Publications by authors named "Noor Rain Abdullah"

26 Publications

  • Page 1 of 1

Bioavailability of Eurycomanone in Its Pure Form and in a Standardised Water Extract.

Pharmaceutics 2018 Jul 11;10(3). Epub 2018 Jul 11.

Herbal Medicine Research Centre, Institute for Medical Research, Jalan Pahang, Kuala Lumpur 50588, Malaysia.

is one of the commonly consumed herbal preparations and its major chemical compound, eurycomanone, has been described to have antimalarial, antipyretic, aphrodisiac, and cytotoxic activities. Today, the consumption of is popular through the incorporation of its extract in food items, most frequently in drinks such as tea and coffee. In the current study, the characterisation of the physicochemical and pharmacokinetic (PK) attributes of eurycomanone were conducted via a series of in vitro and in vivo studies in rats and mice. The solubility and chemical stability of eurycomanone under the conditions of the gastrointestinal tract environment were determined. The permeability of eurycomanone was investigated by determining its distribution coefficient in aqueous and organic environments and its permeability using the parallel artificial membrane permeability assay system and Caco-2 cultured cells. Eurycomanone's stability in plasma and its protein-binding ability were measured by using an equilibrium dialysis method. Its stability in liver microsomes across species (mice, rat, dog, monkey, and human) and rat liver hepatocytes was also investigated. Along with the PK evaluations of eurycomanone in mice and rats, the PK parameters for the Malaysian Standard (MS: 2409:201) standardised water extract of were also evaluated in rats. Both rodent models showed that eurycomanone in both the compound form and extract form had a half-life of 0.30 h. The differences in the bioavailability of eurycomanone in the compound form between the rats (11.8%) and mice (54.9%) suggests that the PK parameters cannot be directly extrapolated to humans. The results also suggest that eurycomanone is not readily absorbed across biological membranes. However, once absorbed, the compound is not easily metabolised (is stable), hence retaining its bioactive properties, which may be responsible for the various reported biological activities.
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http://dx.doi.org/10.3390/pharmaceutics10030090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161288PMC
July 2018

Prevalence of Plasmodium falciparum Molecular Markers of Antimalarial Drug Resistance in a Residual Malaria Focus Area in Sabah, Malaysia.

PLoS One 2016 27;11(10):e0165515. Epub 2016 Oct 27.

Herbal Medicine Research Center, Institute for Medical Research, Kuala Lumpur, Malaysia.

Chloroquine (CQ) and fansidar (sulphadoxine-pyrimethamine, SP) were widely used for treatment of Plasmodium falciparum for several decades in Malaysia prior to the introduction of Artemisinin-based Combination Therapy (ACT) in 2008. Our previous study in Kalabakan, located in south-east coast of Sabah showed a high prevalence of resistance to CQ and SP, suggesting the use of the treatment may no longer be effective in the area. This study aimed to provide a baseline data of antimalarial drug resistant markers on P. falciparum isolates in Kota Marudu located in the north-east coast of Sabah. Mutations on genes associated with CQ (pfcrt and pfmdr1) and SP (pfdhps and pfdhfr) were assessed by PCR amplification and restriction fragment length polymorphism. Mutations on the kelch13 marker (K13) associated with artemisinin resistance were determined by DNA sequencing technique. The assessment of pfmdr1 copy number variation associated with mefloquine resistant was done by real-time PCR technique. A low prevalence (6.9%) was indicated for both pfcrt K76T and pfmdr1 N86Y mutations. All P. falciparum isolates harboured the pfdhps A437G mutation. Prevalence of pfdhfr gene mutations, S108N and I164L, were 100% and 10.3%, respectively. Combining the different resistant markers, only two isolates were conferred to have CQ and SP treatment failure markers as they contained mutant alleles of pfcrt and pfmdr1 together with quintuple pfdhps/pfdhfr mutation (combination of pfdhps A437G+A581G and pfdhfr C59R+S108N+I164L). All P. falciparum isolates carried single copy number of pfmdr1 and wild type K13 marker. This study has demonstrated a low prevalence of CQ and SP resistance alleles in the study area. Continuous monitoring of antimalarial drug efficacy is warranted and the findings provide information for policy makers in ensuring a proper malaria control.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165515PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082862PMC
June 2017

Genetic Diversity of Plasmodium falciparum Populations in Malaria Declining Areas of Sabah, East Malaysia.

PLoS One 2016 29;11(3):e0152415. Epub 2016 Mar 29.

Herbal Medicine Research Center, Institute for Medical Research, Kuala Lumpur, Malaysia.

Malaysia has a national goal to eliminate malaria by 2020. Understanding the genetic diversity of malaria parasites in residual transmission foci can provide invaluable information which may inform the intervention strategies used to reach elimination targets. This study was conducted to determine the genetic diversity level of P. falciparum isolates in malaria residual foci areas of Sabah. Malaria active case detection was conducted in Kalabakan and Kota Marudu. All individuals in the study sites were screened for malaria infection by rapid diagnostic test. Blood from P. falciparum-infected individuals were collected on filter paper prior to DNA extraction. Genotyping was performed using merozoite surface protein-1 (MSP-1), merozoite surface protein-2 (MSP-2), glutamate rich protein (GLURP) and 10 neutral microsatellite loci markers. The size of alleles, multiplicity of infection (MOI), mean number of alleles (Na), expected heterozygosity (He), linkage disequilibrium (LD) and genetic differentiation (FST) were determined. In Kalabakan, the MSP-1 and MSP-2 alleles were predominantly K1 and FC27 family types, respectively. The GLURP genotype VI (751-800 bp) was predominant. The MOI for MSP-1 and MSP-2 were 1.65 and 1.20, respectively. The Na per microsatellite locus was 1.70. The He values for MSP-1, MSP-2, GLURP and neutral microsatellites were 0.17, 0.37, 0.70 and 0.33, respectively. In Kota Marudu, the MSP-1 and MSP-2 alleles were predominantly MAD20 and 3D7 family types, respectively. The GLURP genotype IV (651-700 bp) was predominant. The MOI for both MSP-1 and MSP-2 was 1.05. The Na per microsatellite locus was 3.60. The He values for MSP-1, MSP-2, GLURP and neutral microsatellites were 0.24, 0.25, 0.69 and 0.30, respectively. A significant LD was observed in Kalabakan (0.495, p<0.01) and Kota Marudu P. falciparum populations (0.601, p<0.01). High genetic differentiation between Kalabakan and Kota Marudu P. falciparum populations was observed (FST = 0.532). The genetic data from the present study highlighted the limited diversity and contrasting genetic pattern of P. falciparum populations in the malaria declining areas of Sabah.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152415PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811561PMC
August 2016

Mutations of pvdhfr and pvdhps genes in vivax endemic-malaria areas in Kota Marudu and Kalabakan, Sabah.

Malar J 2016 Feb 5;15:63. Epub 2016 Feb 5.

Faculty of Science and Technology, School of Bioscience and Biotechnology, Universiti Kebangsaan Malaysia, 43600, Bangi, Malaysia.

Background: Malaria cases persist in some remote areas in Sabah and Sarawak despite the ongoing and largely successful malaria control programme conducted by the Vector Borne Disease Control Programme, Ministry Of Health, Malaysia. Point mutations in the genes that encode the two enzymes involved in the folate biosynthesis pathway, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) enzymes confer resistance to pyrimethamine and sulfadoxine respectively, in both Plasmodium falciparum and P. vivax. The aim of the current study was to determine the mutation on both pvdhfr at codon 13, 33, 57, 58, 61, 117, and 173 and pvdhps genes at codon 383 and 553, which are potentially associated with resistance to pyrimethamine and sulfadoxine in P. vivax samples in Sabah.

Methods: Every individual was screened for presence of malaria infection using a commercial rapid dipstick assay, ParaMax-3™ (Zephyr Biomedical, India). Individuals tested positive for P. vivax had blood collected and parasite DNA extracted. The pvdhfr and pvdhps genes were amplified by nested-PCR. Restriction fragment length polymorphism (RFLP) was carried out for detection of specific mutations in pvdhfr at codons 13Leu, 33Leu, 57Ile/Leu, 58Arg, 61Met, 117Asn/Thr, and 173Leu and pvdhps at codons 383Gly and 553Gly. The PCR-RFLP products were analysed using the Agilent 2100 Bioanalyzer (Agilent Technology, AS).

Results: A total of 619 and 2119 individuals from Kalabakan and Kota Marudu, respectively participated in the study. In Kalabakan and Kota Marudu, 9.37 and 2.45 % were tested positive for malaria and the positivity for P. vivax infection was 4.2 and 0.52 %, respectively. No mutation was observed at codon 13, 33 and 173 on pvdhfr and at codon 553 on pvdhps gene on samples from Kalabakan and Kota Marudu. One-hundred per cent mutations on pvdhfr were at 57Leu and 117Thr. Mutation at 58Arg and 61Met was observed to be higher in Kota Marudu 72.73 %. Mutation at 383Gly on pvdhps was highest in Kalabakan with 80.77 %. There are four distinct haplotypes of pvdhfr/pvdhps combination.

Conclusions: The presence of triple and quintuple mutation combination suggest that the P. vivax isolates exhibit a high degree of resistant to sulfadoxine, pyrimethamine and sulfadoxine-pyrimethamine combination therapy.
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http://dx.doi.org/10.1186/s12936-016-1109-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743234PMC
February 2016

Safety Evaluation of Oral Toxicity of Carica papaya Linn. Leaves: A Subchronic Toxicity Study in Sprague Dawley Rats.

Evid Based Complement Alternat Med 2014 29;2014:741470. Epub 2014 Oct 29.

Drug and Herbal Research Center, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.

The subchronic toxicity effect of the leaf extract of Carica papaya Linn. in Sprague Dawley (SD) rats was investigated in this study. The extract was prepared by dissolving the freeze dried extract of the leaves in distilled water and was administered orally to SD rats (consisted of 10 rats/sex/group) at 0 (control), 0.01, 0.14, and 2 g/kg body weight (BW) for 13 weeks. General observation, mortality, and food and water intake were monitored throughout the experimental period. Hematological and biochemical parameters, relative organ weights, and histopathological changes were evaluated. The study showed that leaf extract when administered for 13 weeks did not cause any mortality and abnormalities of behavior or changes in body weight as well as food and water intake. There were no significant differences observed in hematology parameters between treatment and control groups; however significant differences were seen in biochemistry values, for example, LDH, creatinine, total protein, and albumin. However, these changes were not associated with histopathological changes. In conclusion, the results suggested that daily oral administration of rats with C. papaya leaf extract for 13 weeks at a dose up to fourteen times the levels employed in traditional medicine practice did not cause any significant toxic effect.
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http://dx.doi.org/10.1155/2014/741470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4228719PMC
December 2014

Effect of selected local medicinal plants on the asexual blood stage of chloroquine resistant Plasmodium falciparum.

BMC Complement Altern Med 2014 Dec 15;14:492. Epub 2014 Dec 15.

Herbal Medicine Research Centre, Institute for Medical Research, Jalan Pahang, 50588 Kuala Lumpur, Malaysia.

Background: The development of resistant to current antimalarial drugs is a major challenge in achieving malaria elimination status in many countries. Therefore there is a need for new antimalarial drugs. Medicinal plants have always been the major source for the search of new antimalarial drugs. The aim of this study was to screen selected Malaysian medicinal plants for their antiplasmodial properties.

Methods: Each part of the plants were processed, defatted by hexane and sequentially extracted with dichloromethane, methanol and water. The antiplasmodial activities of 54 plant extracts from 14 species were determined by Plasmodium falciparum Histidine Rich Protein II ELISA technique. In order to determine the selectivity index (SI), all plant extracts demonstrating a good antiplasmodial activity were tested for their cytotoxicity activity against normal Madin-Darby Bovine Kidney (MDBK) cell lines by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay.

Results: Twenty three extracts derived from Curcuma zedoaria (rhizome), Curcuma aeruginosa (rhizome), Alpinia galanga (rhizome), Morinda elliptica (leaf), Curcuma mangga (rhizome), Elephantopus scaber (leaf), Vitex negundo (leaf), Brucea javanica (leaf, root and seed), Annona muricata (leaf), Cinnamomun iners (leaf) and Vernonia amygdalina (leaf) showed promising antiplasmodial activities against the blood stage chloroquine resistant P. falciparum (EC50 < 10 μg/ml) with negligible toxicity effect to MDBK cells in vitro (SI ≥10).

Conclusion: The extracts belonging to eleven plant species were able to perturb the growth of chloroquine resistant P. falciparum effectively. The findings justified the bioassay guided fractionation on these plants for the search of potent antimalarial compounds or formulation of standardized extracts which may enhance the antimalarial effect in vitro and in vivo.
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http://dx.doi.org/10.1186/1472-6882-14-492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300612PMC
December 2014

Effect of choline kinase inhibitor hexadecyltrimethylammonium bromide on Plasmodium falciparum gene expression.

Southeast Asian J Trop Med Public Health 2014 Mar;45(2):259-66

Investigations on the fundamental of malaria parasite biology, such as invasion, growth cycle, metabolism and cell signalling have uncovered a number of potential antimalarial drug targets, including choline kinase, a key enzyme involved in the synthesis of phosphatidylcholine, an important component in parasite membrane compartment. The effect on gene expression of Plasmodium falciparum K1 strain following 72 hours exposure to 2 microM (IC50 concentration) of the choline kinase inhibitor, hexadecyltrimethylammonium bromide (HDTAB) was evaluated by DNA microarray analysis. Genes important in P. falciparum intraerythrocytic life cycle, such as invasion, cytoadherance and growth were among those affected by at least 2-fold changes in their expression levels compared with non HDTAB-treated control.
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March 2014

In vitro and in vivo antimalarial evaluations of myrtle extract, a plant traditionally used for treatment of parasitic disorders.

Biomed Res Int 2013 23;2013:316185. Epub 2013 Dec 23.

Traditional Medicine and Materia Medica Research Center (TMRC), Shahid Beheshti University of Medical Sciences, P.O. Box 14155-6354, Tehran 1516745811, Iran ; School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran ; School of Traditional Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Based on the collected ethnobotanical data from the Traditional Medicine and Materia Medica Research Center (TMRC), Iran, Myrtus communis L. (myrtle) was selected for the assessment of in vitro and in vivo antimalarial and cytotoxic activities. Methanolic extract of myrtle was prepared from the aerial parts and assessed for antiplasmodial activity, using the parasite lactate dehydrogenase (pLDH) assay against chloroquine-resistant (K1) and chloroquine-sensitive (3D7) strains of Plasmodium falciparum. The 4-day suppressive test was employed to determine the parasitemia suppression of the myrtle extract against P. berghei in vivo. The IC50 values of myrtle extract were 35.44 µg/ml against K1 and 0.87 µg/ml against 3D7. Myrtle extract showed a significant suppression of parasitaemia (84.8 ± 1.1% at 10 mg/kg/day) in mice infected with P. berghei after 4 days of treatment. Cytotoxic activity was carried out against mammalian cell lines using methyl thiazol tetrazolium (MTT) assay. No cytotoxic effect on mammalian cell lines up to 100 µg/mL was shown. The results support the traditional use of myrtle in malaria. Phytochemical investigation and understanding the mechanism of action would be in our upcoming project.
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http://dx.doi.org/10.1155/2013/316185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885200PMC
July 2014

Plasmodium vivax population structure and transmission dynamics in Sabah Malaysia.

PLoS One 2013 17;8(12):e82553. Epub 2013 Dec 17.

Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia.

Despite significant progress in the control of malaria in Malaysia, the complex transmission dynamics of P. vivax continue to challenge national efforts to achieve elimination. To assess the impact of ongoing interventions on P. vivax transmission dynamics in Sabah, we genotyped 9 short tandem repeat markers in a total of 97 isolates (8 recurrences) from across Sabah, with a focus on two districts, Kota Marudu (KM, n = 24) and Kota Kinabalu (KK, n = 21), over a 2 year period. STRUCTURE analysis on the Sabah-wide dataset demonstrated multiple sub-populations. Significant differentiation (F ST  = 0.243) was observed between KM and KK, located just 130 Km apart. Consistent with low endemic transmission, infection complexity was modest in both KM (mean MOI  = 1.38) and KK (mean MOI  = 1.19). However, population diversity remained moderate (H E  = 0.583 in KM and H E  = 0.667 in KK). Temporal trends revealed clonal expansions reflecting epidemic transmission dynamics. The haplotypes of these isolates declined in frequency over time, but persisted at low frequency throughout the study duration. A diverse array of low frequency isolates were detected in both KM and KK, some likely reflecting remnants of previous expansions. In accordance with clonal expansions, high levels of Linkage Disequilibrium (I A (S) >0.5 [P<0.0001] in KK and KM) declined sharply when identical haplotypes were represented once (I A (S)  = 0.07 [P = 0.0076] in KM, and I A (S) = -0.003 [P = 0.606] in KK). All 8 recurrences, likely to be relapses, were homologous to the prior infection. These recurrences may promote the persistence of parasite lineages, sustaining local diversity. In summary, Sabah's shrinking P. vivax population appears to have rendered this low endemic setting vulnerable to epidemic expansions. Migration may play an important role in the introduction of new parasite strains leading to epidemic expansions, with important implications for malaria elimination.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0082553PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866266PMC
October 2014

High prevalence of mutation in the Plasmodium falciparum dhfr and dhps genes in field isolates from Sabah, Northern Borneo.

Malar J 2013 Jun 12;12:198. Epub 2013 Jun 12.

Background: Sulphadoxine-pyrimethamine (SP) has been in use for the treatment of uncomplicated falciparum malaria in Malaysia since the 1970s and is still widely employed in spite of widespread clinical resistance. Resistance to SP is known to be mediated by mutations in the pfdhfr and pfdhps genes. The aim of the present study was to investigate the distribution of pfdhfr and pfdhps gene polymorphism in Plasmodium falciparum field isolates from Kalabakan, Sabah, in northern Borneo.

Methods: A total number of 619 individuals were screened from 23 study sites of which 31 were positive for P. falciparum. Analysis of restriction fragment length polymorphisms (RFLP) was used to identify polymorphism in the pfdhfr and pfdhps genes at positions 16, 51, 59, 108, 164 and 437, 540, 581, respectively.

Results: All samples had at least one mutation in each of the genes associated with drug resistance. The prevalence of pfdhfr 59arg, 164leu and 108asn were 100%, 80.65% and 58.06%, respectively. Pfdhps mutants 437gly and 581gly accounted for 100% and 74.19% respectively. In pfdhfr, the most common mutant genotypes were combination 59arg + 164leu (22.58%) and 59arg + 108asn + 164leu (51.61%). In pfdhps the most common genotype was 437gly + 581gly (74.19%). One individual (3.22%) harboured parasites with four pfdhfr (16 val + 59arg + 108asn + 164leu) and two pfdhps (437gly + 581gly) mutations. The highest quintuple pfdhfr/pfdhps (41.94%) was three pfdhfr (59arg + 108asn + 164gly) and two pfdhps (437gly + 581gly).

Conclusion: The data suggest a high prevalence of genetic variations conferring resistance to SP which can predict treatment failure before becoming clinically evident. In areas like this, the use of SP may no longer be indicated.
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http://dx.doi.org/10.1186/1475-2875-12-198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706343PMC
June 2013

Linkage disequilibrium between polymorphisms of ABCB1 and ABCC2 to predict the treatment outcome of Malaysians with complex partial seizures on treatment with carbamazepine mono-therapy at the Kuala Lumpur Hospital.

PLoS One 2013 23;8(5):e64827. Epub 2013 May 23.

Bioassay Unit, Herbal Medicine Research Center, Institute for Medical Research, Kuala Lumpur, Malaysia.

Purpose: Carbamazepine (CBZ) is used as the first line of treatment of Complex Partial Seizures (CPS) in the Epilepsy Clinic, Neurology Department of Kuala Lumpur Hospital (KLH). More than 30% of the patients remain drug resistant to CBZ mono-therapy. CBZ is transported by the P-glycoprotein (P-gp). The P-gp encoded by the ABCB1 and ABCC2 genes are expressed in drug resistant patients with epilepsy. A few studies have shown significant association between CBZ resistant epilepsy and Linkage Disequilibrium (LD) with adjacent polymorphisms of these genes. Our study is aimed at determining the correlation between patients' response to CBZ mono-therapy to Single Nucleotide Polymorphisms G2677T and C3435T of the ABCB1 gene as well as G1249A and -24C>T of the ABCC2 gene.

Method: 314 patients with CPS were recruited from the Neurology Department of the KLH based on stringent inclusion and exclusion criteria, of whom 152 were responders and the other 162 were non-responders. DNA was extracted from their blood samples and Taqman technology for allelic discrimination was performed. Results were described as genotype frequencies. The SHEsis analysis platform was used to calculate linkage disequilibrium index and infer haplotype frequencies. Haploview was used to do permutation test to obtain a corrected p-value.

Results: Resistance to treatment with CBZ mono-therapy was significantly associated with the 2677TT and the 3435TT genotypes while it was not significantly associated with the G1249A and -24C>T polymorphisms. The GCGC haplotype combination of the 2677G>T, 3435C>T, 1249G>A and -24C>T respectively was found to be extremely significant (p = 1.10e-20) with good drug response to CBZ mono-therapy.

Conclusion: Linkage disequilibrium between the 2677G>T, 3435C>T, 1249G>A and -24C>T SNPs may be used as a reliable screening marker to determine the treatment outcome of CBZ mono-therapy with CPS irrespective of race or gender.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064827PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662793PMC
January 2014

Carica papaya Leaves Juice Significantly Accelerates the Rate of Increase in Platelet Count among Patients with Dengue Fever and Dengue Haemorrhagic Fever.

Evid Based Complement Alternat Med 2013 11;2013:616737. Epub 2013 Apr 11.

Bioassay Unit, Herbal Medicine Research Center, Institute for Medical Research, Jalan Pahang, 50588 Kuala Lumpur, Malaysia.

The study was conducted to investigate the platelet increasing property of Carica papaya leaves juice (CPLJ) in patients with dengue fever (DF). An open labeled randomized controlled trial was carried out on 228 patients with DF and dengue haemorrhagic fever (DHF). Approximately half the patients received the juice, for 3 consecutive days while the others remained as controls and received the standard management. Their full blood count was monitored 8 hours for 48 hours. Gene expression studies were conducted on the ALOX 12 and PTAFR genes. The mean increase in platelet counts were compared in both groups using repeated measure ANCOVA. There was a significant increase in mean platelet count observed in the intervention group (P < 0.001) but not in the control group 40 hours since the first dose of CPLJ. Comparison of mean platelet count between intervention and control group showed that mean platelet count in intervention group was significantly higher than control group after 40 and 48 hours of admission (P < 0.01). The ALOX 12 (FC  =  15.00) and PTAFR (FC  =  13.42) genes were highly expressed among those on the juice. It was concluded that CPLJ does significantly increase the platelet count in patients with DF and DHF.
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http://dx.doi.org/10.1155/2013/616737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638585PMC
May 2013

Repeated dose 28-days oral toxicity study of Carica papaya L. leaf extract in Sprague Dawley rats.

Molecules 2012 Apr 10;17(4):4326-42. Epub 2012 Apr 10.

Herbal Medicine Research Center, Institute for Medical Research, Jalan Pahang 50588, Kuala Lumpur, Malaysia.

Carica papaya L. leaves have been used in ethnomedicine for the treatment of fevers and cancers. Despite its benefits, very few studies on their potential toxicity have been described. The aim of the present study was to characterize the chemical composition of the leaf extract from 'Sekaki' C. papaya cultivar by UPLC-TripleTOF-ESI-MS and to investigate the sub-acute oral toxicity in Sprague Dawley rats at doses of 0.01, 0.14 and 2 g/kg by examining the general behavior, clinical signs, hematological parameters, serum biochemistry and histopathology changes. A total of twelve compounds consisting of one piperidine alkaloid, two organic acids, six malic acid derivatives, and four flavonol glycosides were characterized or tentatively identified in the C. papaya leaf extract. In the sub-acute study, the C. papaya extract did not cause mortality nor were treatment-related changes in body weight, food intake, water level, and hematological parameters observed between treatment and control groups. Some biochemical parameters such as the total protein, HDL-cholesterol, AST, ALT and ALP were elevated in a non-dose dependent manner. Histopathological examination of all organs including liver did not reveal morphological alteration. Other parameters showed non-significant differences between treatment and control groups. The present results suggest that C. papaya leaf extract at a dose up to fourteen times the levels employed in practical use in traditional medicine in Malaysia could be considered safe as a medicinal agent.
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http://dx.doi.org/10.3390/molecules17044326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6268730PMC
April 2012

High prevalence of pfcrt K76t mutants among Plasmodium falciparum isolates from Sabah, Malaysia.

Southeast Asian J Trop Med Public Health 2011 Nov;42(6):1322-6

Herbal Medicine Research Center, Institute for Medical Research, Kuala Lumpur, Malaysia.

Chloroquine (CQ) remains the first line drug for the prevention and treatment of malaria in Malaysia in spite of the fact that resistance to CQ has been observed in Malaysia since the 1960s. CQ-resistance is associated with various mutations in pfcrt, which encodes a putative transporter located in the digestive vacuolar membrane of P. falciparum. Substitution of lysine (K) to threonine (T) at amino acid 76 (K76T) in pfcrt is the primary genetic marker conferring resistance to CQ. To determine the presence of T76 mutation in pfcrt from selected areas of Kalabakan, Malaysia 619 blood samples were screened for P. falciparum, out of which 31 were positive. Blood samples were collected on 3 MM Whatman filter papers and DNA was extracted using QIAmp DNA mini kit. RFLP-PCR for the detection of the CQ-resistant T76 and sensitive K76 genotype was carried out. Twenty-five samples were shown to have the point mutation in pfcrt whereas the remaining samples were classified as CQ-sensitive (wild-type). In view of the fact that CQ is the first line anti-malarial drug in Malaysia, this finding could be an important indication that treatment with CQ may no longer be effective in the future.
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November 2011

Antiproliferative and phytochemical analyses of leaf extracts of ten Apocynaceae species.

Pharmacognosy Res 2011 Apr;3(2):100-6

School of Science, Monash University Sunway Campus, 46150 Petaling Jaya, Selangor, Malaysia.

Background: The anticancer properties of Apocynaceae species are well known in barks and roots but less so in leaves.

Materials And Methods: In this study, leaf extracts of 10 Apocynaceae species were assessed for antiproliferative (APF) activities using the sulforhodamine B assay. Their extracts were also analyzed for total alkaloid content (TAC), total phenolic content (TPC), and radical scavenging activity (RSA) using the Dragendorff precipitation, Folin-Ciocalteu, and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays, respectively.

Results: Leaf extracts of Alstonia angustiloba, Calotropis gigantea, Catharanthus roseus, Nerium oleander, Plumeria obtusa, and Vallaris glabra displayed positive APF activities. Extracts of Allamanda cathartica, Cerbera odollam, Dyera costulata, and Kopsia fruticosa did not show any APF activity. Dichloromethane (DCM) extract of C. gigantea, and DCM and DCM:MeOH extracts of V. glabra showed strong APF activities against all six human cancer cell lines. Against breast cancer cells of MCF-7 and MDA-MB-231, DCM extracts of C. gigantea and N. oleander were stronger than or comparable to standard drugs of xanthorrhizol, curcumin, and tamoxifen. All four extracts of N. oleander were effective against MCF-7 cells. Extracts of Kopsia fruticosa had the highest TAC while those of Dyera costulata had the highest TPC and RSA. Extracts of C. gigantea and V. glabra inhibited the growth of all six cancer cell lines while all extracts of N. oleander were effective against MCF-7 cells.

Conclusion: Extracts of C. gigantea, V. glabra, and N. oleander therefore showed great promise as potential candidates for anticancer drugs. The wide-spectrum APF activities of these three species are reported for the first time and their bioactive compounds warrant further investigation.
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http://dx.doi.org/10.4103/0974-8490.81957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3129018PMC
April 2011

Assessment of antiproliferative and antiplasmodial activities of five selected Apocynaceae species.

BMC Complement Altern Med 2011 Jan 14;11. Epub 2011 Jan 14.

School of Science, Monash University Sunway Campus, Bandar Sunway, 46150 Petaling Jaya, Selangor, Malaysia.

Background: Studies have shown that the barks and roots of some Apocynaceae species have anticancer and antimalarial properties. In this study, leaf extracts of five selected species of Apocynaceae used in traditional medicine (Alstonia angustiloba, Calotropis gigantea, Dyera costulata, Kopsia fruticosa and Vallaris glabra) were assessed for antiproliferative (APF) and antiplasmodial (APM) activities, and analysed for total alkaloid content (TAC), total phenolic content (TPC) and radical-scavenging activity (RSA). As V. glabra leaf extracts showed wide spectrum APF and APM activities, they were further screened for saponins, tannins, cardenolides and terpenoids.

Methods: APF and APM activities were assessed using the sulphorhodamine B and lactate dehydrogenase assays, respectively. TAC, TPC and RSA were analysed using Dragendorff precipitation, Folin-Ciocalteu and DPPH assays, respectively. Screening for saponins, tannins, cardenolides and terpenoids were conducted using the frothing, ferric chloride, Kedde and vanillin-H2SO4 tests, respectively.

Results: Leaf extracts of A. angustiloba, C. gigantea and V. glabra displayed positive APF activity. Dichloromethane (DCM) extract of C. gigantea, and DCM and DCM:MeOH extracts of V. glabra showed strong APF activity against all six human cancer cell lines tested. DCM extract of A. angustiloba was effective against three cancer cell lines. Against MCF-7 and MDA-MB-231 cell lines, DCM extract of C. gigantea was stronger than standard drugs of xanthorrhizol, curcumin and tamoxifen. All five species were effective against K1 strain of Plasmodium falciparum and three species (C. gigantea, D. costulata and K. fruticosa) were effective against 3D7 strain. Against K1 strain, all four extracts of V. glabra displayed effective APM activity. Extracts of D. costulata were effective against 3D7 strain. Selectivity index values of extracts of A. angustiloba, C. gigantea and V. glabra suggested that they are potentially safe for use to treat malaria. Extracts of K. fruticosa had the highest TAC while D. costulata had the highest TPC and RSA. Phytochemical screening of extracts of V. glabra also showed the presence of terpenoids, tannins and saponins.

Conclusions: Leaf extracts of C. gigantea and V. glabra showed great promise as potential candidates for anticancer drugs as they inhibited the growth of all six cancer cell lines. Against K1 strain of P. falciparum, all four extracts of V. glabra displayed effective APM activity. The wide spectrum APF and APM activities of V. glabra are reported for the first time and this warrants further investigation into its bioactive compounds.
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http://dx.doi.org/10.1186/1472-6882-11-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032759PMC
January 2011

Eurycomanone induce apoptosis in HepG2 cells via up-regulation of p53.

Cancer Cell Int 2009 Jun 10;9:16. Epub 2009 Jun 10.

Institute of Biosciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia.

Background: Eurycomanone is a cytotoxic compound found in Eurycoma longifolia Jack. Previous studies had noted the cytotoxic effect against various cancer cell lines. The aim of this study is to investigate the cytotoxicity against human hepato carcinoma cell in vitro and the mode of action. The cytotoxicity of eurycomanone was evaluated using MTT assay and the mode of cell death was detected by Hoechst 33258 nuclear staining and flow cytometry with Annexin-V/propidium iodide double staining. The protein expression Bax, Bcl-2, p53 and cytochrome C were studied by flow cytometry using a spesific antibody conjugated fluorescent dye to confirm the up-regulation of p53 and Bax in cancer cells.

Results: The findings suggested that eurycomanone was cytotoxic on cancerous liver cell, HepG2 and less toxic on normal cells Chang's liver and WLR-68. Furthermore, various methods proved that apoptosis was the mode of death in eurycomanone-treated HepG2 cells. The characteristics of apoptosis including chromatin condensation, DNA fragmentation and apoptotic bodies were found following eurycomanone treatment. This study also found that apoptotic process triggered by eurycomanone involved the up-regulation of p53 tumor suppressor protein. The up-regulation of p53 was followed by the increasing of pro-apoptotic Bax and decreasing of anti-apoptotic Bcl-2. The increased of cytochrome C levels in cytosol also results in induction of apoptosis.

Conclusion: The data suggest that eurycomanone was cytotoxic on HepG2 cells by inducing apoptosis through the up-regulation of p53 and Bax, and down-regulation of Bcl-2.
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http://dx.doi.org/10.1186/1475-2867-9-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700790PMC
June 2009

Antiproliferative property and apoptotic effect of xanthorrhizol on MDA-MB-231 breast cancer cells.

Anticancer Res 2008 Nov-Dec;28(6A):3677-89

Bioassay Unit, Herbal Medicine Research Center, Institute for Medical Research, Jalan Pahang, Kuala Lumpur, Malaysia.

Xanthorrhizol is a natural sesquiterpenoid compound isolated from the rhizome of Curcuma xanthorrhizza Roxb (Zingerberaceae). Recent studies of xanthorrhizol in cell cultures strongly support the role of xanthorrhizol as an antiproliferative agent. In our study, we tested the antiproliferative effect of xanthorrhizol using different breast cancer cell lines. The invasive breast cancer cell line, MDA-MB-231, was then selected for further investigations. Treatment with xanthorrhizol caused 50% growth inhibition on MDA-MB-231 cells at 8.67 +/- 0.79 microg/ml as determined by sulforhodamine B (SRB) assay. Hoechst 33258 nuclear staining assay showed the rate of apoptosis of MDA-MB-231 cells to increase in response to xanthorrhizol treatment. Immunofluorescence staining using antibody MitoCapture and fluorescein isothiocyanate (FITC)-labeled cytochrome c revealed the possibility of altered mitochondrial transmembrane potential and the release of cytochrome c respectively. This was further confirmed by Western-blotting, where cytochrome c was showed to migrate from mitochondrial fraction to the cytosol fraction of treated MDA-MB-231 cells. Caspase activity assay showed the involvement of caspase-3 and caspase-9, but not caspase-6 or caspase-8 in MDA-MB-231 apoptotic cell death. Subsequently, cleavage of PARP-1 protein is suggested. These data suggest treatment with xanthorrhizol modulates MDA-MB-231 cell apoptosis through the mitochondria-mediated pathway subsequent to the disruption of mitochondrial transmembrane potential, release of cytochrome c, activation of caspase-3 and caspase-9, and the modulation of PARP-1 protein.
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March 2009

Combined xanthorrhizol-curcumin exhibits synergistic growth inhibitory activity via apoptosis induction in human breast cancer cells MDA-MB-231.

Cancer Cell Int 2009 Jan 2;9. Epub 2009 Jan 2.

Bioassay Unit, Herbal Medicine Research Center, Institute for Medical Research, Jalan Pahang, Kuala Lumpur, Malaysia.

Background: It has been suggested that combined effect of natural products may improve the treatment effectiveness in combating proliferation of cancer cells. The present study was undertaken to evaluate the possibility that the combination of xanthorrhizol and curcumin might show synergistic growth inhibitory effect towards MDA-MB-231 human breast cancer cells via apoptosis induction. The effective dose that produced 50% growth inhibition (GI50) was calculated from the log dose-response curve of fixed-combinations of xanthorrhizol and curcumin generated from the sulforhodamine B (SRB) assay. The experimental GI50 value was used to determine the synergistic activity of the combination treatment by isobolographic analysis and combination-index method. Further investigation of mode of cell death induced by the combination treatment was conducted in the present study.

Results: Isobole analysis revealed that substances interaction was synergistic when xanthorrhizol and curcumin were added concurrently to the cultures but merely additive when they were added sequentially. The synergistic combination treatment was then applied to the cultures to investigate the mode of cell death induced by the treatment. Immunofluorescence staining using antibody MitoCapturetrade mark revealed the possibility of altered mitochondrial transmembrane potential, which is one of the hallmark of apoptosis. Hoechst 33258 nuclear staining assay showed the rate of apoptosis of MDA-MB-231 cells to increase in response to the treatment. Apoptotic cell death was further confirmed by DNA fragmentation assay, where internucleosomal excision of DNA was induced upon treatment with xanthorrhizol-curcumin.

Conclusion: This is the first time the combined cytotoxic effect of xanthorrhizol and curcumin on MDA-MB-231 cells has been documented and our findings provide experimental support to the hypothesis that combined xanthorrhizol-curcumin showed synergistic growth inhibitory activity on MDA-MB-231 cells via apoptosis induction.
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http://dx.doi.org/10.1186/1475-2867-9-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2630298PMC
January 2009

Screening of antiplasmodial properties among some traditionally used Iranian plants.

J Ethnopharmacol 2009 Jan 20;121(3):400-4. Epub 2008 Nov 20.

School of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran, Iran.

Ethnopharmacological Relevance: An investigation of plants was undertaken through interviews and literature surveys on plants used to treat malaria or cancer or microbial diseases in Iran.

Aim Of Study: In vitro and in vivo antiplasmodial tests were carried out on selected plants traditionally used in Iran.

Materials And Methods: Thirty-two plants were extracted with methanol and tested for their in vitro (pLDH assay) activity against Plasmodium falciparum, in vivo activity against Plasmodium berghei and assessed for any cytotoxicity against the human cancer cell line MCF7 and the normal cell MDBK.

Results: Extracts from four plants, Buxus hyrcana Pojark. (Buxaceae), Erodium oxyrrhnchum M. Bieb. (Geraniaceae), Glycyrrhiza glabra L. (Fabaceae) and Ferula oopoda (Boiss and Bushe) Boiss. (Apiaceae) were found to have significant antiplasmodial activity (IC50 ranging from 4.7 to 26.6 microg/ml). These findings lend support to the use of Buxus hyrcana and Glycyrrhiza glabra in traditional medicine. The chloroformic fraction also was active against K1 and 3D7 strains. The chloroformic fraction was studied at 10 mg per kg body weight mouse per day. This fraction reduced parasitaemia by 86.1% compared to untreated control mice.

Conclusion: Glycyrrhiza glabra showed antiplasmodial activity and has selectivity for Plasmodium falciparum and Plasmodium berghei when tested on mammalian cells. This is the first report that mentioned in vitro and in vivo antiplasmodial activity of Glycyrrhiza glabra.
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http://dx.doi.org/10.1016/j.jep.2008.10.041DOI Listing
January 2009

Acute toxicity of Orthosiphon stamineus Benth standardized extract in Sprague Dawley rats.

Phytomedicine 2009 Mar 10;16(2-3):222-6. Epub 2007 May 10.

Herbal Medicine Research Center, Institute for Medical Research, Jalan Pahang 50588, Kuala Lumpur, Malaysia.

The acute toxicity of standardized extract of Orthosiphon stamineus was studied in Sprague Dawley rats. The rats were administered a single dose of 5000 mg/kg body weight (BW) orally on Day 0 and observed for 14 days. There were no deaths recorded and the animals did not show signs of toxicity during the experimental period. The effect of the extract on general behavior, BW, food and water intake, relative organ weight per 100 g BW, hematology and clinical biochemistry were measured. All the parameters measured were unaffected as compared to the control. The acute toxicity LD(50) was estimated to be > 5000 mg/kg BW.
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http://dx.doi.org/10.1016/j.phymed.2007.04.013DOI Listing
March 2009

Xanthorrhizol exhibits antiproliferative activity on MCF-7 breast cancer cells via apoptosis induction.

Anticancer Res 2006 Nov-Dec;26(6B):4527-34

Bioassay Unit, Herbal Medicine Research Center, Institute for Medical Research, 50588 Jalan Pahang, Kuala Lumpur, Malaysia.

Xanthorrhizol is a natural sesquiterpenoid compound isolated from the rhizome of Curcuma xanthorrhiza Roxb (Zingiberaceae). Xanthorrhizol was tested for a variety of important pharmacological activities including antioxidant and anti-inflammatory activities. An antiproliferation assay using the MTT method indicated that xanthorrhizol inhibited the proliferation of the human breast cancer cell line, MCF-7, with an EC50 value of 1.71 microg/ml. Three parameters including annexin-V binding assay, Hoechst 33258 staining and accumulation of sub-G1 population in DNA histogram confirmed the apoptosis induction in response to xanthorrhizol treatment. Western-blotting revealed down-regulation of the anti-apoptotic bcl-2 protein expression. However, xanthorrhizol did not affect the expression of the pro-apoptotic protein, bax, at a concentration of 1 microg/ml, 2.5 microg/ml and 5 microg/ml. The level of p53 was greatly increased, whilst PARP-1 was cleaved to 85 kDa subunits, following the treatment with xanthorrhizol at a dose-dependent manner. These results, thereby, suggest that xanthorrhizol has antiproliferative effects on MCF-7 cells by inducing apoptosis through the modulation of bcl-2, p53 and PARP-1 protein levels.
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January 2007

New alkaloids from Phoebe grandis (Nees) Merr.

Nat Prod Res 2006 May;20(6):567-72

Chemistry Department, University Malaya, 50603 Kuala Lumpur, Malaysia.

The alkaloidal extract of the leaves of Phoebe grandis (nees) merr. have provided two new minor alkaloids; phoebegrandine D (1), a proaporphine-tryptamine dimer, and phoebegrandine E (2), an indoloquinolizidine. This is the first report on the occurrence of an indoloquinolizidine in the Phoebe species. The crude extract also exhibited antiplasmodial activity (IC50<8 microg mL-1). The structures of the novel compounds were elucidated by spectroscopic methods, notably 2D NMR and HRMS.
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http://dx.doi.org/10.1080/14786410500183944DOI Listing
May 2006

Biological and molecular docking studies on coagulin-H: Human IL-2 novel natural inhibitor.

Mol Immunol 2006 Apr 10;43(11):1855-63. Epub 2006 Jan 10.

Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical Sciences, University of Karachi, Karachi 75270, Pakistan.

Withanolide, coagulin-H (1), was evaluated for its effect on various cellular functions related to immune response including lymphocyte proliferation, and expression of interleukin-2 (IL-2) cytokine, and results were compared with prednisolone (2), a commonly used immune modulating drug. Coagulin-H (1) was found to have a powerful inhibitory effect on lymphocyte proliferation and Th-1 cytokine production. Inhibition of the phytohaemagglutinin (PHA)-activated T-cell proliferation by coagulin-H (1) was observed in a concentration dependent manner. A complete suppression of PHA-activated T-cell was observed at > or =2.5 microg/mL concentrations of compound (1) and this suppression activity was similar to that of prednisolone (2). Coagulin-H (1) also significantly inhibited IL-2 production by 80%. The interactions of coagulin-H (1) (a natural inhibitor) and prednisolone (2) (a drug) to IL-2 were also investigated in order to understand the differences in their effects on T-cell responses. This paper also describes the results of molecular docking study on IL-2 inhibition. Docking studies predicted that coagulin-H (1) binds to receptor binding site of IL-2 more effectively than prednisolone (2). Based on the computational and the experimental results, coagulin-H (1) was identified as a potential immunosuppressive candidate.
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http://dx.doi.org/10.1016/j.molimm.2005.10.020DOI Listing
April 2006

Semisynthetic 15-O-acyl- and 1,15-di-O-acyleurycomanones from Eurycoma longifolia as potential antimalarials.

Planta Med 2005 Oct;71(10):967-9

School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia.

Among the quassinoids isolated from Eurycoma longifolia Jack, eurycomanone was identified as the most potent and toxic inhibitor of the chloroquine-resistant Gombak A isolate of Plasmodium falciparum. Several diacylated derivatives of eurycomanone, 1,15-di-O-isovaleryleurycomanone, 1,15-di-O-(3,3-dimethylacryloyl)- eurycomanone and 1,15-di-O-benzoyleurycomanone were synthesized by direct acylation with the respective acid chlorides. The monoacylated 15-O-isovaleryleurycomanone was synthesized by selective protection of the other hydroxy groups of eurycomanone with trimethylsilyl trifluoromethanesulphonate to enable the exclusive acylation of its C-15 hydroxy group. This was followed by the removal of the protecting groups with citric acid. The diacylated eurycomanones exhibited lower antiplasmodial activity against the Gombak A isolates and lower toxicity in the brine shrimp assay when compared to eurycomanone. In contrast, the monoacylated derivative displayed comparable antiplasmodial potency to eurycomanone, but its toxicity was reduced. Thus, preliminary studies of the synthesized acylated eurycomanones have shown that acylation only at the C-15 hydroxy group may be worthy of further antimalarial investigation.
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http://dx.doi.org/10.1055/s-2005-864188DOI Listing
October 2005

Antiplasmodial studies of Eurycoma longifolia Jack using the lactate dehydrogenase assay of Plasmodium falciparum.

J Ethnopharmacol 2004 Jun;92(2-3):223-7

School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia.

The roots of Eurycoma longifolia Jack have been used as traditional medicine to treat malaria. A systematic bioactivity-guided fractionation of this plant was conducted involving the determination of the effect of its various extracts and their chemical constituents on the lactate dehydrogenase activity of in vitro chloroquine-resistant Gombak A isolate and chloroquine-sensitive D10 strain of Plasmodium falciparum parasites. Their antiplasmodial activity was also compared with their known in vitro cytotoxicity against KB cells. Four quassinoids, eurycomanone (1), 13,21-dihydroeurycomanone (3), 13 alpha(21)-epoxyeurycomanone (4), eurycomalactone (6) and an alkaloid, 9-methoxycanthin-6-one (7), displayed higher antiplasmodial activity against Gombak A isolate but were less active against the D10 strain when compared with chloroquine. Amongst the compounds tested, 1 and 3 showed higher selectivity indices obtained for the cytotoxicity to antiplasmodial activity ratio than 14,15 beta-dihydroxyklaineanone (2), eurycomanol (5), 6 and 7.
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http://dx.doi.org/10.1016/j.jep.2004.02.025DOI Listing
June 2004