Resistant Plasmodium Research Articles

Pyronaridine-Artesunate Combined With Low Dose Primaquine for Preventing <i>P. falciparum</i> Malaria Transmission: A Single-Blind Randomized Clinical Trial in Ouelessebougou, Mali

Summary: Pyronaridine-artesunate (PA) is a recommended anti-malarial in areas of Plasmodium resistance to first-line artemisinin combination therapies. This study shows that PA may be combined with a single low dose of primaquine for highly effective P. falciparum transmission reduction. Background: Pyronaridine-artesunate (PA) is the most recently licenced artemisinin combination therapies (ACT). The World Health Organization recommends that a single lose dose of primaquine may be added to ACTs to reduce P. falciparum transmission in areas aiming for elimination or threatened by artemisinin resistance. The transmission reducing efficacy of PA and PA combined with primaquine have never been tested. Methods: In a four-arm, single-blind, randomised clinical trial, we determined the effectiveness of PA and dihydroartemisinin-piperaquine (DP) with and without 0.25mg/kg primaquine for reducing gametocyte density and transmission to mosquitoes in asymptomatic Malian P. falciparum gametocyte carriers (n=100). Findings: Before treatment, 66% (66/100) of individuals were infectious to mosquitoes, with an average mosquito infection rate of 15.8% (IQR 5.41-31.94). The percentage of individuals who infected mosquitoes (p 0.129). Interpretation: These data strongly support the use of SLD PQ as an effective supplement to PA for blocking P. falciparum transmission, and are of immediate relevance to African regions in which the containment of ACT resistance and sustainability of ACT efficacy are growing concerns. Trial Registration: The trial was registered on clinicaltrials.gov under identifier NCT04049916. Funding Statement: This work was supported by the Bill and Melinda Gates Foundation (#INV-002098). JB received support from the UK MRC and the UK DFID (#MR/K012126/1) under the MRC/DFID Concordat agreement and as part of the EDCTP2 programme supported by the European Union. TB is further supported by a fellowship from the The Netherlands Organisation for Scientific Research (Vidi fellowship NWO project number 016.158.306). WS is supported by a Sir Henry Wellcome fellowship (218676/Z/19/Z). Declaration of Interests: We have no competing interests. Ethics Approval Statement: Ethical approval was granted by the Ethics Committee of the Faculty of Medicine, Pharmacy, and Dentistry of the University of Science, Techniques, and Technologies of Bamako (Bamako, Mali), and the Research Ethics Committee of the London School of Hygiene and Tropical Medicine (London, UK).Participants provided informed consent (≥18 years), assent with parental consent (12-17 years) or parental consent (<12 years).

Therapeutic Efficacy of Triple Regimen of Artemether, Lumefantrine and &amp;lt;i&amp;gt;Hippocratea africana&amp;lt;/i&amp;gt; in the Treatment of &amp;lt;i&amp;gt;Plasmodium berghei&amp;lt;/i&amp;gt; Infected Mice

Combination therapy is fast replacing monotherapy in the treatment of infectious diseases and Plasmodium resistance to artemisinin–based combination therapies (ACTs) is an emerging challenge. Our study aimed to evaluate the therapeutic efficacy of combining Artemether-Lumefantrine with crude root bark extract of Hippocratea africana, on mice infected with Plasmodium berghei. Forty-five albino mice which weighed 30 - 38g were grouped into five with seven mice in each. The mice were inoculated intraperitoneally with Plasmodium berghei and kept for seven days for the parasitaemia to develop. A daily single dose of 200mg/Kg body weight of extract of H. africana was administered orally for ten days, while therapeutic dose of Artemether-lumefantrine was administered as daily single dose to the relevant groups on the last six days of treatment. A non-parasitized and parasitize untreated groups served as controls. The weights of the animals were recorded before and after treatment. The animals were sacrificed and blood obtained for determination of percentage parasitaemia and the erythrocytes count of the parasitized mice using standard methods. The results showed the mean body weight and percentage body weight changes of parasitized mice treated with combination of ACT plus H. africana not statistically different from those of non-parasitized untreated mice. Parasitized mice treated with ACT plus Extract had a significantly (p < 0.05) reduced percentage parasitaemia when compared with those treated with ACT only. Treatment with ACT plus Extract also showed a significant increase in parasite clearance (100%) when compared to mice treated with either ACT only (93.10%) or Extract only (82.15%). We concluded that combining artemether, lumefantrine and H. africana root bark extract exhibited a good therapeutic efficacy as demonstrated by body weight recovery, parasite clearance and reversion of clinical signs induced by Plasmodium berghei parasitaemia. The triple regimen was more efficacious than ACT alone, and therefore, may be a useful regimen in addressing the emerging problem of resistance of plasmodium species to standards ACTs.

Monitoring Plasmodium vivax resistance to antimalarials: Persisting challenges and future directions

Emerging antimalarial drug resistance may undermine current efforts to control and eliminate Plasmodium vivax, the most geographically widespread yet neglected human malaria parasite. Endemic countries are expected to assess regularly the therapeutic efficacy of antimalarial drugs in use in order to adjust their malaria treatment policies, but proper funding and trained human resources are often lacking to execute relatively complex and expensive clinical studies, ideally complemented by ex vivo assays of drug resistance. Here we review the challenges for assessing in vivo P. vivax responses to commonly used antimalarials, especially chloroquine and primaquine, in the presence of confounding factors such as variable drug absorption, metabolism and interaction, and the risk of new infections following successful radical cure. We introduce a simple modeling approach to quantify the relative contribution of relapses and new infections to recurring parasitemias in clinical studies of hypnozoitocides. Finally, we examine recent methodological advances that may render ex vivo assays more practical and widely used to confirm P. vivax drug resistance phenotypes in endemic settings and review current approaches to the development of robust genetic markers for monitoring chloroquine resistance in P. vivax populations.

Antiplasmodial activity of chalcone derivatives compound through phagocytosis of kupffer cells in experimental malaria hosts

Introduction: Malaria is still one of the major health problems, specifically due to drug resistance in Plasmodium, which encourages extensive research to find effective alternatives. One of the new antimalarial compounds is chalcone-derivative compound (E)-1-(4-aminophenyl)-3-(2,3-dimethoxy phenyl)prop-2-en-1-one. However, its potency is still needed to be evaluated. Therefore, this study aimed to determine the efficacy and identify the pharmacological mechanism of this chalcone-derivative. Methods: An experiment using post-test only with control group design was conducted from May 2016 to July 2017 in the laboratory of Parasitology and Clinical Pathology Faculty of Medicine, Universitas Gadjah Mada. Swiss mice were used and infected with Plasmodium before being divided into nine groups with different concentrations of (E)-1-(4-aminophenyl)-3-(2,3-dimethoxy phenyl)prop-2-en-1-one. Histological examination was conducted to count the number of Kupffer cells and the proportion of Kupffer cells that had phagocytosed the Plasmodium. Results: Both doxycycline and (E)-1-(4-aminophenyl)-3-(2,3-dimethoxy phenyl)prop-2-en-1-one  decreased the parasitemia in the tested mice with higher efficacy was observed in the doxycycline group. Likewise, both compounds also increase the number of Kupffer cells which become phagocytes of erythrocytes containing Plasmodium was higher in the treatment group than in the control group (p 0.000 &lt;0.05). Substance (E)-1-(4-aminophenyl)-3-(2,3-dimethoxy phenyl) prop-2-en-1-one may act as an antimalarial by phagocytes of erythrocytes containing Plasmodium. Conclusion In conclusion, the (E)-1-(4-aminophenyl)-3-(2,3-dimethoxy phenyl)prop-2-en-1-one exhibited potent antimalarial activity via the phagocytic activity of Kupffer cells. This compound may be developed into a new antimalarial drug.

Synthesis and antimalarial activity of sulfonamide-attached coumarin-[1,2,3]-triazoles

Drug resistance in malaria parasites is one of the major stumbling blocks hindering the goal of malaria elimination. One of the major strategies to counter drug resistance is the development of new potent antimalarial drugs. In the present study, a series of novel sulfonamide based coumarin-[1,2,3]-triazole conjugates have been synthesized via Huisgen reaction between azidosulfonamides and 4-hydroxy- or 7-hydroxymethylcoumarinoalkynes. All the compounds have been characterized spectroscopically and screened for their in vitro antimalarial activity against P. falciparum 3D7 strain. Out of the twenty five synthesized compounds, four compounds displayed significant activity (IC50 <10 µM) with the most active compound having an IC50 of 3.64 µM.

Methnaridine is an orally bioavailable, fast-killing and long-acting antimalarial agent that cures Plasmodium infections in mice.

Malaria is one of the deadliest diseases in the world. Novel chemotherapeutic agents are urgently required to combat the widespread Plasmodium resistance to frontline drugs. Here, we report the discovery of a novel benzonaphthyridine antimalarial, methnaridine, which was identified using a structural optimization strategy. An integrated pharmacological approach was used to evaluate the antimalarial profile of methnaridine. The pharmacokinetic properties of methnaridine were investigated along with the associated safety profile. Host immune response patterns were also analysed. Methnaridine exhibited potent antimalarial activity against P. falciparum (3D7: IC50 = 0.0066 μM; Dd2: IC50 = 0.0056 μM). In P. berghei-infected mice, oral administration effectively suppressed parasitemia (ED50 = 0.52 mg·kg-1 ·day-1 ) and cured the established infection (CD50 = 10.13 mg·kg-1 ·day-1 ). These results are equivalent to or better than those of other antimalarial agents in clinical use. Notably, a four-dose oral regimen at a dosage of 25 mg·kg-1 achieved a complete cure of P. berghei infection in mice. Methnaridine exhibited a rapid parasiticidal profile (PCT99 = 36.0 h) and showed no cross-resistance to chloroquine. Pharmacokinetic studies revealed that methnaridine is readily absorbed, long-lasting and slowly cleared. The safety profile of methnaridine is also satisfactory (maximum tolerated dose = 1,125 mg·kg-1 ). In addition, following methnaridine treatment, infection-induced Th1 immune response was almost fully alleviated in mice. Methnaridine is an orally bioavailable, fast-acting and long-lasting agent with excellent antimalarial properties. Our study highlights the potential of methnaridine for clinical development as a promising antimalarial candidate.

Electrochemical and Theoretical Studies on the Artesunate Reduction

Malaria is the most devastating tropical disease in the world and this scenario is worsened by the absence of effective treatment. However, the plasmodium resistance to artemisinin does not show clinical relevance. The drug mechanism of action is associated to the endoperoxide moiety breakage. Artesunate is a semi-synthetic derivative of artemisinin and its absorption is facilitated due to its higher solubility in water. As a sesquiterpene lactone, artesunate can be electrochemically reduced in aqueous media on the glassy carbon electrode, having been studied by cyclic voltammetry, square wave voltammetry and chronoamperometry. The artesunate voltammetric reduction is diffusion-controlled and significantly irreversible. Its reduction is pH-independent, but from pH = 6.0 the cathodic current values increase in alkaline media, indicating that the proton-equilibrium occurs after the electron transfer step. The an values calculated vary from 0.30 to 0.37, leading to the 0.0975 s -1 value for k s . From the chronoamperometric data, two electrons (1.9 ± 0.4) are involved in the reduction process, being confirmed by the exact number of electrons obtained for artemisinin (1.9 ± 0.2). According to these results and computational findings, both drugs have the same reduction mechanism with the breakage of the endoperoxide bridge and consequent diol-derivative formation followed by the deoxy analog stabilization through the existence of a set of reactions involving protonation and charge transfer steps on the electrode surface. DOI: http://dx.doi.org/10.17807/orbital.v12i3.1439

Host Porphobilinogen Deaminase Deficiency Confers Malaria Resistance in Plasmodium chabaudi but Not in Plasmodium berghei or Plasmodium falciparum During Intraerythrocytic Growth.

An important component in host resistance to malaria infection are inherited mutations that give rise to abnormalities and deficiencies in erythrocyte proteins and enzymes. Understanding how such mutations confer protection against the disease may be useful for developing new treatment strategies. A mouse ENU-induced mutagenesis screen for novel malaria resistance-conferring mutations identified a novel non-sense mutation in the gene encoding porphobilinogen deaminase (PBGD) in mice, denoted here as PbgdMRI58155. Heterozygote PbgdMRI58155 mice exhibited ~50% reduction in cellular PBGD activity in both mature erythrocytes and reticulocytes, although enzyme activity was ~10 times higher in reticulocytes than erythrocytes. When challenged with blood-stage P. chabaudi, which preferentially infects erythrocytes, heterozygote mice showed a modest but significant resistance to infection, including reduced parasite growth. A series of assays conducted to investigate the mechanism of resistance indicated that mutant erythrocyte invasion by P. chabaudi was normal, but that following intraerythrocytic establishment a significantly greater proportions of parasites died and therefore, affected their ability to propagate. The Plasmodium resistance phenotype was not recapitulated in Pbgd-deficient mice infected with P. berghei, which prefers reticulocytes, or when P. falciparum was cultured in erythrocytes from patients with acute intermittent porphyria (AIP), which had modest (20–50%) reduced levels of PBGD. Furthermore, the growth of Pbgd-null P. falciparum and Pbgd-null P. berghei parasites, which grew at the same rate as their wild-type counterparts in normal cells, were not affected by the PBGD-deficient background of the AIP erythrocytes or Pbgd-deficient mice. Our results confirm the dispensability of parasite PBGD for P. berghei infection and intraerythrocytic growth of P. falciparum, but for the first time identify a requirement for host erythrocyte PBGD by P. chabaudi during in vivo blood stage infection.

Genetic analysis of the orthologous crt and mdr1 genes in Plasmodium malariae from Thailand and Myanmar

BackgroundPlasmodium malariae is a widely spread but neglected human malaria parasite, which causes chronic infections. Studies on genetic polymorphisms of anti-malarial drug target genes in P. malariae are limited. Previous reports have shown polymorphisms in the P. malariae dihydrofolate reductase gene associated with pyrimethamine resistance and linked to pyrimethamine drug pressure. This study investigated polymorphisms of the P. malariae homologous genes, chloroquine resistant transporter and multidrug resistant 1, associated with chloroquine and mefloquine resistance in Plasmodium falciparum.MethodsThe orthologous P. malariae crt and mdr1 genes were studied in 95 patients with P. malariae infection between 2002 and 2016 from Thailand (N = 51) and Myanmar (N = 44). Gene sequences were analysed using BioEdit, MEGA7, and DnaSP programs. Mutations and gene amplifications were compared with P. falciparum and Plasmodium vivax orthologous genes. Protein topology models derived from the observed pmcrt and pmmdr1 haplotypes were constructed and analysed using Phyre2, SWISS MODEL and Discovery Studio Visualization V 17.2.ResultsTwo non-synonymous mutations were observed in exon 2 (H53P, 40%) and exon 8 (E278D, 44%) of pmcrt. The topology model indicated that H53P and E278D were located outside of the transmembrane domain and were unlikely to affect protein function. Pmmdr1 was more diverse than pmcrt, with 10 non-synonymous and 3 synonymous mutations observed. Non-synonymous mutations were located in the parasite cytoplasmic site, transmembrane 11 and nucleotide binding domains 1 and 2. Polymorphisms conferring amino acid changes in the transmembrane and nucleotide binding domains were predicted to have some effect on PmMDR1 conformation, but were unlikely to affect protein function. All P. malariae parasites in this study contained a single copy of the mdr1 gene.ConclusionsThe observed polymorphisms in pmcrt and pmmdr1 genes are unlikely to affect protein function and unlikely related to chloroquine drug pressure. Similarly, the absence of pmmdr1 copy number variation suggests limited mefloquine drug pressure on the P. malariae parasite population, despite its long time use in Thailand for the treatment of falciparum malaria.

Design, synthesis and biological evaluation of several aromatic substituted chalcones as antimalarial agents.

Malaria is a communicable disease which is caused by protozoan's mainly Plasmodium species (P. falciparum, P. ovale, P. vivax, P. malariae and P. knowlesi). The increasing resistance of Plasmodium to available malarial drugs poses a great responsibility for the researchers in the field of malaria. To overcome this problem of resistance, this study aimed to design and synthesize a new class of antimalarial agent with chalcone as the main moiety. Chalcones, a member of flavanoid family, consist of two aromatic rings of 1,3-diphenyl-2-propen-1-one linked by a three carbon α,β-unsaturated carbonyl system. Five derivatives were designed and among them one was selected. The CC2 was then synthesized by esterification of Para amino acetophenone followed by treatment with hydrazide to form 2-(4 acetylphenoxy)acetohydrazide. This was then coupled with 2-Bromo substituted Diazotized esterified anilines, which was finally linked with substituted benzaldehyde to yield CC2. These were then structurally verified by Infra Red (IR) and Nuclear Magnetic Resonance (NMR) spectroscopy. The chalcone was then tested for in vitro growth inhibition assays using SYBR GREEN-1 Based assay and IC50 values were identified. The compound CC2 showed quite promising antimalarial activity by inhibiting cysteine protease enzyme. The acute toxicity studies of the compound were carried out as per OECD guideline 425 and the results showed no toxic signs and symptoms indicating CC2 as a safe and less toxic compound.

A single point mutation in the Plasmodium falciparum FtsH1 metalloprotease confers actinonin resistance.

The antibiotic actinonin kills malaria parasites (Plasmodium falciparum) by interfering with apicoplast function. Early evidence suggested that actinonin inhibited prokaryote-like post-translational modification in the apicoplast; mimicking its activity against bacteria. However, Amberg Johnson et al. (2017) identified the metalloprotease TgFtsH1 as the target of actinonin in the related parasite Toxoplasma gondii and implicated P. falciparum FtsH1 as a likely target in malaria parasites. The authors were not, however, able to recover actinonin resistant malaria parasites, leaving the specific target of actinonin uncertain. We generated actinonin resistant P. falciparum by in vitro selection and identified a specific sequence change in PfFtsH1 associated with resistance. Introduction of this point mutation using CRISPr-Cas9 allelic replacement was sufficient to confer actinonin resistance in P. falciparum. Our data unequivocally identify PfFtsH1 as the target of actinonin and suggests that actinonin should not be included in the highly valuable collection of 'irresistible' drugs for combatting malaria.

An unlabelled probe-based real time PCR and modified semi-nested PCR as molecular tools for analysis of chloroquine resistant Plasmodium vivax isolates from Afghanistan

BackgroundPlasmodium vivax resistance to chloroquine (CQ) has been reported from many endemic regions in the world. Plasmodium vivax is responsible for 95% of malaria cases in Afghanistan and CQ is the first-line treatment given for vivax malaria. The pvmdr-1 and pvcrt-o (K10 insertion) genes are possible markers for CQ-resistance in P. vivax isolates. There have been no studies done on the presence or absence of molecular markers for CQ-resistance P. vivax in Afghanistan. The present work aimed to evaluate the frequency of mutations in the pvmdr-1 and K10 insertion in the pvcrt-o genes of P. vivax.MethodsPlasmodium vivax isolates were collected from Laghman, Baghlan and Khost provinces. For investigation of polymorphisms of desired regions in pvmdr-1 and pvcrt-o genes, sequencing was applied on the PCR products. A new asymmetric qPCR and melting analysis assay based on unlabelled probe developed for scanning of K10 insertion in pvcrt-o gene.ResultsThe analysis of sequencing data of the pvmdr-1 gene showed wild type Y976 and K997 and mutant M958 and L1076 in 33 isolates from three provinces. Of the 36 samples evaluated for K10 insertion in pvcrt-o, 2/18(11%), 0/10(0%) and 0/8(0%) isolates from Laghman, Baghlan and Khost province, respectively, possessed K10 insertion, confirmed by either sequencing and unlabelled probes.ConclusionTwo samples with K10 insertion and 33 samples with pvmdr1 polymorphism, indicating on the possibility of CQ resistance in P. vivax populations in Afghanistan. Furthermore, unlabelled probes are simple and inexpensive alternative tools for screening of P. vivax mutations.

Associations between Aminoquinoline Resistance Genotypes and Clinical Presentations of Plasmodium falciparum Infection in Uganda.

Mutations that mediate resistance of Plasmodium falciparum to aminoquinoline antimalarials are selected by prior drug use and may alter parasite fitness, but associations with clinical presentations are uncertain. We evaluated genotypes in samples from a case-control study of determinants of severe malaria in Ugandan children 4 months to 10 years of age. We studied 274 cases with severe malaria matched by age and geography to 275 uncomplicated malaria controls and 179 asymptomatic parasitemic controls. The overall prevalence of mutations of interest (considering mixed results as mutant) was 67.0% for PfCRT K76T, 8.5% for PfMDR1 N86Y, 71.5% for PfMDR1 Y184F, and 14.7% for PfMDR1 D1246Y. Compared to asymptomatic controls, the odds of mutant PfCRT 76T were lower for uncomplicated (odds ratio, 0.42 [95% confidence interval, 0.24 to 0.72]; P < 0.001) or severe (0.56 [0.32 to 0.97]; P = 0.031) malaria; the odds of mutant PfMDR1 86Y were lower for uncomplicated (0.33 [0.16 to 0.65]; P < 0.001) or severe (0.21 [0.09 to 0.45]; P < 0.001) malaria; and the odds of mutant PfMDR1 1246Y were higher for uncomplicated (1.83 [0.90 to 3.98]; P = 0.076) or severe (2.06 [1.01 to 4.55]; P = 0.033) malaria. The odds of mutant PfMDR1 184F were lower in severe than asymptomatic (0.59 [0.37 to 0.92]; P = 0.016) or uncomplicated (0.61 [0.41 to 0.90]; P = 0.009) malaria. Overall, the PfCRT 76T and PfMDR1 86Y mutations were associated with decreased risk of symptomatic malaria, PfMDR1 1246Y was associated with increased risk of symptomatic malaria, and PfMDR1 184F was associated with decreased risk of severe malaria. These results offer insights into parasite genotypes in children with different presentations, although the basis for the identified associations is likely complex.

Antiplasmodial Efficacy of Anacardium occidentale in Albino Mice Infected with Plasmodium berghei

Resistance of malaria parasites by most malarial drugs prompted the search for other drugs that are effective against the parasite. In endemic nations of the world, medicinal plants are often used to treat malaria. Among such plants is <em>Anacardium occidentale</em> which in addition to treating malaria, the plant has traditionally been used to treat diarrhoea, dysentery, colonic pains, genital problems, venereal diseases, impotence, bronchitis, cough and syphilis-related skin disorder. This research aimed at exploring the efficacy of <em>A. occidentale</em> in the treatment of malaria.

ANTIMALARIAL, FERRIC REDUCING ANTIOXIDANT POWER AND ELEMENTAL ANALYSIS OF Caesalpinia pulcherrima LEAF EXTRACT

The increasing rise of resistance of malaria parasites to established antimalarial drugs have necessitated the continued search for new drug entities especially those with fresh modes of action. Caesalpinia pulcherrima is a plant with many pharmacological and medicinal properties. The leaf extract and fractions were studied for their antimalarial, ferric reducing antioxidant power and elemental composition.Various fractions of the leaf extracts were obtained using vacuum liquid chromatography (VLC). The in vivo antimalarial activity was evaluated against plasmodium berghei parasites. The required dose was given according to the weight of the animal two hours after inoculation of parasites on D1, then once daily for three more days (D2-D4). The antioxidant activity was carried out using UV-Visible spectrometer at 593 nm. The elemental analysis was done using Atomic Absorption Spectrophotometer. There was a dose dependent increase in percentage chemo-suppression of the parasites by the different groups with maximum effect at 800 mg/kg (61.57-34.86 % from day five (5)to day eight (8) respectively). The highest FRAP activity was observed in 100% ethyl acetate with 314.90 ± 3.94 mmol, while the lowest antioxidant power was observed in 50% ethyl acetate:50% n-hexane fraction with 48.50 ± 1.10. 90%methanol:10% distilled water fraction did not indicate any FRAP activity. The results obtained revealed that the phytochemicals with very potent antioxidant power are more present in the ethyl acetate fraction. Elemental compositions (ppm) in the powdered leaf of C. pulcherrima were, sodium (Na); 20.27 ± 0.12, iron (Fe); 13.50 ± 0.08, calcium (Ca); 9.0 ± 0.14, and copper (Cu); 0.30 ± 0.08. Lead (Pb) was not detected. This study has shown that Lead concentration was below detectable limit, while the concentrations of Fe and Cu were within established permissible limits. Appreciable amount of Na and Ca were also indicated. C. pulcherrima leaf extract and fractions contain biologically active principles that are relevant antimalarial and antioxidant agents with acceptable mineral compositions.

Enhancing the antimalarial activity of artesunate.

The global challenge to the treatment of malaria is mainly the occurrence of resistance of malaria parasites to conventionally used antimalarials. Artesunate, a semisynthetic artemisinin compound, and other artemisinin derivatives are currently used in combination with selected active antimalarial drugs in order to prevent or delay the emergence of resistance to artemisinin derivatives. Several methods, such as preparation of hybrid compounds, combination therapy, chemical modification and the use of synthetic materials to enhance solubility and delivery of artesunate, have been employed over the years to improve the antimalarial activity of artesunate. Each of these methods has advantages it bestows on the efficacy of artesunate. This review discussed the various methods employed in enhancing the antimalarial activity of artesunate and delaying the emergence of resistance of parasite to it.

Suppressive and curative antiplasmodial properties of Nauclea latifolia root extract and fractions against erythrocytic stage of mice-infective chloroquine-sensitive Plasmodium berghei NK-65

Background: Malaria remains a devastating disease, particularly in the tropics, where it is the highest killer of pregnant women and children under the age of 5 years. Significant efforts and resources have been vested in malaria control and eradication programmes, but the unavailability of malaria vaccine and the emergence of resistance of malaria parasite to existing antimalarial drugs have continued to hamper attempts at controlling or eradicating the disease. This warrants the development of new antimalarial drugs. Nauclea latifolia root is widely applied for malaria treatment in Nigeria. Aim: This study investigated the antimalarial property of N. latifolia roots. Setting: N. latifolia roots were collected from Ikwuano, Umuahia, Abia State, Nigeria. Methods: To extract the bioactive constituents, an aqueous infusion of the plant was prepared and fractionated by solvent-solvent extraction with n -hexane, ethyl acetate and butanol, respectively. Antimalarial property was evaluated using suppressive and curative assays in mice infected with chloroquine-sensitive Plasmodium berghei NK-65 strain. Results: The extract and fractions produced significant suppressive and curative antiplasmodial activities ( p < 0.05). The aqueous extract and n -hexane and butanol fractions gave 85.22%, 84.52% and 91.32% chemosuppression, respectively, which were comparable to that of chloroquine used as positive control. The extract and fractions gave considerable curative effects in the range 52.23% – 77.00%. Conclusion: These findings indicate that N. latifolia roots possess antimalarial property and reflect its ethnomedicinal use for malaria treatment. Thus, N. latifolia roots may be exploited for development of herbal formulations and isolation of novel bioactive compounds for malaria treatment.

Early transmission of sensitive strain slows down emergence of drug resistance in Plasmodium vivax.

The spread of drug resistance of Plasmodium falciparum and Plasmodium vivax parasites is a challenge towards malaria elimination. P. falciparum has shown an early and severe drug resistance in comparison to P. vivax in various countries. In fact, P. vivax differs in its life cycle and treatment in various factors: development and duration of sexual parasite forms differ, symptoms severity are unequal, relapses present only in P. vivax cases and the Artemisinin-based combination therapy (ACT) is only mandatory in P. falciparum cases. We compared the spread of drug resistance for both species through two compartmental models using ordinary differential equations. The model structure describes how sensitive and resistant parasite strains infect a human population treated with antimalarials. We found that an early transmission,i.e., before treatment and low effectiveness of drug coverage, supports the prevalence of sensitive parasites delaying the emergence of resistant P. vivax. These results imply that earlier attention of both symptomatic cases and reservoirs of P. vivax are essential in controlling transmission but also accelerate the spread of drug resistance.

Influx of diverse, drug resistant and transmissible Plasmodium falciparum into a malaria-free setting in Qatar

BackgroundSuccessful control programs have impeded local malaria transmission in almost all Gulf Cooperation Council (GCC) countries: Qatar, Bahrain, Kuwait, Oman, the United Arab Emirates (UAE) and Saudi Arabia. Nevertheless, a prodigious influx of imported malaria via migrant workers sustains the threat of local transmission. Here we examine the origin of imported malaria in Qatar, assess genetic diversity and the prevalence of drug resistance genes in imported Plasmodium falciparum, and finally, address the potential for the reintroduction of local transmission.MethodsThis study examined imported malaria cases reported in Qatar, between 2013 and 2016. We focused on P. falciparum infections and estimated both total parasite and gametocyte density, using qPCR and qRT-PCR, respectively. We also examined ten neutral microsatellites and four genes associated with drug resistance, Pfmrp1, Pfcrt, Pfmdr1, and Pfkelch13, to assess the genetic diversity of imported P. falciparum strains, and the potential for propagating drug resistance genotypes respectively.ResultsThe majority of imported malaria cases were P. vivax, while P. falciparum and mixed species infections (P. falciparum / P. vivax) were less frequent. The primary origin of P. vivax infection was the Indian subcontinent, while P. falciparum was mostly presented by African expatriates. Imported P. falciparum strains were highly diverse, carrying multiple genotypes, and infections also presented with early- and late-stage gametocytes. We observed a high prevalence of mutations implicated in drug resistance among these strains, including novel SNPs in Pfkelch13.ConclusionsThe influx of genetically diverse P. falciparum, with multiple drug resistance markers and a high capacity for gametocyte production, represents a threat for the reestablishment of drug-resistant malaria into GCC countries. This scenario highlights the impact of mass international migration on the reintroduction of malaria to areas with absent or limited local transmission.

Antimalarial activity of the aqueous extract of the latex of Aloe pirottae Berger. (Aloaceae) against Plasmodium berghei in mice

Ethnopharmacological relevanceIn spite of worldwide efforts, malaria remains one of the most devastating illnesses in the world. The huge number of lives it takes and the resistance of malaria parasites to current drugs necessitate the search for new effective antimalarial drugs. Medicinal plants have been the major source of such drugs and A. pirottae is one of these plants used traditionally for the treatment of malaria in Ethiopia. AimThis study was aimed at evaluating the antimalarial activity of the aqueous extract of A. pirottae against chloroquine sensitive P. berghei in mice. Materials and methodsThe extract was obtained by macerating the latex of A. pirottae with distilled water. To determine its antiplasmodial activity, a 4-day suppressive model was used by dividing 40 mice into five groups of 8 mice each and given 200, 400 & 600mg/kg of the extract, the standard drug (chloroquine 25mg/kg) and the vehicle (distilled water). Then parasite suppression by the extract, survival time and prevention of loss of body weight, rectal temperature and packed cell volume were assessed. All data were presented as the Mean ± SEM (Standard Error of the Mean) and analyzed using IBM SPSS version 20. ResultsThe extract showed moderate antimalarial activity by significantly (p < 0.001) suppressing parasitemia at all dose levels with maximum parasitemia suppression of 47.0% and significantly (p < 0.01) increasing survival time. Furthermore, 400 mg/kg and 600 mg/kg doses showed significant (p < 0.01) prevention of loss in body weight, rectal temperature and packed cell volume. ConclusionBased to the results of this study, A. pirottae is endowed with a moderate antimalarial activity that is in agreement with the traditional claim of A. pirottae, hence may be used as a basis for further studies to be conducted on antimalarial activity of the plant.