Influence of genetic variability on the clinical pharmacology of carbamazepine and lamotrigine

This research programme investigates the influence of genetic variability on the clinical pharmacology of carbamazepine (CBZ) and lamotrigine (LTG). Common polymorphisms in genes that may influence the response to CBZ and LTG include CYP3A4 g.-392A>G, CYP3A5 g.6986A>G, CYP1A2 g.5734C>A, EPHX1 c.337T>C, EPHX1 c.416A>G, UGT2B7 c.802C>T, ABCB1 c.1236C>T, ABCB1 c.2677G>T/A, ABCB1 c.3435C>T and SCN2A c.56G>A. The prevalence of these common polymorphisms was evaluated in a 400-strong study population from a single research unit. Minor allele frequency ranged between 3.5% (CYP3A4 -392G) and 48.0% (ABCB1 1236T). Allele and genotype distributions were comparable to published data for other Caucasian populations. The influence of common polymorphisms in drug metabolising enzyme (DME) and sodium channel genes on the optimal dose of CBZ was assessed in a cohort of 70 patients. This study revealed that age and common polymorphisms in the EPHX1 gene (c.337T>C and c.416A>G) are potential predictors for optimal dose of CBZ. The significant effects of EPHX1 variants may be explained by their significant contribution to the inactivation of CBZ. These potential predictors explain approximately 15% of the inter-individual variation in CBZ dose requirements. Preliminary findings suggest that common polymorphisms in DME genes do not form a unique profile which increases the risk of developing intolerable CBZ adverse effects. It is unlikely that common polymorphisms in ABCB1 and SCN2A genes influence the expression and/or activity of their respective proteins to the level at which they can dictate response to LTG therapy. The influence of common polymorphisms in ABCB1 and SCN2A genes on the optimal dose of LTG was assessed in a cohort of 94 patients. Optimal dose in this study was defined as the final dose given to the patients that successfully maintained seizure freedom for at least 1 year with LTG monotherapy. Several basic clinical factors such as age and gender were also examined as potential predictors. The effect of predictors on the optimal dose of LTG was investigated using linear regression analysis. This study revealed that gender and common polymorphisms in the ABCB1 gene (c.1236C>T and c.3435C>T) are potential predictors for optimal dose of LTG. These predictors explain approximately 17% of the inter-individual variation in LTG dose requirement. These findings further highlight the potential role of P-gp in the management of epilepsy. The final study investigated the influence of ABCB1 c.1236C>T and ABCB1 c.3435C>T polymorphisms on the pharmacokinetics of LTG. A total of 156 blood samples from 50 patients receiving LTG monotherapy were available for analysis. The influence of ABCB1 variants was evaluated by population pharmacokinetics. This approach successfully estimated the oral clearance of LTG monotherapy at steady-state. However, the absorption rate constant (Ka) and volume of distribution (Vd) of LTG were poorly estimated. The inclusion of common polymorphisms in the ABCB1 gene in the pharmacokinetic model did not improve the estimation of oral clearance. This may indicate that common variants of ABCB1 do not influence clearance of LTG

EFFECT OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN-II RECEPTOR BLOCKERS ON PROTEINURIA OF HYPERTENSIVE PATIENTS IN STANDARD CARE PRACTICE

Objective: This study investigated the effect of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin-ii receptor blockers (ARBs) on protein creatinine index (PCI) of patients with hypertension in a standard care practice. Methods: This retrospective study was carried out in a tertiary hospital. Hypertensive patients were randomly selected and screened based on inclusion and exclusion criteria. PCI values were obtained from the patient’s medical record. Results: No significant differences were observed in the percentage of patients with proteinuria (PCI ≥20 mg/mmol creatinine) at pre-and post-treatment among the patients treated with ACEI, ARB or non-ACEI/ARB. Patients treated with ACEI (-10 mg/mmol creatinine; IQR-37.5-+10; p<0.046) and ARB (-10 mg/mmol creatinine; IQR-30-+10; p<0.048) showed significant reduction in PCI values at post-treatment compared to the non-ACEI/ARB group (+5 mg/mmol creatinine; IQR 0-+32.5). Conclusion: Our findings demonstrated that standard care practice, the therapy of ACEI and ARB did not sufficiently reduce the number of patients with proteinuria but could reduce progression of the proteinuria

LIPID PROFILE PATTERNS AND ASSOCIATION BETWEEN GLYCATED HAEMOGLOBIN (HbA1C) AND ATHEROGENIC INDEX OF PLASMA (AIP) IN DIABETES PATIENTS AT A TERTIARY CARE HOSPITAL IN MALAYSIA

Objective: There is lack of data regarding lipid patterns and the relationship of the atherogenic index of plasma (AIP with glycemic control in Malaysian diabetes patients. This study aimed to assess the lipid patterns and association of AIP with HbA1c in diabetes patients at a tertiary care hospital in Malaysia.Methods: The study was conducted on 72 diabetes patients who were randomly chosen and agreed to participate in the study. AIP values were calculated using log triglycerides/high-density lipoprotein (TG/HDL) ratio. Data were analysed using SPSS 23.Results: Mean age and body mass index (BMI) of the participants were 56.88±8.89 (years) and 28.81±4.78 (kg/m2) respectively. Hypercholesterolemia, hypertriglyceridemia, high low-density lipoprotein (LDL) values were found in 55.5 %, 41.7 %, 45.5 % of total participants respectively and less than desirable HDL values were observed in 25% of total participants. Overall, 37.5% patients were categorised into high-risk AIP category. BMI categories had a significant association with AIP category (p = 0.05). There was a significant positive correlation of AIP with HbA1c (r = 0.34; p = 0.0 04). HDL was negatively correlated with AIP (r = 0.27; p = 0.02). Duration of diabetes and ethnicity showed no significant association with AIP risk values.Conclusion: Diabetes patients in this study exhibited significant lipid abnormalities with increased AIP. AIP was significantly correlated with HbA1c

HEALTH-RELATED QUALITY OF LIFE IN POORLY CONTROLLED TYPE 2 DIABETES PATIENTS - ASSOCIATION OF PATIENTS' CHARACTERISTICS WITH EQ-5D DOMAINS, MEAN EQ-5D SCORES, AND VISAUL ANALOG SCALE SCORE

  Objective: High prevalence of diabetes mellitus in Malaysia demands the appropriate interventions to alleviate or postpone its burden on patients' health-related quality of life (HRQoL). The studies which provide useful knowledge about the components of such interventions are important. The aim of this study was to describe how demographic and clinical characteristics of diabetes patients influence their HRQoL using EQ-5D.Methods: This study used the baseline data of a randomized controlled study carried out to examine the impact of a pharmacist intervention on poorly controlled diabetes patients. A generic HRQoL tool EQ-5D was used to report the data. Logistic regression was used to identify the predictors of problems in individual EQ-5D domains, and ANCOVA was undertaken to examine the effect of patients' characteristic on EQ-5D mean scores and visual analog scale (VAS) mean scores.Results: Pain discomfort was reported to be significantly predicted by high HbA1c levels. Increasing age (OR =1.04; CI 1.01, 1.16) and increasing body mass index (OR = 1.15; CI 1.01, 1.30) were significant predictors of reduced mobility. The presence of complications (OR = 8.03; CI 1.34–48.02) and (5–10 years) diabetes duration predicted the reduced score in anxiety domain (OR = 7.05; CI 1.03, 48.04). Problems in usual activities were significantly predicted by age (OR = 1.4; CI 1.01, 1.18). Self-care was not affected by any of the model covariates. Mean EQ-5D score was (0.89; CI 0.85, 0.92) significantly predicted by HbA1c values (p=0.04). Mean VAS score (70.54) was significantly lower in the group receiving insulin (69.46; CI 73.74, 84.02) than the oral diabetes medication (78.88; CI 64.94, 73.98) (p=0.009).Conclusion: Patients' characteristics were significantly associated with the HRQoL in type 2 diabetes. There was a significant and inverse association of HRQoL with medication group (insulin use), high HbA1c, obesity, and presence of complications

MANAGEMENT OF RHEUMATOID ARTHRITIS: SPECIAL CONSIDERATION FOR BIOLOGIC DISEASE-MODIFYING ANTIRHEUMATIC DRUGS

Rheumatoid arthritis (RA) is a progressive chronic inflammatory disease affecting 0.5–1.0% of the adult population worldwide. Due to the damages caused by this autoimmune disease, new biologic therapies, particularly the biologic disease-modifying antirheumatic drugs (bDMARDs), are now being the treatment of choice in the management of RA. However, special precaution and prescreening before the usage of bDMARDs are needed to ensure better clinical response and avoiding risk of adverse event during treatment with the selected bDMARDs. In this review paper, we will provide overview on the incidence and pathogenesis of the disease, available pharmacological treatment and emphasizing special consideration in need on initiation of bDMARDs among RA patients. A literature review was performed by searching for relevant articles in Medline database through PubMed using medical subject headings terms and keywords: RA, bDMARDs, special consideration, tumor necrosis factor inhibitor, and non-tumor necrosis factor inhibitor. All papers reviewed were from 1999 to 2017 and were written in English. In this article, use of conventional synthetic DMARDs (csDMARDs), bDMARDs and special consideration to be taken upon initiation of biologic therapies in RA will be reviewed

A REVIEW OF ANTIBIOTIC USED IN SUSPECTED EARLY-ONSET NEONATAL SEPSIS FROM MALAYSIAN PERSPECTIVE: WHICH ONES TO CHOOSE AND HOW LONG TO GIVE?

Objective: Suspected early-onset sepsis is a common diagnosis among neonates which warrants admission to the neonatal intensive care unit. Prolonged empiric antibiotic is the biggest concern and treatment duration is still controversial. Antimicrobial stewardship (AMS) program promotes early antibiotic de-escalation to reduce unnecessary antibiotic exposure and its implementation in the intensive care setting seems to be feasible. The primary objective of this review was to compare the existing guidelines and review the literature regarding choice and duration of empiric antibiotic in managing suspected early-onset neonatal sepsis.Methods: Two Malaysian Ministry of Health guidelines were compared with guidelines from America (n=1), Australia (n=1), and United Kingdom (n=2). The literature search was conducted from January to June 2017 through open access journal and databases available at the author's institution library (EBSCOHost, Ovid and Science Direct).Results: All guidelines recommended similar antibiotics range and suggested to review treatment at 36– 72 h post antibiotic exposure. A total of 113 abstracts and full articles were identified, and only 11 full-text articles published in English were related to the subject of interest. All studies show differences either in study design, choice of antibiotics, treatment duration or outcome measures; thus, a meta-analysis was not possible to be conducted.Conclusion: From this review, we found the potential to performed early empiric antibiotic de-escalation especially in clinically well-appearance neonates, and it is best to customize our guidelines based on local evidence which justify the need for more local research in this area

LONG TERM USE OF LITHIUM AND FACTORS ASSOCIATED WITH TREATMENT RESPONSE AMONG PATIENTS WITH BIPOLAR DISORDER

Background: Lithium has been the gold standard in treating bipolar disorder. In recent years, the use of lithium seems to be diminished although it is well tolerated among the bipolar disorder patients. Subjects and methods: This study aimed to evaluate the efficacy and tolerability of lithium as well as to determine factors associated with lithium response among patient with bipolar disorder. A retrospective study was done in a tertiary care hospital in Malaysia which included 47 bipolar disorder patients that were prescribed with lithium maintenance therapy in the time frame of January 2009 until December 2013. Results: Of all the baseline characteristics tested, only psychotic feature differentiated lithium monotherapy group and combination therapy group significantly (χ2=4.732, p=0.03). When compared to period before lithium maintenance, all outcome measures (i.e. annual relapse rate, proportion time spent ill and duration of mood episode) showed significant improvement after lithium maintenance in both treatment groups. Lithium discontinuation only occurred in five cases of adverse effects. Predominant depressive mood episode before lithium maintenance (OR=0.159, p=0.033) and first euthymic interval after lithium maintenance (OR=1.109, p=0.047) significantly predicted lithium response. Discussion: Lithium significantly reduced the frequency and time spent in relapse in patients with bipolar disorder. Predominant depressive mood polarity before lithium maintenance and longer first euthymic interval after lithium maintenance had been identified to predict lithium response significantly

Quantification of BCR-ABL transcripts in peripheral blood cells and plasma of chronic myeloid leukemia patients at different stages of tyrosine kinase inhibitor treatment response

Purpose: To investigate the feasibility of using peripheral blood plasma samples as surrogates for blood cell sampling for quantification of breakpoint cluster region-Abelson oncogene (BCR-ABL) transcript levels to monitor treatment responses in chronic myeloid leukemia (CML) patients.Methods: Peripheral blood samples were collected from 20 healthy individuals and 165 CML patients at various stages of treatment response. Level of BCR-ABL mutation gene transcripts were determined by RNA extraction and quantitative real time polymerase chain reaction (RT-PCR).Results: The ratio of BCR-ABL transcripts/ABL transcripts in blood cells was significantly higher (p < 0.05) than in plasma for untreated and treated patients. Patients who received tyrosine kinase inhibitor (TKI) therapy and achieved major molecular response during treatment had the lowest mean ratio detected in blood cells (0.06 ± 0.0 %) and the ratio was below the detectable limit in plasma samples. Unlike plasma samples, BCR-ABL/ABL transcript ratios in blood cell samples strongly correlated with white cell counts in CML patients undergoing all types of treatment responses.Conclusion: Blood cell sampling is more sensitive than plasma sampling in diagnosis and evaluation of CML treatment response.Keywords: Chronic myeloid leukemia, Peripheral blood cells, Plasma RNA,  Treatment response, Tyrosine kinase inhibitor

The Effectiveness of Feedback using Video Recording as A Potential Teaching Method in Communication and Counselling Among Pharmacy Students

AbstractFourth year pharmacy UKM students will be selected and randomised into three groups, verbal feedback (verbal group), video feedback (video group) or no feedback (control group) for the counselling session. All students will receive a standardised case scenario for the counselling purposes and facilitators (pharmacy lecturers) will assess the students’ communication and counselling skills based on a validated standardised assessment form. Similar exercise will be repeated after 1 month and comparative analysis will be conducted to identify differences between the techniques in relation to students’ communication and counselling skills

Effect of fresh soy milk and its compounds on apoptosis in human leukemic cells and peripheral blood mononuclear cells

Purpose: To determine the effect of fresh soy milk and its compounds (coumestrol, daidzein and genistein) on apoptosis in human leukemic cells and peripheral blood mononuclear cells (PBMC). Methods: The apoptotic effect of fresh soy milk and its compounds on human leukemic cells (K562, Jurkat, U937) and PBMC was determined by flow cytometry. The PBMC from healthy donors were isolated by conducting density gradient centrifugation principle. Lymphoprep and cytotoxicity of the compounds was evaluated by 3-(4,5- ‘;1dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) MTT) assay. Results: PBMC treatment of daidzein and genistein had a significantly higher half-maximal inhibitory concentration (IC50) value (p < 0.01) and (p < 0.0001), compared to the leukemia cells. In addition, soy milk had a significantly higher IC50 value (p < 0.05) in PBMC than the leukemia cells. Coumestrol induced a significantly increased apoptotic cells in K562, U937 cells (p < 0.01) and Jurkat cells (p < 0.05). However, daidzein only increased apoptosis (p < 0.05) in K562 and U937. Genistein reported a significantly increased apoptotic cell in K562, Jurkat (p < 0.01) and U937 cells (p < 0.001). Nonetheless, in PBMC, significant apoptosis by the compounds did not occur. However, only soy milk induced a significantly increased apoptosis in PBMC (p < 0.05). Conclusion: The findings indicate that coumestrol, daidzein, genistein and soy milk inhibits the viability of leukemia cells by apoptosis induction, but they are non-toxic toward normal cells. Therefore, the results suggest that the compound alone, and thus, soy milk might have a therapeutic effect in leukemia