Journal articles: 'Antimalarial infections'

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Dembele, Laurent, Yaw Aniweh, Nouhoum Diallo, Fanta Sogore, Cheick Papa Oumar Sangare, Aboubecrin Sedhigh Haidara, Aliou Traore, et al. "Plasmodium malariae and Plasmodium falciparum comparative susceptibility to antimalarial drugs in Mali." Journal of Antimicrobial Chemotherapy 76, no. 8 (May 22, 2021): 2079–87. http://dx.doi.org/10.1093/jac/dkab133.

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Abstract Objectives To evaluate Plasmodium malariae susceptibility to current and lead candidate antimalarial drugs. Methods We conducted cross-sectional screening and detection of all Plasmodium species malaria cases, which were nested within a longitudinal prospective study, and an ex vivo assessment of efficacy of a panel of antimalarials against P. malariae and Plasmodium falciparum, both PCR-confirmed mono-infections. Reference compounds tested included chloroquine, lumefantrine, artemether and piperaquine, while candidate antimalarials included the imidazolopiperazine GNF179, a close analogue of KAF156, and the Plasmodium phosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor KDU691. Results We report a high frequency (3%–15%) of P. malariae infections with a significant reduction in ex vivo susceptibility to chloroquine, lumefantrine and artemether, which are the current frontline drugs against P. malariae infections. Unlike these compounds, potent inhibition of P. malariae and P. falciparum was observed with piperaquine exposure. Furthermore, we evaluated advanced lead antimalarial compounds. In this regard, we identified strong inhibition of P. malariae using GNF179, a close analogue of KAF156 imidazolopiperazines, which is a novel class of antimalarial drug currently in clinical Phase IIb testing. Finally, in addition to GNF179, we demonstrated that the Plasmodium PI4K-specific inhibitor KDU691 is highly inhibitory against P. malariae and P. falciparum. Conclusions Our data indicated that chloroquine, lumefantrine and artemether may not be suitable for the treatment of P. malariae infections and the potential of piperaquine, as well as new antimalarials imidazolopiperazines and PI4K-specific inhibitor, for P. malariae cure.

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Watson, James, Cindy S. Chu, Joel Tarning, and Nicholas J. White. "Characterizing Blood-Stage Antimalarial Drug MIC ValuesIn VivoUsing Reinfection Patterns." Antimicrobial Agents and Chemotherapy 62, no. 7 (April 16, 2018): e02476-17. http://dx.doi.org/10.1128/aac.02476-17.

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ABSTRACTThe MIC is an essential quantitative measure of the asexual blood-stage effect of an antimalarial drug. In areas of high malaria transmission, and thus frequent individual infection, patients who are treated with slowly eliminated antimalarials become reinfected as drug concentrations decline. In the frequent relapse forms ofPlasmodium vivaxand inPlasmodium ovalemalaria, recurrent infection occurs from relapses which begin to emerge from the liver approximately 2 weeks after the primary illness. An important determinant of the interval from starting treatment of a symptomatic infection to the patency of these recurrent infections is thein vivoconcentration-response relationship and thus thein vivoMIC. Using mechanistic knowledge of parasite asexual replication and the pharmacokinetic and pharmacodynamic properties of the antimalarial drugs, a generative statistical model was derived which relates the concentration-response relationship to time of reinfection patency. This model was used to estimate thein vivoMIC of chloroquine in the treatment ofPlasmodium vivaxmalaria.

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DOBBS, KATHERINE R., and ARLENE E. DENT. "Plasmodium malaria and antimalarial antibodies in the first year of life." Parasitology 143, no. 2 (January 8, 2016): 129–38. http://dx.doi.org/10.1017/s0031182015001626.

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SUMMARYMalaria is one of the most serious infectious diseases with most of the severe disease caused byPlasmodium falciparum(Pf). Naturally acquired immunity develops over time after repeated infections and the development of antimalarial antibodies is thought to play a crucial role. Neonates and young infants are relatively protected from symptomatic malaria through mechanisms that are poorly understood. The prevailing paradigm is that maternal antimalarial antibodies transferred to the fetus in the last trimester of pregnancy protect the infant from early infections. These antimalarial antibodies wane by approximately 6 months of age leaving the infant vulnerable to malaria, however direct evidence supporting this epidemiologically based paradigm is lacking. As infants are the target population for future malaria vaccines, understanding how they begin to develop immunity to malaria and the gaps in their responses is key. This review summarizes the antimalarial antibody responses detected in infants and how they change over time. We focus primarily on Pf antibody responses and will briefly mentionPlasmodium vivaxresponses in infants.

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Pimentel-Quiroz, V. R., M. F. Ugarte-Gil, GB Harvey, D. Wojdyla, G. J. Pons-Estel, R. Quintana, A. Esposto, et al. "Factors predictive of serious infections over time in systemic lupus erythematosus patients: data from a multi-ethnic, multi-national, Latin American lupus cohort." Lupus 28, no. 9 (July 10, 2019): 1101–10. http://dx.doi.org/10.1177/0961203319860579.

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Aim The aim of this study was to identify factors predictive of serious infections over time in patients with systemic lupus erythematosus (SLE). Methods A multi-ethnic, multi-national Latin American SLE cohort was studied. Serious infection was defined as one that required hospitalization, occurred during a hospitalization or led to death. Potential predictors included were sociodemographic factors, clinical manifestations (per organ involved, lymphopenia and leukopenia, independently) and previous infections at baseline. Disease activity (SLEDAI), damage (SLICC/ACR Damage Index), non-serious infections, glucocorticoids, antimalarials (users and non-users), and immunosuppressive drugs use; the last six variables were examined as time-dependent covariates. Cox regression models were used to evaluate the predictors of serious infections using a backward elimination procedure. Univariable and multivariable analyses were performed. Results Of the 1243 patients included, 1116 (89.8%) were female. The median (interquartile range) age at diagnosis and follow-up time were 27 (20–37) years and 47.8 (17.9–68.6) months, respectively. The incidence rate of serious infections was 3.8 cases per 100 person-years. Antimalarial use (hazard ratio: 0.69; 95% confidence interval (CI): 0.48–0.99; p = 0.0440) was protective, while doses of prednisone >15 and ≤60 mg/day (hazard ratio: 4.18; 95 %CI: 1.69–10.31; p = 0.0019) and >60 mg/day (hazard ratio: 4.71; 95% CI: 1.35–16.49; p = 0.0153), use of methylprednisolone pulses (hazard ratio: 1.53; 95% CI: 1.10–2.13; p = 0.0124), increase in disease activity (hazard ratio: 1.03; 95% CI: 1.01–1.04; p = 0.0016) and damage accrual (hazard ratio: 1.22; 95% CI: 1.11–1.34; p < 0.0001) were predictive factors of serious infections. Conclusions Over time, prednisone doses higher than 15 mg/day, use of methylprednisolone pulses, increase in disease activity and damage accrual were predictive of infections, whereas antimalarial use was protective against them in SLE patients.

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D’Alessandro, Sarah, Diletta Scaccabarozzi, Lucia Signorini, Federica Perego, Denise P. Ilboudo, Pasquale Ferrante, and Serena Delbue. "The Use of Antimalarial Drugs against Viral Infection." Microorganisms 8, no. 1 (January 8, 2020): 85. http://dx.doi.org/10.3390/microorganisms8010085.

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In recent decades, drugs used to treat malaria infection have been shown to be beneficial for many other diseases, including viral infections. In particular, they have received special attention due to the lack of effective antiviral drugs against new emerging viruses (i.e., HIV, dengue virus, chikungunya virus, Ebola virus, etc.) or against classic infections due to drug-resistant viral strains (i.e., human cytomegalovirus). Here, we reviewed the in vitro/in vivo and clinical studies conducted to evaluate the antiviral activities of four classes of antimalarial drugs: Artemisinin derivatives, aryl-aminoalcohols, aminoquinolines, and antimicrobial drugs.

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Okoro, Roland Nnaemeka, and Muslim Olakunle Jamiu. "The Cross-Sectional Evaluation of the Use of Artemisinin-Based Combination Therapy for Treatment of Malaria Infection at a Tertiary Hospital in Nigeria." Journal of Tropical Medicine 2018 (2018): 1–6. http://dx.doi.org/10.1155/2018/2025858.

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In 2005, Nigeria changed its antimalarial drug policy to Artemisinin-based Combination Therapies (ACTs) for the treatment of malaria infection, and it is imperative for prescribers to strictly comply with this guideline to harmonize malaria management practices within the country. This study aims to evaluate prescribers’ adherence with the National Antimalarial Treatment Guideline (NATG) in the treatment of malaria infections and to describe the determinants of antimalarial drugs coprescription with antibiotics at a tertiary hospital in Nigeria. A cross-sectional, retrospective study of antimalarial drug prescriptions of one-year period of 2013 was conducted. A simple method for assessing the quality of drug prescribing (DU90%) was adopted. Logistic regression was used to predict antimalarial drugs coprescription with antibiotics. Overall, 95.8% of the total prescriptions contained ACTs, out of which 80.8% were Artemether/Lumefantrine. However, adherence to NATG was 88.2% with an adjusted value of 100.0%. Age was the only predictor for antimalarial drugs coprescription with antibiotics. This study showed high concordance with NATG at the studied hospital. Age less than 5 years is a significant risk factor for antimalarial drugs coprescription with antibiotics.

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Pessanha de Carvalho, Lais, Andrea Kreidenweiss, and Jana Held. "Drug Repurposing: A Review of Old and New Antibiotics for the Treatment of Malaria: Identifying Antibiotics with a Fast Onset of Antiplasmodial Action." Molecules 26, no. 8 (April 15, 2021): 2304. http://dx.doi.org/10.3390/molecules26082304.

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Malaria is one of the most life-threatening infectious diseases and constitutes a major health problem, especially in Africa. Although artemisinin combination therapies remain efficacious to treat malaria, the emergence of resistant parasites emphasizes the urgent need of new alternative chemotherapies. One strategy is the repurposing of existing drugs. Herein, we reviewed the antimalarial effects of marketed antibiotics, and described in detail the fast-acting antibiotics that showed activity in nanomolar concentrations. Antibiotics have been used for prophylaxis and treatment of malaria for many years and are of particular interest because they might exert a different mode of action than current antimalarials, and can be used simultaneously to treat concomitant bacterial infections.

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Patel, Kashyap, Kevin T. Batty, Brioni R. Moore, Peter L. Gibbons, Jürgen B. Bulitta, and Carl M. Kirkpatrick. "Mechanism-Based Model of Parasite Growth and Dihydroartemisinin Pharmacodynamics in Murine Malaria." Antimicrobial Agents and Chemotherapy 57, no. 1 (November 12, 2012): 508–16. http://dx.doi.org/10.1128/aac.01463-12.

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ABSTRACTMurine models are used to study erythrocytic stages of malaria infection, because parasite morphology and development are comparable to those in human malaria infections. Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) models for antimalarials are scarce, despite their potential to optimize antimalarial combination therapy. The aim of this study was to develop a mechanism-based growth model (MBGM) forPlasmodium bergheiand then characterize the parasiticidal effect of dihydroartemisinin (DHA) in murine malaria (MBGM-PK-PD). Stage-specific (ring, early trophozoite, late trophozoite, and schizont) parasite density data from Swiss mice inoculated withPlasmodium bergheiwere used for model development in S-ADAPT. A single dose of intraperitoneal DHA (10 to 100 mg/kg) or vehicle was administered 56 h postinoculation. The MBGM explicitly reflected all four erythrocytic stages of the 24-hourP. bergheilife cycle. Merozoite invasion of erythrocytes was described by a first-order process that declined with increasing parasitemia. An efflux pathway with subsequent return was additionally required to describe the schizont data, thus representing parasite sequestration or trapping in the microvasculature, with a return to circulation. A 1-compartment model with zero-order absorption described the PK of DHA, with an estimated clearance and distribution volume of 1.95 liters h−1and 0.851 liter, respectively. Parasite killing was described by a turnover model, with DHA inhibiting the production of physiological intermediates (IC50, 1.46 ng/ml). Overall, the MBGM-PK-PD described the rise in parasitemia, the nadir following DHA dosing, and subsequent parasite resurgence. This novel model is a promising tool for studying malaria infections, identifying the stage specificity of antimalarials, and providing insight into antimalarial treatment strategies.

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Tshibola Mbuyi, Marie L., Marielle K. Bouyou-Akotet, and Denise P. Mawili-Mboumba. "Molecular Detection of Plasmodium falciparum Infection in Matched Peripheral and Placental Blood Samples from Delivering Women in Libreville, Gabon." Malaria Research and Treatment 2014 (November 17, 2014): 1–6. http://dx.doi.org/10.1155/2014/486042.

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Submicroscopic infections account for more than 50% of all Plasmodium (P.) infections in areas with decreasing malaria prevalence and might contribute to poor pregnancy outcomes. The frequency of submicroscopic P. falciparum infections was assessed in matched peripheral and placental blood samples with microscopy negative or discordant results according to IPTp administration. Methods. P. falciparum infection was detected by nested PCR in matched blood samples collected from delivering women with a history of antimalarial drug treatment and living in Gabon. Results. Submicroscopic P. falciparum infections were detected in 87% (n=33) of the 44 selected matched samples. Plasmodial DNA was found in 90% (n=35/39) and 87% (n=33/38) of microscopy negative peripheral and placental blood samples, respectively. Overall, 95% of samples obtained during the high IPTp-SP coverage period had a submicroscopic infection versus 79% among those from the low coverage period. Conclusion. Submicroscopic infections frequency is high in peripheral and placental blood samples from delivering women with a history of antimalarial treatment whatever the level of IPTp coverage. These data highlight the need of accurate diagnostic tools for a regular antenatal screening of malaria during the pregnancy in endemic areas.

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Nathwani, D., and J. Spiteri. "Information about Antimalarial Chemoprophylaxis in Hospitalised Patients — Is it Adequate?" Scottish Medical Journal 42, no. 1 (February 1997): 13–15. http://dx.doi.org/10.1177/003693309704200105.

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Malaria remains a huge public health problem worldwide, with over 100 million new cases annually, causing one to two million deaths.1 This global problem spills over into the UK, with around 2000 cases of reported annually.2 The proportion of infections due to Plasmodium falciparum (PF) continues to increase and worse still accounts for five to 12 deaths per year. In 1992, Nathwani et al reported the 10 year experience of malaria cases admitted to the Regional Infection Unit, in Aberdeen, Scotland-the “Oil Capital”.3 This study was of interest in that 46% of those British residents who acquired infection had travelled to West or Central Africa on oil related business. The Oil boom of the 1980‘ s appeared to very much centred around Aberdeen and the neighbouring hinterland but did not appear to extend to Dundee which was only 60 miles further down the North-East coast. We, therefore, carried out a retrospective study of patients with malaria admitted to the Regional Infectious Diseases Unit in Dundee over a fifteen year period between 1980 and 1994.

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Koehne, Erik, Nina Zander, Miriam Rodi, Jana Held, Wolfgang Hoffmann, Rella Zoleko-Manego, Michael Ramharter, Ghyslain Mombo-Ngoma, Peter G. Kremsner, and Andrea Kreidenweiss. "Evidence for in vitro and in vivo activity of the antimalarial pyronaridine against Schistosoma." PLOS Neglected Tropical Diseases 15, no. 6 (June 24, 2021): e0009511. http://dx.doi.org/10.1371/journal.pntd.0009511.

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Background Schistosomiasis is highly prevalent in Africa. Praziquantel is effective against adult schistosomes but leaves prepatent stages unaffected—which is a limit to patient management and elimination. Given the large-scale use of praziquantel, development of drug resistance by Schistosoma is feared. Antimalarials are promising drugs for alternative treatment strategies of Schistosoma infections. Development of drugs with activity against both malaria and schistosomiasis is particularly appealing as schistosome infections often occur concomitantly with malaria parasites in sub-Saharan Africa. Therefore, antiplasmodial compounds were progressively tested against Schistosoma in vitro, in mice, and in a clinical study. Results Amongst 16 drugs and 1 control tested, pyronaridine, methylene blue and 5 other antimalarials were highly active in vitro against larval stage schistosomula with a 50% inhibitory concentration below 10 μM. Both drugs were lethal to ex vivo adult worms tested at 30 μM with methylene blue also active at 10 μM. Pyronaridine treatment of mice infected with S. mansoni at the prepatent stage reduced worm burden by 82% and cured 7 out of 12 animals, however in mice adult stages remained viable. In contrast, methylene blue inhibited adult worms by 60% but cure was not achieved. In an observational pilot trial in Gabon in children, the antimalarial drug combination pyronaridine-artesunate (Pyramax) reduced S. haematobium egg excretion from 10/10 ml urine to 0/10 ml urine, and 3 out of 4 children were cured. Conclusion Pyronaridine and methylene blue warrant further investigation as candidates for schistosomiasis treatment. Both compounds are approved for human use and evidence for their potential as antischistosomal compounds can be obtained directly from clinical testing. Particularly, pyronaridine-artesunate, already available as an antimalarial drug, calls for further clinical evaluation. Trial registration ClinicalTrials.gov Identifier NCT03201770.

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Sampaio, Guilherme Marinho, Gabriel Henrique Queiroz Oliveira, Hadassa Fonsêca Silva, Alice Pinho André Gomes Morais, Jatiacynan Andrade Souza, William José Lopes Freitas, Paulo Melo Júnior, et al. "Antimalarial chloroquine indicated for viral infections: myth ou hope?" Research, Society and Development 10, no. 10 (August 16, 2021): e486101018220. http://dx.doi.org/10.33448/rsd-v10i10.18220.

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Aim: this article describes the use of chloroquine as an antimalarial agent with potential antivirotic indications for COVID-19 infections. Methods: On line searches and gray literature have been used in the construction of this articles, whose database include PUBMED Central, BVS/BIREME, Web of Science, Science Direct, Higher Level Personnel Improvement Coordinator (CAPES), Periodic Door (Portal de Periódicos da CAPES, The Cochrane Library and PROSPERO). Results: chloroquine and hydroxychloroquine has shown appropriate clinical reports when associated with the antibiotic Azithromycin. It has been authorized for the clinical treatment of grave acute forms of COVID infections by countries like Brazil and USA. Conclusions: Chloroquine seems to have potential antivirotic properties that may be useful in the treatment of the grave acute forms of COVID-19 associated with Azithromycin. Nevertheless, Its indication must include ECG monitoring due to the risk of cardiac QT prolongation able to cause sudden deaths.

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Tiwari, Mohit K., Dharmendra K. Yadav, and Sandeep Chaudhary. "Recent Developments in Natural Product Inspired Synthetic 1,2,4- Trioxolanes (Ozonides): An Unusual Entry into Antimalarial Chemotherapy." Current Topics in Medicinal Chemistry 19, no. 10 (July 19, 2019): 831–46. http://dx.doi.org/10.2174/1568026619666190412104042.

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According to WHO “World health statistics 2018”, malaria alongside acute respiratory infections and diarrhoea, is one of the major infectious disease causing children’s death in between the age of 1-5 years. Similarly, according to another report (2016) malaria accounts for approximately 3.14% of the total disease burden worldwide. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise due to the rapid spread of malaria parasites that are resistant to antimalarial drugs. Artemisinin (8), a major breakthrough in the antimalarial chemotherapy was isolated from the plant Artemisia annua in 1972. Its semi-synthetic derivatives such as artemether (9), arteether (10), and artesunic acid (11) are quite effective against multi-drug resistant malaria strains and are currently the drug of choice for the treatment of malaria. Inspite of exhibiting excellent antimalarial activity by artemisinin (8) and its derivatives, parallel programmes for the discovery of novel natural and synthetic peroxides were also the area of investigation of medicinal chemists all over the world. In these continuous efforts of extensive research, natural ozonide (1,2,4- trioxolane) was isolated from Adiantum monochlamys (Pteridaceae) and Oleandra wallichii (Davalliaceae) in 1976. These naturally occurring stable ozonides inspired chemists to investigate this novel class for antimalarial chemotherapy. The first identification of unusually stable synthetic antimalarial 1,2,4-trioxolanes was reported in 1992. Thus, an unusual entry of ozonides in the field of antimalarial chemotherapy had occurred in the early nineties. This review highlights the recent advancements and historical developments observed during the past 42 years (1976-2018) focusing mainly on important ventures of the antimalarial 1,2,4-trioxolanes (ozonides).

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PORTER, K. A., C. L. BURCH, C. POOLE, J. J. JULIANO, S. R. COLE, and S. R. MESHNICK. "Uncertain outcomes: adjusting for misclassification in antimalarial efficacy studies." Epidemiology and Infection 139, no. 4 (July 12, 2010): 544–51. http://dx.doi.org/10.1017/s0950268810001652.

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SUMMARYEvaluation of antimalarial efficacy is difficult because recurrent parasitaemia can be due to recrudescence or re-infection. PCR is used to differentiate between recrudescences and re-infections by comparing parasite allelic variants before and after treatment. However, PCR-corrected results are susceptible to misclassification: false positives, due to re-infection by the same variant present in the patient before treatment; and false negatives, due to variants that are present but too infrequent to be detected in the pre-treatment PCR, but are then detectable post-treatment. This paper aimed to explore factors affecting the probability of false positives and proposes a Monte Carlo uncertainty analysis to account for both types of misclassification. Higher levels of transmission intensity, increased multiplicity of infection, and limited allelic variation resulted in more false recrudescences. The uncertainty analysis exploits characteristics of study data to minimize bias in the estimate of efficacy and can be applied to areas of different transmission intensity.

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Mbye, Haddijatou, Fatoumata Bojang, Aminata Seedy Jawara, Bekai Njie, Nuredin Ibrahim Mohammed, Joseph Okebe, Umberto D’Alessandro, and Alfred Amambua-Ngwa. "Tolerance of Gambian Plasmodium falciparum to Dihydroartemisinin and Lumefantrine Detected by Ex Vivo Parasite Survival Rate Assay." Antimicrobial Agents and Chemotherapy 65, no. 1 (October 5, 2020): e00720-20. http://dx.doi.org/10.1128/aac.00720-20.

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ABSTRACTMonitoring of Plasmodium falciparum sensitivity to antimalarial drugs in Africa is vital for malaria elimination. However, the commonly used ex vivo/in vitro 50% inhibitory concentration (IC50) test gives inconsistent results for several antimalarials, while the alternative ring-stage survival assay (RSA) for artemisinin derivatives has not been widely adopted. Here, we applied an alternative two-color flow cytometry-based parasite survival rate assay (PSRA) to detect ex vivo antimalarial tolerance in P. falciparum isolates from The Gambia. The PSRA infers parasite viability by quantifying reinvasion of uninfected cells following 3 consecutive days of drug exposure (10-fold the IC50 of drug for field isolates). The drug survival rate is obtained for each isolate from the slope of the growth/death curve. We obtained parasite survival rates of 41 isolates for dihydroartemisinin (DHA) and lumefantrine (LUM) out of 51 infections tested by ring-stage survival assay (RSA) against DHA. We also determined the genotypes for known drug resistance genetic loci in the P. falciparum genes Pfdhfr, Pfdhps, Pfmdr, Pfcrt, and Pfk13. The PSRA results determined for 41 Gambian isolates showed faster killing and lower variance after treatment with DHA than after treatment with LUM, despite a strong correlation between the two drugs. Four and three isolates were tolerant to DHA and LUM, respectively, with continuous growth during drug exposure. Isolates with the PfMDR1-Y184F mutant variant showed increased LUM survival, though the results were not statistically significant. Sulfadoxine/pyrimethamine (SP) resistance markers were fixed, while all other antimalarial variants were prevalent in more than 50% of the population. The PSRA detected ex vivo antimalarial tolerance in Gambian P. falciparum. This calls for its wider application and for increased vigilance against resistance to artemisinin combination therapies (ACTs) in this population.

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Plucinski, Mateusz M., Ian M. Hastings, Leah F. Moriarty, Meera Venkatesan, Ingrid Felger, and Eric S. Halsey. "Variation in Calculating and Reporting Antimalarial Efficacy against Plasmodium falciparum in Sub-Saharan Africa: A Systematic Review of Published Reports." American Journal of Tropical Medicine and Hygiene 104, no. 5 (May 5, 2021): 1820–29. http://dx.doi.org/10.4269/ajtmh.20-1481.

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ABSTRACTAntimalarials, in particular artemisinin-based combination therapies (ACTs), are critical tools in reducing the global burden of malaria, which is concentrated in sub-Saharan Africa. Performing and reporting antimalarial efficacy studies in a transparent and standardized fashion permit comparison of efficacy outcomes across countries and time periods. This systematic review summarizes study compliance with WHO laboratory and reporting guidance pertaining to antimalarial therapeutic efficacy studies and evaluates how well studies from sub-Saharan Africa adhered to these guidelines. We included all published studies (January 2020 or before) performed in sub-Saharan Africa where ACT efficacy for treatment of uncomplicated Plasmodium falciparum infection was reported. The primary outcome was a composite indicator for study methodology consistent with WHO guidelines for statistical analysis of corrected efficacy, defined as an article presenting a Kaplan–Meier survival analysis of corrected efficacy or reporting a per-protocol analysis where new infections were excluded from the numerator and denominator. Of 581 articles screened, we identified 279 for the review. Molecular correction was used in 83% (232/279) to distinguish new infections from recrudescences in subjects experiencing recurrent parasitemia. Only 45% (99/221) of articles with therapeutic efficacy as a primary outcome and performing molecular correction reported corrected efficacy outcomes calculated in a way consistent with WHO recommendations. These results indicate a widespread lack of compliance with WHO-recommended methods of analysis, which may result in biases in how antimalarial effectiveness is being measured and reported from sub-Saharan Africa.

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Kocken, Clemens H. M., Edmond J. Remarque, Martin A. Dubbeld, Sharon Wein, Annemarie van der Wel, R. Joyce Verburgh, Henri J. Vial, and Alan W. Thomas. "Statistical Model To Evaluate In Vivo Activities of Antimalarial Drugs in a Plasmodium cynomolgi-Macaque Model for Plasmodium vivax Malaria." Antimicrobial Agents and Chemotherapy 53, no. 2 (November 17, 2008): 421–27. http://dx.doi.org/10.1128/aac.00576-08.

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ABSTRACT Preclinical animal models informing antimalarial drug development are scarce. We have used asexual erythrocytic Plasmodium cynomolgi infections of rhesus macaques to model Plasmodium vivax during preclinical development of compounds targeting parasite phospholipid synthesis. Using this malaria model, we accumulated data confirming highly reproducible infection patterns, with self-curing parasite peaks reproducibly preceding recrudescence peaks. We applied nonlinear mixed-effect (NLME) models, estimating treatment effects in three drug studies: G25 (injected) and the bisthiazolium prodrugs TE4gt and TE3 (oral). All compounds fully cured P. cynomolgi-infected macaques, with significant effects on parasitemia height and time of peak. Although all three TE3 doses tested were fully curative, NLME models discriminated dose-dependent differential pharmacological antimalarial activity. By applying NLME modeling treatment effects are readily quantified. Such drug development studies are more informative and contribute to reduction and refinement in animal experimentation.

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Kwiek, Jesse J., Alisa P. Alker, Emily C. Wenink, Marjorie Chaponda, Linda V. Kalilani, and Steven R. Meshnick. "Estimating True Antimalarial Efficacy by Heteroduplex Tracking Assay in Patients with Complex Plasmodium falciparum Infections." Antimicrobial Agents and Chemotherapy 51, no. 2 (November 20, 2006): 521–27. http://dx.doi.org/10.1128/aac.00902-06.

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ABSTRACT Heteroduplex tracking assays (HTAs) of Plasmodium falciparum merozoite surface protein 1 block-2 were used to assess complexity of infection and treatment efficacy in a trial of three antimalarial treatments in 141 Malawian pregnant women. An elevated complexity of infection (COI) was associated with anemia, parasite burden, and human immunodeficiency virus infection but was not associated with age or gravidity. Comparisons of HTA patterns before and after treatment allowed the classification of 20 of 30 (66%) recurrent episodes as either definite treatment failures or reinfections. An elevated COI was strongly associated with treatment failure (P = 0.003). An algorithm was developed to assign a probability of failure for the 10 indeterminate participants, some of whose infections shared a single variant of high prevalence (>10%). By summing these probabilities, treatment efficacy was estimated.

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Chaniad, Prapaporn, Tachpon Techarang, Arisara Phuwajaroanpong, and Chuchard Punsawad. "Antimalarial Activity and Toxicological Assessment of Betula alnoides Extract against Plasmodium berghei Infections in Mice." Evidence-Based Complementary and Alternative Medicine 2019 (November 13, 2019): 1–8. http://dx.doi.org/10.1155/2019/2324679.

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The resistance of malaria parasites to the current antimalarial drugs has led to the search for novel effective drugs. Betula alnoides has been traditionally used for the treatment of malaria, but the scientific evidence to substantiate this claim is still lacking. Therefore, the present study aimed at evaluating the antimalarial activity and toxicity of an aqueous stem extract of B. alnoides in a mouse model. The in vivo antimalarial activity of an aqueous stem extract of B. alnoides was determined by a 4-day suppressive test in mice infected with chloroquine-sensitive Plasmodium berghei ANKA. The B. alnoides extract was administered orally at different doses of 200, 400, and 600 mg/kg body weight. The levels of parasitaemia, survival time, body weight change, and food and water consumption of the mice were determined. The acute toxicity of the extract was assessed in the mice for 14 days after the administration of a single oral dose of 5000 mg/kg. An aqueous stem extract of B. alnoides exhibited a significant dose-dependent reduction of parasitaemia in P. berghei-infected mice at all dose levels compared to the reduction in the negative control. Extract doses of 200, 400, and 600 mg/kg body weight suppressed the levels of parasitaemia by 46.90, 58.39, and 71.26%, respectively. The extract also significantly prolonged the survival times of the P. berghei-infected mice compared to the survival times of the negative control mice. In addition, at all dose levels, the extract prevented body weight loss in P. berghei-infected mice. For the acute toxicity, there were no significant alterations in the biochemical parameters and in the histopathology. In conclusion, the aqueous stem extract of B. alnoides possesses antimalarial properties. A single oral dose of 5000 mg/kg body weight had no significant toxic effects on the function and structure of the kidneys and liver. These results support its use in traditional medicine for the treatment of malaria.

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Su, Zhong, Mariela Segura, Kenneth Morgan, J. Concepcion Loredo-Osti, and Mary M. Stevenson. "Impairment of Protective Immunity to Blood-Stage Malaria by Concurrent Nematode Infection." Infection and Immunity 73, no. 6 (June 2005): 3531–39. http://dx.doi.org/10.1128/iai.73.6.3531-3539.2005.

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ABSTRACT Helminthiases, which are highly prevalent in areas where malaria is endemic, have been shown to modulate or suppress the immune response to unrelated antigens or pathogens. In this study, we established a murine model of coinfection with a gastrointestinal nematode parasite, Heligmosomoides polygyrus, and the blood-stage malaria parasite Plasmodium chabaudi AS in order to investigate the modulation of antimalarial immunity by concurrent nematode infection. Chronic infection with the nematode for 2, 3, or 5 weeks before P. chabaudi AS infection severely impaired the ability of C57BL/6 mice to control malaria, as demonstrated by severe mortality and significantly increased malaria peak parasitemia levels. Coinfected mice produced significantly lower levels of gamma interferon (IFN-γ) during P. chabaudi AS infection than mice infected with malaria alone. Concurrent nematode infection also suppressed production of type 1-associated, malaria-specific immunoglobulin G2a. Mice either infected with the nematode alone or coinfected with the nematode and malaria had high transforming growth factor β1 (TGF-β1) levels, and concurrent nematode and malaria infections resulted in high levels of interleukin-10 in vivo. Splenic CD11c+ dendritic cells (DC) from mice infected with malaria alone and coinfected mice showed similarly increased expression of CD40, CD80, and CD86, but DC from coinfected mice were unable to induce CD4+ T-cell proliferation and optimal IFN-γ production in response to the malaria antigen in vitro. Importantly, treatment of nematode-infected mice with an anthelmintic drug prior to malaria infection fully restored protective antimalarial immunity and reduced TGF-β1 levels. These results demonstrate that concurrent nematode infection strongly modulates multiple aspects of immunity to blood-stage malaria and consequently impairs the development of protective antimalarial immunity.

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Co, Edgie-Mark A., Richard A. Dennull, Drew D. Reinbold, Norman C. Waters, and Jacob D. Johnson. "Assessment of Malaria In Vitro Drug Combination Screening and Mixed-Strain Infections Using the Malaria Sybr Green I-Based Fluorescence Assay." Antimicrobial Agents and Chemotherapy 53, no. 6 (April 6, 2009): 2557–63. http://dx.doi.org/10.1128/aac.01370-08.

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ABSTRACT Several drug development strategies, including optimization of new antimalarial drug combinations, have been used to counter malaria drug resistance. We evaluated the malaria Sybr green I-based fluorescence (MSF) assay for its use in in vitro drug combination sensitivity assays. Drug combinations of previously published synergistic (atovaquone and proguanil), indifferent (chloroquine and azithromycin), and antagonistic (chloroquine and atovaquone) antimalarial drug interactions were tested against Plasmodium falciparum strains D6 and W2 using the MSF assay. Fifty percent inhibitory concentrations (IC50s) were calculated for individual drugs and in fixed ratio combinations relative to their individual IC50s. Subsequent isobologram analysis and fractional inhibitory concentration determinations demonstrated the expected drug interaction pattern for each combination tested. Furthermore, we explored the ability of the MSF assay to examine mixed parasite population dynamics, which are commonly seen in malaria patient isolates. Specifically, the capacity of the MSF assay to discern between single and mixed parasite populations was determined. To simulate mixed infections in vitro, fixed ratios of D6 and W2 strains were cocultured with antimalarial drugs and IC50s were determined using the MSF assay. Dichotomous concentration curves indicated that the sensitive and resistant parasites composing the genetically heterogeneous population were detectable. Biphasic analysis was performed to obtain subpopulation IC50s for comparison to those obtained for the individual malaria strains alone. In conclusion, the MSF assay allows for reliable antimalarial drug combination screening and provides an important method to discern between homogenous and heterogeneous parasite populations.

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Wulandari, Luh Putu Lila, and Virginia Wiseman. "Engaging the private sector to improve antimicrobial use in the community." Public Health and Preventive Medicine Archive 6, no. 2 (December 1, 2018): 79. http://dx.doi.org/10.15562/phpma.v6i2.187.

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Antimicrobial resistance (AMR) is one of the world’s most pressing public health threats. It increases the cost of health care through longer duration of illness and hospital stays, additional tests, and the need for more expensive drugs.AMR refers to the ability of a microorganism to stop an antimicrobial (such as an antibiotic, antiviral or antimalarial) from working against it. As a consequence of AMR, standard treatments become ineffective, and infections persist and may spread to others. The impact of AMR is far-reaching and equates to the situation before the discovery of antibiotics, when even small infections were difficult, or very often impossible to treat, and medical procedures too risky to perform due to the potential of untreatable infection.

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Casertano, Marcello, Marialuisa Menna, Caterina Fattorusso, Nicoletta Basilico, Silvia Parapini, Marco Persico, and Concetta Imperatore. "Antiplasmodial Activity of p-Substituted Benzyl Thiazinoquinone Derivatives and Their Potential against Parasitic Infections." Molecules 25, no. 7 (March 27, 2020): 1530. http://dx.doi.org/10.3390/molecules25071530.

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Malaria is a life-threatening disease and, what is more, the resistance to available antimalarial drugs is a recurring problem. The resistance of Plasmodium falciparum malaria parasites to previous generations of medicines has undermined malaria control efforts and reversed gains in child survival. This paper describes a continuation of our ongoing efforts to investigate the effects against Plasmodium falciparum strains and human microvascular endothelial cells (HMEC-1) of a series of methoxy p-benzyl-substituted thiazinoquinones designed starting from a pointed antimalarial lead candidate. The data obtained from the newly tested compounds expanded the structure–activity relationships (SARs) of the thiazinoquinone scaffold, indicating that antiplasmodial activity is not affected by the inductive effect but rather by the resonance effect of the introduced group at the para position of the benzyl substituent. Indeed, the current survey was based on the evaluation of antiparasitic usefulness as well as the selectivity on mammalian cells of the tested p-benzyl-substituted thiazinoquinones, upgrading the knowledge about the active thiazinoquinone scaffold.

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Upton, L. M., P. M. Brock, T. S. Churcher, A. C. Ghani, P. W. Gething, M. J. Delves, K. A. Sala, D. Leroy, R. E. Sinden, and A. M. Blagborough. "Lead Clinical and Preclinical Antimalarial Drugs Can Significantly Reduce Sporozoite Transmission to Vertebrate Populations." Antimicrobial Agents and Chemotherapy 59, no. 1 (November 10, 2014): 490–97. http://dx.doi.org/10.1128/aac.03942-14.

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ABSTRACTTo achieve malarial elimination, we must employ interventions that reduce the exposure of human populations to infectious mosquitoes. To this end, numerous antimalarial drugs are under assessment in a variety of transmission-blocking assays which fail to measure the single crucial criteria of a successful intervention, namely impact on case incidence within a vertebrate population (reduction in reproductive number/effect size). Consequently, any reduction in new infections due to drug treatment (and how this may be influenced by differing transmission settings) is not currently examined, limiting the translation of any findings. We describe the use of a laboratory population model to assess how individual antimalarial drugs can impact the number of secondaryPlasmodium bergheiinfections over a cycle of transmission. We examine the impact of multiple clinical and preclinical drugs on both insect and vertebrate populations at multiple transmission settings. Both primaquine (>6 mg/kg of body weight) and NITD609 (8.1 mg/kg) have significant impacts across multiple transmission settings, but artemether and lumefantrine (57 and 11.8 mg/kg), OZ439 (6.5 mg/kg), and primaquine (<1.25 mg/kg) demonstrated potent efficacy only at lower-transmission settings. While directly demonstrating the impact of antimalarial drug treatment on vertebrate populations, we additionally calculate effect size for each treatment, allowing for head-to-head comparison of the potential impact of individual drugs within epidemiologically relevant settings, supporting their usage within elimination campaigns.

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Narh, Charles A., Anita Ghansah, Michael F. Duffy, Shazia Ruybal-Pesántez, Christiana O. Onwona, Abraham R. Oduro, Kwadwo A. Koram, Karen P. Day, and Kathryn E. Tiedje. "Evolution of Antimalarial Drug Resistance Markers in the Reservoir of Plasmodium falciparum Infections in the Upper East Region of Ghana." Journal of Infectious Diseases 222, no. 10 (May 27, 2020): 1692–701. http://dx.doi.org/10.1093/infdis/jiaa286.

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Abstract Background The majority of Plasmodium falciparum infections, constituting the reservoir in all ages, are asymptomatic in high-transmission settings in Africa. The role of this reservoir in the evolution and spread of drug resistance was explored. Methods Population genetic analyses of the key drug resistance–mediating polymorphisms were analyzed in a cross-sectional survey of asymptomatic P. falciparum infections across all ages in Bongo District, Ghana. Results Seven years after the policy change to artemisinin-based combination therapies in 2005, the pfcrt K76 and pfmdr1 N86 wild-type alleles have nearly reached fixation and have expanded via soft selective sweeps on multiple genetic backgrounds. By constructing the pfcrt-pfmdr1-pfdhfr-pfdhps multilocus haplotypes, we found that the alleles at these loci were in linkage equilibrium and that multidrug-resistant parasites have not expanded in this reservoir. For pfk13, 32 nonsynonymous mutations were identified; however, none were associated with artemisinin-based combination therapy resistance. Conclusions The prevalence and selection of alleles/haplotypes by antimalarials were similar to that observed among clinical cases in Ghana, indicating that they do not represent 2 subpopulations with respect to these markers. Thus, the P. falciparum reservoir in all ages can contribute to the maintenance and spread of antimalarial resistance.

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Mwesigwa, Moses, Jessica L. Webster, Sam Lubwama Nsobya, Alexander Rowan, Mukunda Singh Basnet, Christina R. Phares, Michelle Weinberg, et al. "Prevalence of Malaria Parasite Infections among U.S.-Bound Congolese Refugees with and without Splenomegaly." American Journal of Tropical Medicine and Hygiene 104, no. 3 (March 3, 2021): 996–99. http://dx.doi.org/10.4269/ajtmh.20-0924.

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ABSTRACTAll U.S.-bound refugees from sub-Saharan Africa receive presumptive antimalarial treatment before departing for the United States. Among U.S.-bound Congolese refugees, breakthrough malaria cases and persistent splenomegaly have been reported. In response, an enhanced malaria diagnostic program was instituted. Here, we report the prevalence of plasmodial infection among 803 U.S.-bound Congolese refugees who received enhanced diagnostics. Infections by either rapid diagnostic test (RDT) or PCR were detected in 187 (23%) refugees, with 78 (10%) by RDT only, 35 (4%) by PCR only, and 74 (9%) by both. Infections identified by PCR included 103 monoinfections (87 Plasmodium falciparum, eight Plasmodium ovale, seven Plasmodium vivax, and one Plasmodium malariae) and six mixed infections. Splenomegaly was associated with malaria detectable by RDT (odds ratio: 1.8, 95% CI: 1.0–3.0), but not by PCR. Splenomegaly was not strongly associated with parasitemia, indicating that active malaria parasitemia is not necessary for splenomegaly.

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Nagaraj, G., M. V. Uma, M. S. Shivayogi, and Hemalatha Balaram. "Antimalarial Activities of Peptide Antibiotics Isolated from Fungi." Antimicrobial Agents and Chemotherapy 45, no. 1 (January 1, 2001): 145–49. http://dx.doi.org/10.1128/aac.45.1.145-149.2001.

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ABSTRACT Malaria caused by Plasmodium falciparum is a major public health problem in the developing countries of the world. Clinical treatment of malaria has become complicated due to the occurrence of infections caused by drug resistant parasites. Secondary metabolites from fungi are an attractive source of chemotherapeutic agents. This work reports the isolation and in vitro antiplasmodial activities of peptide antibiotics of fungal origin. The three peptide antibiotics used in this study were efrapeptins, zervamicins, and antiamoebin. The high-performance liquid chromatography-purified peptides were characterized by nuclear magnetic resonance and mass spectral analysis. All three fungal peptides kill P. falciparum in culture with 50% inhibitory concentrations in the micromolar range. A possible mode of action of these peptide antibiotics on P. falciparum is presented.

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Coppi, Alida, Melissa Cabinian, David Mirelman, and Photini Sinnis. "Antimalarial Activity of Allicin, a Biologically Active Compound from Garlic Cloves." Antimicrobial Agents and Chemotherapy 50, no. 5 (May 2006): 1731–37. http://dx.doi.org/10.1128/aac.50.5.1731-1737.2006.

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ABSTRACT The incidence of malaria is increasing, and there is an urgent need to identify new drug targets for both prophylaxis and chemotherapy. Potential new drug targets include Plasmodium proteases that play critical roles in the parasite life cycle. We have previously shown that the major surface protein of Plasmodium sporozoites, the circumsporozoite protein (CSP), is proteolytically processed by a parasite-derived cysteine protease, and this processing event is temporally associated with sporozoite invasion of host cells. E-64, a cysteine protease inhibitor, inhibits CSP processing and prevents invasion of host cells in vitro and in vivo. Here we tested allicin, a cysteine protease inhibitor found in garlic extracts, for its ability to inhibit malaria infection. At low concentrations, allicin was not toxic to either sporozoites or mammalian cells. At these concentrations, allicin inhibited CSP processing and prevented sporozoite invasion of host cells in vitro. In vivo, mice injected with allicin had decreased Plasmodium infections compared to controls. When sporozoites were treated with allicin before injection into mice, malaria infection was completely prevented. We also tested allicin on erythrocytic stages and found that a 4-day regimen of allicin administered either orally or intravenously significantly decreased parasitemias and increased the survival of infected mice by 10 days. Together, these experiments demonstrate that the same cysteine protease inhibitor can target two different life cycle stages in the vertebrate host.

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Biosca, Arnau, Lorin Dirscherl, Ernest Moles, Santiago Imperial, and Xavier Fernàndez-Busquets. "An ImmunoPEGliposome for Targeted Antimalarial Combination Therapy at the Nanoscale." Pharmaceutics 11, no. 7 (July 16, 2019): 341. http://dx.doi.org/10.3390/pharmaceutics11070341.

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Combination therapies, where two drugs acting through different mechanisms are administered simultaneously, are one of the most efficient approaches currently used to treat malaria infections. However, the different pharmacokinetic profiles often exhibited by the combined drugs tend to decrease treatment efficacy as the compounds are usually eliminated from the circulation at different rates. To circumvent this obstacle, we have engineered an immunoliposomal nanovector encapsulating hydrophilic and lipophilic compounds in its lumen and lipid bilayer, respectively. The antimalarial domiphen bromide has been encapsulated in the liposome membrane with good efficiency, although its high IC50 of ca. 1 µM for living parasites complicates its use as immunoliposomal therapy due to erythrocyte agglutination. The conjugation of antibodies against glycophorin A targeted the nanocarriers to Plasmodium-infected red blood cells and to gametocytes, the sole malaria parasite stage responsible for the transmission from the human to the mosquito vector. The antimalarials pyronaridine and atovaquone, which block the development of gametocytes, have been co-encapsulated in glycophorin A-targeted immunoliposomes. The co-immunoliposomized drugs have activities significantly higher than their free forms when tested in in vitro Plasmodium falciparum cultures: Pyronaridine and atovaquone concentrations that, when encapsulated in immunoliposomes, resulted in a 50% inhibition of parasite growth had no effect on the viability of the pathogen when used as free drugs.

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Mandal, Rabindra K., Rosie J. Crane, James A. Berkley, Wilson Gumbi, Juliana Wambua, Joyce Mwongeli Ngoi, Francis M. Ndungu, and Nathan W. Schmidt. "Longitudinal Analysis of Infant Stool Bacteria Communities Before and After Acute Febrile Malaria and Artemether-Lumefantrine Treatment." Journal of Infectious Diseases 220, no. 4 (December 24, 2018): 687–98. http://dx.doi.org/10.1093/infdis/jiy740.

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Abstract Background Gut microbiota were recently shown to impact malaria disease progression and outcome, and prior studies have shown that Plasmodium infections increase the likelihood of enteric bacteria causing systemic infections. Currently, it is not known whether Plasmodium infection impacts human gut microbiota as a prelude to bacteremia or whether antimalarials affect gut microbiota. Our goal was to determine to what degree Plasmodium infections and antimalarial treatment affect human gut microbiota. Methods One hundred Kenyan infants underwent active surveillance for malaria from birth to 10 months of age. Each malaria episode was treated with artemether-lumefantrine (AL). Any other treatments, including antibiotics, were recorded. Stool samples were collected on an approximately biweekly basis. Ten children were selected on the basis of stool samples having been collected before (n = 27) or after (n = 17) a malaria episode and without antibiotics having been administered between collections. These samples were subjected to 16S ribosomal ribonucleic acid gene (V3–V4 region) sequencing. Results Bacterial community network analysis revealed no obvious differences in the before and after malaria/AL samples, which was consistent with no difference in alpha and beta diversity and taxonomic analysis at the family and genus level with one exception. At the sequence variant (SV) level, akin to bacterial species, only 1 of the top 100 SVs was significantly different. In addition, predicted metagenome analysis revealed no significant difference in metagenomic capacity between before and after malaria/AL samples. The number of malaria episodes, 1 versus 2, explained significant variation in gut microbiota composition of the infants. Conclusions In-depth bioinformatics analysis of stool bacteria has revealed for the first time that human malaria episode/AL treatment have minimal effects on gut microbiota in Kenyan infants.

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TRIPATHI, R., S. DHAWAN, and G. P. DUTTA. "Blood schizontocidal activity of azithromycin and its combination with α/β arteether against multi-drug resistant Plasmodium yoelii nigeriensis, a novel MDR parasite model for antimalarial screening." Parasitology 131, no. 3 (June 8, 2005): 295–301. http://dx.doi.org/10.1017/s003118200500778x.

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Many different drug-resistant lines of rodent malaria are available as screening models. It is obligatory to screen new compounds for antimalarial activity against a series of resistant lines in order to identify a compound with potential for the treatment of multi-drug resistant (MDR) malaria infections. Instead of using a battery of resistant lines, a single MDR Plasmodium yoelii nigeriensis strain that shows a wide spectrum of drug resistance to high doses of chloroquine, mepacrine, amodiaquine, mefloquine, quinine, quinidine, halofantrine as well as tetracyclines, fluoroquinolines and erythromycin, was used to assess the blood schizontocidal efficacy of a new macrolide azithromycin and other antibiotics. The present study shows that only azithromycin has the potential to control an MDR P. y. nigeriensis infection in Swiss mice, provided the treatment with a dose of 50–100 mg/kg/day by oral route is continued for a period of 7 days. Tetracycline, oxytetracycline, doxycyline, erythromycin, ciprofloxacin and norfloxacin, although active in vitro, failed to protect the mice. Tetracycline, ciprofloxacin and norfloxacin combinations with chloroquine did not control the infection. Additionally, the antimalarial efficacy of azithromycin can be potentiated with the addition of arteether, which is an ethyl ether derivative of artemisinin. A total (100%) curative effect has been obtained with a shorter regimen of 4 days only.

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Greenhouse, Bryan, Christian Dokomajilar, Alan Hubbard, Philip J. Rosenthal, and Grant Dorsey. "Impact of Transmission Intensity on the Accuracy of Genotyping To Distinguish Recrudescence from New Infection in Antimalarial Clinical Trials." Antimicrobial Agents and Chemotherapy 51, no. 9 (June 25, 2007): 3096–103. http://dx.doi.org/10.1128/aac.00159-07.

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ABSTRACT Antimalarial clinical trials use genotyping techniques to distinguish new infection from recrudescence. In areas of high transmission, the accuracy of genotyping may be compromised due to the high number of infecting parasite strains. We compared the accuracies of genotyping methods, using up to six genotyping markers, to assign outcomes for two large antimalarial trials performed in areas of Africa with different transmission intensities. We then estimated the probability of genotyping misclassification and its effect on trial results. At a moderate-transmission site, three genotyping markers were sufficient to generate accurate estimates of treatment failure. At a high-transmission site, even with six markers, estimates of treatment failure were 20% for amodiaquine plus artesunate and 17% for artemether-lumefantrine, regimens expected to be highly efficacious. Of the observed treatment failures for these two regimens, we estimated that at least 45% and 35%, respectively, were new infections misclassified as recrudescences. Increasing the number of genotyping markers improved the ability to distinguish new infection from recrudescence at a moderate-transmission site, but using six markers appeared inadequate at a high-transmission site. Genotyping-adjusted estimates of treatment failure from high-transmission sites may represent substantial overestimates of the true risk of treatment failure.

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Puri, S. K., and Naresh Singh. "Azithromycin: Antimalarial Profile against Blood- and Sporozoite-Induced Infections in Mice and Monkeys." Experimental Parasitology 94, no. 1 (January 2000): 8–14. http://dx.doi.org/10.1006/expr.1999.4465.

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Franken, Gabriele, Irmela Müller-Stöver, Martha C. Holtfreter, Susanne Walter, Heinz Mehlhorn, Alfons Labisch, Dieter Häussinger, and Joachim Richter. "Why do Plasmodium malariae infections sometimes occur in spite of previous antimalarial medication?" Parasitology Research 111, no. 2 (February 18, 2012): 943–46. http://dx.doi.org/10.1007/s00436-012-2851-8.

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Lee, Belinda J., Ajay Singh, Peggy Chiang, Scott J. Kemp, Erick A. Goldman, Michael I. Weinhouse, George P. Vlasuk, and Philip J. Rosenthal. "Antimalarial Activities of Novel Synthetic Cysteine Protease Inhibitors." Antimicrobial Agents and Chemotherapy 47, no. 12 (December 2003): 3810–14. http://dx.doi.org/10.1128/aac.47.12.3810-3814.2003.

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ABSTRACT Among promising new targets for antimalarial chemotherapy are the cysteine protease hemoglobinases falcipain-2 and falcipain-3. We evaluated the activities of synthetic peptidyl aldehyde and α-ketoamide cysteine protease inhibitors against these proteases, against cultured Plasmodium falciparum parasites, and in a murine malaria model. Optimized compounds inhibited falcipain-2 and falcipain-3, blocked hemoglobin hydrolysis, and prevented the development of P. falciparum at nanomolar concentrations. The compounds were equally active against multiple strains of P. falciparum with varied sensitivities to standard antimalarial agents. The peptidyl inhibitors were consistently less active against vinckepain-2, the putative falcipain-2 and falcipain-3 ortholog of the rodent malaria parasite Plasmodium vinckei. The lead compound morpholinocarbonyl-leucine-homophenylalanine aldehyde, which blocked P. falciparum development at low nanomolar concentrations, was tested in a murine P. vinckei model. When infused continuously at a rate of 30 mg/kg of body weight/day, the compound delayed the progression of malaria but did not eradicate infections. Our data demonstrate the potent antimalarial activities of novel cysteine protease inhibitors. Additionally, they highlight the importance of consideration of the specific enzyme targets of animal model parasites. In the case of falcipains, differences between P. falciparum and rodent parasites complicate the use of the rodent malaria model in the drug discovery process.

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Chaumeau, Victor, Ladda Kajeechiwa, Bénédicte Fustec, Jordi Landier, Saw Naw Nyo, Saw Nay Hsel, Phabele Phatharakokordbun, et al. "Contribution of Asymptomatic Plasmodium Infections to the Transmission of Malaria in Kayin State, Myanmar." Journal of Infectious Diseases 219, no. 9 (November 29, 2018): 1499–509. http://dx.doi.org/10.1093/infdis/jiy686.

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Abstract Background The objective of mass antimalarial drug administration (MDA) is to eliminate malaria rapidly by eliminating the asymptomatic malaria parasite reservoirs and interrupting transmission. In the Greater Mekong Subregion, where artemisinin-resistant Plasmodium falciparum is now widespread, MDA has been proposed as an elimination accelerator, but the contribution of asymptomatic infections to malaria transmission has been questioned. The impact of MDA on entomological indices has not been characterized previously. Methods MDA was conducted in 4 villages in Kayin State (Myanmar). Malaria mosquito vectors were captured 3 months before, during, and 3 months after MDA, and their Plasmodium infections were detected by polymerase chain reaction (PCR) analysis. The relationship between the entomological inoculation rate, the malaria prevalence in humans determined by ultrasensitive PCR, and MDA was characterized by generalized estimating equation regression. Results Asymptomatic P. falciparum and Plasmodium vivax infections were cleared by MDA. The P. vivax entomological inoculation rate was reduced by 12.5-fold (95% confidence interval [CI], 1.6–100-fold), but the reservoir of asymptomatic P. vivax infections was reconstituted within 3 months, presumably because of relapses. This was coincident with a 5.3-fold (95% CI, 4.8–6.0-fold) increase in the vector infection rate. Conclusion Asymptomatic infections are a major source of malaria transmission in Southeast Asia.

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Cowell, Annie, and Elizabeth Winzeler. "Exploration of the Plasmodium falciparum Resistome and Druggable Genome Reveals New Mechanisms of Drug Resistance and Antimalarial Targets." Microbiology Insights 11 (January 2018): 117863611880852. http://dx.doi.org/10.1177/1178636118808529.

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Plasmodium parasites, the causative agent of malaria infections, rapidly evolve drug resistance and escape detection by the human immune response via the incredible mutability of its genome. Understanding the genetic mechanisms by which Plasmodium parasites develop antimalarial resistance is essential to understanding why most drugs fail in the clinic and designing the next generation of therapies. A systematic genomic analysis of 262 Plasmodium falciparum clones with stable in vitro resistance to 37 diverse compounds with potent antimalarial activity was undertaken with the main goal of identifying new drug targets. Despite several challenges inherent to this method of in vitro drug resistance generation followed by whole genome sequencing, the study was able to identify a likely drug target or resistance gene for every compound for which resistant parasites could be generated. Known and novel P falciparum resistance mediators were discovered along with several new promising antimalarial drug targets. Surprisingly, gene amplification events contributed to one-third of the drug resistance acquisition events. The study can serve as a model for drug discovery and resistance analyses in other similar microbial pathogens amenable to in vitro culture.

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Preuss, Janina, Michael Hedrick, Eduard Sergienko, Anthony Pinkerton, Arianna Mangravita-Novo, Layton Smith, Carolin Marx, et al. "High-Throughput Screening for Small-Molecule Inhibitors of Plasmodium falciparum Glucose-6-Phosphate Dehydrogenase 6-Phosphogluconolactonase." Journal of Biomolecular Screening 17, no. 6 (April 11, 2012): 738–51. http://dx.doi.org/10.1177/1087057112442382.

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Plasmodium falciparum causes severe malaria infections in millions of people every year. The parasite is developing resistance to the most common antimalarial drugs, which creates an urgent need for new therapeutics. A promising and attractive target for antimalarial drug design is the bifunctional enzyme glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase (PfGluPho) of P. falciparum, which catalyzes the key step in the parasites’ pentose phosphate pathway. In this study, we describe the development of a high-throughput screening assay to identify small-molecule inhibitors of recombinant PfGluPho. The optimized assay was used to screen three small-molecule compound libraries—namely, LOPAC (Sigma-Aldrich, 1280 compounds), Spectrum (MicroSource Discovery Systems, 1969 compounds), and DIVERSet (ChemBridge, 49 971 compounds). These pilot screens identified 899 compounds that inhibited PfGluPho activity by at least 50%. Selected compounds were further studied to determine IC50 values in an orthogonal assay, the type of inhibition and reversibility, and effects on P. falciparum growth. Screening results and follow-up studies for selected PfGluPho inhibitors are presented. Our high-throughput screening assay may provide the basis to identify novel and urgently needed antimalarial drugs.

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Xie, Stanley C., Riley D. Metcalfe, Hirotake Mizutani, Tanya Puhalovich, Eric Hanssen, Craig J. Morton, Yawei Du, et al. "Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome." Proceedings of the National Academy of Sciences 118, no. 39 (September 21, 2021): e2107213118. http://dx.doi.org/10.1073/pnas.2107213118.

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The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome (Pf20S) β5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax. They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against P. falciparum infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to Pf20S than to human constitutive 20S (Hs20Sc). Comparison of the cryo-electron microscopy (EM) structures of Pf20S and Hs20Sc in complex with MPI-5 and Pf20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in P. falciparum, underpinning the design of potent and selective antimalarial proteasome inhibitors.

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F.O, Omoya, and Ajayi KO. "Prevalence of Malaria among Febrile Patients attending Government Hospitals in Ondo State, South-West Nigeria." American Journal of Epidemiology & Public Health 4, no. 4 (December 2020): 017–24. http://dx.doi.org/10.37871/ajeph.id40.

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Background: The use of malaria infection prevalence among febrile patients is a valuable epidemiological surveillance tool. In this study, a cross sectional study was conducted among febrile patients in selected government Hospitals in Ondo State for malaria prevalence. Results: Plasmodium falciparum is the only encountered malaria parasite with prevalence values of 82.72% (426/515) and 80.19% (413/515) were obtained for microscopy and RDTs respectively. The prevalence of malaria among the males (86.59%) was higher than the females (80.65%), all age groups in this study were vulnerable with highest infection rate of 89.66% among age group 11-20 years. The parasites densities ranged between 209 and 22310 parasites/μl with a mean parasitaemia of 5522.17 ± 183.30 parasites/μl. The prevalence of malaria among the febrile participants that have taken antimalarial drug before visiting the hospital is 82.94% (389/469) with the mean parasitaemia of 4615.21 ± 188.14 parasites/μl while among the participants that have taken herbs before visiting the hospital the prevalence is 85.03% (142/167) with the mean parasitaemia of 4913.81 ± 330.20 parasites/μl. Conclusion: There was high prevalence of malaria among febrile patients and this fi nding will help improve the diagnosis and treatment of other febrile (non-malaria) infections, limit antimalarial usage to only malaria parasite-based test true positives and serve as a guide to combat malaria drug resistance in the study area.

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Su, Zhong, Mariela Segura, and Mary M. Stevenson. "Reduced Protective Efficacy of a Blood-Stage Malaria Vaccine by Concurrent Nematode Infection." Infection and Immunity 74, no. 4 (April 2006): 2138–44. http://dx.doi.org/10.1128/iai.74.4.2138-2144.2006.

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ABSTRACT Helminth infections, which are prevalent in areas where malaria is endemic, have been shown to modulate immune responses to unrelated pathogens and have been implicated in poor efficacy of malaria vaccines in humans. We established a murine coinfection model involving blood-stage Plasmodium chabaudi AS malaria and a gastrointestinal nematode, Heligmosomoides polygyrus, to investigate the impact of nematode infection on the protective efficacy of a malaria vaccine. C57BL/6 mice immunized with crude blood-stage P. chabaudi AS antigen in TiterMax adjuvant developed strong protection against malaria challenge. The same immunization protocol failed to induce strong protection in H. polygyrus-infected mice. Immunized nematode-infected mice produced significantly lower levels of malaria-specific antibody than nematode-free mice produced. In response to nematode and malarial antigens, spleen cells from immunized nematode-infected mice produced significantly lower levels of gamma interferon but more interleukin-4 (IL-4), IL-13, and IL-10 in vitro than spleen cells from immunized nematode-free mice produced. Furthermore, H. polygyrus infection also induced a strong transforming growth factor β1 response in vivo and in vitro. Deworming treatment of H. polygyrus-infected mice before antimalarial immunization, but not deworming treatment after antimalarial immunization, restored the protective immunity to malaria challenge. These results demonstrate that concurrent nematode infection strongly modulates immune responses induced by an experimental malaria vaccine and consequently suppresses the protective efficacy of the vaccine against malaria challenge.

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Andrews, Katherine T., David P. Fairlie, Praveen K. Madala, John Ray, David M. Wyatt, Petrina M. Hilton, Lewis A. Melville, et al. "Potencies of Human Immunodeficiency Virus Protease Inhibitors In Vitro against Plasmodium falciparum and In Vivo against Murine Malaria." Antimicrobial Agents and Chemotherapy 50, no. 2 (February 2006): 639–48. http://dx.doi.org/10.1128/aac.50.2.639-648.2006.

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ABSTRACT Parasite resistance to antimalarial drugs is a serious threat to human health, and novel agents that act on enzymes essential for parasite metabolism, such as proteases, are attractive targets for drug development. Recent studies have shown that clinically utilized human immunodeficiency virus (HIV) protease inhibitors can inhibit the in vitro growth of Plasmodium falciparum at or below concentrations found in human plasma after oral drug administration. The most potent in vitro antimalarial effects have been obtained for parasites treated with saquinavir, ritonavir, or lopinavir, findings confirmed in this study for a genetically distinct P. falciparum line (3D7). To investigate the potential in vivo activity of antiretroviral protease inhibitors (ARPIs) against malaria, we examined the effect of ARPI combinations in a murine model of malaria. In mice infected with Plasmodium chabaudi AS and treated orally with ritonavir-saquinavir or ritonavir-lopinavir, a delay in patency and a significant attenuation of parasitemia were observed. Using modeling and ligand docking studies we examined putative ligand binding sites of ARPIs in aspartyl proteases of P. falciparum (plasmepsins II and IV) and P. chabaudi (plasmepsin) and found that these in silico analyses support the antimalarial activity hypothesized to be mediated through inhibition of these enzymes. In addition, in vitro enzyme assays demonstrated that P. falciparum plasmepsins II and IV are both inhibited by the ARPIs saquinavir, ritonavir, and lopinavir. The combined results suggest that ARPIs have useful antimalarial activity that may be especially relevant in geographical regions where HIV and P. falciparum infections are both endemic.

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Kisilevsky, Robert, Ian Crandall, Walter A. Szarek, Shridhar Bhat, Christopher Tan, Lee Boudreau, and Kevin C. Kain. "Short-Chain Aliphatic Polysulfonates Inhibit the Entry of Plasmodium into Red Blood Cells." Antimicrobial Agents and Chemotherapy 46, no. 8 (August 2002): 2619–26. http://dx.doi.org/10.1128/aac.46.8.2619-2626.2002.

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ABSTRACT Several steps in the pathogenesis of a Plasmodium falciparum infection depend on interactions of parasite surface proteins with negatively charged sugars on the surface of host cells such as sialate residues or glycosaminoglycans. For these reasons, our previous studies examining agents that interfere with heparan sulfate-protein binding during amyloidogenesis suggested that short-chain aliphatic polysulfonates may prove useful as antimalarial agents. A series of related polysulfonates were synthesized and assessed both in tissue culture with the asexual stages of P. falciparum in human red blood cells and in vivo by use of Plasmodium berghei infections in mice. Poly(vinylsulfonate sodium salt) (molecular weight range, 1,500 to 3,000) proved effective in interfering with P. falciparum merozoite entry into human red blood cells and significantly delaying the increase in the level of P. berghei parasitemia in mice. The concept that anionic molecules that mimic large polysaccharide structures may have antimalarial properties has been suggested and examined previously. Our results suggest that related anionic agents [poly(vinylsulfonate sodium salt)-like molecules] orders of magnitude smaller than those previously considered may prove useful in abrogating merozoite entry into erythrocytes and may potentially block sporozoite entry into liver cells. Structure-activity studies conducted to enhance these properties may provide compounds with scope for significant further analysis and development.

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Degiacomi, Giulia, Laurent Roberto Chiarelli, Deborah Recchia, Elena Petricci, Beatrice Gianibbi, Ersilia Vita Fiscarelli, Lanfranco Fattorini, Fabrizio Manetti, and Maria Rosalia Pasca. "The Antimalarial Mefloquine Shows Activity against Mycobacterium abscessus, Inhibiting Mycolic Acid Metabolism." International Journal of Molecular Sciences 22, no. 16 (August 8, 2021): 8533. http://dx.doi.org/10.3390/ijms22168533.

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Some nontuberculous mycobacteria (NTM) are considered opportunistic pathogens. Nevertheless, NTM infections are increasing worldwide, becoming a major public health threat. Furthermore, there is no current specific drugs to treat these infections, and the recommended regimens generally lack efficacy, emphasizing the need for novel antibacterial compounds. In this paper, we focused on the essential mycolic acids transporter MmpL3, which is a well-characterized target of several antimycobacterial agents, to identify new compounds active against Mycobacterium abscessus (Mab). From the crystal structure of MmpL3 in complex with known inhibitors, through an in silico approach, we developed a pharmacophore that was used as a three-dimensional filter to identify new putative MmpL3 ligands within databases of known drugs. Among the prioritized compounds, mefloquine showed appreciable activity against Mab (MIC = 16 μg/mL). The compound was confirmed to interfere with mycolic acids biosynthesis, and proved to also be active against other NTMs, including drug-resistant clinical isolates. Importantly, mefloquine is a well-known antimalarial agent, opening the possibility of repurposing an already approved drug, which is a useful strategy to reduce the time and cost of disclosing novel drug candidates.

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Supan, Christian, Ghyslain Mombo-Ngoma, Matthias P. Dal-Bianco, Carmen L. Ospina Salazar, Saadou Issifou, Florent Mazuir, Aziz Filali-Ansary, et al. "Pharmacokinetics of Ferroquine, a Novel 4-Aminoquinoline, in Asymptomatic Carriers of Plasmodium falciparum Infections." Antimicrobial Agents and Chemotherapy 56, no. 6 (March 19, 2012): 3165–73. http://dx.doi.org/10.1128/aac.05359-11.

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ABSTRACTFerroquine (SSR97193), a ferrocene-quinoline conjugate, is a promising novel antimalarial currently undergoing clinical evaluation. This study characterizes its pharmacokinetic properties. Young male African volunteers with asymptomaticPlasmodium falciparuminfection were administered a single oral dose (n= 40) or a repeated oral dose (n= 26) given over 3 days of ferroquine in two dose-escalation, double-blind, randomized, placebo-controlled clinical trials. In addition, a food interaction study was performed in a subsample of participants (n= 16). The studies were carried out in Lambaréné, Gabon. After single-dose administration of ferroquine, dose linearity was demonstrated in a dose range of 400 to 1,200 mg for maximum mean blood concentrations ([Cmax] 82 to 270 ng/ml) and in a dose range of 400 to 1,600 mg for overall exposure to ferroquine (area under the concentration-time curve [AUC], 13,100 to 49,200 ng · h/ml). Overall mean estimate for blood apparent terminal half-life of ferroquine was 16 days and 31 days for its active and major metabolite desmethylferroquine (SSR97213). In the 3-day repeated-dose study,Cmaxand overall cumulated exposure to ferroquine (AUCcum) increased in proportion with the dose from day 1 to day 3 between 400 and 800 mg. No major food effect on ferroquine pharmacokinetics was observed after single administration of 100 mg of ferroquine except for a slight delay of time to maximum blood concentration (tmax) by approximately 3 h. The pharmacokinetics of ferroquine and its active main metabolite are characterized by sustained levels in blood, and the properties of ferroquine as a partner drug in antimalarial combination therapy should be evaluated.

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Mideo, Nicole, Jeffrey A. Bailey, Nicholas J. Hathaway, Billy Ngasala, David L. Saunders, Chanthap Lon, Oksana Kharabora, et al. "A deep sequencing tool for partitioning clearance rates following antimalarial treatment in polyclonal infections." Evolution, Medicine, and Public Health 2016, no. 1 (2016): 21–36. http://dx.doi.org/10.1093/emph/eov036.

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Wang, Hongxing, Qigui Li, Sean Reyes, Jing Zhang, Qiang Zeng, Ping Zhang, Lisa Xie, et al. "Nanoparticle formulations of decoquinate increase antimalarial efficacy against liver stage Plasmodium infections in mice." Nanomedicine: Nanotechnology, Biology and Medicine 10, no. 1 (January 2014): 57–65. http://dx.doi.org/10.1016/j.nano.2013.07.010.

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Liu, Shengfa, Hongying Jiang, Xin-zhuan Su, and Jianbing Mu. "Effects of Plasmodium falciparum Mixed Infections on In Vitro Antimalarial Drug Tests and Genotyping." American Journal of Tropical Medicine and Hygiene 79, no. 2 (August 1, 2008): 178–84. http://dx.doi.org/10.4269/ajtmh.2008.79.178.

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Evans, Sandra Gail, and Ivan Havlik. "In vitro drug interaction between amantadine and classical antimalarial drugs in Plasmodium falciparum infections." Transactions of the Royal Society of Tropical Medicine and Hygiene 88, no. 6 (November 1994): 683–86. http://dx.doi.org/10.1016/0035-9203(94)90229-1.

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Namusoke, Fatuma, Niloofar Rasti, Fred Kironde, Mats Wahlgren, and Florence Mirembe. "Malaria Burden in Pregnancy at Mulago National Referral Hospital in Kampala, Uganda." Malaria Research and Treatment 2010 (November 7, 2010): 1–10. http://dx.doi.org/10.4061/2010/913857.

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Pregnancy-associated malaria is a major global health concern. To assess the Plasmodium falciparum burden in pregnancy we conducted a cross-sectional study at Mulago Hospital in Kampala, Uganda. Malaria prevalence by each of three measures—peripheral smear, placental smear, and placental histology was 9% (35/391), 11.3% (44/389), and 13.9% (53/382) respectively. Together, smear and histology data yielded an infection rate of 15.5% (59/380) of active infections and 4.5% (17/380) of past infections; hence 20% had been or were infected when giving birth. A crude parity dependency was observed with main burden being concentrated in gravidae 1 through gravidae 3. Twenty-two percent were afflicted by anaemia and 12.2% delivered low birthweight babies. Active placental infection and anaemia showed strong association (OR=2.8) whereas parity and placental infection had an interactive effect on mean birthweight (P=.036). Primigravidae with active infection and multigravidae with past infection delivered on average lighter babies. Use of bednet protected significantly against infection (OR=0.56) whilst increased haemoglobin level protected against low birthweight (OR=0.83) irrespective of infection status. Albeit a high attendance at antenatal clinics (96.8%), there was a poor coverage of insecticide-treated nets (32%) and intermittent preventive antimalarial treatment (41.5%).Erratum to Malaria Burden in Pregnancy at Mulago National Referral Hospital in Kampala, Uganda

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Journal articles on the topic 'Antimalarial infections'

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