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Fulltext Surveillance of adverse events in the treatment of drug-resistant tuberculosis: A global feasibility study

Akkerman O, Aleksa A, Alffenaar JW, Al-Marzouqi NH, Arias-Guillén M, Belilovski E, et al.

Int J Infect Dis, 2019 Jun;83:72-76.
PMID: 30953827 DOI: 10.1016/j.ijid.2019.03.036

The World Health Organization launched a global initiative, known as aDSM (active TB drug safety monitoring and management) to better describe the safety profile of new treatment regimens for drug-resistant tuberculosis (TB) in real-world settings. However, comprehensive surveillance is difficult to implement in several countries. The aim of the aDSM project is to demonstrate the feasibility of implementing national aDSM registers and to describe the type and the frequency of adverse events (AEs) associated with exposure to the new anti-TB drugs. Following a pilot study carried out in 2016, official involvement of TB reference centres/countries into the project was sought and cases treated with bedaquiline- and/or delamanid-containing regimens were consecutively recruited. AEs were prospectively collected ensuring potential attribution of the AE to a specific drug based on its known safety profile. A total of 309 cases were fully reported from 41 centres in 27 countries (65% males; 268 treated with bedaquiline, 20 with delamanid, and 21 with both drugs) out of an estimated 781 cases the participating countries had committed to report by the first quarter of 2019.

Matched MeSH terms: Drug Therapy, Combination
Fulltext Insulin degludec/insulin aspart once daily in Type 2 diabetes: a comparison of simple or stepwise titration algorithms (BOOST® : SIMPLE USE)

Park SW, Bebakar WM, Hernandez PG, Macura S, Hersløv ML, de la Rosa R

Diabet Med, 2017 02;34(2):174-179.
PMID: 26773557 DOI: 10.1111/dme.13069

AIMS: To compare the efficacy and safety of two titration algorithms for insulin degludec/insulin aspart (IDegAsp) administered once daily with metformin in participants with insulin-naïve Type 2 diabetes mellitus.
METHODS: This open-label, parallel-group, 26-week, multicentre, treat-to-target trial, randomly allocated participants (1:1) to two titration arms. The Simple algorithm titrated IDegAsp twice weekly based on a single pre-breakfast self-monitored plasma glucose (SMPG) measurement. The Stepwise algorithm titrated IDegAsp once weekly based on the lowest of three consecutive pre-breakfast SMPG measurements. In both groups, IDegAsp once daily was titrated to pre-breakfast plasma glucose values of 4.0-5.0 mmol/l. Primary endpoint was change from baseline in HbA1c (%) after 26 weeks.
RESULTS: Change in HbA1c at Week 26 was IDegAspSimple -14.6 mmol/mol (-1.3%) (to 52.4 mmol/mol; 6.9%) and IDegAspStepwise -11.9 mmol/mol (-1.1%) (to 54.7 mmol/mol; 7.2%). The estimated between-group treatment difference was -1.97 mmol/mol [95% confidence interval (CI) -4.1, 0.2] (-0.2%, 95% CI -0.4, 0.02), confirming the non-inferiority of IDegAspSimple to IDegAspStepwise (non-inferiority limit of ≤ 0.4%). Mean reduction in fasting plasma glucose and 8-point SMPG profiles were similar between groups. Rates of confirmed hypoglycaemia were lower for IDegAspStepwise [2.1 per patient years of exposure (PYE)] vs. IDegAspSimple (3.3 PYE) (estimated rate ratio IDegAspSimple /IDegAspStepwise 1.8; 95% CI 1.1, 2.9). Nocturnal hypoglycaemia rates were similar between groups. No severe hypoglycaemic events were reported.
CONCLUSIONS: In participants with insulin-naïve Type 2 diabetes mellitus, the IDegAspSimple titration algorithm improved HbA1c levels as effectively as a Stepwise titration algorithm. Hypoglycaemia rates were lower in the Stepwise arm.

Matched MeSH terms: Drug Therapy, Combination
Rapid response to methylphenidate as an add-on therapy to mirtazapine in the treatment of major depressive disorder in terminally ill cancer patients: a four-week, randomized, double-blinded, placebo-controlled study

Ng CG, Boks MP, Roes KC, Zainal NZ, Sulaiman AH, Tan SB, et al.

Eur Neuropsychopharmacol, 2014 Apr;24(4):491-8.
PMID: 24503279 DOI: 10.1016/j.euroneuro.2014.01.016

This is a 4 week, randomized, double-blind, placebo-controlled study to examine the effects of methylphenidate as add-on therapy to mirtazapine compared to placebo for treatment of depression in terminally ill cancer patients. It involved 88 terminally ill cancer patients from University of Malaya Medical Centre, Kuala Lumpur, Malaysia. They were randomized and treated with either methylphenidate or placebo as add on to mirtazapine. The change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 3 was analyzed by linear regression. Changes of MADRS and Clinical Global Impression-Severity Scale (CGI-S) over 28 days were analyzed using mixed model repeated measures (MMRM). Secondary analysis of MADRS response rates, defined as 50% or more reduction from baseline score. A significantly larger reduction of Montgomery-Åsberg Depression Rating Scale (MADRS) score in the methylphenidate group was observed from day 3 (B=4.14; 95% CI=1.83-6.45). Response rate (defined as 50% or more reduction from baseline MADRS score) in the methylphenidate treated group was superior from day 14. Improvement in Clinical Global Impression-Severity Scale (CGI-S) was greater in the methylphenidate treated group from day 3 until day 28. The drop-out rates were 52.3% in the methylphenidate group and 59.1% in the placebo group (relative risk=0.86, 95%CI=0.54-1.37) due to cancer progression. Nervous system adverse events were more common in methylphenidate treated subjects (20.5% vs 9.1%, p=0.13). In conclusions, methylphenidate as add on therapy to mirtazapine demonstrated an earlier antidepressant response in terminally ill cancer patients, although at an increased risk of the nervous system side effects.

Matched MeSH terms: Drug Therapy, Combination/adverse effects
Fulltext Impact of the additive effect of angiotensin-converting enzyme inhibitors and /or statins with antiplatelet medication on mortality after acute ischaemic stroke

Hassan Y, Al-Jabi SW, Aziz NA, Looi I, Zyoud SH

Basic Clin Pharmacol Toxicol, 2012 Apr;110(4):370-7.
PMID: 22023326 DOI: 10.1111/j.1742-7843.2011.00825.x

There has been recent interest in combining antiplatelets, angiotensin-converting enzyme inhibitors (ACEIs) and statins in primary and secondary ischaemic stroke prevention. This observational study was performed to evaluate the impact of adding ACEIs and/or statins to antiplatelets on post-stroke in-hospital mortality. Ischaemic stroke patients attending a hospital in Malaysia over an 18-month period were evaluated. Patients were categorized according to their vital status at discharge. Data included demographic information, risk factors, clinical characteristics and previous medications with particular attention on antiplatelets, ACEIs and statins. In-hospital mortality was compared among patients who were not taking antiplatelets, ACEIs or statins before stroke onset versus those who were taking antiplatelets alone or in combination with either ACEIs, statins or both. Data analysis was performed using SPSS version 15. Overall, 637 patients met the study inclusion criteria. After controlling for the effects of confounders, adding ACEIs or statins to antiplatelets significantly decreased the incidence of death after stroke attack by 68% (p = 0.036) and 81% (p = 0.010), respectively, compared to patients on antiplatelets alone or none of these medications. Additionally, the addition of both ACEIs and statins to antiplatelet medication resulted in the highest reduction (by 94%) of the occurrence of death after stroke attack (p < 0.001). Our results suggest that adding ACEIs and/or statins to antiplatelets for patients at risk of developing stroke, either as a primary or as a secondary preventive regimen, was associated with a significant reduction in the incidence of mortality after ischaemic stroke than antiplatelets alone. These results might help reduce the rate of ischaemic stroke morbidity and mortality by enhancing the application of specific therapeutic and management strategies for patients at a high risk of acute stroke.

Matched MeSH terms: Drug Therapy, Combination
Effect of prestroke use of angiotensin-converting enzyme inhibitors alone versus combination with antiplatelets and statin on ischemic stroke outcome

Hassan Y, Al-Jabi SW, Aziz NA, Looi I, Zyoud SH

Clin Neuropharmacol, 2011 Nov-Dec;34(6):234-40.
PMID: 21996648 DOI: 10.1097/WNF.0b013e3182348abe

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs), antiplatelets (APs), and statin are increasingly being prescribed for ischemic stroke prevention.
OBJECTIVES: The objective of the study was to examine whether previous combination therapy of ACEI with AP and/or statin has additive effect compared with ACEI alone on functional outcome after ischemic stroke. Furthermore, factors associated with improving functional outcome were investigated.
METHODS: Ischemic stroke patients attending a Malaysian hospital in 2008 were categorized according to Barthel Index at discharge. Favorable outcome was defined as Barthel Index of 75 or greater. Data included demographic information, clinical characteristics, and previous medications with particular attention to ACEI, AP, and statin.
RESULTS: Overall, 505 patients were included. Variables associated with good functional outcome were younger age (P = 0.002), first-ever attack (P = 0.016), lacunar (P = 0.015) or posterior circulation infarct stroke subtype (P = 0.034), minor Glasgow Coma Scale (P < 0.001), and previous use of ACEI alone or combined with AP and/or statin (P = 0.002). Using ACEI alone as the reference for ACEI + AP, ACEI + statin, or ACEI + AP + statin combinations, there was no significant difference among combinations on improving functional outcome (P = 0.852).
CONCLUSIONS: Prestroke use of ACEI either alone or combined with AP and/or statin was associated with better functional outcome. Previous use of ACEI in combination with AP and/or statin did not significantly differ from ACEI alone in their effect on outcome. Our study provides a potential rationale for optimizing the use of ACEI among individuals at risk of developing ischemic stroke.

Matched MeSH terms: Drug Therapy, Combination
Pulmonary miliary tuberculosis with multiple intracerebral tuberculous granulomas--report of two cases

Muin IA, Zurin AR

Br J Neurosurg, 1998 Dec;12(6):585-7.
PMID: 10070474

Although intracerebral tuberculomas are common in countries where tuberculosis is still endemic, miliary tuberculosis with involvement of the central nervous system is exceptionally rare. We report two cases of pulmonary miliary tuberculosis with multiple intracerebral tuberculomas.

Matched MeSH terms: Drug Therapy, Combination
Fulltext Malaysia-ACute CORonary syndromes Descriptive study (ACCORD): evaluation of compliance with existing guidelines in patients with acute coronary syndrome

Ahmad WA, Ramesh SV, Zambahari R

Singapore Med J, 2011 Jul;52(7):508-11.
PMID: 21808962

The ACute CORonary syndromes Descriptive study (ACCORD) is a prospective observational study that evaluates the management of acute coronary syndrome (ACS) in clinical practice and the use of antiplatelet agents in acute settings and after discharge. The secondary objective of this study was to obtain information on risk factors in a large cohort of patients with ACS.
Comment in: Sachithanandan A. Malaysia-ACCORD study: tip of the cardiovascular iceberg--we must do better. Singapore Med J, 2011 Sep;52(9):702;

Matched MeSH terms: Drug Therapy, Combination
Fulltext Antimalarial properties of Goniothalamin in combination with chloroquine against Plasmodium yoelii and Plasmodium berghei growth in mice

Mohd Ridzuan MA, Ruenruetai U, Noor Rain A, Khozirah S, Zakiah I

Trop Biomed, 2006 Dec;23(2):140-6.
PMID: 17322815 MyJurnal

Malaria is a disease which is still endemic and has become a disastrous scourge because of the emergence of antimalarial drug resistant Plasmodium falciparum. A new approach in addressing this is in developing a combination drug. This study is to show the enhancement of antimalarial properties, when single compound, goniothalamin combine with standard drug, chloroquine. Based on 4 Day Test, percentage of parasite growth on treated infected mice were determined. Oral treatment with 1 mg/kg BW of chloroquine on experimental mice suppressed 70% and 76.7% of both Plasmodium yoelii and Plasmodium berghei, respectively. The infection of P. berghei in mice was inhibited less than 50% by goniothalamin individual treatment at all doses in this study. About 27.8% and 18.5% inhibition of infection were observed in P. yoelii infected mice treated with 30 mg/kg and 60 mg/kg of goniothalamin respectively and the suppression exceed more than 50% at higher doses (90 and 120 mg/kg). Combination of 1 mg/kg chloroquine with either 30 mg/kg or 60 mg/kg of goniothalamin decreased the parasitemia of P. yoelii infected mice more than 90% and prolong the survival up to 100% after treatment. Similar treatment to P. berghei infected mice only shows about 60% reduction of parasitemia. The study findings showed that antimalarial property of goniothalamin was enhanced by combination with chloroquine at lower dose of each drug.

Matched MeSH terms: Drug Therapy, Combination
Addition of inhaled salmeterol to inhaled corticosteroids in patients with poorly controlled nocturnal asthma

Norhaya MR, Yap TM, Zainudin BM

Respirology, 1999 Mar;4(1):77-81.
PMID: 10339734 DOI: 10.1046/j.1440-1843.1999.00153.x

The effect of adding inhaled salmeterol to inhaled corticosteroids was studied in patients with poorly controlled nocturnal asthma. In a double-blind, cross-over study, 20 patients were randomized to receive either salmeterol 50 micrograms twice daily or placebo via a Diskhaler after a 1-week run-in period. After 4 weeks of treatment, patients were subsequently crossed over to receive the other treatment for a further 4 weeks with a 2-week wash-out period in between. The response to treatment was assessed by peak expiratory flow rates (PEF) measured in the morning and evening, symptom scores of asthma, number of bronchodilators used, forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) at regular intervals. Patients' preference for the Diskhaler or metered-dose inhaler was assessed at the last visit. The results showed that morning PEF was significantly higher while on salmeterol than on placebo (296.9 +/- 70.2 vs 274.6 +/- 77.4 L/min). Evening PEF showed a trend towards a higher value while on salmeterol than on placebo (321.1 +/- 73.4 vs 288.7 +/- 79.4 L/min), but the difference was not significant. There was no statistically significant improvement in symptom scores, number of rescue bronchodilators used and FEV1 or FVC between the two treatment groups. The occurrence of side effects in terms of tremors and palpitations between treatment and placebo were similar. There were more patients who preferred Diskhaler to metered-dose inhaler (70% vs 30%). We conclude that salmeterol 50 micrograms twice daily produces significant improvement in morning PEF and is well tolerated in patients with nocturnal asthma. Diskhaler is a device which is easy to use and preferred to a metered-dose inhaler.
Study site: Respiratory Clinic, Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), Kuala Lumpur, Malaysia

Matched MeSH terms: Drug Therapy, Combination
Fulltext Oral lichenoid reactions during antimalarial prophylaxis with sulphadoxine-pyrimethamine combination

Zain RB

Southeast Asian J. Trop. Med. Public Health, 1989 Jun;20(2):253-6.
PMID: 2609215

The prevalence of clinically observed oral lichenoid reaction in 186 Malay army personnel using Fansidar for 9 weeks was found to be 4.8%. The prevalence was found to be 0.5% in 186 army personnel who had stopped using Fansidar for 2 months and 0% in 143 army personnel (control group) who had not used Fansidar for at least 4 months. The lesion showed a higher prevalence for the gingiva. There was no correlation between cigarette smoking and the occurrence of these lesions in each group.

Matched MeSH terms: Drug Therapy, Combination
Polymyositis associated with hepatitis B: management with entacavir and prednisolone

Wong MH, Sockalingam S, Zain A

Int J Rheum Dis, 2011 Aug;14(3):e38-41.
PMID: 21816012 DOI: 10.1111/j.1756-185X.2011.01602.x

We report a 57-year-old woman with a 20-year history of hepatitis B presenting with progressive proximal lower limb weakness for the previous 1 month. Previous medical history included a pericardial and pleural effusion, of which no cause was found and pulmonary tuberculosis which has been adequately treated. Examination revealed multiple telangiactasia over face and nail beds and bilateral proximal lower limb weakness of power 4/5. Biochemical investigation revealed a raised erythrocyte sedimentation rate of 36 mm/h, elevated creatinine kinase levels (14,363 IU/L) and raised liver enzymes (alanine aminotransferase 445 IU/L, aspartate aminotransferase 606 IU/L) with high hepatitis B virus DNA (1,021,158 copies/mL). Nerve conduction tests and muscle biopsy were consistent with polymyositis. She received entacavir for hepatitis B treatment. Despite treatment with entacavir for 10 weeks, her weakness persisted and prednisolone was added. Upon commencement of prednisolone, her symptoms and biochemical profiles returned to normal.

Matched MeSH terms: Drug Therapy, Combination
Long-Term Treatment with the Combination of Rivaroxaban and Aspirin in Patients with Chronic Coronary or Peripheral Artery Disease: Outcomes During the Open Label Extension of the COMPASS trial

Eikelboom JW, Bosch J, Connolly SJ, Tyrwitt J, Fox KAA, Muehlhofer E, et al.

Eur Heart J Cardiovasc Pharmacother, 2022 Dec 02;8(8):786-795.
PMID: 35383832 DOI: 10.1093/ehjcvp/pvac023

AIMS: To describe outcomes of patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) randomized trial who were treated with the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily during long-term open-label extension (LTOLE).
METHODS AND RESULTS: Of the 27 395 patients enrolled in COMPASS, 12 964 (mean age at baseline 67.2 years) from 455 sites in 32 countries were enrolled in LTOLE and treated with the combination of rivaroxaban and aspirin for a median of 374 additional days (range 1-1191 days). During LTOLE, the incident events per 100 patient years were as follows: for the primary outcome [cardiovascular death, stroke, or myocardial infarction (MI)] 2.35 [95% confidence interval (CI) 2.11-2.61], mortality 1.87 (1.65-2.10), stroke 0.62 (0.50-0.76), and MI 1.02 (0.86-1.19), with CIs that overlapped those seen during the randomized treatment phase with the combination of rivaroxaban and aspirin. The incidence rates for major and minor bleeding were 1.01 (0.86-1.19) and 2.49 (2.24-2.75), compared with 1.67 (1.48-1.87) and 5.11 (95% CI 4.77-5.47), respectively, during the randomized treatment phase with the combination.
CONCLUSION: In patients with chronic CAD and/or PAD, extended combination treatment for a median of 1 year and a maximum of 3 years was associated with incidence rates for efficacy and bleeding that were similar to or lower than those seen during the randomized treatment phase, without any new safety signals.

Matched MeSH terms: Drug Therapy, Combination
Fulltext Effect of adding aminophylline infusion to nebulised salbutamol in severe acute asthma

Zainudin BM, Ismail O, Yusoff K

Thorax, 1994 Mar;49(3):267-9.
PMID: 8202885

BACKGROUND: The benefit of adding theophylline to beta 2 agonists in acute asthmatic attacks has been debated frequently.
METHODS: In an open randomised study 25 patients with severe acute asthma who presented to the emergency department were treated with either a combined nebulised salbutamol (5 mg/dose) and aminophylline infusion (0.6-0.9 mg/kg/hour), or nebulised salbutamol alone.
RESULTS: The responses to treatment as measured by peak expiratory flow (PEF) and the time taken to achieve maximum PEF were similar in both groups. Side effects were observed more commonly in patients receiving the combined treatment.
CONCLUSIONS: Nebulised salbutamol is equally efficacious in acute asthma when given alone or in combination with aminophylline.
Study site: Emergency department, Hospital Kuala Lumpur, Malaysia

Matched MeSH terms: Drug Therapy, Combination
Fulltext Combined ginger extract & Gelam honey modulate Ras/ERK and PI3K/AKT pathway genes in colon cancer HT29 cells

Tahir AA, Sani NF, Murad NA, Makpol S, Ngah WZ, Yusof YA

Nutr J, 2015;14:31.
PMID: 25889965 DOI: 10.1186/s12937-015-0015-2

The interconnected Ras/ERK and PI3K/AKT pathways play a central role in colorectal tumorigenesis, and they are targets for elucidating mechanisms involved in attempts to induce colon cancer cell death. Both ginger (Zingiber officinale) and honey have been shown to exhibit anti-tumor and anti-inflammation properties against many types of cancer, including colorectal cancer. However, there are currently no reports showing the combined effect of these two dietary compounds in cancer growth inhibition. The aim of this study was to evaluate the synergistic effect of crude ginger extract and Gelam honey in combination as potential cancer chemopreventive agents against the colorectal cancer cell line HT29.

Matched MeSH terms: Drug Therapy, Combination/methods
Fulltext A combination of doxycycline and ribavirin alleviated chikungunya infection

Rothan HA, Bahrani H, Mohamed Z, Teoh TC, Shankar EM, Rahman NA, et al.

PLoS One, 2015;10(5):e0126360.
PMID: 25970853 DOI: 10.1371/journal.pone.0126360

Lack of vaccine and effective antiviral drugs against chikungunya virus (CHIKV) outbreaks have led to significant impact on health care in the developing world. Here, we evaluated the antiviral effects of tetracycline (TETRA) derivatives and other common antiviral agents against CHIKV. Our results showed that within the TETRA derivatives group, Doxycycline (DOXY) exhibited the highest inhibitory effect against CHIKV replication in Vero cells. On the other hand, in the antiviral group Ribavirin (RIBA) showed higher inhibitory effects against CHIKV replication compared to Aciclovir (ACIC). Interestingly, RIBA inhibitory effects were also higher than all but DOXY within the TETRA derivatives group. Docking studies of DOXY to viral cysteine protease and E2 envelope protein showed non-competitive interaction with docking energy of -6.6±0.1 and -6.4±0.1 kcal/mol respectively. The 50% effective concentration (EC50) of DOXY and RIBA was determined to be 10.95±2.12 μM and 15.51±1.62 μM respectively, while DOXY+RIBA (1:1 combination) showed an EC50 of 4.52±1.42 μM. When compared, DOXY showed higher inhibition of viral infectivity and entry than RIBA. In contrast however, RIBA showed higher inhibition against viral replication in target cells compared to DOXY. Assays using mice as animal models revealed that DOXY+RIBA effectively inhibited CHIKV replication and attenuated its infectivity in vivo. Further experimental and clinical studies are warranted to investigate their potential application for clinical intervention of CHIKV disease.

Matched MeSH terms: Drug Therapy, Combination
Bioequivalence and pharmacokinetic comparison of two fixed dose combination of Metformin/ Glibenclamide formulations in healthy subjects under fed condition

Chang CT, Ang JY, Wong JM, Tan SS, Chin SK, Lim AB, et al.

Med J Malaysia, 2020 05;75(3):286-291.
PMID: 32467546

AIM: This study is conducted to compare the pharmacokinetic profiles of two fixed dose combination of metformin/glibenclamide tablets (500mg/5 mg per tablet).
MATERIALS AND METHODS: This is a single-center, single-dose, open-label, randomized, 2-treatment, 2-sequence and 2- period crossover study with a washout period of 7 days. All 28 adult male subjects were required to fast for at least 10 hours prior to drug administration and they were given access to water ad libitum during this period. Thirty minutes prior to dosing, all subjects were served with a standardized high-fat and high-calorie breakfast with a total calorie of 1000 kcal which was in accordance to the EMA Guideline on the Investigation of Bioequivalence. Subsequently, subjects were administered either the test or reference preparation with 240mL of plain water in the first trial period. During the second trial period, they received the alternate preparation. Plasma levels of glibenclamide and metformin were analysed separately using two different high performance liquid chromatography methods.
RESULTS: The 90% confidence interval (CI) for the ratio of the AUC0-t, AUC0-∞, and Cmax of the test preparation over those of the reference preparation were 0.9693-1.0739, 0.9598- 1.0561 and 0.9220 - 1.0642 respectively. Throughout the study period, no serious drug reaction was observed. However, a total of 26 adverse events (AE)/side effects were reported, including 24 that were definitely related to the study drugs, namely giddiness (n=17), while diarrheoa (n=3), headache (n=2) and excessive hunger (n=2) were less commonly reported by the subjects.
CONCLUSION: It can be concluded that the test preparation is bioequivalent to the reference preparation.

Matched MeSH terms: Drug Therapy, Combination
Combination cancer chemotherapy--a clinical trial on outpatients

Ti TK, Yong NK

Med J Malaysia, 1974 Mar;28(3):165-70.
PMID: 4278036
Matched MeSH terms: Drug Therapy, Combination*
Fulltext Artesunate-mefloquine versus chloroquine for treatment of uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT KNOW): an open-label, randomised controlled trial

Grigg MJ, William T, Menon J, Dhanaraj P, Barber BE, Wilkes CS, et al.

Lancet Infect Dis, 2016 Feb;16(2):180-188.
PMID: 26603174 DOI: 10.1016/S1473-3099(15)00415-6

BACKGROUND: The zoonotic parasite Plasmodium knowlesi has become the most common cause of human malaria in Malaysia and is present throughout much of southeast Asia. No randomised controlled trials have been done to identify the optimum treatment for this emerging infection. We aimed to compare artesunate-mefloquine with chloroquine to define the optimum treatment for uncomplicated P knowlesi malaria in adults and children.
METHODS: We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P knowlesi malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate-mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876.
FINDINGS: Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate-mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76-91]) of 115 patients in the artesunate-mefloquine group versus 61 (55% [45-64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0-40·8]; p<0·0001). Parasite clearance was faster in patients given artesunate-mefloquine than in those given chloroquine (18·0 h [range 6·0-48·0] vs 24·0 h [6·0-60·0]; p<0·0001), with faster clearance of ring stages in the artesunate-mefloquine group (mean time to 50% clearance of baseline parasites 8·6 h [95% CI 7·9-9·4] vs 13·8 h [12·1-15·4]; p<0·0001). Risk of anaemia within 28 days was lower in patients in the artesunate-mefloquine group (71 [62%; 95% CI 52·2-70·6]) than in those in the chloroquine group (83 [75%; 65·6-82·5]; p=0·035). Gametocytaemia as detected by PCR for pks25 was present in 44 (86%) of 51 patients in the artesunate-mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate-mefloquine group (mean 11·5 h [95% CI 8·3-14·6]) than in the chloroquine group (14·8 h [11·7-17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate-mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95% CI 0·812-0·906]; p<0·0001). One (<1%) patient in the artesunate-mefloquine group had a serious neuropsychiatric event regarded as probably related to study drug.
INTERPRETATION: Artesunate-mefloquine is highly efficacious for treatment of uncomplicated P knowlesi malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas.
FUNDING: Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network.

Matched MeSH terms: Drug Therapy, Combination
Fulltext Combined spinal-epidural analgesia in labour: its effects on delivery outcome

Singh SK, Yahya N, Misiran K, Masdar A, Nor NM, Yee LC

Braz J Anesthesiol, 2016 May-Jun;66(3):259-64.
PMID: 27108822 DOI: 10.1016/j.bjane.2014.09.006

BACKGROUND AND OBJECTIVES: Combined spinal-epidural (CSE) has become an increasingly popular alternative to traditional labour epidural due to its rapid onset and reliable analgesia provided. This was a prospective, convenient sampling study to determine the effects of CSE analgesia on labour outcome.

METHODS: One hundred and ten healthy primigravida parturients with a singleton pregnancy of ≥37 weeks gestation and in the active phase of labour were studied. They were enrolled to the CSE (n=55) or Non-CSE (n=55) group based on whether they consented to CSE analgesia. Non-CSE parturients were offered other methods of labour analgesia. The duration of the first and second stage of labour, rate of instrumental vaginal delivery and emergency cesarean section, and Apgar scores were compared.

RESULTS: The mean duration of the first and second stage of labour was not significantly different between both groups. Instrumental delivery rates between the groups were not significantly different (CSE group, 11% versus Non-CSE group, 16%). The slightly higher incidence of cesarean section in the CSE group (16% versus 15% in the Non-CSE group) was not statistically significant. Neonatal outcome in terms of Apgar score of less than 7 at 1 and 5min was similar in both groups.

CONCLUSION: There were no significant differences in the duration of labour, rate of instrumental vaginal delivery and emergency cesarean section, and neonatal outcome in parturients who received compared to those who did not receive CSE for labour analgesia.

Matched MeSH terms: Drug Therapy, Combination
Fulltext Ondansetron against metoclopramide/dexamethasone--a comparative study

Lim AKH, Haron MR, Yap TM

Med J Malaysia, 1994 Sep;49(3):231-8.
PMID: 7845271

This trial was carried out in Hospital Kuala Lumpur. Fifty-two patients who were scheduled to receive their first or subsequent courses of cancer chemotherapy with single dose cisplatinum containing chemotherapy regimens were evaluated. Thirty-four patients were given ondansetron in one group while 18 in the other group received metoclopramide with dexamethasone. The response to treatment was categorised as complete (0 emetic episode), major (1 or 2 emetic episodes), minor (3 to 5 emetic episodes) or failure (> 5 emetic episodes or rescue medication). Among the 52 patients, a complete or major control (0 to 2 emetic episodes) was achieved in 23/34 patients (68%) from the ondansetron group and in 3/18 patients (17%) from the metoclopramide with dexamethasone group (p < 0.002) on day 1. Similarly, the control of nausea was greater in the ondansetron group compared with the metoclopramide with dexamethasone group (p < 0.0009) on day 1. Two patients were excluded (dropped out) after day one from each of the two study groups due to excessive vomiting subsequent to cisplatinum therapy. From days 2 to 6, there was a trend in favour of ondansetron. Both treatments were well tolerated. The results of this trial show that in the prophylaxis of nausea and vomiting induced by cisplatinum containing chemotherapy, the efficacy of ondansetron is superior to that of a standard anti-emetic combination, metoclopramide with dexamethasone.

Matched MeSH terms: Drug Therapy, Combination

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