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VKORC1 and CYP2C9 genotypic data-based dose prediction alone does not accurately predict warfarin dose requirements in some Malaysian patients

Chua YA, Abdullah WZ, Yusof Z, Gan SH

Turk J Med Sci, 2015;45(4):913-8.
PMID: 26422867

BACKGROUND/AIM: VKORC1 and CYP2C9 genetic polymorphisms may not accurately predict warfarin dose requirements. We evaluated an existing warfarin dosing algorithm developed for Malaysian patients that was based only on VKORC1 and CYP2C9 genes.
MATERIALS AND METHODS: Five Malay patients receiving warfarin maintenance therapy were investigated for their CYP2C9*2, CYP2C9*3, and VKORC1-1639G>A genotypes and their vitamin K-dependent (VKD) clotting factor activities. The records of their daily warfarin doses and international normalized ratio (INR) 2 years prior to and after the measurement of VKD clotting factors activities were acquired. The mean warfarin doses were compared with predicted warfarin doses calculated from a genotypic-based dosing model developed for Asians.
RESULTS: A patient with the VKORC1-1639 GA genotype, who was supposed to have higher dose requirements, had a lower mean warfarin dose similar to those having the VKORC1-1639 AA genotype. This discrepancy may be due to the coadministration of celecoxib, which has the potential to decrease warfarins metabolism. Not all patients' predicted mean warfarin doses based on a previously developed dosing algorithm for Asians were similar to the actual mean warfarin dose, with the worst predicted dose being 54.34% higher than the required warfarin dose.
CONCLUSION: Multiple clinical factors can significantly change the actual required dose from the predicted dose from time to time. The additions of other dynamic variables, especially INR, VKD clotting factors, and concomitant drug use, into the dosing model are important in order to improve its accuracy.

Matched MeSH terms: Drug Interactions
In vivo interactions between neurotoxin, cardiotoxin and phospholipases A2 isolated from Malayan cobra (Naja naja sputatrix) venom

Tan NH, Armugam A

Toxicon, 1990;28(10):1193-8.
PMID: 2264068

The in vivo interactions between alpha-neurotoxin, cardiotoxin and two phospholipases A2 (sputa-phospholipase A2-1 and 3) isolated from Malayan cobra venom were assessed by examining the effects of simultaneous injection of sub-LD50 dose of one toxin on (i) i.v. LD50 S of the other toxins in mice; and (ii) mean survival times of mice injected with lethal doses of the other toxins. While LD50 measurements did not reveal any interaction between the toxins in vivo, survival time measurements suggest a synergy between the neurotoxin and sputa-phospholipase A2-1 and between sputa-phospholipase A2-1 and sputa-phospholipase A2-3. Our results also suggest that both sputa-phospholipases A2 interfere with the lethal action of the cardiotoxin, resulting in prolongation of the mean survival time of mice injected with a lethal dose of cardiotoxin. The patterns of in vivo interactions between phospholipase A2 and other venom toxins appear to depend on the nature and mode of pharmacological action of the phospholipase A2.

Matched MeSH terms: Drug Interactions
Insight into the molecular mechanism of P-glycoprotein mediated drug toxicity induced by bioflavonoids: an integrated computational approach

Wongrattanakamon P, Lee VS, Nimmanpipug P, Sirithunyalug B, Chansakaow S, Jiranusornkul S

Toxicol. Mech. Methods, 2017 May;27(4):253-271.
PMID: 27996361 DOI: 10.1080/15376516.2016.1273428

In this work, molecular docking, pharmacophore modeling and molecular dynamics (MD) simulation were rendered for the mouse P-glycoprotein (P-gp) (code: 4Q9H) and bioflavonoids; amorphigenin, chrysin, epigallocatechin, formononetin and rotenone including a positive control; verapamil to identify protein-ligand interaction features including binding affinities, interaction characteristics, hot-spot amino acid residues and complex stabilities. These flavonoids occupied the same binding site with high binding affinities and shared the same key residues for their binding interactions and the binding region of the flavonoids was revealed that overlapped the ATP binding region with hydrophobic and hydrophilic interactions suggesting a competitive inhibition mechanism of the compounds. Root mean square deviations (RMSDs) analysis of MD trajectories of the protein-ligand complexes and NBD2 residues, and ligands pointed out these residues were stable throughout the duration of MD simulations. Thus, the applied preliminary structure-based molecular modeling approach of interactions between NBD2 and flavonoids may be gainful to realize the intimate inhibition mechanism of P-gp at NBD2 level and on the basis of the obtained data, it can be concluded that these bioflavonoids have the potential to cause herb-drug interactions or be used as lead molecules for the inhibition of P-gp (as anti-multidrug resistance agents) via the NBD2 blocking mechanism in future.

Matched MeSH terms: Herb-Drug Interactions
Fulltext Treatment of allergic rhinitis and urticaria: a review of the newest antihistamine drug bilastine

Wang XY, Lim-Jurado M, Prepageran N, Tantilipikorn P, Wang de Y

Ther Clin Risk Manag, 2016;12:585-97.
PMID: 27110120 DOI: 10.2147/TCRM.S105189

Allergic rhinitis and urticaria are common allergic diseases that may have a major negative impact on patients' quality of life. Bilastine, a novel new-generation antihistamine that is highly selective for the H1 histamine receptor, has a rapid onset and prolonged duration of action. This agent does not interact with the cytochrome P450 system and does not undergo significant metabolism in humans, suggesting that it has very low potential for drug-drug interactions, and does not require dose adjustment in renal impairment. As bilastine is not metabolized and is excreted largely unchanged, hepatic impairment is not expected to increase systemic exposure above the drug's safety margin. Bilastine has demonstrated similar efficacy to cetirizine and desloratadine in patients with seasonal allergic rhinitis and, in a Vienna Chamber study, a potentially longer duration of action than fexofenadine in patients with asymptomatic seasonal allergic rhinitis. It has also shown significant efficacy (similar to that of cetirizine) and safety in the long-term treatment of perennial allergic rhinitis. Bilastine showed similar efficacy to levocetirizine in patients with chronic spontaneous urticaria and can be safely used at doses of up to fourfold higher than standard dosage (80 mg once daily). The fourfold higher than standard dose is specified as an acceptable second-line treatment option for urticaria in international guidelines. Bilastine is generally well tolerated, both at standard and at supratherapeutic doses, appears to have less sedative potential than other second-generation antihistamines, and has no cardiotoxicity. Based on its pharmacokinetic properties, efficacy, and tolerability profile, bilastine will be valuable in the management of allergic rhinitis and urticaria.

Matched MeSH terms: Drug Interactions
Fulltext Effectiveness and prescription pattern of lipid-lowering therapy and its associated factors among patients with type 2 diabetes mellitus in Malaysian primary care settings

Elnaem MH, Mohamed MHN, Huri HZ, Shah ASM

Ther Clin Risk Manag, 2019;15:137-145.
PMID: 30705590 DOI: 10.2147/TCRM.S182716

Background: Cardiovascular diseases (CVDs) are the main complication leading to morbidity and mortality among patients with type 2 diabetes mellitus (T2DM). There is a large amount of evidence to support the use of lipid-lowering therapy (LLT) for the prevention of CVD. This study aimed to assess the effectiveness and prescription quality of LLT among T2DM patients and to identify its associated factors.

Methods: A multicenter cross-sectional study included 816 T2DM patients from four different primary care centers in Pahang, Malaysia. We involved LLT-eligible T2DM patients as per the national clinical practice guidelines (CPG). The assessment of therapy effectiveness focused on the attainment of target lipid measures stated in the CPG. Evaluation of the prescription quality was classified into appropriate, potentially inappropriate, and inappropriate, based on the compliance with guidelines and existence of potential safety concerns. Binomial logistic regression was employed to identify the predictors of LLT effectiveness and prescription quality.

Results: The overall percentage of T2DM patients receiving statin therapy was 87.6% (715/816). Statin therapy was appropriately prescribed in 71.5% of the cases. About 17.5% of the LLT prescriptions have at least one significant drug interaction with co-prescribed medications. The achievement of the primary target of low-density lipoprotein cholesterol (LDL-C) levels was observed in only 37% of T2DM patients. The LLT indication and appropriateness of prescription were significantly associated with the attainment of LDL-C treatment goals. Primary prevention, Malay race, and hypertension were identified as predictors for appropriate prescribing of LLT among T2DM subjects.

Conclusion: There is a need to enhance the quality of LLT prescribing in the primary care setting to cover all eligible high-risk patients and ensure patient safety. Strategies to improve the achievement of LDL-C goals among patients with T2DM, such as investigating the potential role of the combination therapy and high-intensity statin therapy, are required.

Matched MeSH terms: Drug Interactions
Fulltext Moxifloxacin-warfarin interaction

Yew KL, Lee WC

Med J Malaysia, 2012 Aug;67(4):420-1.
PMID: 23082454 MyJurnal
Matched MeSH terms: Drug Interactions
Fulltext Pattern of potential drug-drug interactions in diabetic out-patients in a tertiary care teaching hospital in Nepal

Dinesh KU, Subish P, Pranaya M, Shankar PR, Anil SK, Durga B

Med J Malaysia, 2007 Oct;62(4):294-8.
PMID: 18551932

A prospective study was conducted at Manipal Teaching Hospital, Pokhara, Nepal to identify and analyze the pattern of the potential DDIs (drug-drug interaction) in diabetes patients. A total of 182 patients who were prescribed 685 drugs (average, 3.76 drugs per prescription) were enrolled. Patients 51 to 60 years of age had a higher risk [43 patients, or (23.6%)] of developing DDIs. It was found that 174 (92.1%) of the potential DDIs were of "moderate" severity. Cardiovascular drugs carried a risk of DDIs (187 drugs, or 49.5%). The most common potential DDI observed was between metformin and enalapril (n = 64).

Matched MeSH terms: Drug Interactions*
Fulltext Herbal use amongst multiethnic medical patients in Penang Hospital: pattern and perceptions

Saw JT, Bahari MB, Ang HH, Lim YH

Med J Malaysia, 2006 Oct;61(4):422-32.
PMID: 17243519

A cross sectional survey on pattern and perception of herbal use among medical patients in Penang Hospital was conducted. Among 250 patients surveyed, 67.9% were using herbal medicine and conventional medicine concomitantly. A majority of the patients used herbs for health maintenance (51.3%) purpose. More than 90% of herbal users did not disclose herbal use to their physician and "Doctor never asked" was the major reason given (54.2%). The Chinese reported the highest rate of herbal use but was least likely to disclose. These findings are important for health professionals to ensure medication safety and recognise potential drug herb interaction.

Matched MeSH terms: Herb-Drug Interactions
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.

Matched MeSH terms: Drug Interactions*
Fulltext Positive direct antiglobulin test with Unasyn--a case report

Leong CF, Cheong SK, Fadilah SA

Med J Malaysia, 1999 Dec;54(4):517-9.
PMID: 11072473

A 56-year-old Chinese lady with valvular heart disease and atrial fibrillation was referred to us from a private hospital for further management of autoimmune haemolytic anaemia. Physical examination and laboratory investigations did not support the diagnosis of haemolytic anaemia. However, direct antiglobulin test (DAT) was strongly positive with anti-IgG and negative with anti-C3d. There was also mild anaemia and reticulocytosis, which was attributable to persistent haematuria. The DAT became positive after commencing Unasyn and cessation was associated with decreasing reactivity of the positive DAT. We believe that the positive DAT in this patient was most likely due to the Unasyn therapy.

Matched MeSH terms: Drug Interactions
Fulltext Warfarin--topical salicylate interactions: case reports

Ramanathan M

Med J Malaysia, 1995 Sep;50(3):278-9.
PMID: 8926909

This paper deals with two patients on warfarin in whom the use of topical methylsalicylate preparations led to clinically significant bleeding problems. The first patient required fresh frozen plasma to tide over the crisis while the second patient recovered spontaneously on stopping the warfarin temporarily. The possible mechanisms by which salicylates potentiate the anticoagulant effect of warfarin are briefly outlined.

Matched MeSH terms: Drug Interactions
Resistant hypertension during antituberculosis treatment: how is rifampicin implicated?

Lee SL, Lim WJ, Chai ST

Med J Malaysia, 2020 09;75(5):591-593.
PMID: 32918434

A 67-year-old mental institute resident was treated for smear-positive pulmonary tuberculosis. His background history included chronic essential hypertension which was well-controlled with amlodipine 10mg daily. However, his blood pressure became suboptimal one week into antitubercular treatment, necessitating escalation of antihypertensive therapy up to six medications. Following completion of antitubercular treatment, his blood pressure improved markedly. The number of antihypertensives was able to be reduced to only two after a month. We postulate that rifampicin has attenuated the therapeutic effect of amlodipine via potent induction of hepatic CYP3A4 but the failure to control the blood pressure even with medications unrelated to cytochrome P450 pathways raises the spectre of an additional interaction.

Matched MeSH terms: Drug Interactions
Mechanism of hyperthermia in the interaction between pethidine or imipramine and monoamine oxidase inhibitors

Gong NC, Rogers KJ

Med J Malaysia, 1973 Jun;27(4):280-3.
PMID: 4270786
Matched MeSH terms: Drug Interactions*
Fulltext Histopathological study of the hepatic and renal toxicity associated with the co-administration of imatinib and acetaminophen in a preclinical mouse model

Nassar I, Pasupati T, Judson JP, Segarra I

Malays J Pathol, 2010 Jun;32(1):1-11.
PMID: 20614720 MyJurnal

Imatinib, a selective tyrosine kinase inhibitor, is the first line treatment against chronic myelogenous leukaemia (CML) and gastrointestinal stromal tumors (GIST). Several fatal cases have been associated with imatinib hepatotoxicity. Acetaminophen, an over-the-counter analgesic, anti-pyretic drug, which can cause hepatotoxicity, is commonly used in cancer pain management. We assessed renal and hepatic toxicity after imatinib and acetaminophen co-administration in a preclinical model. Four groups of male ICR mice (30-35 g) were fasted overnight and administered either saline solution orally (baseline control), imatinib 100 mg/kg orally (control), acetaminophen 700 mg/kg intraperitoneally (positive control) or co-administered imatinib 100 mg/kg orally and acetaminophen 700 mg/kg intraperitoneally (study group), and sacrificed at 15 min, 30 min, 1 h, 2 h, 4 h and 6 h post-administration (n = 4 per time point). The liver and kidneys were harvested for histopathology assessment. The liver showed reversible cell damage like feathery degeneration, microvesicular fatty change, sinusoidal congestion and pyknosis, when imatinib or acetaminophen were administered separately. The damage increased gradually with time, peaked at 2 h but resolved by 4 h. When both drugs were administered concurrently, the liver showed irreversible damage (cytolysis, karyolysis and karyorrhexis) which did not resolve by 6 h. Very minor renal changes were observed. Acetaminophen and imatinib co-administration increased hepatoxicity which become irreversible, probably due to shared P450 biotransformation pathways and transporters in the liver.

Matched MeSH terms: Drug Interactions
In-vitro inhibitory effect of Tualang honey on cytochrome P450 2C8 activity

Muthiah YD, Ong CE, Sulaiman SA, Tan SC, Ismail R

J Pharm Pharmacol, 2012 Dec;64(12):1761-9.
PMID: 23146039 DOI: 10.1111/j.2042-7158.2012.01551.x

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

Matched MeSH terms: Food-Drug Interactions*
Metronidazole leads to enhanced uptake of imatinib in brain, liver and kidney without affecting its plasma pharmacokinetics in mice

Tan SY, Kan E, Lim WY, Chay G, Law JH, Soo GW, et al.

J Pharm Pharmacol, 2011 Jul;63(7):918-25.
PMID: 21635257 DOI: 10.1111/j.2042-7158.2011.01296.x

The pharmacokinetic interaction between metronidazole, an antibiotic-antiparasitic drug used to treat anaerobic bacterial and protozoal infections, and imatinib, a CYP3A4, P-glycoprotein substrate kinase inhibitor anticancer drug, was evaluated.

Matched MeSH terms: Drug Interactions
Quinine interactions with tryptophan and tyrosine in malaria patients, and implications for quinine responses in the clinical setting

Islahudin F, Pleass RJ, Avery SV, Ting KN

J Antimicrob Chemother, 2012 Oct;67(10):2501-5.
PMID: 22763566 DOI: 10.1093/jac/dks253

OBJECTIVES: Recent work with the yeast model revealed that the antiprotozoal drug quinine competes with tryptophan for uptake via a common transport protein, causing cellular tryptophan starvation. In the present work, it was hypothesized that similar interactions may occur in malaria patients receiving quinine therapy.
PATIENTS AND METHODS: A direct observational study was conducted in which plasma levels of drug and amino acids (tryptophan, tyrosine and phenylalanine) were monitored during quinine treatment of malaria patients with Plasmodium falciparum infections.
RESULTS: Consistent with competition for uptake from plasma into cells, plasma tryptophan and tyrosine levels increased ≥2-fold during quinine therapy. Plasma quinine levels in individual plasma samples were significantly and positively correlated with tryptophan and tyrosine in the same samples. Control studies indicated no effect on phenylalanine. Chloroquine treatment of Plasmodium vivax-infected patients did not affect plasma tryptophan or tyrosine. During quinine treatment, plasma tryptophan was significantly lower (and quinine significantly higher) in patients experiencing adverse drug reactions.
CONCLUSIONS: Plasma quinine levels during therapy are related to patient tryptophan and tyrosine levels, and these interactions can determine patient responses to quinine. The study also highlights the potential for extrapolating insights directly from the yeast model to human malaria patients.

Matched MeSH terms: Drug Interactions*
Genetic polymorphisms and drug interactions leading to clopidogrel resistance: why the Asian population requires special attention

Hasan MS, Basri HB, Hin LP, Stanslas J

Int J Neurosci, 2013 Mar;123(3):143-54.
PMID: 23110469 DOI: 10.3109/00207454.2012.744308

Ischemic heart disease and stroke are the two leading causes of death worldwide. Antiplatelet therapy plays the most significant role in the management of these cardiovascular and cerebrovascular occlusive events to prevent recurrent ischemic attack. Clopidogrel, an antiplatelet drug, is widely prescribed either alone or in combination with aspirin as dual antiplatelet therapy for the prevention of vascular occlusive events. The antiplatelet response to clopidogrel varies widely. Hyporesponders and nonresponders are likely to have adverse cardiovascular events during follow-up. Some drugs, such as proton pump inhibitors (omeprazole), calcium channel blockers, selective serotonin reuptake inhibitors (nefazadone), coumarin derivatives (phenprocoumon), benzodiazepines, sulfonylurea, erythromycin, and itraconazole, decrease the antiplatelet effect of clopidogrel when administered concomitantly. Decreased response to clopidogrel is common among Asians due to genetic polymorphisms associated with clopidogrel resistance, and it is nearly 70% in some of the Asian communities. It is necessary to study Asian populations, because there are a large number of Asians throughout the world due to increased migration. Current guidelines do not make genetic testing or platelet response testing mandatory prior to clopidogrel prescription. Therefore, it is important for clinicians treating Asian patients to keep in mind the interindividual variability in response to clopidogrel when prescribing the drug.

Matched MeSH terms: Drug Interactions/physiology
Vitamin E, glutathione S-transferase and gamma-glutamyl transpeptidase activities in cultured hepatocytes of rats treated with carcinogens

Ong FB, Wan Ngah WZ, Top AG, Khalid BA, Shamaan NA

Int. J. Biochem., 1994 Mar;26(3):397-402.
PMID: 7910569

1. The effects of alpha-tocopherol and gamma-tocotrienol on glutathione S-transferase (GST) and gamma-glutamyl transpeptidase (gamma-GT) activities in cultured hepatocytes prepared from rats treated with diethylnitrosamine (DEN) and 2-acetylaminofluorene (AAF) were investigated. 2. Both the alpha-tocopherol and gamma-tocotrienol treated hepatocytes showed significantly higher (P < 0.05) GST activities than untreated hepatocytes prepared from the carcinogen treated rats in the first 3 days of culture. Treatment with alpha-tocopherol and gamma-tocotrienol generally resulted in a tendency to increase the GST activities above that in the untreated hepatocytes. 3. Treatment with high doses (125-250 microM) of alpha-tocopherol and low doses (12.5-25 microM) of gamma-tocotrienol generally resulted in a significant reduction in gamma-GT activities at 1-3 days. gamma-GT activities are reduced as the dose of alpha-tocopherol and gamma-tocotrienol are increased.

Matched MeSH terms: Drug Interactions
Fulltext Drug interaction between cyclosporine A and quinine in a renal transplant patient with malaria

Tan HW, Ch'ng SL

Singapore Med J, 1991 Jun;32(3):189-90.
PMID: 1876897

We report a previously undocumented drug interaction between cyclosporine A and quinine. A 39 year old Asian with a recent renal transplant was diagnosed to have a mild cerebral falciparum malaria. He was treated with seven days of oral quinine (600 mg, 8 hourly), followed by a stat dose of pyrimethamine (75 mg)--sulfadoxime (1200mg) because of a strong suspicion of chloroquine resistant falciparum malaria. Using a polyclonal radioimmunoassay method, we measured morning trough cyclosporine A level before, during and after the quinine treatment. Results showed a gradual decrease in the cyclosporine A level from a baseline value of 328 ng/ml to 107 ng/ml after seven days of oral quinine with a subsequent rise to pre-treatment level after discontinuation of quinine. There was no significant change in the dose of cyclosporine A administered during the period of quinine treatment (4.05 to 3.83 mg/kg body weight). Biochemical liver function tests, serum creatinine and hematological parameters were also essentially unchanged during this period. In vitro study showed no significant methodological interference in the cyclosporine assay by quinine dihydrochloride. These findings suggest an in vivo drug interaction between cyclosporine A and quinine. The mechanism of this interaction is not clear. Further studies are required to confirm the significance of this observation. Quinine and its stereoisomer, quinidine should be used with caution until further information is available.

Matched MeSH terms: Drug Interactions

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