.16%. The mean EC was 0.636 ± 0.001, and the mean TDS was 316.92 ± 0.92. The mean color was 120.58 ± 0.64 mm Pfund, and the mean 5-hydroxymethylfurfural (HMF) content was 21.49 mg/kg. The mean total sugar and reducing sugar contents were 67.03 ± 0.68 g/mL and 64.72 ± 0.52 g/g, respectively. The mean sucrose content was 2.29 ± 0.65%. High mean values of phenolic (459.83 ± 1.92 mg gallic acid/kg), flavonoid (54.23 ± 0.62 mg catechin/kg), ascorbic acid (159.70 ± 0.78 mg/kg), AEAC (278.15 ± 4.34 mg/kg), protein (3381.83 ± 6.19 mg/kg) and proline (2131.47 ± 0.90) contents, as well as DPPH (39.57% ± 4.18) and FRAP activities [337.77 ± 1.01 µM Fe (II)/100 g], were also detected, indicating that Algerian honey has a high antioxidant potential. Strong positive correlations were found between flavonoid, proline and ascorbic acid contents and color intensity with DPPH and FRAP values. Thus, the present study revealed that Algerian honey is a good source of antioxidants.
Fulltext Gamma irradiation increases the antioxidant properties of Tualang honey stored under different conditions

Khalil MI, Sulaiman SA, Alam N, Moniruzzaman M, Bai'e S, Man CN, et al.

Molecules, 2012 Jan 11;17(1):674-87.
PMID: 22237682 DOI: 10.3390/molecules17010674

This study was conducted to evaluate the effects of evaporation, gamma irradiation and temperature on the total polyphenols, flavonoids and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activities of Tualang honey samples (n = 14) following storage over three, six or twelve months. The mean polyphenol concentrations of the six gamma irradiated honey samples at three, six and twelve months, respectively, were 96.13%, 98.01% and 102.03% higher than the corresponding values of the eight non-gamma irradiated samples. Similarly, the mean values for flavonoids at three, six and twelve months were 111.52%, 114.81% and 110.04% higher, respectively, for the gamma irradiated samples. The mean values for DPPH radical-scavenging activities at three, six and twelve months were also 67.09%, 65.26% and 44.65% higher, respectively, for the gamma irradiated samples. These data indicate that all gamma irradiated honey samples had higher antioxidant potential following gamma irradiation, while evaporation and temperature had minor effects on antioxidant potential.
Fulltext Tilianin: A Potential Natural Lead Molecule for New Drug Design and Development for the Treatment of Cardiovascular Disorders

Khattulanuar FS, Sekar M, Fuloria S, Gan SH, Rani NNIM, Ravi S, et al.

Molecules, 2022 Jan 20;27(3).
PMID: 35163934 DOI: 10.3390/molecules27030673

Cardiovascular disorders (CVDs) are the leading risk factor for death worldwide, and research into the processes and treatment regimens has received a lot of attention. Tilianin is a flavonoid glycoside that can be found in a wide range of medicinal plants and is most commonly obtained from Dracocephalum moldavica. Due to its extensive range of biological actions, it has become a well-known molecule in recent years. In particular, numerous studies have shown that tilianin has cardioprotective properties against CVDs. Hence, this review summarises tilianin's preclinical research in CVDs, as well as its mechanism of action and opportunities in future drug development. The physicochemical and drug-likeness properties, as well as the toxicity profile, were also highlighted. Tilianin can be a natural lead molecule in the therapy of CVDs such as coronary heart disease, angina pectoris, hypertension, and myocardial ischemia, according to scientific evidence. Free radical scavenging, inflammation control, mitochondrial function regulation, and related signalling pathways are all thought to play a role in tilianin's cardioprotective actions. Finally, we discuss tilianin-derived compounds, as well as the limitations and opportunities of using tilianin as a lead molecule in drug development for CVDs. Overall, the scientific evidence presented in this review supports that tilianin and its derivatives could be used as a lead molecule in CVD drug development initiatives.
Fulltext Genistein: A Potential Natural Lead Molecule for New Drug Design and Development for Treating Memory Impairment

Fuloria S, Yusri MAA, Sekar M, Gan SH, Rani NNIM, Lum PT, et al.

Molecules, 2022 Jan 01;27(1).
PMID: 35011497 DOI: 10.3390/molecules27010265

Genistein is a naturally occurring polyphenolic molecule in the isoflavones group which is well known for its neuroprotection. In this review, we summarize the efficacy of genistein in attenuating the effects of memory impairment (MI) in animals. Scopus, PubMed, and Web of Science databases were used to find the relevant articles and discuss the effects of genistein in the brain, including its pharmacokinetics, bioavailability, behavioral effects, and some of the potential mechanisms of action on memory in several animal models. The results of the preclinical studies highly suggested that genistein is highly effective in enhancing the cognitive performance of the MI animal models, specifically in the memory domain, including spatial, recognition, retention, and reference memories, through its ability to reduce oxidative stress and attenuate neuroinflammation. This review also highlighted challenges and opportunities to improve the drug delivery of genistein for treating MI. Along with that, the possible structural modifications and derivatives of genistein to improve its physicochemical and drug-likeness properties are also discussed. The outcomes of the review proved that genistein can enhance the cognitive performance and ameliorate MI in different preclinical studies, thus indicating its potential as a natural lead for the design and development of a novel neuroprotective drug.
Correlation of Serum Estradiol and Duration of Anastrazole Therapy with Treatment Related Adverse Effects Among Postmenopausal Breast Cancer Women: A Cross-sectional Study

Abubakar MB, Gan SH

Niger J Physiol Sci, 2017 Dec 30;32(2):219-225.
PMID: 29485645

Although anastrozole (Anas) plays a key role in the management of endocrine sensitive post-menopausal (PM) breast cancer (BC), there is much variability in its efficacy and tolerability. Anas-associated musculoskeletal symptoms (MS) and other adverse reactions, such as hot flashes (HF) and vaginal dryness/dyspareunia (VDD), are common and can affect the quality of life of BC patients, even sometimes leading to treatment withdrawal. The aim of this study was to determine the clinical and demographic factors associated with these adverse events. This is a cross-sectional study in estrogen receptor (ER) positive PM women (n = 92) with stages I to III BC receiving Anas. Multivariate analyses were performed to investigate the factors associated with Anas-induced adverse effects such as MS, HF and VDD. A serum estradiol concentration was undetectable (< 36.7 pmol/L) in 68.1% of patients but was detectable within a normal range (>36.7-88.1 pmol/L) in the other 31.9% of patients, and this group was found to have a lower odds of having at least one adverse effect (AE) compared to those with undetectable levels [adjusted odds ratio (AOR) 0.12, 95% confidence interval (CI) 0.02 to 0.64, p = 0.013]. Women with grades II and III tumors and a family history of BC had a higher odds of AE (grade II: AOR 12.22, CI 1.48 to 100.80, p = 0.020; grade III: AOR 12.95, CI 1.25 to 134.33, p = 0.032) and VDD (AOR 5.99, CI 1.30 to 27.52, p = 0.021), respectively. Patients who received Anas treatment for more than one year had a higher odds of VDD (one to three years: AOR 34.57, CI 3.86, 309.50, p = 0.002; more than 3 years: AOR 27.90, CI 2.21 to 351.84, p = 0.010). Advanced age also lowered the odds of HF (AOR 0.90, CI 0.83 to 1.00, p = 0.049). In conclusion, patients' hormonal environments and durations of Anas treatment may play a role in developing Anas-induced adverse effects.
Molecular Targets in Advanced Therapeutics of Cancers: The Role of Pharmacogenetics

Abubakar MB, Gan SH

Oncology, 2016;91(1):3-12.
PMID: 27233906 DOI: 10.1159/000446437

The advent of advanced molecular targeted therapy has resulted in improved prognoses for patients with advanced malignancies. However, despite the significant success and specificity of this advocated targeted therapy, significant on- and off-target adverse effects and inter-individual variability in treatment responses have been reported. The interpatient variability in drug response has been suggested to be partly due to variations in patient genomes. Therefore, the identification of genetic biomarkers by conducting pharmacogenetics studies can help predict patient responses to targeted therapy and may serve as a basis for individualized treatment. In this review, both clinically established and potential molecular targets are highlighted. Overall, current literature suggests that individualization of targeted therapy is promising; however, integrating the clinical benefits of identified biomarkers into clinical practice for personalized medicine remains a major challenge, and further studies to validate these markers and identify novel therapeutic approaches are needed.
Fulltext Impact of CYP3A4*18 and CYP3A5*3 Polymorphisms on Imatinib Mesylate Response Among Chronic Myeloid Leukemia Patients in Malaysia

Maddin N, Husin A, Gan SH, Aziz BA, Ankathil R

Oncol Ther, 2016;4(2):303-314.
PMID: 28261657 DOI: 10.1007/s40487-016-0035-x

INTRODUCTION: Imatinib mesylate (IM), a selective inhibitor of the BCR-ABL tyrosine kinase, is a well-established first-line treatment for chronic myeloid leukemia (CML). IM is metabolized mainly by cytochrome P450 (CYP) in the liver, specifically the CYP3A4 and CYP3A5 enzymes. Polymorphisms in these genes can alter the enzyme activity of IM and may affect its response. In this study, the impact of two single-nucleotide polymorphisms (SNPs), CYP3A5*3 (6986A>G) and CYP3A4*18 (878T>C), on IM treatment response in CML patients (n = 270; 139 IM resistant and 131 IM good responders) was investigated.
METHODS: Genotyping of CYP3A4*18 and CYP3A5*3 was performed using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The association between allelic variants and treatment response was assessed by means of odds ratio (OR) with 95% confidence intervals calculated by logistic regression.
RESULTS: Our results indicated that CML patients carrying the heterozygous (AG) and homozygous variant (GG) genotype of CYP3A5*3 were associated with a significantly lower risk of acquiring resistance with OR 0.171; 95% CI: 0.090-0.324, p
Fulltext A Review on Oxidative Stress, Diabetic Complications, and the Roles of Honey Polyphenols

Pasupuleti VR, Arigela CS, Gan SH, Salam SKN, Krishnan KT, Rahman NA, et al.

Oxid Med Cell Longev, 2020;2020:8878172.
PMID: 33299532 DOI: 10.1155/2020/8878172

Despite the availability of various antidiabetic drugs, diabetes mellitus (DM) remains one of the world's most prevalent chronic diseases and is a global burden. Hyperglycaemia, a characteristic of type 2 diabetes mellitus (T2DM), substantially leads to the generation of reactive oxygen species (ROS), triggering oxidative stress as well as numerous cellular and molecular modifications such as mitochondrial dysfunction affecting normal physiological functions in the body. In mitochondrial-mediated processes, oxidative pathways play an important role, although the responsible molecular mechanisms remain unclear. The impaired mitochondrial function is evidenced by insulin insensitivity in various cell types. In addition, the roles of master antioxidant pathway nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)/antioxidant response elements (ARE) are being deciphered to explain various molecular pathways involved in diabetes. Dietary factors are known to influence diabetes, and many natural dietary factors have been studied to improve diabetes. Honey is primarily rich in carbohydrates and is also abundant in flavonoids and phenolic acids; thus, it is a promising therapeutic antioxidant for various disorders. Various research has indicated that honey has strong wound-healing properties and has antibacterial, anti-inflammatory, antifungal, and antiviral effects; thus, it is a promising antidiabetic agent. The potential antidiabetic mechanisms of honey were proposed based on its major constituents. This review focuses on the various prospects of using honey as an antidiabetic agent and the potential insights.
Fulltext Tualang Honey Protects the Rat Midbrain and Lung against Repeated Paraquat Exposure

Tang SP, Kuttulebbai Nainamohamed Salam S, Jaafar H, Gan SH, Muzaimi M, Sulaiman SA

Oxid Med Cell Longev, 2017;2017:4605782.
PMID: 28127418 DOI: 10.1155/2017/4605782

Paraquat (PQ) is a dopaminergic neurotoxin and a well-known pneumotoxicant that exerts its toxic effect via oxidative stress-mediated cellular injuries. This study investigated the protective effects of Tualang honey against PQ-induced toxicity in the midbrain and lungs of rats. The rats were orally treated with distilled water (2 mL/kg/day), Tualang honey (1.0 g/kg/day), or ubiquinol (0.2 g/kg/day) throughout the experimental period. Two weeks after the respective treatments, the rats were injected intraperitoneally with saline (1 mL/kg/week) or PQ (10 mg/kg/week) once per week for four consecutive weeks. After four weekly exposures to PQ, the glutathione peroxidase activity and the number of tyrosine-hydroxylase immunopositive neurons in the midbrain were significantly decreased in animals from group PQ (p < 0.05). The lungs of animals from group PQ showed significantly decreased activity of superoxide dismutase and glutathione-S-transferase. Treatment with Tualang honey ameliorated the toxic effects observed in the midbrain and lungs. The beneficial effects of Tualang honey were comparable to those of ubiquinol, which was used as a positive control. These findings suggest that treatment with Tualang honey may protect against PQ-induced toxicity in the rat midbrain and lung.
Dietary Phytochemicals: Natural Swords Combating Inflammation and Oxidation-Mediated Degenerative Diseases

Islam MA, Alam F, Solayman M, Khalil MI, Kamal MA, Gan SH

Oxid Med Cell Longev, 2016;2016:5137431.
PMID: 27721914

Cumulatively, degenerative disease is one of the most fatal groups of diseases, and it contributes to the mortality and poor quality of life in the world while increasing the economic burden of the sufferers. Oxidative stress and inflammation are the major pathogenic causes of degenerative diseases such as rheumatoid arthritis (RA), diabetes mellitus (DM), and cardiovascular disease (CVD). Although a number of synthetic medications are used to treat these diseases, none of the current regimens are completely safe. Phytochemicals (polyphenols, carotenoids, anthocyanins, alkaloids, glycosides, saponins, and terpenes) from natural products such as dietary fruits, vegetables, and spices are potential sources of alternative medications to attenuate the oxidative stress and inflammation associated with degenerative diseases. Based on in vitro, in vivo, and clinical trials, some of these active compounds have shown good promise for development into novel agents for treating RA, DM, and CVD by targeting oxidative stress and inflammation. In this review, phytochemicals from natural products with the potential of ameliorating degenerative disease involving the bone, metabolism, and the heart are described.

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