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1.
J Enzyme Inhib Med Chem ; 34(1): 1388-1399, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31392901

RESUMO

Fourteen novel dipeptide carboxamide derivatives bearing benzensulphonamoyl propanamide were synthesized and characterized using 1H NMR, 13C NMR, FTIR and MS spectroscopic techniques. In vivo antimalarial and in vitro antimicrobial studies were carried out on these synthesized compounds. Molecular docking, haematological analysis, liver and kidney function tests were also evaluated to assess the effect of the compounds on the organs. At 200 mg/kg body weight, 7i inhibited the multiplication of the parasite by 81.38% on day 12 of post-treatment exposure. This was comparable to the 82.34% reduction with artemisinin. The minimum inhibitory concentration (MIC) in µM ranged from 0.03 to 2.34 with 7h having MIC of 0.03 µM against Plasmodium falciparium. The in vitro antibacterial activity of the compounds against some clinically isolated bacteria strains showed varied activities with some of the new compounds showing better activities against the bacteria and the fungi more than the reference drug ciprofloxacin and fluconazole.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Dipeptídeos/química , Dipeptídeos/farmacologia , Sulfonamidas/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antimaláricos/síntese química , Bactérias/efeitos dos fármacos , Dipeptídeos/síntese química , Fungos/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Ratos , Sulfonamidas/química
2.
Gene ; 716: 144016, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31377318

RESUMO

Drug resistance of malaria parasites remains a problem affecting antimalarial treatment and control of the disease. We previously synthesized an antimalarial endoperoxide, N-89, having high antimalarial effects in vitro and in vivo. In this study we seek to understand the resistant mechanism against N-89 by establishing a highly N-89-resistant clone, named NRC10H, of the Plasmodium falciparum FCR-3 strain. We describe gene mutations in the parent FCR-3 strain and the NRC10H clone using whole-genome sequencing and subsequently by expression profiling using quantitative real-time PCR. Seven genes related to drug resistance, proteolysis, glycophosphatidylinositol anchor biosynthesis, and phosphatidylethanolamine biosynthesis exhibited a single amino acid substitution in the NRC10H clone. Among these seven genes, the multidrug resistance protein 2 (mdr2) variant A532S was found only in NRC10H. The genetic status of the P. falciparum endoplasmic reticulum-resident calcium binding protein (PfERC), a potential target of N-89, was similar between the NRC10H clone and the parent FCR-3 strain. These findings suggest that the genetic alterations of the identified seven genes, in particular mdr2, in NRC10H could give rise to resistance of the antimalarial endoperoxide N-89.


Assuntos
Antimaláricos/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Compostos de Espiro/farmacologia , Resistência a Medicamentos/genética , Genômica , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , RNA Mensageiro/metabolismo , Sequenciamento Completo do Genoma
3.
Planta Med ; 85(13): 1073-1079, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31365939

RESUMO

Zanthoxylum zanthoxyloides, syn. Fagara zanthoxyloides, is a tree growing in West Africa and is used in traditional medicine against a variety of diseases, including malaria. In the work reported here, root bark and stem bark extracts of this tree, as well as compounds isolated from the extracts, have been investigated for activity in vitro against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. In addition, toxicity against nauplii of the brine shrimp Artemia salina has been studied. Dichloromethane extracts of the root bark and stem bark, and a methanol extract of the stem bark, showed anti-parasitic activity towards chloroquine-sensitive as well as chloroquine-resistant P. falciparum, with IC50 values between 1 and 10 µg/mL. Among the isolated compounds, bis-dihydrochelerythrinyl ether, buesgenine, chelerythrine, γ-fagarine, skimmianine, and pellitorine were the most active, with IC50 values of less than 5 µg/mL. The dichloromethane extracts were toxic to brine shrimp nauplii, with LC50 values of less than 1 µg/mL. Methanol extracts were much less toxic (LC50 between 50 and 100 µg/mL). Among the isolated substances, bis-dihydrochelethrinyl ether was the most toxic (LC50 ca. 2 µg/mL).


Assuntos
Antimaláricos/farmacologia , Extratos Vegetais/farmacologia , Zanthoxylum/química , Casca de Planta/química , Folhas de Planta/química , Raízes de Plantas/química , Plasmodium falciparum/efeitos dos fármacos
4.
Chem Biodivers ; 16(8): e1900318, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31364803

RESUMO

Sponges from freshwater environments, unlike marine's, are poorly known producers of natural compounds with medicinal purposes. Amazonian sponges produce massive large specimens and are widely spread, taxonomically diverse and their metabolites could represent a new frontier on unusual natural products to treat diseases such as Alzheimer's and Malaria. Species of Metania and Drulia (Metaniidae) genera are major contributors to the fauna of Amazonian freshwater sponges. Methanolic extracts from several species from these genera had their inhibitory activities evaluated in vitro, for parasite Plasmodium falciparum and acetyl and butyrylcholinesterase enzymes (AChE and BChE). All extracts were able to inhibit AChE, although no activity was observed towards BChE. Drulia uruguayensis extract was the most potent, inhibiting AChE with IC50 =1.04 mg/mL. For antiplasmodial activity, all species showed inhibition to P. falciparum, but Metania reticulata being the most efficient with IC50 =2.7 µg/mL. Mass spectrometry analyses evidenced the presence of fatty acids and sterols in active extracts.


Assuntos
Antiprotozoários/química , Inibidores da Colinesterase/química , Poríferos/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Antiprotozoários/isolamento & purificação , Antiprotozoários/farmacologia , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/metabolismo , Ácidos Graxos/análise , Ácidos Graxos/química , Plasmodium falciparum/efeitos dos fármacos , Poríferos/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Esteróis/química
5.
Chem Pharm Bull (Tokyo) ; 67(7): 654-665, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257321

RESUMO

Quassinoids, one kind of triterpenoids with multiple bioactivities such as anti-cancer, anti-malarial, anti-oxidative, anti-microbial, anti-diabetic, anti-viral, and anti-inflammatory effects, have drawn much attention in recent years. Between 2004 and 2018, the structural characteristics and plant sources of 190 quassinoids were reported. Herein, the structure-activity relationships (SARs) of quassinoids along with the anti-cancer mechanisms of four representative quassinoids, eurycomanone, bruceine D, dehydrobruceine B, and brusatol are discussed. This review might be useful for further research and development of quassinoids.


Assuntos
Antineoplásicos Fitogênicos/química , Quassinas/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Antiprotozoários/química , Antiprotozoários/isolamento & purificação , Antiprotozoários/farmacologia , Antivirais/química , Antivirais/isolamento & purificação , Antivirais/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Plantas/química , Plantas/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Quassinas/isolamento & purificação , Quassinas/farmacologia , Relação Estrutura-Atividade , Vírus do Mosaico do Tabaco/efeitos dos fármacos
6.
Nat Commun ; 10(1): 2665, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209259

RESUMO

Estimates of Plasmodium falciparum migration may inform strategies for malaria elimination. Here we elucidate fine-scale parasite population structure and infer recent migration across Southeast Asia using identity-by-descent (IBD) approaches based on genome-wide single nucleotide polymorphisms called in 1722 samples from 54 districts. IBD estimates are consistent with isolation-by-distance. We observe greater sharing of larger IBD segments between artemisinin-resistant parasites versus sensitive parasites, which is consistent with the recent spread of drug resistance. Our IBD analyses reveal actionable patterns, including isolated parasite populations, which may be prioritized for malaria elimination, as well as asymmetrical migration identifying potential sources and sinks of migrating parasites.


Assuntos
Resistência a Medicamentos/genética , Monitoramento Epidemiológico , Genoma de Protozoário/genética , Malária Falciparum/microbiologia , Plasmodium falciparum/genética , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Ásia Sudeste , Biodiversidade , Genótipo , Geografia Médica , Malária Falciparum/tratamento farmacológico , Malária Falciparum/prevenção & controle , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/isolamento & purificação , Polimorfismo de Nucleotídeo Único
7.
Malar J ; 18(1): 192, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31185976

RESUMO

BACKGROUND: Mutational analysis of the Plasmodium falciparum kelch 13 (k13) gene is routinely performed to track the emergence and spread of artemisinin resistance. Surveillance of resistance markers has been impeded by the difficulty of extracting sufficient DNA from low parasite density infections common in low-transmission settings, such as Southeast Asia. This problem can be overcome by collecting large volumes of venous blood. Efficient methods for extracting and amplifying k13 from dried blood spots (DBS) would facilitate resistance surveillance. METHODS: Methods for k13 amplification from standard Whatman 3MM DBS (stored for 14 days at 28 °C with 80% relative humidity) were optimized by systematically testing different extraction conditions. Conditions that improved parasite DNA recovery as assessed by quantitative polymerase chain reaction (PCR) of 18S rDNA were then tested for their impact on k13 PCR amplification. RESULTS: The optimized protocol for amplification of k13 from DBS is markedly more sensitive than standard methods using commercial kits. Using this method, k13 was successfully amplified from laboratory-created DBS samples with parasite densities as low as 500 parasites/mL. Importantly, the method recovers both DNA and RNA, making it compatible with RNA-based ultrasensitive techniques currently in use. CONCLUSIONS: The optimized DBS protocol should facilitate drug resistance surveillance, especially in low-transmission settings where clinical malaria infections with high parasite densities are rare.


Assuntos
Artemisininas/farmacologia , Sangue/parasitologia , DNA de Protozoário/isolamento & purificação , Resistência a Medicamentos , Malária Falciparum/parasitologia , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Antimaláricos/farmacologia , Ásia Sudeste , DNA de Protozoário/química , DNA de Protozoário/genética , Dessecação/métodos , Humanos , Plasmodium falciparum/efeitos dos fármacos , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Manejo de Espécimes/métodos
8.
Parasit Vectors ; 12(1): 293, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182154

RESUMO

BACKGROUND: Lingering post-treatment parasite antigen in blood complicates malaria diagnosis through antigen detection. Characterization of antigen clearance dynamics is important for interpretation of positive antigen detection tests. RESULTS: We used a bead-based serological assay to measure lactate dehydrogenase (LDH), aldolase (Aldo), and histidine-rich protein 2 (HRP2) levels in 196 children with Plasmodium falciparum malaria treated with effective antimalarials and followed for 28 to 42 days as part of therapeutic efficacy studies in Angola. Compared to pre-treatment levels, antigen concentrations two days after treatment declined by 99.7% for LDH, 96.3% for Aldo, and 54.6% for HRP2. After Day 2, assuming a first-order kinetics clearance model, half-lives of the antigens were 1.8 days (95% CI: 1.5-2.3) for LDH, 3.2 days (95% CI: 3.0-3.4) for Aldo, and 4.8 days (95% CI: 4.7-4.9) for HRP2. CONCLUSIONS: LDH and Aldo show substantially different clearance rates than HRP2, and their presence is largely indicative of active infection.


Assuntos
Antígenos de Protozoários/sangue , Antimaláricos/uso terapêutico , Frutose-Bifosfato Aldolase/sangue , L-Lactato Desidrogenase/sangue , Malária Falciparum/tratamento farmacológico , Angola , Criança , Teste em Amostras de Sangue Seco , Humanos , Cinética , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/sangue , Testes Sorológicos
9.
Curr Top Med Chem ; 19(10): 861-873, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31161990

RESUMO

The malaria parasite resistance to the existing drugs is a serious problem to the currently used antimalarials and, thus, highlights the urgent need to develop new and effective anti-malarial molecules. This could be achieved either by the identification of the new drugs for the validated targets or by further refining/improving the existing antimalarials; or by combining previously effective agents with new/existing drugs to have a synergistic effect that counters parasite resistance; or by identifying novel targets for the malarial chemotherapy. In this review article, a comprehensive collection of some of the novel molecular targets has been enlisted for the antimalarial drugs. The targets which could be deliberated for developing new anti-malarial drugs could be: membrane biosynthesis, mitochondrial system, apicoplasts, parasite transporters, shikimate pathway, hematin crystals, parasite proteases, glycolysis, isoprenoid synthesis, cell cycle control/cycline dependent kinase, redox system, nucleic acid metabolism, methionine cycle and the polyamines, folate metabolism, the helicases, erythrocyte G-protein, and farnesyl transferases. Modern genomic tools approaches such as structural biology and combinatorial chemistry, novel targets could be identified followed by drug development for drug resistant strains providing wide ranges of novel targets in the development of new therapy. The new approaches and targets mentioned in the manuscript provide a basis for the development of new unique strategies for antimalarial therapy with limited off-target effects in the near future.


Assuntos
Antimaláricos/farmacologia , Malária/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/química , Humanos , Testes de Sensibilidade Parasitária
10.
Mem Inst Oswaldo Cruz ; 114: e190088, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31188952

RESUMO

BACKGROUND: Despite treatment with effective antimalarial drugs, the mortality rate is still high in severe cases of the disease, highlighting the need to find adjunct therapies that can inhibit the adhesion of Plasmodium falciparum-infected erythrocytes (Pf-iEs). OBJECTIVES: In this context, we evaluated a new heparan sulfate (HS) from Nodipecten nodosus for antimalarial activity and inhibition of P. falciparum cytoadhesion and rosetting. METHODS: Parasite inhibition was measured by SYBR green using a cytometer. HS was assessed in rosetting and cytoadhesion assays under static and flow conditions using Chinese hamster ovary (CHO) and human lymphatic endothelial cell (HLEC) cells expressing intercellular adhesion molecule-1 (ICAM1) and chondroitin sulfate A (CSA), respectively. FINDINGS: This HS inhibited merozoite invasion similar to heparin. Moreover, mollusk HS decreased cytoadherence of P. falciparum to CSA and ICAM-1 on the surface of endothelial cells under static and flow conditions. In addition, this glycan efficiently disrupted rosettes. CONCLUSIONS: These findings support a potential use for mollusk HS as adjunct therapy for severe malaria.


Assuntos
Heparitina Sulfato/farmacologia , Merozoítos/efeitos dos fármacos , Moluscos/química , Plasmodium falciparum/efeitos dos fármacos , Animais , Adesão Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Proteínas de Protozoários/efeitos dos fármacos , Reprodutibilidade dos Testes , Fatores de Tempo
11.
Chem Commun (Camb) ; 55(52): 7434-7437, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31155628

RESUMO

Mortiamides A-D (1-4) are head-to-tail cyclic heptapeptides that were identified from a novel Mortierella sp. isolate obtained from marine sediments from Northern Canada. Herein we report the first total synthesis of mortiamides A-D (1-4) on a solid support by concomitant cyclization/cleavage without any oligomerization side reactions, and overall yields up to 48%. We also report on the antiplasmodial activity of mortiamides A-D (1-4). We show that three out of the four tested mortiamides (A, B and D) have moderate antiplasmodial activity, while mortiamide D (4) exhibits low micromolar activity.


Assuntos
Antimaláricos/síntese química , Peptídeos Cíclicos/síntese química , Antimaláricos/farmacologia , Ciclização , Peptídeos Cíclicos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Polimerização
12.
Chem Biodivers ; 16(7): e1900141, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31087758

RESUMO

Bioguided fractionation of Xylopia sericea antiplasmodial dichloromethane leaves extract led to the isolation of (-)-7-oxo-ent-kaur-16-en-19-oic acid (C20 H28 O3 ) that was identified by a combination of 1D and 2D NMR experiments (COSY, HMBC, HSQC, HSQC-TOCSY, HSQC-NOESY and NOESY) and by X-ray crystallography. A feature to be pointed out is its (4R) configuration that was inferred from the NOE experiments (HSQC-NOESY and NOESY) and X-ray crystallography. In vitro evaluation of this rare diterpene acid against the chloroquine-resistant strain Plasmodium falciparum W2 by the PfLDH method showed it disclosed a low antiplasmodial activity and was not cytotoxic to HepG2 cells (CC50 862.6±6.7 µm) by the MTT assay. The unequivocal NMR signals assignments, the X-ray crystallographic structure, the assessment to the bioactivities and the occurrence this diterpene in X. sericea are reported here for the first time.


Assuntos
Antimaláricos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Diterpenos de Caurano/farmacologia , Diterpenos/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Plasmodium falciparum/efeitos dos fármacos , Xylopia/química , Antimaláricos/química , Antimaláricos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos de Caurano/química , Diterpenos de Caurano/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Relação Estrutura-Atividade
13.
BMC Infect Dis ; 19(1): 354, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035938

RESUMO

BACKGROUND: Quinine (QN) remains an effective drug for malaria treatment. However, quinine resistance (QNR) in Plasmodium falciparum has been reported in many malaria-endemic regions particularly in African countries. Genetic polymorphism of the P. falciparum Na+/H+ exchanger (pfnhe1) is considered to influence QN susceptibility. Here, ms4760 alleles of pfnhe1 were analysed from imported African P. falciparum parasites isolated from returning travellers in Wuhan, Central China. METHODS: A total of 204 dried-blood spots were collected during 2011-2016. The polymorphisms of the pfnhe1 gene were determined using nested PCR with DNA sequencing. RESULTS: Sequences were generated for 99.51% (203/204) of the PCR products and 68.63% (140/204) of the isolates were analysed successfully for the pfnhe1 ms4760 haplotypes. In total, 28 distinct ms4760 alleles containing 0 to 5 DNNND and 1 to 3 NHNDNHNNDDD repeats were identified. For the alleles, ms4760-1 (22.86%, 32/140), ms4760-3 (17.86%, 25/140), and ms4760-7 (10.71%, 15/140) were the most prevalent profiles. Furthermore, 5 undescribed ms4760 alleles were reported. CONCLUSIONS: The study offers an initial comprehensive analysis of pfnhe1 ms4760 polymorphisms from imported P. falciparum isolates in Wuhan. Pfnhe1 may constitute a good genetic marker to evaluate the prevalence of QNR in malaria-endemic and non-endemic regions.


Assuntos
Malária Falciparum/diagnóstico , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/genética , Trocadores de Sódio-Hidrogênio/genética , Alelos , Animais , Antimaláricos/farmacologia , China/epidemiologia , DNA de Protozoário/metabolismo , Resistência a Medicamentos/genética , Genótipo , Haplótipos , Humanos , Malária Falciparum/epidemiologia , Repetições de Microssatélites/genética , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/isolamento & purificação , Polimorfismo Genético , Quinina/farmacologia
14.
Molecules ; 24(9)2019 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-31060249

RESUMO

Co-infection of malaria and tuberculosis, although not thoroughly investigated, has been noted. With the increasing prevalence of tuberculosis in the African region, wherein malaria is endemic, it is intuitive to suggest that the probability of co-infection with these diseases is likely to increase. To avoid the issue of drug-drug interactions when managing co-infections, it is imperative to investigate new molecules with dual activities against the causal agents of these diseases. To this effect, a small library of quinolone-thiosemicarbazones was synthesised and evaluated in vitro against Plasmodium falciparum and Mycobacterium tuberculosis, the causal agents of malaria and tuberculosis, respectively. The compounds were also evaluated against HeLa cells for overt cytotoxicity. Most compounds in this series exhibited activities against both organisms, with compound 10, emerging as the hit; with an MIC90 of 2 µM against H37Rv strain of M. tuberculosis and an IC50 of 1 µM against the 3D7 strain of P. falciparum. This study highlights quinolone-thiosemicarabazones as a class of compounds that can be exploited further in search of novel, safe agents with potent activities against both the causal agents of malaria and tuberculosis.


Assuntos
Anti-Infecciosos/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Quinolonas/química , Bibliotecas de Moléculas Pequenas/síntese química , Tiossemicarbazonas/química , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Doces , Interações de Medicamentos , Células HeLa , Humanos , Concentração Inibidora 50 , Malária Falciparum/tratamento farmacológico , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Tuberculose
15.
Malar J ; 18(1): 180, 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31126288

RESUMO

BACKGROUND: HIV-infected individuals on antiretroviral therapy (ART) require treatment with artemisinin-based combination therapy (ACT) when infected with malaria. Artemether-lumefantrine (AL) is the most commonly used ACT for treatment of falciparum malaria in Africa but there is limited evidence on the safety and efficacy of AL in HIV-infected individuals on ART, among whom drug-drug interactions are expected. Day-42 adequate clinical and parasitological response (ACPR) and incidence of adverse events was assessed in HIV-infected individuals on efavirenz-based ART with uncomplicated falciparum malaria treated with AL. METHODS: A prospective, open label, non-randomized, interventional clinical trial was conducted at St Paul's Hospital in northern Zambia, involving 152 patients aged 15-65 years with uncomplicated falciparum malaria, who were on efavirenz-based ART. They received a 3-day directly observed standard treatment of AL and were followed up until day 63. Day-42 polymerase chain reaction (PCR)-corrected ACPRs (95% confidence interval [CI]) were calculated for the intention-to-treat population. RESULTS: Enrolled patients had a baseline geometric mean (95% CI) parasite density of 1108 (841-1463) parasites/µL; 16.4% (25/152) of the participants had a recurrent malaria episode by day 42. However, PCR data was available for 17 out of the 25 patients who had malaria recurrence. Among all the 17 patients, PCR findings demonstrated malaria re-infection, making the PCR-adjusted day-42 ACPR 100% in the 144 patients who could be evaluated. Even when eight patients with missing PCR data were considered very conservatively as failures, the day-42 ACPR was over 94%. None of the participants, disease or treatment characteristics, including day-7 lumefantrine concentrations, predicted the risk of malaria recurrence by day 42. AL was well tolerated following administration. There were only two cases of grade 3 neutropaenia and one serious adverse event of lobar pneumonia, none of which was judged as probably related to intake of AL. CONCLUSIONS: AL was well tolerated and efficacious in treating uncomplicated falciparum malaria in HIV co-infected adults on efavirenz-based ART. However, a higher than anticipated proportion of participants experienced malaria re-infection, which highlights the need for additional malaria prevention measures in this sub-population after treatment with AL. Trial registration Pan African Clinical Trials Registry (PACTR): PACTR201311000659400. Registered on 4 October 2013. https://pactr.samrc.ac.za/Search.aspx.


Assuntos
Antimaláricos/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Benzoxazinas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Inibidores da Transcriptase Reversa/uso terapêutico , Adolescente , Adulto , Idoso , Antimaláricos/efeitos adversos , Combinação Arteméter e Lumefantrina/efeitos adversos , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Reação em Cadeia da Polimerase , Estudos Prospectivos , Adulto Jovem , Zâmbia
16.
J Vector Borne Dis ; 56(1): 32-40, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31070163

RESUMO

The World Malaria Report 2018 published by the World Health Organization highlights that no significant progress in reducing global malaria cases was achieved for the period 2015-2017. India carries 4% of the global malaria burden and contributes 87% of the total malaria cases in South-East Asia. India is in malaria elimination mode, and set targets for malaria-free status by 2030. Diagnosis and treatment of asymptomatic falciparum malaria cases continues to be a challenge for health care providers. To overcome these hurdles innovative solutions along with the existing tools and strategies involving vector control, mass drug administration, disease surveillance hold the key to solve this gigantic health problem.


Assuntos
Erradicação de Doenças/métodos , Malária/prevenção & controle , Animais , Infecções Assintomáticas/epidemiologia , Erradicação de Doenças/tendências , Humanos , Índia/epidemiologia , Malária/tratamento farmacológico , Malária/epidemiologia , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Malária Vivax/epidemiologia , Malária Vivax/prevenção & controle , Administração Massiva de Medicamentos , Controle de Mosquitos , Plasmodium falciparum/efeitos dos fármacos , Plasmodium vivax/efeitos dos fármacos , Saúde Pública
17.
J Vector Borne Dis ; 56(1): 41-45, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31070164

RESUMO

Since the declaration of the vision of malaria eradication in 2007, the overall burden of malaria has been reduced substantially in many countries in the endemic world. This progress has, however, recently slowed worldwide and even an increase of morbidity and mortality has been observed in some regions. That reality has led to reflection on the strategy for malaria elimination, noting that focusing only on low transmission sites has competed with the efforts in countries that still have foci with high malaria burdens. This opinion piece outlines the collaboration of the ICMR-National Institute of Malaria Research (ICMR-NIMR) and other partner Institutions in India with the WorldWide Antimalarial Resistance Network (WWARN), one part of a global effort to manage the spread of Plasmodium falciparum parasites associated with antimalarial resistance.


Assuntos
Erradicação de Doenças/organização & administração , Saúde Global , Malária/prevenção & controle , Animais , Antimaláricos/farmacologia , Erradicação de Doenças/métodos , Resistência a Medicamentos , Geografia , Humanos , Índia/epidemiologia , Colaboração Intersetorial , Malária/epidemiologia , Malária/transmissão , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Saúde Pública , Estações do Ano , Viagem
18.
Malar J ; 18(1): 119, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30947717

RESUMO

BACKGROUND: Traditional medicinal plants are one of the potential sources of anti-malarial drugs and there is an increasing interest in the use and development of traditional herbal remedies for the treatment of malaria and other ailments. This study was carried out with the aim to investigate the phytochemical screening, cytotoxic effect and antiplasmodial activities of Dichrostachys cinerea and Commiphora africana. Both plants are used by the Maasai in Tanzania in suspected malaria and other diseases. No previous work appears to have investigated the potential anti-malarial activity of the two plants. METHODS: This study aimed to investigate the in vitro anti-malarial activity of methanol and dichloromethane extracts of the two plants against chloroquine sensitive (D6) and chloroquine resistant (Dd2) strains of Plasmodium falciparum. The anti-malarial property was assessed by the lactate dehydrogenase method (pLDH). The in vivo anti-malarial study was carried out using the Peters' 4-day suppressive test in Plasmodium berghei in Balb/c mice. Cytotoxic tests were carried out using monkey kidney epithelial cell line in [3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay. Qualitative phytochemical screening was carried out using standard methods of analysis. RESULTS: The phytochemical screening of plant extracts revealed the presence of alkaloids, flavonoids, tannins, steroids, triterpenoids, glycosides and saponins. However, alkaloids were absent in most plant extracts. The dichloromethane extracts of C. africana (stem bark); D. cinerea (stem bark) and methanol extracts of D. cinerea (whole stem) all showed promising in vitro anti-malarial activities. All other extracts did not show any significant anti-malarial activity. The two most promising extracts based on in vitro studies, DCM extracts of C. africana (stem bark) and D. cinerea (stems bark), equally exhibited very significant anti-malarial activities in the mouse model. They exhibited parasite suppression rates of 64.24 and 53.12%, respectively, and considerable improvement in weight and survival rate. Most plant extracts were not cytotoxic except for DCM extract of D. cinerea (whole stem) CC50 (29.44 µg/mL). CONCLUSION: The findings of this study provide scientific evidence supporting the traditional use of the plants in the treatment of malaria by the Maasai in Arusha region, Tanzania. Consequently, further work including bioassay-guided fractionation and advanced toxicity testing may yield new anti-malarial drug candidates from the two plants.


Assuntos
Antimaláricos/farmacologia , Commiphora/química , Fabaceae/química , Extratos Vegetais/farmacologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Animais , Cloroquina/farmacologia , Resistência a Medicamentos , Feminino , Técnicas In Vitro , Malária/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Casca de Planta/química , Extratos Vegetais/química , Plantas Medicinais/química , Plasmodium berghei/fisiologia , Plasmodium falciparum/fisiologia
19.
Malar J ; 18(1): 126, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30967148

RESUMO

BACKGROUND: Today, the development of new and well-tolerated anti-malarial drugs is strongly justified by the emergence of Plasmodium falciparum resistance. In 2014-2015, a phase 2b clinical study was conducted to evaluate the efficacy of a single oral dose of Artefenomel (OZ439)-piperaquine (PPQ) in Asian and African patients presenting with uncomplicated falciparum malaria. METHODS: Blood samples collected before treatment offered the opportunity to investigate the proportion of multidrug resistant parasite genotypes, including P. falciparum kelch13 mutations and copy number variation of both P. falciparum plasmepsin 2 (Pfpm2) and P. falciparum multidrug resistance 1 (Pfmdr1) genes. RESULTS: Validated kelch13 resistance mutations including C580Y, I543T, P553L and V568G were only detected in parasites from Vietnamese patients. In Africa, isolates with multiple copies of the Pfmdr1 gene were shown to be more frequent than previously reported (21.1%, range from 12.4% in Burkina Faso to 27.4% in Uganda). More strikingly, high proportions of isolates with multiple copies of the Pfpm2 gene, associated with piperaquine (PPQ) resistance, were frequently observed in the African sites, especially in Burkina Faso and Uganda (> 30%). CONCLUSIONS: These findings were considered to sharply contrast with the recent description of increased sensitivity to PPQ of Ugandan parasite isolates. This emphasizes the necessity to investigate in vitro susceptibility profiles to PPQ of African isolates with multiple copies of the Pfpm2 gene and estimate the risk of development of PPQ resistance in Africa. Trial registration Clinicaltrials.gov reference: NCT02083380. Study title: Phase II efficacy study of artefenomel and piperaquine in adults and children with P. falciparum malaria. https://clinicaltrials.gov/ct2/results?cond=&term=NCT02083380&cntry=&state=&city=&dist= . FSFV: 23-Jul-2014; LSLV: 09-Oct-2015.


Assuntos
Adamantano/análogos & derivados , Antimaláricos/farmacologia , Ácido Aspártico Endopeptidases/genética , Resistência a Medicamentos/genética , Peróxidos/farmacologia , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Quinolinas/farmacologia , Adamantano/farmacologia , Adolescente , Adulto , África , Idoso , Ácido Aspártico Endopeptidases/metabolismo , Biomarcadores/análise , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Combinação de Medicamentos , Feminino , Genótipo , Humanos , Lactente , Malária Falciparum , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/metabolismo , Vietnã , Adulto Jovem
20.
BMC Bioinformatics ; 20(1): 186, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30987583

RESUMO

BACKGROUND: Malaria is a major global health problem, with the Plasmodium falciparum protozoan parasite causing the most severe form of the disease. Prevalence of drug-resistant P. falciparum highlights the need to understand the biology of resistance and to identify novel combination therapies that are effective against resistant parasites. Resistance has compromised the therapeutic use of many antimalarial drugs, including chloroquine, and limited our ability to treat malaria across the world. Fortunately, chloroquine resistance comes at a fitness cost to the parasite; this can be leveraged in developing combination therapies or to reinstate use of chloroquine. RESULTS: To understand biological changes induced by chloroquine treatment, we compared transcriptomics data from chloroquine-resistant parasites in the presence or absence of the drug. Using both linear models and a genome-scale metabolic network reconstruction of the parasite to interpret the expression data, we identified targetable pathways in resistant parasites. This study identified an increased importance of lipid synthesis, glutathione production/cycling, isoprenoids biosynthesis, and folate metabolism in response to chloroquine. CONCLUSIONS: We identified potential drug targets for chloroquine combination therapies. Significantly, our analysis predicts that the combination of chloroquine and sulfadoxine-pyrimethamine or fosmidomycin may be more effective against chloroquine-resistant parasites than either drug alone; further studies will explore the use of these drugs as chloroquine resistance blockers. Additional metabolic weaknesses were found in glutathione generation and lipid synthesis during chloroquine treatment. These processes could be targeted with novel inhibitors to reduce parasite growth and reduce the burden of malaria infections. Thus, we identified metabolic weaknesses of chloroquine-resistant parasites and propose targeted chloroquine combination therapies.


Assuntos
Cloroquina/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Malária Falciparum/parasitologia , Parasitos/efeitos dos fármacos , Animais , Antimaláricos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Quimioterapia Combinada , Ácido Fólico/metabolismo , Humanos , Plasmodium falciparum/efeitos dos fármacos , Terpenos/metabolismo
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