Ethanol extract of Bergenia ciliata (Haw.) Sternb. (rhizome) impedes the propagation of the malaria parasite.

ETHNOPHARMACOLOGICAL RELEVANCE: The increasing resistant cases even against artemisinin-based combination therapy have necessitated the need to develop new antimalarials. Phytomedicinal therapy is a benchmark for malaria in the Himalayan region. As the dialect and traditional variations have been seen along with this, usage of medicinal plant, its portion (shoot and root system) and mode of preparation also varies. There is no scientific evidence available for illustrating the antiplasmodial activity of the rhizomes of Bergenia ciliata (Saxifragaceae), which is known to be an antipyretic (fever akin to malaria), hepato-protective, and also for spleen enlargement. AIM OF THE STUDY: The present study evaluates the antimalarial activity of ethanol extract of B. ciliata rhizomes (EREBC). MATERIALS AND METHODS: HPTLC was performed to identify and quantify three marker compounds in EREBC. The in vitro antimalarial activity was evaluated by schizont maturation inhibition assay. MTT assay was employed to test the cytotoxicity of EREBC. Peter's 4-day test and Peters method was employed to discern the suppressive and preventive activity of the extract respectively. RESULTS: HPTLC analysis revealed the presence of bergenin, epicatechin and gallic acid in the extract. EREBC exhibited considerable inhibition (IC50 < 5 µg/mL) of schizont maturation of both RKL-9 and MRC-2 strains of P. falciparum. EREBC was non-toxic to both HeLa cells and normal dermal fibroblasts (CC50 > 1000 µg/mL). The selectivity index was > 200 for both strains. Acute toxicity of EREBC was > 4 g/kg. EREBC exhibited considerable in vivo suppressive activity with 96.48% inhibition at 500 mg/kg in comparison to chloroquine (96.08%). The ED50 of the extract was < 50 mg/kg. No mortality was evident in mice administered with different doses of EREBC (50-500 mg/kg) throughout the follow up period of 28 days. EREBC exhibited safety to liver and kidney function of mice as observed from biochemical analysis. CONCLUSION: Overall, the study illustrates the marked efficacy and potential of EREBC as an antimalarial agent with bergenin, epicatechin and gallic acid its major constituents, which played a pivotal role in the generation of the immune response.

Ethno medical knowledge and traditional use of Aristolochia bracteolata Lam. for malaria among local communities in Jubek State of South Sudan: A cross-sectional survey.

ETHNOPHARMACOLOGICAL RELEVANCE: The recognized challenges to access conventional antimalarial medicines could have contributed to the extensive use of Aristolochia bracteolata Lam. (Aristolochiaceae)to manage malaria in South Sudan traditionally. However, the use and acquired experiences are notwell documented. AIM OF THE STUDY: This study aimed to document the traditional use of A. bracteolata for malaria treatment and experiences among the local communities in Jubek State of South Sudan. METHODS: We performed a cross-sectional study in four counties in Jubek State and interviewed 396 community members, including traditional healers, using a semi-structured questionnaire. Four focused group discussions (FGDs) were also conducted using the interviewer guide. The inclusion criteria were; adults 18 years and older, men andwomen participants, at least one year residing in the study area before the study, and those with a history of medicinal plant use. Data were summarized and presented as proportions. Qualitative data were analyzed using a thematic content approach. The major themes that emerged were discussed. We applied the Pearson Chi-Square test at α = 0.05 to test the study's significant differences in responses. The statistical package for social sciences version 21 software was used for data analysis. RESULTS: Women accounted for 208 (52.5%) of participants, with the majority 321 (81.1%) were between 18 and 45 years. Interestingly, most 312 (78.8%) had formal education. Moreover, about 208 (52.5%) participants collect the plant in their vicinity, where leaves were the most commonly used part 277 (46.4%), followed by the roots, seeds, and stems at 245(41.0%), 71 (11.9%), and 4 (0.7%), respectively. Furthermore, about 63 (15.9%) of the participants experienced side effects, including early abortions, heartburns, sweating, and stomach discomforts. Conversely, a total of 387 (96.0%) reported getting cured of malaria. Generally, the quantity of medicine taken per day differs concerning parts of the plant, with leaves ranging from 1 to 10 pieces, roots at 0.4-1 g, and seeds at 0.1-0.5 g. The locals used these plant parts to prepare infusion and decoction traditional dosage forms for oral use. CONCLUSION: The documented medicinal plant's therapeutic uses provided critical information on the traditional use of A. bracteolata by the community in Jubek state of South Sudan to treat malaria. Although most users reported getting cured of malaria, a notable proportion of them experienced side effects, including early-stage abortion and stomach discomforts. Thus, the use of A. bracteolata preparations, particularly in pregnant women, should be avoided. Finally, further studies are needed to devise a strategy to neutralize the toxic compounds and create community awareness on best practices to minimize side effects.

Assessment of a combined strategy of seasonal malaria chemoprevention and supplementation with vitamin A, zinc and Plumpy'Doz™ to prevent malaria and malnutrition in children under 5 years old in Burkina Faso: a randomized open-label trial (SMC-NUT).

BACKGROUND: Malaria and malnutrition represent major public health concerns worldwide especially in Sub-Sahara Africa. Despite implementation of seasonal malaria chemoprophylaxis (SMC), an intervention aimed at reducing malaria incidence among children aged 3-59 months, the burden of malaria and associated mortality among children below age 5 years remains high in Burkina Faso. Malnutrition, in particular micronutrient deficiency, appears to be one of the potential factors that can negatively affect the effectiveness of SMC. Treating micronutrient deficiencies is known to reduce the incidence of malaria in highly prevalent malaria zone such as rural settings. Therefore, we hypothesized that a combined strategy of SMC together with a daily oral nutrients supplement will enhance the immune response and decrease the incidence of malaria and malnutrition among children under SMC coverage. METHODS: Children (6-59 months) under SMC coverage receiving vitamin A supplementation will be randomly assigned to one of the three study arms (a) SMC + vitamin A alone, (b) SMC + vitamin A + zinc, or (c) SMC + vitamin A + Plumpy'Doz™ using 1:1:1 allocation ratio. After each SMC monthly distribution, children will be visited at home to confirm drug administration and followed-up for 1 year. Anthropometric indicators will be recorded at each visit and blood samples will be collected for microscopy slides, haemoglobin measurement, and spotted onto filter paper for further PCR analyses. The primary outcome measure is the incidence of malaria in each arm. Secondary outcome measures will include mid-upper arm circumference and weight gain from baseline measurements, coverage and compliance to SMC, occurrence of adverse events (AEs), and prevalence of molecular markers of antimalarial resistance comprising Pfcrt, Pfmdr1, Pfdhfr, and Pfdhps. DISCUSSION: This study will demonstrate an integrated strategy of malaria and malnutrition programmes in order to mutualize resources for best impact. By relying on existing strategies, the policy implementation of this joint intervention will be scalable at country and regional levels. TRIAL REGISTRATION: ClinicalTrials.gov NCT04238845 . Registered on 23 January 2020 https://clinicaltrials.gov/ct2/show/NCT04238845.

The preclinical discovery and development of rectal artesunate for the treatment of malaria in young children: a review of the evidence.

INTRODUCTION: Plasmodium falciparum, the deadliest malaria parasite, kills hundreds of thousands of people per year, mainly young children in Sub-Saharan Africa. Artesunate suppositories are recommended as pre-referral malaria treatment in remote endemic areas for severely ill children to prevent progression of the disease and to provide extra time for patients until the definitive severe malaria treatment can be administered. AREAS COVERED: The authors provide an overview of the discovery of artesunate and its different formulations focusing on rectal administration, summarizing key studies concerning the pharmacokinetic, pharmacodynamic, safety, tolerability and efficacy of rectal artesunate leading to WHO recommendation and market authorization in Africa. In addition, studies on acceptance and adherence to rectal artesunate administration and the post-launch status are also covered. EXPERT OPINION: Efforts by ministries of health in malaria endemic countries together with international health organizations should establish and enforce guidelines to ensure the correct use of artesunate suppositories only as pre-referral medication in presumed severe malaria cases to minimize the risk of abuse as a monotherapy for treatment of uncomplicated malaria. The priority is to not jeopardize the efficacy of artesunate and to prevent resistance development against this valuable drug class in Africa.

[Safety and Efficacy of Artemether-Lumefantrine and Artesunate-Amodiaquine in Niger]. / Étude de l'efficacité thérapeutique et de la tolérance de l'artéméther­luméfantrine et de l'artésunate­amodiaquine au Niger.

This study aims to evaluate the therapeutic efficacy and tolerance of two ACTs widely used for the treatment of uncomplicated malaria due to Plasmodium falciparum in Niger. The study was conducted from September to November 2017, at the Integrated Health Centers of Dogondoutchi and Birni N'Gaouré, in patients aged from 6 months to 15 years, with uncomplicated malaria due to Plasmodium falciparum. They were treated with either Artemether-Lumefantrine (AL) or Artesunate-Amodiaquine (ASAQ). The primary endpoint was the appropriate clinical and parasitological response (RCPA) to D28, after PCR correction. The secondary criteria were the clearing time of fever, parasites, and gametocytes and then the occurrence of adverse events. A total of 459 patients were examined, of whom 312 patients met the inclusion criteria for therapeutic efficacy evaluation. We have followed 299 patients up to J28 including 146 in the AL arm and 153 in the ASAQ arm. After PCR correction at J28, RCPA were 95.8% and 96% (P = 0.7185) for arms AL and ASAQ, respectively, compared to 93.1% and 94.1% respectively before PCR correction (P = 0.7892). The number of patients on AL and ASAQ treatment who developed an adverse reaction were 6 (7.6%) and 23 (28%) respectively. AL and ASAQ associations are effective and well tolerated. No serious adverse event was noted. However, their monitoring must continue to detect possible resistance.

Cette étude vise à évaluer l'efficacité thérapeutique et la tolérance de deux combinaisons thérapeutiques à base d'artémisinine (CTA), largement utilisées pour le traitement du paludisme non compliqué à Plasmodium falciparum au Niger. L'étude a été conduite de septembre à novembre 2017, au niveau des centres de santé intégrée (CSI) de Dogondoutchi et de Birni N'Gaouré, chez des patients âgés de 6 mois à 15 ans, atteints de paludisme non compliqué. Ils ont été traités par l'artéméther-luméfantrine (AL) ou l'artésunate­amodiaquine (ASAQ). Le critère de jugement principal était la réponse clinique et parasitologique adéquate (RCPA) à j28, après correction PCR. Les critères secondaires étaient le temps de clairance de la fièvre, des parasites et des gamétocytes puis la survenue des événements indésirables. Au total, 459 patients ont été examinés : 312 patients répondaient aux critères d'inclusion, 299 patients ont été suivis jusqu'à j28 dont 146 dans le bras AL, 153 dans le bras ASAQ. Les RCPA après correction PCR à j28 étaient de 95,8 et 96 % (p = 0,7185) respectivement pour AL et ASAQ alors qu'elles étaient respectivement de 93,1 et 94,1 % avant correction PCR (p = 0,7892). Le nombre de patients sous traitement AL et ASAQ ayant développé une réaction indésirable sont respectivement de 6, soit 7,6 %, et 23, soit 28 %. Les associations AL et ASAQ sont efficaces et bien tolérées, la première étant mieux tolérée. Aucun événement indésirable grave n'a été noté. Cependant, la surveillance des effets indésirables et de l'efficacité doit se poursuivre.Cette étude vise à évaluer l'efficacité thérapeutique et la tolérance de deux combinaisons thérapeutiques à base d'artémisinine (CTA), largement utilisées pour le traitement du paludisme non compliqué à Plasmodium falciparum au Niger. L'étude a été conduite de septembre à novembre 2017, au niveau des centres de santé intégrée (CSI) de Dogondoutchi et de Birni N'Gaouré, chez des patients âgés de 6 mois à 15 ans, atteints de paludisme non compliqué. Ils ont été traités par l'artéméther-luméfantrine (AL) ou l'artésunate­amodiaquine (ASAQ). Le critère de jugement principal était la réponse clinique et parasitologique adéquate (RCPA) à j28, après correction PCR. Les critères secondaires étaient le temps de clairance de la fièvre, des parasites et des gamétocytes puis la survenue des événements indésirables. Au total, 459 patients ont été examinés : 312 patients répondaient aux critères d'inclusion, 299 patients ont été suivis jusqu'à j28 dont 146 dans le bras AL, 153 dans le bras ASAQ. Les RCPA après correction PCR à j28 étaient de 95,8 et 96 % (p = 0,7185) respectivement pour AL et ASAQ alors qu'elles étaient respectivement de 93,1 et 94,1 % avant correction PCR (p = 0,7892). Le nombre de patients sous traitement AL et ASAQ ayant développé une réaction indésirable sont respectivement de 6, soit 7,6 %, et 23, soit 28 %. Les associations AL et ASAQ sont efficaces et bien tolérées, la première étant mieux tolérée. Aucun événement indésirable grave n'a été noté. Cependant, la surveillance des effets indésirables et de l'efficacité doit se poursuivre.

Design and tests of prospective property predictions for novel antimalarial 2-aminopropylaminoquinolones.

There is a pressing need to improve the efficiency of drug development, and nowhere is that need more clear than in the case of neglected diseases like malaria. The peculiarities of pyrimidine metabolism in Plasmodium species make inhibition of dihydroorotate dehydrogenase (DHODH) an attractive target for antimalarial drug design. By applying a pair of complementary quantitative structure-activity relationships derived for inhibition of a truncated, soluble form of the enzyme from Plasmodium falciparum (s-PfDHODH) to data from a large-scale phenotypic screen against cultured parasites, we were able to identify a class of antimalarial leads that inhibit the enzyme and abolish parasite growth in blood culture. Novel analogs extending that class were designed and synthesized with a goal of improving potency as well as the general pharmacokinetic and toxicological profiles. Their synthesis also represented an opportunity to prospectively validate our in silico property predictions. The seven analogs synthesized exhibited physicochemical properties in good agreement with prediction, and five of them were more active against P. falciparum growing in blood culture than any of the compounds in the published lead series. The particular analogs prepared did not inhibit s-PfDHODH in vitro, but advanced biological assays indicated that other examples from the class did inhibit intact PfDHODH bound to the mitochondrial membrane. The new analogs, however, killed the parasites by acting through some other, unidentified mechanism 24-48 h before PfDHODH inhibition would be expected to do so.

Insights in Chloroquine Action: Perspectives and Implications in Malaria and COVID-19.

Malaria is a threat to human mankind and kills about half a million people every year. On the other hand, COVID-19 resulted in several hundred thousand deaths since December 2019 and remains without an efficient and safe treatment. The antimalarials chloroquine (CQ) and its analog, hydroxychloroquine (HCQ), have been tested for COVID-19 treatment, and several conflicting evidence has been obtained. Therefore, the aim of this review was to summarize the evidence regarding action mechanisms of these compounds against Plasmodium and SARS-CoV-2 infection, together with cytometry applications. CQ and HCQ act on the renin angiotensin system, with possible implications on the cardiorespiratory system. In this context, flow and image cytometry emerge as powerful technologies to investigate the mechanism of therapeutic candidates, as well as for the identification of the immune response and prognostics of disease severity. Data from the large randomized trials support the conclusion that CQ and HCQ do not provide any clinical improvements in disease severity and progression of SARS-CoV-2 patients, as well as they do not present any solid evidence of increased serious side effects. These drugs are safe and effective antimalarials agents, but in SARS-CoV-2 patients, they need further studies in the context of clinical trials. © 2020 International Society for Advancement of Cytometry.

Practice considerations on the use of investigational anti-COVID-19 medications: Dosage, administration and monitoring.

WHAT IS KNOWN AND OBJECTIVE: Understanding investigational medications is important. Many older drugs are being investigated for repurposing against COVID-19. We comment on various drugs currently undergoing such trials to optimize their safe use. COMMENT: We describe medications used during early COVID-19 outbreaks in South Korea, focusing on practice aspects including the method of drug administration, drug formulation, patient-monitoring for adverse reactions and drug interactions informed by our experience during the 2015 outbreak of Middle East respiratory syndrome (MERS). We comment on hydroxychloroquine, chloroquine, lopinavir/ritonavir with zinc supplement, remdesivir, tocilizumab, ciclesonide, niclosamide and high-dose intravenous immunoglobulin (IVIG). WHAT IS NEW AND CONCLUSION: Effective therapies are urgently needed to manage COVID-19, and existing drugs such as antivirals and antimalarials are under investigation for repurposing to meet this need. This process requires up-to-date drug information to ensure optimum use, particularly safety and efficacy profiles of the medications, until convincing evidence is reported.

Anti-malarial activity of traditional Kampo medicine Coptis rhizome extract and its major active compounds.

BACKGROUND: Herbal medicine has been a rich source of new drugs exemplified by quinine and artemisinin. In this study, a variety of Japanese traditional herbal medicine ('Kampo') were examined for their potential anti-malarial activities. METHODS: A comprehensive screening methods were designed to identify novel anti-malarial drugs from a library of Kampo herbal extracts (n = 120) and related compounds (n = 96). The anti-malarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and-resistant (Dd2) strains of Plasmodium falciparum. The cytotoxicity was also evaluated using primary adult mouse brain cells. After being selected through the first in vitro assay, positive extracts and compounds were examined for possible in vivo anti-malarial activity. RESULTS: Out of 120 herbal extracts, Coptis rhizome showed the highest anti-malarial activity (IC50 1.9 µg/mL of 3D7 and 4.85 µg/mL of Dd2) with a high selectivity index (SI) > 263 (3D7) and > 103 (Dd2). Three major chlorinated compounds (coptisine, berberine, and palmatine) related to Coptis rhizome also showed anti-malarial activities with IC50 1.1, 2.6, and 6.0 µM (against 3D7) and 3.1, 6.3, and 11.8 µM (against Dd2), respectively. Among them, coptisine chloride exhibited the highest anti-malarial activity (IC50 1.1 µM against 3D7 and 3.1 µM against Dd2) with SI of 37.8 and 13.2, respectively. Finally, the herbal extract of Coptis rhizome and its major active compound coptisine chloride exhibited significant anti-malarial activity in mice infected with Plasmodium yoelii 17X strain with respect to its activity on parasite suppression consistently from day 3 to day 7 post-challenge. The effect ranged from 50.38 to 72.13% (P < 0.05) for Coptis rhizome and from 81 to 89% (P < 0.01) for coptisine chloride. CONCLUSION: Coptis rhizome and its major active compound coptisine chloride showed promising anti-malarial activity against chloroquine-sensitive (3D7) and -resistant (Dd2) strains in vitro as well as in vivo mouse malaria model. Thus, Kampo herbal medicine is a potential natural resource for novel anti-malarial agents.

Antimalarial plants with potential male-factor antifertility properties.

Malaria, caused mainly by Plasmodium falciparum among other Plasmodium species, is one of the main causes of death from parasitic diseases. Malaria is still a health problem mainly because of the cost of effective antimalarial drugs and the growing parasite resistance to conventional antimalarial drugs, making a great proportion of the people in malaria endemic countries dependent on plants for its treatment. Corollary, a large number of the rural populations consume antimalarial herbal preparations in large or excessive quantities despite the fact that it has been reported that some of them could cause male-factor infertility, a growing global health concern. Few studies have compiled information on the scientifically validated male-factor antifertility effects of these antimalarial plant remedies. The aim of this review therefore is to compile information on commonly used antimalarial plant remedies that have been experimentally validated as having male-factor antifertility effects. Thus, antimalarial plant remedies with experimentally confirmed male-factor antifertility potentials and compounds isolated from them are identified and discussed. The male-factor antifertility effects of these plants include reduction of sperm quality, regulation of reproductive hormone levels and induction of lipid peroxidation. Indiscriminate use of such antimalarial plants is discouraged when male contraception is not desired.

A randomized, control and comparative study of polyherbal formulation use for Malaria (Plasmodium falciparum).

Plasmodium falciparum is the most well-known reason for extreme and life-debilitating malaria. Falciparum malaria causes more than 1 million deaths annually. Malaria remains a noteworthy reason for major morbidity and mortality in the tropics, with Plasmodium falciparum accountable for the mainstream of the disease weight and Plasmodium vivax being the geologically greatest broadly dispersed cause of malaria. The controlling of severe malaria comprises quick direction of suitable parenteral anti-malarial agents and initial acknowledgement and treatment of the complications. This clinical trial was piloted in 100 patients, in which 50 received the test drug (Malarina) and 50 received the control drug (Quinine Bisulphate). The age range of patients was 12 years to above 50 years. The sample paired t-test was applied to evaluate the significant level. Malarina was very effective in treating malaria sign and symptoms. The new treatment Malarina was safe and well tolerated in all patients.

Efficacy and Tolerability Outcomes of a Phase II, Randomized, Open-Label, Multicenter Study of a New Water-Dispersible Pediatric Formulation of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in African Infants.

Artemisinin combination therapies are considered the mainstay of malaria treatment, but pediatric-friendly formulations for the treatment of infants are scarce. We sought to evaluate the efficacy and safety of a new dispersible-tablet formulation of dihydroartemisinin/piperaquine phosphate (DHA/PQP) in comparison to the marketed tablet (Eurartesim) in the treatment of infants with uncomplicated Plasmodium falciparum malaria. Reported here are the results of a large phase II, randomized, open-label, multicenter trial conducted in African infants (6 to 12 months of age) from Mozambique, Burkina Faso, The Gambia, the Democratic Republic of the Congo, and Tanzania. Primary efficacy endpoint was the PCR-corrected adequate clinical and parasitological response (ACPR) at day 28. Analysis was performed for the intention-to-treat (ITT) and per-protocol (PP) populations. A total of 201 patients received the dispersible-tablet formulation, and 99 received the conventional one administered as crushed tablets. At day 28, the PCR-corrected ACPRs were 86.9% (ITT) and 98.3% (PP) in the dispersible-tablet group and 84.9% (ITT) and 100% (PP) in the crushed-tablet group. At day 42, these values were 85.9% (ITT) and 96.5% (PP) in the dispersible-tablet group and 82.8% (ITT) and 96.4% (PP) in the crushed-tablet group. The comparison between survival curves for time to new infections showed no statistically significant differences (P = 0.409). The safety and tolerability profile for the two groups was similar in terms of type and frequency of adverse events and was consistent with that expected in African infants with malaria. A standard 3-day treatment with the new dispersible DHA/PQP formulation is as efficacious as the currently used tablet in African infants and has a comparable safety profile. (This trial was registered at ClinicalTrials.gov under registration no. NCT01992900.).

Toxicological investigation of acute and chronic treatment with Gnidia stenophylla Gilg root extract on some blood parameters and histopathology of spleen, liver and kidney in mice.

BACKGROUND: In southeast Ethiopia, people locally use the roots of Gnidia stenophylla Gilg (Thymelaeaceae) to cure malaria and other diseases with no literature evidence substantiating its safety. The aim of this study was, therefore, to investigate the safety of the aqueous root extract of G. stenophylla after acute (single dose) and repeated sub chronic oral administration in mice. RESULTS: A single oral administration of the extract at 500, 1000, 2000 and 4000 mg/kg body weight did not induce any behavioral change and mortality in both sexes. The oral LD50 of the extract was found to be above 6000 mg/kg body weight in mice. Chronic treatment with the extract for 13 weeks did not induce any sign of illness and/or death and had no adverse effect on the body weight. Dose-related elevations of erythrocytes, hematocrit, hemoglobin, platelets and neutrophils differential and significant decrease in the number of lymphocyte were observed. Liver sections of mice treated with 800 mg/kg body weight, revealed mild inflammations around the portal triads and central veins; whereas the spleen and kidneys appeared normal with no detectable gross morphological and histopathological alteration at both doses. CONCLUSIONS: The results of this study revealed that aqueous root extract of G. stenophylla Gilg at antimalarial dose is safe even when taken for a longer period. At a higher dose, the extract may have a potential to increase some hematological indices but may induce mild hepatotoxicity as a side effect.

In vivo anti-malarial activity and toxicity studies of triterpenic esters isolated form Keetia leucantha and crude extracts.

BACKGROUND: Considering the need for new anti-malarial drugs, further investigations on Keetia leucantha (Rubiaceae), an in vitro antiplasmodial plant traditionally used to treat malaria, were carried out. This paper aimed to assess the in vivo anti-malarial efficacy of K. leucantha triterpenic esters previously identified as the most in vitro active components against Plasmodium falciparum and their potential toxicity as well as those of anti-malarial extracts. RESULTS: These eight triterpenic esters and the major antiplasmodial triterpenic acids, ursolic and oleanolic acids, were quantified in the twigs dichloromethane extract by validated HPLC-UV methods. They account for about 19% of this extract (16.9% for acids and 1.8% for esters). These compounds were also identified in trace in the twigs decoction by HPLC-HRMS. Results also showed that extracts and esters did not produce any haemolysis, and were devoid of any acute toxicity at a total cumulative dose of 800 and 150 mg/kg respectively. Moreover, esters given intraperitoneally at 50 mg/kg/day to Plasmodium berghei-infected mice showed a very significant (p < 0.01) parasitaemia inhibition (27.8 ± 5.4%) on day 4 post-infection compared to vehicle-treated mice. CONCLUSIONS: These results bring out new information on the safety of K. leucantha use and on the identification of anti-malarial compounds from its dichloromethane extract. Its activity can be explained by the presence of triterpenic acids and esters which in vivo activity and safety were demonstrated for the first time.

Glucose-6-phosphate dehydrogenase deficiency and the use of primaquine: top-down and bottom-up estimation of professional costs.

The aim of this study has been to study whether the top-down method, based on the average value identified in the Brazilian Hospitalization System (SIH/SUS), is a good estimator of the cost of health professionals per patient, using the bottom-up method for comparison. The study has been developed from the context of hospital care offered to the patient carrier of glucose-6-phosphate dehydrogenase (G6PD) deficiency with severe adverse effect because of the use of primaquine, in the Brazilian Amazon. The top-down method based on the spending with SIH/SUS professional services, as a proxy for this cost, corresponded to R$60.71, and the bottom-up, based on the salaries of the physician (R$30.43), nurse (R$16.33), and nursing technician (R$5.93), estimated a total cost of R$52.68. The difference was only R$8.03, which shows that the amounts paid by the Hospital Inpatient Authorization (AIH) are estimates close to those obtained by the bottom-up technique for the professionals directly involved in the care.

Antimalarial activity and safety assessment of Flueggea virosa leaves and its major constituent with special emphasis on their mode of action.

A clinical emergency stands due to the appearance of drug resistant Plasmodium strains necessitate novel and effective antimalarial chemotypes, where plants seem as the prime option, especially after the discovery of quinine and artemisinin. The present study was aimed towards bioprospecting leaves of Flueggea virosa for its antimalarial efficacy and active principles. Crude hydro-ethanolic extract along with solvent derived fractions were tested in vitro against Plasmodium falciparum CQ sensitive (3D7) and resistant (K1) strains, where all the fractions exhibited potential activity (IC50 values <10µg/mL) against both the strains. Interestingly, under in vivo conditions against P. berghei in Swiss mice, preferential chemo-suppression was recorded for crude hydro-ethanolic extract (77.38%) and ethyl acetate fraction (86.09%) at the dose of 500mg/kg body weight. Additionally, ethyl acetate fraction was found to be capable of normalizing the host altered pharmacological parameters and enhanced oxidative stress augmented during the infection. The bioactivity guided fractionation lead to the isolation of bergenin as a major and active constituent (IC50, 8.07±2.05µM) of ethyl acetate fraction with the inhibition of heme polymerization pathway of malaria parasite being one of the possible chemotherapeutic target. Furthermore, bergenin exhibited a moderate antimalarial activity against P. berghei and also ameliorated parasite induced systemic inflammation in host (mice). Safe toxicity profile elucidated through in vitro cytotoxicity and in silico ADME/T predications evidently suggest that bergenin possess drug like properties. Hence, the present study validates the traditional usage of F. indica as an antimalarial remedy and also insists for further chemical modifications of bergenin to obtain more effective antimalarial chemotypes.

Piperaquine Population Pharmacokinetics and Cardiac Safety in Cambodia.

Despite the rising rates of resistance to dihydroartemisinin-piperaquine (DP), DP remains a first-line therapy for uncomplicated malaria in many parts of Cambodia. While DP is generally well tolerated as a 3-day DP (3DP) regimen, compressed 2-day DP (2DP) regimens were associated with treatment-limiting cardiac repolarization effects in a recent clinical trial. To better estimate the risks of piperaquine on QT interval prolongation, we pooled data from three randomized clinical trials conducted between 2010 and 2014 in northern Cambodia. A population pharmacokinetic model was developed to compare exposure-response relationships between the 2DP and 3DP regimens while accounting for differences in regimen and sample collection times between studies. A 2-compartment model with first-order absorption and elimination without covariates best fit the data. The linear slope-intercept model predicted a 0.05-ms QT prolongation per ng/ml of piperaquine (5 ms per 100 ng/ml) in this largely male population. Though the plasma half-life was similar in both regimens, peak and total piperaquine exposures were higher in those treated with the 2DP regimen. Furthermore, the correlation between the plasma piperaquine concentration and the QT interval prolongation was stronger in the population receiving the 2DP regimen. Neither the time since the previous meal nor the baseline serum magnesium or potassium levels had additive effects on QT interval prolongation. As electrocardiographic monitoring is often nonexistent in areas where malaria is endemic, 2DP regimens should be avoided and the 3DP regimen should be carefully considered in settings where viable alternative therapies exist. When DP is employed, the risk of cardiotoxicity can be mitigated by combining a 3-day regimen, enforcing a 3-h fast before and after administration, and avoiding the concomitant use of QT interval-prolonging medications. (This study used data from three clinical trials that are registered at ClinicalTrials.gov under identifiers NCT01280162, NCT01624337, and NCT01849640.).

Modelling primaquine-induced haemolysis in G6PD deficiency.

Primaquine is the only drug available to prevent relapse in vivax malaria. The main adverse effect of primaquine is erythrocyte age and dose-dependent acute haemolytic anaemia in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDd). As testing for G6PDd is often unavailable, this limits the use of primaquine for radical cure. A compartmental model of the dynamics of red blood cell production and destruction was designed to characterise primaquine-induced haemolysis using a holistic Bayesian analysis of all published data and was used to predict a safer alternative to the currently recommended once weekly 0.75 mg/kg regimen for G6PDd. The model suggests that a step-wise increase in daily administered primaquine dose would be relatively safe in G6PDd. If this is confirmed, then were this regimen to be recommended for radical cure patients would not require testing for G6PDd in areas where G6PDd Viangchan or milder variants are prevalent.

Estimation of the In Vivo MIC of Cipargamin in Uncomplicated Plasmodium falciparum Malaria.

The MIC of an antimalarial drug for a particular infection is the drug level associated with a net parasite multiplication rate of one per asexual cycle. To ensure the cure of malaria, the MIC must be exceeded until all parasites have been eliminated. The development of highly sensitive and accurate PCR quantitation of low-density malaria parasitemia enables the prospective pharmacokinetic-pharmacodynamic (PK-PD) characterization of antimalarial drug effects and now allows identification of the in vivo MIC. An adaptive design and a PK-PD modeling approach were used to determine prospectively the MIC of the new antimalarial cipargamin (KAE609) in adults with uncomplicated Plasmodium falciparum malaria in an open-label, dose-ranging phase 2a study. Vietnamese adults with acute P. falciparum malaria were allocated sequentially to treatment with a single 30-mg (n = 6), 20-mg (n = 5), 10-mg (n = 7), or 15-mg (n = 7) dose of cipargamin. Artemisinin-based combination therapy was given after parasite densities had fallen and then risen as cipargamin levels declined below the MIC but before a return of signs or symptoms. The rates of parasite clearance were dose dependent, with near saturation of the effect being seen at an adult dose of 30 mg. The developed PK-PD model accurately predicted the therapeutic responses in 23/25 patients. The predicted median in vivo MIC was 0.126 ng/ml (range, 0.038 to 0.803 ng/ml). Pharmacometric characterization of the relationship between antimalarial drug concentrations and parasite clearance rates following graded subtherapeutic antimalarial drug dosing is safe and provides a rational framework for dose finding in antimalarial drug development. (This study has been registered at ClinicalTrials.gov under identifier NCT01836458.).