MyMedR

Chloramphenicol in children: dose, plasma levels and clinical effects

Ismail R, Teh LK, Choo EK

Ann Trop Paediatr, 1998 Jun;18(2):123-8.

Despite concerns about adverse effects, chloramphenicol (CMC) continues to be used in certain situations and, due to its low therapeutic index and variable pharmacokinetics, therapeutic drug monitoring (TDM) is often recommended. At our centre, CMC finds applications in typhoid and meningitis and TDM is routinely performed. Elsewhere in Malaysia, however, CMC is used without TDM. We therefore decided to evaluate our TDM for CMC in relation to its roles in CMC therapy in children, who constitute most of our patients. Our objective was also to develop strategies to improve our TDM for CMC use. Data were collected from 168 children given CMC for various indications and monitored by the TDM service. Plasma CMC was determined by HPLC and used to adjust doses to maintain concentrations within a range of 10-25 micrograms/ml. Outcomes measured included daily temperatures and haematological indices. Daily doses and plasma CMC varied greatly. Doses averaged 40.5 mg/kg for neonates and 75.5 for older children. Average peak concentrations were therapeutic in 60% and trough in 42%. Average duration of fever was 6.3 days and it was unaffected by plasma CMC. Typhoid was eradicated in 97% but nine children with other diagnoses died. Side-effects were confined to mild reversible haematological abnormalities which developed in 11% of children at plasma concentrations which tended to be high. We conclude that CMC remains useful in children with typhoid. Its use for other indications, however, should be reviewed. Routine TDM for CMC is probably not warranted, at least until a clearer role is defined by well designed prospective studies.

Fulltext The risk of recurrence in breast cancer patients treated with tamoxifen: polymorphisms of CYP2D6 and ABCB1

Teh LK, Mohamed NI, Salleh MZ, Rohaizak M, Shahrun NS, Saladina JJ, et al.

AAPS J, 2012 Mar;14(1):52-9.

PMID: 22183189 DOI: 10.1208/s12248-011-9313-6

CYP2D6 plays a major role in the metabolism of tamoxifen, and polymorphism of P-glycoprotein has been associated with resistance of many drug therapies. This study investigates the clinical impact of genetic variants of CYP2D6 and ABCB1 in breast cancer patients treated with tamoxifen. Blood samples from 95 breast cancer patients treated with tamoxifen were collected and genotyped for CYP2D6 and ABCB1 variants using allele-specific PCR method. Recurrence risks were calculated using Kaplan-Meier analysis and compared using the log-rank test. Patients carrying CYP2D6*10/*10 and heterozygous null allele (IM) showed higher risks of developing recurrence and metastasis (OR 13.14; 95% CI 1.57-109.94; P = 0.004) than patients with CYP2D6*1/*1 and *1/*10 genotypes. Patients with homozygous CC genotypes of ABCB1 C3435T showed a shorter time to recurrence. Patients who were CYP2D6 IM and homozygous CC genotype of C3435T have statistically significant higher risks of recurrence (P = 0.002). Similarly, median time to recurrence in these patients was only 12 months (95% CI = 0.79-23.2) compared to those without this combination which was 48 months (95% CI = 14.7-81.2). Patients with CYP2D6 IM and homozygous CC genotype of ABCB1 C3435T have shorter times to recurrence. The results confirmed the findings of previous studies and support FDA recommendation to perform pre-genotyping in patients before the choice of therapy is determined in breast cancer patients.

The use of Taqman genotyping assays for rapid confirmation of β-thalassaemia mutations in the Malays: accurate diagnosis with low DNA concentrations

Teh LK, Lee TY, Tan JA, Lai MI, George E

Int J Lab Hematol, 2015 Feb;37(1):79-89.

PMID: 24725998 DOI: 10.1111/ijlh.12240

In Malaysia, β-thalassaemia is a common inherited blood disorder in haemoglobin synthesis with a carrier rate of 4.5%. Currently, PCR-incorporating techniques such as amplification refractory mutation system (ARMS) or reverse dot blot hybridization (RDBH) are used in β-thalassaemia mutation detection. ARMS allows single-mutation identification using two reactions, one for wild type and another for mutant alleles. RDBH requires probe immobilization and optimization of hybridization and washing temperatures which is time consuming. The aim of our study was to investigate whether β-thalassaemia mutations can be identified in samples with low DNA concentrations.

Fulltext Analysis of α1 and α2 globin genes among patients with hemoglobin Adana in Malaysia

Lee TY, Lai MI, Ismail P, Ramachandran V, Tan JA, Teh LK, et al.

Genet. Mol. Res., 2016 Apr 07;15(2).

PMID: 27173219 DOI: 10.4238/gmr.15027400

Hemoglobin (Hb) Adana [HBA2: c179G>A (or HBA1); p.Gly60Asp] is a non-deletional α-thalassemia variant found in Malaysia. An improvement in the molecular techniques in recent years has made identification of Hb Adana much easier. For this study, a total of 26 Hb Adana α-thalassemia intermedia and 10 Hb Adana trait blood samples were collected from patients. Common deletional and non-deletional α-thalassemia genotypes were determined using multiplex gap polymerase chain reaction (PCR) and multiplex ARMS PCR techniques. Identification of the Hb Adana location on the α-globin gene was carried out using genomic sequencing and the location of the mutation was confirmed via restriction fragment length polymorphism-PCR. Among the 36 samples, 24 (66.7%) had the -α(3.7)/α(Cd59)α mutation, while the -α(3.7)/α(Cd59)α mutation accounted for 2 samples (5.6%) and the remaining 10 (27.8%) samples were α/α(Cd59)α. All 36 samples were found to have the Hb Adana mutation on the α2-globin gene. The position of the α-globin gene mutation found in our cases was similar to that reported in Indonesia (16%) but not to that in Turkey (0.6%). Our results showed that the Hb Adana mutation was preferentially present in the α2-globin genes in Malays compared to the other ethnicities in Malaysia. Thus, the Malays might have similar ancestry based on the similarities in the Hb Adana position.

Rapid detection of α-thalassaemia variants using droplet digital PCR

Lee TY, Lai MI, Ramachandran V, Tan JA, Teh LK, Othman R, et al.

Int J Lab Hematol, 2016 Aug;38(4):435-43.

PMID: 27349818 DOI: 10.1111/ijlh.12520

INTRODUCTION: Alpha thalassaemia is a highly prevalent disease globally and is a well-known public health problem in Malaysia. The deletional forms of the mutation are the most common forms found in alpha thalassaemia. The three most common deletional alpha thalassaemia found in this region include --(SEA) deletion, -α(3.7) rightward and -α(4.2) leftward deletions. The prevalence rate of triplication alpha cases such as ααα(anti3.7) and ααα(anti4.2) is not known in Malaysia although it plays a role in exacerbating the clinical phenotypes in beta thalassaemia carriers. Recently, there have been more reported cases of rare alpha thalassaemia mutations due to the advancement of molecular techniques involved in thalassaemia detections. Therefore, it is essential to develop a new method which allows the detection of different alpha thalassaemia mutations including the rare ones simultaneously and accurately.

METHODS: The purpose of this study was to design an assay for the detection of triplications, common and rare deletional alpha thalassaemia using droplet digital PCR (ddPCR).

RESULTS: This is a quantitative detection method to measure the changes of copy number which can detect deletions, duplications and triplications of the alpha globin gene simultaneously.

CONCLUSION: In conclusion, ddPCR is an alternative method for rapid detection of alpha thalassaemia variants in Malaysia.

Single step PCR for detection of allelic variation of MDR1 gene (P-glycoprotein) among three ethnic groups in Malaysia

Teh LK, Lee WL, Amir J, Salleh MZ, Ismail R

J Clin Pharm Ther, 2007 Jun;32(3):313-9.

PMID: 17489883

P-glycoprotein (PgP) is the most extensively studied ATP-binding cassette (ABC) coded by MDR1 gene. To date, 29 single nucleotide polymorphisms (SNPs) have been identified; but only SNP C3435T has been correlated with intestinal PgP expression levels and shown to influence the absorption of orally taken drugs that are PgP substrates. Individuals homozygous for the T allele have more than fourfold lower PgP expression compared with C/C individuals. We developed a one step primer based allele specific PCR method to detect SNP at C3435T to investigate the distribution of this genotype in the local population.

An improved rapid genotyping method for the study of beta-2 adrenergic receptor gene polymorphisms using single tube allele specific multiplex PCR

Zilfalil BA, Hoh BP, Nizam MZ, Liza-Sharmini AT, Teh LK, Ismail R

J Clin Pharm Ther, 2006 Dec;31(6):637-40.

PMID: 17176369

Seventeen single nucleotide polymorphisms (SNPs) have been identified so far, within the beta-2 receptor (beta(2) AR) gene. The presence of so many SNPs within the beta(2) AR gene causes a problem, for those studying beta(2) AR pharmacogenetics, in relation to which SNPs to choose. Most of the work has focused on the three common SNPs within the coding block (alleles 16, 27 and 164) and the techniques developed have been for these three functionally important alleles.

CYP2A6 polymorphisms in Malays, Chinese and Indians

Nurfadhlina M, Foong K, Teh LK, Tan SC, Mohd Zaki S, Ismail R

Xenobiotica, 2006 Aug;36(8):684-92.

PMID: 16891249

The genetically polymorphic cytochrome P450 (CYP) 2A6 is the major nicotine-oxidase in humans that may contribute to nicotine dependence and cancer susceptibility. The authors investigated the types and frequencies of CYP2A6 alleles in the three major ethnic groups in Malaysia and CYP2A6*1A, CYP2A6*1B, CYP2A6*1x2, CYP2A6*2, CYP2A6*3, CYP2A6*4, CYP2A6*5, CYP2A6*7, CYP2A6*8 and CYP2A6*10 were determined by allele-specific polymerase chain reaction (PCR) in 270 Malays, 172 Chinese and 174 Indians. Except for CYP2A6*2 and *3 that were not detected in the Malays and Chinese, all the other alleles were detected. Frequencies for the CYP2A6*4 allele were 7, 5 and 2%, respectively, in Malays, Chinese and Indians. A statistically significant high frequency of the duplicated CYP2A6*1x2 allele occurred among Chinese. Among Malays and Chinese, the most common allele was CYP2A6*1B, but it was CYP2A6*1A among Indians. These ethnic difference in frequencies suggested that further studies are required to investigate the implications on diseases such as cancer and smoking behaviour among these major ethnic groups in Malaysia.

Malaysian Indians are genetically similar to Caucasians: CYP2C9 polymorphism

Zainuddin Z, Teh LK, Suhaimi AW, Ismail R

J Clin Pharm Ther, 2006 Apr;31(2):187-91.

PMID: 16635054

CYP2C9 is one of the major drug metabolizing enzymes for many drugs including warfarin, NSAIDs and losartan. It is polymorphic in many populations. Data on the distribution of CYP2C9 and the implication of CYP2C9 polymorphism in the Malaysian population is lacking. Our objectives were therefore to investigate the prevalence of CYP2C9 variants among unrelated healthy volunteers of Malays, Chinese and Indians in Malaysia.

Genetic polymorphism of CYP2D6 in patients with cardiovascular disease -- a cohort study

Teh LK, Zilfalil BA, Marina I, Rosemi BS, Ismail R

J Clin Pharm Ther, 2004 Dec;29(6):559-64.

PMID: 15584944 DOI: 10.1111/j.1365-2710.2004.00600.x

BACKGROUND: Cardiovascular diseases are complex diseases that are influenced by both environmental and genetic factors. CYP2D6 found in the brain and the heart is involved in the metabolism of many environmental and some endogenous substances and neurotransmitters responsible for maintaining homeostasis. This raises an interesting hypothesis that it may have a role in the development of or protection against cardiovascular diseases.
OBJECTIVE: To study the distribution of genotypes of CYP2D6 among patients with cardiovascular diseases in Malaysia.
METHOD:We obtained DNA from 128 patients who were followed up for cardiovascular diseases. Polymerase chain reaction-based methods were used to determine common CYP2D6 alleles.
RESULTS: One hundred and twenty-eight patients were enrolled. Most of the patients also had concurrent illnesses. Eleven genotypes were identified in the patients and 41% carried CYP2D6*1/*10. The second most common genotype was homozygous for the wild type gene, followed by homozygous CYP2D6*10/*10 at 14.48 %. A small percentage of the patients were heterozygous CYP2D6*1/*4. One patient was genotyped homozygous CYP2D6*4/*4 predicting a poor metabolizer prevalence of 0.78% (95% CI +/- 1.52%). Analysis using Hardy-Weinberg equilibrium showed that all of the gnotypes were consistent with equilibrium except for CYP2D6*1/*10 (chi(2); P < 0.05).
CONCLUSION: Our study suggests a possible involvement of CYP2D6 genotypes in cardiovascular system diseases, which need to be validated by further studies.

Genetic polymorphism of CYP2C8 in three Malaysian ethnics: CYP2C8*2 and CYP2C8*3 are found in Malaysian Indians

Muthiah YD, Lee WL, Teh LK, Ong CE, Ismail R

J Clin Pharm Ther, 2005 Oct;30(5):487-90.

PMID: 16164496

CYP2C8 is genetically polymorphic. Four variants, CYP2C8*2, CYP2C8*3, CYP2C8*4 and CYP2C8*5, which contain mutations in the coding regions have been reported to exhibit different enzyme activity as compared with CYP2C8*1.

Fulltext Involvement of cytochromes p450 in drug-drug interactions: an overview

Ong CE, Teh LK, Ismail R

Med J Malaysia, 2002 Jun;57(2):251-60.

PMID: 24326665

Drug interactions can cause iatrogenic disease. If concurrent medications are taken, the potential exists for a drug interaction to occur. Renewed interest in the topic interactions has been generated by the fatal interactions involving non-sedating histamine H-1 antagonists and the recent intriduction of two therapeutic agents, the selective serotonin reuptake inhibitors (SSRIs) and HIV protease inhibitors, for the treatment of depression and AIDS, respectively. These three therapeutic agents have been implicated in clinically significant drug interactions. The consequences of these interactions vary in clinical significance, extent, and effect. Some interactions are theoretical whereas others may lead to severe iatrogenic adverse experiences including lethal consequences.The purpose of this review is to alert the medical practioner to potential drug interactions that may occur when these drugs are prescribed to patients. The pharmacological basis and clinical signficance of these interactions are reviewed. The pharmacological mechanisms underlying these interactions are illustrative of those that may be involved for many other medications. Doctors should be aware of the potential pitfall that may occur when certain groups of drugs are prescribed with concurrent medications.

A simple and rapid genotyping method for beta-2 receptor (beta2 AR) gene using allele specific multiplex PCR

Romaino SM, Teh LK, Zilfalil BA, Thong CP, Ismail AA, Amir J, et al.

J Clin Pharm Ther, 2004 Feb;29(1):47-52.

PMID: 14748897 DOI: 10.1046/j.1365-2710.2003.00535.x

Polymorphism of the beta2-adrenergic receptor (beta2 AR) gene is an important determinant of the function of this receptor. It affects receptor down-regulation and beta2-agonist responses. It has also been a focus of interest in attempts to elucidate the genetic basis of asthma, hypertension, obesity and cystic fibrosis. Several different techniques have been established to determine beta2 AR genotypes but none of these methods are simple enough to detect simultaneously all the five alleles of our research interest (Arg16/Gly16, -20T/C, Gln27/Glu27, -47T/C and Thr164/Ile164).

A simple multiplex PCR method for the concurrent detection of three CYP2C8 variants

Muthiah YD, Lee WL, Teh LK, Ong CE, Salleh MZ, Ismail R

Clin Chim Acta, 2004 Nov;349(1-2):191-8.

PMID: 15469873 DOI: 10.1016/j.cccn.2004.06.024

BACKGROUND: Cytochrome P450 (CYP) 2C8 is a principle enzyme responsible for the metabolism of many clinically important drugs as well as endogenous compounds such as arachidonic acid. The enzyme is genetically polymorphic but a simple method is not available to study its genetic polymorphism. We developed and optimized a variant-specific PCR techniques to detect CYP2C8*2, CYP2C8*3 and CYP2C8*4.
METHOD: Genomic DNA was extracted from blood using standard extraction methods. A two-step PCR method was developed to detect simultaneously three CYP2C8 variants. In the first PCR (PCR1), specific regions from exons 3, 5 and 8 of the CYP2C8 gene were amplified. The products were used as templates in parallel alleles-specific PCR (PCR2). This method was tested against DNA samples obtained from 57 healthy Malaysian volunteers.
RESULT: The bands of interest were successfully amplified. This method showed specific and reproducible results when tested on healthy volunteers. DNA sequencing further confirmed genotype results obtained from current method.
CONCLUSION: We have successfully developed and optimized a multiplex PCR method suitable for use in population studies of CYP2C8 polymorphism.

A simple method for the detection of CYP2C9 polymorphisms: nested allele-specific multiplex polymerase chain reaction

Zainuddin Z, Teh LK, Suhaimi AW, Salleh MZ, Ismail R

Clin Chim Acta, 2003 Oct;336(1-2):97-102.

PMID: 14500040 DOI: 10.1016/s0009-8981(03)00319-x

BACKGROUND: Cytochrome P4502C9 (CYP2C9), a principle drug-metabolizing enzyme is polymorphic in humans and is responsible for important pharmacokinetic and pharmacodynamic variations of CYP2C9 substrates. We developed an allele-specific multiplex polymerase chain reaction (PCR) method for the detection of common CYP2C9 alleles.
METHOD: Genomic DNA was extracted from blood obtained from 40 unrelated healthy Malaysian Indian volunteers. The DNA was subjected to a first PCR that was used to amplify both exons 3 and 7 simultaneously in one reaction tube and a second PCR that was used to detect the polymorphic sites of CYP2C9 alleles using allele-specific primers. Sequencing was performed to validate the test results.
RESULTS: We were successful in amplifying the fragments of interest from the DNA samples. The method was also reproducible and specific. The amplified sequences showed 100% homology to CYP2C9 sequence.
CONCLUSION: This is the first nested allele-specific multiplex PCR method reported to allow for the simultaneously detection of five CYP2C9 alleles.

An assessment of three noncommercial DNA extraction methods from dried blood spots for beta-thalassaemia mutation identification

Karthipan SN, George E, Jameela S, Lim WF, Teh LK, Lee TY, et al.

Int J Lab Hematol, 2011 Oct;33(5):540-4.

PMID: 21884505 DOI: 10.1111/j.1751-553X.2011.01304.x

Dried blood spots (DBS) are currently the recommended sample collection method for newborn screening programmes in America. Early diagnosis of beta-thalassaemia screening is essential as it provides an added advantage especially in sickle cell disease. Beta-thalassaemia frequency is high in many poor countries, and the cost of using commercial DNA extraction kits can be prohibitive. Our study assessed three methods that use minimal reagents and materials to extract DNA from DBS for beta-thalassaemia identification.

In vivo antinociceptive and anti-inflammatory activities of dried and fermented processed virgin coconut oil

Zakaria ZA, Somchit MN, Mat Jais AM, Teh LK, Salleh MZ, Long K

Med Princ Pract, 2011;20(3):231-6.

PMID: 21454992 DOI: 10.1159/000323756

The present study was carried out to investigate the antinociceptive and anti-inflammatory activities of virgin coconut oil (VCO) produced by the Malaysian Agriculture Research and Development Institute (MARDI) using various in vivo models.

Fulltext Hepatoprotective activity of dried- and fermented-processed virgin coconut oil

Zakaria ZA, Rofiee MS, Somchit MN, Zuraini A, Sulaiman MR, Teh LK, et al.

Evid Based Complement Alternat Med, 2011;2011:142739.

PMID: 21318140 DOI: 10.1155/2011/142739

The present study aims to determine the hepatoprotective effect of MARDI-produced virgin coconut oils, prepared by dried- or fermented-processed methods, using the paracetamol-induced liver damage in rats. Liver injury induced by 3 g/kg paracetamol increased the liver weight per 100 g bodyweight indicating liver damage. Histological observation also confirms liver damage indicated by the presence of inflammations and necrosis on the respective liver section. Interestingly, pretreatment of the rats with 10, but not 1 and 5, mL/kg of both VCOs significantly (P < .05) reduced the liver damage caused by the administration of paracetamol, which is further confirmed by the histological findings. In conclusion, VCO possessed hepatoprotective effect that requires further in-depth study.

Genetic polymorphism of CYP2D6 in Chinese subjects in Malaysia

Ismail R, Teh LK, Amir J, Alwi Z, Lopez CG

J Clin Pharm Ther, 2003 Aug;28(4):279-84.

PMID: 12911679

Although Malaysian Chinese share an origin with the mainland Chinese, their evolution has been influenced by intermarriages. With a gene such as CYP2D6, which is highly polymorphic, it is expected that the Malaysian Chinese would exhibit a polymorphism profile different from those of the Chinese populations in other geographical locations.

CYP2D6 phenotypes among Malays in Malaysia

Ismail R, Hussein A, Teh LK, Nizam Isa M

J Clin Pharm Ther, 2000 Oct;25(5):379-83.

PMID: 11123490

Although they originated from China, Malays have undergone a lot of intermarriages. A study suggested that CYP2D6 poor metabolism (PM) phenotype was more common in Malays compared to Chinese. CYP2D6 is highly polymorphic and is involved in the metabolism of many drugs and has been implicated in some environmentally-induced diseases. It is therefore useful to further study this polymorphism in Malays.

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