Displaying publications 61 - 80 of 86 in total

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  1. Differential effects of ketoconazole and primaquine on the pharmacokinetics and tissue distribution of imatinib in mice
    Soo GW, Law JH, Kan E, Tan SY, Lim WY, Chay G, et al.
    Anticancer Drugs, 2010 Aug;21(7):695-703.
    PMID: 20629201
    Imatinib, a selective inhibitor of c-KIT and Bcr-Abl tyrosine kinases, approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors, shows further therapeutic potential for gliomas, glioblastoma, renal cell carcinoma, autoimmune nephritis and other neoplasms. It is metabolized by CYP3A4, is highly bound to alpha-1-acid glycoprotein and is a P-glycoprotein substrate limiting its brain distribution. We assess imatinib's protein binding interaction with primaquine, which also binds to alpha-1-acid glycoprotein, and its metabolic interaction with ketoconazole, which is a CYP3A4 inhibitor, on its pharmacokinetics and biodistribution. Male ICR mice, 9-12 weeks old were given imatinib PO (50 mg/kg) alone or co-administered with primaquine (12.5 mg/kg), ketoconazole (50 mg/kg) or both, and imatinib concentration in the plasma, kidney, liver and brain was measured at prescheduled time points by HPLC. Noncompartmental pharmacokinetic parameters were estimated. Primaquine increased 1.6-fold plasma AUC(0)--> infinity, C(Max) decreased 24%, T(Max) halved and t(1/2) and mean residence time were longer. Ketoconazole increased plasma AUC(0)-->infinity 64% and doubled the C(Max), but this dose did not affect t(1/2) or mean residence time. When ketoconazole and primaquine were co-administered, imatinib AUC(0)-->infinity and C(Max) increased 32 and 35%, respectively. Ketoconazole did not change imatinib's distribution efficiency in the liver and kidney, primaquine increased it two-fold and it was larger when both the drugs were co-administered with imatinib. Ketoconazole did not change brain penetration but primaquine increased it approximately three-fold. Ketoconazole and primaquine affect imatinib clearance, bioavailability and distribution pattern, which could improve the treatment of renal and brain tumors, but also increase toxicity. This would warrant hepatic and renal functions monitoring.
    Matched MeSH terms: Antimalarials/pharmacology*
  2. ent-Dioncophylleine A and related dehydrogenated naphthylisoquinoline alkaloids, the first Asian dioncophyllaceae-type alkaloids, from the "new"plant species Ancistrocladus benomensis
    Bringmann G, Dreyer M, Kopff H, Rischer H, Wohlfarth M, Hadi HA, et al.
    J Nat Prod, 2005 May;68(5):686-90.
    PMID: 15921410
    Three new fully dehydrogenated naphthylisoquinoline alkaloids, the 7,1'-coupled ent-dioncophylleine A (3a), the likewise 7,1'-coupled 5'-O-demethyl-ent-dioncophylleine A (4), and the 7,8'-linked dioncophylleine D (5), have been isolated from the leaves of the recently described Malaysian highland liana Ancistrocladusbenomensis. All of them lack an oxygen function at C-6; this so-called Dioncophyllaceae-type structural subclass had previously been found only in naphthylisoquinoline alkaloids from West and Central African plants. Moreover, compounds 3a and 4 are the first fully dehydrogenated, i.e., only axially chiral, naphthylisoquinoline alkaloids of this type that are optically active; compound 5, by contrast, is fully racemic, due to its configurationally unstable biaryl axis. The structural elucidation was achieved by spectroscopic and chiroptical methods. Biological activities of these alkaloids against different protozoan parasites are described.
    Matched MeSH terms: Antimalarials/pharmacology
  3. The screening of extracts from Goniothalamus scortechinii, Aralidium pinnatifidum and Andrographis paniculata for anti-malarial activity using the lactate dehydrogenase assay
    Siti Najila MJ, Noor Rain A, Mohamad Kamel AG, Syed Zahir SI, Khozirah S, Lokman Hakim S, et al.
    J Ethnopharmacol, 2002 Oct;82(2-3):239-42.
    PMID: 12242001
    Goniothalamus scortechinii, Andrographis paniculata and Aralidium pinnatifidum were selected for the study based on their ethnomedicinal values. They were screened for anti-malarial activity towards Plasmodium falciparum in vitro using the lactate dehydrogenase (LDH) assay. The crude extract of G. scortechinii exhibited the most potent schizonticidal activity compared to the other extracts. It is effective against both the chloroquine resistant isolate, Gombak A and the sensitive strain, D10 of Plasmodium falciparum. Furthermore a better IC(50) value was obtained against the resistant strain, (9 microg/ml) compared to the sensitive strain, 40 microg/ml. When the crude extract was fractionated into 3 fractions, the chloroform fraction yielded the best activity, exhibiting equipotency against both strains of parasite used; IC(50) of 23.53 microg/ml against Gombak A and 21.06 microg/ml against D10.
    Matched MeSH terms: Antimalarials/pharmacology*
  4. Fulltext Malaria resurgence after significant reduction by mass drug administration on Ngodhe Island, Kenya
    Kagaya W, Gitaka J, Chan CW, Kongere J, Md Idris Z, Deng C, et al.
    Sci Rep, 2019 12 13;9(1):19060.
    PMID: 31836757 DOI: 10.1038/s41598-019-55437-8
    Although WHO recommends mass drug administration (MDA) for malaria elimination, further evidence is required for understanding the obstacles for the optimum implementation of MDA. Just before the long rain in 2016, two rounds of MDA with artemisinin/piperaquine (Artequick) and low-dose primaquine were conducted with a 35-day interval for the entire population of Ngodhe Island (~500 inhabitants) in Lake Victoria, Kenya, which is surrounded by areas with moderate and high transmission. With approximately 90% compliance, Plasmodium prevalence decreased from 3% to 0% by microscopy and from 10% to 2% by PCR. However, prevalence rebounded to 9% by PCR two months after conclusion of MDA. Besides the remained local transmission, parasite importation caused by human movement likely contributed to the resurgence. Analyses of 419 arrivals to Ngodhe between July 2016 and September 2017 revealed Plasmodium prevalence of 4.6% and 16.0% by microscopy and PCR, respectively. Risk factors for infection among arrivals included age (0 to 5 and 11 to 15 years), and travelers from Siaya County, located to the north of Ngodhe Island. Parasite importation caused by human movement is one of major obstacles to sustain malaria elimination, suggesting the importance of cross-regional initiatives together with local vector control.
    Matched MeSH terms: Antimalarials/pharmacology
  5. Fulltext Suppression of Plasmodium berghei parasitemia by LiCl in an animal infection model
    Nurul Aiezzah Z, Noor E, Hasidah MS
    Trop Biomed, 2010 Dec;27(3):624-31.
    PMID: 21399604 MyJurnal
    Malaria, caused by the Plasmodium parasite is still a health problem worldwide due to resistance of the pathogen to current anti-malarials. The search for new anti-malarial agents has become more crucial with the emergence of chloroquine-resistant Plasmodium falciparum strains. Protein kinases such as mitogen-activated protein kinase (MAPK), MAPK kinase, cyclin-dependent kinase (CDK) and glycogen synthase kinase- 3(GSK-3) of parasitic protozoa are potential drug targets. GSK-3 is an enzyme that plays a vital role in multiple cellular processes, and has been linked to pathogenesis of several diseases such as type II diabetes and Alzheimer's disease. In the present study, the antiplasmodial property of LiCl, a known GSK-3 inhibitor, was evaluated in vivo for its antimalarial effect against mice infected with Plasmodium berghei. Infected ICR mice were intraperitoneally administered with LiCl for four consecutive days before (prophylactic test) and after (suppressive test) inoculation of P. berghei-parasitised erythrocytes. Results from the suppressive test (post-infection LiCl treatment) showed inhibition of erythrocytic parasitemia development by 62.06%, 85.67% and 85.18% as compared to nontreated controls for the 100 mg/kg, 300 mg/kg and 600 mg/kg dosages respectively. Both 300 mg/kg and 600 mg/kg LiCl showed similar significant (P<0.05) suppressive values to that obtained with chloroquine-treated mice (86% suppression). The prophylactic test indicated a significantly (P<0.05) high protective effect on mice pre-treated with LiCl with suppression levels relatively comparable to chloroquine (84.07% and 86.26% suppression for the 300 mg/kg and 600 mg/kg LiCl dosages respectively versus 92.86% suppression by chloroquine). In both the suppressive and prophylactic tests, LiCl-treated animals survived longer than their non-treated counterparts. Mortality of the non-treated mice was 100% within 6 to 7 days of parasite inoculation whereas mice administered with LiCl survived beyond 9 days. Healthy non-infected mice administered with 600 mg/ kg LiCl for four consecutive days also showed decreased mortality compared to animals receiving lower doses of LiCl; three of the seven mice intraperitoneally injected with the former dose of LiCl did not survive more than 24 h after administration of LiCl whereas animals given the lower LiCl doses survived beyond four days of LiCl administration. To date, no direct evidence of anti-malarial activity in vivo or in vitro has been reported for LiCl. Evidence of anti-plasmodial activity of lithium in a mouse infection model is presented in this study.
    Matched MeSH terms: Antimalarials/pharmacology
  6. Fulltext Influence of the pfmdr1 Gene on In Vitro Sensitivities of Piperaquine in Thai Isolates of Plasmodium falciparum
    Mungthin M, Watanatanasup E, Sitthichot N, Suwandittakul N, Khositnithikul R, Ward SA
    Am J Trop Med Hyg, 2017 03;96(3):624-629.
    PMID: 28044042 DOI: 10.4269/ajtmh.16-0668
    Piperaquine combined with dihydroartemisinin is one of the artemisinin derivative combination therapies, which can replace artesunate-mefloquine in treating uncomplicated falciparum malaria in Thailand. The aim of this study was to determine the in vitro sensitivity of Thai Plasmodium falciparum isolates against piperaquine and the influence of the pfmdr1 gene on in vitro response. One hundred and thirty-seven standard laboratory and adapted Thai isolates of P. falciparum were assessed for in vitro piperaquine sensitivity. Polymorphisms of the pfmdr1 gene were determined by polymerase chain reaction methods. The mean and standard deviation of the piperaquine IC50 in Thai isolates of P. falciparum were 16.7 ± 6.3 nM. The parasites exhibiting chloroquine IC50 of ≥ 100 nM were significantly less sensitive to piperaquine compared with the parasite with chloroquine IC50 of < 100 nM. No significant association between the pfmdr1 copy number and piperaquine IC50 values was found. In contrast, the parasites containing the pfmdr1 86Y allele exhibited significantly reduced piperaquine sensitivity. Before nationwide implementation of dihydroartemisinin-piperaquine as the first-line treatment in Thailand, in vitro and in vivo evaluations of this combination should be performed especially in areas where parasites containing the pfmdr1 86Y allele are predominant such as the Thai-Malaysian border.
    Matched MeSH terms: Antimalarials/pharmacology
  7. Anti-malarial and cytokine-modulating effects of andrographolide in a murine model of malarial infection
    Hassan WRM, Basir R, Ali AH, Embi N, Sidek HM
    Trop Biomed, 2019 Sep 01;36(3):776-791.
    PMID: 33597499
    Malarial pathogenesis involves among others, uncontrolled or excessive cytokine production arising from dysregulated immune responses mounted by the host to eliminate the plasmodial parasite. The ubiquitous serine/threonine kinase, glycogen synthase kinase3β (GSK3β) is a crucial regulator of the balance between pro- and anti-inflammatory cytokine productions in the inflammatory response to pathogenic infections. Andrographolide, a bioactive compound in Andrographis paniculata, displays GSK3- inhibitory effects. A previous study elsewhere has shown that this compound has antimalarial activity but the molecular basis of its action is yet to be elucidated. Here we aimed to study the anti-malarial activity of andrographolide in a murine model of malarial infection to investigate whether its mechanism of action involves cytokine modulation and inhibition of GSK3β. Andrographolide showed strong and selective anti-plasmodial activity (IC50 = 13.70±0.71 µM; SI = 30.43) when tested against cultures of P. falciparum 3D7. Intraperitoneal administration of andrographolide (5 mg/kg body weight (bw)) into P. berghei NK65-infected ICR mice resulted in chemo-suppression of 60.17±2.12%, and significantly (P<0.05) improved median survival time of infected mice compared to nontreated control. In addition, andrographolide treatment significantly (P<0.05) decreased the level of serum pro-inflammatory cytokine, IFN-γ (1.4-fold) whilst the anti-inflammatory cytokines, IL-10 and IL-4 were increased 2.3- and 2.6-fold respectively. Western blot analyses revealed that andrographolide treatment of P. berghei NK65-infected mice resulted in an increased level of phosphorylated GSK3β (Ser9) in liver of infected mice. Andrographolide administration also decreased the levels of phosphorylated NF-κB p65 (Ser536) and phosphorylated Akt (Ser473) in liver of malaria- infected animals. Taken together, our findings demonstrate that the cytokine-modulating effect of andrographolide in experimental malarial infection involves at least in part inhibition of NF-κB activation as a consequence of GSK3β inhibition. Based on its cytokine-modulating effects, andrographolide is thus a plausible candidate for adjunctive therapy in malaria subject to clinical evaluations.
    Matched MeSH terms: Antimalarials/pharmacology*
  8. Molecular markers associated with resistance to commonly used antimalarial drugs among Plasmodium falciparum isolates from a malaria-endemic area in Taiz governorate-Yemen during the transmission season
    Alareqi LMQ, Mahdy MAK, Lau YL, Fong MY, Abdul-Ghani R, Mahmud R
    Acta Trop, 2016 Oct;162:174-179.
    PMID: 27343362 DOI: 10.1016/j.actatropica.2016.06.016
    Since 2005, artesunate (AS) plus sulfadoxine/pyrimethamine (SP) combination has been adopted as the first-line treatment for uncomplicated malaria in Yemen in response to the high level of Plasmodium falciparum resistance to chloroquine (CQ). Therefore, the aim of the present study was to determine the frequency distribution of molecular markers associated with resistance to CQ and AS plus SP combination among P. falciparum isolates from a malaria-endemic area in Taiz governorate, Yemen. Fifty P. falciparum isolates were collected during a cross-sectional study in Mawza district, Taiz, in the period from October 2013 to April 2014. The isolates were investigated for drug resistance-associated molecular markers in five genes, including P. falciparum CQ resistance transporter (pfcrt) 76T and P. falciparum multidrug resistance 1 (pfmdr1) 86Y as markers of resistance to CQ, mutations in the Kelch 13 (K13) propeller domain for resistance to AS, and P. falciparum dihydrofolate reductase (pfdhfr) and P. falciparum dihydropteroate synthase (pfdhps) genes for resistance to SP. Nested polymerase chain reaction was used to amplify target genes in DNA extracts of the isolates followed by restriction fragment length polymorphism for detecting 76T and 86Y mutations in pfcrt and pfmdr1, respectively, and by DNA sequencing for detecting mutations in K13, pfdhfr and pfdhps. All the investigated isolates from Mawza district were harboring the pfcrt 76T mutant and the pfmdr1 N86 wild-type alleles. The pfdhfr 51I/108N double mutant allele was found in 2.2% (1/45) of the isolates; however, no mutations were detected at codons 436, 437, 540, 581 and 613 of pfdhps. All P. falciparum isolates that were successfully sequenced (n=47) showed the K13 Y493, R539, I543 and C580 wild-type alleles. In conclusion, the pfcrt 76T mutant allele is fixed in the study area about six years after the official withdrawal of CQ, possibly indicating its over-the-counter availability and continued use as a self-medication in the study area. However, the almost predominant wild-type alleles of the genes associated with resistance to AS and SP among P. falciparum isolates in the present study indicates the sustained efficacy of the currently adopted first-line treatment of AS plus SP in the study area.
    Matched MeSH terms: Antimalarials/pharmacology*
  9. The effects of hydroxychloroquine on endothelial dysfunction
    Rahman R, Murthi P, Singh H, Gurusinghe S, Mockler JC, Lim R, et al.
    Pregnancy Hypertens, 2016 Oct;6(4):259-262.
    PMID: 27939463 DOI: 10.1016/j.preghy.2016.09.001
    Hydroxychloroquine is an anti-malarial drug which, due to its anti-inflammatory and immunomodulatory effects, is widely used for the treatment of autoimmune diseases. In a model of systemic lupus erythematosus hydroxychloroquine has been shown to exert protective endothelial effects. In this study, we aimed to investigate whether hydroxychloroquine was endothelial protective in an in vitro model of TNF-α and preeclamptic serum induced dysfunction. We showed that hydroxychloroquine significantly reduced the production of TNF-α and preeclamptic serum induced endothelin-1 (ET-1). Hydroxychloroquine also significantly mitigated TNF-α induced impairment of angiogenesis. These findings support the further assessment of hydroxychloroquine as an adjuvant therapy in preeclampsia.
    Matched MeSH terms: Antimalarials/pharmacology*
  10. Smart nanocrystals of artemether: fabrication, characterization, and comparative in vitro and in vivo antimalarial evaluation
    Shah SM, Ullah F, Khan S, Shah SM, de Matas M, Hussain Z, et al.
    Drug Des Devel Ther, 2016;10:3837-3850.
    PMID: 27920499
    Artemether (ARTM) is a very effective antimalarial drug with poor solubility and consequently low bioavailability. Smart nanocrystals of ARTM with particle size of 161±1.5 nm and polydispersity index of 0.172±0.01 were produced in <1 hour using a wet milling technology, Dena(®) DM-100. The crystallinity of the processed ARTM was confirmed using differential scanning calorimetry and powder X-ray diffraction. The saturation solubility of the ARTM nanocrystals was substantially increased to 900 µg/mL compared to the raw ARTM in water (145.0±2.3 µg/mL) and stabilizer solution (300.0±2.0 µg/mL). The physical stability studies conducted for 90 days demonstrated that nanocrystals stored at 2°C-8°C and 25°C were very stable compared to the samples stored at 40°C. The nanocrystals were also shown to be stable when processed at acidic pH (2.0). The solubility and dissolution rate of ARTM nanocrystals were significantly increased (P<0.05) compared to those of its bulk powder form. The results of in vitro studies showed significant antimalarial effect (P<0.05) against Plasmodium falciparum and Plasmodium vivax. The IC50 (median lethal oral dose) value of ARTM nanocrystals was 28- and 54-fold lower than the IC50 value of unprocessed drug and 13- and 21-fold lower than the IC50 value of the marketed tablets, respectively. In addition, ARTM nanocrystals at the same dose (2 mg/kg) showed significantly (P<0.05) higher reduction in percent parasitemia (89%) against P. vivax compared to the unprocessed (27%), marketed tablets (45%), and microsuspension (60%). The acute toxicity study demonstrated that the LD50 value of ARTM nanocrystals is between 1,500 mg/kg and 2,000 mg/kg when given orally. This study demonstrated that the wet milling technology (Dena(®) DM-100) can produce smart nanocrystals of ARTM with enhanced antimalarial activities.
    Matched MeSH terms: Antimalarials/pharmacology*
  11. Fulltext Prevalence of Plasmodium falciparum Molecular Markers of Antimalarial Drug Resistance in a Residual Malaria Focus Area in Sabah, Malaysia
    Norahmad NA, Mohd Abd Razak MR, Abdullah NR, Sastu UR, Imwong M, Muniandy PK, et al.
    PLoS One, 2016;11(10):e0165515.
    PMID: 27788228 DOI: 10.1371/journal.pone.0165515
    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.
    Matched MeSH terms: Antimalarials/pharmacology*
  12. Fulltext Updates on k13 mutant alleles for artemisinin resistance in Plasmodium falciparum
    Zaw MT, Emran NA, Lin Z
    J Microbiol Immunol Infect, 2018 Apr;51(2):159-165.
    PMID: 28711439 DOI: 10.1016/j.jmii.2017.06.009
    BACKGROUND: In the fight against malaria caused by Plasmodium falciparum, the successes achieved by artemisinin were endangered by resistance of the parasites to the drug. Whole genome sequencing approach on artemisinin resistant parasite line discovered k13 gene associated with drug resistance. In vitro and in vivo studies indicated mutations in the k13 gene were linked to the artemisinin resistance.

    METHODOLOGY: The literatures published after April, 2015 up to December, 2016 on k13 mutant alleles for artemisinin resistance in Plasmodium falciparum and relevant literatures were comprehensively reviewed.

    RESULTS: To date, 13 non-synonymous mutations of k13 gene have been observed to have slow parasite clearance. Worldwide mapping of k13 mutant alleles have shown mutants associated with artemisinin resistance were confined to southeast Asia and China and did not invade to African countries. Although in vitro ring stage survival assay of 0-3 h was a recently developed assay, it was useful for rapid detection of artemisinin resistance associated k13 allelic marker in the parasite. Recently, dissemination of k13 mutant alleles was recommended to be investigated by identity of haplotypes. Significant characteristics of well described alleles in the reports were mentioned in this review for the benefit of future studies.

    CONCLUSION: According to the updates in the review, it can be concluded artemisinin resistance does not disseminate to India and African countries within short period whereas regular tracking of these mutants is necessary.

    Matched MeSH terms: Antimalarials/pharmacology*
  13. Evaluation of ethnopharmacologically selected Vitex negundo L. for In vitro antimalarial activity and secondary metabolite profiling
    Dwivedi MK, Shukla R, Sharma NK, Manhas A, Srivastava K, Kumar N, et al.
    J Ethnopharmacol, 2021 Jul 15;275:114076.
    PMID: 33789139 DOI: 10.1016/j.jep.2021.114076
    ETHANOPHARMACOLOGICAL RELEVANCE: Limited drugs, rise in drug resistance against frontline anti-malarial drugs, non-availability of efficacious vaccines and high cost of drug development hinders malaria intervention programs. Search for safe, effective and affordable plant based anti-malarial agents, thus becomes crucial and vital in the current scenario. The Vitex negundo L. is medicinal plant possessing a variety of pharmaceutically important compounds. The plant is used traditionally worldwide for the treatment of malaria including India and Malaysia by the indigenous tribes. In vitro studies have reported the anti-malarial use of the plant in traditional medicinal systems.

    AIM OF THE STUDY: The aim of the current study is to evaluate the traditionally used medicinal plants for in vitro anti-malarial activity against human malaria parasite Plasmodium falciparum and profiling secondary metabolite using spectroscopic and chromatographic methods. Chemical profiling of active secondary metabolites in the extracts was undertaken using LC-MS.

    MATERIALS AND METHODS: Based on the ethno-botanical data V. negundo L. was selected for in vitro anti-malarial activity against P. falciparum chloroquine-sensitive (3D7) and multidrug resistant (K1) strains using SYBR Green-I based fluorescence assay. Cytotoxicity of extracts was evaluated in VERO cell line using the MTT assay. Haemolysis assay was performed using human red blood cells. Secondary metabolites profiling was undertaken using chromatographic and spectroscopic analysis. Liquid chromatography analysis was performed using a C18, 150 X 2.1, 2.6 μm column with gradient mobile phase Solvent A: 95% (H2O: ACN), Solvent B: Acetonitrile, Solvent C: Methanol, Solvent D: 5 mM NH4 in 95:5 (H2O: ACN) at a constant flow rate of 0.250 ml/min. The LC-MS spectra were acquired in both positive and negative ion modes with electrospray ionization (ESI) source.

    RESULTS: The anti-malarial active extract of V. negundo L. leaf exhibited potent anti-malarial activity with IC50 values of 7.21 μg/ml and 7.43 μg/ml against 3D7 and K1 strains, respectively with no evidence of significant cytotoxicity against mammalian cell line (VERO) and no toxicity as observed in haemolysis assay. The HPLC-LC-MS analysis of the extract led to identification of 73 compounds. We report for the first time the presence of Sabinene hydrate acetate, 5-Hydroxyoxindole, 2(3,4-dimethoxyphenyl)-6, 7-dimethoxychromen-4-one, Cyclotetracosa-1, 13-diene and 5, 7-Dimethoxyflavanone in the anti-malarial active extract of V. negundo L. leaf. Agnuside, Behenic acid and Globulol are some of the novel compounds with no reports of anti-malarial activity so far and require further evaluation in pure form for the development of potent anti-malarial compounds.

    CONCLUSIONS: The result report and scientifically validate the traditional use of V. negundo L. for the treatment of malaria providing new avenues for anti-malarial drug development. Several novel and unknown compounds were identified that need to be further characterized for anti-malarial potential.

    Matched MeSH terms: Antimalarials/pharmacology*
  14. Antiplasmodial studies of Eurycoma longifolia Jack using the lactate dehydrogenase assay of Plasmodium falciparum
    Chan KL, Choo CY, Abdullah NR, Ismail Z
    J Ethnopharmacol, 2004 Jun;92(2-3):223-7.
    PMID: 15138004 DOI: 10.1016/j.jep.2004.02.025
    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.
    Matched MeSH terms: Antimalarials/pharmacology*
  15. Semisynthetic 15-O-acyl- and 1,15-di-O-acyleurycomanones from Eurycoma longifolia as potential antimalarials
    Chan KL, Choo CY, Abdullah NR
    Planta Med, 2005 Oct;71(10):967-9.
    PMID: 16254833 DOI: 10.1055/s-2005-864188
    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.
    Matched MeSH terms: Antimalarials/pharmacology*
  16. Antiplasmodial and antioxidant isoquinoline alkaloids from Dehaasia longipedicellata
    Zahari A, Cheah FK, Mohamad J, Sulaiman SN, Litaudon M, Leong KH, et al.
    Planta Med, 2014 May;80(7):599-603.
    PMID: 24723007 DOI: 10.1055/s-0034-1368349
    The crude extract of the bark of Dehaasia longipedicellata exhibited antiplasmodial activity against the growth of Plasmodium falciparum K1 isolate (resistant strain). Phytochemical studies of the extract led to the isolation of six alkaloids: two morphinandienones, (+)-sebiferine (1) and (-)-milonine (2); two aporphines, (-)-boldine (3) and (-)-norboldine (4); one benzlyisoquinoline, (-)-reticuline (5); and one bisbenzylisoquinoline, (-)-O-O-dimethylgrisabine (6). Their structures were determined on the basis of 1D and 2D NMR, IR, UV, and LCMS spectroscopic techniques and upon comparison with literature values. Antiplasmodial activity was determined for all of the isolated compounds. They showed potent to moderate activity with IC50 values ranging from 0.031 to 30.40 µM. (-)-O-O-dimethylgrisabine (6) and (-)-milonine (2) were the two most potent compounds, with IC50 values of 0.031 and 0.097 µM, respectively, that were comparable to the standard, chloroquine (0.090 µM). The compounds were also assessed for their antioxidant activities with di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium (IC50 = 18.40-107.31 µg/mL), reducing power (27.40-87.40 %), and metal chelating (IC50 = 64.30 to 257.22 µg/mL) having good to low activity. (-)-O-O-dimethylgrisabine (6) exhibited a potent antioxidant activity of 44.3 % reducing power, while di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium and metal chelating activities had IC50 values of 18.38 and 64.30 µg/mL, respectively. Thus it may be considered as a good reductant with the ability to chelate metal and prevent pro-oxidant activity. In addition to the antiplasmodial and antioxidant activities, the isolated compounds were also tested for their cytotoxicity against a few cancer and normal cell lines. (-)-Norboldine (4) exhibited potent cytotoxicity towards pancreatic cancer cell line BxPC-3 with an IC50 value of 27.060 ± 1.037 µM, and all alkaloids showed no toxicity towards the normal pancreatic cell line (hTERT-HPNE).
    Matched MeSH terms: Antimalarials/pharmacology*
  17. A novel nano-anti-malarial induces redox damage and elicits cytokine response to the parasite
    Das S, Tripathy S, Pramanik P, Saha B, Roy S
    Cytokine, 2021 08;144:155555.
    PMID: 33992538 DOI: 10.1016/j.cyto.2021.155555
    Emergence and spread of resistant parasites to the newest chemotherapeutic anti-malarial agents are the biggest challenges against malaria control programs. Therefore, developing a novel effective treatment to reduce the overgrowing burden of multidrug resistant malaria is a pressing need. Herein, we have developed a biocompatible and biodegradable, non-toxic chitosan-tripolyphosphate-chloroquine (CS-TPP CQ) nanoparticle. CS-TPP CQ nanoparticles effectively kill the parasite through redox generation and induction of the pro- and anti-inflammatory cytokines in both sensitive and resistant parasite in vitro. The in vitro observations showed a strong inhibitory effect (p 
    Matched MeSH terms: Antimalarials/pharmacology*
  18. Exploring Promising Immunomodulatory Potential of Natural and Synthetic 1,3-Diphenyl-2-propen-1-one Analogs: A Review of Mechanistic Insight
    Safdar MH, Hasan H, Afzal S, Hussain Z
    Mini Rev Med Chem, 2018;18(12):1047-1063.
    PMID: 29173165 DOI: 10.2174/1389557517666171123212039
    The immune system is an intricate and coordinated nexus serving as a natural defense to preclude internal and external pathogenic insults. The deregulation in the natural balance of immunological functions as a consequence of either over expression or under expression of immune cells tends to cause disruption of homeostasis in the body and may lead to development of numerous immune system disorders. Chalcone moieties (1,3-diphenyl-2-propen-1-one) have been well-documented as ideal lead compounds or precursors to design a wide range of pharmacologically active agents to down-regulate various immune disorders. Owing to their unique structural and molecular framework, these α, β-unsaturated carbonyl-based moieties have also gained remarkable recognition due to their other multifarious pharmacological properties including antifungal, anti-inflammatory, anti-malarial, antibacterial, anti-tuberculosis, and anticancer potential. Though a great number of methodologies are currently being employed for their synthesis, this review mainly focuses on the natural and synthetic chalcone derivatives that are exclusively synthesized via Claisen-Schmidt condensation reaction and their immunomodulatory prospects. We have critically reviewed the literature and provided convincing evidence for the promising efficacy of chalcone derivatives to modulate functioning of various innate and adaptive immune players including granulocytes, mast cells, monocytes, macrophages, platelets, dendritic cells, natural killer cells, and T-lymphocytes.
    Matched MeSH terms: Antimalarials/pharmacology
  19. Fulltext Synthesis and Evaluation of N-(3-Trifluoroacetyl-indol-7-yl) Acetamides for Potential In Vitro Antiplasmodial Properties
    Mphahlele MJ, Mmonwa MM, Choong YS
    Molecules, 2017 Jul 02;22(7).
    PMID: 28671598 DOI: 10.3390/molecules22071099
    A series of novel N-((2,5-diaryl-3-trifluoroacetyl)-1H-indol-7-yl)acetamides has been prepared via a successive and one-pot reaction sequence involving initial trifluoroacetic acid-mediated Beckmann rearrangement of the oximes derived from the 1-(2,5-diaryl-1H-indol-7-yl)ethanones, followed by trifluoroacetylation of the incipient N-(2,5-diaryl-1H-indol-7-yl)-acetamides with trifluoroacetic anhydride. The prepared compounds were evaluated for potential in vitro antiplasmodial properties. Preliminary results from antiplasmodial activity against the chloroquine-sensitive 3D7 strain of Plasmodium falciparum revealed that a combination of 2-(4-flurophenyl)- and 5-(4-fluorophenyl) or 2-(4-flurophenyl)- and 4-fluorostyryl groups in compounds 3(a,f) and 4(a,g), for example, is required for biological activity for both series of compounds. Their possible mode of action against the plasmodial parasite is explained theoretically through molecular docking of the most active compounds against the parasite lactate dehydrogenase (pLDH). These compounds were docked at the entrance of NAD+ in pLDH presumably hindering entry of lactate to cause the observed inhibition effect of pLDH. The four compounds were found to exhibit low toxicity against monkey kidney Vero cells at the highest concentrations tested.
    Matched MeSH terms: Antimalarials/pharmacology*
  20. Fulltext Molecular characterization of Plasmodium falciparum antifolate resistance markers in Thailand between 2008 and 2016
    Sugaram R, Suwannasin K, Kunasol C, Mathema VB, Day NPJ, Sudathip P, et al.
    Malar J, 2020 Mar 04;19(1):107.
    PMID: 32127009 DOI: 10.1186/s12936-020-03176-x
    BACKGROUND: Resistance to anti-malarials is a major threat to the control and elimination of malaria. Sulfadoxine-pyrimethamine (SP) anti-malarial treatment was used as a national policy for treatment of uncomplicated falciparum malaria in Thailand from 1973 to 1990. In order to determine whether withdrawal of this antifolate drug has led to restoration of SP sensitivity, the prevalence of genetic markers of SP resistance was assessed in historical Thai samples.

    METHODS: Plasmodium falciparum DNA was collected from the Thailand-Myanmar, Thailand-Malaysia and Thailand-Cambodia borders during 2008-2016 (N = 233). Semi-nested PCR and nucleotide sequencing were used to assess mutations in Plasmodium falciparum dihydrofolate reductase (pfdhfr), P. falciparum dihydropteroate synthase (pfdhps). Gene amplification of Plasmodium falcipaurm GTP cyclohydrolase-1 (pfgch1) was assessed by quantitative real-time PCR. The association between pfdhfr/pfdhps mutations and pfgch1 copy numbers were evaluated.

    RESULTS: Mutations in pfdhfr/pfdhsp and pfgch1 copy number fluctuated overtime through the study period. Altogether, 14 unique pfdhfr-pdfhps haplotypes collectively containing quadruple to octuple mutations were identified. High variation in pfdhfr-pfdhps haplotypes and a high proportion of pfgch1 multiple copy number (51% (73/146)) were observed on the Thailand-Myanmar border compared to other parts of Thailand. Overall, the prevalence of septuple mutations was observed for pfdhfr-pfdhps haplotypes. In particular, the prevalence of pfdhfr-pfdhps, septuple mutation was observed in the Thailand-Myanmar (50%, 73/146) and Thailand-Cambodia (65%, 26/40) border. In Thailand-Malaysia border, majority of the pfdhfr-pfdhps haplotypes transaction from quadruple (90%, 9/10) to quintuple (65%, 24/37) during 2008-2016. Within the pfdhfr-pfdhps haplotypes, during 2008-2013 the pfdhps A/S436F mutation was observed only in Thailand-Myanmar border (9%, 10/107), while it was not identified later. In general, significant correlation was observed between the prevalence of pfdhfr I164L (ϕ = 0.213, p-value = 0.001) or pfdhps K540E/N (ϕ = 0.399, p-value ≤ 0.001) mutations and pfgch1 gene amplification.

    CONCLUSIONS: Despite withdrawal of SP as anti-malarial treatment for 17 years, the border regions of Thailand continue to display high prevalence of antifolate and anti-sulfonamide resistance markers in falciparum malaria. Significant association between pfgch1 amplification and pfdhfr (I164L) or pfdhps (K540E) resistance markers were observed, suggesting a compensatory mutation.

    Matched MeSH terms: Antimalarials/pharmacology*
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