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Sample records for artemisinin-based antimalarial combination

  1. Estimating antimalarial drugs consumption in Africa before the switch to artemisinin-based combination therapies (ACTs

    Vreeke Ed

    2007-07-01

    Full Text Available Abstract Background Having reliable forecasts is critical now for producers, malaria-endemic countries and agencies in order to adapt production and procurement of the artemisinin-based combination treatments (ACTs, the new first-line treatments of malaria. There is no ideal method to quantify drug requirements for malaria. Morbidity data give uncertain estimations. This study uses drug consumption to provide elements to help estimate quantities and financial requirements of ACTs. Methods The consumption of chloroquine, sulphadoxine/pyrimethamine and quinine both through the private and public sector was assessed in five sub-Saharan Africa countries with different epidemiological patterns (Senegal, Rwanda, Tanzania, Malawi, Zimbabwe. From these data the number of adult treatments per capita was calculated and the volumes and financial implications derived for the whole of Africa. Results Identifying and obtaining data from the private sector was difficult. The quality of information on drug supply and distribution in countries must be improved. The number of adult treatments per capita and per year in the five countries ranged from 0.18 to 0.50. Current adult treatment prices for ACTs range US$ 1–1.8. Taking the upper range for both volumes and costs, the highest number of adult treatments consumed for Africa was estimated at 314.5 million, corresponding to an overall maximum annual need for financing ACT procurement of US$ 566.1 million. In reality, both the number of cases treated and the cost of treatment are likely to be lower (projections for the lowest consumption estimate with the least expensive ACT would require US $ 113 million per annum. There were substantial variations in the market share between public and private sources among these countries (the public sector share ranging from 98% in Rwanda to 33% in Tanzania. Conclusion Additional studies are required to build a more robust methodology, and to assess current consumptions

  2. Substandard artemisinin-based antimalarial medicines in licensed retail pharmaceutical outlets in Ghana

    M. El-Duah & K. Ofori-Kwakye

    2012-09-01

    Full Text Available Background & objectives: The artemisinin-based antimalarial medicines are first line medicines in the treatmentof severe and uncomplicated falciparum malaria. Numerous brands of these medicines manufactured in variouscountries are available in the Ghanaian market. The study was aimed at evaluating the authenticity and qualityof selected brands of artemisinin-based antimalarial medicines marketed in Ghana.Methods: In all, 14 artemisinin-based antimalarial medicines were purchased from pharmacies (P and licensedchemical shops (LCSs in the Kumasi metropolis, Ghana. Simple field tests based on colorimetry and thin layerchromatography were employed in determining the authenticity of the samples. Important quality assessmenttests, namely uniformity of mass, crushing strength, disintegration time, and the percentage content of activepharmaceutical ingredients (APIs were determined.Results: All the brands tested contained the stipulated APIs. Artesunate tablet AT2 failed the uniformity of masstest while artesunate tablets AT3 & AT4 as well as amodiaquine tablets AM4 & AM6 failed the crushing strengthtest. All the six artemether-lumefantrine tablet brands passed the uniformity of mass, crushing strength anddisintegration tests. Only artemether-lumefantrine tablet brand AL1 contained the correct amount of the drugs.The other 13 artemisinin products contained either a lower (underdose or higher (overdose amount of thespecified drug. Artesunate monotherapy tablets were readily available in pharmacies and licensed chemicalshops.Interpretation & conclusion: All the artemisinin-based medicines tested (except AL1 were of substandardquality. The results demonstrate the need for continuous monitoring and evaluation of the quality of artemisininbased antimalarials in the Ghanaian market. Also, the practice of artemisinin antimalarial monotherapy is prevalentin Ghana. Determined efforts should, therefore, be made to eradicate the practice to prevent the development

  3. Degradation of Artemisinin-Based Combination Therapies Under Tropical Conditions.

    Hall, Zoe; Allan, Elizabeth Louise; van Schalkwyk, Donelly Andrew; van Wyk, Albert; Kaur, Harparkash

    2016-05-01

    Poor quality antimalarials, including falsified, substandard, and degraded drugs, are a serious health concern in malaria-endemic countries. Guidelines are lacking on how to distinguish between substandard and degraded drugs. "Forced degradation" in an oven was carried out on three common artemisinin-based combination therapy (ACT) brands to detect products of degradation using liquid chromatography mass spectrometry and help facilitate classification of degraded drugs. "Natural aging" of 2,880 tablets each of ACTs artemether/lumefantrine and artesunate/amodiaquine was undertaken to evaluate their long-term stability in tropical climates. Samples were aged in the presence and absence of light on-site in Ghana and in a stability chamber (London), removed at regular intervals, and analyzed to determine loss of the active pharmaceutical ingredients (APIs) over time and detect products of degradation. Loss of APIs in naturally aged tablets (both in Ghana and the pharmaceutical stability chamber) was 0-7% over 3 years (∼12 months beyond expiry) with low levels of degradation products detected. Using this developed methodology, it was found that a quarter of ACTs purchased in Enugu, Nigeria (concurrent study), that would have been classified as substandard, were in fact degraded. Presence of degradation products together with evidence of insufficient APIs can be used to classify drugs as degraded. PMID:26951346

  4. Degradation of Artemisinin-Based Combination Therapies under Tropical Conditions

    Hall, Zoe; Allan, Elizabeth Louise; van Schalkwyk, Donelly Andrew; van Wyk, Albert; Kaur, Harparkash

    2016-01-01

    Poor quality antimalarials, including falsified, substandard, and degraded drugs, are a serious health concern in malaria-endemic countries. Guidelines are lacking on how to distinguish between substandard and degraded drugs. “Forced degradation” in an oven was carried out on three common artemisinin-based combination therapy (ACT) brands to detect products of degradation using liquid chromatography mass spectrometry and help facilitate classification of degraded drugs. “Natural aging” of 2,880 tablets each of ACTs artemether/lumefantrine and artesunate/amodiaquine was undertaken to evaluate their long-term stability in tropical climates. Samples were aged in the presence and absence of light on-site in Ghana and in a stability chamber (London), removed at regular intervals, and analyzed to determine loss of the active pharmaceutical ingredients (APIs) over time and detect products of degradation. Loss of APIs in naturally aged tablets (both in Ghana and the pharmaceutical stability chamber) was 0–7% over 3 years (∼12 months beyond expiry) with low levels of degradation products detected. Using this developed methodology, it was found that a quarter of ACTs purchased in Enugu, Nigeria (concurrent study), that would have been classified as substandard, were in fact degraded. Presence of degradation products together with evidence of insufficient APIs can be used to classify drugs as degraded. PMID:26951346

  5. Evaluation of the Quality of Artemisinin-Based Antimalarial Medicines Distributed in Ghana and Togo

    Dorcas Osei-Safo

    2014-01-01

    Full Text Available This study, conducted as part of our overall goal of regular pharmacovigilance of antimalarial medicines, reports on the quality of 132 artemisinin-based antimalarial medicines distributed in Ghana and Togo. Three methods were employed in the quality evaluation—basic (colorimetric tests for establishing the identity of the requisite active pharmaceutical ingredients (APIs, semi-quantitative TLC assay for the identification and estimation of API content, and HPLC assay for a more accurate quantification of API content. From the basic tests, only one sample totally lacked API. The HPLC assay, however, showed that 83.7% of the ACTs and 57.9% of the artemisinin-based monotherapies failed to comply with international pharmacopoeia requirements due to insufficient API content. In most of the ACTs, the artemisinin component was usually the insufficient API. Generally, there was a good correlation between the HPLC and SQ-TLC assays. The overall failure rates for both locally manufactured (77.3% and imported medicines (77.5% were comparable. Similarly the unregistered medicines recorded a slightly higher overall failure rate (84.7% than registered medicines (70.8%. Only two instances of possible cross-border exchange of medicines were observed and there was little difference between the medicine quality of collections from border towns and those from inland parts of both countries.

  6. Increasing use of artemisinin-based combination therapy for treatment of malaria infection in Nigerian hospitals

    Igboeli NU

    2010-12-01

    Full Text Available Objectives: This study aimed at describing the pattern of outpatient antimalarial drug prescribing in a secondary and a tertiary hospital, and to assess adherence to the National Antimalarial Treatment Guideline (ATG. Methods: An audit of antimalarial prescription files from the two health facilities for a period of six months in 2008 was conducted. Semi structured questionnaires were used to collect information from the doctors and pharmacists on their awareness and knowledge of the National Antimalarial Treatment Guideline. Results: Artemisinin-based combination therapies (ACTs were the most prescribed antimalarials. Overall, 81.4% of the total prescriptions contained ACTs, out of which 56.8% were artemether-lumefantrine. However, adherence to the drugs indicated by national guideline within the DU90% was 38.5% for the tertiary and 66.7 % for the secondary hospital. The standard practice of prescribing with generic name was still not adhered to as evidenced in the understudied hospitals. The percentage of health care providers that were aware of the ATG was 88.2% for doctors and 85.1% for pharmacists. However, 13.3% and 52.2% of doctors and pharmacists respectively could not properly list the drugs specified in the guideline. Amodiaquine was the most commonly preferred option for managing children aged 0 – 3 months with malaria infection against the indicated oral quinine.Conclusion: This study showed an increased use of artemisinin-based combination therapy for the treatment of uncomplicated malaria compared previous reports in Nigeria. This study also highlights the need for periodic in-service quality assurance among health professionals with monitoring of adherence to and assessment of knowledge of clinical guidelines to ensure the practice of evidence based medicine.

  7. Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: A review

    Olliaro P

    2004-01-01

    clinical research that aims to bring artemisinin based combinations to those that need them most.

  8. Pyrrolidine-Acridine hybrid in Artemisinin-based combination: a pharmacodynamic study.

    Pandey, Swaroop Kumar; Biswas, Subhasish; Gunjan, Sarika; Chauhan, Bhavana Singh; Singh, Sunil Kumar; Srivastava, Kumkum; Singh, Sarika; Batra, Sanjay; Tripathi, Renu

    2016-09-01

    Aiming to develop new artemisinin-based combination therapy (ACT) for malaria, antimalarial effect of a new series of pyrrolidine-acridine hybrid in combination with artemisinin derivatives was investigated. Synthesis, antimalarial and cytotoxic evaluation of a series of hybrid of 2-(3-(substitutedbenzyl)pyrrolidin-1-yl)alkanamines and acridine were performed and mode of action of the lead compound was investigated. In vivo pharmacodynamic properties (parasite clearance time, parasite reduction ratio, dose and regimen determination) against multidrug resistant (MDR) rodent malaria parasite and toxicological parameters (median lethal dose, liver function test, kidney function test) were also investigated. 6-Chloro-N-(4-(3-(3,4-dimethoxybenzyl)pyrrolidin-1-yl)butyl)-2-methoxyacridin-9-amine (15c) has shown a dose dependent haem bio-mineralization inhibition and was found to be the most effective and safe compound against MDR malaria parasite in Swiss mice model. It displayed best antimalarial potential with artemether (AM) in vitro as well as in vivo. The combination also showed favourable pharmacodynamic properties and therapeutic response in mice with established MDR malaria infection and all mice were cured at the determined doses. The combination did not show toxicity at the doses administered to the Swiss mice. Taken together, our findings suggest that compound 15c is a potential partner with AM for the ACT and could be explored for further development. PMID:27230403

  9. Possible artemisinin-based combination therapy-resistant malaria in Nigeria: a report of three cases

    Nnennaya Anthony Ajayi

    2013-07-01

    Full Text Available Artemisinin-based combination therapy-resistant malaria is rare in Sub-Saharan Africa. The World Health Organization identifies monitoring and surveillance using day-3 parasitaemia post-treatment as the standard test for identifying suspected artemisinin resistance. We report three cases of early treatment failure due to possible artemisinin-based combination therapy-resistant Plasmodium falciparum malaria. All cases showed adequate clinical and parasitological responses to quinine. This study reveals a need to re-evaluate the quality and efficacy of artemisinin-based combination therapy agents in Nigeria and Sub-Saharan Africa.

  10. Subsidizing artemisinin-based combination therapies: a preliminary investigation of the Affordable Medicines Facility – malaria

    Bate R

    2012-07-01

    Full Text Available Roger Bate,1,2 Kimberly Hess,2 Richard Tren,2 Lorraine Mooney,3 Franklin Cudjoe,4 Thompson Ayodele,5 Amir Attaran61American Enterprise Institute, Washington, DC, USA; 2Africa Fighting Malaria, Washington, DC, USA; 3Africa Fighting Malaria, Cambridge, United Kingdom; 4IMANI Center for Policy and Education, Accra, Ghana; 5Initiative for Public Policy Analysis, Lagos, Nigeria; 6University of Ottawa, Ottawa, ON, CanadaBackground: The Affordable Medicines Facility – malaria (AMFm is a subsidy mechanism to lower the price of, and hence increase access to, the best antimalarial medicines, artemisinin-based combination therapies (ACTs. While the AMFm stipulates that only quality-approved products are eligible for subsidy, it is not known whether those products, when actually supplied, are of good quality and comport with established pharmacopeial guidance on formulation and content of active ingredients. This study aimed to assess price and quality of AMFm ACTs, to compare AMFm ACTs with non-AMFm ACTs and artemisinin monotherapies, and to assess whether AMFm ACTs have been pilfered and diverted to a nearby country.Methods: In all, 140 artemisinin-based antimalarial drugs were acquired from 37 pharmacies in Lagos, Nigeria, and Accra, Ghana. An additional ten samples of AMFm ACTs were collected from Lomé, Togo (not participating in the AMFm. Samples were analyzed using high-performance liquid chromatography.Results: The AMFm ACTs were lower in price than many of the other drugs collected, but by less than anticipated or stipulated by the participating governments of Nigeria and Ghana. The quality of the AMFm ACTs was not universally good: overall, 7.7% had too little active pharmaceutical ingredient (API and none had too much – these results are not likely to be as a result of random chance. AMFm ACTs were also found to have been diverted, both to pharmacies in Lagos not participating in the AMFm and to a foreign city (Lomé where the AMFm is not

  11. Increasing Access to Subsidized Artemisinin-based Combination Therapy through Accredited Drug Dispensing Outlets in Tanzania

    Gabra Michael

    2011-06-01

    Full Text Available Abstract Background In Tanzania, many people seek malaria treatment from retail drug sellers. The National Malaria Control Program identified the accredited drug dispensing outlet (ADDO program as a private sector mechanism to supplement the distribution of subsidized artemisinin-based combination therapies (ACTs from public facilities and increase access to the first-line antimalarial in rural and underserved areas. The ADDO program strengthens private sector pharmaceutical services by improving regulatory and supervisory support, dispenser training, and record keeping practices. Methods The government's pilot program made subsidized ACTs available through ADDOs in 10 districts in the Morogoro and Ruvuma regions, covering about 2.9 million people. The program established a supply of subsidized ACTs, created a price system with a cost recovery plan, developed a plan to distribute the subsidized products to the ADDOs, trained dispensers, and strengthened the adverse drug reactions reporting system. As part of the evaluation, 448 ADDO dispensers brought their records to central locations for analysis, representing nearly 70% of ADDOs operating in the two regions. ADDO drug register data were available from July 2007-June 2008 for Morogoro and from July 2007-September 2008 for Ruvuma. This intervention was implemented from 2007-2008. Results During the pilot, over 300,000 people received treatment for malaria at the 448 ADDOs. The percentage of ADDOs that dispensed at least one course of ACT rose from 26.2% during July-September 2007 to 72.6% during April-June 2008. The number of malaria patients treated with ACTs gradually increased after the start of the pilot, while the use of non-ACT antimalarials declined; ACTs went from 3% of all antimalarials sold in July 2007 to 26% in June 2008. District-specific data showed substantial variation among the districts in ACT uptake through ADDOs, ranging from ACTs representing 10% of all antimalarial sales

  12. Factors associated with non-adherence to Artemisinin-based combination therapy (ACT) to malaria in a rural population from holoendemic region of western Kenya

    Onyango Elizabeth O; Ayodo George; Watsierah Carren A; Were Tom; Okumu Wilson; Anyona Samuel B; Raballah Evans; Okoth John M; Gumo Sussy; Orinda George O; Ouma Collins

    2012-01-01

    Abstract Background Over the years, reports implicate improper anti-malarial use as a major contributor of morbidity and mortality amongst millions of residents in malaria endemic areas, Kenya included. However, there are limited reports on improper use of Artemisinin-based Combination Therapy (ACT) which is a first-line drug in the treatment of malaria in Kenya. Knowing this is important for ensured sustainable cure rates and also protection against the emergence of resistant malarial parasi...

  13. Predicting Global Fund grant disbursements for procurement of artemisinin-based combination therapies

    O'Brien Megan E

    2008-10-01

    Full Text Available Abstract Background An accurate forecast of global demand is essential to stabilize the market for artemisinin-based combination therapy (ACT and to ensure access to high-quality, life-saving medications at the lowest sustainable prices by avoiding underproduction and excessive overproduction, each of which can have negative consequences for the availability of affordable drugs. A robust forecast requires an understanding of the resources available to support procurement of these relatively expensive antimalarials, in particular from the Global Fund, at present the single largest source of ACT funding. Methods Predictive regression models estimating the timing and rate of disbursements from the Global Fund to recipient countries for each malaria grant were derived using a repeated split-sample procedure intended to avoid over-fitting. Predictions were compared against actual disbursements in a group of validation grants, and forecasts of ACT procurement extrapolated from disbursement predictions were evaluated against actual procurement in two sub-Saharan countries. Results Quarterly forecasts were correlated highly with actual smoothed disbursement rates (r = 0.987, p Conclusion This analysis derived predictive regression models that successfully forecasted disbursement patterning for individual Global Fund malaria grants. These results indicate the utility of this approach for demand forecasting of ACT and, potentially, for other commodities procured using funding from the Global Fund. Further validation using data from other countries in different regions and environments will be necessary to confirm its generalizability.

  14. The challenges of changing national malaria drug policy to artemisinin-based combinations in Kenya

    Otieno Dorothy N

    2007-05-01

    Full Text Available Abstract Backgound Sulphadoxine/sulphalene-pyrimethamine (SP was adopted in Kenya as first line therapeutic for uncomplicated malaria in 1998. By the second half of 2003, there was convincing evidence that SP was failing and had to be replaced. Despite several descriptive investigations of policy change and implementation when countries moved from chloroquine to SP, the different constraints of moving to artemisinin-based combination therapy (ACT in Africa are less well documented. Methods A narrative description of the process of anti-malarial drug policy change, financing and implementation in Kenya is assembled from discussions with stakeholders, reports, newspaper articles, minutes of meetings and email correspondence between actors in the policy change process. The narrative has been structured to capture the timing of events, the difficulties and hurdles faced and the resolutions reached to the final implementation of a new treatment policy. Results Following a recognition that SP was failing there was a rapid technical appraisal of available data and replacement options resulting in a decision to adopt artemether-lumefantrine (AL as the recommended first-line therapy in Kenya, announced in April 2004. Funding requirements were approved by the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM and over 60 million US$ were agreed in principle in July 2004 to procure AL and implement the policy change. AL arrived in Kenya in May 2006, distribution to health facilities began in July 2006 coincidental with cascade in-service training in the revised national guidelines. Both training and drug distribution were almost complete by the end of 2006. The article examines why it took over 32 months from announcing a drug policy change to completing early implementation. Reasons included: lack of clarity on sustainable financing of an expensive therapeutic for a common disease, a delay in release of funding, a lack of comparative efficacy data

  15. Subsidising artemisinin-based combination therapy in the private retail sector

    Opiyo, Newton; Yamey, Gavin; Garner, Paul

    2016-01-01

    Background Malaria causes ill health and death in Africa. Treating illness promptly with artemisinin-based combination therapy (ACT) is likely to cure people and avoid the disease progressing to more severe forms and death. In many countries, ACT use remains low. Part of the problem is that most people seek treatment from the retail sector where ACTs are expensive; this expense is a barrier to their use. The Global Fund and other international organisations are subsidising the cost of ACTs fo...

  16. Comparative safety of artemether-lumefantrine and other artemisinin-based combinations in children: a systematic review

    Egunsola, Oluwaseun; Oshikoya, Kazeem A

    2013-01-01

    Background The purpose of the study was to compare the safety of artemether-lumefantrine (AL) with other artemisinin-based combinations in children. Methods A search of EMBASE (from 1974 to April 2013), MEDLINE (from 1946 to April 2013) and the Cochrane library of registered controlled trials for randomized controlled trials (RCTs) which compared AL with other artemisinin-based combinations was done. Only studies involving children ≤ 17 years old in which safety of AL was an outcom...

  17. Adherence to prescribed artemisinin-based combination therapy in Garissa and Bunyala districts, Kenya

    Munga Stephen

    2011-09-01

    Full Text Available Abstract Background Following the development of resistance to anti-malarial mono-therapies, malaria endemic countries in Africa now use artemisinin-based combination therapy (ACT as recommended first-line treatment for uncomplicated malaria. Patients' adherence to ACT is an important factor to ensure treatment efficacy, as well as to reduce the likelihood of parasite resistance to these drugs. This study reports adherence to a specific ACT, artemether-lumefantrine (AL, under conditions of routine clinical practice in Kenya. Method The study was undertaken in Garissa and Bunyala districts among outpatients of five government health facilities. Patients treated with AL were visited at home four days after having been prescribed the drug. Respondents (patients ≥ 15 years and caregivers of patients Results Of the 918 patients included in the study, 588 (64.1% were 'probably adherent', 291 (31.7% were 'definitely non-adherent' and 39 (4.2% were 'probably non-adherent'. Six factors were found to be significant predictors of adherence: patient knowledge of the ACT dosing regimen (odds ratio (OR = 1.76; 95% CI = 1.32-2.35, patient age (OR = 1.65; 95% CI = 1.02-1.85, respondent age (OR = 1.37; 95% CI = 1.10-2.48, whether a respondent had seen AL before (OR = 1.46; 95% CI = 1.08-1.98, whether a patient had reported dislikes to AL (OR = 0.62 95% CI = 0.47-0.82 and whether a respondent had waited more than 24 hours to seek treatment (OR = 0.73; 95% CI = 0.54-0.99. Conclusion Overall, adherence to AL was found to be low in both Garissa and Bunyala districts, with patient knowledge of the AL dosing regimen found to be the strongest predictor of adherence. Interventions aimed at increasing community awareness of the AL dosing regimen, use of child friendly formulations and improving health workers' prescribing practices are likely to ensure higher adherence to AL and eventual treatment success.

  18. Willingness and ability to pay for artemisinin-based combination therapy in rural Tanzania

    Montgomery Scott M

    2008-10-01

    Full Text Available Abstract Background The aim of this study was to analyse willingness to pay (WTP and ability to pay (ATP for ACT for children below five years of age in a rural setting in Tanzania before the introduction of artemisinin-based combination therapy (ACT as first-line treatment for uncomplicated malaria. Socio-economic factors associated with WTP and expectations on anti-malaria drugs, including ACT, were also explored. Methods Structured interviews and focus group discussions were held with mothers, household heads, health-care workers and village leaders in Ishozi, Gera and Ishunju wards in north-west Tanzania in 2004. Contingent valuation method (CVM was used with "take-it-or-leave-it" as the eliciting method, expressed as WTP for a full course of ACT for a child and households' opportunity cost of ACT was used to assess ATP. The study included descriptive analyses with multivariate adjustment for potential confounding factors. Results Among 265 mothers and household heads, 244 (92%, CI = 88%–95% were willing to pay Tanzanian Shillings (TSh 500 (US$ 0.46 for a child's dose of ACT, but only 55% (49%–61% were willing to pay more than TSh 500. Mothers were more often willing to pay than male household heads (adjusted odds ratio = 2.1, CI = 1.2–3.6. Socio-economic status had no significant effect on WTP. The median annual non-subsidized ACT cost for clinical malaria episodes in an average household was calculated as US$ 6.0, which would represent 0.9% of the average total consumption expenditures as estimated from official data in 2001. The cost of non-subsidized ACT represented 7.0% of reported total annual expenditure on food and 33.0% of total annual expenditure on health care. "Rapid effect," "no adverse effect" and "inexpensive" were the most desired features of an anti-malarial drug. Conclusion WTP for ACT in this study was less than its real cost and a subsidy is, therefore, needed to enable its equitable affordability. The decision

  19. Subsidising artemisinin-based combination therapy in the private retail sector

    Opiyo, Newton; Yamey, Gavin; Garner, Paul

    2016-01-01

    very low. The ACT subsidy programmes decreased the median cost of ACTs for children under five years of age by US$ 0.84 (median cost per ACT course without subsidy: US$ 1.08 versus with subsidy: US$ 0.24; 1 study, high certainty evidence). The ACT subsidy programmes increased the market share of ACTs for children under five years of age by between 23.6 and 63.0 percentage points (1 study, high certainty evidence). The ACT subsidy programmes decreased the use of older antimalarial drugs (such as amodiaquine and sulphadoxine-pyrimethamine) among children under five years of age by 10.4 percentage points (95% CI 3.9 to 16.9 percentage points; 1 study, high certainty evidence). None of the three studies of ACT subsidies reported the number of patients treated who had confirmed malaria. Vouchers increased the likelihood that an illness is treated with an ACT by 16 to 23 percentage points; however, vouchers were associated with a high rate of over-treatment of malaria (only 56% of patients taking ACTs from the drug shop tested positive for malaria under the 92% subsidy; 1 study, high certainty evidence). Authors' conclusions Programmes that include substantive subsidies for private sector retailers combined with training of providers and social marketing improved use and availability of ACTs for children under five years of age with suspected malaria in research studies from three countries in East Africa. These programmes also reduced prices of ACTs, improved market share of ACTs and reduced the use of older antimalarial drugs among febrile children under five years of age. The research evaluates drug delivery but does not assess whether the patients had confirmed (parasite-diagnosed) malaria. None of the included studies assessed patient outcomes; it is therefore not known whether the effects seen in the studies would translate to an impact on health. PLAIN LANGUAGE SUMMARY Subsidising artemisinin-based combination therapy in drug shops and pharmacies We conducted a review

  20. Quality of Artemisinin-Based Combination Formulations for Malaria Treatment: Prevalence and Risk Factors for Poor Quality Medicines in Public Facilities and Private Sector Drug Outlets in Enugu, Nigeria

    Harparkash Kaur; Elizabeth Louise Allan; Ibrahim Mamadu; Zoe Hall; Ogochukwu Ibe; Mohamed El Sherbiny; Albert van Wyk; Shunmay Yeung; Isabel Swamidoss; Green, Michael D.; Prabha Dwivedi; Maria Julia Culzoni; Siân Clarke; David Schellenberg; Fernández, Facundo M.

    2015-01-01

    Background Artemisinin-based combination therapies are recommended by the World Health Organisation (WHO) as first-line treatment for Plasmodium falciparum malaria, yet medication must be of good quality for efficacious treatment. A recent meta-analysis reported 35% (796/2,296) of antimalarial drug samples from 21 Sub-Saharan African countries, purchased from outlets predominantly using convenience sampling, failed chemical content analysis. We used three sampling strategies to purchase artem...

  1. Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies.

    Veiga, M Isabel; Dhingra, Satish K; Henrich, Philipp P; Straimer, Judith; Gnädig, Nina; Uhlemann, Anne-Catrin; Martin, Rowena E; Lehane, Adele M; Fidock, David A

    2016-01-01

    Antimalarial chemotherapy, globally reliant on artemisinin-based combination therapies (ACTs), is threatened by the spread of drug resistance in Plasmodium falciparum parasites. Here we use zinc-finger nucleases to genetically modify the multidrug resistance-1 transporter PfMDR1 at amino acids 86 and 184, and demonstrate that the widely prevalent N86Y mutation augments resistance to the ACT partner drug amodiaquine and the former first-line agent chloroquine. In contrast, N86Y increases parasite susceptibility to the partner drugs lumefantrine and mefloquine, and the active artemisinin metabolite dihydroartemisinin. The PfMDR1 N86 plus Y184F isoform moderately reduces piperaquine potency in strains expressing an Asian/African variant of the chloroquine resistance transporter PfCRT. Mutations in both digestive vacuole-resident transporters are thought to differentially regulate ACT drug interactions with host haem, a product of parasite-mediated haemoglobin degradation. Global mapping of these mutations illustrates where the different ACTs could be selectively deployed to optimize treatment based on regional differences in PfMDR1 haplotypes. PMID:27189525

  2. Adherence and uptake of artemisinin-based combination treatments for uncomplicated malaria: a qualitative study in northern Ghana.

    Samuel Chatio

    Full Text Available Based on the recommendations of the World Health Organization in 2004, Ghana changed her antimalarial drug policy from mono-therapy to Artemisinin-based Combination Therapy (ACTs. The country is currently using three first line drugs artesunate-amodiaquine, artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated malaria. Despite this policy, little or no qualitative studies have been conducted to establish the factors influencing adherence to the new treatment for malaria. This study explored factors influencing adherence to the use of ACTs in northern Ghana.This was a qualitative study comprising forty (40 in-depth interviews with patients with malaria who visited selected public and private health facilities and received ACTs. Systematic sampling technique was used to select participants who were given ACTs for the interviews. Nvivo 9 software was used to code the data into themes for further analysis.The study revealed very important differences in knowledge about ACTs. As expected, the less or illiterates could not mention the type of ACT they would prefer to use for treating their malaria. The educated ones had a good knowledge on ACTs and preferred artemether-lumefantrinee in treating their malaria. The reason was that the drug was good and it had minimal or no side effects. Individual attitudes toward the use of medications and the side effects associated with the use of these ACTs were found to be the main factors affecting adherence to the use of ACTs. Perceived cure of illness after the initial dose greatly affected adherence. Other factors such as forgetfulness and lack of information also influenced patient adherence to ACTs use.Individual knowledge, attitudes and behaviors greatly influence patients' adherence to ACTs use. Since ACTs take a number of days to complete, continuous education by health professionals could improve on adherence to ACTs use by patients with malaria.

  3. Prediction of potential antimalarial targets of artemisinin based on protein information from whole genome of Plasmodium falciparum

    HAN LiPing; HUANG Qiang; NAN Peng; ZHONG Yang

    2009-01-01

    On the basis of the genomic data and protein pathway information about Plasmodium falciparum clone 3D7 from the NCBI taxonomy database and the KEGG database,eight key protein enzymes in the signal pathways were selected to perform molecular docking with artemisinin.The binding modes obtained from the molecular docking suggested that purine nucleoside phosphorylase (pfPNP),peptide deformylase (pfPDF),and ribose 5-phosphate isomerase (pfRpiA) may be involved in the antimalarial mode of action of artemisinin.Artemisinin exhibited its antimalarial activity probably by interfering with the metabolic pathways of purine,pyrimidine,methionine,glyoxylate and dicarboxylate,or pentose phosphate.

  4. A pharmacy too far? Equity and spatial distribution of outcomes in the delivery of subsidized artemisinin-based combination therapies through private drug shops

    Ward Lorrayne

    2010-07-01

    Full Text Available Abstract Background Millions of individuals with malaria-like fevers purchase drugs from private retailers, but artemisinin-based combination therapies (ACTs, the only effective treatment in regions with high levels of resistance to older drugs, are rarely obtained through these outlets due to their relatively high cost. To encourage scale up of ACTs, the Affordable Medicines Facility – malaria is being launched to subsidize their price. The Government of Tanzania and the Clinton Foundation piloted this subsidized distribution model in two Tanzanian districts to examine concerns about whether the intervention will successfully reach poor, rural communities. Methods Stocking of ACTs and other antimalarial drugs in all retail shops was observed at baseline and in four subsequent surveys over 15 months. Exit interviews were conducted with antimalarial drug customers during each survey period. All shops and facilities were georeferenced, and variables related to population density and proximity to distribution hubs, roads, and other facilities were calculated. To understand the equity of impact, shops stocking ACTs and consumers buying them were compared to those that did not, according to geographic and socioeconomic variables. Patterning in ACT stocking and sales was evaluated against that of other common antimalarials to identify factors that may have impacted access. Qualitative data were used to assess motivations underlying stocking, distribution, and buying disparities. Results Results indicated that although total ACT purchases rose from negligible levels to nearly half of total antimalarial sales over the course of the pilot, considerable geographic variation in stocking and sales persisted and was related to a variety of socio-spatial factors; ACTs were stocked more often in shops located closer to district towns (p Conclusions As this subsidy model is scaled up across multiple countries, these results confirm the potential for increased

  5. Priority setting for the implementation of artemisinin-based combination therapy policy in Tanzania: evaluation against the accountability for reasonableness framework

    Mori Amani

    2012-03-01

    Full Text Available Abstract Background Priority setting for artemisinin-based antimalarial drugs has become an integral part of malaria treatment policy change in malaria-endemic countries. Although these drugs are more efficacious, they are also more costly than the failing drugs. When Tanzania changed its National Malaria Treatment Policy in 2006, priority setting was an inevitable challenge. Artemether-lumefantrine was prioritised as the first-line drug for the management of uncomplicated malaria to be available at a subsidized price at public and faith-based healthcare facilities. Methods This paper describes the priority-setting process, which involved the selection of a new first-line antimalarial drug in the implementation of artemisinin-based combination therapy policy. These descriptions were further evaluated against the four conditions of the accountability for reasonableness framework. According to this framework, fair decisions must satisfy a set of publicity, relevance, appeals, and revision and enforcement conditions. In-depth interviews were held with key informants using pretested interview guides, supplemented with a review of the treatment guideline. Purposeful sampling was used in order to explore the perceptions of people with different backgrounds and perspectives. The analysis followed an editing organising style. Results Publicity: The selection decision of artemether-lumefantrine but not the rationale behind it was publicised through radio, television, and newspaper channels in the national language, Swahili. Relevance: The decision was grounded on evidences of clinical efficacy, safety, affordability, and formulation profile. Stakeholders were not adequately involved. There was neither an appeals mechanism to challenge the decision nor enforcement mechanisms to guarantee fairness of the decision outcomes. Conclusions The priority-setting decision to use artemether-lumefantrine as the first-line antimalarial drug failed to satisfy the four

  6. From chloroquine to artemisinin-based combination therapy: the Sudanese experience

    Elhassan AH

    2006-07-01

    Full Text Available Abstract Background In Sudan, chloroquine (CQ remains the most frequently used drug for falciparum malaria for more than 40 years. The change to artemisinin-based combination therapy (ACT was initiated in 2004 using the co-blister of artesunate + sulfadoxine/pyrimethamine (AS+SP and artemether + lumefantrine (ART+LUM, as first- and second-line, respectively. This article describes the evidence-base, the process for policy change and it reflects the experience of one year implementation. Relevant published and unpublished documents were reviewed. Data and information obtained were compiled into a structured format. Case description Sudan has used evidence to update its malaria treatment to ACTs. The country moved without interim period and proceeded with country-wide implementation instead of a phased introduction of the new policy. The involvement of care providers and key stakeholders in a form of a technical advisory committee is considered the key issue in the process. Development and distribution of guidelines, training of care providers, communication to the public and provision of drugs were given great consideration. To ensure presence of high quality drugs, a system for post-marketing drugs surveillance was established. Currently, ACTs are chargeable and chiefly available in urban areas. With the input from the Global Fund to fight AIDs, Tuberculosis and Malaria, AS+SP is now available free of charge in 10 states. Conclusion Implementation of the new policy is affected by the limited availability of the drugs, their high cost and limited pre-qualified manufacturers. Substantial funding needs to be mobilized by all partners to increase patients' access for this life-saving intervention.

  7. The costs of introducing artemisinin-based combination therapy: evidence from district-wide implementation in rural Tanzania

    Abdulla Salim

    2008-01-01

    Full Text Available Abstract Background The development of antimalarial drug resistance has led to increasing calls for the introduction of artemisinin-based combination therapy (ACT. However, little evidence is available on the full costs associated with changing national malaria treatment policy. This paper presents findings on the actual drug and non-drug costs associated with deploying ACT in one district in Tanzania, and uses these data to estimate the nationwide costs of implementation in a setting where identification of malaria cases is primarily dependant on clinical diagnosis. Methods Detailed data were collected over a three year period on the financial costs of providing ACT in Rufiji District as part of a large scale effectiveness evaluation, including costs of drugs, distribution, training, treatment guidelines and other information, education and communication (IEC materials and publicity. The district-level costs were scaled up to estimate the costs of nationwide implementation, using four scenarios to extrapolate variable costs. Results The total district costs of implementing ACT over the three year period were slightly over one million USD, with drug purchases accounting for 72.8% of this total. The composite (best estimate of nationwide costs for the first three years of ACT implementation was 48.3 million USD (1.29 USD per capita, which varied between 21 and 67.1 million USD in the sensitivity analysis (2003 USD. In all estimates drug costs constituted the majority of total costs. However, non-drug costs such as IEC materials, drug distribution, communication, and health worker training were also substantial, accounting for 31.4% of overall ACT implementation costs in the best estimate scenario. Annual implementation costs are equivalent to 9.5% of Tanzania's recurrent health sector budget, and 28.7% of annual expenditure on medical supplies, implying a 6-fold increase in the national budget for malaria treatment. Conclusion The costs of

  8. Routine delivery of artemisinin-based combination treatment at fixed health facilities reduces malaria prevalence in Tanzania: an observational study

    Khatib Rashid A

    2012-04-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT has been promoted as a means to reduce malaria transmission due to their ability to kill both asexual blood stages of malaria parasites, which sustain infections over long periods and the immature derived sexual stages responsible for infecting mosquitoes and onward transmission. Early studies reported a temporal association between ACT introduction and reduced malaria transmission in a number of ecological settings. However, these reports have come from areas with low to moderate malaria transmission, been confounded by the presence of other interventions or environmental changes that may have reduced malaria transmission, and have not included a comparison group without ACT. This report presents results from the first large-scale observational study to assess the impact of case management with ACT on population-level measures of malaria endemicity in an area with intense transmission where the benefits of effective infection clearance might be compromised by frequent and repeated re-infection. Methods A pre-post observational study with a non-randomized comparison group was conducted at two sites in Tanzania. Both sites used sulphadoxine-pyrimethamine (SP monotherapy as a first-line anti-malarial from mid-2001 through 2002. In 2003, the ACT, artesunate (AS co-administered with SP (AS + SP, was introduced in all fixed health facilities in the intervention site, including both public and registered non-governmental facilities. Population-level prevalence of Plasmodium falciparum asexual parasitaemia and gametocytaemia were assessed using light microscopy from samples collected during representative household surveys in 2001, 2002, 2004, 2005 and 2006. Findings Among 37,309 observations included in the analysis, annual asexual parasitaemia prevalence in persons of all ages ranged from 11% to 28% and gametocytaemia prevalence ranged from Interpretation The introduction of ACT at

  9. Feasibility and acceptability of artemisinin-based combination therapy for the home management of malaria in four African sites

    Munguti Kaendi

    2008-01-01

    Full Text Available Abstract Background The Home Management of Malaria (HMM strategy was developed using chloroquine, a now obsolete drug, which has been replaced by artemisinin-based combination therapy (ACT in health facility settings. Incorporation of ACT in HMM would greatly expand access to effective antimalarial therapy by the populations living in underserved areas in malaria endemic countries. The feasibility and acceptability of incorporating ACT in HMM needs to be evaluated. Methods A multi-country study was performed in four district-size sites in Ghana (two sites, Nigeria and Uganda, with populations ranging between 38,000 and 60,000. Community medicine distributors (CMDs were trained in each village to dispense pre-packaged ACT to febrile children aged 6–59 months, after exclusion of danger signs. A community mobilization campaign accompanied the programme. Artesunate-amodiaquine (AA was used in Ghana and artemether-lumefantrine (AL in Nigeria and Uganda. Harmonized qualitative and quantitative data collection methods were used to evaluate CMD performance, caregiver adherence and treatment coverage of febrile children with ACTs obtained from CMDs. Results Some 20,000 fever episodes in young children were treated with ACT by CMDs across the four study sites. Cross-sectional surveys identified 2,190 children with fever in the two preceding weeks, of whom 1,289 (59% were reported to have received ACT from a CMD. Coverage varied from 52% in Nigeria to 75% in Ho District, Ghana. Coverage rates did not appear to vary greatly with the age of the child or with the educational level of the caregiver. A very high proportion of children were reported to have received the first dose on the day of onset or the next day in all four sites (range 86–97%, average 90%. The proportion of children correctly treated in terms of dose and duration was also high (range 74–97%, average 85%. Overall, the proportion of febrile children who received prompt treatment and the

  10. Efficacy of non-artemisinin- and artemisinin-based combination therapies for uncomplicated falciparum malaria in Cameroon

    Thalabard Jean-Christophe

    2010-02-01

    Full Text Available Abstract Background The use of drug combinations, including non-artemisinin-based and artemisinin-based combination therapy (ACT, is a novel strategy that enhances therapeutic efficacy and delays the emergence of multidrug-resistant Plasmodium falciparum. Its use is strongly recommended in most sub-Saharan African countries, namely Cameroon, where resistance to chloroquine is widespread and antifolate resistance is emerging. Methods Studies were conducted in Cameroonian children with acute uncomplicated P. falciparum malaria according to the standard World Health Organization protocol at four sentinel sites between 2003 and 2007. A total of 1,401 children were enrolled, of whom 1,337 were assigned to randomized studies and 64 were included in a single non-randomized study. The proportions of adequate clinical and parasitological response (PCR-uncorrected on day 14 and PCR-corrected on day 28 were the primary endpoints to evaluate treatment efficacy on day 14 and day 28. The relative effectiveness of drug combinations was compared by a multi-treatment Bayesian random-effect meta-analysis. Findings The results based on the meta-analysis suggested that artesunate-amodiaquine (AS-AQ is as effective as other drugs (artesunate-sulphadoxine-pyrimethamine [AS-SP], artesunate-chlorproguanil-dapsone [AS-CD], artesunate-mefloquine [AS-MQ], dihydroartemisinin-piperaquine [DH-PP], artemether-lumefantrine [AM-LM], amodiaquine, and amodiaquine-sulphadoxine-pyrimethamine [AQ-SP]. AM-LM appeared to be the most effective with no treatment failure due to recrudescence, closely followed by DH-PP. Conclusion Although AM-LM requires six doses, rather than three doses for other artemisinin-based combinations, it has potential advantages over other forms of ACT. Further studies are needed to evaluate the clinical efficacy and tolerance of these combinations in different epidemiological context.

  11. Artemisinin-based combination therapy: knowledge and perceptions of patent medicine dealers in Owerri Metropolis, Imo State, Nigeria and implications for compliance with current malaria treatment protocol.

    Chukwuocha, Uchechukwu Madukaku; Nwakwuo, Geoffrey Chima; Mmerole, Ikechukwu

    2013-08-01

    This study was done to access the knowledge and perceptions of Patent Medicine Dealers (PMDs) in Owerri Metropolis of Nigeria about Artemisinin Based Combination Therapy as first line treatment for malaria using structured pre-tested questionnaires administered to 80 randomly selected and consenting respondents. About 67.5 and 32.5 % of males and females respectively participated in the study. Most of them (56.3 %) had secondary school education with about 50 % having 5-10 years experience in the business. The level of knowledge was shown to be high (82.5 %), with 81.3 % having proper understanding of the term "artemisinin-based combination therapies (ACTs)" and 80 % knowing the correct dosage for ACTs. But despite the level of awareness, only 32.5 % knew the correct timing for administration of the drugs. The result of this study showed no significant relationship between the level of knowledge and either educational attainment (χ(2) = 4.889, df = 4, p value = 0.558) or the years of experience (χ(2) = 29.095, df = 4, p value = 0.000) although knowledge improved a bit as experience increased. 93.8 % in the study reported that ACTs are more effective than other anti-malarial drugs. The quantity of ACT available on counters are low and there is no significant relationship (χ(2) = 18.833, df = 6, p value = 0.004) between the availability of ACT and the quantity of ACT available in stock at the time of this study. This study shows that awareness on ACTs has improved among PMDs, even though other anti-malarial drugs are still in use and are marketed by them. It becomes necessary that efforts towards awareness be scaled up with emphasis on recommended time of administration and correct prescriptions to enhance and sustain intermittent presumptive treatment as an effective method of malaria control since this group of people still provide the major access to drugs in Nigeria and other tropical endemic areas. PMID:23539134

  12. Willingness-to-pay for a rapid malaria diagnostic test and artemisinin-based combination therapy from private drug shops in Mukono District, Uganda.

    Hansen, Kristian Schultz; Pedrazzoli, Debora; Mbonye, Anthony; Clarke, Sian; Cundill, Bonnie; Magnussen, Pascal; Yeung, Shunmay

    2013-03-01

    In Uganda, as in many parts of Africa, the majority of the population seek treatment for malaria in drug shops as their first point of care; however, parasitological diagnosis is not usually offered in these outlets. Rapid diagnostic tests (RDTs) for malaria have attracted interest in recent years as a tool to improve malaria diagnosis, since they have proved accurate and easy to perform with minimal training. Although RDTs could feasibly be performed by drug shop vendors, it is not known how much customers would be willing to pay for an RDT if offered in these settings. We conducted a contingent valuation survey among drug shop customers in Mukono District, Uganda. Exit interviews were undertaken with customers aged 15 years and above after leaving a drug shop having purchased an antimalarial and/or paracetamol. The bidding game technique was used to elicit the willingness-to-pay (WTP) for an RDT and a course of artemisinin-based combination therapy (ACT) with and without RDT confirmation. Factors associated with WTP were investigated using linear regression. The geometric mean WTP for an RDT was US$0.53, US$1.82 for a course of ACT and US$2.05 for a course of ACT after a positive RDT. Factors strongly associated with a higher WTP for these commodities included having a higher socio-economic status, no fever/malaria in the household in the past 2 weeks and if a malaria diagnosis had been obtained from a qualified health worker prior to visiting the drug shop. The findings further suggest that the WTP for an RDT and a course of ACT among drug shop customers is considerably lower than prevailing and estimated end-user prices for these commodities. Increasing the uptake of ACTs in drug shops and restricting the sale of ACTs to parasitologically confirmed malaria will therefore require additional measures. PMID:22589226

  13. Molecular monitoring of plasmodium falciparum drug susceptibility at the time of the introduction of artemisinin-based combination therapy in Yaoundé, Cameroon: Implications for the future

    Menard Sandie

    2012-04-01

    Full Text Available Abstract Background Regular monitoring of the levels of anti-malarial resistance of Plasmodium falciparum is an essential policy to adapt therapy and improve malaria control. This monitoring can be facilitated by using molecular tools, which are easier to implement than the classical determination of the resistance phenotype. In Cameroon, chloroquine (CQ, previously the first-line therapy for uncomplicated malaria was officially withdrawn in 2002 and replaced initially by amodiaquine (AQ monotherapy. Then, artemisinin-based combination therapy (ACT, notably artesunate-amodiaquine (AS-AQ or artemether-lumefantrine (AL, was gradually introduced in 2004. This situation raised the question of the evolution of P. falciparum resistance molecular markers in Yaoundé, a highly urbanized Cameroonian city. Methods The genotype of pfcrt 72 and 76 and pfmdr1 86 alleles and pfmdr1 copy number were determined using real-time PCR in 447 P. falciparum samples collected between 2005 and 2009. Results This study showed a high prevalence of parasites with mutant pfcrt 76 (83% and pfmdr1 86 (93% codons. On the contrary, no mutations in the pfcrt 72 codon and no samples with duplication of the pfmdr1 gene were observed. Conclusion The high prevalence of mutant pfcrt 76T and pfmdr1 86Y alleles might be due to the choice of alternative drugs (AQ and AS-AQ known to select such genotypes. Mutant pfcrt 72 codon was not detected despite the prolonged use of AQ either as monotherapy or combined with artesunate. The absence of pfmdr1 multicopies suggests that AL would still remain efficient. The limited use of mefloquine or the predominance of mutant pfmdr1 86Y codon could explain the lack of pfmdr1 amplification. Indeed, this mutant codon is rarely associated with duplication of pfmdr1 gene. In Cameroon, the changes of therapeutic strategies and the simultaneous use of several formulations of ACT or other anti-malarials that are not officially recommended result in a

  14. Importance of the long-acting partner drug in artemisinin-based combination therapy.

    Kurtzhals, Jørgen Al

    2008-11-01

    The 1st African Health Research Organization International Malaria Symposium on Clinical Pharmacology of Antimalarial Drugs collected approximately 60 health professionals, scientists, policy makers and nongovernmental organization representatives from Africa, Europe and the USA for updates on recent developments in malaria therapy. It was the first African Health Research Organization symposium in Africa aimed at taking an African leadership in the fight against malaria. The intention is to start a tradition of annually recurring symposia that will eventually grow to become a leading international event in malaria research. Apart from scientific presentations, substantial time was dedicated to discussions and brainstorming, with a view to developing tools that can realistically be used to address challenges relating to all aspects of malaria treatment and control. The meeting was funded partly by the Medicines for Malaria Venture and Dafra Pharma International Ltd., Belgium, both of which were represented by some of the speakers. PMID:24410604

  15. Stabilizing supply of artemisinin and artemisinin-based combination therapy in an era of wide-spread scale-up.

    Shretta, Rima; Yadav, Prashant

    2012-01-01

    The global demand for artemisinin-based combination therapy (ACT) has grown sharply since its recommendation by the World Health Organization in 2002. However, a combination of financing and programmatic uncertainties, limited suppliers of finished products, information opacity across the different tiers in the supply chain, and widespread fluctuations in raw material prices have together contributed to a market fraught with demand and supply uncertainties and price volatility. Various short-term solutions have been deployed to alleviate supply shortages caused by these challenges; however, new mechanisms are required to build resilience into the supply chain. This review concludes that a mix of strategies is required to stabilize the artemisinin and ACT market. First, better and more effective pooling of demand and supply risks and better contracting to allow risk sharing among the stakeholders are needed. Physical and financial buffer stocks will enable better matching of demand and supply in the short and medium term. Secondly, physical buffers will allow stable supplies when there are procurement and supply management challenges while financial buffer funds will address issues around funding disruptions. Finally, in the medium to long term, significant investments in country level system strengthening will be required to minimize national level demand uncertainties. In addition a voluntary standard for extractors to ensure appropriate purchasing and sales practices as well as minimum quality and ethical standards could help stabilize the artemisinin market in the long term. PMID:23198961

  16. Stabilizing supply of artemisinin and artemisinin-based combination therapy in an era of wide-spread scale-up

    Shretta Rima

    2012-12-01

    Full Text Available Abstract The global demand for artemisinin-based combination therapy (ACT has grown sharply since its recommendation by the World Health Organization in 2002. However, a combination of financing and programmatic uncertainties, limited suppliers of finished products, information opacity across the different tiers in the supply chain, and widespread fluctuations in raw material prices have together contributed to a market fraught with demand and supply uncertainties and price volatility. Various short-term solutions have been deployed to alleviate supply shortages caused by these challenges; however, new mechanisms are required to build resilience into the supply chain. This review concludes that a mix of strategies is required to stabilize the artemisinin and ACT market. First, better and more effective pooling of demand and supply risks and better contracting to allow risk sharing among the stakeholders are needed. Physical and financial buffer stocks will enable better matching of demand and supply in the short and medium term. Secondly, physical buffers will allow stable supplies when there are procurement and supply management challenges while financial buffer funds will address issues around funding disruptions. Finally, in the medium to long term, significant investments in country level system strengthening will be required to minimize national level demand uncertainties. In addition a voluntary standard for extractors to ensure appropriate purchasing and sales practices as well as minimum quality and ethical standards could help stabilize the artemisinin market in the long term.

  17. A pharmacy too far? Equity and spatial distribution of outcomes in the delivery of subsidized artemisinin-based combination therapies through private drug shops

    Ward Lorrayne; Ipuge Yahya; Odhiambo Moses; Gross Isaac; Bishop David; Gordon Megumi; Sabot Kate; Sabot Oliver; Cohen Justin M; Mwita Alex; Goodman Catherine

    2010-01-01

    Abstract Background Millions of individuals with malaria-like fevers purchase drugs from private retailers, but artemisinin-based combination therapies (ACTs), the only effective treatment in regions with high levels of resistance to older drugs, are rarely obtained through these outlets due to their relatively high cost. To encourage scale up of ACTs, the Affordable Medicines Facility – malaria is being launched to subsidize their price. The Government of Tanzania and the Clinton Foundation ...

  18. Piloting the Global Subsidy: The Impact of Subsidized Artemisinin-Based Combination Therapies Distributed Through Private Drug Shops in Rural Tanzania.

    Sabot, OJ; Mwita, A; Cohen, JM; Ipuge, Y; Gordon, M.; Bishop, D.; Odhiambo, M; Ward, L; Goodman, C

    2009-01-01

    BACKGROUND: WHO estimates that only 3% of fever patients use recommended artemisinin-based combination therapies (ACTs), partly reflecting their high prices in the retail sector from where many patients seek treatment. To overcome this challenge, a global ACT subsidy has been proposed. We tested this proposal through a pilot program in rural Tanzania. METHODS/PRINCIPAL FINDINGS: Three districts were assigned to serve either as a control or to receive the subsidy plus a package of supporting i...

  19. Factors associated with non-adherence to Artemisinin-based combination therapy (ACT to malaria in a rural population from holoendemic region of western Kenya

    Onyango Elizabeth O

    2012-06-01

    Full Text Available Abstract Background Over the years, reports implicate improper anti-malarial use as a major contributor of morbidity and mortality amongst millions of residents in malaria endemic areas, Kenya included. However, there are limited reports on improper use of Artemisinin-based Combination Therapy (ACT which is a first-line drug in the treatment of malaria in Kenya. Knowing this is important for ensured sustainable cure rates and also protection against the emergence of resistant malarial parasites. We therefore investigated ACT adherence level, factors associated with non-adherence and accessibility in households (n = 297 in rural location of Southeast Alego location in Siaya County in western Kenya. Methods ACT Adherence level was assessed with reference to the duration of treatment and number of tablets taken. Using systematic random sampling technique, a questionnaire was administered to a particular household member who had the most recent malaria episode ( Results Adherence to ACT prescription remained low at 42.1% and 57.9% among individuals above 13 and less than 13 years, respectively. Stratification by demographic and socio-economic characteristics in relation to ACT adherence revealed that age (P = 0.011, education level (P P P = 0.002 significantly affected the level of ACT adherence. Consistently, logistic regression model demonstrated that low age (OR, 0.571, 95% CI, 0.360-0.905; P = 0.017, higher education level (OR, 0.074; 95% CI 0.017-0.322; P P  9000; OR, 0.340; 95% CI, 0.167-0.694; P = 0.003 were associated with ACT adherence. In addition, about 52.9% of the respondents reported that ACT was not always available at the source and that drug availability (P = 0.020 and distance to drug source (P  Conclusions This study demonstrates that more than half of those who get ACT prescription do not take recommended dose and that accessibility is of concern. The findings of this study suggest a

  20. Plasmodium falciparum clearance with artemisinin-based combination therapy (ACT in patients with glucose-6-phosphate dehydrogenase deficiency in Mali

    Djimde Abdoulaye

    2010-11-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is currently the most effective medicine for the treatment of uncomplicated malaria. Artemisinin has previously been shown to increase the clearance of Plasmodium falciparum in malaria patients with haemoglobin E trait, but it did not increase parasite inhibition in an in vitro study using haemoglobin AS erythrocytes. The current study describes the efficacy of artemisinin derivatives on P. falciparum clearance in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD, a haemoglobin enzyme deficiency, not yet studied in the same context, but nonetheless is a common in malaria endemic areas, associated with host protection against uncomplicated and severe malaria. The impact of G6PD deficiency on parasite clearance with ACT treatment was compared between G6PD-deficient patients and G6PD-normal group. Methods Blood samples from children and adults participants (1 to 70 years old with uncomplicated P. falciparum malaria residing in Kambila, Mali were analysed. Study participants were randomly assigned to receive either artemether-lumefantrine (Coartem® or artesunate plus mefloquine (Artequin™. A restriction-fragment length polymorphism analysis of PCR-amplified DNA samples was used to identify the (A- allele of the gene mutation responsible for G6PD deficiency (G6PD*A-. 470 blood samples were thus analysed and of these, DNA was extracted from 315 samples using the QIAamp kit for PCR to identify the G6PD*A- gene. Results The DNA amplified from 315 samples using PCR showed that G6PD*A- deficiency was present in 56 participants (17.8%. The distribution of the specific deficiency was 1%, 7% and, 9.8% respectively for homozygous, hemizygous, and heterozygous genotypes. Before treatment, the median parasitaemia and other baseline characteristics (mean haemoglobin, sex and age groups between G6PD deficiency (hemizygous, heterozygous, and homozygous and G6PD-normal participants

  1. Quality of Artemisinin-Based Combination Formulations for Malaria Treatment: Prevalence and Risk Factors for Poor Quality Medicines in Public Facilities and Private Sector Drug Outlets in Enugu, Nigeria

    Kaur, Harparkash; Allan, Elizabeth Louise; Mamadu, Ibrahim; Hall, Zoe; Ibe, Ogochukwu; El Sherbiny, Mohamed; van Wyk, Albert; Yeung, Shunmay; Swamidoss, Isabel; Green, Michael D.; Dwivedi, Prabha; Culzoni, Maria Julia; Clarke, Siân; Schellenberg, David; Fernández, Facundo M.; Onwujekwe, Obinna

    2015-01-01

    Background Artemisinin-based combination therapies are recommended by the World Health Organisation (WHO) as first-line treatment for Plasmodium falciparum malaria, yet medication must be of good quality for efficacious treatment. A recent meta-analysis reported 35% (796/2,296) of antimalarial drug samples from 21 Sub-Saharan African countries, purchased from outlets predominantly using convenience sampling, failed chemical content analysis. We used three sampling strategies to purchase artemisinin-containing antimalarials (ACAs) in Enugu metropolis, Nigeria, and compared the resulting quality estimates. Methods ACAs were purchased using three sampling approaches - convenience, mystery clients and overt, within a defined area and sampling frame in Enugu metropolis. The active pharmaceutical ingredients were assessed using high-performance liquid chromatography and confirmed by mass spectrometry at three independent laboratories. Results were expressed as percentage of APIs stated on the packaging and used to categorise each sample as acceptable quality, substandard, degraded, or falsified. Results Content analysis of 3024 samples purchased from 421 outlets using convenience (n=200), mystery (n=1,919) and overt (n=905) approaches, showed overall 90.8% ACAs to be of acceptable quality, 6.8% substandard, 1.3% degraded and 1.2% falsified. Convenience sampling yielded a significantly higher prevalence of poor quality ACAs, but was not evident by the mystery and overt sampling strategies both of which yielded results that were comparable between each other. Artesunate (n=135; 4 falsified) and dihydroartemisinin (n=14) monotherapy tablets, not recommended by WHO, were also identified. Conclusion Randomised sampling identified fewer falsified ACAs than previously reported by convenience approaches. Our findings emphasise the need for specific consideration to be given to sampling frame and sampling approach if representative information on drug quality is to be obtained

  2. Quality of artemisinin-based combination formulations for malaria treatment: prevalence and risk factors for poor quality medicines in public facilities and private sector drug outlets in Enugu, Nigeria.

    Harparkash Kaur

    Full Text Available Artemisinin-based combination therapies are recommended by the World Health Organisation (WHO as first-line treatment for Plasmodium falciparum malaria, yet medication must be of good quality for efficacious treatment. A recent meta-analysis reported 35% (796/2,296 of antimalarial drug samples from 21 Sub-Saharan African countries, purchased from outlets predominantly using convenience sampling, failed chemical content analysis. We used three sampling strategies to purchase artemisinin-containing antimalarials (ACAs in Enugu metropolis, Nigeria, and compared the resulting quality estimates.ACAs were purchased using three sampling approaches--convenience, mystery clients and overt, within a defined area and sampling frame in Enugu metropolis. The active pharmaceutical ingredients were assessed using high-performance liquid chromatography and confirmed by mass spectrometry at three independent laboratories. Results were expressed as percentage of APIs stated on the packaging and used to categorise each sample as acceptable quality, substandard, degraded, or falsified.Content analysis of 3024 samples purchased from 421 outlets using convenience (n=200, mystery (n=1,919 and overt (n=905 approaches, showed overall 90.8% ACAs to be of acceptable quality, 6.8% substandard, 1.3% degraded and 1.2% falsified. Convenience sampling yielded a significantly higher prevalence of poor quality ACAs, but was not evident by the mystery and overt sampling strategies both of which yielded results that were comparable between each other. Artesunate (n=135; 4 falsified and dihydroartemisinin (n=14 monotherapy tablets, not recommended by WHO, were also identified.Randomised sampling identified fewer falsified ACAs than previously reported by convenience approaches. Our findings emphasise the need for specific consideration to be given to sampling frame and sampling approach if representative information on drug quality is to be obtained.

  3. Feasibility and acceptability of home-based management of malaria strategy adapted to Sudan's conditions using artemisinin-based combination therapy and rapid diagnostic test

    Mudather Mahmoud A

    2009-03-01

    Full Text Available Abstract Background Malaria remains a major public health problem especially in sub-Saharan Africa. Despite the efforts exerted to provide effective anti-malarial drugs, still some communities suffer from getting access to these services due to many barriers. This research aimed to assess the feasibility and acceptability of home-based management of malaria (HMM strategy using artemisinin-based combination therapy (ACT for treatment and rapid diagnostic test (RDT for diagnosis. Methods This is a study conducted in 20 villages in Um Adara area, South Kordofan state, Sudan. Two-thirds (66% of the study community were seeking treatment from heath facilities, which were more than 5 km far from their villages with marked inaccessibility during rainy season. Volunteers (one per village were trained on using RDTs for diagnosis and artesunate plus sulphadoxine-pyrimethamine for treating malaria patients, as well as referral of severe and non-malaria cases. A system for supply and monitoring was established based on the rural health centre, which acted as a link between the volunteers and the health system. Advocacy for the policy was done through different tools. Volunteers worked on non-monetary incentives but only a consultation fee of One Sudanese Pound (equivalent to US$0.5. Pre- and post-intervention assessment was done using household survey, focus group discussion with the community leaders, structured interview with the volunteers, and records and reports analysis. Results and discussion The overall adherence of volunteers to the project protocol in treating and referring cases was accepted that was only one of the 20 volunteers did not comply with the study guidelines. Although the use of RDTs seemed to have improved the level of accuracy and trust in the diagnosis, 30% of volunteers did not rely on the negative RDT results when treating fever cases. Almost all (94.7% the volunteers felt that they were satisfied with the spiritual outcome of

  4. Antimalarial drug resistance and combination chemotherapy.

    White, N.

    1999-01-01

    Antimarial drug resistance develops when spontaneously occurring parasite mutants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susceptibility are particularly vulnerable. Low clearance and a shallow concentration-effect relationship increase the chance of selection. Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the cha...

  5. Community response to artemisinin-based combination therapy for childhood malaria: a case study from Dar es Salaam, Tanzania

    Nyato Daniel J

    2010-02-01

    Full Text Available Abstract Background New malaria treatment guidelines in Tanzania have led to the large-scale deployment of artemether-lumefantrine (Coartem®, popularly known as ALu or dawa mseto. Very little is known about how people in malaria endemic areas interpret policy makers' decision to replace existing anti-malarials, such as sulphadoxine-pyrimethamine (SP with "new" treatment regimens, such as ALu or other formulations of ACT. This study was conducted to examine community level understandings and interpretations of ALu's efficacy and side-effects. The paper specifically examines the perceived efficacy of ALu as articulated by the mothers of young children diagnosed with malaria and prescribed ALu. Methods Participant observation, six focus group discussions in two large villages, followed by interviews with a random sample of 110 mothers of children less than five years of age, who were diagnosed with malaria and prescribed ALu. Additionally, observations were conducted in two village dispensaries involving interactions between mothers/caretakers and health care providers. Results While more than two-thirds of the mothers had an overall negative disposition toward SP, 97.5% of them spoke favourably about ALu, emphasizing it's ability to help their children to rapidly recover from malaria, without undesirable side-effects. 62.5% of the mothers reported that they were spending less money dealing with malaria than previously when their child was treated with SP. 88% of the mothers had waited for 48 hours or more after the onset of fever before taking their child to the dispensary. Mothers' knowledge and reporting of ALu's dosage was, in many cases, inconsistent with the recommended dosage schedule for children. Conclusion Deployment of ALu has significantly changed community level perceptions of anti-malarial treatment. However, mothers continue to delay seeking care before accessing ALu, limiting the impact of highly subsidized rollout of the drug

  6. Therapeutic efficacy trial of artemisinin-based combination therapy for the treatment of uncomplicated malaria and investigation of mutations in k13 propeller domain in Togo, 2012–2013

    Dorkenoo, Améyo M.; Yehadji, Degninou; Agbo, Yao M.; Layibo, Yao; Agbeko, Foli; Adjeloh, Poukpessi; Yakpa, Kossi; Sossou, Efoe; Awokou, Fantchè; Ringwald, Pascal

    2016-01-01

    Background Since 2005, the Togo National Malaria Control Programme has recommended two different formulations of artemisinin-based combination therapy (ACT), artesunate–amodiaquine (ASAQ) and artemether-lumefantrine (AL), for the treatment of uncomplicated malaria. Regular efficacy monitoring of these two combinations is conducted every 2 or 3 years. This paper reports the latest efficacy assessment results and the investigation of mutations in the k13 propeller domain. Methods The study was ...

  7. Malaria Control Dynamics in Rural Tanzania: Evaluation of implementation of Artemisinin based Anti-malarial Combination Therapy

    Khatib, Rashid Ali

    2010-01-01

    Malaria is the most important parasitic disease caused by protozoans of the genus plasmodia that are transmitted by female anophelene mosquitoes. Plasmodium falciparum is the most important species owing to its distribution, virulence and pathogenicity. World-wide some 500 million infections, 200-300 million episodes and about 1 million malaria-related deaths occur every year amounting to a burden of some 45 million DALYs (Disability Adjusted Life Years) [1]. At least 80% of this intolerable ...

  8. Malaria control dynamics in rural Tanzania : evaluation of implementation of artemisinin based anti-malarial combination therapy

    Khatib, Rashid Ali

    2010-01-01

    Malaria is the most important parasitic disease caused by protozoans of the genus plasmodia that are transmitted by female anophelene mosquitoes. Plasmodium falciparum is the most important species owing to its distribution, virulence and pathogenicity. World-wide some 500 million infections, 200-300 million episodes and about 1 million malaria-related deaths occur every year amounting to a burden of some 45 million DALYs (Disability Adjusted Life Years) [1]. At least 80% of...

  9. Piloting the global subsidy: the impact of subsidized artemisinin-based combination therapies distributed through private drug shops in rural Tanzania.

    Oliver J Sabot

    Full Text Available WHO estimates that only 3% of fever patients use recommended artemisinin-based combination therapies (ACTs, partly reflecting their high prices in the retail sector from where many patients seek treatment. To overcome this challenge, a global ACT subsidy has been proposed. We tested this proposal through a pilot program in rural Tanzania.Three districts were assigned to serve either as a control or to receive the subsidy plus a package of supporting interventions. From October 2007, ACTs were sold at a 90% subsidy through the normal private supply chain to intervention district drug shops. Data were collected at baseline and during intervention using interviews with drug shop customers, retail audits, mystery shoppers, and audits of public and NGO facilities. The proportion of consumers in the intervention districts purchasing ACTs rose from 1% at baseline to 44.2% one year later (p<0.001, and was significantly higher among consumers purchasing for children under 5 than for adults (p = 0.005. No change in ACT usage was observed in the control district. Consumers paid a mean price of $0.58 for ACTs, which did not differ significantly from the price paid for sulphadoxine-pyrimethamine, the most common alternative. Drug shops in population centers were significantly more likely to stock ACTs than those in more remote areas (p<0.001.A subsidy introduced at the top of the private sector supply chain can significantly increase usage of ACTs and reduce their retail price to the level of common monotherapies. Additional interventions may be needed to ensure access to ACTs in remote areas and for poorer individuals who appear to seek treatment at drug shops less frequently.Controlled-Trials.com ISRCTN39125414.

  10. Prevalence of malaria parasitemia and purchase of artemisinin-based combination therapies (ACTs among drug shop clients in two regions in Tanzania with ACT subsidies.

    Melissa A Briggs

    Full Text Available BACKGROUND: Throughout Africa, many people seek care for malaria in private-sector drug shops where diagnostic testing is often unavailable. Recently, subsidized artemisinin-based combination therapies (ACTs, a first-line medication for uncomplicated malaria, were made available in these drug shops in Tanzania. This study assessed the prevalence of malaria among and purchase of ACTs by drug shop clients in the setting of a national ACT subsidy program and sub-national drug shop accreditation program. METHOD AND FINDINGS: A cross-sectional survey of drug shop clients was performed in two regions in Tanzania, one with a government drug shop accreditation program and one without, from March-May, 2012. Drug shops were randomly sampled from non-urban districts. Shop attendants were interviewed about their education, training, and accreditation status. Clients were interviewed about their symptoms and medication purchases, then underwent a limited physical examination and laboratory testing for malaria. Malaria prevalence and predictors of ACT purchase were assessed using univariate analysis and multiple logistic regression. Amongst 777 clients from 73 drug shops, the prevalence of laboratory-confirmed malaria was 12% (95% CI: 6-18%. Less than a third of clients with malaria had purchased ACTs, and less than a quarter of clients who purchased ACTs tested positive for malaria. Clients were more likely to have purchased ACTs if the participant was 5 years, experience (aOR: 2.8; 95% CI: 1.2-6.3. Having malaria was only a predictor of ACT purchase in the region with a drug shop accreditation program (aOR: 3.4; 95% CI: 1.5-7.4. CONCLUSION: Malaria is common amongst persons presenting to drug shops with a complaint of fever. The low proportion of persons with malaria purchasing ACTs, and the high proportion of ACTs going to persons without malaria demonstrates a need to better target who receives ACTs in these drug shops.

  11. Piloting the Global Subsidy: The Impact of Subsidized Artemisinin-Based Combination Therapies Distributed through Private Drug Shops in Rural Tanzania

    Sabot, Oliver J.; Mwita, Alex; Cohen, Justin M.; Ipuge, Yahya; Gordon, Megumi; Bishop, David; Odhiambo, Moses; Ward, Lorrayne; Goodman, Catherine

    2009-01-01

    Background WHO estimates that only 3% of fever patients use recommended artemisinin-based combination therapies (ACTs), partly reflecting their high prices in the retail sector from where many patients seek treatment. To overcome this challenge, a global ACT subsidy has been proposed. We tested this proposal through a pilot program in rural Tanzania. Methods/Principal Findings Three districts were assigned to serve either as a control or to receive the subsidy plus a package of supporting interventions. From October 2007, ACTs were sold at a 90% subsidy through the normal private supply chain to intervention district drug shops. Data were collected at baseline and during intervention using interviews with drug shop customers, retail audits, mystery shoppers, and audits of public and NGO facilities. The proportion of consumers in the intervention districts purchasing ACTs rose from 1% at baseline to 44.2% one year later (p<0.001), and was significantly higher among consumers purchasing for children under 5 than for adults (p = 0.005). No change in ACT usage was observed in the control district. Consumers paid a mean price of $0.58 for ACTs, which did not differ significantly from the price paid for sulphadoxine-pyrimethamine, the most common alternative. Drug shops in population centers were significantly more likely to stock ACTs than those in more remote areas (p<0.001). Conclusions A subsidy introduced at the top of the private sector supply chain can significantly increase usage of ACTs and reduce their retail price to the level of common monotherapies. Additional interventions may be needed to ensure access to ACTs in remote areas and for poorer individuals who appear to seek treatment at drug shops less frequently. Trial Registration Controlled-Trials.com ISRCTN39125414. PMID:19724644

  12. Antimalarial qinghaosu/artemisinin: The therapy worthy of a Nobel Prize

    Jerapan Krungkrai; Sudaratana Rochanakij Krungkrai

    2016-01-01

    Malaria is a major cause of human morbidity and mortality in the tropical endemic countries worldwide. This is largely due to the emergence and spread of resistance to most antimalarial drugs currently available. Based on the World Health Organization recommendation, artemisinin-based combination therapies are now used as first-line treatment for Plasmodium falciparum malaria. Artemisinin or qinghaosu (Chinese name) and its derivatives are highly potent, rapidly acting antimalarial drugs. Art...

  13. Comparative assessment of two Artemisinin based combination Therapies in the treatment of Uncomplicated Malaria among University students in Nigeria

    Okonta Matthew J

    2013-06-01

    Full Text Available Background: In line with the recommendation of artemisininbased combination therapy (ACT by WHO in the effective treatment of uncomplicated malaria, African nations including Nigeria changed their malaria treatment policy to combination therapies. To date, about 15 African nations adopted artesunate /amodiaquine (AA as their first line agent while Nigeria adopted artemether /lumefantrine (AL. Objective: The objective of this study is to compare the treatment outcome among patients treated with AA to those treated with AL for acute uncomplicated malaria. Method: The study was conducted at Nnamdi Azikiwe University campuses using quantitative methods. Two hundered and ninety six patients were randomly allocated to one of two treatment group- AA and AL with 148 patients per group. All the patients were educated about the drugs and adherence. Adherence and treatment outcomes including parasite clearance and the drugs’ effects on biochemical parameters among others were assessed by follow up visits on third, seventh, fourteenth and twenty eighth-day post treatment. Data were analysed using Cox Regression model on SPSS 17.0. Result: Both drugs were well adhered to and tolerated. One case of Steven Johnson-like reaction was observed with AL. Fever resolution and parasite clearance was similar in both groups with adequate clinical and parasitological response (ACPR by day 28 for AL and AA being 70.3% and 85.1% respectively. Conclusion: Our findings is in favour of higher efficacy of AA with respect to their ACPR. More controlled studies will be needed to ascertain the adoption of AL as first line drug in malaria treatment in Nigeria.

  14. Plasmodium falciparum susceptibility to anti-malarial drugs in Dakar, Senegal, in 2010: an ex vivo and drug resistance molecular markers study

    Fall, Bécaye; Pascual, Aurélie; Sarr, Fatoumata; Wurtz, Nathalie; Richard, Vincent; Baret, Eric; Diémé, Yaya; Briolant, Sébastien; Bercion, Raymond; Wade, Boubacar; Tall, Adama; Pradines, Bruno

    2013-01-01

    BACKGROUND: In 2006, the Senegalese National Malaria Control Programme recommended artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria. Since the introduction of ACT, there have been very few reports on the level of resistance of P. falciparum to anti-malarial drugs. To determine whether parasite susceptibility has been affected by the new anti-malarial policies, an ex vivo susceptibility and drug resistance molecular marker study was conducted on...

  15. Adverse drug events resulting from use of drugs with sulphonamide-containing anti-malarials and artemisinin-based ingredients: findings on incidence and household costs from three districts with routine demographic surveillance systems in rural Tanzania

    Njau, JD; Kabanywanyi, AM; Goodman, CA; Macarthur, JR; Kapella, BK; Gimnig, JE; Kahigwa, E.; Bloland, PB; Abdulla, SM; Kachur, SP

    2013-01-01

    Background: Anti-malarial regimens containing sulphonamide or artemisinin ingredients are widely used in malaria-endemic countries. However, evidence of the incidence of adverse drug reactions (ADR) to these drugs is limited, especially in Africa, and there is a complete absence of information on the economic burden such ADR place on patients. This study aimed to document ADR incidence and associated household costs in three high malaria transmission districts in rural Tanzania covered by dem...

  16. Drug resistant falciparum malaria and the use of artesunate-based combinations : focus on clinical trials sponsored by TDR

    Walter R.J. Taylor, Jean Rigal & Piero L. Olliaro

    2003-01-01

    Antimalarial drug resistance has now become a serious global challenge and is the principal reasonfor the decline in antimalarial drug efficacy. Malaria endemic countries need inexpensive and efficaciousdrugs. Preserving the life spans of antimalarial drugs is a key part of the strategy for rollingback malaria. Artemisinin-based combinations offer a new and potentially highly effective way tocounter drug resistance. Clinical trials conducted in African children have attested to the good toler...

  17. Willingness-to-pay for a rapid malaria diagnostic test and artemisinin-based combination therapy from private drug shops in Mukono district, Uganda

    Hansen, Kristian Schultz; Pedrazzoli, Debora; Mbonye, Anthony;

    2013-01-01

    In Uganda, as in many parts of Africa, the majority of the population seek treatment for malaria in drug shops as their first point of care; however, parasitological diagnosis is not usually offered in these outlets. Rapid diagnostic tests (RDTs) for malaria have attracted interest in recent years...... contingent valuation survey among drug shop customers in Mukono District, Uganda. Exit interviews were undertaken with customers aged 15 years and above after leaving a drug shop having purchased an antimalarial and/or paracetamol. The bidding game technique was used to elicit the willingness-to-pay (WTP...... RDT. Factors strongly associated with a higher WTP for these commodities included having a higher socio-economic status, no fever/malaria in the household in the past 2 weeks and if a malaria diagnosis had been obtained from a qualified health worker prior to visiting the drug shop. The findings...

  18. Plasmodium falciparum gametocyte carriage, sex ratios and asexual parasite rates in Nigerian children before and after a treatment protocol policy change instituting the use of artemisinin-based combination therapies

    Grace Olusola Gbotosho

    2011-09-01

    Full Text Available The effects of artemisinin-based combination therapies (ACTs on transmission of Plasmodium falciparum were evaluated after a policy change instituting the use of ACTs in an endemic area. P. falciparum gametocyte carriage, sex ratios and inbreeding rates were examined in 2,585 children at presentation with acute falciparum malaria during a 10-year period from 2001-2010. Asexual parasite rates were also evaluated from 2003-2010 in 10,615 children before and after the policy change. Gametocyte carriage declined significantly from 12.4% in 2001 to 3.6% in 2010 (@@χ2 for trend = 44.3, p < 0.0001, but sex ratios and inbreeding rates remained unchanged. Additionally, overall parasite rates remained unchanged before and after the policy change (47.2% vs. 45.4%, but these rates declined significantly from 2003-2010 (@@χ2 for trend 35.4, p < 0.0001. Chloroquine (CQ and artemether-lumefantrine (AL were used as prototype drugs before and after the policy change, respectively. AL significantly shortened the duration of male gametocyte carriage in individual patients after treatment began compared with CQ (log rank statistic = 7.92, p = 0.005. ACTs reduced the rate of gametocyte carriage in children with acute falciparum infections at presentation and shortened the duration of male gametocyte carriage after treatment. However, parasite population sex ratios, inbreeding rates and overall parasite rate were unaffected.

  19. High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations.

    Mott, Bryan T; Eastman, Richard T; Guha, Rajarshi; Sherlach, Katy S; Siriwardana, Amila; Shinn, Paul; McKnight, Crystal; Michael, Sam; Lacerda-Queiroz, Norinne; Patel, Paresma R; Khine, Pwint; Sun, Hongmao; Kasbekar, Monica; Aghdam, Nima; Fontaine, Shaun D; Liu, Dongbo; Mierzwa, Tim; Mathews-Griner, Lesley A; Ferrer, Marc; Renslo, Adam R; Inglese, James; Yuan, Jing; Roepe, Paul D; Su, Xin-Zhuan; Thomas, Craig J

    2015-01-01

    Drug resistance in Plasmodium parasites is a constant threat. Novel therapeutics, especially new drug combinations, must be identified at a faster rate. In response to the urgent need for new antimalarial drug combinations we screened a large collection of approved and investigational drugs, tested 13,910 drug pairs, and identified many promising antimalarial drug combinations. The activity of known antimalarial drug regimens was confirmed and a myriad of new classes of positively interacting drug pairings were discovered. Network and clustering analyses reinforced established mechanistic relationships for known drug combinations and identified several novel mechanistic hypotheses. From eleven screens comprising >4,600 combinations per parasite strain (including duplicates) we further investigated interactions between approved antimalarials, calcium homeostasis modulators, and inhibitors of phosphatidylinositide 3-kinases (PI3K) and the mammalian target of rapamycin (mTOR). These studies highlight important targets and pathways and provide promising leads for clinically actionable antimalarial therapy. PMID:26403635

  20. The challenge to avoid anti-malarial medicine stock-outs in an era of funding partners: the case of Tanzania

    Mikkelsen-Lopez, Inez; Shango, Winna; Barrington, Jim; Ziegler, Rene; Smith, Tom; de Savigny, Don

    2014-01-01

    Background Between 2007 and 2013, the Tanzanian public sector received 93.1 million doses of first-line anti-malarial artemisinin-based combination therapy (ACT) in the form of artemether-lumefantrine entirely supplied by funding partners. The introduction of a health facility ACT stock monitoring system using SMS technology by the National Malaria Control Programme in mid 2011 revealed a high frequency of stock-outs of ACT in primary care public health facilities. The objective of this study...

  1. Stability profiling of anti-malarial drug piperaquine phosphate and impurities by HPLC-UV, TOF-MS, ESI-MS and NMR

    Yan, Fang; Liu, Jie; Zeng, Xuefang; Zhang, Yuan; Hang, Taijun

    2014-01-01

    Background Piperaquine, 1,3-bis-[4-(7-chloroquinolyl-4)-piperazinyl-1]-propane, is an anti-malarial compound belonging to the 4-aminoquinolines, which has received renewed interest in treatment of drug resistant falciparum malaria in artemisinin-based combination therapy with dihydroartemisinin. The impurity profile of this drug product is paid an ever-increasing attention. However, there were few published studies of the complete characterization of related products or impurities in piperaqu...

  2. In Silico Mining for Antimalarial Structure-Activity Knowledge and Discovery of Novel Antimalarial Curcuminoids

    Birgit Viira

    2016-06-01

    Full Text Available Malaria is a parasitic tropical disease that kills around 600,000 patients every year. The emergence of resistant Plasmodium falciparum parasites to artemisinin-based combination therapies (ACTs represents a significant public health threat, indicating the urgent need for new effective compounds to reverse ACT resistance and cure the disease. For this, extensive curation and homogenization of experimental anti-Plasmodium screening data from both in-house and ChEMBL sources were conducted. As a result, a coherent strategy was established that allowed compiling coherent training sets that associate compound structures to the respective antimalarial activity measurements. Seventeen of these training sets led to the successful generation of classification models discriminating whether a compound has a significant probability to be active under the specific conditions of the antimalarial test associated with each set. These models were used in consensus prediction of the most likely active from a series of curcuminoids available in-house. Positive predictions together with a few predicted as inactive were then submitted to experimental in vitro antimalarial testing. A large majority from predicted compounds showed antimalarial activity, but not those predicted as inactive, thus experimentally validating the in silico screening approach. The herein proposed consensus machine learning approach showed its potential to reduce the cost and duration of antimalarial drug discovery.

  3. Antimalarial qinghaosu/artemisinin: The therapy worthy of a Nobel Prize

    Jerapan Krungkrai

    2016-05-01

    Full Text Available Malaria is a major cause of human morbidity and mortality in the tropical endemic countries worldwide. This is largely due to the emergence and spread of resistance to most antimalarial drugs currently available. Based on the World Health Organization recommendation, artemisinin-based combination therapies are now used as first-line treatment for Plasmodium falciparum malaria. Artemisinin or qinghaosu (Chinese name and its derivatives are highly potent, rapidly acting antimalarial drugs. Artemisinin was discovered in 1971 by a Chinese medical scientist Youyou Tu, who was awarded the Nobel Prize in 2015 on her discovering the antimalarial properties of qinghaosu from the traditional Chinese qinghao plant. Nevertheless, artemisinin resistance in falciparum malaria patients has first emerged on the Thai-Cambodian border in 2009, which is now prevalent across mainland Southeast Asia from Vietnam to Myanmar. Here, we reviewed malaria disease severity, history of artemisinin discovery, chemical structure, mechanism of drug action, artemisinin-based combination therapies, emergence and spread of drug resistance, including the recent findings on mechanism of resistance in the falciparum malaria parasite. This poses a serious threat to global malaria control and prompts renewed efforts for the urgent development of new antimalarial drugs.

  4. Antimalarial qinghaosu/artemisinin:The therapy worthy of a Nobel Prize

    Jerapan Krungkrai

    2016-01-01

    Malaria is a major cause of human morbidity and mortality in the tropical endemic countries worldwide. This is largely due to the emergence and spread of resistance to most antimalarial drugs currently available. Based on the World Health Organization recommendation, artemisinin-based combination therapies are now used as first-line treatment for Plasmodium falciparum malaria. Artemisinin or qinghaosu (Chinese name) and its derivatives are highly potent, rapidly acting antimalarial drugs. Artemisinin was discovered in 1971 by a Chinese medical scientist Youyou Tu, who was awarded the Nobel Prize in 2015 on her discovering the antimalarial properties of qinghaosu from the traditional Chinese qinghao plant. Nevertheless, artemisinin resistance in falciparum malaria patients has first emerged on the Thai-Cambodian border in 2009, which is now prevalent across mainland Southeast Asia from Vietnam to Myanmar. Here, we reviewed malaria disease severity, history of artemisinin discovery, chemical structure, mechanism of drug action, artemisinin-based combination therapies, emergence and spread of drug resistance, including the recent findings on mechanism of resistance in the falciparum malaria parasite. This poses a serious threat to global malaria control and prompts renewed efforts for the urgent development of new antimalarial drugs.

  5. Acquired resistance of malarial parasites against artemisinin-based drugs: social and economic impacts

    Johanna M Porter-Kelley

    2010-08-01

    Full Text Available Johanna M Porter-Kelley1, Joann Cofie2, Sophonie Jean2, Mark E Brooks1, Mia Lassiter1, DC Ghislaine Mayer21Life Sciences Department, ­Winston-Salem State University, Winston Salem, NC, USA; 2Department of Biology, Virginia Commonwealth University, Richmond, VA, USAAbstract: Malaria, a disease of poverty and high morbidity and mortality in the tropical world, has led to a worldwide search for control measures. To that end, good antimalarial chemotherapies have been difficult to find in the global market and those that seem to be most effective are rapidly becoming ineffective due to the emergence and spread of drug resistance. Artemisinin, a very effective yet expensive antimalarial, has quickly become the recommended drug of choice when all other possibilities fail. However, for all its promise as the next great antimalarial, the outlook is bleak. Resistance is developing to artemisinin while another effective antimalarial is not in sight. Malaria endemic areas which are mostly in developing countries must deal with the multifaceted process of changing and implementing new national malaria treatment guidelines. This requires complex interactions between several sectors of the affected society which in some cases take place within the context of political instability. Moreover, the cost associated with preventing and containing the spread of antimalarial resistance is detrimental to economic progress. This review addresses the impact of artemisinin resistance on the socioeconomic structure of malaria endemic countries.Keywords: artemisinin-based drugs, social, economic, malarial parasite resistance

  6. Quality of antimalarials at the epicenter of antimalarial drug resistance: results from an overt and mystery client survey in Cambodia.

    Yeung, Shunmay; Lawford, Harriet L S; Tabernero, Patricia; Nguon, Chea; van Wyk, Albert; Malik, Naiela; DeSousa, Mikhael; Rada, Ouk; Boravann, Mam; Dwivedi, Prabha; Hostetler, Dana M; Swamidoss, Isabel; Green, Michael D; Fernandez, Facundo M; Kaur, Harparkash

    2015-06-01

    Widespread availability of monotherapies and falsified antimalarials is thought to have contributed to the historical development of multidrug-resistant malaria in Cambodia. This study aimed to document the quality of artemisinin-containing antimalarials (ACAs) and to compare two methods of collecting antimalarials from drug outlets: through open surveyors and mystery clients (MCs). Few oral artemisinin-based monotherapies and no suspected falsified medicines were found. All 291 samples contained the stated active pharmaceutical ingredient (API) of which 69% were considered good quality by chemical analysis. Overall, medicine quality did not differ by collection method, although open surveyors were less likely to obtain oral artemisinin-based monotherapies than MCs. The results are an encouraging indication of the positive impact of the country's efforts to tackle falsified antimalarials and artemisinin-based monotherapies. However, poor-quality medicines remain an ongoing challenge that demands sustained political will and investment of human and financial resources. PMID:25897063

  7. Fake anti-malarials: start with the facts.

    Kaur, Harparkash; Clarke, Siȃn; Lalani, Mirza; Phanouvong, Souly; Guérin, Philippe; McLoughlin, Andrew; Wilson, Benjamin K; Deats, Michael; Plançon, Aline; Hopkins, Heidi; Miranda, Debora; Schellenberg, David

    2016-01-01

    This meeting report presents the key findings and discussion points of a 1-day meeting entitled 'Fake anti-malarials: start with the facts' held on 28th May 2015, in Geneva, Switzerland, to disseminate the findings of the artemisinin combination therapy consortium's drug quality programme. The teams purchased over 10,000 samples, using representative sampling approaches, from six malaria endemic countries: Equatorial Guinea (Bioko Island), Cambodia, Ghana, Nigeria, Rwanda and Tanzania. Laboratory analyses of these samples showed that falsified anti-malarials (<8 %) were found in just two of the countries, whilst substandard artemisinin-based combinations were present in all six countries and, artemisinin-based monotherapy tablets are still available in some places despite the fact that the WHO has urged regulatory authorities in malaria-endemic countries to take measures to halt the production and marketing of these oral monotherapies since 2007. This report summarizes the presentations that reviewed the public health impact of falsified and substandard drugs, sampling strategies, techniques for drug quality analysis, approaches to strengthen health systems capacity for the surveillance of drug quality, and the ensuing discussion points from the dissemination meeting. PMID:26873700

  8. Antimalarial Drug Resistance: Literature Review and Activities and Findings of the ICEMR Network.

    Cui, Liwang; Mharakurwa, Sungano; Ndiaye, Daouda; Rathod, Pradipsinh K; Rosenthal, Philip J

    2015-09-01

    Antimalarial drugs are key tools for the control and elimination of malaria. Recent decreases in the global malaria burden are likely due, in part, to the deployment of artemisinin-based combination therapies. Therefore, the emergence and potential spread of artemisinin-resistant parasites in southeast Asia and changes in sensitivities to artemisinin partner drugs have raised concerns. In recognition of this urgent threat, the International Centers of Excellence for Malaria Research (ICEMRs) are closely monitoring antimalarial drug efficacy and studying the mechanisms underlying drug resistance. At multiple sentinel sites of the global ICEMR network, research activities include clinical studies to track the efficacies of antimalarial drugs, ex vivo/in vitro assays to measure drug susceptibilities of parasite isolates, and characterization of resistance-mediating parasite polymorphisms. Taken together, these efforts offer an increasingly comprehensive assessment of the efficacies of antimalarial therapies, and enable us to predict the emergence of drug resistance and to guide local antimalarial drug policies. Here we briefly review worldwide antimalarial drug resistance concerns, summarize research activities of the ICEMRs related to drug resistance, and assess the global impacts of the ICEMR programs. PMID:26259943

  9. Blood schizontocidal activity of methylene blue in combination with antimalarials against Plasmodium falciparum

    Garavito G.

    2007-06-01

    Full Text Available Methylene blue (MB is the oldest synthetic antimalarial. It is not used anymore as antimalarial but should be reconsidered. For this purpose we have measured its impact on both chloroquine sensitive and resistant Plasmodium strains. We showed that around 5 nM of MB were able to inhibit 50% of the parasite growth in vitro and that late rings and early trophozoites were the most sensitive stages; while early rings, late trophozoites and schizonts were less sensitive. Drug interaction study following fractional inhibitory concentrations (FIC method showed antagonism with amodiaquine, atovaquone, doxycycline, pyrimethamine; additivity with artemether, chloroquine, mefloquine, primaquine and synergy with quinine. These results confirmed the interest of MB that could be integrated in a new low cost antimalarial combination therapy.

  10. Anti-malarial activities of Andrographis paniculata and Hedyotis corymbosa extracts and their combination with curcumin

    Swain Bijay K

    2009-02-01

    Full Text Available Abstract Background Herbal extracts of Andrographis paniculata (AP and Hedyotis corymbosa (HC are known as hepato-protective and fever-reducing drugs since ancient time and they have been used regularly by the people in the south Asian sub-continent. Methanolic extracts of these two plants were tested in vitro on choloroquine sensitive (MRC-pf-20 and resistant (MRC-pf-303 strains of Plasmodium falciparum for their anti-malarial activity. Methods Growth inhibition was determined using different concentrations of these plant extracts on synchronized P. falciparum cultures at the ring stage. The interactions between these two plant extracts and individually with curcumin were studied in vitro. The performance of these two herbal extracts in isolation and combination were further evaluated in vivo on Balb/c mice infected with Plasmodium berghei ANKA and their efficacy was compared with that of curcumin. The in vivo toxicity of the plant derived compounds as well as their parasite stage-specificity was studied. Results The 50% inhibitory concentration (IC50 of AP (7.2 μg/ml was found better than HC (10.8 μg/ml. Combination of these two herbal drugs showed substantial enhancement in their anti-malarial activity. Combinatorial effect of each of these with curcumin also revealed anti-malarial effect. Additive interaction between the plant extracts (AP + HC and their individual synergism with curcumin (AP+CUR, HC+CUR were evident from this study. Increased in vivo potency was also observed with the combination of plant extracts over the individual extracts and curcumin. Both the plant extracts were found to inhibit the ring stage of the parasite and did not show any in vivo toxicity, whether used in isolation or in combination. Conclusion Both these two plant extracts in combination with curcumin could be an effective, alternative source of herbal anti-malarial drugs.

  11. A rapid stability-indicating, fused-core HPLC method for simultaneous determination of β-artemether and lumefantrine in anti-malarial fixed dose combination products

    Wega, Sultan Suleman; Vandercruyssen, Kirsten; Wynendaele, Evelien; D'Hondt, Matthias; Bracke, Nathalie; Duchateau, Luc; Burvenich, Christian; Peremans, Kathelijne; De Spiegeleer, Bart

    2013-01-01

    Background: Artemisinin-based fixed dose combination (FDC) products are recommended by World Health Organization (WHO) as a first-line treatment. However, the current artemisinin FDC products, such as beta-artemether and lumefantrine, are inherently unstable and require controlled distribution and storage conditions, which are not always available in resource-limited settings. Moreover, quality control is hampered by lack of suitable analytical methods. Thus, there is a need for a rapid and s...

  12. Efficacy of amodiaquine, sulphadoxine-pyrimethamine and their combination for the treatment of uncomplicated Plasmodium falciparum malaria in children in Cameroon at the time of policy change to artemisinin-based combination therapy

    Hallett Rachel

    2010-01-01

    Full Text Available Abstract Background The efficacy of amodiaquine (AQ, sulphadoxine-pyrimethamine (SP and the combination of SP+AQ in the treatment of Cameroonian children with clinical malaria was investigated. The prevalence of molecular markers for resistance to these drugs was studied to set the baseline for surveillance of their evolution with time. Methods Seven hundred and sixty children aged 6-59 months with uncomplicated falciparum malaria were studied in three ecologically different regions of Cameroon - Mutengene (littoral equatorial forest, Yaoundé (forest-savannah mosaic and Garoua (guinea-savannah. Study children were randomized to receive either AQ, SP or the combination AQ+SP. Clinical outcome was classified according to WHO criteria, as either early treatment failure (ETF, late clinical failure (LCF, late parasitological failure (LPF or adequate clinical and parasitological response (ACPR. The occurrence of mutations in pfcrt, pfmdr1, dhfr and dhps genes was studied by either RFLP or dot blot techniques and the prevalence of these mutations related to parasitological and therapeutic failures. Results After correction for the occurrence of re-infection by PCR, ACPRs on day 28 for AQ, SP and AQ+SP were 71.2%, 70.1% and 80.9%, in Garoua, 79.2%, 62.5%, and 81.9% in Mutengene, and 80.3%, 67.5% and 76.2% in Yaoundé respectively. High levels of Pfcrt 76T (87.11% and Pfmdr1 86Y mutations (73.83% were associated with quinoline resistance in the south compared to the north, 31.67% (76T and 22.08% (86Y. There was a significant variation (p dhps gene was extremely rare (0.3% and occurred only in Mutengene while the pfmdr1 1034K and 1040D mutations were not detected in any of the three sites. Conclusion In this study the prevalence of molecular markers for quinoline and anti-folate resistances showed high levels and differed between the south and north of Cameroon. AQ, SP and AQ+SP treatments were well tolerated but with low levels of efficacy that

  13. Artemisinin-Naphthoquine Combination (ARCO®: An Overview of the Progress

    Qingyun Huang

    2010-12-01

    Full Text Available With the rapidly spreading resistance of Plasmodium falciparum to available non-artemisinin antimalarial drugs, new and novel pharmaceuticals are needed. ARCO® is a new generation ACT, one of several artemisinin-based combinations developed in China to counter antimalarial drug resistance. ARCO® is a derivative of two independently developed antimalarials, artemisinin and naphthoquine phosphate, which were combined to form the artemisinin-naphthoquine combination. Both artemisinin and naphthoquine drugs have proven to be efficacious, safe and well tolerated as monotherapies. The artemisinin-naphthoquine combination offers a novel advantage over existing ACTs: it can be administered as a single oral dose (or a 1-day treatment. Several therapeutic studies conducted recently indicate that a single oral dose administration of artemisinin-naphthoquine combination is equally effective and safe as the 3-day treatment with artemether-lumefantrine combination and other existing ACTs. This would make ARCO® the next generation ACT for the treatment of uncomplicated falciparum malaria.

  14. In vitro and in vivo anti-malarial activity of tigecycline, a glycylcycline antibiotic, in combination with chloroquine

    Sahu, Rajnish; Walker, Larry A.; Tekwani, Babu L.

    2014-01-01

    Background Several antibiotics have shown promising anti-malarial effects and have been useful for malarial chemotherapy, particularly in combination with standard anti-malarial drugs. Tigecycline, a semi-synthetic derivative of minocycline with a unique and novel mechanism of action, is the first clinically available drug in a new class of glycylcycline antibiotics. Methods Tigecycline was tested in vitro against chloroquine (CQ)-sensitive (D6) and resistant strains (W2) of Plasmodium falcip...

  15. Antimalarial activity of Ageratum conyzoides in combination with chloroquine and artesunate

    Ukwe Chinwe V; Ekwunife Obinna I; Epueke Ebele A; Ubaka Chukwuemeka M

    2010-01-01

    Objective: To determine the suppressive and curative activity of aqueous leaf extract of Ageratum conyzoides (A. conyzoides) in combination with chloroquine and artesunate, respectively against Plasmodium berghei infection in mice. Methods: Using malaria (Plasmodium berghei) infected albino mice of both sexes, aqueous extracts of A. conyzoides in combination with chloroquine and artesunate were tested for antimalarial activity, respectively. Four-day suppressive test and Rane's curative test were carried out. Results: Suppressive tests showed significant dose dependent reduction in parasitemia level produced by the extract-chloroquine and extract-artesunate combinations. Suppressive activities of both extract-drug combinations were greater than the individual drugs alone. Extract-chloroquine (100:5) produced the highest suppressive effect (98% suppression). Curative tests showed absolute survival in two extract-drug combinations. Two extract-drug combinations produced higher curative effects than the individual drugs alone. The highest dose combinations of extract-chloroquine (100:5) and extract-artesunate (100:5) produced absolute parasitemia clearance (cure) in the infected mice. Conclusions: The study indicated that aqueous extract of A. conyzoides had the ability to potentiate the antimalarial activity of chloroquine and artesunate against induced plasmodiasis in mice. It contributes a lot in the malaria endemic and poverty stricken tropics.

  16. Cost-effectiveness study of three antimalarial drug combinations in Tanzania.

    Virginia Wiseman

    2006-10-01

    Full Text Available BACKGROUND: As a result of rising levels of drug resistance to conventional monotherapy, the World Health Organization (WHO and other international organisations have recommended that malaria endemic countries move to combination therapy, ideally with artemisinin-based combinations (ACTs. Cost is a major barrier to deployment. There is little evidence from field trials on the cost-effectiveness of these new combinations. METHODS AND FINDINGS: An economic evaluation of drug combinations was designed around a randomised effectiveness trial of combinations recommended by the WHO, used to treat Tanzanian children with non-severe slide-proven malaria. Drug combinations were: amodiaquine (AQ, AQ with sulfadoxine-pyrimethamine (AQ+SP, AQ with artesunate (AQ+AS, and artemether-lumefantrine (AL in a six-dose regimen. Effectiveness was measured in terms of resource savings and cases of malaria averted (based on parasitological failure rates at days 14 and 28. All costs to providers and to patients and their families were estimated and uncertain variables were subjected to univariate sensitivity analysis. Incremental analysis comparing each combination to monotherapy (AQ revealed that from a societal perspective AL was most cost-effective at day 14. At day 28 the difference between AL and AQ+AS was negligible; both resulted in a gross savings of approximately US1.70 dollars or a net saving of US22.40 dollars per case averted. Varying the accuracy of diagnosis and the subsistence wage rate used to value unpaid work had a significant effect on the number of cases averted and on programme costs, respectively, but this did not change the finding that AL and AQ+AS dominate monotherapy. CONCLUSIONS: In an area of high drug resistance, there is evidence that AL and AQ+AS are the most cost-effective drugs despite being the most expensive, because they are significantly more effective than other options and therefore reduce the need for further treatment. This is

  17. Complex polymorphisms in the Plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response.

    Veiga, Maria Isabel; Osório, Nuno S; Ferreira, Pedro Eduardo; Franzén, Oscar; Dahlstrom, Sabina; Lum, J Koji; Nosten, Francois; Gil, José Pedro

    2014-12-01

    Plasmodium falciparum has the capacity to escape the actions of essentially all antimalarial drugs. ATP-binding cassette (ABC) transporter proteins are known to cause multidrug resistance in a large range of organisms, including the Apicomplexa parasites. P. falciparum genome analysis has revealed two genes coding for the multidrug resistance protein (MRP) type of ABC transporters: Pfmrp1, previously associated with decreased parasite drug susceptibility, and the poorly studied Pfmrp2. The role of Pfmrp2 polymorphisms in modulating sensitivity to antimalarial drugs has not been established. We herein report a comprehensive account of the Pfmrp2 genetic variability in 46 isolates from Thailand. A notably high frequency of 2.8 single nucleotide polymorphisms (SNPs)/kb was identified for this gene, including some novel SNPs. Additionally, we found that Pfmrp2 harbors a significant number of microindels, some previously not reported. We also investigated the potential association of the identified Pfmrp2 polymorphisms with altered in vitro susceptibility to several antimalarials used in artemisinin-based combination therapy and with parasite clearance time. Association analysis suggested Pfmrp2 polymorphisms modulate the parasite's in vitro response to quinoline antimalarials, including chloroquine, piperaquine, and mefloquine, and association with in vivo parasite clearance. In conclusion, our study reveals that the Pfmrp2 gene is the most diverse ABC transporter known in P. falciparum with a potential role in antimalarial drug resistance. PMID:25267670

  18. Measuring the Association between Artemisinin-Based Case Management and Malaria Incidence in Southern Vietnam, 1991–2010

    Peak, Corey M.; Thuan, Phung Duc; Britton, Amadea; Nguyen, Tran Dang; Wolbers, Marcel; Thanh, Ngo Viet; Buckee, Caroline O.; Boni, Maciej F.

    2015-01-01

    In addition to being effective, fast-acting, and well tolerated, artemisinin-based combination therapies (ACTs) are able to kill certain transmission stages of the malaria parasite. However, the population-level impacts of ACTs on reducing malaria transmission have been difficult to assess. In this study on the history of malaria control in Vietnam, we assemble annual reporting on malaria case counts, coverage with insecticide-treated nets (ITN) and indoor residual spraying (IRS), and drug pu...

  19. Monitoring antimalarial safety and tolerability in clinical trials: A case study from Uganda

    Mpimbaza Arthur

    2008-06-01

    Full Text Available Abstract Background New antimalarial regimens, including artemisinin-based combination therapies (ACTs, have been adopted widely as first-line treatment for uncomplicated malaria. Although these drugs appear to be safe and well-tolerated, experience with their use in Africa is limited and continued assessment of safety is a priority. However, no standardized guidelines for evaluating drug safety and tolerability in malaria studies exist. A system for monitoring adverse events in antimalarial trials conducted in Uganda was developed. Here the reporting system is described, and difficulties faced in analysing and interpreting the safety results are illustrated, using data from the trials. Case description Between 2002 and 2007, eleven randomized, controlled clinical trials were conducted to compare the efficacy, safety, and tolerability of different antimalarial regimens for treatment of uncomplicated malaria in Uganda. The approach to adverse event monitoring was similar in all studies. A total of 5,614 treatments were evaluated in 4,876 patients. Differences in baseline characteristics and patterns of adverse event reporting were noted between the sites, which limited the ability to pool and analyse data. Clinical failure following antimalarial treatment confounded associations between treatment and adverse events that were also common symptoms of malaria, particularly in areas of lower transmission intensity. Discussion and evaluation Despite prospectively evaluating for adverse events, limitations in the monitoring system were identified. New standardized guidelines for monitoring safety and tolerability in antimalarial trials are needed, which should address how to detect events of greatest importance, including serious events, those with a causal relationship to the treatment, those which impact on adherence, and events not previously reported. Conclusion Although the World Health Organization has supported the development of

  20. In Vitro Cardiovascular Effects of Dihydroartemisin-Piperaquine Combination Compared with Other Antimalarials

    Crumb, William; Pace, Silvia; Ubben, David; Wible, Barb; Yan, Gan-Xin; Funck-Brentano, Christian

    2012-01-01

    The in vitro cardiac properties of dihydroartemisinin (DHA) plus piperaquine phosphate (PQP) were compared with those of other antimalarial compounds. Results with antimalarial drugs, chosen on the basis of their free therapeutic maximum concentration in plasma (Cmax), were expressed as the fold of that particular effect with respect to their Cmax. The following tests were used at 37°C: hERG (human ether-à-go-go-related gene) blockade and trafficking, rabbit heart ventricular preparations, and sodium and slow potassium ion current interference (INa and IKs, respectively). Chloroquine, halofantrine, mefloquine, and lumefantrine were tested in the hERG studies, but only chloroquine, dofetilide, lumefantrine, and the combination of artemether-lumefantrine were used in the rabbit heart ventricular preparations, hERG trafficking studies, and INa and IKs analyses. A proper reference was used in each test. In hERG studies, the high 50% inhibitory concentration (IC50) of halofantrine, which was lower than its Cmax, was confirmed. All the other compounds blocked hERG, with IC50s ranging from 3- to 30-fold their Cmaxs. In hERG trafficking studies, the facilitative effects of chloroquine at about 30-fold its Cmax were confirmed and DHA blocked it at a concentration about 300-fold its Cmax. In rabbit heart ventricular preparations, dofetilide, used as a positive control, revealed a high risk of torsades de pointes, whereas chloroquine showed a medium risk. Neither DHA-PQP nor artemether-lumefantrine displayed an in vitro signal for a significant proarrhythmic risk. Only chloroquine blocked the INa ion current and did so at about 30-fold its Cmax. No effect on IKs was detected. In conclusion, despite significant hERG blockade, DHA-PQP and artemether-lumefantrine do not appear to induce potential torsadogenic effects in vitro, affect hERG trafficking, or block sodium and slow potassium ion currents. PMID:22391528

  1. Understanding Private Sector Antimalarial Distribution Chains: A Cross-Sectional Mixed Methods Study in Six Malaria-Endemic Countries

    Palafox, Benjamin; Patouillard, Edith; Tougher, Sarah; Goodman, Catherine; Hanson, Kara; Kleinschmidt, Immo; Rueda, Sergio Torres; Kiefer, Sabine; O’Connell, Kathryn A.; Zinsou, Cyprien; Phok, Sochea; Akulayi, Louis; Arogundade, Ekundayo; Buyungo, Peter; Mpasela, Felton; Chavasse, Desmond

    2014-01-01

    Background Private for-profit outlets are important treatment sources for malaria in most endemic countries. However, these outlets constitute only the last link in a chain of businesses that includes manufacturers, importers and wholesalers, all of which influence the availability, price and quality of antimalarials patients can access. We present evidence on the composition, characteristics and operation of these distribution chains and of the businesses that comprise them in six endemic countries (Benin, Cambodia, Democratic Republic of Congo, Nigeria, Uganda and Zambia). Methods and Findings We conducted nationally representative surveys of antimalarial wholesalers during 2009–2010 using an innovative sampling approach that captured registered and unregistered distribution channels, complemented by in-depth interviews with a range of stakeholders. Antimalarial distribution chains were pyramidal in shape, with antimalarials passing through a maximum of 4–6 steps between manufacturer and retailer; however, most likely pass through 2–3 steps. Less efficacious non-artemisinin therapies (e.g. chloroquine) dominated weekly sales volumes among African wholesalers, while volumes for more efficacious artemisinin-based combination therapies (ACTs) were many times smaller. ACT sales predominated only in Cambodia. In all countries, consumer demand was the principal consideration when selecting products to stock. Selling prices and reputation were key considerations regarding supplier choice. Business practices varied across countries, with large differences in the proportions of wholesalers offering credit and delivery services to customers, and the types of distribution models adopted by businesses. Regulatory compliance also varied across countries, particularly with respect to licensing. The proportion of wholesalers possessing any up-to-date licence from national regulators was lowest in Benin and Nigeria, where vendors in traditional markets are important

  2. Understanding private sector antimalarial distribution chains: a cross-sectional mixed methods study in six malaria-endemic countries.

    Benjamin Palafox

    Full Text Available BACKGROUND: Private for-profit outlets are important treatment sources for malaria in most endemic countries. However, these outlets constitute only the last link in a chain of businesses that includes manufacturers, importers and wholesalers, all of which influence the availability, price and quality of antimalarials patients can access. We present evidence on the composition, characteristics and operation of these distribution chains and of the businesses that comprise them in six endemic countries (Benin, Cambodia, Democratic Republic of Congo, Nigeria, Uganda and Zambia. METHODS AND FINDINGS: We conducted nationally representative surveys of antimalarial wholesalers during 2009-2010 using an innovative sampling approach that captured registered and unregistered distribution channels, complemented by in-depth interviews with a range of stakeholders. Antimalarial distribution chains were pyramidal in shape, with antimalarials passing through a maximum of 4-6 steps between manufacturer and retailer; however, most likely pass through 2-3 steps. Less efficacious non-artemisinin therapies (e.g. chloroquine dominated weekly sales volumes among African wholesalers, while volumes for more efficacious artemisinin-based combination therapies (ACTs were many times smaller. ACT sales predominated only in Cambodia. In all countries, consumer demand was the principal consideration when selecting products to stock. Selling prices and reputation were key considerations regarding supplier choice. Business practices varied across countries, with large differences in the proportions of wholesalers offering credit and delivery services to customers, and the types of distribution models adopted by businesses. Regulatory compliance also varied across countries, particularly with respect to licensing. The proportion of wholesalers possessing any up-to-date licence from national regulators was lowest in Benin and Nigeria, where vendors in traditional markets are

  3. Antimalarial medicine diversion: stock-outs and other public health problems

    Roger Bate

    2010-09-01

    Full Text Available Roger Bate1,2, Kimberly Hess2, Lorraine Mooney31American Enterprise Institute, Washington, D.C., USA; 2Africa Fighting Malaria, Washington, D.C., USA; 3Africa Fighting Malaria, Cambridge, UKBackground: Antimalarial medicine diversion has been seen across numerous African markets and can lead to serious stock-outs in the public sector, which can be dangerous to countries with high burdens of disease. This study discusses the numbers of diverted antimalarial medicines from several samplings in Africa.Methods: A total of 894 samples of antimalarial medicines were covertly purchased from private pharmacies in 11 African cities from late 2007 to early 2010. All medicine packages were visually inspected for correctness, in line with the protocol established by the Global Pharma Health Fund e.V. Minilab®, as well as for signs of diversion.Results: Overall, 6.5% (58 out of 894 of collected antimalarial medicines were found to be diverted, comprising 2.4% (5/210 of medicines collected in 2007 from six African cities, all of which were artemisinin-based combination therapies (ACTs; 2.3% (3/129 of medicines collected in 2008 in Lagos, Nigeria, two of which were ACTs; and 9% (50/555 of medicines collected in 2010 in 10 African cities, 35 of which were ACTs. ACT was by far the most diverted treatment in this study: 15.6% (5/32 of ACTs collected in 2007, and 30.7% (35/114 of ACTs collected in 2010.Conclusion: The number of diverted ACTs over the 33 months covered by this study is probably related to the laudable provision of vast amounts of donated or low-priced ACTs across African nations and the actual increase in diversion of these medicines into the private sector. The small sample sizes in this study might exaggerate any problem, but a potentially serious problem may well exist. To the extent that diversion of medicines exacerbates stock-outs, this is a public health problem, and a perversion of donor intent, but there are other possible harms of

  4. The ACTwatch project: methods to describe anti-malarial markets in seven countries

    Chapman Steven

    2011-10-01

    Full Text Available Abstract Background Policy makers, governments and donors are faced with an information gap when considering ways to improve access to artemisinin-based combination therapy (ACT and malaria diagnostics including rapid diagnostic tests (RDTs. To help address some of these gaps, a five-year multi-country research project called ACTwatch was launched. The project is designed to provide a comprehensive picture of the anti-malarial market to inform national and international anti-malarial drug policy decision-making. Methods The project is being conducted in seven malaria-endemic countries: Benin, Cambodia, the Democratic Republic of Congo, Madagascar, Nigeria, Uganda and Zambia from 2008 to 2012. ACTwatch measures which anti-malarials are available, where they are available and at what price and who they are used by. These indicators are measured over time and across countries through three study components: outlet surveys, supply chain studies and household surveys. Nationally representative outlet surveys examine the market share of different anti-malarials passing through public facilities and private retail outlets. Supply chain research provides a picture of the supply chain serving drug outlets, and measures mark-ups at each supply chain level. On the demand side, nationally representative household surveys capture treatment seeking patterns and use of anti-malarial drugs, as well as respondent knowledge of anti-malarials. Discussion The research project provides findings on both the demand and supply side determinants of anti-malarial access. There are four key features of ACTwatch. First is the overlap of the three study components where nationally representative data are collected over similar periods, using a common sampling approach. A second feature is the number and diversity of countries that are studied which allows for cross-country comparisons. Another distinguishing feature is its ability to measure trends over time. Finally, the

  5. Responding to the challenge of antimalarial drug resistance by routine monitoring to update national malaria treatment policies

    Vestergaard, Lasse S; Ringwald, Pascal

    2007-01-01

    of rational and updated malaria treatment policies, but defining and updating such policies requires a sufficient volume of high-quality drug-resistance data collected at national and regional levels. Three main tools are used for drug resistance monitoring, including therapeutic efficacy tests, in......Reduced sensitivity of Plasmodium falciparum to formerly recommended cheap and well-known antimalarial drugs places an increasing burden on malaria control programs and national health systems in endemic countries. The high costs of the new artemisinin-based combination treatments underline the use...... additional information about changing patterns of resistance. However, some of the tests are technically demanding, and thus there is a need for more resources for training and capacity building in endemic countries to be able to adequately respond to the challenge of drug resistance....

  6. Incidence of malaria and efficacy of combination antimalarial therapies over 4 years in an urban cohort of Ugandan children.

    Tamara D Clark

    Full Text Available BACKGROUND: Combination therapies are now recommended to treat uncomplicated malaria. We used a longitudinal design to assess the incidence of malaria and compare the efficacies of 3 combination regimens in Kampala, Uganda. METHODOLOGY/PRINCIPAL FINDINGS: Children aged 1-10 years were enrolled from randomly selected households in 2004-05 and 2007, and were followed at least monthly through 2008. Insecticide-treated bednets (ITNs were provided in 2006. Children were randomized upon their first episode, and then treated for all episodes of uncomplicated malaria with amodiaquine/sulfadoxine-pyrimethamine (AQ/SP, artesunate/amodiaquine (AS/AQ, or artemether/lumefantrine (AL. Risks of parasitological failure were determined for each episode of uncomplicated malaria and clinical parameters were followed. A total of 690 children experienced 1464 episodes of malaria. 96% of these episodes were uncomplicated malaria and treated with study drugs; 94% were due to Plasmodium falciparum. The rank order of treatment efficacy was AL > AS/AQ > AQ/SP. Failure rates increased over time for AQ/SP, but not the artemisinin-based regimens. Over the 4-year course of the study the prevalence of asymptomatic parasitemia decreased from 11.8% to 1.4%, the incidence of malaria decreased from 1.55 to 0.32 per person year, and the prevalence of anemia (hemoglobin <10 gm/dL decreased from 5.9% to 1.0%. No episodes of severe malaria (based on WHO criteria and no deaths were seen. CONCLUSIONS/SIGNIFICANCE: With ready access to combination therapies and distribution of ITNs, responses were excellent for artemisinin-containing regimens, severe malaria was not seen, and the incidence of malaria and prevalence of parasitemia and anemia decreased steadily over time. TRIAL REGISTRATION: isrctn.org ISRCTN37517549.

  7. High-content live cell imaging with RNA probes: advancements in high-throughput antimalarial drug discovery

    Cervantes, Serena; Prudhomme, Jacques; Carter, David; Gopi, Krishna G; Li, Qian; Chang, Young-Tae; Le Roch, Karine G

    2009-01-01

    Background Malaria, a major public health issue in developing nations, is responsible for more than one million deaths a year. The most lethal species, Plasmodium falciparum, causes up to 90% of fatalities. Drug resistant strains to common therapies have emerged worldwide and recent artemisinin-based combination therapy failures hasten the need for new antimalarial drugs. Discovering novel compounds to be used as antimalarials is expedited by the use of a high-throughput screen (HTS) to detect parasite growth and proliferation. Fluorescent dyes that bind to DNA have replaced expensive traditional radioisotope incorporation for HTS growth assays, but do not give additional information regarding the parasite stage affected by the drug and a better indication of the drug's mode of action. Live cell imaging with RNA dyes, which correlates with cell growth and proliferation, has been limited by the availability of successful commercial dyes. Results After screening a library of newly synthesized stryrl dyes, we discovered three RNA binding dyes that provide morphological details of live parasites. Utilizing an inverted confocal imaging platform, live cell imaging of parasites increases parasite detection, improves the spatial and temporal resolution of the parasite under drug treatments, and can resolve morphological changes in individual cells. Conclusion This simple one-step technique is suitable for automation in a microplate format for novel antimalarial compound HTS. We have developed a new P. falciparum RNA high-content imaging growth inhibition assay that is robust with time and energy efficiency. PMID:19515257

  8. Efficacy and tolerability of four antimalarial combinations in the treatment of uncomplicated Plasmodium falciparum malaria in Senegal

    Faye Oumar

    2007-06-01

    Full Text Available Abstract Background In view of the high level of chloroquine resistance in many countries, WHO has recommended the use of combination therapy with artemisinin derivatives in the treatment of uncomplicated malaria due to Plasmodium falciparum. Four antimalarial drug combinations, artesunate plus amodiaquine (Arsucam®, artesunate plus mefloquine (Artequin®, artemether plus lumefantrine (Coartem®; four doses and six doses, and amodiaquine plus sulphadoxine-pyrimethamine, were studied in five health districts in Senegal. Methods This is a descriptive, analytical, open, randomized study to evaluate the efficacy and tolerability of these four antimalarial combinations in the treatment of uncomplicated falciparum malaria using the 2002 WHO protocol. Results All drug combinations demonstrated good efficacy. On day 28, all combinations resulted in an excellent clinical and parasitological response rate of 100% after correction for PCR results, except for the four-dose artemether-lumefantrine regimen (96.4%. Follow-up of approximately 10% of each treatment group on day 42 demonstrated an efficacy of 100%. The combinations were well tolerated clinically and biologically. No unexpected side-effect was observed and all side-effects disappeared at the end of treatment. No serious side-effect requiring premature termination of treatment was observed. Conclusion The four combinations are effective and well-tolerated.

  9. Substandard anti-malarial drugs in Burkina Faso

    Sie Ali

    2008-05-01

    now wider available and substantially more costly artemisinin-based combination therapies.

  10. In vitro interaction of artemisinin derivatives or the fully synthetic peroxidic anti-malarial OZ277 with thapsigargin in Plasmodium falciparum strains

    Abiodun Oyindamola O

    2013-01-01

    Full Text Available Abstract Background Semi-synthetic artemisinin derivatives are powerful peroxidic drugs in artemisinin-based combination therapy (ACT recommended as first-line treatment of Plasmodium falciparum malaria in disease-endemic countries. Studies by Eckstein-Ludwig and co-workers showed both thapsigargin and artemisinin specifically inhibit the sarcoplasmic reticulum Ca2+−ATPase of Plasmodium falciparum (PfATP6. In the present study the type of interaction between thapsigargin and artemisinin derivatives as well as the ozonide OZ277 (RBx11160 or arterolane was evaluated in parasite cultures. The latter compound is an adamantane-based peroxide and the first fully synthetic clinical candidate recently registered in India by Ranbaxy Laboratories Ltd. for anti-malarial combination therapy. Methods Drug interaction studies were performed using a previously described fixed ratio method and anti-malarial activity measured using the [3H] hypoxanthine incorporation assay. Results The sum 50% and 90% fractional inhibitory concentration (∑FIC50, 90 of the interaction of thapsigargin with OZ277, artemether or artesunate, against NF54 and K1 strains of P. falciparum ranged from 0.9 to 1.4. Conclusion The interaction of thapsigargin with OZ277, artesunate or artemether was additive, data consistent with previous observations indicating that activity of anti-malarial peroxides does not derive from reversible interactions with parasite targets.

  11. Got ACTs? Availability, price, market share and provider knowledge of anti-malarial medicines in public and private sector outlets in six malaria-endemic countries

    O'Connell Kathryn A

    2011-10-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is the first-line malaria treatment throughout most of the malaria-endemic world. Data on ACT availability, price and market share are needed to provide a firm evidence base from which to assess the current situation concerning quality-assured ACT supply. This paper presents supply side data from ACTwatch outlet surveys in Benin, the Democratic Republic of Congo (DRC, Madagascar, Nigeria, Uganda and Zambia. Methods Between March 2009 and June 2010, nationally representative surveys of outlets providing anti-malarials to consumers were conducted. A census of all outlets with the potential to provide anti-malarials was conducted in clusters sampled randomly. Results 28,263 outlets were censused, 51,158 anti-malarials were audited, and 9,118 providers interviewed. The proportion of public health facilities with at least one first-line quality-assured ACT in stock ranged between 43% and 85%. Among private sector outlets stocking at least one anti-malarial, non-artemisinin therapies, such as chloroquine and sulphadoxine-pyrimethamine, were widely available (> 95% of outlets as compared to first-line quality-assured ACT ( Conclusions These standardized, nationally representative results demonstrate the typically low availability, low market share and high prices of ACT, in the private sector where most anti-malarials are accessed, with some exceptions. The results confirm that there is substantial room to improve availability and affordability of ACT treatment in the surveyed countries. The data will also be useful for monitoring the impact of interventions such as the Affordable Medicines Facility for malaria.

  12. Metabolite identification of the antimalarial piperaquine in vivo using liquid chromatography-high-resolution mass spectrometry in combination with multiple data-mining tools in tandem.

    Yang, Aijuan; Zang, Meitong; Liu, Huixiang; Fan, Peihong; Xing, Jie

    2016-08-01

    Artemisinin-based combination therapy is widely used for the treatment of uncomplicated Plasmodium falciparum malaria, and piperaquine (PQ) is one of important partner drugs. The pharmacokinetics of PQ is characterized by a low clearance and a large volume of distribution; however, metabolism of PQ has not been thoroughly investigated. In this work, the metabolite profiling of PQ in human and rat was studied using liquid chromatography tandem high-resolution LTQ-Orbitrap mass spectrometry (HRMS). The biological samples were pretreated by solid-phase extraction. Data processes were carried out using multiple data-mining techniques in tandem, i.e., isotope pattern filter followed by mass defect filter. A total of six metabolites (M1-M6) were identified for PQ in human (plasma and urine) and rat (plasma, urine and bile). Three reported metabolites were also found in this study, which included N-oxidation (M1, M2) and carboxylic products (M3). The subsequent N-oxidation of M3 resulted in a new metabolite M4 detected in urine and bile samples. A new metabolic pathway N-dealkylation was found for PQ in human and rat, leading to two new metabolites (M5 and M6). This study demonstrated that LC-HRMS(n) in combination with multiple data-mining techniques in tandem can be a valuable analytical strategy for rapid metabolite profiling of drugs. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26821381

  13. Treatment of Plasmodium chabaudi Parasites with Curcumin in Combination with Antimalarial Drugs: Drug Interactions and Implications on the Ubiquitin/Proteasome System

    Zoraima Neto; Marta Machado; Ana Lindeza; Virgílio do Rosário; Gazarini, Marcos L.; Dinora Lopes

    2013-01-01

    Antimalarial drug resistance remains a major obstacle in malaria control. Evidence from Southeast Asia shows that resistance to artemisinin combination therapy (ACT) is inevitable. Ethnopharmacological studies have confirmed the efficacy of curcumin against Plasmodium spp. Drug interaction assays between curcumin/piperine/chloroquine and curcumin/piperine/artemisinin combinations and the potential of drug treatment to interfere with the ubiquitin proteasome system (UPS) were analyzed. In vivo...

  14. Antimalarial potential of China 30 and Chelidonium 30 in combination therapy against lethal rodent malaria parasite: Plasmodium berghei.

    Rajan, Aswathy; Bagai, Upma

    2013-01-01

    Homeopathy is a therapeutic method based on the application of similia principle, utilizing ultra-low doses of medicinal substances made from natural products. The present study has been designed to evaluate the efficacy of Cinchona officinalis (Chin.) 30C and Chelidonium majus (Chel.) 30C in combination therapy against lethal murine malaria. Five groups having twelve BALB/c mice each were administered orally with 0.2 ml/mouse/day of different drugs, and their antimalarial potential was evaluated by Peter's 4-day test. The combination of Chin. 30 and Chel. 30 exhibited complete parasite clearance by the 28th day post-inoculation which was similar to the positive control [artesunate (4 mg/kg)+sulphadoxine-primethamine (1.2 mg/kg)] group. Both the groups exhibited enhanced mean survival time (MST) 28±0 days,whereas, the mice of infected control group survived up to 7.6±0.4 days only. The preventive and curative activities of the combination in comparison to the positive controls [pyrimethamine (1.2 mg/Kg) and chloroquine (20 mg/Kg), respectively] were also evaluated. The combination had a significant preventive activity (p<0.0005), with 89.2% chemosuppression which was higher than the standard drug, pyrimethamine (83.8%). It also showed a moderate curative activity with complete clearance of parasite in 50% of surviving mice, and enhancing the MST of mice up to 26.8±2.8 days. These findings point to the significant antiplasmodial efficacy of the combination of these homeopathic drugs against Plasmodium berghei. PMID:23652641

  15. Saleability of anti-malarials in private drug shops in Muheza, Tanzania: a baseline study in an era of assumed artemisinin combination therapy (ACT)

    Ringsted Frank M; Massawe Isolide S; Lemnge Martha M; Bygbjerg Ib C

    2011-01-01

    Abstract Background Artemether-lumefantrine (ALu) replaced sulphadoxine-pymimethamine (SP) as the official first-line anti-malarial in Tanzania in November 2006. So far, artemisinin combination therapy (ACT) is contra-indicated during pregnancy by the national malaria treatment guidelines, and pregnant women depend on SP for Intermittent Preventive Treatment (IPTp) during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may u...

  16. Determination of artemether and lumefantrine in anti-malarial fixed-dose combination tablets by microemulsion electrokinetic chromatography with short-end injection procedure

    Amin, N’Cho Christophe; Fabre, Huguette; Blanchin, Marie-Dominique; Montels, Jérôme; Aké, Michèle

    2013-01-01

    Background Artemether-lumefantrine (AL) combination therapy is now the most used anti-malarial treatment in the world. Quality control of AL formulations is still a major challenge in developing countries. Until now, only liquid chromatographic methods have been reported in the literature for their analysis. Capillary electrophoretic methods, which present various advantages (low price of capillary, low volumes of electrolyte consumption), may be an alternative to liquid chromatography method...

  17. A combination of the leaves and tuber ofIcacina senegalensis A. Juss (Icacinaceae) improves the antimalarial activity of the plant in mice

    Esien David-Oku; Juliet Ifeoma Obiajunwa-Otteh

    2015-01-01

    Objective:To investigate the possibility of increased antimalarial activity ofIcacina senegalensis A. Juss (Icacinaceae) upon a combination of its leaves and tubers against Plasmodium berghei malaria in mice. Methods: Chloroquine sensitiveANKA clones ofPlasmodium berghei were used to develop experimental models based on intraperitoneal injection of 107 parasitized erythrocytes in phosphate buffer saline (pH 7.2) and subsequent development of parasitemia. The models were employed to investigate prophylactic and curative anti-malarial activities of tuber and tuber-leaf methanol extracts of the plant at selected dosages (25, 50 and 100 mg/kg body weight). Chloroquine with a curative dosage of 10 mg/kg body weight was used as positive control in both studies. Results:Tuber and tuber-leaf extracts produced a dose-dependent chemosuppression of the parasites, with higher activity and mean survival time exhibited by the combined extract. Conclusions:Anti-plasmodia activity has been discovered in methanol extract ofIcacina senegalensis tuber extract. The observed optimization of the antimalarial actions of the plant upon a combination of its leaf and tuber opens a new area of medicinal plant research.

  18. Antagonistic antimalarial properties of pawpaw leaf aqueous extract in combination with artesunic acid in Plasmodium berghei-infected mice

    L.O. Onaku, A.A. Attama, V.C. Okore, A.Y. Tijani, A.A. Ngene & C.O. Esimone

    2011-06-01

    Full Text Available Background & objectives: Artemisinins, the main stay in the treatment of malaria are used in combinationswith other antimalarials to forestall resistance, as artemisinin-combination therapies (ACTs. However, ACTsare expensive and some of the non-artemisinin components are not well-tolerated by patients. There areseveral folkloric and scientific proofs of the efficacy of herbal remedies for malaria. Mature leaves of Caricapapaya is widely used to treat malaria in several African countries. An ACT involving a medicinal herb extractor its active constituent(s will provide an indigenous alternative/herbal ACT.Methods: Mature fresh leaves of Carica papaya were grounded and macerated in cold distilled water for 24 hand the extract (PCE was stored in the refrigerator for seven days. Fresh extracts were made as needed. Theantiplasmodial activity of PCE and/or artesunic acid were determined by using the Peter’s 4-day suppressivetest in Plasmodium berghei-infected mice. The ED50 and ED90 were calculated from the dose-responserelationships.Results: The combination of 50 mg/kg of PCE and 15 mg/kg of artesunic acid produced a significant reductionof parasitemia (81.25%, compared to 50 mg/kg PCE alone (37.7%. The mean survival time of the combinationsof PCE and 15 mg/kg of artesunic acid, and PCE alone followed a dose-dependent manner. The ED50 of PCEshowed that it has a very good activity. The isobolar equivalent (IE calculated from the ED90 of PCE incombination with artesunic acid showed that the interaction was antagonistic.Interpretation & conclusion: Although pawpaw alone was found to have a very good activity, its combinationwith artesunic acid is antagonistic. Combinations of artemisinins and pawpaw show little promise forcombination therapy development.

  19. High School Students Are a Target Group for Fight against Self-Medication with Antimalarial Drugs: A Pilot Study in University of Kinshasa, Democratic Republic of Congo.

    Kabongo Kamitalu, Ramsès; Aloni, Michel Ntetani

    2016-01-01

    Aim. To assess the self-medication against malaria infection in population of Congolese students in Kinshasa, Democratic Republic of Congo (DRC). Methods. A cross-sectional study was carried out in University of Kinshasa, Kinshasa, Democratic Republic of Congo. Medical records of all students with malaria admitted to Centre de Santé Universitaire of University of Kinshasa from January 1, 2008, to April 30, 2008, were reviewed retrospectively. Results. The median age of the patients was 25.4 years (range: from 18 to 36 years). The majority of them were male (67.9%). Artemisinin-based combination treatments (ACTs) was the most used self-prescribed antimalarial drugs. However, self-medication was associated with the ingestion of quinine in 19.9% of cases. No case of ingestion of artesunate/artemether in monotherapy was found. All the medicines taken were registered in DRC. In this series, self-prescribed antimalarial was very irrational in terms of dose and duration of treatment. Conclusion. This paper highlights self-medication by a group who should be aware of malaria treatment protocols. The level of self-prescribing quinine is relatively high among students and is disturbing for a molecule reserved for severe disease in Congolese health care policy in management of malaria. PMID:27340411

  20. Antiretroviral Choice for HIV Impacts Antimalarial Exposure and Treatment Outcomes in Ugandan Children

    Parikh, Sunil; Kajubi, Richard; Huang, Liusheng; Ssebuliba, Joshua; Kiconco, Sylvia; Gao, Qin; Li, Fangyong; Were, Moses; Kakuru, Abel; Achan, Jane; Mwebaza, Norah; Aweeka, Francesca T.

    2016-01-01

    Background. The optimal treatment of malaria in human immunodeficiency virus (HIV)–infected children requires consideration of critical drug–drug interactions in coinfected children, as these may significantly impact drug exposure and clinical outcomes. Methods. We conducted an intensive and sparse pharmacokinetic/pharmacodynamic study in Uganda of the most widely adopted artemisinin-based combination therapy, artemether-lumefantrine. HIV-infected children on 3 different first-line antiretroviral therapy (ART) regimens were compared to HIV-uninfected children not on ART, all of whom required treatment for Plasmodium falciparum malaria. Pharmacokinetic sampling for artemether, dihydroartemisinin, and lumefantrine exposure was conducted through day 21, and associations between drug exposure and outcomes through day 42 were investigated. Results. One hundred forty-five and 225 children were included in the intensive and sparse pharmacokinetic analyses, respectively. Compared with no ART, efavirenz (EFV) reduced exposure to all antimalarial components by 2.1- to 3.4-fold; lopinavir/ritonavir (LPV/r) increased lumefantrine exposure by 2.1-fold; and nevirapine reduced artemether exposure only. Day 7 concentrations of lumefantrine were 10-fold lower in children on EFV vs LPV/r-based ART, changes that were associated with an approximate 4-fold higher odds of recurrent malaria by day 28 in those on EFV vs LPV/r-based ART. Conclusions. The choice of ART in children living in a malaria-endemic region has highly significant impacts on the pharmacokinetics and pharmacodynamics of artemether-lumefantrine treatment. EFV-based ART reduces all antimalarial components and is associated with the highest risk of recurrent malaria following treatment. For those on EFV, close clinical follow-up for recurrent malaria following artemether-lumefantrine treatment, along with the study of modified dosing regimens that provide higher exposure, is warranted. PMID:27143666

  1. Saleability of anti-malarials in private drug shops in Muheza, Tanzania: a baseline study in an era of assumed artemisinin combination therapy (ACT

    Ringsted Frank M

    2011-08-01

    Full Text Available Abstract Background Artemether-lumefantrine (ALu replaced sulphadoxine-pymimethamine (SP as the official first-line anti-malarial in Tanzania in November 2006. So far, artemisinin combination therapy (ACT is contra-indicated during pregnancy by the national malaria treatment guidelines, and pregnant women depend on SP for Intermittent Preventive Treatment (IPTp during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may undermine its official use for IPTp through induction of resistance. The main study objective was to perform a baseline study of the private market for anti-malarials in Muheza town, an area with widespread anti-malarial drug resistance, prior to the implementation of a provider training and accreditation programme that will allow accredited drug shops to sell subsidized ALu. Methods All drug shops selling prescription-only anti-malarials, in Muheza town, Tanga Region voluntarily participated from July to December 2009. Qualitative in-depth interviews were conducted with owners or shopkeepers on saleability of anti-malarials, and structured questionnaires provided quantitative data on drugs sales volume. Results All surveyed drug shops illicitly sold SP and quinine (QN, and legally amodiaquine (AQ. Calculated monthly sale was 4,041 doses, in a town with a population of 15,000 people. Local brands of SP accounted for 74% of sales volume, compared to AQ (13%, QN (11% and ACT (2%. Conclusions In community practice, the saleability of ACT was negligible. SP was best-selling, and use was not reserved for IPTp, as stipulated in the national anti-malarial policy. It is a major reason for concern that such drug-pressure in the community equals de facto intermittent presumptive treatment. In an area where SP drug resistance remains high, unregulated SP dispensing to people other than pregnant women runs the risk of eventually jeopardizing the effectiveness of the IPTp

  2. Anti-malarial market and policy surveys in sub-Saharan Africa

    Sevcsik Ann-Marie

    2010-04-01

    Full Text Available Abstract At a recent meeting (Sept 18, 2009 in which reasons for the limited access to artemisinin-based combination therapy (ACT in sub-Saharan Africa were discussed, policy and market surveys on anti-malarial drug availability and accessibility in Burundi and Sierra Leone were presented in a highly interactive brainstorming session among key stakeholders across private, public, and not-for-profit sectors. The surveys, the conduct of which directly involved the national malaria control programme managers of the two countries, provides the groundwork for evidence-based policy implementation. The results of the surveys could be extrapolated to other countries with similar socio-demographic and malaria profiles. The meeting resulted in recommendations on key actions to be taken at the global, national, and community level for better ACT accessibility. At the global level, both public and private sectors have actions to take to strengthen policies that lead to the replacement of loose blister packs with fixed-dose ACT products, develop strategies to ban inappropriate anti-malarials and regulate those bans, and facilitate technology and knowledge transfer to scale up production of fixed-dose ACT products, which should be readily available and affordable to those patients who are in the greatest need of these medicines. At the national level, policies that regulate the anti-malarial medicines market should be enacted and enforced. The public sector, including funding donors, should participate in ensuring that the private sector is engaged in the ACT implementation process. Research similar to the surveys discussed is important for other countries to develop and evaluate the right incentives at a local level. At the community level, community outreach and education about appropriate preventive and treatment measures must continue and be strengthened, with service delivery systems developed within both public and private sectors, among other measures

  3. Measuring the association between artemisinin-based case management and malaria incidence in southern Vietnam, 1991-2010.

    Peak, Corey M; Thuan, Phung Duc; Britton, Amadea; Nguyen, Tran Dang; Wolbers, Marcel; Thanh, Ngo Viet; Buckee, Caroline O; Boni, Maciej F

    2015-04-01

    In addition to being effective, fast-acting, and well tolerated, artemisinin-based combination therapies (ACTs) are able to kill certain transmission stages of the malaria parasite. However, the population-level impacts of ACTs on reducing malaria transmission have been difficult to assess. In this study on the history of malaria control in Vietnam, we assemble annual reporting on malaria case counts, coverage with insecticide-treated nets (ITN) and indoor residual spraying (IRS), and drug purchases by provincial malaria control programs from 1991 to 2010 in Vietnam's 20 southern provinces. We observe a significant negative association between artemisinin use and malaria incidence, with a 10% absolute increase in the purchase proportion of artemisinin-containing regimens being associated with a 29.1% (95% confidence interval: 14.8-41.0%) reduction in slide-confirmed malaria incidence, after accounting for changes in urbanization, ITN/IRS coverage, and two indicators of health system capacity. One budget-related indicator of health system capacity was found to have a smaller association with malaria incidence, and no other significant factors were found. Our findings suggest that including an artemisinin component in malaria drug regimens was strongly associated with reduced malaria incidence in southern Vietnam, whereas changes in urbanization and coverage with ITN or IRS were not. PMID:25667053

  4. Treatment of Plasmodium chabaudi Parasites with Curcumin in Combination with Antimalarial Drugs: Drug Interactions and Implications on the Ubiquitin/Proteasome System

    Zoraima Neto

    2013-01-01

    Full Text Available Antimalarial drug resistance remains a major obstacle in malaria control. Evidence from Southeast Asia shows that resistance to artemisinin combination therapy (ACT is inevitable. Ethnopharmacological studies have confirmed the efficacy of curcumin against Plasmodium spp. Drug interaction assays between curcumin/piperine/chloroquine and curcumin/piperine/artemisinin combinations and the potential of drug treatment to interfere with the ubiquitin proteasome system (UPS were analyzed. In vivo efficacy of curcumin was studied in BALB/c mice infected with Plasmodium chabaudi clones resistant to chloroquine and artemisinin, and drug interactions were analyzed by isobolograms. Subtherapeutic doses of curcumin, chloroquine, and artemisinin were administered to mice, and mRNA was collected following treatment for RT-PCR analysis of genes encoding deubiquitylating enzymes (DUBs. Curcumin was found be nontoxic in BALB/c mice. The combination of curcumin/chloroquine/piperine reduced parasitemia to 37% seven days after treatment versus the control group’s 65%, and an additive interaction was revealed. Curcumin/piperine/artemisinin combination did not show a favorable drug interaction in this murine model of malaria. Treatment of mice with subtherapeutic doses of the drugs resulted in a transient increase in genes encoding DUBs indicating UPS interference. If curcumin is to join the arsenal of available antimalarial drugs, future studies exploring suitable drug partners would be of interest.

  5. Insights following change in drug policy: A descriptive study for antimalarial prescription practices in children of public sector health facilities in Jharkhand state of India

    Neelima Mishra

    2013-12-01

    Full Text Available Background & objectives: Widespread resistance to chloroquine was the mainstay to implement artemisininbased combination therapy (ACT in the year 2007 in few malaria endemic states in India including Jharkhand as the first line of treatment for uncomplicated Plasmodium falciparum malaria. This study was conducted in Jharkhand state of the country just after the implementation of ACT to assess the prevailing antimalarial drug prescribing practices, availability of antimalarial drugs and the acceptability of the new policy by the health professionals for the treatment of uncomplicated P. falciparum malaria patients particularly in children ≤15 yr of age. Methods: This is a cross-sectional study in children aged ≤15 yr with malaria or to whom antimalarial drug was prescribed. Main outcome measure was prescription of recommended ACT in children aged ≤15 yr with malaria in the selected areas of Jharkhand. Results: In the year 2008, artemisinin-based combination therapy (ACT was implemented in 12 districts of the studied state; however, the availability of ACT was confirmed only in five districts. Antimalarial prescription was prevalent amongst the undiagnosed (8.4%, malaria negative (64.3% and unknown blood test result (1.2% suggesting the prevalence of irrational treatment practices. ACT prescription was very low with only 3.2% of confirmed falciparum malaria patients receiving it while others received either non-artesunate (NA treatment (88.1% including chloroquine (CQ alone, CQ + Primaquine (PQ/other drugs, sulphadoxine-pyrimethamine (SP alone, SP + other drugs or artemisinin monotherapy (AM treatment (6.3%. Still others were given nonantimalarial treatment (NM in both malaria positive (0.3% and malaria negative (2.1% cases. Interpretation & conclusion: Despite the change in drug policy in the studied state the availability and implementation of ACT was a major concern. Nevertheless, the non-availability of blister packs for children aged

  6. Artemisinin combination therapies price disparity between government and private health sectors and its implication on antimalarial drug consumption pattern in Morogoro Urban District, Tanzania

    Malisa Allen

    2012-03-01

    Full Text Available Abstract Background Universal access to effective treatments is a goal of the Roll Back Malaria Partnership. However, despite official commitments and substantial increases in financing, this objective remains elusive, as development assistance continue to be routed largely through government channels, leaving the much needed highly effective treatments inaccessible or unaffordable to those seeking services in the private sector. Methods To quantify the effect of price disparity between the government and private health systems, this study have audited 92 government and private Drug Selling Units (DSUs in Morogoro urban district in Tanzania to determine the levels, trend and consumption pattern of antimalarial drugs in the two health systems. A combination of observation, interviews and questionnaire administered to the service providers of the randomly selected DSUs were used to collect data. Results ALU was the most selling antimalarial drug in the government health system at a subsidized price of 300 TShs (0.18 US$. By contrast, ALU that was available in the private sector (coartem was being sold at a price of about 10,000 TShs (5.9 US$, the price that was by far unaffordable, prompting people to resort to cheap but failed drugs. As a result, metakelfin (the phased out drug was the most selling drug in the private health system at a price ranging from 500 to 2,000 TShs (0.29–1.18 US$. Conclusions In order for the prompt diagnosis and treatment with effective drugs intervention to have big impact on malaria in mostly low socioeconomic malaria-endemic areas of Africa, inequities in affordability and access to effective treatment must be eliminated. For this to be ensued, subsidized drugs should be made available in both government and private health sectors to promote a universal access to effective safe and affordable life saving antimalarial drugs.

  7. The impact of text message reminders on adherence to antimalarial treatment in northern Ghana: a randomized trial.

    Julia R G Raifman

    Full Text Available BACKGROUND: Low rates of adherence to artemisinin-based combination therapy (ACT regimens increase the risk of treatment failure and may lead to drug resistance, threatening the sustainability of current anti-malarial efforts. We assessed the impact of text message reminders on adherence to ACT regimens. METHODS: Health workers at hospitals, clinics, pharmacies, and other stationary ACT distributors in Tamale, Ghana provided flyers advertising free mobile health information to individuals receiving malaria treatment. The messaging system automatically randomized self-enrolled individuals to the control group or the treatment group with equal probability; those in the treatment group were further randomly assigned to receive a simple text message reminder or the simple reminder plus an additional statement about adherence in 12-hour intervals. The main outcome was self-reported adherence based on follow-up interviews occurring three days after treatment initiation. We estimated the impact of the messages on treatment completion using logistic regression. RESULTS: 1140 individuals enrolled in both the study and the text reminder system. Among individuals in the control group, 61.5% took the full course of treatment. The simple text message reminders increased the odds of adherence (adjusted OR 1.45, 95% CI [1.03 to 2.04], p-value 0.028. Receiving an additional message did not result in a significant change in adherence (adjusted OR 0.77, 95% CI [0.50 to 1.20], p-value 0.252. CONCLUSION: The results of this study suggest that a simple text message reminder can increase adherence to antimalarial treatment and that additional information included in messages does not have a significant impact on completion of ACT treatment. Further research is needed to develop the most effective text message content and frequency. TRIAL REGISTRATION: ClinicalTrials.gov NCT01722734.

  8. Drug resistance genomics of the antimalarial drug artemisinin.

    Winzeler, Elizabeth A; Manary, Micah J

    2014-01-01

    Across the globe, over 200 million annual malaria infections result in up to 660,000 deaths, 77% of which occur in children under the age of five years. Although prevention is important, malaria deaths are typically prevented by using antimalarial drugs that eliminate symptoms and clear parasites from the blood. Artemisinins are one of the few remaining compound classes that can be used to cure multidrug-resistant Plasmodium falciparum infections. Unfortunately, clinical trials from Southeast Asia are showing that artemisinin-based treatments are beginning to lose their effectiveness, adding renewed urgency to the search for the genetic determinants of parasite resistance to this important drug class. We review the genetic and genomic approaches that have led to an improved understanding of artemisinin resistance, including the identification of resistance-conferring mutations in the P. falciparum kelch13 gene. PMID:25470531

  9. The effect of dose on the antimalarial efficacy of artemether-lumefantrine

    Anstey, N. M.; Davis, T. M E; Karunajeewa, H. A.;

    2015-01-01

    Background: Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic sett...

  10. Pharmacologic inhibition of CXCL10 in combination with anti-malarial therapy eliminates mortality associated with murine model of cerebral malaria.

    Nana O Wilson

    Full Text Available Despite appropriate anti-malarial treatment, cerebral malaria (CM-associated mortalities remain as high as 30%. Thus, adjunctive therapies are urgently needed to prevent or reduce such mortalities. Overproduction of CXCL10 in a subset of CM patients has been shown to be tightly associated with fatal human CM. Mice with deleted CXCL10 gene are partially protected against experimental cerebral malaria (ECM mortality indicating the importance of CXCL10 in the pathogenesis of CM. However, the direct effect of increased CXCL10 production on brain cells is unknown. We assessed apoptotic effects of CXCL10 on human brain microvascular endothelial cells (HBVECs and neuroglia cells in vitro. We tested the hypothesis that reducing overexpression of CXCL10 with a synthetic drug during CM pathogenesis will increase survival and reduce mortality. We utilized atorvastatin, a widely used synthetic blood cholesterol-lowering drug that specifically targets and reduces plasma CXCL10 levels in humans, to determine the effects of atorvastatin and artemether combination therapy on murine ECM outcome. We assessed effects of atorvastatin treatment on immune determinants of severity, survival, and parasitemia in ECM mice receiving a combination therapy from onset of ECM (day 6 through 9 post-infection and compared results with controls. The results indicate that CXCL10 induces apoptosis in HBVECs and neuroglia cells in a dose-dependent manner suggesting that increased levels of CXCL10 in CM patients may play a role in vasculopathy, neuropathogenesis, and brain injury during CM pathogenesis. Treatment of ECM in mice with atorvastatin significantly reduced systemic and brain inflammation by reducing the levels of the anti-angiogenic and apoptotic factor (CXCL10 and increasing angiogenic factor (VEGF production. Treatment with a combination of atorvastatin and artemether improved survival (100% when compared with artemether monotherapy (70%, p<0.05. Thus, adjunctively

  11. Systematic Review and Meta-Analysis of Artemisinin Based Therapies for the Treatment and Prevention of Schistosomiasis

    Pérez del Villar, Luis; Burguillo, Francisco J.; López-Abán, Julio; Muro, Antonio

    2012-01-01

    Background Chemotherapy based on repeated doses of praziquantel is still the most effective control strategy against Schistosomiasis, however artemisinin derivatives emerged as a family of compounds with schistomicide activity. The aim of the present work is to compare the efficacy of artemisinin-based therapies in the treatment and prophylaxis of human schistosomiasis. The design of this work involved a quantitative systematic review and meta-analysis. Methodology/Principal Findings Retrieva...

  12. Spread of anti-malarial drug resistance: Mathematical model with implications for ACT drug policies

    Dondorp Arjen M

    2008-11-01

    Full Text Available Abstract Background Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT. The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. Methods A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. Results The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with

  13. First Assessment in Humans of the Safety, Tolerability, Pharmacokinetics, and Ex Vivo Pharmacodynamic Antimalarial Activity of the New Artemisinin Derivative Artemisone▿

    Nagelschmitz, Johannes; Voith, Barbara; Wensing, Georg; Roemer, Axel; Fugmann, Burkhard; Haynes, Richard K.; Kotecka, Barbara M.; Rieckmann, Karl H.; Edstein, Michael D.

    2008-01-01

    In preclinical studies, artemisone (BAY 44-9585), a new artemisinin derivative, was shown to possess enhanced efficacy over artesunate, and it does not possess the neurotoxicity characteristic of the current artemisinins. In a phase I program with double-blind, randomized, placebo-controlled, single and multiple ascending oral-dose studies, we evaluated the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of artemisone. Single doses (10, 20, 30, 40, and 80 mg) and multiple doses (40 and 80 mg daily for 3 days) of artemisone were administered orally to healthy subjects. Plasma concentrations of artemisone and its metabolites were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS). Artemisone was well tolerated, with no serious adverse events and no clinically relevant changes in laboratory and vital parameters. The pharmacokinetics of artemisone over the 10- to 80-mg range demonstrated dose linearity. After the single 80-mg dose, artemisone had a geometric mean maximum concentration of 140.2 ng/ml (range, 86.6 to 391.0), a short elimination half-life (t1/2) of 2.79 h (range, 1.56 to 4.88), a high oral clearance of 284.1 liters/h (range, 106.7 to 546.7), and a large volume of distribution of 14.50 liters/kg (range, 3.21 to 51.58). Due to artemisone's short t1/2, its pharmacokinetics were comparable after single and multiple dosing. Plasma samples taken after multiple dosing showed marked ex vivo pharmacodynamic antimalarial activities against two multidrug-resistant Plasmodium falciparum lines. Artemisone equivalent concentrations measured by bioassay revealed higher activity than artemisone measured by LC/MS-MS, confirming the presence of active metabolites. Comparable to those of other artemisinin's, artemisone's t1/2 is well suited for artemisinin-based combination therapy for the treatment of P. falciparum malaria. PMID:18559649

  14. First assessment in humans of the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of the new artemisinin derivative artemisone.

    Nagelschmitz, Johannes; Voith, Barbara; Wensing, Georg; Roemer, Axel; Fugmann, Burkhard; Haynes, Richard K; Kotecka, Barbara M; Rieckmann, Karl H; Edstein, Michael D

    2008-09-01

    In preclinical studies, artemisone (BAY 44-9585), a new artemisinin derivative, was shown to possess enhanced efficacy over artesunate, and it does not possess the neurotoxicity characteristic of the current artemisinins. In a phase I program with double-blind, randomized, placebo-controlled, single and multiple ascending oral-dose studies, we evaluated the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of artemisone. Single doses (10, 20, 30, 40, and 80 mg) and multiple doses (40 and 80 mg daily for 3 days) of artemisone were administered orally to healthy subjects. Plasma concentrations of artemisone and its metabolites were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS). Artemisone was well tolerated, with no serious adverse events and no clinically relevant changes in laboratory and vital parameters. The pharmacokinetics of artemisone over the 10- to 80-mg range demonstrated dose linearity. After the single 80-mg dose, artemisone had a geometric mean maximum concentration of 140.2 ng/ml (range, 86.6 to 391.0), a short elimination half-life (t(1/2)) of 2.79 h (range, 1.56 to 4.88), a high oral clearance of 284.1 liters/h (range, 106.7 to 546.7), and a large volume of distribution of 14.50 liters/kg (range, 3.21 to 51.58). Due to artemisone's short t(1/2), its pharmacokinetics were comparable after single and multiple dosing. Plasma samples taken after multiple dosing showed marked ex vivo pharmacodynamic antimalarial activities against two multidrug-resistant Plasmodium falciparum lines. Artemisone equivalent concentrations measured by bioassay revealed higher activity than artemisone measured by LC/MS-MS, confirming the presence of active metabolites. Comparable to those of other artemisinin's, artemisone's t(1/2) is well suited for artemisinin-based combination therapy for the treatment of P. falciparum malaria. PMID:18559649

  15. Expanding the Antimalarial Drug Arsenal—Now, But How?

    Rajeev K. Mehlotra

    2011-04-01

    Full Text Available The number of available and effective antimalarial drugs is quickly dwindling. This is mainly because a number of drug resistance-associated mutations in malaria parasite genes, such as crt, mdr1, dhfr/dhps, and others, have led to widespread resistance to all known classes of antimalarial compounds. Unfortunately, malaria parasites have started to exhibit some level of resistance in Southeast Asia even to the most recently introduced class of drugs, artemisinins. While there is much need, the antimalarial drug development pipeline remains woefully thin, with little chemical diversity, and there is currently no alternative to the precious artemisinins. It is difficult to predict where the next generation of antimalarial drugs will come from; however, there are six major approaches: (i re-optimizing the use of existing antimalarials by either replacement/rotation or combination approach; (ii repurposing drugs that are currently used to treat other infections or diseases; (iii chemically modifying existing antimalarial compounds; (iv exploring natural sources; (v large-scale screening of diverse chemical libraries; and (vi through parasite genome-based (“targeted” discoveries. When any newly discovered effective antimalarial treatment is used by the populus, we must maintain constant vigilance for both parasite-specific and human-related factors that are likely to hamper its success. This article is neither comprehensive nor conclusive. Our purpose is to provide an overview of antimalarial drug resistance, associated parasite genetic factors (1. Introduction; 2. Emergence of artemisinin resistance in P. falciparum, and the antimalarial drug development pipeline (3. Overview of the global pipeline of antimalarial drugs, and highlight some examples of the aforementioned approaches to future antimalarial treatment. These approaches can be categorized into “short term” (4. Feasible options for now and “long term” (5. Next generation of

  16. On peroxide antimalarials

    IGOR OPSENICA

    2007-12-01

    Full Text Available Several dicyclohexylidene tetraoxanes were prepared in order to gain a further insight into structure–activity relationship of this kind of antimalarials. The tetraoxanes 2–5, obtained as a cis/trans mixture, showed pronounced antimalarial activity against Plasmodium falciparum chloroquine susceptible D6, chloroquine resistant W2 and multidrug-resistant TM91C235 (Thailand strains. They have better than or similar activity to the corresponding desmethyl dicyclohexylidene derivatives. Two chimeric endoperoxides with superior antimalarial activity to the natural product ascaridole were also synthesized.

  17. Atovaquone and ELQ-300 Combination Therapy as a Novel Dual-Site Cytochrome bc1 Inhibition Strategy for Malaria.

    Stickles, Allison M; Smilkstein, Martin J; Morrisey, Joanne M; Li, Yuexin; Forquer, Isaac P; Kelly, Jane X; Pou, Sovitj; Winter, Rolf W; Nilsen, Aaron; Vaidya, Akhil B; Riscoe, Michael K

    2016-08-01

    Antimalarial combination therapies play a crucial role in preventing the emergence of drug-resistant Plasmodium parasites. Although artemisinin-based combination therapies (ACTs) comprise the majority of these formulations, inhibitors of the mitochondrial cytochrome bc1 complex (cyt bc1) are among the few compounds that are effective for both acute antimalarial treatment and prophylaxis. There are two known sites for inhibition within cyt bc1: atovaquone (ATV) blocks the quinol oxidase (Qo) site of cyt bc1, while some members of the endochin-like quinolone (ELQ) family, including preclinical candidate ELQ-300, inhibit the quinone reductase (Qi) site and retain full potency against ATV-resistant Plasmodium falciparum strains with Qo site mutations. Here, we provide the first in vivo comparison of ATV, ELQ-300, and combination therapy consisting of ATV plus ELQ-300 (ATV:ELQ-300), using P. yoelii murine models of malaria. In our monotherapy assessments, we found that ATV functioned as a single-dose curative compound in suppressive tests whereas ELQ-300 demonstrated a unique cumulative dosing effect that successfully blocked recrudescence even in a high-parasitemia acute infection model. ATV:ELQ-300 therapy was highly synergistic, and the combination was curative with a single combined dose of 1 mg/kg of body weight. Compared to the ATV:proguanil (Malarone) formulation, ATV:ELQ-300 was more efficacious in multiday, acute infection models and was equally effective at blocking the emergence of ATV-resistant parasites. Ultimately, our data suggest that dual-site inhibition of cyt bc1 is a valuable strategy for antimalarial combination therapy and that Qi site inhibitors such as ELQ-300 represent valuable partner drugs for the clinically successful Qo site inhibitor ATV. PMID:27270285

  18. Closing the access barrier for effective anti-malarials in the private sector in rural Uganda: consortium for ACT private sector subsidy (CAPSS pilot study

    Talisuna Ambrose O

    2012-10-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT, the treatment of choice for uncomplicated falciparum malaria, is unaffordable and generally inaccessible in the private sector, the first port of call for most malaria treatment across rural Africa. Between August 2007 and May 2010, the Uganda Ministry of Health and the Medicines for Malaria Venture conducted the Consortium for ACT Private Sector Subsidy (CAPSS pilot study to test whether access to ACT in the private sector could be improved through the provision of a high level supply chain subsidy. Methods Four intervention districts were purposefully selected to receive branded subsidized medicines - “ACT with a leaf”, while the fifth district acted as the control. Baseline and evaluation outlet exit surveys and retail audits were conducted at licensed and unlicensed drug outlets in the intervention and control districts. A survey-adjusted, multivariate logistic regression model was used to analyse the intervention’s impact on: ACT uptake and price; purchase of ACT within 24 hours of symptom onset; ACT availability and displacement of sub-optimal anti-malarial. Results At baseline, ACT accounted for less than 1% of anti-malarials purchased from licensed drug shops for children less than five years old. However, at evaluation, “ACT with a leaf” accounted for 69% of anti-malarial purchased in the interventions districts. Purchase of ACT within 24 hours of symptom onset for children under five years rose from 0.8% at baseline to 26.2% (95% CI: 23.2-29.2% at evaluation in the intervention districts. In the control district, it rose modestly from 1.8% to 5.6% (95% CI: 4.0-7.3%. The odds of purchasing ACT within 24 hours in the intervention districts compared to the control was 0.46 (95% CI: 0.08-2.68, p=0.4 at baseline and significant increased to 6.11 (95% CI: 4.32-8.62, p Conclusions These data demonstrate that a supply-side subsidy and an intensive communications campaign

  19. Tyrosine kinase inhibitors: New class of antimalarials on the horizon?

    Pathak, Vrushali; Colah, Roshan; Ghosh, Kanjaksha

    2015-08-01

    Development of the antimalarial drug resistant strains has currently become a major public health challenge. There is an urgent need to develop new antimalarial drugs. Tyrosine kinase inhibitors (TKIs) are receiving increasing attention as anticancer therapy. It has revolutionarised the management of CML to say the least. TKIs are also increasingly being implicated in complicated but vital life cycle of malaria parasite. Hence we tested two commonly used but different classes of TKIs (imatinib and sorafenib) in-vitro for their antimalarial activity and possible synergistic activity with existing antimalarial drug. Antimalarial activity was tested with the help of modified WHO microtest technique in-vitro for five different Plasmodium falciparum laboratory strains (3D7, Dd2, 7G8, MRC2, PKL9). Imatinib and sorafenib showed a promising antimalarial activity with all the strains. These compounds caused dose dependent inhibition of parasite maturation. The isobologram analysis of the interactions of these TKIs with standard antimalarial drug, artesunate revealed distinct patterns of synergism, additivity and antagonism at different ratios. Imatinib showed worthwhile synergism with artesunate indicating imatinib and other tyrosine kinase inhibitors may have significant antimalarial activity and can be used in combination therapy. PMID:26142327

  20. Anti-malarial activities of Andrographis paniculata and Hedyotis corymbosa extracts and their combination with curcumin

    Swain Bijay K; Dash Aditya P; Mishra Kirti; Dey Nrisingha

    2009-01-01

    Abstract Background Herbal extracts of Andrographis paniculata (AP) and Hedyotis corymbosa (HC) are known as hepato-protective and fever-reducing drugs since ancient time and they have been used regularly by the people in the south Asian sub-continent. Methanolic extracts of these two plants were tested in vitro on choloroquine sensitive (MRC-pf-20) and resistant (MRC-pf-303) strains of Plasmodium falciparum for their anti-malarial activity. Methods Growth inhibition was determined using diff...

  1. Artemisinin resistance containment project in Thailand. II: responses to mefloquine-artesunate combination therapy among falciparum malaria patients in provinces bordering Cambodia

    Satimai Wichai

    2012-08-01

    Full Text Available Abstract Background The area along the Thai-Cambodian border is considered an epicenter of anti-malarial drug resistance. Recently, parasite resistance to artemisinin-based therapies has been reported in the area. The artemisinin resistance containment project was initiated in November 2008, with the aim to limit resistant parasites and eliminate malaria in this region. This study describes the response to artemisinin-based therapy among falciparum malaria patients in the area, using data from the malaria surveillance programmed under the containment project. Methods The study was conducted in seven provinces of Thailand along the Thai-Cambodian border. Data of Plasmodium falciparum-positive patients during January 2009 to December 2011 were obtained from the electronic malaria information system (eMIS Web-based reporting system. All P. falciparum cases were followed for 42 days, as the routine case follow-up protocol. The demographic characteristics of the patients were described. Statistical analysis was performed to determine the cure rate of the current standard anti-malarial drug regimen--mefloquine-artesunate combination therapy (MAS. The proportion of patients who remained parasite-positive at each follow-up day was calculated. In addition, factors related to the delayed parasite clearance on day-3 post-treatment, were explored. Results A total of 1,709 P. falciparum-positive cases were reported during the study period. Almost 70% of falciparum cases received MAS therapy (n = 1,174. The majority of cases were males, aged between 31 and 50 years. The overall MAS cure rate was >90% over the three-year period. Almost all patients were able to clear the parasite within 7 to 14 days post-treatment. Approximately 14% of patients undergoing MAS remained parasite-positive on day-3. Delayed parasite clearance was not significantly associated with patient gender, age, or citizenship. However, delayed parasite clearance varied across the

  2. Antimalarial Synergy of Cysteine and Aspartic Protease Inhibitors

    Semenov, Andrey; Olson, Jed E.; Rosenthal, Philip J.

    1998-01-01

    It has been proposed that the Plasmodium falciparum cysteine protease falcipain and aspartic proteases plasmepsin I and plasmepsin II act cooperatively to hydrolyze hemoglobin as a source of amino acids for erythrocytic parasites. Inhibitors of each of these proteases have potent antimalarial effects. We have now evaluated the antimalarial effects of combinations of cysteine and aspartic protease inhibitors. When incubated with cultured P. falciparum parasites, cysteine and aspartic protease ...

  3. Antimalarial drug resistance: An overview

    Antony, Hiasindh Ashmi; Parija, Subhash Chandra

    2016-01-01

    Malaria is a major public health burden throughout the world. Resistance to the antimalarial drugs has increased the mortality and morbidity rate that is achieved so far through the malaria control program. Monitoring the drug resistance to the available antimalarial drugs helps to implement effective drug policy, through the in vivo efficacy studies, in vitro drug susceptibility tests and detection of molecular markers. It is important to understand the mechanism of the antimalarial drugs, a...

  4. Low efficacy of chloroquine: time to switchover to artemisinin-based combination therapy for falciparum malaria in India.

    Valecha, N; Joshi, H; Mallick, P K; Sharma, S K; Kumar, A; Tyagi, P K; Shahi, B; Das, M K; Nagpal, B N; Dash, A P

    2009-07-01

    Drug resistance in Plasmodium falciparum poses a major threat to malaria control globally; including India. Chloroquine is still the most widely used drug in the country because of its safety and cost effectiveness. Although chloroquine resistance was first reported in 1973 in North Eastern India, the extent of the problem was realized only after the more intensive 28-day drug efficacy studies were used to monitor drug resistance. In the present study, efficacy of chloroquine in treatment of uncomplicated falciparum malaria was investigated using standard World Health Organization (WHO) procedures in three distinct epidemiological settings. The prevalence of molecular markers of drug resistance, Pfcrt K76T, Pfmdr1 N86Y, was also studied. A total of 374 children and adults with uncomplicated P. falciparum malaria were enrolled at six sites in four states, treated with chloroquine and follow-up was done for 28 days. The cumulative incidence of success of chloroquine at Day 28 by the Kaplan Meier analysis in the state of Orissa (District Sundargarh, CHC Bisra and Kuarmunda) was 57 (95% CI 43-68) and 54 (95% CI 40-66); in the state of Jharkhand (District Ranchi, PHC Angara and District Simdega, PHC Jaldega) it was 72 (95% CI 59-81) and 65 (95% CI 50-76); in the state of Goa (District North-Goa, Panaji Town), it was 20 (95% CI 10-2) and in the state of Rajasthan (District Udaipur, PHC Rishabdev), it was 96 (95% CI 85-99). Treatment failure was related to Pfcrt mutations but not Pfmdr mutations. Early treatment failure was observed only in 15.8% out of total failures, probably due to the semi-immune nature of the population. This type of response may give false perception about efficacy of the failing drug to patients, clinicians and National Authorities. In a large country like India it is not feasible to conduct in vivo studies in all districts and lack of direct correlation between molecular markers, in vitro studies and treatment outcome makes it difficult to predict the areas requiring change of policy. In this scenario, it is a challenge for National Programmes to make evidence-based revisions in the drug policy. However, considering the global, especially Southeast Asian, scenario and interpretation of available in vivo data, trends of mutations, availability of effective drugs and support of international donors, India should consider changing the first line treatment, at least for all diagnosed P. falciparum cases. PMID:19426658

  5. Brazilian Plasmodium falciparum isolates: investigation of candidate polymorphisms for artemisinin resistance before introduction of artemisinin-based combination therapy

    Rosenthal Philip J

    2010-12-01

    Full Text Available Abstract Background This study was performed to better understand the genetic diversity of known polymorphisms in pfatpase6 and pfmdr1 genes before the introduction of ACT in Brazil, in order to get a genotypic snapshot of Plasmodium falciparum parasites that may be used as baseline reference for future studies. Methods Parasites from P. falciparum samples collected in 2002, 2004 and 2006-2007 were genotyped using PCR and DNA sequencing at codons 86, 130, 184, 1034, 1042, 1109 and 1246 for pfmdr1 gene, and 243, 263, 402, 431, 623, 630, 639, 683, 716, 776, 769 and 771 for pfatpase6 gene. Results A pfmdr1 haplotype NEF/CDVY was found in 97% of the samples. In the case of pfatpase6, four haplotypes, wild-type (37%, 630 S (35%, 402 V (5% and double-mutant 630 S + 402 V (23%, were detected. Conclusion Although some polymorphism in pfmdr1 and pfatpase6 were verified, no reported haplotypes in both genes that may mediate altered response to ACT was detected before the introduction of this therapy in Brazil. Thus, the haplotypes herein described can be very useful as a baseline reference of P. falciparum populations without ACT drug pressure.

  6. Antimalarial drug resistance: An overview.

    Antony, Hiasindh Ashmi; Parija, Subhash Chandra

    2016-01-01

    Malaria is a major public health burden throughout the world. Resistance to the antimalarial drugs has increased the mortality and morbidity rate that is achieved so far through the malaria control program. Monitoring the drug resistance to the available antimalarial drugs helps to implement effective drug policy, through the in vivo efficacy studies, in vitro drug susceptibility tests and detection of molecular markers. It is important to understand the mechanism of the antimalarial drugs, as it is one of the key factors in the emergence and spread of drug resistance. This review summarizes the commonly used antimalarial drugs, their mechanism of action and the genetic markers validated so far for the detection of drug-resistant parasites. PMID:26998432

  7. Antimalarial Activity of Azadipeptide Nitriles

    Löser, Reik; Gut, Jiri; Rosenthal, Philip J.; Frizler, Maxim; Gütschow, Michael; Andrews, Katherine T.

    2009-01-01

    Azadipeptide nitriles – novel cysteine protease inhibitors – display structure-dependent antimalarial activity against both chloroquine-sensitive and chloroquine-resistant lines of cultured Plasmodium falciparum malaria parasites. Inhibition of parasite’s haemoglobin-degrading cysteine proteases was also investigated, revealing the azadipeptide nitriles as potent inhibitors of falcipain-2 and -3. A correlation between the cysteine protease-inhibiting activity and the antimalarial potential of...

  8. In vitro interaction of artemisinin derivatives or the fully synthetic peroxidic anti-malarial OZ277 with thapsigargin in Plasmodium falciparum strains

    Abiodun Oyindamola O; Brun Reto; Wittlin Sergio

    2013-01-01

    Abstract Background Semi-synthetic artemisinin derivatives are powerful peroxidic drugs in artemisinin-based combination therapy (ACT) recommended as first-line treatment of Plasmodium falciparum malaria in disease-endemic countries. Studies by Eckstein-Ludwig and co-workers showed both thapsigargin and artemisinin specifically inhibit the sarcoplasmic reticulum Ca2+−ATPase of Plasmodium falciparum (PfATP6). In the present study the type of interaction between thapsigargin and artemisinin der...

  9. Factors related to compliance to anti-malarial drug combination: example of amodiaquine/sulphadoxine-pyrimethamine among children in rural Senegal

    Sow Diarietou

    2009-06-01

    Full Text Available Abstract Background The introduction of new anti-malarial treatment that is effective, but more expensive, raises questions about whether the high level of effectiveness observed in clinical trials can be found in a context of family use. The objective of this study was to determine the factors related to adherence, when using the amodiaquine/sulphadoxine-pyrimethamine (AQ/SP association, a transitory strategy before ACT implementation in Senegal. Methods The study was conducted in five rural dispensaries. Children, between two and 10 years of age, who presented mild malaria were recruited at the time of the consultation and were prescribed AQ/SP. The child's primary caretaker was questioned at home on D3 about treatment compliance and factors that could have influenced his or her adherence to treatment. A logistic regression model was used for the analyses. Results The study sample included 289 children. The adherence rate was 64.7%. Two risks factors for non-adherence were identified: the children's age (8–10 years (ORa = 3.07 [1.49–6.29]; p = 0.004; and the profession of the head of household (retailer/employee versus farmer (ORa = 2.71 [1.34–5.48]; p = 0.006. Previously seeking care (ORa = 0.28 [0.105–0.736], p=0.001] satisfaction with received information (ORa = 0.45 [0.24–0.84]; p = 0.013, and the quality of history taking (ORa = 0.38 [0.21–0.69]; p = 0.001 were significantly associated with good compliance. Conclusion The results of the study show the importance of information and communication between caregivers and health center staff. The experience gained from this therapeutic transition emphasizes the importance of information given to the patients at the time of the consultation and drug delivery in order to improve drug use and thus prevent the emergence of rapid drug resistance.

  10. Artemisinin versus nonartemisinin combination therapy for uncomplicated malaria: randomized clinical trials from four sites in Uganda.

    Adoke Yeka

    2005-07-01

    Full Text Available BACKGROUND: Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination antimalarial therapy including artemisinins has been advocated recently to improve efficacy and limit the spread of resistance, but artemisinins are expensive and relatively untested in highly endemic areas. We compared artemisinin-based and other combination therapies in four districts in Uganda with varying transmission intensity. METHODS AND FINDINGS: We enrolled 2,160 patients aged 6 mo or greater with uncomplicated falciparum malaria. Patients were randomized to receive chloroquine (CQ + sulfadoxine-pyrimethamine (SP; amodiaquine (AQ + SP; or AQ + artesunate (AS. Primary endpoints were the 28-d risks of parasitological failure either unadjusted or adjusted by genotyping to distinguish recrudescence from new infections. A total of 2,081 patients completed follow-up, of which 1,749 (84% were under the age of 5 y. The risk of recrudescence after treatment with CQ + SP was high, ranging from 22% to 46% at the four sites. This risk was significantly lower (p < 0.01 after AQ + SP or AQ + AS (7%-18% and 4%-12%, respectively. Compared to AQ + SP, AQ + AS was associated with a lower risk of recrudescence but a higher risk of new infection. The overall risk of repeat therapy due to any recurrent infection (recrudescence or new infection was similar at two sites and significantly higher for AQ + AS at the two highest transmission sites (risk differences = 15% and 16%, p < 0.003. CONCLUSION: AQ + AS was the most efficacious regimen for preventing recrudescence, but this benefit was outweighed by an increased risk of new infection. Considering all recurrent infections, the efficacy of AQ + SP was at least as efficacious at all sites and superior to AQ + AS at the highest transmission sites. The high endemicity of malaria in Africa may impact on the efficacy of artemisinin-based combination therapy. The registration number for this trial is ISRCTN

  11. Cajachalcone: An Antimalarial Compound from Cajanus cajan Leaf Extract

    E. O. Ajaiyeoba

    2013-01-01

    Full Text Available Cajanus cajan L, a member of the family Fabaceae, was identified from the Nigerian antimalarial ethnobotany as possessing antimalarial properties. The bioassay-guided fractionation of the crude methanol extract of C. cajan leaves was done in vitro using the multiresistant strain of Plasmodium falciparum (K1 in the parasite lactate dehydrogenase assay. Isolation of compound was achieved by a combination of chromatographic techniques, while the structure of the compound was elucidated by spectroscopy. This led to the identification of a cajachalcone, 2′,6′-dihydroxy-4-methoxy chalcone, as the biologically active constituent from the ethyl acetate fraction. Cajachalcone had an IC50 value of 2.0 μg/mL (7.4 μM and could be a lead for anti-malarial drug discovery.

  12. From hybrid compounds to targeted drug delivery in antimalarial therapy.

    Oliveira, Rudi; Miranda, Daniela; Magalhães, Joana; Capela, Rita; Perry, Maria J; O'Neill, Paul M; Moreira, Rui; Lopes, Francisca

    2015-08-15

    The discovery of new drugs to treat malaria is a continuous effort for medicinal chemists due to the emergence and spread of resistant strains of Plasmodium falciparum to nearly all used antimalarials. The rapid adaptation of the malaria parasite remains a major limitation to disease control. Development of hybrid antimalarial agents has been actively pursued as a promising strategy to overcome the emergence of resistant parasite strains. This review presents the journey that started with simple combinations of two active moieties into one chemical entity and progressed into a delivery/targeted system based on major antimalarial classes of drugs. The rationale for providing different mechanisms of action against a single or additional targets involved in the multiple stages of the parasite's life-cycle is highlighted. Finally, a perspective for this polypharmacologic approach is presented. PMID:25913864

  13. Malaria treatment failures after artemisinin-based therapy in three expatriates: could improved manufacturer information help to decrease the risk of treatment failure ?

    Loutan Louis

    2006-10-01

    Full Text Available Abstract Background Artemisinin-containing therapies are highly effective against Plasmodium falciparum malaria. Insufficient numbers of tablets and inadequate package inserts result in sub-optimal dosing and possible treatment failure. This study reports the case of three, non-immune, expatriate workers with P. falciparum acquired in Africa, who failed to respond to artemisinin-based therapy. Sub-therapeutic dosing in accordance with the manufacturers' recommendations was the probable cause. Method Manufacturers information and drug content included in twenty-five artemisinin-containing specialities were reviewed. Results A substantial number of manufacturers do not follow current WHO recommendations regarding treatment duration and doses. Conclusion This study shows that drug packaging and their inserts should be improved.

  14. The interaction of x-rays and antimalarials

    Full text: The radiation sensitivity of malaria parasites has three potential clinical applications, namely i) to prevent the transmission of malaria by blood transfusion, ii) as adjunctive therapy when a radioactive isotope is complexed to a conventional antimalarial drug, and iii) to attenuate the pathogenicity of specific parasite stages as part of the development of a vaccine. In the first two applications, detailed information relating to parasite radiosensitivity and the interaction of ionising radiation with antimalarials is of vital importance because dosimetry must allow for the exposure of normal cells. Malaria parasite cultures (Plasmodium falciparum) were exposed to a logarithmic series of concentrations of antimalarial agents and irradiated using a Siemens Stabilipan orthovoltage radiotherapy unit. The irradiation was performed at room temperature and ambient oxygen concentration. Control samples were also irradiated. The DNA synthesis in each culture was measured 48 hours post irradiation by using a 3H-hypoxanthine incorporation assay. The antimalarials studied are: artesunate, quinine, retinol and chloroquine. The radiosensitivity of Plasmodium falciparum is not dependent on the strain of parasite with the dose required to inhibit 50% of DNA synthesis (ID50) equal to 24.7 ± 3.0 Gy. This applies equally for the drug resistant and drug sensitive strains studied. Because the measured radiosensitivity is dependent on the sera oxygen concentration, the reported value for the ID50 may not apply in hypoxic situations. The interaction of ionising radiation with the antimalarials shows synergy with retinol and choloquine, additivity with quinine and slight antagonism with artesunate. Radionuclide therapy may emerge as a novel treatment for malaria. If this does occur, then, although all strains appear to be equally radiosensitive, care must be taken when combining ionising radiation with existing antimalarials for the treatment of malaria. Copyright (2001

  15. Poor quality vital anti-malarials in Africa - an urgent neglected public health priority.

    Newton Paul N; Green Michael D; Mildenhall Dallas C; Plançon Aline; Nettey Henry; Nyadong Leonard; Hostetler Dana M; Swamidoss Isabel; Harris Glenn A; Powell Kristen; Timmermans Ans E; Amin Abdinasir A; Opuni Stephen K; Barbereau Serge; Faurant Claude

    2011-01-01

    Abstract Background Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT) at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. Methods Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African coun...

  16. Active case detection, treatment of falciparum malaria with combined chloroquine and sulphadoxine/pyrimethamine and vivax malaria with chloroquine and molecular markers of anti-malarial resistance in the Republic of Vanuatu

    Rogers William O

    2010-04-01

    Full Text Available Abstract Background Chloroquine-resistant Plasmodium falciparum was first described in the Republic of Vanuatu in the early 1980s. In 1991, the Vanuatu Ministry of Health instituted new treatment guidelines for uncomplicated P. falciparum infection consisting of chloroquine/sulphadoxine-pyrimethamine combination therapy. Chloroquine remains the recommended treatment for Plasmodium vivax. Methods In 2005, cross-sectional blood surveys at 45 sites on Malo Island were conducted and 4,060 adults and children screened for malaria. Of those screened, 203 volunteer study subjects without malaria at the time of screening were followed for 13 weeks to observe peak seasonal incidence of infection. Another 54 subjects with malaria were followed over a 28-day period to determine efficacy of anti-malarial therapy; chloroquine alone for P. vivax and chloroquine/sulphadoxine-pyrimethamine for P. falciparum infections. Results The overall prevalence of parasitaemia by mass blood screening was 6%, equally divided between P. falciparum and P. vivax. Twenty percent and 23% of participants with patent P. vivax and P. falciparum parasitaemia, respectively, were febrile at the time of screening. In the incidence study cohort, after 2,303 person-weeks of follow-up, the incidence density of malaria was 1.3 cases per person-year with P. vivax predominating. Among individuals participating in the clinical trial, the 28-day chloroquine P. vivax cure rate was 100%. The 28-day chloroquine/sulphadoxine-pyrimethamine P. falciparum cure rate was 97%. The single treatment failure, confirmed by merozoite surface protein-2 genotyping, was classified as a day 28 late parasitological treatment failure. All P. falciparum isolates carried the Thr-76 pfcrt mutant allele and the double Asn-108 + Arg-59 dhfr mutant alleles. Dhps mutant alleles were not detected in the study sample. Conclusion Peak seasonal malaria prevalence on Malo Island reached hypoendemic levels during the study

  17. Review of pyronaridine anti-malarial properties and product characteristics

    Croft Simon L

    2012-08-01

    Full Text Available Abstract Pyronaridine was synthesized in 1970 at the Institute of Chinese Parasitic Disease and has been used in China for over 30 years for the treatment of malaria. Pyronaridine has high potency against Plasmodium falciparum, including chloroquine-resistant strains. Studies in various animal models have shown pyronaridine to be effective against strains resistant to other anti-malarials, including chloroquine. Resistance to pyronaridine appears to emerge slowly and is further retarded when pyronaridine is used in combination with other anti-malarials, in particular, artesunate. Pyronaridine toxicity is generally less than that of chloroquine, though evidence of embryotoxicity in rodents suggests use with caution in pregnancy. Clinical pharmacokinetic data for pyronaridine indicates an elimination T1/2 of 13.2 and 9.6 days, respectively, in adults and children with acute uncomplicated falciparum and vivax malaria in artemisinin-combination therapy. Clinical data for mono or combined pyronaridine therapy show excellent anti-malarial effects against P. falciparum and studies of combination therapy also show promise against Plasmodium vivax. Pyronaridine has been developed as a fixed dose combination therapy, in a 3:1 ratio, with artesunate for the treatment of acute uncomplicated P. falciparum malaria and blood stage P. vivax malaria with the name of Pyramax® and has received Positive Opinion by European Medicines Agency under the Article 58 procedure.

  18. Antimalarial natural products: a review

    Faraz Mojab

    2012-03-01

    Results and Conclusion: There is an urgent need for the development of new treatments for malaria. Many countries have a vast precedence in the use of medicinal plants and the required knowledge spans many centuries. Although malaria is controlled in Iran, some researchers tend to study malaria and related subjects. In vitro biological tests for the detection of antimalarial activities in plant extracts are currently available. It is vital that the efficacy and safety of traditional medicines be validated and their active constituents be identified in order to establish reliable quality control measures.

  19. The Curative and Prophylactic Effects of Xylopic Acid on Plasmodium berghei Infection in Mice

    J.N. Boampong; Ameyaw, E. O.; B. Aboagye; Asare, K.; Kyei, S; Donfack, J. H.; Woode, E.

    2013-01-01

    Efforts have been intensified to search for more effective antimalarial agents because of the observed failure of some artemisinin-based combination therapy (ACT) treatments of malaria in Ghana. Xylopic acid, a pure compound isolated from the fruits of the Xylopia aethiopica, was investigated to establish its attributable prophylactic, curative antimalarial, and antipyretic properties. The antimalarial properties were determined by employing xylopic acid (10–100 mg/kg) in ICR mice infected wi...

  20. A database of antimalarial drug resistance

    Ringwald Pascal

    2006-06-01

    Full Text Available Abstract A large investment is required to develop, license and deploy a new antimalarial drug. Too often, that investment has been rapidly devalued by the selection of parasite populations resistant to the drug action. To understand the mechanisms of selection, detailed information on the patterns of drug use in a variety of environments, and the geographic and temporal patterns of resistance is needed. Currently, there is no publically-accessible central database that contains information on the levels of resistance to antimalaria drugs. This paper outlines the resources that are available and the steps that might be taken to create a dynamic, open access database that would include current and historical data on clinical efficacy, in vitro responses and molecular markers related to drug resistance in Plasmodium falciparum and Plasmodium vivax. The goal is to include historical and current data on resistance to commonly used drugs, like chloroquine and sulfadoxine-pyrimethamine, and on the many combinations that are now being tested in different settings. The database will be accessible to all on the Web. The information in such a database will inform optimal utilization of current drugs and sustain the longest possible therapeutic life of newly introduced drugs and combinations. The database will protect the valuable investment represented by the development and deployment of novel therapies for malaria.

  1. Pricing, distribution, and use of antimalarial drugs.

    Foster, S. D.

    1991-01-01

    Prices of new antimalarial drugs are targeted at the "travellers' market" in developed countries, which makes them unaffordable in malaria-endemic countries where the per capita annual drug expenditures are US$ 5 or less. Antimalarials are distributed through a variety of channels in both public and private sectors, the official malaria control programmes accounting for 25-30% of chloroquine distribution. The unofficial drug sellers in markets, streets, and village shops account for as much a...

  2. Willingness-to-pay for a rapid malaria diagnostic test and artemisinin-based combination therapy from private drug shops in Mukono district, Uganda

    Hansen, Kristian Schultz; Pedrazzoli, Debora; Mbonye, Anthony; Clarke, Sian; Cundill, Bonnie; Magnussen, Pascal; Yeung, Shunmay

    2012-01-01

    In Uganda, as in many parts of Africa, the majority of the population seek treatment for malaria in drug shops as their first point of care; however, parasitological diagnosis is not usually offered in these outlets. Rapid diagnostic tests (RDTs) for malaria have attracted interest in recent years as a tool to improve malaria diagnosis, since they have proved accurate and easy to perform with minimal training. Although RDTs could feasibly be performed by drug shop vendors, it is not known how...

  3. Monoclonal Antibodies That Recognize the Alkylation Signature of Antimalarial Ozonides OZ277 (Arterolane) and OZ439 (Artefenomel)

    Jourdan, Joëlle; Matile, Hugues; Reift, Ellen; Biehlmaier, Oliver; Dong, Yuxiang; Wang, Xiaofang; Mäser, Pascal; Vennerstrom, Jonathan L.; Wittlin, Sergio

    2015-01-01

    The singular structure of artemisinin, with its embedded 1,2,4-trioxane heterocycle, has inspired the discovery of numerous semisynthetic artemisinin and structurally diverse synthetic peroxide antimalarials, including ozonides OZ277 (arterolane) and OZ439 (artefenomel). Despite the critical importance of artemisinin combination therapies (ACTs), the precise mode of action of peroxidic antimalarials is not fully understood. However, it has long been proposed that the peroxide bond in artemisi...

  4. Seasonal distribution of anti-malarial drug resistance alleles on the island of Sumba, Indonesia

    Asih, P.B.; Rogers, W.O.; Susanti, A.I.; Rahmat, A.; Rozi, I.E.; Kusumaningtyas, M.A.; Dewi, R.M.; Coutrier, F.N.; Sutamihardja, A.; Ven, A.J.A.M. van der; Sauerwein, R.W.; Syafruddin, D.

    2009-01-01

    BACKGROUND: Drug resistant malaria poses an increasing public health problem in Indonesia, especially eastern Indonesia, where malaria is highly endemic. Widespread chloroquine (CQ) resistance and increasing sulphadoxine-pyrimethamine (SP) resistance prompted Indonesia to adopt artemisinin-based com

  5. Recent developments in naturally derived antimalarials: cryptolepine analogues.

    Wright, Colin W

    2007-06-01

    Increasing resistance of Plasmodium falciparum to commonly used antimalarial drugs has made the need for new agents increasingly urgent. In this paper, the potential of cryptolepine, an alkaloid from the West African shrub Cryptolepis sanguinolenta, as a lead towards new antimalarial agents is discussed. Several cryptolepine analogues have been synthesized that have promising in-vitro and in-vivo antimalarial activity. Studies on the antimalarial modes of action of these analogues indicate that they may have different or additional modes of action to the parent compound. Elucidation of the mode of action may facilitate the development of more potent antimalarial cryptolepine analogues. PMID:17637183

  6. Probing the antimalarial mechanism of artemisinin and OZ277 (arterolane) with nonperoxidic isosteres and nitroxyl radicals.

    Fügi, Matthias A; Wittlin, Sergio; Dong, Yuxiang; Vennerstrom, Jonathan L

    2010-03-01

    Peroxidic antimalarials such as the semisynthetic artemisinins are critically important in the treatment of drug-resistant malaria. Nevertheless, their peroxide bond-dependent mode of action is still not well understood. Using combination experiments with cultured Plasmodium falciparum cells, we investigated the interactions of the nitroxide radical spin trap, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), and four of its analogs with artemisinin and the ozonide drug development candidate OZ277. The antagonism observed for combinations of artemisinin or OZ277 with the TEMPO analogs supports the hypothesis that the formation of carbon-centered radicals is critical for the activity of these two antimalarial peroxides. The TEMPO analogs showed a trend toward greater antagonism with artemisinin than they did with OZ277, an observation that can be explained by the greater tendency of artemisinin-derived carbon-centered radicals to undergo internal self-quenching reactions, resulting in a lower proportion of radicals available for subsequent chemical reactions such as the alkylation of heme and parasite proteins. In a further mechanistic experiment, we tested both artemisinin and OZ277 in combination with their nonperoxidic analogs. The latter had no effect on the antimalarial activities of the former. These data indicate that the antimalarial properties of peroxides do not derive from reversible interactions with parasite targets. PMID:20028825

  7. Case management of malaria fever in Cambodia: results from national anti-malarial outlet and household surveys

    Littrell Megan

    2011-10-01

    Full Text Available Abstract Background Continued progress towards global reduction in morbidity and mortality due to malaria requires scale-up of effective case management with artemisinin-combination therapy (ACT. The first case of artemisinin resistance in Plasmodium falciparum was documented in western Cambodia. Spread of artemisinin resistance would threaten recent gains in global malaria control. As such, the anti-malarial market and malaria case management practices in Cambodia have global significance. Methods Nationally-representative household and outlet surveys were conducted in 2009 among areas in Cambodia with malaria risk. An anti-malarial audit was conducted among all public and private outlets with the potential to sell anti-malarials. Indicators on availability, price and relative volumes sold/distributed were calculated across types of anti-malarials and outlets. The household survey collected information about management of recent "malaria fevers." Case management in the public versus private sector, and anti-malarial treatment based on malaria diagnostic testing were examined. Results Most public outlets (85% and nearly half of private pharmacies, clinics and drug stores stock ACT. Oral artemisinin monotherapy was found in pharmacies/clinics (9%, drug stores (14%, mobile providers (4% and grocery stores (2%. Among total anti-malarial volumes sold/distributed nationally, 6% are artemisinin monotherapies and 72% are ACT. Only 45% of people with recent "malaria fever" reportedly receive a diagnostic test, and the most common treatment acquired is a drug cocktail containing no identifiable anti-malarial. A self-reported positive diagnostic test, particularly when received in the public sector, improves likelihood of receiving anti-malarial treatment. Nonetheless, anti-malarial treatment of reportedly positive cases is low among people who seek treatment exclusively in the public (61% and private (42% sectors. Conclusions While data on the anti-malarial

  8. Efficacy of fixed-dose combination artesunate-amodiaquine versus artemether-lumefantrine for uncomplicated childhood Plasmodium falciparum malaria in Democratic Republic of Congo: a randomized non-inferiority trial

    Espié Emmanuelle

    2012-05-01

    Full Text Available Abstract Background In 2005, the Democratic Republic of Congo (DRC adopted artesunate and amodiaquine (ASAQ as first-line anti-malarial treatment. In order to compare the efficacy of the fixed-dose formulation ASAQ versus artemether-lumefantrine (AL, a randomized, non-inferiority open-label trial was conducted in Katanga. Methods Children aged six and 59 months with uncomplicated Plasmodium falciparum malaria were enrolled and randomly allocated into one of the two regimens. The risk of recurrent parasitaemia by day 42, both unadjusted and adjusted by PCR genotyping to distinguish recrudescence from new infection, was analysed. Results Between April 2008 and March 2009, 301 children were included: 156 with ASAQ and 145 with AL. No early treatment failures were reported. Among the 256 patients followed-up at day 42, 32 patients developed late clinical or parasitological failure (9.9% (13/131 in the ASAQ group and 15.2% (19/125 in the AL group. After PCR correction, cure rates were 98.3% (95%CI, 94.1-99.8 in the ASAQ group and 99.1% (95%CI, 94.9-99.9 in the AL group (difference −0.7%, one sided 95% CI −3.1. Kaplan-Meier PCR-adjusted cure rates were similar. Both treatment regimens were generally well tolerated. Conclusion Both ASAQ and AL are highly effective and currently adequate as the first-line treatment of uncomplicated falciparum malaria in this area of Katanga, DRC. However, in a very large country, such as DRC, and because of possible emergence of resistance from other endemic regions, surveillance of efficacy of artemisinin-based combination treatments, including other evaluations of the resistance of ASAQ, need to be done in other provinces. Trial registration The protocol was registered with the clinicaltrials.gov, open clinical trial registry under the identifier number NCT01567423.

  9. Deployment of ACT antimalarials for treatment of malaria: challenges and opportunities

    Leslie Toby

    2008-12-01

    Full Text Available Abstract Following a long period when the effectiveness of existing mono-therapies for antimalarials was steadily declining with no clear alternative, most malaria-endemic countries in Africa and Asia have adopted artemisinin combination therapy (ACT as antimalarial drug policy. Several ACT drugs exist and others are in the pipeline. If properly targeted, they have the potential to reduce mortality from malaria substantially. The major challenge now is to get the drugs to the right people. Current evidence suggests that most of those who need the drugs do not get them. Simultaneously, a high proportion of those who are given antimalarials do not in fact have malaria. Financial and other barriers mean that, in many settings, the majority of those with malaria, particularly the poorest, do not access formal healthcare, so the provision of free antimalarials via this route has only limited impact. The higher cost of ACT creates a market for fake drugs. Addressing these problems is now a priority. This review outlines current evidence, possible solutions and research priorities.

  10. Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance

    Lee Sue J

    2009-11-01

    Full Text Available Abstract Background Preventing the emergence of anti-malarial drug resistance is critical for the success of current malaria elimination efforts. Prevention strategies have focused predominantly on qualitative factors, such as choice of drugs, use of combinations and deployment of multiple first-line treatments. The importance of anti-malarial treatment dosing has been underappreciated. Treatment recommendations are often for the lowest doses that produce "satisfactory" results. Methods The probability of de-novo resistant malaria parasites surviving and transmitting depends on the relationship between their degree of resistance and the blood concentration profiles of the anti-malarial drug to which they are exposed. The conditions required for the in-vivo selection of de-novo emergent resistant malaria parasites were examined and relative probabilities assessed. Results Recrudescence is essential for the transmission of de-novo resistance. For rapidly eliminated anti-malarials high-grade resistance can arise from a single drug exposure, but low-grade resistance can arise only from repeated inadequate treatments. Resistance to artemisinins is, therefore, unlikely to emerge with single drug exposures. Hyperparasitaemic patients are an important source of de-novo anti-malarial drug resistance. Their parasite populations are larger, their control of the infection insufficient, and their rates of recrudescence following anti-malarial treatment are high. As use of substandard drugs, poor adherence, unusual pharmacokinetics, and inadequate immune responses are host characteristics, likely to pertain to each recurrence of infection, a small subgroup of patients provides the particular circumstances conducive to de-novo resistance selection and transmission. Conclusion Current dosing recommendations provide a resistance selection opportunity in those patients with low drug levels and high parasite burdens (often children or pregnant women. Patients with

  11. [Historical overview of antimalarials used in Venezuela].

    Zerpa de Artiles, N

    1993-06-01

    A historical review of antimalarials used in Venezuela is presented from the time when the bark of quina was used until the massive distribution of quinine and metoquine by the Dirección de Malariología y Saneamiento Ambiental. The utility of chloroquine and primaquine against sensible parasite isolates and of sulfadoxine-pyrimethamine and quinine, currently used against P. falciparum resistant strains, is thoroughly discussed. The author suggests use of artemisimine and its derivatives as a very promising antimalarial drug. She also stresses the possibility of the application of new antimalaria vaccine against P. falciparum blood states, presently assayed in the country as an additional tool in malaria control programs. PMID:11640680

  12. The antimalarial ferroquine: from bench to clinic

    Biot C.

    2011-08-01

    Full Text Available Ferroquine (FQ, SSR97193 is currently the most advanced organometallic drug candidate and about to complete phase II clinical trials as a treatment for uncomplicated malaria. This ferrocenecontaining compound is active against both chloroquine-susceptible and chloroquine-resistant Plasmodium falciparum and P. vivax strains and/or isolates. This article focuses on the discovery of FQ, its antimalarial activity, the hypothesis of its mode of action, the current absence of resistance in vitro and recent clinical trials.

  13. Potential antimalarial activity of indole alkaloids

    Frederich, Michel; Tits, Monique; Angenot, Luc

    2008-01-01

    New antimalarial treatments are now urgently required, following the emergence of resistance to the most used drugs. Natural products contribute greatly to the therapeutic arsenal in this area, including artemisinin and quinine (and atovaquone, semi-synthetic). Among the natural products, indole alkaloids represent an interesting class of compounds. Screening carried out to date has revealed several substances active in vitro under the micromolar range and with a good selectivity index. This ...

  14. Pricing, distribution, and use of antimalarial drugs.

    Foster, S D

    1991-01-01

    Prices of new antimalarial drugs are targeted at the "travellers' market" in developed countries, which makes them unaffordable in malaria-endemic countries where the per capita annual drug expenditures are US$ 5 or less. Antimalarials are distributed through a variety of channels in both public and private sectors, the official malaria control programmes accounting for 25-30% of chloroquine distribution. The unofficial drug sellers in markets, streets, and village shops account for as much as half of antimalarials distributed in many developing countries. Use of antimalarials through the health services is often poor; drug shortages are common and overprescription and overuse of injections are significant problems. Anxiety over drug costs may prevent patients from getting the necessary treatment for malaria, especially because of the seasonal appearance of this disease when people's cash reserves are very low. The high costs may lead them to unofficial sources, which will sell a single tablet instead of a complete course of treatment, and subsequently to increased, often irrational demand for more drugs and more injections. Increasingly people are resorting to self-medication for malaria, which may cause delays in seeking proper treatment in cases of failure, especially in areas where chloroquine resistance has increased rapidly. Self-medication is now widespread, and measures to restrict the illicit sale of drugs have been unsuccessful. The "unofficial" channels thus represent an unacknowledged extension of the health services in many countries; suggestions are advanced to encourage better self-medication by increasing the knowledge base among the population at large (mothers, schoolchildren, market sellers, and shopkeepers), with an emphasis on correct dosing and on the importance of seeking further treatment without delay, if necessary. PMID:1893512

  15. Antimalarial activity of some Colombian medicinal plants

    Garavito, G. (G.); Rincon, J.; Arteaga, L.; Hata, Y; Bourdy, Geneviève; Gimenez, A.; Pinzon, R.; Deharo, Eric

    2006-01-01

    Antimalarial activity of 10 vegetal extracts (9 ethanolic extracts and 1 crude alkaloid extract), obtained from eight species traditionally used in Colombia to treat malaria symptoms, was evaluated in culture using Plasmodium falciparum chloroquine resistant (FcB2) strain and in vivo on rodent malaria Plasmodium berghei. The activity on ferriprotoporphyrin biomineralization inhibition test (FBIT) was also assessed. Against Plasmodium falciparum, eight extracts displayed good activity Abuta gr...

  16. Extensive Drug Resistance in Malaria and Tuberculosis

    Wongsrichanalai, Chansuda; Varma, Jay K.; Juliano, Jonathan J; Kimerling, Michael E.; MacArthur, John R

    2010-01-01

    Drug resistance in malaria and in tuberculosis (TB) are major global health problems. Although the terms multidrug-resistant TB and extensively drug-resistant TB are precisely defined, the term multidrug resistance is often loosely used when discussing malaria. Recent declines in the clinical effectiveness of antimalarial drugs, including artemisinin-based combination therapy, have prompted the need to revise the definitions of and/or to recategorize antimalarial drug resistance to include ex...

  17. Prevalence of molecular markers of Plasmodium falciparum drug resistance in Dakar, Senegal.

    Wurtz Nathalie; Fall Bécaye; Pascual Aurélie; Diawara Silmane; Sow Kowry; Baret Eric; Diatta Bakary; Fall Khadidiatou B; Mbaye Pape S; Fall Fatou; Diémé Yaya; Rogier Christophe; Bercion Raymond; Briolant Sébastien; Wade Boubacar

    2012-01-01

    Abstract Background As a result of the widespread resistance to chloroquine and sulphadoxine-pyrimethamine, artemisinin-based combination therapy (ACT) (including artemether-lumefantrine and artesunate-amodiaquine) has been recommended as a first-line anti-malarial regimen in Senegal since 2006. Intermittent preventive treatments with anti-malarial drugs based on sulphadoxine-pyrimethamine are also given to children or pregnant women once per month during the transmission season. Since 2006, ...

  18. Poor quality vital anti-malarials in Africa - an urgent neglected public health priority

    Newton Paul N

    2011-12-01

    Full Text Available Abstract Background Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. Methods Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis and botanical investigations were performed. Results Counterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA containing paracetamol (acetaminophen, counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa. Conclusions Criminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems.

  19. Linking Murine and Human Plasmodium falciparum Challenge Models in a Translational Path for Antimalarial Drug Development.

    McCarthy, James S; Marquart, Louise; Sekuloski, Silvana; Trenholme, Katharine; Elliott, Suzanne; Griffin, Paul; Rockett, Rebecca; O'Rourke, Peter; Sloots, Theo; Angulo-Barturen, Iñigo; Ferrer, Santiago; Jiménez-Díaz, María Belén; Martínez, María-Santos; Hooft van Huijsduijnen, Rob; Duparc, Stephan; Leroy, Didier; Wells, Timothy N C; Baker, Mark; Möhrle, Jörg J

    2016-06-01

    Effective progression of candidate antimalarials is dependent on optimal dosing in clinical studies, which is determined by a sound understanding of pharmacokinetics and pharmacodynamics (PK/PD). Recently, two important translational models for antimalarials have been developed: the NOD/SCID/IL2Rγ(-/-) (NSG) model, whereby mice are engrafted with noninfected and Plasmodium falciparum-infected human erythrocytes, and the induced blood-stage malaria (IBSM) model in human volunteers. The antimalarial mefloquine was used to directly measure the PK/PD in both models, which were compared to previously published trial data for malaria patients. The clinical part was a single-center, controlled study using a blood-stage Plasmodium falciparum challenge inoculum in volunteers to characterize the effectiveness of mefloquine against early malaria. The study was conducted in three cohorts (n = 8 each) using different doses of mefloquine. The characteristic delay in onset of action of about 24 h was seen in both NSG and IBSM systems. In vivo 50% inhibitory concentrations (IC50s) were estimated at 2.0 μg/ml and 1.8 μg/ml in the NSG and IBSM models, respectively, aligning with 1.8 μg/ml reported previously for patients. In the IBSM model, the parasite reduction ratios were 157 and 195 for the 10- and 15-mg/kg doses, within the range of previously reported clinical data for patients but significantly lower than observed in the mouse model. Linking mouse and human challenge models to clinical trial data can accelerate the accrual of critical data on antimalarial drug activity. Such data can guide large clinical trials required for development of urgently needed novel antimalarial combinations. (This trial was registered at the Australian New Zealand Clinical Trials Registry [http://anzctr.org.au] under registration number ACTRN12612000323820.). PMID:27044554

  20. Anticancer properties of distinct antimalarial drug classes.

    Rob Hooft van Huijsduijnen

    Full Text Available We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor, emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings.

  1. Antimalarial Activity of Ultra-Short Peptides

    María Yolanda Rios

    2009-12-01

    Full Text Available Ultra-short peptides 1-9 were designed and synthesized with phenylalanine, ornithine and proline amino acid residues and their effect on antimalarial activity was analyzed. On the basis of the IC50 data for these compounds, the effects of nature, polarity, and amino acid sequence on Plasmodium berghei schizont cultures were analyzed too. Tetrapeptides Phe-Orn-Phe-Orn (4 and Lys-Phe-Phe-Orn (5 showed a very important activity with IC50 values of 3.31 and 2.57 μM, respectively. These two tetrapeptides are candidates for subsequent in vivo assays and SARS investigations.

  2. Chitosan-based nanocarriers for antimalarials

    Dreve, Simina; Kacso, Iren; Popa, Adriana; Raita, Oana; Bende, A.; Borodi, Gh.; Bratu, I.

    2012-02-01

    The objective of this research was to synthesize and characterize chitosan-based liquid and solid materials with unique absorptive and mechanical properties as carriers for quinine - one of the most used antimalarial drug. The use of chitosan (CTS) as base in polyelectrolyte complex systems, to prepare solid release systems as sponges is presented. The preparation by double emulsification of CTS hydrogels carrying quinine as anti-malarial drug is reported. The concentration of quinine in the CTS hydrogel was 0.08 mmol. Chitosan - drug loaded hydrogel was used to generate solid sponges by freeze-drying at -610°C and 0.09 atm. Structural investigations of the solid formulations were done by Fourier-transformed infrared spectroscopy (FTIR), ultraviolet-visible spectroscopy (UV-VIS), spectrofluorimetry, differential scanning calorimetry (DSC) and X-ray diffractometry. The results indicated that the drug molecule is forming temporary chelates in CTS hydrogels and sponges. Electron paramagnetic resonance (EPR) demonstrates the presence of free radicals in a wide range and the antioxidant activity for chitosan - drug supramolecular cross-linked assemblies.

  3. In-vitro antimalarial activity of azithromycin against chloroquine sensitive and chloroquine resistant Plasmodium falciparum.

    Biswas S

    2001-10-01

    Full Text Available BAKGROUND: The spread of drug resistance in Plasmodium falciparum has made the situation essential to look into new effective therapeutic agents like antibiotics. Azithromycin is a potential, chemotherapeutic agent which possesses antimalarial activity and favourable pharmacokinetic properties. It is an azalide microbiocide derived semi-synthetically from macrolide erythromycin. Like other antibiotics, the azalide azithromycin has ability to inhibit protein synthesis on 70S ribosomes. SETTINGS: Experimental study. SUBJECTS AND METHODS: The parasiticidal profile was studied in five chloroquine sensitive and five chloroquine resistant P. falciparum isolates obtained from various places of India. The antimalarial activity was evaluated in P. falciparum schizont maturation by short term culture for 24 hours and by exposing the parasites to the drug for 96 hours. Parasites synchronized at ring stage were put for culture with various concentrations of azithromycin dihydrate (0.01-40 micro/ml. RESULTS: At highest concentration (40 micro/ml, parasite growth was inhibited totally in all 10 isolates. Antimalarial activity at 96 hours was greater than at 24 hours in both chloroquine sensitive and resistant parasites, which may indicate that the inhibition of parasite growth may occur at clinically achievable concentration of the drug when parasites were exposed for several asexual cycles. CONCLUSION: Azithromycin shows a potential for eventual use alone or in combination in the treatment of chloroquine sensitive and resistant P. falciparum malaria.

  4. The contribution of microscopy to targeting antimalarial treatment in a low transmission area of Tanzania

    Mwerinde Ombeni

    2006-01-01

    Full Text Available Abstract Background There is a need for improved targeting of antimalarial treatment if artemisinin combination therapy is to be successfully introduced in Africa. This study aimed to explore why malaria slides are requested and how their results guide treatment decisions in an area of low transmission of P. falciparum. Methods Outpatients attending a district hospital in a highland area of Tanzania were studied over a 3-week period. Clinical and social data were collected from patients who had been prescribed an antimalarial or sent for a malaria slide. Hospital slides were re-read later by research methods. Results Of 1,273 consultations 132(10% were treated presumptively for malaria and 214(17% were sent for a malaria slide; only 13(6% of these were reported positive for P. falciparum but 96(48% of the 201 slide-negative cases were treated for malaria anyway. In a logistic regression model, adults (OR 3.86, P Conclusion Progress in targeting of antimalarials in low malaria transmission settings is likely to depend on consistent use of malaria microscopy and on the willingness of health workers to be guided by negative slide results. Further studies are needed to identify how this can be achieved.

  5. Artemisinin anti-malarial drugs in China.

    Guo, Zongru

    2016-03-01

    Discovered by Youyou Tu, one of the 2015 Nobel Prize winners in Physiology or Medicine, together with many other Chinese scientists, artemisinin, artemether and artesunate, as well as other artemisinins, have brought the global anti-malarial treatment to a new era, saving millions of lives all around the world for the past 40 years. The discoveries of artemisinins were carried out beginning from the 1970s, a special period in China, by hundreds of scientists all together under the "whole nation" system. This article focusing on medicinal chemistry research, briefly introduced the discovery and invention course of the scientists according to the published papers, and highlighted their academic contribution and achievements. PMID:27006895

  6. Synthesis and evaluation of antimalarial activity of curcumin derivatives

    ne of the main challenges in the development of new antimalarial drugs is to achieve a viable lead candidate with good pharmacokinetic properties. Curcumin has a broad range of biological activities, including antimalarial activity. Herein, we report the antimalarial activity of six curcumin derivatives (6-12) and an initial analysis of their pharmacokinetic properties. Five compounds have demonstrated potent activity against the P. falciparum in vitro (IC50 values ranging from 1.7 to 15.2 μg mL-1), with moderate or low cytotoxicity against the HeLa cell line. The substitution of the carbonyl group in 6 by a 2,4-dinitrophenylhydrazone group (to afford 11) increases the Selective Index. These preliminary results indicate curcumin derivatives as potential antimalarial compounds. (author)

  7. Antimalarial activity of plumbagin in vitro and in animal models

    Sumsakul, Wiriyaporn; Plengsuriyakarn, Tullayakorn; Chaijaroenkul, Wanna; Viyanant, Vithoon; Karbwang, Juntra; Na-Bangchang, Kesara

    2014-01-01

    Background Plumbagin is the major active constituent in several plants including Plumbago indica Linn. (root). This compound has been shown to exhibit a wide spectrum of biological and pharmacological activities. The present study aimed to evaluate the in vitro and in vivo antimalarial activity of plumbagin including its acute and subacute toxicity in mice. Methods In vitro antimalarial activity of plumbagin against K1 and 3D7 Plasmodium falciparum clones were assessed using SYBR Green I base...

  8. Towards optimal design of anti-malarial pharmacokinetic studies.

    White Nicholas J; Price Ric N; Jamsen Kris M; Simpson Julie A; Lindegardh Niklas; Tarning Joel; Duffull Stephen B

    2009-01-01

    Abstract Background Characterization of anti-malarial drug concentration profiles is necessary to optimize dosing, and thereby optimize cure rates and reduce both toxicity and the emergence of resistance. Population pharmacokinetic studies determine the drug concentration time profiles in the target patient populations, including children who have limited sampling options. Currently, population pharmacokinetic studies of anti-malarial drugs are designed based on logistical, financial and ethi...

  9. The role of anti-malarial drugs in eliminating malaria.

    White, NJ

    2008-01-01

    Effective anti-malarial drug treatment reduces malaria transmission. This alone can reduce the incidence and prevalence of malaria, although the effects are greater in areas of low transmission where a greater proportion of the infectious reservoir is symptomatic and receives anti-malarial treatment. Effective treatment has greater effects on the transmission of falciparum malaria, where gametocytogenesis is delayed, compared with the other human malarias in which peak gametocytaemia and tran...

  10. The role of anti-malarial drugs in eliminating malaria

    White Nicholas J

    2008-01-01

    Abstract Effective anti-malarial drug treatment reduces malaria transmission. This alone can reduce the incidence and prevalence of malaria, although the effects are greater in areas of low transmission where a greater proportion of the infectious reservoir is symptomatic and receives anti-malarial treatment. Effective treatment has greater effects on the transmission of falciparum malaria, where gametocytogenesis is delayed, compared with the other human malarias in which peak gametocytaemia...

  11. Antimalarial activity of Malaysian Plectranthus amboinicus against Plasmodium berghei

    Ramli, Norazsida; Ahamed, Pakeer Oothuman Syed; Elhady, Hassan Mohamed; Taher, Muhammad

    2014-01-01

    Context: Malaria is a mosquito-borne disease caused by parasitic protozoa from the genus of Plasmodium. The protozoans have developed resistance against many of current drugs. It is urgent to find an alternative source of new antimalarial agent. In the effort to discover new antimalarial agents, this research has been conducted on Plectranthus amboinicus. Aims: This study was conducted to evaluate the toxicity and antiplasmodial properties of P. amboinicus. Materials and Methods: Acute oral t...

  12. Expanding the Antimalarial Drug Arsenal—Now, But How?

    MEHLOTRA, RAJEEV K.; Grimberg, Brian T

    2011-01-01

    The number of available and effective antimalarial drugs is quickly dwindling. This is mainly because a number of drug resistance-associated mutations in malaria parasite genes, such as crt, mdr1, dhfr/dhps, and others, have led to widespread resistance to all known classes of antimalarial compounds. Unfortunately, malaria parasites have started to exhibit some level of resistance in Southeast Asia even to the most recently introduced class of drugs, artemisinins. While there is much need, th...

  13. In Vitro Antimalarial Activity of Novel Semisynthetic Nocathiacin I Antibiotics

    Sharma, Indu; Sullivan, Margery; McCutchan, Thomas F.

    2015-01-01

    Presently, the arsenal of antimalarial drugs is limited and needs to be replenished. We evaluated the potential antimalarial activity of two water-soluble derivatives of nocathiacin (BMS461996 and BMS411886) against the asexual blood stages of Plasmodium falciparum. Nocathiacins are a thiazolyl peptide group of antibiotics, are structurally related to thiostrepton, have potent activity against a wide spectrum of multidrug-resistant Gram-positive bacteria, and inhibit protein synthesis. The in...

  14. Inhibition of cytochrome bc1 as a strategy for single-dose, multi-stage antimalarial therapy.

    Stickles, Allison M; Ting, Li-Min; Morrisey, Joanne M; Li, Yuexin; Mather, Michael W; Meermeier, Erin; Pershing, April M; Forquer, Isaac P; Miley, Galen P; Pou, Sovitj; Winter, Rolf W; Hinrichs, David J; Kelly, Jane X; Kim, Kami; Vaidya, Akhil B; Riscoe, Michael K; Nilsen, Aaron

    2015-06-01

    Single-dose therapies for malaria have been proposed as a way to reduce the cost and increase the effectiveness of antimalarial treatment. However, no compound to date has shown single-dose activity against both the blood-stage Plasmodium parasites that cause disease and the liver-stage parasites that initiate malaria infection. Here, we describe a subset of cytochrome bc1 (cyt bc1) inhibitors, including the novel 4(1H)-quinolone ELQ-400, with single-dose activity against liver, blood, and transmission-stage parasites in mouse models of malaria. Although cyt bc1 inhibitors are generally classified as slow-onset antimalarials, we found that a single dose of ELQ-400 rapidly induced stasis in blood-stage parasites, which was associated with a rapid reduction in parasitemia in vivo. ELQ-400 also exhibited a low propensity for drug resistance and was active against atovaquone-resistant P. falciparum strains with point mutations in cyt bc1. Ultimately, ELQ-400 shows that cyt bc1 inhibitors can function as single-dose, blood-stage antimalarials and is the first compound to provide combined treatment, prophylaxis, and transmission blocking activity for malaria after a single oral administration. This remarkable multi-stage efficacy suggests that metabolic therapies, including cyt bc1 inhibitors, may be valuable additions to the collection of single-dose antimalarials in current development. PMID:25918204

  15. Safety, efficacy and population pharmacokinetics of fixed-dose combination of artesunate-mefloquine in the treatment of acute uncomplicated Plasmodium falciparum malaria in India

    Neena Valecha; Bina Srivastava; N. G. Dubhashi; B. H. Krishnamoorthy Rao; Ashwani Kumar; S.K. GHOSH; Jai Prakash Narayan Singh; Kiechel, J. R.; Bhawna Sharma; Jullien, V; A. P. Dash; Taylor, W. R. J.; Anvikar, Anupkumar R.

    2013-01-01

    Background & objectives: India has switched over to artemisinin-based combination therapy (ACT) for the treatment of acute uncomplicated Plasmodium falciparum malaria and the ACT used in the national programme is artesunate + sulphadoxine-pyrimethamine. Since the efficacy of ACT is dependent also on the partner drug, there is a need to evaluate and deploy multiple ACTs. Methods: This multicentre, single-arm, open-label clinical trial was carried out to assess the efficacy, safety and popul...

  16. The search for natural bioactive compounds through a multidisciplinary approach in Bolivia. Part II. Antimalarial activity of some plants used by Mosetene indians.

    Muñoz, V; Sauvain, M; Bourdy, G; Callapa, J; Rojas, I; Vargas, L; Tae, A; Deharo, E

    2000-02-01

    Forty-six different species collected in the Mosetene ethnia, dwelling in the Andean Piedmont of Bolivia, were screened for antimalarial properties. Thirty-three extracts were screened for antimalarial activity in vitro on Plasmodium falciparum chloroquine resistant strain (Indo), and forty-seven extracts were evaluated in vivo on the rodent malaria P. vinckei petteri 279BY. Only two plants are specifically used in combination by the Mosetene against malaria attack (Hymenachne donacifolia and Tesseria integrifolia), but they did not display any activity in vivo at 1000 mg/kg. The in vivo most active extracts were Swietenia macrophylla bark, Trema micrantha bark and Triplaris americana bark, not all of them were used for antimalarial purposes by the Mosetene. The following extracts were moderately active: Jacaratia digitata inner bark and Momordica charantia aerial part (both traditionally used as febrifuge), Kalanchoe pinnate aerial part (used in inflammatory processes), Lunania parviflora twigs and leaves, Phyllanthus acuminatus (used as piscicide), Tynanthus schumannianus fruit (used against diarrhoea), Triumfetta semitrilobata (used as febrifuge, to alleviate kidney and gynecological pain) and finally Solanum mammosum fruit (used against scabies). We present here the results of this screening, emphazing on the in vivo antimalarial activity of the selected plants. The antimalarial in vivo activity of the selected species, in relation with their traditional Mosetene use is then discussed. PMID:10687870

  17. Antimalarial activity of some Colombian medicinal plants.

    Garavito, G; Rincón, J; Arteaga, L; Hata, Y; Bourdy, G; Gimenez, A; Pinzón, R; Deharo, E

    2006-10-11

    Antimalarial activity of 10 vegetal extracts (9 ethanolic extracts and 1 crude alkaloid extract), obtained from eight species traditionally used in Colombia to treat malaria symptoms, was evaluated in culture using Plasmodium falciparum chloroquine resistant (FcB2) strain and in vivo on rodent malaria Plasmodium berghei. The activity on ferriprotoporphyrin biomineralization inhibition test (FBIT) was also assessed. Against Plasmodium falciparum, eight extracts displayed good activity Abuta grandifolia (Mart.) Sandwith (Menispermaceae) leaves, Acacia farnesiana (L.) Willd. (Mimosaceae) leaves, Acnistus arborescens (L.) Schltdl. (Solanaceae) aerial part, Croton leptostachyus Kunth (Euphorbiaceae) aerial part, Piper cumanense Kunth (Piperaceae) fruits and leaves, Piper holtonii C. DC. (Piperaceae) aerial part and Xylopia aromatica (Lam.) Mart. (Annonaceae) bark with IC(50) values ranging from <1 to 2.1 microg/ml, while in the in vivo model only Abuta grandifolia alkaloid crude extract exhibits activity, inhibiting 66% of the parasite growth at 250 mg/kg/day. In the FBIT model, five extracts were active (Abuta grandifolia, Croton leptostachyus, Piper cumanense fruit and leaves and Xylopia aromatica). PMID:16713157

  18. Use and quality of antimalarial drugs in the private sector in Viet Nam.

    Cong, L D; Yen, P. T.; Nhu, T. V.; Binh, L N

    1998-01-01

    This study examines the use and quality of antimalarial drugs in the growing private sector of Viet Nam. The practices of drug vendors (called alternative treatment providers (ATPs)) as well as their stocks and the quality of drugs sold by them, and the local production and distribution of antimalarials were investigated. Antimalarials were sold by the vast majority of ATPs, almost all the common antimalarials being available for sale. The practices and indications for sale, however, varied. ...

  19. Prices and mark-ups on antimalarials: evidence from nationally representative studies in six malaria-endemic countries

    Palafox, Benjamin; Patouillard, Edith; Tougher, Sarah; Goodman, Catherine; Hanson, Kara; Kleinschmidt, Immo; Torres Rueda, Sergio; Kiefer, Sabine; O’Connell, Kate; Zinsou, Cyprien; Phok, Sochea; Akulayi, Louis; Arogundade, Ekundayo; Buyungo, Peter; Mpasela, Felton

    2015-01-01

    The private for-profit sector is an important source of treatment for malaria. However, private patients face high prices for the recommended treatment for uncomplicated malaria, artemisinin combination therapies (ACTs), which makes them more likely to receive cheaper, less effective non-artemisinin therapies (nATs). This study seeks to better understand consumer antimalarial prices by documenting and exploring the pricing behaviour of retailers and wholesalers. Using data collected in 2009–1...

  20. Role of PfATP6 and pfMRP1 in Plasmodium falciparum resistance to antimalarial drugs

    Dahlström, Sabina

    2009-01-01

    Half of the world s population live at risk for malaria and nearly one million people die from the disease every year. The malaria burden is greatest in children and pregnant women in sub-Saharan Africa. As effective treatment is crucial for malaria control, the spread of antimalarial drug resistance has contributed significantly to malaria attributed morbidity and mortality. The current cornerstones in malaria treatment are artemisininbased combination therapy (ACT) for tre...

  1. Probing the Antimalarial Mechanism of Artemisinin and OZ277 (Arterolane) with Nonperoxidic Isosteres and Nitroxyl Radicals ▿

    Fügi, Matthias A.; Wittlin, Sergio; Dong, Yuxiang; Vennerstrom, Jonathan L.

    2009-01-01

    Peroxidic antimalarials such as the semisynthetic artemisinins are critically important in the treatment of drug-resistant malaria. Nevertheless, their peroxide bond-dependent mode of action is still not well understood. Using combination experiments with cultured Plasmodium falciparum cells, we investigated the interactions of the nitroxide radical spin trap, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), and four of its analogs with artemisinin and the ozonide drug development candidate OZ27...

  2. Antimalarial Preclinical Drug Development: A Single Oral Dose of A 5-Carbon-linked Trioxane Dimer Plus Mefloquine Cures Malaria-Infected Mice.

    Moon, Deuk Kyu; Singhal, Vandana; Kumar, Nirbhay; Shapiro, Theresa A; Posner, Gary H

    2009-01-01

    Three new 5-carbon-linked trioxane dimer carboxylate esters have been prepared from the natural trioxane, artemisinin in only 3-steps and 40-50% overall yields. Each one of these new chemical entities is at least as efficacious as the clinically used trioxane antimalarial drug artemether when combined with mefloquine hydrochloride in a low single oral dose cure. PMID:20686674

  3. Anti-malarial Drug Design by Targeting Apicoplasts: New Perspectives

    Avinaba Mukherjee

    2016-03-01

    Full Text Available Objectives: Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the ‘apicoplast’, which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites. Methods: The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs. Results: Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle’s function, which wouldimpede the survival of the parasite. Conclusion: Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug

  4. Antimalarial activity of extracts of Malaysian medicinal plants.

    Najib Nik A Rahman, N; Furuta, T; Kojima, S; Takane, K; Ali Mohd, M

    1999-03-01

    In vitro and in vivo studies revealed that Malaysian medicinal plants, Piper sarmentosum, Andrographis paniculata and Tinospora crispa produced considerable antimalarial effects. Chloroform extract in vitro did show better effect than the methanol extract. The chloroform extract showed complete parasite growth inhibition as low as 0.05 mg/ml drug dose within 24 h incubation period (Andrographis paniculata) as compared to methanol extract of drug dose of 2.5 mg/ml but under incubation time of 48 h of the same plant spesies. In vivo activity of Andrographis paniculata also demonstrated higher antimalarial effect than other two plant species. PMID:10363840

  5. Fighting fire with fire: mass antimalarial drug administrations in an era of antimalarial resistance.

    von Seidlein, Lorenz; Dondorp, Arjen

    2015-06-01

    The emergence and spread of antimalarial resistance has been a major liability for malaria control. The spread of chloroquine-resistant Plasmodium falciparum strains had catastrophic consequences for people in malaria-endemic regions, particularly in sub-Saharan Africa. The recent emergence of artemisinin-resistant P. falciparum strains is of highest concern. Current efforts to contain artemisinin resistance have yet to show success. In the absence of more promising plans, it has been suggested to eliminate falciparum malaria from foci of artemisinin resistance using a multipronged approach, including mass drug administrations. The use of mass drug administrations is controversial as it increases drug pressure. Based on current knowledge it is difficult to conceptualize how targeted malaria elimination could contribute to artemisinin resistance, provided a full treatment course is ensured. PMID:25831482

  6. In vitro Potentiation of Antimalarial Activities by Daphnetin Derivatives Against Plasmodium falciparum

    FANG HUANG; LIN-HUA TANG; LIN-QIAN YU; YI-CHANG NI; QIN-MEI WANG; FA-JUN NAN

    2006-01-01

    Objective To screen the antimalarial compounds of daphnetin derivatives against Plasmodium falciparum in vitro. Method Plasmodium faciparum (FCC1) was cultured in vitro by a modified method of Trager and Jensen. Antimalarial compounds were screened by microscopy-based assay and microfluorimetric method. Results DA79 and DA78 showed potent antimalarial activity against Plasmodium falciparum cultured in vitro. Conclusion Though the relationship between the structures of daphnetin derivatives and their antimalarial activities has not been clarified yet, this study may provide a new direction for discovery of more potential antimalarial compounds.

  7. Andrographolide: A Novel Antimalarial Diterpene Lactone Compound from Andrographis paniculata and Its Interaction with Curcumin and Artesunate

    Kirti Mishra

    2011-01-01

    Full Text Available Andrographolide (AND, the diterpene lactone compound, was purified by HPLC from the methanolic fraction of the plant Andrographis paniculata. The compound was found to have potent antiplasmodial activity when tested in isolation and in combination with curcumin and artesunate against the erythrocytic stages of Plasmodium falciparum in vitro and Plasmodium berghei ANKA in vivo. IC50s for artesunate (AS, andrographolide (AND, and curcumin (CUR were found to be 0.05, 9.1 and 17.4 μM, respectively. The compound (AND was found synergistic with curcumin (CUR and addictively interactive with artesunate (AS. In vivo, andrographolide-curcumin exhibited better antimalarial activity, not only by reducing parasitemia (29%, compared to the control (81%, but also by extending the life span by 2-3 folds. Being nontoxic to the in vivo system this agent can be used as template molecule for designing new derivatives with improved antimalarial properties.

  8. Molecular Farming in Artemisia annua, a Promising Approach to Improve Anti-malarial Drug Production.

    Pulice, Giuseppe; Pelaz, Soraya; Matías-Hernández, Luis

    2016-01-01

    Malaria is a parasite infection affecting millions of people worldwide. Even though progress has been made in prevention and treatment of the disease; an estimated 214 million cases of malaria occurred in 2015, resulting in 438,000 estimated deaths; most of them occurring in Africa among children under the age of five. This article aims to review the epidemiology, future risk factors and current treatments of malaria, with particular focus on the promising potential of molecular farming that uses metabolic engineering in plants as an effective anti-malarial solution. Malaria represents an example of how a health problem may, on one hand, influence the proper development of a country, due to its burden of the disease. On the other hand, it constitutes an opportunity for lucrative business of diverse stakeholders. In contrast, plant biofarming is proposed here as a sustainable, promising, alternative for the production, not only of natural herbal repellents for malaria prevention but also for the production of sustainable anti-malarial drugs, like artemisinin (AN), used for primary parasite infection treatments. AN, a sesquiterpene lactone, is a natural anti-malarial compound that can be found in Artemisia annua. However, the low concentration of AN in the plant makes this molecule relatively expensive and difficult to produce in order to meet the current worldwide demand of Artemisinin Combination Therapies (ACTs), especially for economically disadvantaged people in developing countries. The biosynthetic pathway of AN, a process that takes place only in glandular secretory trichomes of A. annua, is relatively well elucidated. Significant efforts have been made using plant genetic engineering to increase production of this compound. These include diverse genetic manipulation approaches, such as studies on diverse transcription factors which have been shown to regulate the AN genetic pathway and other biological processes. Results look promising; however, further

  9. Pharmaco-Epidemiology of Artemisinin-Based Combination Therapy in the Context of Impact Evaluation of Artemether-Lumefantrine on Malaria Morbidity and Mortality During Programmatic Implementation in Rural Tanzania

    Kabanywanyi, Abdunoor Mulokozi

    2012-01-01

    In sub-Saharan Africa previous efforts to control malaria have proved less successful mostly due to prolonged use of less efficacious mono-therapy drugs to which Plasmodium falciparum has developed drug resistance. In most parts of malaria endemic regions chloroquine (CQ) was found to be poorly effective for several decades but it was still being prescribed until recently. In Tanzania, for instance, P.falciparum was already resistant to CQ in more than 60% of all P. falciparum ...

  10. Prevalence of Single Nucleotide Polymorphisms in the Plasmodium falciparum Multidrug Resistance Gene (Pfmdr-1) in Korogwe District in Tanzania Before and After Introduction of Artemisinin-Based Combination Therapy

    Thomsen, Thomas T; Ishengoma, Deus S; Mmbando, Bruno P;

    2011-01-01

    Abstract. Tanzania implemented artemether-lumefantrine (AL) as the first-line treatment for uncomplicated malaria in November of 2006 because of resistance to sulfadoxine-pyrimethamine. AL remains highly efficacious, but widespread use may soon facilitate emergence of artemisinin tolerance...

  11. Safety, pharmacokinetics and efficacy of artemisinins in pregnancy

    Veronica Ades

    2011-05-01

    Full Text Available Malaria in pregnancy can lead to serious maternal and fetal morbidity and mortality. Access to the most effective antimalarials in pregnancy is essential. Resistance to current therapies is high for all antimalarial therapies except artemisinins. Artemisinin-based combination therapy is current the first line of malaria treatment recommended by the WHO for children, adults and pregnant women in second or third trimester. Due to potential embryotoxicity of artemisinins identified in animal studies, artemisinins are not considered safe for use in first trimester of pregnancy. Artemisinins are more rapidly metabolized in pregnant women, but this does not seem to reduce efficacy. Most studies show very high cure rates for pregnant women. Areas for further research include the safety profile in first trimester of pregnancy, the effect of HIV infection on artemisinin use in pregnancy, the relationship between the pharmacokinetic profile and efficacy, and the use of artemisinin-based combination therapy for intermittent preventive treatment in pregnancy.  

  12. Detecting Counterfeit Antimalarial Tablets by Near-Infrared Spectroscopy

    Counterfeit antimalarial drugs are found in many developing countries, but it is challenging to differentiate between genuine and fakes due to their increasing sophistication. Near-infrared spectroscopy (NIRS) is a powerful tool in pharmaceutical forensics, and we tested this technique for discrim...

  13. In vitro antimalarial activity of novel semisynthetic nocathiacin I antibiotics.

    Sharma, Indu; Sullivan, Margery; McCutchan, Thomas F

    2015-01-01

    Presently, the arsenal of antimalarial drugs is limited and needs to be replenished. We evaluated the potential antimalarial activity of two water-soluble derivatives of nocathiacin (BMS461996 and BMS411886) against the asexual blood stages of Plasmodium falciparum. Nocathiacins are a thiazolyl peptide group of antibiotics, are structurally related to thiostrepton, have potent activity against a wide spectrum of multidrug-resistant Gram-positive bacteria, and inhibit protein synthesis. The in vitro growth inhibition assay was done using three laboratory strains of P. falciparum displaying various levels of chloroquine (CQ) susceptibility. Our results indicate that BMS461996 has potent antimalarial activity and inhibits parasite growth with mean 50% inhibitory concentrations (IC50s) of 51.55 nM for P. falciparum 3D7 (CQ susceptible), 85.67 nM for P. falciparum Dd2 (accelerated resistance to multiple drugs [ARMD]), and 99.44 nM for P. falciparum K1 (resistant to CQ, pyrimethamine, and sulfadoxine). Similar results at approximately 7-fold higher IC50s were obtained with BMS411886 than with BMS461996. We also tested the effect of BMS491996 on gametocytes; our results show that at a 20-fold excess of the mean IC50, gametocytes were deformed with a pyknotic nucleus and growth of stage I to IV gametocytes was arrested. This preliminary study shows a significant potential for nocathiacin analogues to be developed as antimalarial drug candidates and to warrant further investigation. PMID:25779576

  14. The antimalarial drug quinine interferes with serotonin biosynthesis and action

    Islahudin, Farida; Tindall, Sarah M.; Mellor, Ian R.;

    2014-01-01

    The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor of the neurotransmit...

  15. Quality of anti-malarials collected in the private and informal sectors in Guyana and Suriname

    Evans Lawrence

    2012-06-01

    Full Text Available Abstract Background Despite a significant reduction in the number of malaria cases in Guyana and Suriname, this disease remains a major problem in the interior of both countries, especially in areas with gold mining and logging operations, where malaria is endemic. National malaria control programmes in these countries provide treatment to patients with medicines that are procured and distributed through regulated processes in the public sector. However, availability to medicines in licensed facilities (private sector and unlicensed facilities (informal sector is common, posing the risk of access to and use of non-recommended treatments and/or poor quality products. Methods To assess the quality of circulating anti-malarial medicines, samples were purchased in the private and informal sectors of Guyana and Suriname in 2009. The sampling sites were selected based on epidemiological data and/or distance from health facilities. Samples were analysed for identity, content, dissolution or disintegration, impurities, and uniformity of dosage units or weight variation according to manufacturer, pharmacopeial, or other validated method. Results Quality issues were observed in 45 of 77 (58% anti-malarial medicines sampled in Guyana of which 30 failed visual & physical inspection and 18 failed quality control tests. The proportion of monotherapy and ACT medicines failing quality control tests was 43% (13/30 and 11% (5/47 respectively. A higher proportion of medicines sampled from the private sector 34% (11/32 failed quality control tests versus 16% (7/45 in the informal sector. In Suriname, 58 medicines were sampled, of which 50 (86% were Artecom®, the fixed-dose combination of piperaquine-dihydroartemisinin-trimethoprim co-blistered with a primaquine phosphate tablet. All Artecom samples were found to lack a label claim for primaquine, thus failing visual and physical inspection. Conclusions The findings of the studies in both countries point to

  16. Changes in key constituents of clonally propagated Artemisia annua L. during preparation of compressed leaf tablets for possible therapeutic use

    Weathers, Pamela J.; Towler, Melissa J.

    2014-01-01

    Artemisia annua L., long used as a tea infusion in traditional Chinese medicine, produces artemisinin. Although artemisinin is currently used as artemisinin-based combination therapy (ACT) against malaria, oral consumption of dried leaves from the plant showed efficacy and will be less costly than ACT. Many compounds in the plant have some antimalarial activity. Unknown, however, is how these plant components change as leaves are processed into tablets for oral consumption. Here we compared e...

  17. The interplay between drug resistance and fitness in malaria parasites

    Rosenthal, Philip J.

    2013-01-01

    Controlling the spread of antimalarial drug resistance, especially resistance of Plasmodium falciparum to artemisinin-based combination therapies, is a high priority. Available data indicate that, as with other microorganisms, the spread of drug-resistant malaria parasites is limited by fitness costs that frequently accompany resistance. Resistance-mediating polymorphisms in malaria parasites have been identified in putative drug transporters and in target enzymes. The impacts of these polymo...

  18. Drug-Resistant Malaria: The Era of ACT

    Lin, Jessica T.; Juliano, Jonathan J; Wongsrichanalai, Chansuda

    2010-01-01

    As drug-resistant falciparum malaria has continued to evolve and spread worldwide, artemisinin-based combination therapies (ACT) have become the centerpiece of global malaria control over the past decade. This review discusses how advances in antimalarial drug resistance monitoring and rational use of the array of ACTs now available can maximize the impact of this highly efficacious therapy, even as resistance to artemisinins is emerging in Southeast Asia.

  19. New emerging drug-resistant malaria

    Viroj Wiwanitkit

    2010-01-01

    Viroj WiwanitkitWiwanitkit House, Bangkhae, Bangkok ThailandDate of preparation: 20th August 2008Conflict of interest: None declaredClinical question: What is the best treatment for artemisinin-resistant malaria?Results: There is still no better treatment than the presently used artemisinin-based combination therapies. A new antimalarial drug for this problem needs to be found.Implementation: Pitfalls to avoid when treating drug-resistant malaria:Keywords: malaria, drug resistance

  20. Are Patent Medicine Vendors Effective Agents in Malaria Control? Using Lot Quality Assurance Sampling to Assess Quality of Practice in Jigawa, Nigeria

    Sima Berendes; Olusegun Adeyemi; Edward Adekola Oladele; Olusola Bukola Oresanya; Festus Okoh; Joseph J Valadez

    2012-01-01

    BACKGROUND: Patent medicine vendors (PMV) provide antimalarial treatment and care throughout Sub-Saharan Africa, and can play an important role in the fight against malaria. Their close-to-client infrastructure could enable lifesaving artemisinin-based combination therapy (ACT) to reach patients in time. However, systematic assessments of drug sellers' performance quality are crucial if their role is to be managed within the health system. Lot quality assurance sampling (LQAS) could be an eff...

  1. Gas chromatographic method for the determination of lumefantrine in antimalarial finished pharmaceutical products

    Sultan Suleman

    2015-09-01

    Full Text Available A simple method has been developed and validated for quantitative determination of lumefantrine in antimalarial finished pharmaceutical products using gas chromatography coupled to flame ionization detector. Lumefantrine was silylated with N,O–bis(trimethyl-silyltrifluoro-acetamide at 70°C for 30 minutes, and chromatographic separation was conducted on a fused silica capillary (HP-5, 30 m length × 0.32 mm i.d., 0.25 μm film thickness column. Evaluation of the method within analytical quality-by-design principles, including a central composite face-centered design for the sample derivatization process and Plackett–Burman robustness verification of the chromatographic conditions, indicated that the method has acceptable specificity toward excipients and degradants, accuracy [mean recovery = 99.5%, relative standard deviation (RSD = 1.0%], linearity (=0.9986, precision (intraday = 96.1% of the label claim, RSD = 0.9%; interday = 96.3% label claim, RSD = 0.9%, and high sensitivity with detection limits of 0.01 μg/mL. The developed method was successfully applied to analyze the lumefantrine content of marketed fixed-dose combination antimalarial finished pharmaceutical products.

  2. Virtual Screening and Docking Studies of Synthesized Chalcones: Potent Anti-Malarial Drug

    Prashant Singh

    2016-03-01

    Full Text Available A novel series of Chalcones were synthesized targets asexual blood stages of Plasmodium falciparum has been analyzed by utilizing a combination of molecular modeling techniques. Statistically significant structure-based quantitative structure activity relationships models were generated and validated through acceptable predictive ability to support internal and external set of compounds. Screening of most valuable drug among of pre-synthesized drug on the basis of binding efficiency to target receptor was carried out by docking view. Prior this pre-computed Mean IC50 and MIC value were also taken in consideration. The most effective compound on the basis all consideration was found. Previous studies have suggested that Ca2+-ATPase (PfATP6 of P. falciparum is the target of many anti-malarial drugs. However, the mechanism of inhibition of Ca2+- ATPase (PfATP6 is not known. Here we address this issue using bioinformatics tools. We generated a molecular model of Ca2+-ATPase (PfATP6 of P. falciparum and performed molecular docking of all chalcones. Molecular docking programme Glide iGEMDock was used to determine binding feasibility of 52 analogues of chalcones. The comparison of docking parameters showed, more than 5 analogues are better ligands of PfATP6. The binding of chalocones to PFATP6 is mediated by both hydrogen bonding, hydrophobic and polar interactions. Our results suggest that chalcones analogues are promising lead compounds for the development of anti-malarial drugs

  3. Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach

    Wright, Megan H.; Clough, Barbara; Rackham, Mark D.; Rangachari, Kaveri; Brannigan, James A.; Grainger, Munira; Moss, David K.; Bottrill, Andrew R.; Heal, William P.; Broncel, Malgorzata; Serwa, Remigiusz A.; Brady, Declan; Mann, David J.; Leatherbarrow, Robin J.; Tewari, Rita; Wilkinson, Anthony J.; Holder, Anthony A.; Tate, Edward W.

    2014-02-01

    Malaria is an infectious disease caused by parasites of the genus Plasmodium, which leads to approximately one million deaths per annum worldwide. Chemical validation of new antimalarial targets is urgently required in view of rising resistance to current drugs. One such putative target is the enzyme N-myristoyltransferase, which catalyses the attachment of the fatty acid myristate to protein substrates (N-myristoylation). Here, we report an integrated chemical biology approach to explore protein myristoylation in the major human parasite P. falciparum, combining chemical proteomic tools for identification of the myristoylated and glycosylphosphatidylinositol-anchored proteome with selective small-molecule N-myristoyltransferase inhibitors. We demonstrate that N-myristoyltransferase is an essential and chemically tractable target in malaria parasites both in vitro and in vivo, and show that selective inhibition of N-myristoylation leads to catastrophic and irreversible failure to assemble the inner membrane complex, a critical subcellular organelle in the parasite life cycle. Our studies provide the basis for the development of new antimalarials targeting N-myristoyltransferase.

  4. New quinoline derivatives demonstrate a promising antimalarial activity against Plasmodium falciparum in vitro and Plasmodium berghei in vivo.

    Soares, Roberta Reis; da Silva, José Marcio Fernandes; Carlos, Bianca Cecheto; da Fonseca, Camila Campos; de Souza, Laila Salomé Araújo; Lopes, Fernanda Valério; de Paula Dias, Rafael Mafra; Moreira, Paulo Otávio Lourenço; Abramo, Clarice; Viana, Gustavo Henrique Ribeiro; de Pila Varotti, Fernando; da Silva, Adilson David; Scopel, Kézia Katiani Gorza

    2015-06-01

    Malaria continues to be an important public health problem in the world. Nowadays, the widespread parasite resistance to many drugs used in antimalarial therapy has made the effective treatment of cases and control of the disease a constant challenge. Therefore, the discovery of new molecules with good antimalarial activity and tolerance to human use can be really important in the further treatment of the disease. In this study we have investigated the antiplasmodial activity of 10 synthetic compounds derived from quinoline, five of them combined to sulfonamide and five to the hydrazine or hydrazide group. The compounds were evaluated according to their cytotoxicity against HepG2 and HeLa cell lines, their antimalarial activity against CQ-sensitive and CQ-resistant Plasmodium falciparum strains and, finally, their schizonticide blood action in mice infected with Plasmodium berghei NK65. The compounds exhibited no cytotoxic action in HepG2 and HeLa cell lines when tested up to a concentration of 100 μg/mL. In addition, the hydrazine or hydrazide derivative compounds were less cytotoxic against cell lines and more active against CQ-sensitive and CQ-resistant P. falciparum strains, showing high SI (>1000 when SI was calculated using the CC50 from the 3D7 strain as reference). When tested in vivo, the hydrazine derivative 1f compound showed activity against the development of blood parasites similar to that observed with CQ, the reference drug. Interestingly, the 1f compound demonstrated the best LipE value (4.84) among all those tested in vivo. Considering the in vitro and in vivo activities of the compounds studied here and the LipE values, we believe the 1f compound to be the most promising molecule for further studies in antimalarial chemotherapy. PMID:25920564

  5. The Curative and Prophylactic Effects of Xylopic Acid on Plasmodium berghei Infection in Mice

    J. N. Boampong

    2013-01-01

    Full Text Available Efforts have been intensified to search for more effective antimalarial agents because of the observed failure of some artemisinin-based combination therapy (ACT treatments of malaria in Ghana. Xylopic acid, a pure compound isolated from the fruits of the Xylopia aethiopica, was investigated to establish its attributable prophylactic, curative antimalarial, and antipyretic properties. The antimalarial properties were determined by employing xylopic acid (10–100 mg/kg in ICR mice infected with Plasmodium berghei. Xylopic acid exerted significant (P<0.05 effects on P. berghei infection similar to artemether/lumefantrine, the standard drug. Furthermore, it significantly (P<0.05 reduced the lipopolysaccharide- (LPS- induced fever in Sprague-Dawley rats similar to prednisolone. Xylopic acid therefore possesses prophylactic and curative antimalarial as well as antipyretic properties which makes it an ideal antimalarial agent.

  6. Natural products as starting points for future anti-malarial therapies: going back to our roots?

    Wells Timothy NC

    2011-03-01

    Full Text Available Abstract Background The discovery and development of new anti-malarials are at a crossroads. Fixed dose artemisinin combination therapy is now being used to treat a hundred million children each year, with a cost as low as 30 cents per child, with cure rates of over 95%. However, as with all anti-infective strategies, this triumph brings with it the seeds of its own downfall, the emergence of resistance. It takes ten years to develop a new medicine. New classes of medicines to combat malaria, as a result of infection by Plasmodium falciparum and Plasmodium vivax are urgently needed. Results Natural product scaffolds have been the basis of the majority of current anti-malarial medicines. Molecules such as quinine, lapachol and artemisinin were originally isolated from herbal medicinal products. After improvement with medicinal chemistry and formulation technologies, and combination with other active ingredients, they now make up the current armamentarium of medicines. In recent years advances in screening technologies have allowed testing of millions of compounds from pharmaceutical diversity for anti-malarial activity in cellular assays. These initiatives have resulted in thousands of new sub-micromolar active compounds – starting points for new drug discovery programmes. Against this backdrop, the paucity of potent natural products identified has been disappointing. Now is a good time to reflect on the current approach to screening herbal medicinal products and suggest revisions. Nearly sixty years ago, the Chinese doctor Chen Guofu, suggested natural products should be approached by dao-xing-ni-shi or ‘acting in the reversed order’, starting with observational clinical studies. Natural products based on herbal remedies are in use in the community, and have the potential unique advantage that clinical observational data exist, or can be generated. The first step should be the confirmation and definition of the clinical activity of herbal

  7. Discovery and optimisation studies of antimalarial phenotypic hits

    Mital, Alka; Murugesan, Dinakaran; Kaiser, Marcel; Yeates, Clive; Gilbert, Ian H.

    2015-01-01

    There is an urgent need for the development of new antimalarial compounds. As a result of a phenotypic screen, several compounds with potent activity against the parasite Plasmodium falciparum were identified. Characterization of these compounds is discussed, along with approaches to optimise the physicochemical properties. The in vitro antimalarial activity of these compounds against P. falciparum K1 had EC50 values in the range of 0.09–29 μM, and generally good selectivity (typically >100-fold) compared to a mammalian cell line (L6). One example showed no significant activity against a rodent model of malaria, and more work is needed to optimise these compounds. PMID:26408453

  8. Potential antimalarials from African natural products: a review

    Bashir Lawal

    2015-12-01

    Full Text Available Ethnopharmacological relevance: Malaria remains an overwhelming infectious disease with significant health challenges in African and other endemic countries globally. Resistance to antimalarial drugs has become one of the most momentous challenges to human health and thus has necessitated the hunt for new and effective drugs. Consequently, few decades have witnessed a surfeit of research geared to validate the effectiveness of commonly used traditionally medicines against malaria fever. The present review work focuses on documenting natural products from African whose activity has been reported in-vivo or invi-tro against malaria parasite. Methods: Literature was collected using electronic search of published articles (Google Scholar, PubMed, Medline, Sciencedirect, Science domain that report on antiplasmodial activity of natural products from differernts Africa region. Results: A Total of 652 plant taxa from 146 families, 134 isolated antimalarial compounds from 39 plants species, 2 herbal formulations and 4 insect/products were found to be reported in literature from 1996 to 2015. Plants species from family Asteraceae (11.04%, Fababceae (8.128%, Euphorbiaceae (5.52%, Rubiaceas (5.52% and Apocyanaceae (5.214%, have received more scientific validation than others. Conclusion: African natural products possess remarkable healing properties as revealed in the various citations as promising antimalarial agents. Some of these natural products from Africa demonstrate high, promising or low activities against plasmodium parasite. This study also shows that natural products from Africa have a huge amount of novel antimalarial compounds that could serve as a leads for the development of new and effective antiplasmodial drugs. However, in a view of bridging the gap in knowledge, clinical validation of these natural products is of paramount importance. [J Intercult Ethnopharmacol 2015; 4(4.000: 318-343

  9. Drug resistance genomics of the antimalarial drug artemisinin

    Elizabeth A Winzeler; Manary, Micah J

    2014-01-01

    Across the globe, over 200 million annual malaria infections result in up to 660,000 deaths, 77% of which occur in children under the age of five years. Although prevention is important, malaria deaths are typically prevented by using antimalarial drugs that eliminate symptoms and clear parasites from the blood. Artemisinins are one of the few remaining compound classes that can be used to cure multidrug-resistant Plasmodium falciparum infections. Unfortunately, clinical trials from Southeast...

  10. Antimicrobial peptides: a new class of antimalarial drugs?

    Nuno eVale

    2014-12-01

    Full Text Available A range of antimicrobial peptides (AMP exhibit activity on malaria parasites, Plasmodium spp, in their blood or mosquito stages, or both. These peptides include a diverse array of both natural and synthetic molecules varying greatly in size, charge, hydrophobicity and secondary structure features. Along with an overview of relevant literature reports regarding AMP that display antiplasmodial activity, this review makes a few considerations about those molecules as a potential new class of antimalarial drugs.

  11. Antimalarial drug resistance in Africa: key lessons for the future

    Takala-Harrison, Shannon; Laufer, Miriam K

    2015-01-01

    Drug-resistant parasites repeatedly arise as a result of widespread use of antimalarial drugs and have contributed significantly to the failure to control and eradicate malaria throughout the world. In this review, we describe the spread of resistance to chloroquine and sulfadoxine–pyrimethamine, two old drugs that are no longer used owing to high rates of resistance, and examine the effect of the removal of drug pressure on the survival of resistant parasites. Artemisinin-resistant malaria i...

  12. Intermittent Preventive Antimalarial Treatment for Children with Anaemia.

    Athuman, Mwaka; Kabanywanyi, Abdunoor M; Rohwer, Anke C

    2015-01-01

    Background Anaemia is a global public health problem. Children under five years of age living in developing countries (mostly Africa and South-East Asia) are highly affected. Although the causes for anaemia are multifactorial, malaria has been linked to anaemia in children living in malaria-endemic areas. Administering intermittent preventive antimalarial treatment (IPT) to children might reduce anaemia, since it could protect children from new Plasmodium parasite infection (the parasites tha...

  13. Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine

    Islahudin, Farida; Khozoie, Combiz; Bates, Steven; Ting, Kang-Nee; Pleass, Richard J.; Avery, Simon V.

    2013-01-01

    Chloroquine (CQ) has been a mainstay of antimalarial drug treatment for several decades. Additional therapeutic actions of CQ have been described, including some reports of fungal inhibition. Here we investigated the action of CQ in fungi, including the yeast model Saccharomyces cerevisiae. A genomewide yeast deletion strain collection was screened against CQ, revealing that bck1Δ and slt2Δ mutants of the cell wall integrity pathway are CQ hypersensitive. This phenotype was rescued with sorbi...

  14. Antimalarial effect of agmatine on Plasmodium berghei K173 strain

    SURui-Bin; WEIXiao-Li; LIUYin; LIJin

    2003-01-01

    AIM: To study the antimalarial effect of agmatine (Agm) on chloroquine-susceptible Plasmodium berghei K173strain (S strain) and the P berghei K173 resistant strain (R strain). METHODS: The antimalarial effects of Agm onP berghei K173 S strain and R strain were evaluated by Peters 4-d suppression test in mice. RESULTS: Agm(12.5-200 mg/kg,ig,daily) decreased the parasitemia for both P berghei K173 S strain (IC50=139 mg/kg) and Rstrain (IC50=126mg/kg) in mice. Subcutaneous injection (sc) of Agm (5-40mg/kg,tid) showed relatively strongerantimalarial effect than intragastric gavage (IC50=30 mg/kg) in P berghei K 173 S strain. Spermidine antagonized theantimalarial effect of Agm for P berghei K173 S strain and R strain. Agm did not reverse the chloroquine resistanceof P berghei K173 S strain, dl-α-Difluoromethylornithine (DFMO, sc) decreased the parasitemia of P BergheiK173 S strain and this effect was antagonized by spermidine. CONCLUSION: Agm has an antimalarial effect andthe mechanism is related to its inhibition of polyamine synthesis.

  15. Antimalarials and the fight against malaria in Brazil

    Luiz MA Carmargo

    2009-04-01

    Full Text Available Luiz MA Carmargo1, Saulo de Oliveira2, Sergio Basano3, Célia RS Garcia21ICBV-USP, Monte Negro, Rondônia, Brasil; 2Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, SP, Brazil; 3CEMETRON, Porto Velho, Guaporé, BrazilAbstract: Malaria, known as the “fevers,” has been treated for over three thousand years in China with extracts of plants of the genus Artemisia (including Artemisia annua, A. opiacea, and A. lancea from which the active compound is artemisin, a sesquiterpene that is highly effective in the treatment of the disease, especially against young forms of the parasite. South American Indians in the seventeenth century already used an extract of the bark of chinchona tree, commonly named “Jesuits’ powder.” Its active compound was isolated in 1820 and its use spread all over the world being used as a prophylactic drug during the construction of the Madeira–Mamoré railroad in the beginning of the twentieth century. During the 1920s to the 1940s, new antimalarial drugs were synthesized to increase the arsenal against this parasite. However, the parasite has presented systematic resistence to conventional antimalarial drugs, driving researchers to find new strategies to treat the disease. In the present review we discuss how Brazil treats Plasmodium-infected patients.Keywords: Plasmodium falciparum, malaria, antimalarials, calcium

  16. Anti-Malarial Plants of Jonai, India: an Ethnobotanical Approach

    Tonlong WANGPAN

    2016-03-01

    Full Text Available North-East India represents a unique ecosystem with treasured medicinal plant wealth closely related with Folk medicines. A large number of plants having medicinal properties and their folk uses have remained confined to the natives of this region. The tribal community of Jonai, Assam was explored to expose the indigenous herbal remedy for malaria. Sixteen antimalarial plants belonging to 13 families were reported. The analysis revealed highest fidelity level (FL value for Ajuga integrifolia (100% followed by Ricinus communis (94%, Alstonia scholaris (88%, Oroxylum indicum (86% and Achyranthes aspera (82%. The percentage of respondent’s knowledge (PRK about anti-malarial plants showed Alstonia scholaris as the most commonly known antimalarial species (53% within this region. Preference ranking (PR unveiled eight species to be very effective against malarial parasite, which includes Allium sativum, Artemisia indica, Azadirachta indica, Carica papaya, Clerodendrum glandulosum, Ocimum tenuiflorum, Oroxylum indicum, Piper longum and Piper nigrum. All medicine preparations are made using water as the medium and are orally administered in the form of crude extract, powder, juice and decoction. Overall analysis suggested Ajuga integrifolia, Achyranthes aspera, Alstonia scholaris, Artemisia indica, Oroxylum indicum and Ricinus communis to be used for the development of novel, economical, effective and ecofriendly herbal formulations for healthcare management.

  17. Effect of antimalarial drugs on stimulation and interleukin 2 production of human lymphocytes

    Bygbjerg, I C; Svenson, M; Theander, T G;

    1987-01-01

    Effect of pyrimethamine, an antimalarial antifolate, and of mefloquine, chloroquine, and quinine, which belong to the quinoline group of antimalarials, on proliferation and interleukin 2 (IL-2) production of human lymphocytes was studied in vitro. Pyrimethamine at concentrations above therapeutic...... action on human mononuclear cells of the various antimalarial drugs and the potential adverse effects of antimalarial chemotherapy are discussed....... at concentrations twice as high as those required to suppress lymphocyte proliferation. Addition of exogenous IL-2 only partially reversed the suppressive effect on lymphocyte proliferation. Delayed addition of the quinolines decreased their suppressive effect, but not completely. The mechanisms of...

  18. Antimalarial activity and toxicity of Garcinia mangostana Linn.

    Ratchanu; Bunyong; Wanna; Chaijaroenkul; Tullayakorn; Plengsuriyakarn; Kesara; Na-Bangchang

    2014-01-01

    Objective:To investigate the antimalarial activity and toxicity of the crude ethanolic extract of its pericarp both in vitro and in vim.Methods:The antimalarial activity of Gareinja mangostana(G.mangostana)Linn.extract against 3D7 and Kl Plasmodium falciparum(P.falciparum)clone were assessed using SYBR green I-based assay.A 4-day suppressive test of Plasmodium berghei{P.berghei)infected mouse was performed to investigate in vivo antimalarial activity.Results:The in vitro antimalarial activity was seleclive(SI>5?and classified as weak and good lo moderate activity against both 3D7 and K1 P.falciparum,clones with median IC50(range)values of 11.12(10.94-11.29)and 7.54(6.80-7.68)μg/mL,respectively.The extract was considered nontoxic to mice.The maximum tolerated doses for acute and subacute toxicity in mice were 5 000and 2 000 mg/kg,respectively.Median(range)parasite density on day 4 of the negative control group(25%Tween-80),mice treated with 250,500,1000,and 2 000 mg/kg body weight of the extract,and 10 mg/kg body weight of chloroquine for 14 d were 12.8(12.2-13.7),11.4(9.49-13.8),11.6(9.9-12.5),11.7(10.6-12.8),10.9(9.4-11.6)and 0(0-0)%respectively.Parasite density on day 4in the control group treated with Tween-80 was higher than the groups treated with chloroquine and all dose levels of the extract.Conclusions:G.mangostana linn,showed weak antimalarial activity of the extract both in vitro and in vivo could be due to limitation of absorption of the active compounds.

  19. Hemolysis after Oral Artemisinin Combination Therapy for Uncomplicated Plasmodium falciparum Malaria

    Lingscheid, Tilman; Steiner, Florian; Stegemann, Miriam S.; Bélard, Sabine; Menner, Nikolai; Pongratz, Peter; Kim, Johanna; von Bernuth, Horst; Mayer, Beate; Damm, Georg; Seehofer, Daniel; Salama, Abdulgabar; Suttorp, Norbert; Zoller, Thomas

    2016-01-01

    Episodes of delayed hemolysis 2–6 weeks after treatment of severe malaria with intravenous artesunate have been described. We performed a prospective observational study of patients with uncomplicated malaria to investigate whether posttreatment hemolysis also occurs after oral artemisinin-based combination therapy. Eight of 20 patients with uncomplicated malaria who were given oral artemisinin-based combination therapy met the definition of posttreatment hemolysis (low haptoglobin level and increased lactate dehydrogenase level on day 14). Five patients had hemolysis persisting for 1 month. Patients with posttreatment hemolysis had a median decrease in hemoglobin level of 1.3 g/dL (interquartile range 0.3–2.0 g/dL) in the posttreatment period, and patients without posttreatment hemolysis had a median increase of 0.3 g/dL (IQR −0.1 to 0.7 g/dL; p = 0.002). These findings indicate a need for increased vigilance for hemolytic events in malaria patients, particularly those with predisposing factors for anemia. PMID:27434054

  20. The Interactions of P-Glycoprotein with Antimalarial Drugs, Including Substrate Affinity, Inhibition and Regulation.

    Senarathna, S M D K Ganga; Page-Sharp, Madhu; Crowe, Andrew

    2016-01-01

    The combination of passive drug permeability, affinity for uptake and efflux transporters as well as gastrointestinal metabolism defines net drug absorption. Efflux mechanisms are often overlooked when examining the absorption phase of drug bioavailability. Knowing the affinity of antimalarials for efflux transporters such as P-glycoprotein (P-gp) may assist in the determination of drug absorption and pharmacokinetic drug interactions during oral absorption in drug combination therapies. Concurrent administration of P-gp inhibitors and P-gp substrate drugs may also result in alterations in the bioavailability of some antimalarials. In-vitro Caco-2 cell monolayers were used here as a model for potential drug absorption related problems and P-gp mediated transport of drugs. Artemisone had the highest permeability at around 50 x 10-6 cm/sec, followed by amodiaquine around 20 x 10-6 cm/sec; both mefloquine and artesunate were around 10 x 10-6 cm/sec. Methylene blue was between 2 and 6 x 10-6 cm/sec depending on the direction of transport. This 3 fold difference was able to be halved by use of P-gp inhibition. MRP inhibition also assisted the consolidation of the methylene blue transport. Mefloquine was shown to be a P-gp inhibitor affecting our P-gp substrate, Rhodamine 123, although none of the other drugs impacted upon rhodamine123 transport rates. In conclusion, mefloquine is a P-gp inhibitor and methylene blue is a partial substrate; methylene blue may have increased absorption if co-administered with such P-gp inhibitors. An upregulation of P-gp was observed when artemisone and dihydroartemisinin were co-incubated with mefloquine and amodiaquine. PMID:27045516

  1. Adherence of community caretakers of children to pre-packaged antimalarial medicines (HOMAPAK) among internally displaced people in Gulu district, Uganda.

    Opwonya John; Ojok Naptalis; Kolaczinski Jan H; Meek Sylvia; Collins Andrew

    2006-01-01

    Abstract Background In 2002, home-based management of fever (HBMF) was introduced in Uganda, to improve access to prompt, effective antimalarial treatment of all fevers in children under 5 years. Implementation is through community drug distributors (CDDs) who distribute pre-packaged chloroquine plus sulfadoxine-pyrimethamine (HOMAPAK®) free of charge to caretakers of febrile children. Adherence of caretakers to this regimen has not been studied. Methods A questionnaire-based survey combined ...

  2. In vivo antimalarial activity of extracts of Tanzanian medicinal plants used for the treatment of malaria.

    Nondo, Ramadhani S O; Erasto, Paul; Moshi, Mainen J; Zacharia, Abdallah; Masimba, Pax J; Kidukuli, Abdul W

    2016-01-01

    Plants used in traditional medicine have been the source of a number of currently used antimalarial medicines and continue to be a promising resource for the discovery of new classes of antimalarial compounds. The aim of this study was to evaluate in vivo antimalarial activity of four plants; Erythrina schliebenii Harms, Holarrhena pubescens Buch-Ham, Phyllanthus nummulariifolius Poir, and Caesalpinia bonducella (L.) Flem used for treatment of malaria in Tanzania. In vivo antimalarial activity was assessed using the 4-day suppressive antimalarial assay. Mice were infected by injection via tail vein with 2 × 10(7) erythrocytes infected with Plasmodium berghei ANKA. Extracts were administered orally, once daily, for a total of four daily doses from the day of infection. Chloroquine (10 mg/kg/day) and solvent (5 mL/kg/day) were used as positive and negative controls, respectively. The extracts of C. bonducella, E. schliebenii, H. pubescens, and P. nummulariifolius exhibited dose-dependent suppression of parasite growth in vivo in mice, with the highest suppression being by C. bonducella extract. While each of the plant extracts has potential to yield useful antimalarial compounds, the dichloromethane root extract of C. bonducella seems to be the most promising for isolation of active antimalarial compound(s). In vivo antimalarial activity presented in this study supports traditional uses of C. bonducella roots, E. schliebenii stem barks, H. pubescens roots, and P. nummulariifolius for treatment of malaria. PMID:27144154

  3. Antimalarial activity of Malaysian Plectranthus amboinicus against Plasmodium berghei

    Norazsida Ramli

    2014-01-01

    Full Text Available Context: Malaria is a mosquito-borne disease caused by parasitic protozoa from the genus of Plasmodium. The protozoans have developed resistance against many of current drugs. It is urgent to find an alternative source of new antimalarial agent. In the effort to discover new antimalarial agents, this research has been conducted on Plectranthus amboinicus. Aims: This study was conducted to evaluate the toxicity and antiplasmodial properties of P. amboinicus. Materials and Methods: Acute oral toxicity dose at 5000 mg/kg was conducted to evaluate the safety of this extract. Twenty mice were divided into control and experimental group. All the mice were observed for signs of toxicity, mortality, weight changes and histopathological changes. Antimalarial activity of different extract doses of 50, 200, 400 and 1000 mg/kg were tested in vivo against Plasmodium berghei infections in mice (five mice for each group during early, established and residual infections. Results: The acute oral toxicity test revealed that no mortality or evidence of adverse effects was seen in the treated mice. The extract significantly reduced the parasitemia by the 50 (P = 0.000, 200 (P = 0.000 and 400 mg/kg doses (P = 0.000 in the in vivo prophylactic assay. The percentage chemo-suppression was calculated as 83.33% for 50 mg/kg dose, 75.62% for 200 mg/kg dose and 90.74% for 400 mg/kg dose. Body weight of all treated groups; T1, T2, T3 and T4 also showed enhancement after 7 days posttreatment. Statistically no reduction of parasitemia calculated for curative and suppressive test. Conclusion: Thus, this extract may give a promising agent to be used as a prophylactic agent of P. berghei infection.

  4. Proteomics analysis of antimalarial targets of Garcinia mangostana Linn.

    Wanna Chaijaroenkul; Artitiya Thiengsusuk; Kanchana Rungsihirunrat; Stephen Andrew Ward; Kesara Na-Bangchang

    2014-01-01

    Objective: To investigate possible protein targets for antimalarial activity of Garcinia mangostana Linn. (G. mangostana) (pericarp) in 3D7 Plasmodium falciparum clone using 2-dimensional electrophoresis and liquid chromatography mass-spectrometry (LC/MS/MS). Methods: 3D7 Plasmodium falciparum was exposed to the crude ethanolic extract of G. mangostana Linn. (pericarp) at the concentrations of 12μg/mL (IC50 level: concentration that inhibits parasite growth by 50%) and 30 μg/mL (IC90 level...

  5. Home treatment of febrile children with antimalarial drugs in Togo.

    Deming, M. S.; Gayibor, A.; Murphy, K; Jones, T. S.; Karsa, T.

    1989-01-01

    In Togo, the principal strategy for preventing death from malaria in children is prompt treatment of fever with antimalarial drugs. A household survey was conducted in a rural area of south-central Togo in which information was collected from mothers on the treatment received by 507 children under 5 years of age who, according to their mothers, had recently had fever. Altogether, 20% of the children (95% confidence interval (Cl): 15-25%) were seen at a health centre during their illness, whil...

  6. Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance

    Dea Shahinas

    2013-02-01

    Full Text Available Malaria continues to exact a great human toll in tropical settings. Antimalarial resistance is rife and the parasite inexorably develops mechanisms to outwit our best drugs, including the now first-line choice, artesunate. Novel strategies to circumvent resistance are needed. Here we detail drug development focusing on heat shock protein 90 and its central role as a chaperone. A growing body of evidence supports the role for Hsp90 inhibitors as adjunctive drugs able to restore susceptibility to traditionally efficacious compounds like chloroquine.

  7. Mono- and bis-thiazolium salts have potent antimalarial activity.

    Hamzé, Abdallah; Rubi, Eric; Arnal, Pascal; Boisbrun, Michel; Carcel, Carole; Salom-Roig, Xavier; Maynadier, Marjorie; Wein, Sharon; Vial, Henri; Calas, Michèle

    2005-05-19

    Three new series comprising 24 novel cationic choline analogues and consisting of mono- or bis (N or C-5-duplicated) thiazolium salts have been synthesized. Bis-thiazolium salts showed potent antimalarial activity (much superior to monothiazoliums). Among them, bis-thiazolium salts 12 and 13 exhibited IC(50) values of 2.25 nM and 0.65 nM, respectively, against P. falciparum in vitro. These compounds also demonstrated good in vivo activity (ED(50)

  8. Cloroquine – miscellaneous properties of the antimalarial drug

    Robert Jarzyna

    2002-06-01

    Full Text Available Chloroquine is a drug with over 60 years of safe clinical use in the treatment of malaria. The multiple mechanisms of chloroquine action have appeared to be useful in the therapy of many miscellaneous disorders well beyond its original antimalarial purposes. This paper is focused on the application of chloroquine for the treatment of malaria, porphyria cutanea tarda, rheumatoid arthritis, palindromic rheumatism and lupus. The possibility of the use of chloroquine in the therapy of other disorders such as diabetes mellitus, AIDS, hyperlipidemia, sarcoidosis, hypercalcemia, and melanoma is reviewed. Mechanisms of action of the drug as well as side effects on metabolism are discussed in view of recent discoveries.

  9. Proteomics analysis of antimalarial targets of Garcinia mangostana Linn.

    Wanna Chaijaroenkul; Artitiya Thiengsusuk; Kanchana Rungsihirunrat; Stephen Andrew Ward; Kesara Na-Bangchang

    2014-01-01

    Objective: To investigate possible protein targets for antimalarial activity of Garcinia mangostana Linn. (G. mangostana) (pericarp) in 3D7 Plasmodium falciparum clone using 2-dimensional electrophoresis and liquid chromatography mass-spectrometry (LC/MS/MS). Methods: 3D7 Plasmodium falciparum was exposed to the crude ethanolic extract of G.mangostana Linn. (pericarp) at the concentrations of 12µg/mL (IC50 level: concentration that inhibits parasite growth by 50%) and 30 µg/mL (IC90 level: concentration that inhibits parasite growth by 90%) for 12 h. Parasite proteins were separated by 2-dimensional electrophoresis and identified by LC/MS/MS.Results:At the IC50 concentration, about 82% of the expressed parasite proteins were matched with the control (non-exposed), while at the IC90 concentration, only 15% matched proteins were found. The selected protein spots from parasite exposed to the plant extract at the concentration of 12 µg/mL were identified as enzymes that play role in glycolysis pathway, i.e., phosphoglycerate mutase putative, L-lactate dehydrogenase/glyceraldehyde-3-phosphate dehydrogenase, and fructose-bisphosphate aldolase/phosphoglycerate kinase. The proteosome was found in parasite exposed to 30 µg/mL of the extract.Conclusions:Results suggest that proteins involved in the glycolysis pathway may be the targets for antimalarial activity of G. mangostana Linn. (pericarp).

  10. Proteomics analysis of antimalarial targets of Garcinia mangostana Linn.

    Wanna; Chaijaroenkul; Artitiya; Thiengsusuk; Kanchana; Rungsihirunrat; Stephen; Andrew; Ward; Kesara; Na-Bangchang

    2014-01-01

    Objective:To investigate possible protein targets for antimalarial activity of Garcina mangostana Linn.(G.mangostana)(pericarp)in 3D7 Plasmodium falciparum clone using 2-dimensional electrophoresis and liquid chromatography mass-spectrometry(LC/MS/MS).Methods:3D7 Plasmodium falciparum was exposed to the crude ethanolic extract of G.mangostana Linn.(pericarp)at the concentrations of 12μg/mL(1C50level:concentration that inhibits parasite growth by 50%)and 30μg/mL(1C90level:concentration that inhibits parasite growth by 90%)for 12 h.Parasite proteins were separated by 2-dimensional electrophoresis and identified by LC/MS/MS.Results:At the IC50concentration,about 82%of the expressed parasite proteins were matched with the control(non-exposed),while at the IC90concentration,only 15%matched proteins were found.The selected protein spots from parasite exposed to the plant extract at the concentration of 12μg/mL were identified as eneymes that play role in glycolysis pathway,i.e.,phosphoglyeerate mutase putative,L-lactate dehydrogenase/glyceraldehyde-3-phosphate dehydrogenase,and fruetose-bisphosphate aldolase/phosphoglyeerate kinase.The proteosome was found in parasite exposed to 30μg/mL of the extract.Conclusions:Results suggest that proteins involved in the glycolysis pathway may be the targets for antimalarial activity of G.mangostana Linn.(pericarp).

  11. Antimalarials and the fight against malaria in Brazil.

    Carmargo, Luiz Ma; de Oliveira, Saulo; Basano, Sergio; Garcia, Célia Rs

    2009-08-01

    Malaria, known as the "fevers," has been treated for over three thousand years in China with extracts of plants of the genus Artemisia (including Artemisia annua, A. opiacea, and A. lancea) from which the active compound is artemisin, a sesquiterpene that is highly effective in the treatment of the disease, especially against young forms of the parasite. South American Indians in the seventeenth century already used an extract of the bark of chinchona tree, commonly named "Jesuits' powder." Its active compound was isolated in 1820 and its use spread all over the world being used as a prophylactic drug during the construction of the Madeira-Mamoré railroad in the beginning of the twentieth century. During the 1920s to the 1940s, new antimalarial drugs were synthesized to increase the arsenal against this parasite. However, the parasite has presented systematic resistence to conventional antimalarial drugs, driving researchers to find new strategies to treat the disease. In the present review we discuss how Brazil treats Plasmodium-infected patients. PMID:19753125

  12. Discovery of potent, novel, non-toxic anti-malarial compounds via quantum modelling, virtual screening and in vitro experimental validation

    Kaludov Nikola

    2011-09-01

    Full Text Available Abstract Background Developing resistance towards existing anti-malarial therapies emphasize the urgent need for new therapeutic options. Additionally, many malaria drugs in use today have high toxicity and low therapeutic indices. Gradient Biomodeling, LLC has developed a quantum-model search technology that uses quantum similarity and does not depend explicitly on chemical structure, as molecules are rigorously described in fundamental quantum attributes related to individual pharmacological properties. Therapeutic activity, as well as toxicity and other essential properties can be analysed and optimized simultaneously, independently of one another. Such methodology is suitable for a search of novel, non-toxic, active anti-malarial compounds. Methods A set of innovative algorithms is used for the fast calculation and interpretation of electron-density attributes of molecular structures at the quantum level for rapid discovery of prospective pharmaceuticals. Potency and efficacy, as well as additional physicochemical, metabolic, pharmacokinetic, safety, permeability and other properties were characterized by the procedure. Once quantum models are developed and experimentally validated, the methodology provides a straightforward implementation for lead discovery, compound optimizzation and de novo molecular design. Results Starting with a diverse training set of 26 well-known anti-malarial agents combined with 1730 moderately active and inactive molecules, novel compounds that have strong anti-malarial activity, low cytotoxicity and structural dissimilarity from the training set were discovered and experimentally validated. Twelve compounds were identified in silico and tested in vitro; eight of them showed anti-malarial activity (IC50 ≤ 10 μM, with six being very effective (IC50 ≤ 1 μM, and four exhibiting low nanomolar potency. The most active compounds were also tested for mammalian cytotoxicity and found to be non-toxic, with a

  13. Prices and mark-ups on antimalarials: evidence from nationally representative studies in six malaria-endemic countries.

    Palafox, Benjamin; Patouillard, Edith; Tougher, Sarah; Goodman, Catherine; Hanson, Kara; Kleinschmidt, Immo; Torres Rueda, Sergio; Kiefer, Sabine; O'Connell, Kate; Zinsou, Cyprien; Phok, Sochea; Akulayi, Louis; Arogundade, Ekundayo; Buyungo, Peter; Mpasela, Felton; Poyer, Stephen; Chavasse, Desmond

    2016-03-01

    The private for-profit sector is an important source of treatment for malaria. However, private patients face high prices for the recommended treatment for uncomplicated malaria, artemisinin combination therapies (ACTs), which makes them more likely to receive cheaper, less effective non-artemisinin therapies (nATs). This study seeks to better understand consumer antimalarial prices by documenting and exploring the pricing behaviour of retailers and wholesalers. Using data collected in 2009-10, we present survey estimates of antimalarial retail prices, and wholesale- and retail-level price mark-ups from six countries (Benin, Cambodia, the Democratic Republic of Congo, Nigeria, Uganda and Zambia), along with qualitative findings on factors affecting pricing decisions. Retail prices were lowest for nATs, followed by ACTs and artemisinin monotherapies (AMTs). Retailers applied the highest percentage mark-ups on nATs (range: 40% in Nigeria to 100% in Cambodia and Zambia), whereas mark-ups on ACTs (range: 22% in Nigeria to 71% in Zambia) and AMTs (range: 22% in Nigeria to 50% in Uganda) were similar in magnitude, but lower than those applied to nATs. Wholesale mark-ups were generally lower than those at retail level, and were similar across antimalarial categories in most countries. When setting prices wholesalers and retailers commonly considered supplier prices, prevailing market prices, product availability, product characteristics and the costs related to transporting goods, staff salaries and maintaining a property. Price discounts were regularly used to encourage sales and were sometimes used by wholesalers to reward long-term customers. Pricing constraints existed only in Benin where wholesaler and retailer mark-ups are regulated; however, unlicensed drug vendors based in open-air markets did not adhere to the pricing regime. These findings indicate that mark-ups on antimalarials are reasonable. Therefore, improving ACT affordability would be most readily

  14. Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development

    Zaloumis Sophie

    2012-08-01

    Full Text Available Abstract Background Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD model for predicting within-host parasite response was performed. Methods Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50, derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach. Results The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle. The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i

  15. Development of ELISA-based methods to measure the anti-malarial drug chloroquine in plasma and in pharmaceutical formulations

    Ronn Anita

    2011-08-01

    antibodies for the drugs used in artemisinin-based combination therapy (ACT.

  16. Analysis of the electrochemical reactivity of natural hemozoin and β-hemozoin in the presence of antimalarial drugs

    We report an evaluation of the reactivity of hemozoin (HZ) and β-hemozoin (β-HZ) obtained from the Triatoma Meccus longipennis, alone and in combination with quinine and amodiaquine. Using cyclic voltammetry and carbon paste electrodes, the redox processes that these compounds undergo were analysed. The results indicated that the atom Fe presence, the substance concentration, the drugs existence and the nature of the electrolytic medium are important in the redox processes. The strongest reactivity was for β-HZ from Triatoma, which suggests that cellular molecules are embedded in an oxidising environment due to the presence of β-HZ and indicates that like HZ, β-HZ could be associate with phospholipid bilayers and interfere with their physical and chemical integrity, contributing to membrane breakdown and hyper-oxidation of molecules. It was further observed that when measuring the reactivity of HZ and β-HZ with quinine and amodiaquine, a more oxidative stress was generated between the second one and the β-HZ, which could explain the effectiveness of amodiaquine as a better antimalarial drug. Finally, it was concluded that electrochemical evaluation may be a convenient tool in determining the efficiency of antimalarial drugs and the identification of their redox processes.

  17. Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials.

    Norcross, Neil R; Baragaña, Beatriz; Wilson, Caroline; Hallyburton, Irene; Osuna-Cabello, Maria; Norval, Suzanne; Riley, Jennifer; Stojanovski, Laste; Simeons, Frederick R C; Porzelle, Achim; Grimaldi, Raffaella; Wittlin, Sergio; Duffy, Sandra; Avery, Vicky M; Meister, Stephan; Sanz, Laura; Jiménez-Díaz, Belén; Angulo-Barturen, Iñigo; Ferrer, Santiago; Martínez, María Santos; Gamo, Francisco Javier; Frearson, Julie A; Gray, David W; Fairlamb, Alan H; Winzeler, Elizabeth A; Waterson, David; Campbell, Simon F; Willis, Paul; Read, Kevin D; Gilbert, Ian H

    2016-07-14

    In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting. PMID:27314305

  18. New 1-Aryl-3-Substituted Propanol Derivatives as Antimalarial Agents

    Antonio Monge

    2009-10-01

    Full Text Available This paper describes the synthesis and in vitro antimalarial activity against a P. falciparum 3D7 strain of some new 1-aryl-3-substituted propanol derivatives. Twelve of the tested compounds showed an IC50 lower than 1 μM. These compounds were also tested for cytotoxicity in murine J774 macrophages. The most active compounds were evaluated for in vivo activity against P. berghei in a 4-day suppressive test. Compound 12 inhibited more than 50% of parasite growth at a dose of 50 mg/kg/day. In addition, an FBIT test was performed to measure the ability to inhibit ferriprotoporphyrin biocrystallization. This data indicates that 1-aryl-3-substituted propanol derivatives hold promise as a new therapeutic option for the treatment of malaria.

  19. Screening Mangrove Endophytic Fungi for Antimalarial Natural Products

    Laurent Calcul

    2013-12-01

    Full Text Available We conducted a screening campaign to investigate fungi as a source for new antimalarial compounds. A subset of our fungal collection comprising Chinese mangrove endophytes provided over 5000 lipophilic extracts. We developed an accelerated discovery program based on small-scale cultivation for crude extract screening and a high-throughput malaria assay. Criteria for hits were developed and high priority hits were subjected to scale-up cultivation. Extracts from large scale cultivation were fractionated and these fractions subjected to both in vitro malaria and cytotoxicity screening. Criteria for advancing fractions to purification were developed, including the introduction of a selectivity index and by dereplication of known metabolites. From the Chinese mangrove endophytes, four new compounds (14–16, 18 were isolated including a new dimeric tetrahydroxanthone, dicerandrol D (14, which was found to display the most favorable bioactivity profile.

  20. Triterpenes from Minquartia guianensis (Olacaceae) and in vitro antimalarial activity

    Cursino, Lorena Mayara de Carvalho; Nunez, Cecilia Veronica [Instituto Nacional de Pesquisas da Amazonia (INPA), Manaus, AM (Brazil). Lab. de Bioprospeccao e Biotecnologia; Paula, Renata Cristina de; Nascimento, Maria Fernanda Alves do [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Fac. de Farmacia. Dept. de Produtos Farmaceuticos; Santos, Pierre Alexandre dos, E-mail: cecilia@inpa.gov.br [Universidade Federal do Amazonas (UFAM), Manaus, AM (Brazil). Fac. de Ciencias Farmaceuticas

    2012-07-01

    Minquartia guianensis, popularly known as acariquara, was phytochemically investigated. The following triterpenes were isolated from the dichloromethane extract of leaves: lupen-3-one (1), taraxer-3-one (2) and oleanolic acid (3). The dichloromethane extract of branches yielded the triterpene 3{beta}-methoxy-lup-20(29)-ene (4). The chemical structures were characterized by NMR data. Plant extracts, substance 3, squalene (5) and taraxerol (6), (5 and 6 previously isolated), were evaluated by in vitro assay against chloroquine resistant Plasmodium falciparum. The dichloromethane extract of leaves and the three triterpenes assayed have shown partial activity. Thus, these results demonstrated that new potential antimalarial natural products can be found even in partially active extracts. (author)

  1. Epidemiological models for the spread of anti-malarial resistance

    Antia R

    2003-02-01

    Full Text Available Abstract Background The spread of drug resistance is making malaria control increasingly difficult. Mathematical models for the transmission dynamics of drug sensitive and resistant strains can be a useful tool to help to understand the factors that influence the spread of drug resistance, and they can therefore help in the design of rational strategies for the control of drug resistance. Methods We present an epidemiological framework to investigate the spread of anti-malarial resistance. Several mathematical models, based on the familiar Macdonald-Ross model of malaria transmission, enable us to examine the processes and parameters that are critical in determining the spread of resistance. Results In our simplest model, resistance does not spread if the fraction of infected individuals treated is less than a threshold value; if drug treatment exceeds this threshold, resistance will eventually become fixed in the population. The threshold value is determined only by the rates of infection and the infectious periods of resistant and sensitive parasites in untreated and treated hosts, whereas the intensity of transmission has no influence on the threshold value. In more complex models, where hosts can be infected by multiple parasite strains or where treatment varies spatially, resistance is generally not fixed, but rather some level of sensitivity is often maintained in the population. Conclusions The models developed in this paper are a first step in understanding the epidemiology of anti-malarial resistance and evaluating strategies to reduce the spread of resistance. However, specific recommendations for the management of resistance need to wait until we have more data on the critical parameters underlying the spread of resistance: drug use, spatial variability of treatment and parasite migration among areas, and perhaps most importantly, cost of resistance.

  2. Discovery of Novel Liver-Stage Antimalarials through Quantum Similarity.

    David J Sullivan

    Full Text Available Without quantum theory any understanding of molecular interactions is incomplete. In principal, chemistry, and even biology, can be fully derived from non-relativistic quantum mechanics. In practice, conventional quantum chemical calculations are computationally too intensive and time consuming to be useful for drug discovery on more than a limited basis. A previously described, original, quantum-based computational process for drug discovery and design bridges this gap between theory and practice, and allows the application of quantum methods to large-scale in silico identification of active compounds. Here, we show the results of this quantum-similarity approach applied to the discovery of novel liver-stage antimalarials. Testing of only five of the model-predicted compounds in vitro and in vivo hepatic stage drug inhibition assays with P. berghei identified four novel chemical structures representing three separate quantum classes of liver-stage antimalarials. All four compounds inhibited liver-stage Plasmodium as a single oral dose in the quantitative PCR mouse liver-stage sporozoites-challenge model. One of the newly identified compounds, cethromycin [ABT-773], a macrolide-quinoline hybrid, is a drug with an extensive (over 5,000 people safety profile warranting its exploitation as a new weapon for the current effort of malaria eradication. The results of our molecular modeling exceed current state-of-the-art computational methods. Drug discovery through quantum similarity is data-driven, agnostic to any particular target or disease process that can evaluate multiple phenotypic, target-specific, or co-crystal structural data. This allows the incorporation of additional pharmacological requirements, as well as rapid exploration of novel chemical spaces for therapeutic applications.

  3. Time Series Analysis of Trends in Malaria Cases and Deaths at Hospitals and the Effect of Antimalarial Interventions, 2001–2011, Ethiopia

    Aregawi, Maru; Lynch, Michael; Bekele, Worku; Kebede, Henok; Jima, Daddi; Taffese, Hiwot Solomon; Yenehun, Meseret Aseffa; Lilay, Abraham; Williams, Ryan; Thomson, Madeleine; Nafo-Traore, Fatoumata; Admasu, Kesetebirhan; Gebreyesus, Tedros Adhanom; Coosemans, Marc

    2014-01-01

    Background The Government of Ethiopia and its partners have deployed artemisinin-based combination therapies (ACT) since 2004 and long-lasting insecticidal nets (LLINs) since 2005. Malaria interventions and trends in malaria cases and deaths were assessed at hospitals in malaria transmission areas during 2001–2011. Methods Regional LLINs distribution records were used to estimate the proportion of the population-at-risk protected by LLINs. Hospital records were reviewed to estimate ACT availability. Time-series analysis was applied to data from 41 hospitals in malaria risk areas to assess trends of malaria cases and deaths during pre-intervention (2001–2005) and post-interventions (2006–2011) periods. Findings The proportion of the population-at-risk potentially protected by LLINs increased to 51% in 2011. The proportion of facilities with ACTs in stock exceeded 87% during 2006–2011. Among all ages, confirmed malaria cases in 2011 declined by 66% (95% confidence interval [CI], 44–79%) and SPR by 37% (CI, 20%–51%) compared to the level predicted by pre-intervention trends. In children under 5 years of age, malaria admissions and deaths fell by 81% (CI, 47%–94%) and 73% (CI, 48%–86%) respectively. Optimal breakpoint of the trendlines occurred between January and June 2006, consistent with the timing of malaria interventions. Over the same period, non-malaria cases and deaths either increased or remained unchanged, the number of malaria diagnostic tests performed reflected the decline in malaria cases, and rainfall remained at levels supportive of malaria transmission. Conclusions Malaria cases and deaths in Ethiopian hospitals decreased substantially during 2006–2011 in conjunction with scale-up of malaria interventions. The decrease could not be accounted for by changes in hospital visits, malaria diagnostic testing or rainfall. However, given the history of variable malaria transmission in Ethiopia, more data would be required to exclude the

  4. Distillation Time as Tool for Improved Antimalarial Activity and Differential Oil Composition of Cumin Seed Oil

    A steam distillation extraction kinetics experiment was conducted to estimate essential oil yield, composition, antimalarial, and antioxidant capacity of cumin (Cuminum cyminum L.) seed (fruits). Furthermore, regression models were developed to predict essential oil yield and composition for a given...

  5. Post-marketing surveillance of anti-malarial medicines used in Malawi

    Chikowe, Ibrahim; Osei-Safo, Dorcas; Harrison, Jerry JEK; Konadu, Daniel Y; Addae-Mensah, Ivan

    2015-01-01

    Background The growing concern over the extent of anti-malarial medicine resistance in sub-Saharan Africa, driven largely by administration of sub-therapeutic doses derived from falsified and substandard medicines necessitates regular monitoring of the quality of these medicines to avert any potential public health disaster. This study aimed at determining the active pharmaceutical ingredient (API) content of anti-malarial medicines available in Malawi with respect to the manufacturers’ label...

  6. Self-Medication with Antibiotics and Antimalarials in the Community of Silte Zone, South Ethiopia

    Nasir Tajure Wabe; Dargicho Ahmed; Mulugeta Tarekegn Angamo

    2012-01-01

    AIM: Self-medication with antibiotics and antimalarials occurs among the population in Ethiopian. We studied to estimate the prevalence of self-medication with antibiotics and antimalarials in Ethiopia and evaluate factors associated with self-medications. METHODS: A cross-sectional study was conducted on 405 households, selected from Silte Zone in South Ethiopia, using a random sampling technique by employing a pretested questionnaire. Data were analyzed using SPSS for windows version 16.0. ...

  7. Public Awareness and Identification of Counterfeit Drugs in Tanzania: A View on Antimalarial Drugs

    Mhando, Linus; Jande, Mary B.; Liwa, Anthony; Mwita, Stanley; Marwa, Karol J.

    2016-01-01

    Background. The illicit trade in counterfeit antimalarial drugs is a major setback to the fight against malaria. Information on public awareness and ability to identify counterfeit drugs is scanty. Aim. Therefore, the present study aimed at assessing public awareness and the ability to identify counterfeit antimalarial drugs based on simple observations such as appearance of the drugs, packaging, labelling, and leaflets. Methodology. A cross-sectional study was conducted using interviewer adm...

  8. In vitro antimalarial activity of different extracts of Eremostachys macrophylla Montbr. & Auch.

    Solmaz Asnaashari; Fariba Heshmati Afshar; Atefeh Ebrahimi; Sedigheh Bamdad Moghaddam; Abbas Delazar

    2015-01-01

    Introduction: The risk of drug resistance and the use of medicinal plants in malaria prevention and treatment have led to the search for new antimalarial compounds with natural origin. Methods: In the current study, six extracts with different polarity from aerial parts and rhizomes of Eremostachys macrophylla Montbr. & Auch., were screened for their antimalarial properties by cell-free beta-hematin formation assay. Results: Dichloromethane (DCM) extracts of both parts of plant showed s...

  9. Evaluation of plants used for antimalarial treatment by the Maasai of Kenya.

    Koch, A; Tamez, P; Pezzuto, J; Soejarto, D

    2005-10-01

    Semi-structured interviews with three Maasai herbalists led to the identification and collection of 21 species of plants used to treat malaria. Extracts were evaluated using in vitro antimalarial and cytotoxicity assays. Of the species tested, over half were antiplasmodial (IC5020 microg/ml) against cultured KB cells. The results of this preliminary investigation support the traditional knowledge of Maasai herbalists and justify ethnomedical inquiry as a promising method, specifically, in antimalarial therapy, to yield leads for drug discovery. PMID:15878245

  10. Study of the antimalarial properties of hydroxyethylamine derivatives using green fluorescent protein transformed Plasmodium berghei

    Mariana Conceição Souza

    2015-06-01

    Full Text Available A rapid decrease in parasitaemia remains the major goal for new antimalarial drugs and thus, in vivo models must provide precise results concerning parasitaemia modulation. Hydroxyethylamine comprise an important group of alkanolamine compounds that exhibit pharmacological properties as proteases inhibitors that has already been proposed as a new class of antimalarial drugs. Herein, it was tested the antimalarial property of new nine different hydroxyethylamine derivatives using the green fluorescent protein (GFP-expressing Plasmodium berghei strain. By comparing flow cytometry and microscopic analysis to evaluate parasitaemia recrudescence, it was observed that flow cytometry was a more sensitive methodology. The nine hydroxyethylamine derivatives were obtained by inserting one of the following radical in the para position: H, 4Cl, 4-Br, 4-F, 4-CH3, 4-OCH3, 4-NO2, 4-NH2 and 3-Br. The antimalarial test showed that the compound that received the methyl group (4-CH3 inhibited 70% of parasite growth. Our results suggest that GFP-transfected P. berghei is a useful tool to study the recrudescence of novel antimalarial drugs through parasitaemia examination by flow cytometry. Furthermore, it was demonstrated that the insertion of a methyl group at the para position of the sulfonamide ring appears to be critical for the antimalarial activity of this class of compounds.

  11. Does anti-malarial drug knowledge predict anti-malarial dispensing practice in drug outlets? A survey of medicine retailers in western Kenya

    Rusk Andria

    2012-08-01

    Full Text Available Abstract Background Malaria is a major cause of morbidity and mortality in Kenya, where it is the fifth leading cause of death in both children and adults. Effectively managing malaria is dependent upon appropriate treatment. In Kenya, between 17 to 83 percent of febrile individuals first seek treatment for febrile illness over the counter from medicine retailers. Understanding medicine retailer knowledge and behaviour in treating suspected malaria and dispensing anti-malarials is crucial. Methods To investigate medicine retailer knowledge about anti-malarials and their dispensing practices, a survey was conducted of all retail drug outlets that sell anti-malarial medications and serve residents of the Webuye Health and Demographic Surveillance Site in the Bungoma East District of western Kenya. Results Most of the medicine retailers surveyed (65% were able to identify artemether-lumefantrine (AL as the Kenyan Ministry of Health recommended first-line anti-malarial therapy for uncomplicated malaria. Retailers who correctly identified this treatment were also more likely to recommend AL to adult and paediatric customers. However, the proportion of medicine retailers who recommend the correct treatment is disappointingly low. Only 48% would recommend AL to adults, and 37% would recommend it to children. It was discovered that customer demand has an influence on retailer behaviour. Retailer training and education were found to be correlated with anti-malarial drug knowledge, which in turn is correlated with dispensing practices. Medicine retailer behaviour, including patient referral practice and dispensing practices, are also correlated with knowledge of the first-line anti-malarial medication. The Kenya Ministry of Health guidelines were found to influence retailer drug stocking and dispensing behaviours. Conclusion Most medicine retailers could identify the recommended first-line treatment for uncomplicated malaria, but the percentage that could

  12. Assessment of Malaria In Vitro Drug Combination Screening and Mixed-Strain Infections Using the Malaria Sybr Green I-Based Fluorescence Assay▿

    Co, Edgie-Mark A.; Dennull, Richard A.; Reinbold, Drew D.; Waters, Norman C; Johnson, Jacob D.

    2009-01-01

    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 ag...

  13. Plasmodium falciparum Thioredoxin Reductase (PfTrxR) and Its Role as a Target for New Antimalarial Discovery

    Sara E. McCarty; Amanda Schellenberger; Douglas C. Goodwin; Ngolui Rene Fuanta; Tekwani, Babu L.; Calderón, Angela I.

    2015-01-01

    The growing resistance to current antimalarial drugs is a major concern for global public health. The pressing need for new antimalarials has led to an increase in research focused on the Plasmodium parasites that cause human malaria. Thioredoxin reductase (TrxR), an enzyme needed to maintain redox equilibrium in Plasmodium species, is a promising target for new antimalarials. This review paper provides an overview of the structure and function of TrxR, discusses similarities and differences...

  14. Molecular markers of anti-malarial drug resistance in Lahj Governorate, Yemen: baseline data and implications

    Chance Michael L

    2011-08-01

    Full Text Available Abstract Background This is an investigation of anti-malarial molecular markers coupled with a therapeutic efficacy test of chloroquine (CQ against falciparum malaria in an area of unstable malaria in Lahj Governorate, Yemen. The study was aimed at assessment of therapeutic response to CQ and elucidation of baseline information on molecular markers for Plasmodium falciparum resistance against CQ and sulphadoxine/pyrimethamine (SP. Methods Between 2002 and 2003 the field test was conducted according to the standard WHO protocol to evaluate the therapeutic efficacy of CQ in 124 patients with falciparum malaria in an endemic area in Lahj Governorate in Yemen. Blood samples collected during this study were analysed for P. falciparum chloroquine resistance transporter gene (pfcrt-76 polymorphisms, mutation pfcrt-S163R and the antifolate resistance-associated mutations dihydrofolate reductase (dhfr-C59R and dihydropteroate synthase (dhps-K540E. Direct DNA sequencing of the pfcrt gene from three representative field samples was carried out after DNA amplification of the 13 exons of the pfcrt gene. Results Treatment failure was detected in 61% of the 122 cases that completed the 14-day follow-up. The prevalence of mutant pfcrt T76 was 98% in 112 amplified pre-treatment samples. The presence of pfcrt T76 was poorly predictive of in vivo CQ resistance (PPV = 61.8%, 95% CI = 52.7-70.9. The prevalence of dhfr Arg-59 mutation in 99 amplified samples was 5%, while the dhps Glu-540 was not detected in any of 119 amplified samples. Sequencing the pfcrt gene confirmed that Yemeni CQ resistant P. falciparum carry the old world (Asian and African CQ resistant haplotype CVIETSESI at positions 72,73,74,75,76,220,271, 326 and 371. Conclusion This is the first study to report baseline information on the characteristics and implications of anti-malarial drug resistance markers in Yemen. It is also the first report of the haplotype associated with CQR P. falciparum

  15. The heat shock protein 90 of Plasmodium falciparum and antimalarial activity of its inhibitor, geldanamycin

    Barik Sailen

    2003-09-01

    Full Text Available Abstract Background The naturally occurring benzoquinone ansamycin compound, geldanamycin (GA, is a specific inhibitor of heat shock protein 90 (Hsp90 and is a potential anticancer agent. Since Plasmodium falciparum has been reported to have an Hsp90 ortholog, we tested the possibility that GA might inhibit it and thereby display antiparasitic activity. Results We provide direct recombinant DNA evidence for the Hsp90 protein of Plasmodium falciparum, the causative agent of fatal malaria. While the mRNA of Hsp90 was mainly expressed in ring and trophozoite stages, the protein was found in all stages, although schizonts contained relatively lower amounts. In vitro the parasitic Hsp90 exhibited an ATP-binding activity that could be specifically inhibited by GA. Plasmodium growth in human erythrocyte culture was strongly inhibited by GA with an IC50 of 20 nM, compared to the IC50 of 15 nM for chloroquine (CQ under identical conditions. When used in combination, the two drugs acted synergistically. GA was equally effective against CQ-sensitive and CQ-resistant strains (3D7 and W2, respectively and on all erythrocytic stages of the parasite. Conclusions Together, these results suggest that an active and essential Hsp90 chaperone cycle exists in Plasmodium and that the ansamycin antibiotics will be an important tool to dissect its role in the parasite. Additionally, the favorable pharmacology of GA, reported in human trials, makes it a promising antimalarial drug.

  16. Hemin potentiates the anti-hepatitis C virus activity of the antimalarial drug artemisinin

    We report that the antimalarial drug artemisinin inhibits hepatitis C virus (HCV) replicon replication in a dose-dependent manner in two replicon constructs at concentrations that have no effect on the proliferation of the exponentially growing host cells. The 50% effective concentration (EC5) for inhibition of HCV subgenomic replicon replication in Huh 5-2 cells (luciferase assay) by artemisinin was 78 ± 21 μM. Hemin, an iron donor, was recently reported to inhibit HCV replicon replication [mediated by inhibition of the viral polymerase (C. Fillebeen, A.M. Rivas-Estilla, M. Bisaillon, P. Ponka, M. Muckenthaler, M.W. Hentze, A.E. Koromilas, K. Pantopoulos, Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus, J. Biol. Chem. 280 (2005) 9049-9057.)] at a concentration that had no adverse effect on the host cells. When combined, artemisinin and hemin resulted, over a broad concentration range, in a pronounced synergistic antiviral activity. Also at a concentration (2 μM) that alone had no effect on HCV replication, hemin still potentiated the anti-HCV activity of artemisinin

  17. Straightforward conversion of decoquinate into inexpensive tractable new derivatives with significant antimalarial activities.

    Beteck, Richard M; Coertzen, Dina; Smit, Frans J; Birkholtz, Lyn-Marie; Haynes, Richard K; N'Da, David D

    2016-07-01

    As part of a programme aimed at identifying rational new triple drug combinations for treatment of malaria, tuberculosis and toxoplasmosis, we have selected quinolones as one component, given that selected examples exhibit exceptionally good activities against the causative pathogens of the foregoing diseases. The quinolone decoquinate (DQ), an old and inexpensive coccidiostat, displays anti-malarial activity in vitro against Plasmodium falciparum (Pf). However, because of its exceedingly poor solubility in water or organic solvents, development of DQ as a drug is problematical. We have therefore converted DQ in straightforward fashion into tractable new derivatives that display good activities in vitro against chloroquine-sensitive NF54 and multidrug-resistant K1 and W2 Pf, and relatively low toxicities against human fibroblast cells. The most active compound, the N-acetyl derivative 30, is 5-fold more active than DQ against NF54 and K1 and equipotent with DQ against W2. It possesses an activity profile against all strains comparable with that of the artemisinin derivative artesunate. Overall, this compound and the other accessible and active derivatives serve as an attractive template for development of new and economic lead quinolones. PMID:27210430

  18. Accessibility, availability and affordability of anti-malarials in a rural district in Kenya after implementation of a national subsidy scheme

    Simiyu Chrispinus

    2011-10-01

    Full Text Available Abstract Background Poor access to prompt and effective treatment for malaria contributes to high mortality and severe morbidity. In Kenya, it is estimated that only 12% of children receive anti-malarials for their fever within 24 hours. The first point of care for many fevers is a local medicine retailer, such as a pharmacy or chemist. The role of the medicine retailer as an important distribution point for malaria medicines has been recognized and several different strategies have been used to improve the services that these retailers provide. Despite these efforts, many mothers still purchase ineffective drugs because they are less expensive than effective artemisinin combination therapy (ACT. One strategy that is being piloted in several countries is an international subsidy targeted at anti-malarials supplied through the retail sector. The goal of this strategy is to make ACT as affordable as ineffective alternatives. The programme, called the Affordable Medicines Facility - malaria was rolled out in Kenya in August 2010. Methods In December 2010, the affordability and accessibility of malaria medicines in a rural district in Kenya were evaluated using a complete census of all public and private facilities, chemists, pharmacists, and other malaria medicine retailers within the Webuye Demographic Surveillance Area. Availability, types, and prices of anti-malarials were assessed. There are 13 public or mission facilities and 97 medicine retailers (registered and unregistered. Results The average distance from a home to the nearest public health facility is 2 km, but the average distance to the nearest medicine retailer is half that. Quinine is the most frequently stocked anti-malarial (61% of retailers. More medicine retailers stocked sulphadoxine-pyramethamine (SP; 57% than ACT (44%. Eleven percent of retailers stocked AMFm subsidized artemether-lumefantrine (AL. No retailers had chloroquine in stock and only five were selling artemisinin

  19. Compound antimalarial ethosomal cataplasm: preparation, evaluation, and mechanism of penetration enhancement.

    Shen, Shuo; Liu, Shu-Zhi; Zhang, Yu-Shi; Du, Mao-Bo; Liang, Ai-Hua; Song, Li-Hua; Ye, Zu-Guang

    2015-01-01

    Malaria is still a serious public health problem in some parts of the world. The problems of recurrence and drug resistance are increasingly more serious. Thus, it is necessary to develop a novel antimalarial agent. The objectives of this study were to construct a novel compound antimalarial transdermal nanosystem-ethosomal cataplasm, to investigate its characteristics and efficiency, and to systematically explore the penetration-enhancing mechanisms of ethosomal cataplasm. Artesunate-loaded ethosomes and febrifugine-loaded ethosomes were prepared, and their characteristics were evaluated. Drug-loaded ethosomes were incorporated in the matrix of cataplasm to form the compound antimalarial ethosomal cataplasm. With the help of ethosomal technology, the accumulated permeation quantity of artesunate significantly increased at 8 hours after administration, which was 1.57 times as much as that of conventional cataplasm. Soon after administration, the ethosomal cataplasm could make a large quantity of antimalarial drug quickly penetrate through skin, then the remaining drug in the ethosomal cataplasm could be steadily released. These characteristics of ethosomal cataplasm are favorable for antimalarial drugs to kill Plasmodium spp. quickly and prevent the resurgence of Plasmodium spp. As expected, the ethosomal cataplasm showed good antimalarial efficiency in this experiment. The negative conversion rates were 100% and the recurrence rates were 0% at all dosages. The mechanism of penetration enhancement of the ethosomal cataplasm was systematically explored using an optics microscope, polarization microscope, and transmission electron microscopy. The microstructure, ultrastructure, and birefringent structure in skin were observed. Data obtained in this study showed that the application of ethosomal technology to antimalarial cataplasm could improve the transdermal delivery of drug, enhance the efficacy, and facilitate practical application in clinic. PMID:26170661

  20. Targeting Plasmodium Metabolism to Improve Antimalarial Drug Design.

    Avitia-Domínguez, Claudia; Sierra-Campos, Erick; Betancourt-Conde, Irene; Aguirre-Raudry, Miriam; Vázquez-Raygoza, Alejandra; Luevano-De la Cruz, Artemisa; Favela-Candia, Alejandro; Sarabia-Sanchez, Marie; Ríos-Soto, Lluvia; Méndez-Hernández, Edna; Cisneros-Martínez, Jorge; Palacio-Gastélum, Marcelo Gómez; Valdez-Solana, Mónica; Hernández-Rivera, Jessica; De Lira-Sánchez, Jaime; Campos-Almazán, Mara; Téllez-Valencia, Alfredo

    2016-01-01

    Malaria is one of the main infectious diseases in tropical developing countries and represents high morbidity and mortality rates nowadays. The principal etiological agent P. falciparum is transmitted through the bite of the female Anopheles mosquito. The issue has escalated due to the emergence of resistant strains to most of the antimalarials used for the treatment including Chloroquine, Sulfadoxine-Pyrimethamine, and recently Artemisinin derivatives, which has led to diminished effectiveness and by consequence increased the severity of epidemic outbreaks. Due to the lack of effective compounds to treat these drug-resistant strains, the discovery or development of novel anti-malaria drugs is important. In this context, one strategy has been to find inhibitors of enzymes, which play an important role for parasite survival. Today, promising results have been obtained in this regard, involving the entire P. falciparum metabolism. These inhibitors could serve as leads in the search of a new chemotherapy against malaria. This review focuses on the achievements in recent years with regard to inhibition of enzymes used as targets for drug design against malaria. PMID:26983887

  1. Public Awareness and Identification of Counterfeit Drugs in Tanzania: A View on Antimalarial Drugs

    Linus Mhando

    2016-01-01

    Full Text Available Background. The illicit trade in counterfeit antimalarial drugs is a major setback to the fight against malaria. Information on public awareness and ability to identify counterfeit drugs is scanty. Aim. Therefore, the present study aimed at assessing public awareness and the ability to identify counterfeit antimalarial drugs based on simple observations such as appearance of the drugs, packaging, labelling, and leaflets. Methodology. A cross-sectional study was conducted using interviewer administered structured questionnaire and a checklist. Respondents were required to spot the difference between genuine and counterfeit antimalarial drugs given to them. Data was analysed using SPSS version 20. Results. The majority of respondents, 163 (55.6%, were able to distinguish between genuine and counterfeit antimalarial drugs. Respondents with knowledge on health effects of counterfeit drugs were more likely to identify genuine and counterfeit drugs than their counterparts (P=0.003; OR = 2.95; 95% CI: 1.47–5.65. The majority of respondents, 190 (64.8%, perceived the presence of counterfeit drugs to be a big problem to the community. Conclusions. A substantial proportion of respondents were able to distinguish between genuine and counterfeit antimalarial drugs. Public empowerment in identifying counterfeit drugs by simple observations is a major step towards discouraging the market of counterfeit drugs.

  2. Targeting protein kinases in the malaria parasite: update of an antimalarial drug target.

    Zhang, Veronica M; Chavchich, Marina; Waters, Norman C

    2012-01-01

    Millions of deaths each year are attributed to malaria worldwide. Transmitted through the bite of an Anopheles mosquito, infection and subsequent death from the Plasmodium species, most notably P. falciparum, can readily spread through a susceptible population. A malaria vaccine does not exist and resistance to virtually every antimalarial drug predicts that mortality and morbidity associated with this disease will increase. With only a few antimalarial drugs currently in the pipeline, new therapeutic options and novel chemotypes are desperately needed. Hit-to-Lead diversity may successfully provide novel inhibitory scaffolds when essential enzymes are targeted, for example, the plasmodial protein kinases. Throughout the entire life cycle of the malaria parasite, protein kinases are essential for growth and development. Ongoing efforts continue to characterize these kinases, while simultaneously pursuing them as antimalarial drug targets. A collection of structural data, inhibitory profiles and target validation has set the foundation and support for targeting the malarial kinome. Pursuing protein kinases as cancer drug targets has generated a wealth of information on the inhibitory strategies that can be useful for antimalarial drug discovery. In this review, progress on selected protein kinases is described. As the search for novel antimalarials continues, an understanding of the phosphor-regulatory pathways will not only validate protein kinase targets, but also will identify novel chemotypes to thwart malaria drug resistance. PMID:22242850

  3. Monitoring the efficacy of antimalarial medicines in India via sentinel sites: Outcomes and risk factors for treatment failure

    Neelima Mishra

    2016-01-01

    Interpretation & conclusion: Till 2012, India′s national antimalarial drug resistance monitoring system proved highly efficacious and safe towards first-line antimalarials used in the country, except in Northeastern region where a decline in efficacy of AS+SP has been observed. This led to change in first-line treatment for P. falciparum to artemether-lumefantrine in Northeastern region.

  4. Reduction of transmission from malaria patients by artemisinin combination therapies: a pooled analysis of six randomized trials

    Bousema Teun; Ghani Azra C; Drakeley Chris J; Okell Lucy C; Sutherland Colin J

    2008-01-01

    Abstract Background Artemisinin combination therapies (ACT), which are increasingly being introduced for treatment of Plasmodium falciparum malaria, are more effective against sexual stage parasites (gametocytes) than previous first-line antimalarials and therefore have the potential to reduce parasite transmission. The size of this effect is estimated in symptomatic P. falciparum infections. Methods Data on 3,174 patients were pooled from six antimalarial trials conducted in The Gambia and K...

  5. Collaborative health and enforcement operations on the quality of antimalarials and antibiotics in southeast Asia.

    Yong, Yuk Lin; Plançon, Aline; Lau, Yen Hui; Hostetler, Dana M; Fernández, Facundo M; Green, Michael D; Sounvoravong, Sourisak; Nara, Suon; Boravann, Mam; Dumrong, Thitikornkovit; Bangsawan, Nurjaya; Low, Min Yong; Lim, Chin-Chin; Ai, Ruth Lee Choo; Newton, Paul N

    2015-06-01

    Counterfeit (or falsified) and substandard medicines pose a major public health risk. We describe the findings of Operation Storm I and II conducted in 2008-2009 to combat counterfeit medicines through partnership between national customs, Drug Regulatory Agencies (DRAs), and police in Cambodia, Indonesia, Laos, Myanmar, Singapore, Thailand, and Vietnam. Samples were obtained from seizures and market surveillance by national DRAs. Laboratory analysis using spectroscopic and chromatographic techniques and examination of packaging were performed. Ninety-three suspect antibiotics and 95 antimalarial samples were collected. Of the 93 antibiotics, 29 (31%) had % active pharmaceutical ingredient content (%API) 115% (including one counterfeit). Of the 95 antimalarials, 30 (32%) had %API 115% API (including one counterfeit). A significant minority of samples, antimalarials (13%) and antibiotics (15%), were collected in plastic bags with minimal or no labeling. Of 20 ampicillin samples, 13 (65%) contained medicines. PMID:25897069

  6. Influence of smoking on disease severity and antimalarial therapy in cutaneous lupus erythematosus

    Kuhn, A; Sigges, J; Biazar, C;

    2014-01-01

    BACKGROUND: In recent years it has been controversially discussed in the literature if smoking is associated with the activity of cutaneous lupus erythematosus (CLE) and the efficacy of antimalarial agents. OBJECTIVES: To investigate the influence of smoking on disease severity and antimalarial...... treatment in patients with CLE using the Core Set Questionnaire of the European Society of Cutaneous Lupus Erythematosus (EUSCLE). METHODS: A total of 1002 patients (768 female, 234 male) with different CLE subtypes were included in this cross-sectional study, which was performed in 14 different countries....... Smoking behaviour was assessed by the EUSCLE Core Set Questionnaire in 838 patients and statistically analysed using an SPSS database. The results were correlated with the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the efficacy of antimalarial treatment. RESULTS: A high...

  7. Investigation of Traditional Palestinian Medicinal Plant Inula viscosa as Potential Anti-malarial Agent

    M. Akkawi

    2014-10-01

    Full Text Available Malaria is a life threatening parasitic disease which is prevalent mainly in developing countries; it is the main cause of global mortality and morbidity. Development and search of novel and effective anti-malarial agents to overcome chloroquine resistance have become a very important issue. Most anti-malarial drugs target the erythrocytic stage of malaria infection, where hemozoin synthesis takes place and is considered a crucial process for the parasite survival. Throughout last decades, natural products have been a significant source of chemotherapeutics especially against malaria. Inula viscosa, Inula viscosa , is a shrub that grows around the Mediterranean basin and considered as an important Palestinian traditional medicinal herb. In this research it was found that the Palestinian flora Inula viscosa alcoholic extract has a significant and promising anti-malarial effect in both in vitro and in vivo systems. The crude alcoholic extract of Inula viscosa has the capability to impede the formation of &beta-hematin in vitro; with an efficiency of about 93% when compared to the standard chloroquine which gave 94% at comparable concentrations. in vivo studies showed that this crude extract inhibited the growth of Plasmodium parasites in the red blood cells at a rate of about 96.6%, with an EC50 value of 0.55 ng/mL. Several secondary plant metabolites may be responsible for this anti-malarial activity; the effect also may be most probably due to the presence of high concentrations of nerolidol which has often been found at high concentrationsin this plant. Nerolidol shows a stronger inhibition of hypoxanthine incorporation than quinine. Its anti-malarial effect is potentiated by other essential oils. Nerolidol is also found in several Artemisia species and in Cymbopogon citratus (lemongrass and Virola surinamensis, all plants known for their anti-malarial properties.

  8. In vitro and in vivo assessment of the anti-malarial activity of Caesalpinia pluviosa

    Eberlin Marcos N

    2011-05-01

    Full Text Available Abstract Background To overcome the problem of increasing drug resistance, traditional medicines are an important source for potential new anti-malarials. Caesalpinia pluviosa, commonly named "sibipiruna", originates from Brazil and possess multiple therapeutic properties, including anti-malarial activity. Methods Crude extract (CE was obtained from stem bark by purification using different solvents, resulting in seven fractions. An MTT assay was performed to evaluate cytotoxicity in MCF-7 cells. The CE and its fractions were tested in vitro against chloroquine-sensitive (3D7 and -resistant (S20 strains of Plasmodium falciparum and in vivo in Plasmodium chabaudi-infected mice. In vitro interaction with artesunate and the active C. pluviosa fractions was assessed, and mass spectrometry analyses were conducted. Results At non-toxic concentrations, the 100% ethanolic (F4 and 50% methanolic (F5 fractions possessed significant anti-malarial activity against both 3D7 and S20 strains. Drug interaction assays with artesunate showed a synergistic interaction with the F4. Four days of treatment with this fraction significantly inhibited parasitaemia in mice in a dose-dependent manner. Mass spectrometry analyses revealed the presence of an ion corresponding to m/z 303.0450, suggesting the presence of quercetin. However, a second set of analyses, with a quercetin standard, showed distinct ions of m/z 137 and 153. Conclusions The findings show that the F4 fraction of C. pluviosa exhibits anti-malarial activity in vitro at non-toxic concentrations, which was potentiated in the presence of artesunate. Moreover, this anti-malarial activity was also sustained in vivo after treatment of infected mice. Finally, mass spectrometry analyses suggest that a new compound, most likely an isomer of quercetin, is responsible for the anti-malarial activity of the F4.

  9. Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands

    Timothy J. Hubin; Amoyaw, Prince N. -A.; Roewe, Kimberly D.; Simpson, Natalie C.; Maples, Randall D.; Carder Freeman, TaRynn N.; Amy N. Cain; Le, Justin G.; Stephen J Archibald; Khan, Shabana I.; Tekwani, Babu L.; Khan, M. O. Faruk

    2014-01-01

    Using transition metals such as manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and zinc(II), several new metal complexes of cross-bridged tetraazamacrocyclic chelators namely, cyclen- and cyclam-analogs with benzyl groups, were synthesized and screened for in vitro antimalarial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of Plasmodium falciparum. The metal-free chelators tested showed little or no antimalarial activity. All the metal comple...

  10. Evaluation of the effect of pyrimethamine, an anti-malarial drug, on HIV-1 replication

    Oguariri, Raphael M.; Joseph W Adelsberger; Michael W Baseler; Imamichi, Tomozumi

    2010-01-01

    Co-infection of human immunodeficiency virus (HIV) with malaria is one of the pandemic problems in Africa and parts of Asia. Here we investigated the impact of PYR and two other clinical anti-malarial drugs (chloroquine [CQ] or artemisinin [ART]) on HIV-1 replication. Peripheral blood mononuclear cells (PBMCs) or MT-2 cells were infected with HIVNL4.3 strain and treated with different concentrations of the anti-malarial drugs. HIV-1 replication was measured using p24 ELISA. We show that 10 μM...

  11. Availability of antimalarial drugs and evaluation of the attitude and practices for the treatment of uncomplicated malaria in bangui, central african republic.

    Manirakiza, Alexandre; Njuimo, Siméon Pierre; Le Faou, Alain; Malvy, Denis; Millet, Pascal

    2010-01-01

    National malaria management policy is based upon the availability of effective and affordable antimalarial drugs. This study was undertaken to evaluate the quality of the treatment of uncomplicated malaria cases in Bangui, an area with multidrug-resistant parasites, at a time preceding implementation of a new therapeutic policy relying on the artemisinin derivative combined treatment artemether-lumefantrine. A cross-sectional study was carried out in Bangui city to assess availability of antimalarial drugs and the performances of health workers in the management of uncomplicated malaria. Availability of drugs was recorded in all drugs wholesalers (n = 3), all pharmacies in health facilities (n = 14), private drugstores (n = 15), and in 60 non-official drug shops randomly chosen in the city. Despite a limited efficacy at the time of the survey, chloroquine remained widely available in the official and nonofficial markets. Artemisinin derivatives used in monotherapy or in combination were commonly sold. In health care facilities, 93% of the uncomplicated malaria cases were treated in the absence of any laboratory confirmation and the officially recommended treatment, amodiaquine-sulfadoxine/pyrimethamine, was seldom prescribed. Thus, the national guidelines for the treatment of uncomplicated malaria are not followed by health professionals in Bangui. Its use should be implemented while a control of importation of drug has to be reinforced. PMID:20339579

  12. Prospective strategies to delay the evolution of anti-malarial drug resistance: weighing the uncertainty

    McKenzie F Ellis

    2010-07-01

    Full Text Available Abstract Background The evolution of drug resistance in malaria parasites highlights a need to identify and evaluate strategies that could extend the useful therapeutic life of anti-malarial drugs. Such strategies are deployed to best effect before resistance has emerged, under conditions of great uncertainty. Methods Here, the emergence and spread of resistance was modelled using a hybrid framework to evaluate prospective strategies, estimate the time to drug failure, and weigh uncertainty. The waiting time to appearance was estimated as the product of low mutation rates, drug pressure, and parasite population sizes during treatment. Stochastic persistence and the waiting time to establishment were simulated as an evolving branching process. The subsequent spread of resistance was simulated in simple epidemiological models. Results Using this framework, the waiting time to the failure of artemisinin combination therapy (ACT for malaria was estimated, and a policy of multiple first-line therapies (MFTs was evaluated. The models quantify the effects of reducing drug pressure in delaying appearance, reducing the chances of establishment, and slowing spread. By using two first-line therapies in a population, it is possible to reduce drug pressure while still treating the full complement of cases. Conclusions At a global scale, because of uncertainty about the time to the emergence of ACT resistance, there was a strong case for MFTs to guard against early failure. Our study recommends developing operationally feasible strategies for implementing MFTs, such as distributing different ACTs at the clinic and for home-based care, or formulating different ACTs for children and adults.

  13. Mind the gaps - the epidemiology of poor-quality anti-malarials in the malarious world - analysis of the WorldWide Antimalarial Resistance Network database

    Tabernero, Patricia; Facundo M Fernández; Green, Michael; Guerin, Philippe J; Newton, Paul N.

    2014-01-01

    Background Poor quality medicines threaten the lives of millions of patients and are alarmingly common in many parts of the world. Nevertheless, the global extent of the problem remains unknown. Accurate estimates of the epidemiology of poor quality medicines are sparse and are influenced by sampling methodology and diverse chemical analysis techniques. In order to understand the existing data, the Antimalarial Quality Scientific Group at WWARN built a comprehensive, open-access, global datab...

  14. Prioritization of anti-malarial hits from nature: chemo-informatic profiling of natural products with in vitro antiplasmodial activities and currently registered anti-malarial drugs

    Egieyeh, Samuel Ayodele; Syce, James; Malan, Sarel F.; Christoffels, Alan

    2016-01-01

    Background A large number of natural products have shown in vitro antiplasmodial activities. Early identification and prioritization of these natural products with potential for novel mechanism of action, desirable pharmacokinetics and likelihood for development into drugs is advantageous. Chemo-informatic profiling of these natural products were conducted and compared to currently registered anti-malarial drugs (CRAD). Methods Natural products with in vitro antiplasmodial activities (NAA) we...

  15. A fixed-dose 24-hour regimen of artesunate plus sulfamethoxypyrazine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum malaria in eastern Sudan

    Adam, Ishag; Magzoub, Mamoun; Osman, Maha E;

    2006-01-01

    BACKGROUND: Artemisinin-based combination therapy is increasingly being adopted as first-line antimalarial therapy. The choice of appropriate therapy depends on efficacy, cost, side effects, and simplicity of administration. METHODS: the efficacy of fixed co-formulated (f) artesunate...... the patients. CONCLUSION: both regimens of AS+SMP were effective and safe for the treatment of uncomplicated P. falciparum malaria in eastern Sudan. Due to its simplicity, the fixed dose one-day treatment regimen may improve compliance and therefore may be the preferred choice....

  16. A Cluster Randomised Trial Introducing Rapid Diagnostic Tests into Registered Drug Shops in Uganda: Impact on Appropriate Treatment of Malaria

    Mbonye, AK; Magnussen, P; Lal, S; Hansen, KS; Cundill, B; Chandler, C.; Clarke, SE

    2015-01-01

    Background Inappropriate treatment of malaria is widely reported particularly in areas where there is poor access to health facilities and self-treatment of fevers with anti-malarial drugs bought in shops is the most common form of care-seeking. The main objective of the study was to examine the impact of introducing rapid diagnostic tests for malaria (mRDTs) in registered drug shops in Uganda, with the aim to increase appropriate treatment of malaria with artemisinin-based combination therap...

  17. A SAR and QSAR Study of New Artemisinin Compounds with Antimalarial Activity

    Cleydson Breno R. Santos

    2013-12-01

    Full Text Available The Hartree-Fock method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with antimalarial activity. Maps of molecular electrostatic potential (MEPs and molecular docking were used to investigate the interaction between ligands and the receptor (heme. Principal component analysis and hierarchical cluster analysis were employed to select the most important descriptors related to activity. The correlation between biological activity and molecular properties was obtained using the partial least squares and principal component regression methods. The regression PLS and PCR models built in this study were also used to predict the antimalarial activity of 30 new artemisinin compounds with unknown activity. The models obtained showed not only statistical significance but also predictive ability. The significant molecular descriptors related to the compounds with antimalarial activity were the hydration energy (HE, the charge on the O11 oxygen atom (QO11, the torsion angle O1-O2-Fe-N2 (D2 and the maximum rate of R/Sanderson Electronegativity (RTe+. These variables led to a physical and structural explanation of the molecular properties that should be selected for when designing new ligands to be used as antimalarial agents.

  18. Amazonian Plant Natural Products: Perspectives for Discovery of New Antimalarial Drug Leads

    Lucio H. Freitas-Junior

    2013-08-01

    Full Text Available Plasmodium falciparum and P. vivax malaria parasites are now resistant, or showing signs of resistance, to most drugs used in therapy. Novel chemical entities that exhibit new mechanisms of antiplasmodial action are needed. New antimalarials that block transmission of Plasmodium spp. from humans to Anopheles mosquito vectors are key to malaria eradication efforts. Although P. vivax causes a considerable number of malaria cases, its importance has for long been neglected. Vivax malaria can cause severe manifestations and death; hence there is a need for P. vivax-directed research. Plants used in traditional medicine, namely Artemisia annua and Cinchona spp. are the sources of the antimalarial natural products artemisinin and quinine, respectively. Based on these compounds, semi-synthetic artemisinin-derivatives and synthetic quinoline antimalarials have been developed and are the most important drugs in the current therapeutic arsenal for combating malaria. In the Amazon region, where P. vivax predominates, there is a local tradition of using plant-derived preparations to treat malaria. Here, we review the current P. falciparum and P. vivax drug-sensitivity assays, focusing on challenges and perspectives of drug discovery for P. vivax, including tests against hypnozoites. We also present the latest findings of our group and others on the antiplasmodial and antimalarial chemical components from Amazonian plants that may be potential drug leads against malaria.

  19. Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity

    Rijpma, S.R.; Heuvel, J. J.; van de Velden, M.; Sauerwein, R. W.; Russel, F. G.; Koenderink, J.B.

    2014-01-01

    BACKGROUND: Therapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment. Pharmacokinetics of pharmaceutical compounds are dependent of adsorption, distribution, metabolism, and excretion. ATP binding cassette (ABC) transport proteins are particularly involved in drug deposition, as they are located at membranes of many uptake and excretory organs and at protective barriers, where they export endogenous and xenobiotic compounds, including pharmaceutica...

  20. New anti-HIV-1, antimalarial, and antifungal compounds from Terminalia bellerica

    Valsaraj, R; Pushpangadan, P; Smitt, U W;

    1997-01-01

    A bioactivity-guided fractionation of an extract of Terminalia bellerica fruit rind led to the isolation of two new lignans named termilignan (1) and thannilignan (2), together with 7-hydroxy-3',4'-(methylenedioxy)flavan (3) and anolignan B (4). All four compounds possessed demonstrable anti-HIV-......, antimalarial, and antifungal activity in vitro....

  1. Compound antimalarial ethosomal cataplasm: preparation, evaluation, and mechanism of penetration enhancement

    Shen S

    2015-06-01

    Full Text Available Shuo Shen, Shu-Zhi Liu, Yu-Shi Zhang, Mao-Bo Du, Ai-Hua Liang, Li-Hua Song, Zu-Guang Ye Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China Abstract: Malaria is still a serious public health problem in some parts of the world. The problems of recurrence and drug resistance are increasingly more serious. Thus, it is necessary to develop a novel antimalarial agent. The objectives of this study were to construct a novel compound antimalarial transdermal nanosystem–ethosomal cataplasm, to investigate its characteristics and efficiency, and to systematically explore the penetration-enhancing mechanisms of ethosomal cataplasm. Artesunate-loaded ethosomes and febrifugine-loaded ethosomes were prepared, and their characteristics were evaluated. Drug-loaded ethosomes were incorporated in the matrix of cataplasm to form the compound antimalarial ethosomal cataplasm. With the help of ethosomal technology, the accumulated permeation quantity of artesunate significantly increased at 8 hours after administration, which was 1.57 times as much as that of conventional cataplasm. Soon after administration, the ethosomal cataplasm could make a large quantity of antimalarial drug quickly penetrate through skin, then the remaining drug in the ethosomal cataplasm could be steadily released. These characteristics of ethosomal cataplasm are favorable for antimalarial drugs to kill Plasmodium spp. quickly and prevent the resurgence of Plasmodium spp. As expected, the ethosomal cataplasm showed good antimalarial efficiency in this experiment. The negative conversion rates were 100% and the recurrence rates were 0% at all dosages. The mechanism of penetration enhancement of the ethosomal cataplasm was systematically explored using an optics microscope, polarization microscope, and transmission electron microscopy. The microstructure, ultrastructure, and birefringent structure in skin were observed. Data

  2. In vitro antimalarial activity of extracts of some plants from a biological reserve in Costa Rica.

    Chinchilla, Misael; Valerio, Idalia; Sánchez, Ronald; Mora, Víctor; Bagnarello, Vanessa; Martínez, Laura; Gonzalez, Antonieta; Vanegas, Juan Carlos; Apestegui, Alvaro

    2012-06-01

    Treatment with the usual antimalarial drugs, have induced parasite resistance, reinforcing the need to finding natural antimalarial components that would be found on plants from the forest. Therefore, we decided to look for these components in Costa Rican plants from a protected forest area. Fresh and dry extracts of roots, bark, leaves, flowers and fruits of 25 plants from a biological reserve in Costa Rica, Reserva Biol6gica Alberto Manuel Brenes (REBAMB), were studied in vitro for the presence of substances with antimalarial activity. By studying the inhibition of P berghei schizogony, we assessed the antimalarial activity of several plant extracts: Aphelandra aurantiaca, A. tridentata (Acanthaceae); Xanthosoma undipes (Araceae); Iriartea deltoidea (Arecaceae); Neurolaena lobata (Asteraceae); Senna papillosa, Pterocarpus hayessi, Lonchocarpus pentaphyllus (Fabaceae); Nectandra membranacea, Persea povedae, Cinamomum chavarrianum (Lauraceae); Hampea appendiculata (Malvaceae); Ruagea glabra, Guarea glabra (Meliaceae); Psidium guajava (Myrtaceae); Bocconia frutescens (Papaveraceae); Piper friedrichsthalii (Piperaceae); Clematis dioica (Ranunculaceae); Prunus annularis (Rosaceae); Siparuna thecaphora (Siparunaceae); Solanum arboreum, Witheringia solanacea (Solanaceae); Ticodendrum incognitum (Ticodendraceae); Heliocarpus appendiculatus (Tiliaceae) and Myriocarpa longipes (Urticaceae). We used different parts of the plants as well as fresh and dried extracts for testing IC50. The solid content of the extracts ranged from 1-71.9 microg/mL. The fresh extracts showed stronger activity than the dry ones. Since the plants showing the strongest antimalarial activity are very common in Central America, and some similar genera of these plants have shown positives results in South America, we considered important to present these findings for discussion. On the other hand, this is the first systematic study of this kind ever realized in a circumscribed and protected area of

  3. Anti-malarial effect of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one and green tea extract on erythrocyte-stage Plasmodium berghei in mice

    Phitsinee; Thipubon; Wachiraporn; Tipsuwan; Chairat; Uthaipibull; Sineenart; Santitherakul; Somdet; Srichiratanakool

    2015-01-01

    Objective: To examine the efficacy of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one(CM1) iron chelator and green tea extract(GTE) as anti-malarial activity in Plasmodium berghei(P. berghei) infected mice.Methods: The CM1(0–100 mg/kg/day) and GTE(0–100 mg(-)-epigallocatechin 3-gallate equivalent/kg/day) were orally administered to P. berghei infected mice for consecutive 4 days. Parasitized red blood cells(PRBC) were enumerated by using Giemsa staining microscopic method.Results: CM1 lowered percentage of PRBC in dose-dependent manner with an ED50 value of 56.91 mg/kg, when compared with pyrimethamine(PYR)(ED50= 0.76 mg/kg).GTE treatment did not show any inhibition of the malaria parasite growth. In combined treatment, CM1 along with 0.6 mg/kg PYR significantly inhibited the growth of P. berghei in mice while GTE did not enhance the PYR anti-malarial activity.Conclusions: CM1 would be effective per se and synergize with PYR in inhibiting growth of murine malaria parasites, possibly by limiting iron supply from plasma transferrin and host PRBC cytoplasm, and chelating catalytic iron cstitutive in parasites’ mitochondrial cytochromes and cytoplasmic ribonucleotide reductase. CM1 would be a promising adjuvant to enhance PYR anti-malarial activity and minimize the drug resistance.

  4. Anti-malarial effect of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one and green tea extract on erythrocyte-stage Plasmodium berghei in mice

    Phitsinee Thipubon; Wachiraporn Tipsuwan; Chairat Uthaipibull; Sineenart Santitherakul; Somdet Srichiratanakool

    2015-01-01

    Objective:To examine the efficacy of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) iron chelator and green tea extract (GTE) as anti-malarial activity in Plasmodium berghei (P. berghei ) infected mice. Methods:The CM1 (0–100 mg/kg/day) and GTE (0–100 mg (-)-epigallocatechin 3-gallate equivalent/kg/day) were orally administered to P. berghei infected mice for consecutive 4 days. Parasitized red blood cells (PRBC) were enumerated by using Giemsa staining microscopic method. Results: CM1 lowered percentage of PRBC in dose-dependent manner with an ED50 value of 56.91 mg/kg, when compared with pyrimethamine (PYR) (ED50=0.76 mg/kg). GTE treatment did not show any inhibition of the malaria parasite growth. In combined treatment, CM1 along with 0.6 mg/kg PYR significantly inhibited the growth of P. berghei in mice while GTE did not enhance the PYR anti-malarial activity. Conclusions: CM1 would be effective per se and synergize with PYR in inhibiting growth of murine malaria parasites, possibly by limiting iron supply from plasma transferrin and host PRBC cytoplasm, and chelating catalytic iron constitutive in parasites’ mitochondrial cytochromes and cytoplasmic ribonucleotide reductase. CM1 would be a promising adjuvant to enhance PYR anti-malarial activity and minimize the drug resistance.

  5. A study of toxicity and differential gene expression in murine liver following exposure to anti-malarial drugs: amodiaquine and sulphadoxine-pyrimethamine

    Rath Srikanta

    2011-05-01

    Full Text Available Abstract Background Amodiaquine (AQ along with sulphadoxine-pyrimethamine (SP offers effective and cheaper treatment against chloroquine-resistant falciparum malaria in many parts of sub-Saharan Africa. Considering the previous history of hepatitis, agranulocytosis and neutrocytopenia associated with AQ monotherapy, it becomes imperative to study the toxicity of co-administration of AQ and SP. In this study, toxicity and resulting global differential gene expression was analyzed following exposure to these drugs in experimental Swiss mice. Methods The conventional markers of toxicity in serum, oxidative stress parameters in tissue homogenates, histology of liver and alterations in global transcriptomic expression were evaluated to study the toxic effects of AQ and SP in isolation and in combination. Results The combination therapy of AQ and SP results in more pronounced hepatotoxicity as revealed by elevated level of serum ALT, AST with respect to their individual drug exposure regimen. Furthermore, alterations in the activity of major antioxidant enzymes (glutathione peroxidase, superoxide dismutase, catalase, glutathione reductase, indicating the development of oxidative stress, was more significant in AQ+SP combination therapy. cDNA microarray results too showed considerably more perturbed gene expression following combination therapy of AQ and SP as compared to their individual drug treatment. Moreover, a set of genes were identified whose expression pattern can be further investigated for identifying a good biomarker for potential anti-malarial hepatotoxicity. Conclusion These observations clearly indicate AQ+SP combination therapy is hepatotoxic in experimental Swiss mice. Microarray results provide a considerable number of potential biomarkers of anti-malarial drug toxicity. These findings hence will be useful for future drug toxicity studies, albeit implications of this study in clinical conditions need to be monitored with cautions.

  6. Synthesis and evaluation of antimalarial activity of curcumin derivatives; Sintese e avaliacao da atividade antimalarica de compostos derivados da curcumina

    Gomes, Patricia Ramos; Miguel, Fabio Balbino; Almeida, Mauro Vieira de; Couri, Mara Rubia Costa [Universidade Federal de Juiz de Fora (UFSJ), MG (Brazil). Instituto de Ciencias Exatas. Departamento de Quimica; Oliveira, Michael Eder de; Ferreira, Vanessa Viana; Guimaraes, Daniel Silqueira Martins; Lima, Aline Brito de; Barbosa, Camila de Souza; Oliveira, Mariana Amorim de; Almeida, Mauro Vieira de; Viana, Gustavo Henrique Ribeiro; Varotti, Fernando de Pilla, E-mail: varotti@ufsj.edu.br [Universidade Federal de Sao Joao Del Rei (UFSJ), MG (Brazil). Centro de Ciencias da Saude; and others

    2014-05-15

    ne of the main challenges in the development of new antimalarial drugs is to achieve a viable lead candidate with good pharmacokinetic properties. Curcumin has a broad range of biological activities, including antimalarial activity. Herein, we report the antimalarial activity of six curcumin derivatives (6-12) and an initial analysis of their pharmacokinetic properties. Five compounds have demonstrated potent activity against the P. falciparum in vitro (IC{sub 50} values ranging from 1.7 to 15.2 μg mL{sup -1}), with moderate or low cytotoxicity against the HeLa cell line. The substitution of the carbonyl group in 6 by a 2,4-dinitrophenylhydrazone group (to afford 11) increases the Selective Index. These preliminary results indicate curcumin derivatives as potential antimalarial compounds. (author)

  7. Gel versus capillary electrophoresis genotyping for categorizing treatment outcomes in two anti-malarial trials in Uganda

    Hubbard Alan E; Dorsey Grant; Gupta Vinay; Rosenthal Philip J; Greenhouse Bryan

    2010-01-01

    Abstract Background Molecular genotyping is performed in anti-malarial trials to determine whether recurrent parasitaemia after therapy represents a recrudescence (treatment failure) or new infection. The use of capillary instead of agarose gel electrophoresis for genotyping offers technical advantages, but it is unclear whether capillary electrophoresis will result in improved classification of anti-malarial treatment outcomes. Methods Samples were genotyped using both gel and capillary elec...

  8. Evaluation of antimalarial activity of leaves of Acokanthera schimperi and Croton macrostachyus against Plasmodium berghei in Swiss albino mice

    Mohammed, Tigist; Erko, Berhanu; Giday, Mirutse

    2014-01-01

    Background Malaria is one of the most important tropical diseases and the greatest cause of hospitalization and death. Recurring problems of drug resistance are reinforcing the need for finding new antimalarial drugs. In this respect, natural plant products are the main sources of biologically active compounds and have potential for the development of novel antimalarial drugs. A study was conducted to evaluate extracts of the leaves of Croton macrostachyus and Acokanthera schimperi for their ...

  9. Development of a Specific Monoclonal Antibody-Based ELISA to Measure the Artemether Content of Antimalarial Drugs

    Suqin Guo; Yongliang Cui; Lishan He; Liang Zhang; Zhen Cao; Wei Zhang; Rui Zhang; Guiyu Tan; Baomin Wang; Liwang Cui

    2013-01-01

    Artemether is one of the artemisinin derivatives that are active ingredients in antimalarial drugs. Counterfeit and substandard antimalarial drugs have become a serious problem, which demands reliable analytical tools and implementation of strict regulation of drug quality. Structural similarity among artemisinin analogs is a challenge to develop immunoassays that are specific to artemisinin derivatives. To produce specific antibodies to artemether, we used microbial fermentation of artemethe...

  10. Antimalarial potential of homeopathic medicines against schizont maturation of Plasmodium berghei in short-term in vitro culture

    Upma Bagai; Aswathy Rajan

    2012-01-01

    In vitro assessment of antimalarial drug susceptibility of Plasmodium has been a major research success, which has paved the way for the understanding of parasite and rapid screening of antimalarial drugs for their effectiveness. In the present study a preliminary screening to check the antiplasmodial activity of mother tincture (ϕ) and various potencies (6C, 30C, 200C) of homeopathic medicines Cinchona officinalis/china (Chin.), Chelidonium majus (Chel.) and Arsenicum album (Ars.) were done ...

  11. Stage-specific activity of potential antimalarial compounds measured in vitro by flow cytometry in comparison to optical microscopy and hypoxanthine uptake

    Carmen E Contreras

    2004-03-01

    Full Text Available The evaluation of new antimalarial agents using older methods of monitoring sensitivity to antimalarial drugs are laborious and poorly suited to discriminate stage-specific activity. We used flow cytometry to study the effect of established antimalarial compounds, cysteine protease inhibitors, and a quinolone against asexual stages of Plasmodium falciparum. Cultured P. falciparum parasites were treated for 48 h with different drug concentrations and the parasitemia was determined by flow cytometry methods after DNA staining with propidium iodide. P. falciparum erythrocytic life cycle stages were readily distinguished by flow cytometry. Activities of established and new antimalarial compounds measured by flow cytometry were equivalent to results obtained with microscopy and metabolite uptake assays. The antimalarial activity of all compounds was higher against P. falciparum trophozoite stages. Advantages of flow cytometry analysis over traditional assays included higher throughput for data collection, insight into the stage-specificity of antimalarial activity avoiding use of radioactive isotopes.

  12. CPP-ZFN: A potential DNA-targeting anti-malarial drug

    Nain Vikrant

    2010-09-01

    Full Text Available Abstract Background Multidrug-resistant Plasmodium is of major concern today. Effective vaccines or successful applications of RNAi-based strategies for the treatment of malaria are currently unavailable. An unexplored area in the field of malaria research is the development of DNA-targeting drugs that can specifically interact with parasitic DNA and introduce deleterious changes, leading to loss of vital genome function and parasite death. Presentation of the hypothesis Advances in the development of zinc finger nuclease (ZFN with engineered DNA recognition domains allow us to design and develop nuclease of high target sequence specificity with a mega recognition site that typically occurs only once in the genome. Moreover, cell-penetrating peptides (CPP can cross the cell plasma membrane and deliver conjugated protein, nucleic acid, or any other cargo to the cytoplasm, nucleus, or mitochondria. This article proposes that a drug from the combination of the CPP and ZFN systems can effectively enter the intracellular parasite, introduce deleterious changes in its genome, and eliminate the parasite from the infected cells. Testing the hypothesis Availability of a DNA-binding motif for more than 45 triplets and its modular nature, with freedom to change number of fingers in a ZFN, makes development of customized ZFN against diverse target DNA sequence of any gene feasible. Since the Plasmodium genome is highly AT rich, there is considerable sequence site diversity even for the structurally and functionally conserved enzymes between Plasmodium and humans. CPP can be used to deliver ZFN to the intracellular nucleus of the parasite. Signal-peptide-based heterologous protein translocation to Plasmodium-infected RBCs (iRBCs and different Plasmodium organelles have been achieved. With successful fusion of CPP with mitochondrial- and nuclear-targeting peptides, fusion of CPP with 1 more Plasmodium cell membrane translocation peptide seems achievable

  13. Screening of the antimalarial activity of plants of the Cucurbitaceae family

    Cláudia Zuany Amorim

    1991-01-01

    Full Text Available Crude ethanolic extracts (CEEs from two species of Cucurbitaceae, Cucurbita maxima and Momordica charantia (commonly called "abóbora moranga" and melão de São Caetano", respectively were assayed for antimalarial activity by the 4-d suppressive test. The CEE of dry C. maxima seeds showed strong antimalarial activity following oral administration (259 and 500 mg/kg, reducing by 50% the levels of parasistemia in Plasmodium berghey-infected mice. Treatment of normal animals with 500 mg/Kg of the extract three days before intravenous injection of P. berghei caused a significant 30% reduction in parasitemic levels. No effect was observed when the animals were treated with the CEE only on the day of inoculation. Oral administration of the CEE of dry M. charantia leaves adminstered orally was ineffective up to 500 mg/Kg in lowering the parasitemic levels of malarious mice.

  14. A novel multiple-stage antimalarial agent that inhibits protein synthesis

    Baragaña, Beatriz; Hallyburton, Irene; Lee, Marcus C. S.; Norcross, Neil R.; Grimaldi, Raffaella; Otto, Thomas D.; Proto, William R.; Blagborough, Andrew M.; Meister, Stephan; Wirjanata, Grennady; Ruecker, Andrea; Upton, Leanna M.; Abraham, Tara S.; Almeida, Mariana J.; Pradhan, Anupam; Porzelle, Achim; Martínez, María Santos; Bolscher, Judith M.; Woodland, Andrew; Norval, Suzanne; Zuccotto, Fabio; Thomas, John; Simeons, Frederick; Stojanovski, Laste; Osuna-Cabello, Maria; Brock, Paddy M.; Churcher, Tom S.; Sala, Katarzyna A.; Zakutansky, Sara E.; Jiménez-Díaz, María Belén; Sanz, Laura Maria; Riley, Jennifer; Basak, Rajshekhar; Campbell, Michael; Avery, Vicky M.; Sauerwein, Robert W; Dechering, Koen J.; Noviyanti, Rintis; Campo, Brice; Frearson, Julie A.; Angulo-Barturen, Iñigo; Ferrer-Bazaga, Santiago; Gamo, Francisco Javier; Wyatt, Paul G.; Leroy, Didier; Siegl, Peter; Delves, Michael J.; Kyle, Dennis E.; Wittlin, Sergio; Marfurt, Jutta; Price, Ric N.; Sinden, Robert E.; Winzeler, Elizabeth; Charman, Susan A.; Bebrevska, Lidiya; Gray, David W.; Campbell, Simon; Fairlamb, Alan H.; Willis, Paul; Rayner, Julian C.; Fidock, David A.; Read, Kevin D.; Gilbert, Ian H.

    2015-01-01

    Summary There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. We describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the parasite, with good pharmacokinetic properties, and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along mRNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery. PMID:26085270

  15. Saleability of anti-malarials in private drug shops in Muheza, Tanzania

    Ringsted, Frank M; Massawe, Isolide S; Lemnge, Martha M;

    2011-01-01

    women depend on SP for Intermittent Preventive Treatment (IPTp) during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may undermine its official use for IPTp through induction of resistance. The main study objective was to perform a...... baseline study of the private market for anti-malarials in Muheza town, an area with widespread anti-malarial drug resistance, prior to the implementation of a provider training and accreditation programme that will allow accredited drug shops to sell subsidized ALu. Methods: All drug shops selling...... resistance remains high, unregulated SP dispensing to people other than pregnant women runs the risk of eventually jeopardizing the effectiveness of the IPTp strategy. Further studies are recommended to find out barriers for ACT utilization and preference for self-medication and to train private drug...

  16. A novel multiple-stage antimalarial agent that inhibits protein synthesis

    Baragaña, Beatriz; Hallyburton, Irene; Lee, Marcus C. S.; Norcross, Neil R.; Grimaldi, Raffaella; Otto, Thomas D.; Proto, William R.; Blagborough, Andrew M.; Meister, Stephan; Wirjanata, Grennady; Ruecker, Andrea; Upton, Leanna M.; Abraham, Tara S.; Almeida, Mariana J.; Pradhan, Anupam; Porzelle, Achim; Martínez, María Santos; Bolscher, Judith M.; Woodland, Andrew; Norval, Suzanne; Zuccotto, Fabio; Thomas, John; Simeons, Frederick; Stojanovski, Laste; Osuna-Cabello, Maria; Brock, Paddy M.; Churcher, Tom S.; Sala, Katarzyna A.; Zakutansky, Sara E.; Jiménez-Díaz, María Belén; Sanz, Laura Maria; Riley, Jennifer; Basak, Rajshekhar; Campbell, Michael; Avery, Vicky M.; Sauerwein, Robert W.; Dechering, Koen J.; Noviyanti, Rintis; Campo, Brice; Frearson, Julie A.; Angulo-Barturen, Iñigo; Ferrer-Bazaga, Santiago; Gamo, Francisco Javier; Wyatt, Paul G.; Leroy, Didier; Siegl, Peter; Delves, Michael J.; Kyle, Dennis E.; Wittlin, Sergio; Marfurt, Jutta; Price, Ric N.; Sinden, Robert E.; Winzeler, Elizabeth A.; Charman, Susan A.; Bebrevska, Lidiya; Gray, David W.; Campbell, Simon; Fairlamb, Alan H.; Willis, Paul A.; Rayner, Julian C.; Fidock, David A.; Read, Kevin D.; Gilbert, Ian H.

    2015-06-01

    There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.

  17. Exploring the 3-piperidin-4-yl-1H-indole scaffold as a novel antimalarial chemotype.

    Santos, Sofia A; Lukens, Amanda K; Coelho, Lis; Nogueira, Fátima; Wirth, Dyann F; Mazitschek, Ralph; Moreira, Rui; Paulo, Alexandra

    2015-09-18

    A series of 3-piperidin-4-yl-1H-indoles with building block diversity was synthesized based on a hit derived from an HTS whole-cell screen against Plasmodium falciparum. Thirty-eight compounds were obtained following a three-step synthetic approach and evaluated for anti-parasitic activity. The SAR shows that 3-piperidin-4-yl-1H-indole is intolerant to most N-piperidinyl modifications. Nevertheless, we were able to identify a new compound (10d) with lead-like properties (MW = 305; cLogP = 2.42), showing antimalarial activity against drug-resistant and sensitive strains (EC50 values ∼ 3 μM), selectivity for malaria parasite and no cross-resistance with chloroquine, thus representing a potential new chemotype for further optimization towards novel and affordable antimalarial drugs. PMID:26295174

  18. Detection of In Vitro Antimalarial Activity of Some Myanmar Medicinal Plants

    In order to find out the novel effective antimalarials. six medicinal plants, namely Erythrina stricta Roxb. (Kathit), Luffa acutangula Roxb. (Thabut - Kja), Cordia rothii Roem. and Schult. (Thanet), Tribulus terrestris Linn. (Sule). Zizphus oenoplia Mill. (Paung - pe) and Mimusops elengi Roxb. (Khaye) were selected and tested for their antimalarial activity by using in vitro microdilution technique. According to the in vitro test results, Erythrina stricta Roxb. (Kathit) was found to possess significant suppressive effect on Plasmodium falciparum. With the serially diluted extract dosage concentrations ranging from 1.250 ng/ml to 40,000 ng/ml, the schizont suppressive percentage of Eryhrina stricta Roxb. (Kathi) was observed to be 19.57%, 35.44%, 55.18%, 96.04%,100% and 100% respectively

  19. In vitro inhibition of Plasmodium falciparum by substances isolated from Amazonian antimalarial plants

    Valter F de Andrade-Neto

    2007-06-01

    Full Text Available In the present study, a quassinoid, neosergeolide, isolated from the roots and stems of Picrolemma sprucei (Simaroubaceae, the indole alkaloids ellipticine and aspidocarpine, isolated from the bark of Aspidosperma vargasii and A. desmanthum (Apocynaceae, respectively, and 4-nerolidylcatechol, isolated from the roots of Pothomorphe peltata (Piperaceae, all presented significant in vitro inhibition (more active than quinine and chloroquine of the multi-drug resistant K1 strain of Plasmodium falciparum. Neosergeolide presented activity in the nanomolar range. This is the first report on the antimalarial activity of these known, natural compounds. This is also the first report on the isolation of aspidocarpine from A. desmanthum. These compounds are good candidates for pre-clinical tests as novel lead structures with the aim of finding new antimalarial prototypes and lend support to the traditional use of the plants from which these compounds are derived.

  20. Hallazgos complementarios sobre la actividad antimalarica del azul de metileno = Complementary findings on the antimalarial activity and toxicity of methylene blue

    G. Garavito; Bertani, S; Deharo, Eric

    2008-01-01

    Methylene blue was reported as the first synthetic antimalarial by Ehrlich in 1881. It is currently no longer used for that purpose but it should be reconsidered since new economic alternatives are urgently needed in the arsenal of antimalarial drugs. The antimalarial activity of methylene blue is investigated here in vivo against rodent malaria parasites. 15 mg/kg daily dose of methylene blue inhibits 50% of the erythrocytic parasite growth of Plasmodium berghei and R yoelii nigeriensis, whi...

  1. Effect of Disposition of Mannich Antimalarial Agents on Their Pharmacology and Toxicology

    Ruscoe, J. E.; Tingle, M. D.; O’Neill, P. M.; S.A. Ward; Park, B K

    1998-01-01

    The use of the antimalarial agent amodiaquine has been curtailed due to drug-induced idiosyncratic reactions. These have been attributed to the formation of a protein-reactive quinoneimine species via oxidation of the 4-aminophenol group. Therefore, the effects of chemical modifications on the disposition of amodiaquine in relation to its metabolism, distribution, and pharmacological activity have been investigated. The inclusion of a group at the C-5′ position of amodiaquine reduced or elimi...

  2. Novel Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Anti-malarial Activity in the Mouse Model*

    Booker, Michael L.; Bastos, Cecilia M.; Kramer, Martin L.; Barker, Robert H.; Skerlj, Renato; Sidhu, Amar Bir; Deng, Xiaoyi; Celatka, Cassandra; Cortese, Joseph F.; Guerrero Bravo, Jose E.; Crespo Llado, Keila N.; Serrano, Adelfa E.; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Viera, Sara

    2010-01-01

    Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. A high throughput screen and subsequent medicinal chemistry program identified a series of N-alkyl-5-(1H-benzimidazol-1-yl)thiophene-2-carboxamides with low ...

  3. Preliminary assessment of medicinal plants used as antimalarials in the southeastern Venezuelan Amazon

    Caraballo Alejandro

    2004-01-01

    Full Text Available Eighteen species of medicinal plants used in the treatment of malaria in Bolívar State, Venezuela were recorded and they belonged to Compositae, Meliaceae, Anacardiaceae, Bixaceae, Boraginaceae, Caricaceae, Cucurbitaceae, Euphorbiaceae, Leguminosae, Myrtaceae, Phytolaccaceae, Plantaginaceae, Scrophulariaceae, Solanaceae and Verbenaceae families. Antimalarial plant activities have been linked to a range of compounds including anthroquinones, berberine, flavonoids, limonoids, naphthquinones, sesquiterpenes, quassinoids, indol and quinoline alkaloids.

  4. Medicines informal market in Congo, Burundi and Angola: counterfeit and sub-standard antimalarials

    Bertocchi Paola; Antoniella Eleonora; Cocchieri Emilia; Di Maggio Anna; Gaudiano Maria; Alimonti Stefano; Valvo Luisa

    2007-01-01

    Abstract Background The presence of counterfeits and sub-standards in African medicines market is a dramatic problem that causes many deaths each year. The increase of the phenomenon of pharmaceutical counterfeiting is due to the rise of the illegal market and to the impossibility to purchase branded high cost medicines. Methods In this paper the results of a quality control on antimalarial tablet samples purchased in the informal market in Congo, Burundi and Angola are reported. The quality ...

  5. Antimalarial Chemotherapy: Natural Product Inspired Development of Preclinical and Clinical Candidates with Diverse Mechanisms of Action.

    Fernández-Álvaro, Elena; Hong, W David; Nixon, Gemma L; O'Neill, Paul M; Calderón, Félix

    2016-06-23

    Natural products have played a pivotal role in malaria chemotherapy progressing from quinine and artemisinin to ozonide-based compounds. Many of these natural products have served as template for the design and development of antimalarial drugs currently in the clinic or in the development phase. In this review, we will detail those privileged scaffolds that have guided medicinal chemistry efforts yielding molecules that have reached the clinic. PMID:26791529

  6. Surveillance of antimalarial drug resistance in China in the 1980s–1990s

    Liu, De-Quan

    2014-01-01

    Since the successful preparation of the microplates and the medium for field application, the resistance degree and its geographical distribution of chloroquine-resistant Plasmodium falciparum, the fluctuation of the resistance degree of P. falciparum to chloroquine, and the sensitivity of the parasite to commonly used antimalarial drugs were investigated between 1980 and 2003 by the in vitro microtest and the in vivo four-week test recommended by the World Health Organization (WHO). The resu...

  7. A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya.

    Jason P Wendler

    Full Text Available BACKGROUND: Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs. METHODS AND PRINCIPAL FINDINGS: Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set. CONCLUSIONS/SIGNIFICANCE: Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ.

  8. Anti-malarial drugs and the prevention of malaria in the population of malaria endemic areas

    Greenwood Brian

    2010-01-01

    Abstract Anti-malarial drugs can make a significant contribution to the control of malaria in endemic areas when used for prevention as well as for treatment. Chemoprophylaxis is effective in preventing deaths and morbidity from malaria, but it is difficult to sustain for prolonged periods, may interfere with the development of naturally acquired immunity and will facilitate the emergence and spread of drug resistant strains if applied to a whole community. However, chemoprophylaxis targeted ...

  9. Synthesis and in vitro antimalarial activity of novel chalcone derivatives / Frans Johannes Smit

    Smit, Frans Johannes

    2014-01-01

    Malaria is endemic in 106 countries worldwide. This disease is caused by a parasite from the genus Plasmodium. Of the five species that infect humans, Plasmodium falciparum is the most virulent, with over three billion people at risk and around 660 000 deaths reported in 2011. Of these deaths, 91% were in the African region, while 86% were children under the age of five. In light of the widespread development of resistance by malaria parasites against the classic antimalarial drugs, such as c...

  10. Amazonian plant natural products:perspectives for discovery of new antimalarial drug leads

    Lucio H Freitas-Junior; Pedro Cravo; Marcus Vinícius Guimarães Lacerda; André Machado Siqueira; Carolina Borsoi Moraes; Gina Frausin; Luiz Francisco Rocha e Silva; Stefanie Costa Pinto Lopes; Renata Braga Souza Lima; Fabio Trindade Maranhão Costa; Adrian Martin Pohlit

    2013-01-01

    Plasmodium falciparum and P. vivax malaria parasites are now resistant, or showing signs of resistance, to most drugs used in therapy. Novel chemical entities that exhibit new mechanisms of antiplasmodial action are needed. New antimalarials that block transmission of Plasmodium spp. from humans to Anopheles mosquito vectors are key to malaria eradication efforts. Although P. vivax causes a considerable number of malaria cases, its importance has for long been neglected. Vivax malaria can cau...

  11. ANTIMALARIAL DRUGS IN THERAPY OF SYSTEMIC LUPUS ERYTHEMATOSUS: PAST, PRESENT, FUTURE

    Tatyana Andreyevna Lisitsyna; N. M. Kosheleva

    2010-01-01

    The data available in the literature on experience in using antimalarial drugs in the treatment of systemic lupus erythematosus are summarized. A major emphasis is placed on therapy with hydroxychlorochine (plaquenil) versus chlorine. Possible mechanisms of action of the drug and its effect on the course of the disease itself and concomitant abnormalities are described. Data on the toxicity of the drug and its safe use in pregnancy and lactation are also discussed

  12. ANTIMALARIAL DRUGS IN THERAPY OF SYSTEMIC LUPUS ERYTHEMATOSUS: PAST, PRESENT, FUTURE

    Tatyana Andreyevna Lisitsyna

    2010-01-01

    Full Text Available The data available in the literature on experience in using antimalarial drugs in the treatment of systemic lupus erythematosus are summarized. A major emphasis is placed on therapy with hydroxychlorochine (plaquenil versus chlorine. Possible mechanisms of action of the drug and its effect on the course of the disease itself and concomitant abnormalities are described. Data on the toxicity of the drug and its safe use in pregnancy and lactation are also discussed

  13. Serine Proteases of Malaria Parasite Plasmodium falciparum: Potential as Antimalarial Drug Targets

    Asrar Alam

    2014-01-01

    Malaria is a major global parasitic disease and a cause of enormous mortality and morbidity. Widespread drug resistance against currently available antimalarials warrants the identification of novel drug targets and development of new drugs. Malarial proteases are a group of molecules that serve as potential drug targets because of their essentiality for parasite life cycle stages and feasibility of designing specific inhibitors against them. Proteases belonging to various mechanistic classes...

  14. Antimalarial and cytotoxic properties of Chukrasia tabularis A. Juss and Turraea vogelii Hook F. Ex. Benth.

    Ogbole, Omonike O; Saka, Yusuf A; Fasinu, Pius S; Fadare, Adenike A; Ajaiyeoba, Edith O

    2016-04-01

    Malaria, caused by plasmodium parasite, is at the moment the highest cause of morbidity and mortality in the tropics. Recently, there is increasing efforts to develop more potent antimalarials from plant sources that will have little or no adverse effects. This study is aimed at investigating the in vivo mice antimalarial and in vitro antiplasmodial effects of two Meliaceae plants commonly used in Nigerian ethnomedicine as part of recipe for treating malaria infection: Chukrasia tabularis and Turraea vogelii. Hot water decoction and methanol extract of both plants were evaluated for their antimalarial activity in vivo using the mice model assay and in vitro using the parasite lactate dehydrogenase (pLDH) assay. The extracts were also assessed for toxicity with brine shrimp lethality assay and in mammalian cell lines using the neural red assay. The in vivo mice model antimalarial study showed that the methanol extract of the stem bark of C. tabularis exhibited the highest % chemosuppression (83.65 ± 0.66) at the highest dosage administered (800 mg/kg) when compared with chloroquine diphosphate, the standard reference drug which had a % suppression of 90.36 ± 0.04 (p < 0.05). The in vitro antiplasmodial study indicated that the aqueous extract of the stem bark of C. tabularis displayed good activity against Plasmodium falciparum chloroquine-sensitive (D6) strain (IC50 of 10.739 μg/mL) and chloroquine-resistant (W2) strain. Chloroquine and artemisinin had <0.163 and <0.0264, respectively. PMID:26911147

  15. Altered plasmodial surface anion channel activity and in vitro resistance to permeating antimalarial compounds

    Lisk, Godfrey; Pain, Margaret; Sellers, Morgan; Gurnev, Philip A.; Pillai, Ajay D.; Bezrukov, Sergey M.; Desai, Sanjay A.

    2010-01-01

    Erythrocytes infected with malaria parasites have increased permeability to various solutes. These changes may be mediated by an unusual small conductance ion channel known as the plasmodial surface anion channel (PSAC). While channel activity benefits the parasite by permitting nutrient acquisition, it can also be detrimental because water-soluble antimalarials may more readily access their parasite targets via this channel. Recently, two such toxins, blasticidin S and leupeptin, were used t...

  16. Natural polyhydroxyalkanoate–gold nanocomposite based biosensor for detection of antimalarial drug artemisinin

    The worrisome trend of antimalarial resistance has already highlighted the importance of artemisinin as a potent antimalarial agent. The current investigation aimed at fabricating a biosensor based on natural polymer polyhydroxyalkanoate–gold nanoparticle composite mounting on an indium-tin oxide glass plate for the analysis of artemisinin. The biosensor was fabricated using an adsorbing horse-radish peroxidase enzyme on the electrode surface for which cyclic voltammetry was used to monitor the electro-catalytic reduction of artemisinin under diffusion controlled conditions. Electrochemical interfacial properties and immobilization of enzyme onto a polyhydroxyalkanoate–gold nanoparticle film were evaluated, and confirmed by cyclic voltammetry, electrochemical impedance spectroscopy and scanning electron microscopy. The differential pulse voltammetric peak current for artemisinin was increased linearly (concentration range of 0.01–0.08 μg mL−1) with sensitivity of 0.26 μA μg mL−1. The greater sensitivity of the fabricated biosensor to artemisinin (optimum limits of detection were 0.0035 μg mL−1 and 0.0036 μg mL−1 in bulk and spiked human serum, respectively) could be of much aid in medical diagnosis. - Highlights: • Extraction of PHA from indigenously isolated Pseudomonas aeruginosa BPC2 • Developed PHA/AuNPs/HRP/ITO based biosensor without the use of chemical cross linker • Detection of antimalarial drug artemisinin using the nanocomposite based biosensor

  17. Safety, Tolerability, and Compliance with Long-Term Antimalarial Chemoprophylaxis in American Soldiers in Afghanistan.

    Saunders, David L; Garges, Eric; Manning, Jessica E; Bennett, Kent; Schaffer, Sarah; Kosmowski, Andrew J; Magill, Alan J

    2015-09-01

    Long-term antimalarial chemoprophylaxis is currently used by deployed U.S. military personnel. Previous small, short-term efficacy studies have shown variable rates of side effects among patients taking various forms of chemoprophylaxis, though reliable safety and tolerability data on long-term use are limited. We conducted a survey of troops returning to Fort Drum, NY following a 12-month deployment to Operation Enduring Freedom, Afghanistan from 2006 to 2007. Of the 2,351 respondents, 95% reported taking at least one form of prophylaxis during their deployment, and 90% were deployed for > 10 months. Compliance with daily doxycycline was poor (60%) compared with 80% with weekly mefloquine (MQ). Adverse events (AEs) were reported by approximately 30% with both MQ and doxycycline, with 10% discontinuing doxycycline compared with 4% of MQ users. Only 6% and 31% of soldiers reported use of bed nets and skin repellents, respectively. Compliance with long-term malaria prophylaxis was poor, and there were substantial tolerability issues based on these anonymous survey results, though fewer with MQ than doxycycline. Given few long-term antimalarial chemoprophylaxis options, there is an unmet medical need for new antimalarials safe for long-term use. PMID:26123954

  18. Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum

    Vaidya, Akhil B.; Morrisey, Joanne M.; Zhang, Zhongsheng; Das, Sudipta; Daly, Thomas M.; Otto, Thomas D.; Spillman, Natalie J.; Wyvratt, Matthew; Siegl, Peter; Marfurt, Jutta; Wirjanata, Grennady; Sebayang, Boni F.; Price, Ric N.; Chatterjee, Arnab; Nagle, Advait; Stasiak, Marcin; Charman, Susan A.; Angulo-Barturen, Iñigo; Ferrer, Santiago; Belén Jiménez-Díaz, María; Martínez, María Santos; Gamo, Francisco Javier; Avery, Vicky M.; Ruecker, Andrea; Delves, Michael; Kirk, Kiaran; Berriman, Matthew; Kortagere, Sandhya; Burrows, Jeremy; Fan, Erkang; Bergman, Lawrence W.

    2014-01-01

    The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na+ regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na+ homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na+ homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes. PMID:25422853

  19. Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum.

    Vaidya, Akhil B; Morrisey, Joanne M; Zhang, Zhongsheng; Das, Sudipta; Daly, Thomas M; Otto, Thomas D; Spillman, Natalie J; Wyvratt, Matthew; Siegl, Peter; Marfurt, Jutta; Wirjanata, Grennady; Sebayang, Boni F; Price, Ric N; Chatterjee, Arnab; Nagle, Advait; Stasiak, Marcin; Charman, Susan A; Angulo-Barturen, Iñigo; Ferrer, Santiago; Belén Jiménez-Díaz, María; Martínez, María Santos; Gamo, Francisco Javier; Avery, Vicky M; Ruecker, Andrea; Delves, Michael; Kirk, Kiaran; Berriman, Matthew; Kortagere, Sandhya; Burrows, Jeremy; Fan, Erkang; Bergman, Lawrence W

    2014-01-01

    The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na(+) homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes. PMID:25422853

  20. Metabolic Dysregulation Induced in Plasmodium falciparum by Dihydroartemisinin and Other Front-Line Antimalarial Drugs.

    Cobbold, Simon A; Chua, Hwa H; Nijagal, Brunda; Creek, Darren J; Ralph, Stuart A; McConville, Malcolm J

    2016-01-15

    Detailed information on the mode of action of antimalarial drugs can be used to improve existing drugs, identify new drug targets, and understand the basis of drug resistance. In this study we describe the use of a time-resolved, mass spectrometry (MS)-based metabolite profiling approach to map the metabolic perturbations induced by a panel of clinical antimalarial drugs and inhibitors on Plasmodium falciparum asexual blood stages. Drug-induced changes in metabolite levels in P. falciparum-infected erythrocytes were monitored over time using gas chromatography-MS and liquid chromatography-MS and changes in specific metabolic fluxes confirmed by nonstationary [(13)C]-glucose labeling. Dihydroartemisinin (DHA) was found to disrupt hemoglobin catabolism within 1 hour of exposure, resulting in a transient decrease in hemoglobin-derived peptides. Unexpectedly, it also disrupted pyrimidine biosynthesis, resulting in increased [(13)C]-glucose flux toward malate production, potentially explaining the susceptibility of P. falciparum to DHA during early blood-stage development. Unique metabolic signatures were also found for atovaquone, chloroquine, proguanil, cycloguanil and methylene blue. We also show that this approach can be used to identify the mode of action of novel antimalarials, such as the compound Torin 2, which inhibits hemoglobin catabolism. PMID:26150544

  1. Natural polyhydroxyalkanoate–gold nanocomposite based biosensor for detection of antimalarial drug artemisinin

    Phukon, Pinkee [Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur 784028, Assam (India); Radhapyari, Keisham [Analytical Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam (India); Konwar, Bolin Kumar [Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur 784028, Assam (India); Nagaland University (Central), Lumami, Zunheboto, Nagaland 798627 (India); Khan, Raju, E-mail: khan.raju@gmail.com [Analytical Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam (India)

    2014-04-01

    The worrisome trend of antimalarial resistance has already highlighted the importance of artemisinin as a potent antimalarial agent. The current investigation aimed at fabricating a biosensor based on natural polymer polyhydroxyalkanoate–gold nanoparticle composite mounting on an indium-tin oxide glass plate for the analysis of artemisinin. The biosensor was fabricated using an adsorbing horse-radish peroxidase enzyme on the electrode surface for which cyclic voltammetry was used to monitor the electro-catalytic reduction of artemisinin under diffusion controlled conditions. Electrochemical interfacial properties and immobilization of enzyme onto a polyhydroxyalkanoate–gold nanoparticle film were evaluated, and confirmed by cyclic voltammetry, electrochemical impedance spectroscopy and scanning electron microscopy. The differential pulse voltammetric peak current for artemisinin was increased linearly (concentration range of 0.01–0.08 μg mL{sup −1}) with sensitivity of 0.26 μA μg mL{sup −1}. The greater sensitivity of the fabricated biosensor to artemisinin (optimum limits of detection were 0.0035 μg mL{sup −1} and 0.0036 μg mL{sup −1} in bulk and spiked human serum, respectively) could be of much aid in medical diagnosis. - Highlights: • Extraction of PHA from indigenously isolated Pseudomonas aeruginosa BPC2 • Developed PHA/AuNPs/HRP/ITO based biosensor without the use of chemical cross linker • Detection of antimalarial drug artemisinin using the nanocomposite based biosensor.

  2. EVALUATION OF NEPETA LEAVIGATA, NEPETA KURRAMENSIS AND RHYNCHOSIA RENIFORMIS ON ANTIMALARIAL AND ANTILEISHMANIAL ACTIVITIES

    Memoona A, Amir MK, Sultan A, Razia P, Sumera P, Lal M, Nisar Ahmed*

    2012-10-01

    Full Text Available The pharmacological investigation of methanolic extracts and different fractions of the Nepeta leavigata, Nepeta kurramensis and Rhynchosia reniformis were designed to assess the antimalarial and antileishmanial screening of medicinal plants for development of drugs. Materials and Methods: The shade-dried whole plant material of Nepeta leavigata was soaked in methanol for 10 days. The powdered drug was extracted with 80 % methanol three times and filtered at room temperature. The filtrate was evaporated in rotary to get a dark-greenish residue (extract, which was further suspended in water and partitioned successively with n-hexane, chloroform, ethyl acetate and n-butanol to obtain n-hexane-soluble, chloroform-soluble, ethyl acetate-soluble, n-butanol-soluble and aqueous fractions, respectively (Khan, et al., 2010a. Same extraction and fractionation procedure was adopted for Nepeta kurramensis and Rhynchosia reniformis. The antimalarial / antileishmanial activity of crude extracts/fractions was determined through standard protocol (Kerharo & Adam, 1974/. Results: The crude extract, chloroform fraction of Nepeta leavigata and fractions chloroform and ethyl acetate of Nepeta kurramensis showed promising antileishmanial and antimalarial activity against parasites of leishmania and malaria (promistogetes and schizonts by observing 1 or 0 number of parasites on slide field where ≤ 1 level is significant, while all fractions of Rhynchosia reniformis did not showed any action against promistigotes and schizonts. Conclusions: The bioassays guided isolation and phytochemical screening of active fractions against these activities will further enhance research in the field of pharmacology.

  3. Natural and Semi synthetic Antimalarial Compounds: Emphasis on the Terpene Class.

    Silva, G N S; Rezende, L C D; Emery, F S; Gosmann, G; Gnoatto, S C B

    2015-01-01

    Malaria is one of the most important tropical diseases since more than 40% of the world population is at risk. This disease is endemic to more than 100 nations and remains one of the main leading causes of death in children less than five years of age worldwide. Natural product-derived compounds have played a major role in drug discovery, often as prototypes to obtain more active semi synthetic derivatives. Antimalarial pharmacotherapy is a significant example of plant-derived medicines, such as quinine and artemisinin. This review highlights studies on terpenes and their semi synthetic derivatives from natural sources with antimalarial activity reported in the literature during eleven years (2002-2013). A total of 114 compounds are found among terpenes and their semi synthetic derivatives. Cytotoxicity of the compounds is also found in this review. Furthermore, the physicochemical properties of the terpenes addressed are discussed based on seven well established descriptors, which provide a useful source for the elaboration of a terpene library of antimalarial compounds. PMID:25553426

  4. Microbial hara-kiri: Exploiting lysosomal cell death in malaria parasites

    Jun-Hong Ch’ng

    2015-01-01

    Full Text Available The antimalarial drug chloroquine (CQ has been sidelined in the fight against falciparum malaria due to wide-spread CQ resistance. Replacement drugs like sulfadoxine, pyrimethamine and mefloquine have also since been surpassed with the evolution of multi-drug resistant parasites. Even the currently recommended artemisinin-based combination therapies show signs of compromise due to the recent spread of artemisinin delayed-clearance parasites. Though there have been promising breakthroughs in the pursuit of new effective antimalarials, the development and strategic deployment of such novel chemical entities takes time. We therefore argue that there is a crucial need to re-examine the usefulness of ‘outdated’ drugs like chloroquine, and explore if they might be effective alternative therapies in the interim. We suggest that a novel parasite cell death (pCD pathway may be exploited through the reformulation of CQ to address this need.

  5. Challenges of drug-resistant malaria.

    Sinha, Shweta; Medhi, Bikash; Sehgal, Rakesh

    2014-01-01

    Over the past six decades, the drug resistance of Plasmodium falciparum has become an issue of utmost concern. Despite the remarkable progress that has been made in recent years in reducing the mortality rate to about 30% with the scaling-up of vector control, introduction of artemisinin-based combination therapies and other malaria control strategies, the confirmation of artemisinin resistance on the Cambodia-Thailand border threatened all the previous success. This review addresses the global scenario of antimalarial resistance and factors associated with it, with the main emphasis on futuristic approaches like nanotechnology and stem cell therapy that may impede resistant malaria, along with novel medications which are preparing to enter the global antimalarial market. These novel studies are likely to escalate over the coming years and will hopefully help to reduce the burden of malaria. PMID:25402734

  6. Challenges of drug-resistant malaria

    Sinha Shweta

    2014-01-01

    Full Text Available Over the past six decades, the drug resistance of Plasmodium falciparum has become an issue of utmost concern. Despite the remarkable progress that has been made in recent years in reducing the mortality rate to about 30% with the scaling-up of vector control, introduction of artemisinin-based combination therapies and other malaria control strategies, the confirmation of artemisinin resistance on the Cambodia–Thailand border threatened all the previous success. This review addresses the global scenario of antimalarial resistance and factors associated with it, with the main emphasis on futuristic approaches like nanotechnology and stem cell therapy that may impede resistant malaria, along with novel medications which are preparing to enter the global antimalarial market. These novel studies are likely to escalate over the coming years and will hopefully help to reduce the burden of malaria.

  7. A review of age-old antimalarial drug to combat malaria:efficacy upgradation by nanotechnology based drug delivery

    Satyajit; Tripathy; Somenath; Roy

    2014-01-01

    Malaria is uncontrolled burden in the world till now.Despite of different efforts to develop antimalarial drug for decades,any anti-malarial drug can able to eradicate completely till now.Many anti-malarial substances are practically ineffectual because of their physicochemical limitations,cytotoxicity,chemical instability and degradation,and limited activities against intracellular parasites.Taking into consideration,the amount of research is going to conduct in the field of nanoparticle based drug delivery systems,lead to new ways of improving the treatment of infectious diseases.The study has focused on the progress and advancement of research on nanotechnology based drug delivery to eradicate the malaria.We like to focus the efficacy of nanotechnology based drug application for the opening out of novel chemotherapeutics in laboratory research,which may show the way to better use with age-old antimalarial drug and may draw the attention of pharmaceutical industries for the improvement and designing of effective anti-malarial drugs in future.

  8. Deciphering the Late Biosynthetic Steps of Antimalarial Compound FR-900098

    Johannes, Tyler W.; DeSieno, Matthew A.; Griffin, Benjamin M.; Thomas, Paul M.; Kelleher, Neil L.; Metcalf, William W.; Zhao, Huimin

    2010-01-01

    FR-900098 is a potent chemotherapeutic agent for the treatment of malaria. Here we report the heterologous production of this compound in E. coli by re-constructing the entire biosynthetic pathway using a three plasmid system. Based on this system, whole cell feeding assays in combination with in vitro enzymatic activity assays reveal an unprecedented functional role of nucleotide conjugation and lead to the complete elucidation of the previously unassigned late biosynthetic steps. These stud...

  9. CRIMALDDI: a co-ordinated, rational, and integrated effort to set logical priorities in anti-malarial drug discovery initiatives

    Doerig Christian

    2010-07-01

    Full Text Available Abstract Despite increasing efforts and support for anti-malarial drug R&D, globally anti-malarial drug discovery and development remains largely uncoordinated and fragmented. The current window of opportunity for large scale funding of R&D into malaria is likely to narrow in the coming decade due to a contraction in available resources caused by the current economic difficulties and new priorities (e.g. climate change. It is, therefore, essential that stakeholders are given well-articulated action plans and priorities to guide judgments on where resources can be best targeted. The CRIMALDDI Consortium (a European Union funded initiative has been set up to develop, through a process of stakeholder and expert consultations, such priorities and recommendations to address them. It is hoped that the recommendations will help to guide the priorities of the European anti-malarial research as well as the wider global discovery agenda in the coming decade.

  10. In vitro antimalarial activity and cytotoxicity of cochlospermum tinctorium and C. planchonii leaf extracts and essential oils.

    Benoit-Vical, F; Valentin, A; Mallié, M; Bastide, J M; Bessière, J M

    1999-05-01

    The antimalarial and toxicological properties of Cochlospermum tinctorium and C. planchonii extracts and essential oils prepared from their leaves were studied. The oil components were extracted by hydrodistillation of the plant leaves and characterized by gas chromatography and mass spectrometry. Crude extracts and oils were tested for in vitro antimalarial activity on Plasmodium falciparum. The IC50 were evaluated after 24 and 72 h contact between the oils and the parasite culture, and ranged from 22 to 500 micrograms/ml. C. planchonii leaf oil yielded the best antimalarial effect (IC50: 22-35 micrograms/ml), while the most potent effect from crude leaf extracts was induced by C. tinctorium. The cytotoxicity of the leaf crude extracts and oils was assessed on the K562 cell line and showed IC50 values ranging between 33 and 2000 micrograms/ml. PMID:10364849

  11. Antimalarial activity of extracts and alkaloids isolated from six plants used in traditional medicine in Mali and Sao Tome.

    Ancolio, C; Azas, N; Mahiou, V; Ollivier, E; Di Giorgio, C; Keita, A; Timon-David, P; Balansard, G

    2002-11-01

    Methanol and chloroform extracts were prepared from various parts of four plants collected in Mali: Guiera senegalensis (Gmel.) Combretaceae, Feretia apodanthera (Del.) Rubiaceae, Combretum micranthum (Don.) Combretaceae, Securidaca longepedunculata (Fres.) Polygalaceae and two plants -collected in Sao Tome: Pycnanthus angolensis (Welw.) Myristicaceae and Morinda citrifolia (Benth.) Rubiaceae were assessed for their in vitro antimalarial activity and their cytotoxic effects on human monocytes (THP1 cells) by flow cytometry. The methanol extract of leaves of Feretia apodanthera and the chloroform extract of roots of Guiera senegalensis exhibited a pronounced antimalarial activity. Two alkaloids isolated from the active extract of Guiera senegalensis, harman and tetrahydroharman, showed antimalarial activity (IC(50) lower than 4 microg/mL) and displayed low toxicity against THP1. Moreover, the decrease of THP1 cells in S phase of the cell cycle, after treatment with harman and tetrahydroharman, was probably due to an inhibition of total protein synthesis. PMID:12410545

  12. Effect of selenium (Se) deficiency on the anti-malarial action of Qinghaosu (QHS) in mice

    Levander, O.A.; Ager, A.L.; May, R.

    1986-03-01

    QHS is an endoperoxide, so it occurred to the authors that its anti-malarial action might be potentiated by low glutathione peroxidase (GSH-Px) activity. Weanling female mice were fed 1 of 4 diets: chow or a Torula yeast-based diet supplemented with 0, 0.1 or 0.5 ppm Se as Na/sub 2/SeO/sub 3/. After 6 weeks, mean hepatic GSH-Px activities and plasma Se levels in these 4 dietary groups were 17.3, 0.1, 5.4, and 14.5 munits/mg protein and 242, 4, 230, and 532 ng/ml, respectively. At this time, all mice were inoculated i.p. with asexual blood stages of Plasmodium yoelii. Then groups of 7 or 8 mice fed each diet were given 0, 4, 16, or 64 mg QHS/kg orally bid at 3, 4, and 5 days post inoculation. On the 6th day, blood films were taken and antimalarial activity was assessed by determining % parasitemia (% PARA). Mice given 0 or 4 mg QHS/kg averaged 47% PARA and this was not affected by diet. Mice receiving 64 mg QHS/kg averaged about 1% PARA irrespective of diet. However, mice given 16 mg QHS/kg had 25% PARA when fed chow but only 8 to 11% PARA when fed the Torula diet, regardless of Se intake. Thus, while Se status did not appear to influence the antimalarial potency of QHS, some factor(s) in the Torula diet enhanced its activity at intermediate doses vs. the chow diet.

  13. In vitro and in vivo characterization of the antimalarial lead compound SSJ-183 in Plasmodium models

    Schleiferböck S

    2013-11-01

    Full Text Available Sarah Schleiferböck,1,2 Christian Scheurer,1,2 Masataka Ihara,3,4 Isamu Itoh,3,4 Ian Bathurst,5,† Jeremy N Burrows,5 Pascal Fantauzzi,5 Julie Lotharius,5 Susan A Charman,6 Julia Morizzi,6 David M Shackleford,6 Karen L White,6 Reto Brun,1,2 Sergio Wittlin1,21Swiss Tropical and Public Health Institute, Basel, 2University of Basel, Basel, Switzerland; 3Drug Discovery Science Research Center, Hoshi University, Shinagawa, Tokyo, Japan; 4Synstar Japan Co, Ltd, Odawara, Japan; 5Medicines for Malaria Venture, Geneva, Switzerland; 6Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia †Ian Bathurst passed away on 26 June 2011Abstract: The objective of this work was to characterize the in vitro (Plasmodium falciparum and in vivo (Plasmodium berghei activity profile of the recently discovered lead compound SSJ-183. The molecule showed in vitro a fast and strong inhibitory effect on growth of all P. falciparum blood stages, with a tendency to a more pronounced stage-specific action on ring forms at low concentrations. Furthermore, the compound appeared to be equally efficacious on drug-resistant and drug-sensitive parasite strains. In vivo, SSJ-183 showed a rapid onset of action, comparable to that seen for the antimalarial drug artesunate. SSJ-183 exhibited a half-life of about 10 hours and no significant differences in absorption or exposure between noninfected and infected mice. SSJ-183 appears to be a promising new lead compound with an attractive antimalarial profile.Keywords: antimalarial studies, cross-resistance, stage-specificity, Plasmodium falciparum

  14. Innovative public-private partnerships to maximize the delivery of anti-malarial medicines: lessons learned from the ASAQ Winthrop experience

    Sebbag Robert

    2011-05-01

    Full Text Available Abstract Background This case study describes how a public-private partnership initiated to develop a new anti-malarial combination, ASAQ Winthrop, has evolved over time to address issues posed by its effective deployment in the field. Case description In 2002, DNDi created the FACT project to develop two fixed-dose combinations, artesunate-amodiaquine and artesunate-mefloquine, to meet the WHO anti-malarial treatment recommendations and international regulatory agencies approval standards. In 2002, Sanofi-aventis had started a development programme for a fixed-dose combination of artesunate and amodiaquine, to replace its co-blister combination. DNDi and sanofi-aventis joined forces in 2004, with the objective of developing within the shortest possible time frame a non-patented, affordable and easy to use fixed-dose combination of artesunate and amodiaquine adapted to the needs of patients, in particular, those of children. The partners developed Coarsucam®/Artesunate Amodiaquine Winthrop® ("ASAQ Winthrop" which was prequalified by the WHO in 2008. Additional partnerships have since been established by DNDi and sanofi-aventis to ensure: 1 the adoption of this new medicine by malaria-endemic countries, 2 its appropriate usage through a broad range of information tools, and 3 the monitoring of its safety and efficacy in the field through an innovative Risk Management Plan. Discussion and evaluation The partnership between DNDi and sanofi-aventis has enabled the development and pre-qualification of ASAQ Winthrop in a short timeframe. As a result of the multiple collaborations established by the two partners, as of late 2010, ASAQ Winthrop was registered in 30 sub-Saharan African countries and in India, with over 80 million treatments distributed in 21 countries. To date, 10 clinical studies, involving 3432 patients with ASAQ Winthrop were completed to document efficacy and safety issues identified in the Risk Management Plan. Conclusions The

  15. Evaluation of the ex vivo antimalarial activity of organotin (IV) ethylphenyldithiocarbamate on erythrocytes infected with Plasmodium berghei NK 65.

    Awang, Normah; Jumat, Hafizah; Ishak, Shafariatul Akmar; Kamaludin, Nurul Farahana

    2014-06-01

    Malaria is the most destructive and dangerous parasitic disease. The commonness of this disease is getting worse mainly due to the increasing resistance of Plasmodium falciparum against antimalarial drugs. Therefore, the search for new antimalarial drug is urgently needed. This study was carried out to evaluate the effects of dibutyltin (IV) ethylphenyldithiocarbamate (DBEP), diphenyltin (IV) ethylphenyldithiocarbamate (DPEP) and triphenyltin (IV) ethylphenyldithiocarbamate (TPEP) compounds as antimalarial agents. These compounds were evaluated against erythrocytes infected with Plasmodium berghei NK65 via ex vivo. Organotin (IV) ethylphenyldithiocarbamate, [R(n)Sn(C9H10NS2)(4-n)] with R = C4H9 and C6H5 for n = 2; R = C6H5 for n = 3 is chemically synthesised for its potential activities. pLDH assay was employed for determination of the concentration that inhibited 50% of the Plasmodium's activity (IC50) after 24 h treatment at concentration range of 10-0.0000001 mg mL(-1). Plasmodium berghei NK65 was cultured in vitro to determine the different morphology of trophozoite and schizont. Only DPEP and TPEP compounds have antimalarial activity towards P. berghei NK65 at IC50 0.094±0.011 and 0.892±0.088 mg mL(-1), respectively. The IC50 of DPEP and TPEP were lowest at 30% parasitemia with IC50 0.001±0.00009 and 0.0009±0.0001 mg mL(-1), respectively. In vitro culture showed that TPEP was effective towards P. berghei NK65 in trophozoite and schizont morphology with IC50 0.0001±0.00005 and 0.00009±0.00003 μg mL(-1), respectively. In conclusion, DPEP and TPEP have antimalarial effect on erythrocytes infected with P. berghei NK65 and have potential as antimalarial and schizonticidal agents. PMID:26035957

  16. Antibacterial, antimalarial and leishmanicidal activities of Cu (II) and nickel (II) complexes of diclofenac sodium

    Metal complexes are famous for a wide array of chemotherapeutic effects. The current study was designed to synthesize and evaluate unexplored chemotherapeutic effects of Cu (II) and Nickel (II) complexes of the non-steroidal anti-inflammatory drug diclofenac. Nickel complex exhibited significant leishmanicidal activity against Lieshmania major, while the copper complex was found to possess low activity against the same pathogen. Both of the complexes revealed low antibacterial activities and were interestingly failed to produce any considerable antimalarial activity against Plasmodium falciparum 3D7. Selective leishmanicidal activities of Nickel (II) complex of diclofenac needs further improvement to be developed as potential new metal-based leishmanicidal agent.(author)

  17. Targeting the Plasmodium vivax equilibrative nucleoside transporter 1 (PvENT1 for antimalarial drug development

    Roman Deniskin

    2016-04-01

    Full Text Available Infection with Plasmodium falciparum and vivax cause most cases of malaria. Emerging resistance to current antimalarial medications makes new drug development imperative. Ideally a new antimalarial drug should treat both falciparum and vivax malaria. Because malaria parasites are purine auxotrophic, they rely on purines imported from the host erythrocyte via Equilibrative Nucleoside Transporters (ENTs. Thus, the purine import transporters represent a potential target for antimalarial drug development. For falciparum parasites the primary purine transporter is the P. falciparum Equilibrative Nucleoside Transporter Type 1 (PfENT1. Recently we identified potent PfENT1 inhibitors with nanomolar IC50 values using a robust, yeast-based high throughput screening assay. In the current work we characterized the Plasmodium vivax ENT1 (PvENT1 homologue and its sensitivity to the PfENT1 inhibitors. We expressed a yeast codon-optimized PvENT1 gene in Saccharomyces cerevisiae. PvENT1-expressing yeast imported both purines ([3H]adenosine and pyrimidines ([3H]uridine, whereas wild type (fui1Δ yeast did not. Based on radiolabel substrate uptake inhibition experiments, inosine had the lowest IC50 (3.8 μM, compared to guanosine (14.9 μM and adenosine (142 μM. For pyrimidines, thymidine had an IC50 of 183 μM (vs. cytidine and uridine; mM range. IC50 values were higher for nucleobases compared to the corresponding nucleosides; hypoxanthine had a 25-fold higher IC50 than inosine. The archetypal human ENT1 inhibitor 4-nitrobenzylthioinosine (NBMPR had no effect on PvENT1, whereas dipyridamole inhibited PvENT1, albeit with a 40 μM IC50, a 1000-fold less sensitive than human ENT1 (hENT1. The PfENT1 inhibitors blocked transport activity of PvENT1 and the five known naturally occurring non-synonymous single nucleotide polymorphisms (SNPs with similar IC50 values. Thus, the PfENT1 inhibitors also target PvENT1. This implies that development of novel

  18. Four-step synthesis of the antimalarial cardamom peroxide via an oxygen stitching strategy.

    Hu, Xirui; Maimone, Thomas J

    2014-04-01

    A four-step synthesis of the antimalarial terpene cardamom peroxide, a 1,2-dioxepane-containing natural product, is reported from (-)-myrtenal and molecular oxygen. This highly concise route was guided by biosynthetic logic and enabled by an unusual manganese-catalyzed, tandem hydroperoxidation reaction. The absolute configuration of the cardamom peroxide is reported, and its mode of fragmentation following Fe(II)-mediated endoperoxide reduction is established. These studies reveal the generation of reactive intermediates distinct from previously studied endoperoxide natural products. PMID:24673099

  19. Synthesis, antimalarial properties and 2D-QSAR studies of novel triazole-quinine conjugates.

    Faidallah, Hassan M; Panda, Siva S; Serrano, Juan C; Girgis, Adel S; Khan, Khalid A; Alamry, Khalid A; Therathanakorn, Tanya; Meyers, Marvin J; Sverdrup, Francis M; Eickhoff, Christopher S; Getchell, Stephen G; Katritzky, Alan R

    2016-08-15

    Click chemistry technique led to novel 1,2,3-triazole-quinine conjugates 8a-g, 10a-o, 11a-h and 13 utilizing benzotriazole-mediated synthetic approach with excellent yields. Some of the synthesized analogs (11a, 11d-h) exhibited antimalarial properties against Plasmodium falciparum strain 3D7 with potency higher than that of quinine (standard reference used) through in vitro standard procedure bio-assay. Statistically significant BMLR-QSAR model describes the bio-properties, validates the observed biological observations and identifies the most important parameters governing bio-activity. PMID:27298002

  20. In vitro antimalarial drug susceptibility in Thai border areas from 1998–2003

    Mungthin Mathirut

    2005-08-01

    Full Text Available Abstract Background The Thai-Myanmar and Thai-Cambodia borders have been historically linked with the emergence and spread of Plasmodium falciparum parasites resistant to antimalarial drugs. Indeed, the areas are often described as harbouring multi-drug resistant parasites. These areas of Thailand have experienced significant changes in antimalarial drug exposure patterns over the past decade. This study describes the in vitro antimalarial susceptibility patterns of 95 laboratory-adapted P. falciparum isolates, collected between 1998 and 2003,. Methods Ninety five P. falciparum isolates were collected from five sites in Thailand between 1998 and 2003. After laboratory adaptation to in vitro culture, the susceptibility of these parasites to a range of established antimalarial drugs (chloroquine [CQ], mefloquine [MQ], quinine [QN] and dihydroartemisinin [DHA] was determined by the isotopic microtest. Results Mefloquine (MQ sensitivity remained poorest in areas previously described as MQ-resistant areas. Sensitivity to MQ of parasites from this area was significantly lower than those from areas reported to harbour moderate (p = 0.002 of low level MQ resistance (p = 000001. Importantly for all drugs tested, there was a considerable range in absolute parasite sensitivities. There was a weak, but statistically positive correlation between parasite sensitivity to CQ and sensitivity to both QN and MQ and a positive correlation between MQ and QN. In terms of geographical distribution, parasites from the Thai-Cambodia were tended to be less sensitive to all drugs tested compared to the Thai-Myanmar border. Parasite sensitivity to all drugs was stable over the 6-year collection period with the exception of QN. Conclusion This study highlights the high degree of variability in parasite drug sensitivity in Thailand. There were geographical differences in the pattern of resistance which might reflect differences in drug usage in each area. In contrast to many

  1. Compound antimalarial ethosomal cataplasm: preparation, evaluation, and mechanism of penetration enhancement

    Shen S; Liu SZ; Zhang YS; Du MB; Liang AH; Song LH; Ye ZG

    2015-01-01

    Shuo Shen, Shu-Zhi Liu, Yu-Shi Zhang, Mao-Bo Du, Ai-Hua Liang, Li-Hua Song, Zu-Guang Ye Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China Abstract: Malaria is still a serious public health problem in some parts of the world. The problems of recurrence and drug resistance are increasingly more serious. Thus, it is necessary to develop a novel antimalarial agent. The objectives of this study were to construct a novel ...

  2. Characterization of PfTrxR inhibitors using antimalarial assays and in silico techniques

    Munigunti, Ranjith; Gathiaka, Symon; Acevedo, Orlando; Sahu, Rajnish; Tekwani, Babu; Calderón, Angela I.

    2013-01-01

    Background The compounds 1,4-napthoquinone (1,4-NQ), bis-(2,4-dinitrophenyl)sulfide (2,4-DNPS), 4-nitrobenzothiadiazole (4-NBT), 3-dimethylaminopropiophenone (3-DAP) and menadione (MD) were tested for antimalarial activity against both chloroquine (CQ)-sensitive (D6) and chloroquine (CQ)-resistant (W2) strains of Plasmodium falciparum through an in vitro assay and also for analysis of non-covalent interactions with P. falciparum thioredoxin reductase (PfTrxR) through in silico docking studies...

  3. A new phloroglucinol derivative from Hypericum calycinum with antifungal and in vitro antimalarial activity.

    Decosterd, L A; Hoffmann, E; Kyburz, R; Bray, D; Hostettmann, K

    1991-12-01

    The new phloroglucinol derivative 1 has been isolated from the light petroleum ether extract of the aerial parts of Hypericum calycinum. Its structure has been established by means of 1H- and 13C-NMR spectroscopy and by nOe, MHQC, and HMBC experiments on its monomethyl ether derivative 3. Compound 1 was fungicidal against Cladosporium cucumerinum in a TLC bioassay. In addition, this new phloroglucinol derivative was also found to exert an interesting antimalarial activity in an in vitro test system. PMID:1818346

  4. Evaluation on antimalarial activity of 3 artemisinin drugs using SYBR green Ⅰ and flow cytometry in vitro%用SYBR green Ⅰ法和流式细胞术体外评价3种青蒿素类药物的抗疟活性

    薛丹; 程慧芳; 毋海兰; 赵青; 王锐利; 张淑秋

    2014-01-01

    rate was measured using SYBR green Ⅰ,the 50% inhibitory concentration (IC50) and 95% inhibition concentration (IC95) were used to reflect the inhibition activity,then compared with the changes of DNA content of malaria parasites measured by flow cytometry.Results SYBR green Ⅰ showed the inhibition rates increased as dose of ART increased,The IC5o values of ART,AM and DHA were 11.29,3.32,0.66 nmol/L; IC95 values were 42.55,17.89,4.02 nmol/L respectively.At the same time,the results of the flow cytometry showed the content of DNA decreased with the increase of drug concentration,agreeing with the results of SYBR green Ⅰ and being objectively perceived.Conclusion The sensitivity of SYBR green Ⅰ and intuitiveness of flow cytometry could meet the requirements of evaluation on antimalarial activity of artemisinin-based antimalarial drugs against Plasmodiumfalciparum in vitro; The order from high to low of antimalarial activity is DHA>AM>ART.

  5. Stability-indicating HPLC-DAD/UV-ESI/MS impurity profiling of the anti-malarial drug lumefantrine

    Duchateau Luc

    2011-02-01

    Full Text Available Abstract Background Lumefantrine (benflumetol is a fluorene derivative belonging to the aryl amino alcohol class of anti-malarial drugs and is commercially available in fixed combination products with β-artemether. Impurity characterization of such drugs, which are widely consumed in tropical countries for malaria control programmes, is of paramount importance. However, until now, no exhaustive impurity profile of lumefantrine has been established, encompassing process-related and degradation impurities in active pharmaceutical ingredients (APIs and finished pharmaceutical products (FPPs. Methods Using HPLC-DAD/UV-ESI/ion trap/MS, a comprehensive impurity profile was established based upon analysis of market samples as well as stress, accelerated and long-term stability results. In-silico toxicological predictions for these lumefantrine related impurities were made using Toxtree® and Derek®. Results Several new impurities are identified, of which the desbenzylketo derivative (DBK is proposed as a new specified degradant. DBK and the remaining unspecified lumefantrine related impurities are predicted, using Toxtree® and Derek®, to have a toxicity risk comparable to the toxicity risk of the API lumefantrine itself. Conclusions From unstressed, stressed and accelerated stability samples of lumefantrine API and FPPs, nine compounds were detected and characterized to be lumefantrine related impurities. One new lumefantrine related compound, DBK, was identified and characterized as a specified degradation impurity of lumefantrine in real market samples (FPPs. The in-silico toxicological investigation (Toxtree® and Derek® indicated overall a toxicity risk for lumefantrine related impurities comparable to that of the API lumefantrine itself.

  6. Phytochemical screening, antimalarial and histopathological studies of Allophylus africanus and Tragia benthamii

    Oladosu I.A.; Balogun S.O.; Ademowo G.O.

    2013-01-01

    The anti-malarial potential of different parts ofAllophylus africanus P.Beauv and Tragia benthamii Baker were determined in vivo for suppressive,curative and cytotoxic activities in mice receiving 0.2 mL of a standard inoculum size of 1 × 107 infected erythrocytes of Plasmodium berghei (NK-65) intraperitoneally.The A.africanus extracts suppressed parasitaemia following administration to infected mice by 92.82%-97.81% on day 7 post-infection against 96.81% for chloroquine.The infected extract-treated animals had significantly moderate (P < 0.05) packed cell volume (PCV) compared with the infected,untreated animals.Phytochemical screening revealed a predominance of tannins,saponins,flavonoids and carbohydrates in all parts of A.africanus,and alkaloids instead of flavonoids in the extract of T.benthamii.The results suggest that the extract possesses considerable antimalarial activity.These results support further studies on A.africanus.

  7. Synthesis, Cytotoxic and Antimalarial Activities of Benzoyl Thiosemicarbazone Analogs of Isoquinoline and Related Compounds

    Somsak Ruchirawat

    2010-02-01

    Full Text Available Thiosemicarbazone analogs of papaveraldine and related compounds 1–6 were synthesized and evaluated for cytotoxic and antimalarial activities. The cytotoxic activity was tested against HuCCA-1, HepG2, A549 and MOLT-3 human cancer cell lines. Thiosemicarbazones 1–5 displayed cytotoxicity toward all the tested cell lines, while compounds 2–5 selectively showed potent activity against the MOLT-3 cell lines. Significantly, N(4-phenyl-2-benzoylpyridine thiosemicarbazone 4 exhibited the most potent activity against HuCCA-1, HepG2, A549 and MOLT-3 cell lines with IC50 values of 0.03, 4.75, 0.04 and 0.004 µg/mL, respectively. In addition, 2-benzoylpyridine thio-semicarbazones 3 and 4 showed antimalarial activity against Plasmodium falciparum with IC50 of 10-7 to < 10-6 M. The study demonstrates the quite promising activity of analog 4 as a lead molecule for further development.

  8. Investigation of Indolglyoxamide and Indolacetamide Analogues of Polyamines as Antimalarial and Antitrypanosomal Agents

    Jiayi Wang

    2014-05-01

    Full Text Available Pure compound screening has previously identified the indolglyoxy lamidospermidine ascidian metabolites didemnidine A and B (2 and 3 to be weak growth inhibitors of Trypanosoma brucei rhodesiense (IC50 59 and 44 μM, respectively and Plasmodium falciparum (K1 dual drug resistant strain (IC50 41 and 15 μM, respectively, but lacking in selectivity (L6 rat myoblast, IC50 24 μM and 25 μM, respectively. To expand the structure–activity relationship of this compound class towards both parasites, we have prepared and biologically tested a library of analogues that includes indoleglyoxyl and indoleacetic “capping acids”, and polyamines including spermine (PA3-4-3 and extended analogues PA3-8-3 and PA3-12-3. 7-Methoxy substituted indoleglyoxylamides were typically found to exhibit the most potent antimalarial activity (IC50 10–92 nM but with varying degrees of selectivity versus the L6 rat myoblast cell line. A 6-methoxyindolglyoxylamide analogue was the most potent growth inhibitor of T. brucei (IC50 0.18 μM identified in the study: it, however, also exhibited poor selectivity (L6 IC50 6.0 μM. There was no apparent correlation between antimalarial and anti-T. brucei activity in the series. In vivo evaluation of one analogue against Plasmodium berghei was undertaken, demonstrating a modest 20.9% reduction in parasitaemia.

  9. Basigin is a druggable target for host-oriented antimalarial interventions.

    Zenonos, Zenon A; Dummler, Sara K; Müller-Sienerth, Nicole; Chen, Jianzhu; Preiser, Peter R; Rayner, Julian C; Wright, Gavin J

    2015-07-27

    Plasmodium falciparum is the parasite responsible for the most lethal form of malaria, an infectious disease that causes a large proportion of childhood deaths and poses a significant barrier to socioeconomic development in many countries. Although antimalarial drugs exist, the repeated emergence and spread of drug-resistant parasites limit their useful lifespan. An alternative strategy that could limit the evolution of drug-resistant parasites is to target host factors that are essential and universally required for parasite growth. Host-targeted therapeutics have been successfully applied in other infectious diseases but have never been attempted for malaria. Here, we report the development of a recombinant chimeric antibody (Ab-1) against basigin, an erythrocyte receptor necessary for parasite invasion as a putative antimalarial therapeutic. Ab-1 inhibited the PfRH5-basigin interaction and potently blocked erythrocyte invasion by all parasite strains tested. Importantly, Ab-1 rapidly cleared an established P. falciparum blood-stage infection with no overt toxicity in an in vivo infection model. Collectively, our data demonstrate that antibodies or other therapeutics targeting host basigin could be an effective treatment for patients infected with multi-drug resistant P. falciparum. PMID:26195724

  10. In vitro and in vivo anti-malarial activity of Boerhavia elegans and Solanum surattense

    Khodakarim Nastaran

    2010-05-01

    Full Text Available Abstract Background There is an urgent need to identify new anti-malarial drug targets for both prophylaxis and chemotherapy, due to the increasing problem of drug resistance to malaria parasites. In the present study, the aim was to discover novel, effective plant-based extracts for the activity against malaria. Methods Ten plants found in Iran were selected by ethnobotanical survey of medicinal plants. The crude ethanolic extracts were tested for in vitro anti-plasmodial activity against two strains of Plasmodium falciparum: K1 (chloroquine-resistant strain and CY27 (chloroquine-sensitive strain, using the parasite lactate dehydrogenase (pLDH assay. The anti-plasmodial activity of the extracts was also assessed in the 4-day suppressive anti-malarial assay in mice inoculated with Plasmodium berghei (ANKA strain. Crude ethanolic extracts showed good anti-plasmodial activity were further fractionated by partitioning in water and dichloromethane. Results Of 10 plant species assayed, three species: Boerhavia elegans (Choisy, Solanum surattense (Burm.f. and Prosopis juliflora (Sw. showed promising anti-plasmodial activity in vitro (IC50 ≤ 50 μg/ml and in vivo with no toxicity. The dichloromethane fraction of three extracts revealed stronger anti-plasmodial activity than the total extracts. Conclusion Anti-plasmodial activities of extracts of B. elegans and S. surattense are reported for the first time.

  11. Antimalarial properties of Artemisia vulgaris L. ethanolic leaf extract in a Plasmodium berghei murine malaria model

    Gayan S. Bamunuarachchi

    2013-12-01

    Full Text Available Background & objectives: Artemisinin isolated from Artemisia annua is the most potent antimalarial drug against chloroquine-resistant Plasmodium falciparum malaria. Artemisia vulgaris, an invasive weed, is the only Artemisia species available in Sri Lanka. A pilot study was undertaken to investigate the antiparasitic activity of an A. vulgaris ethanolic leaf extract (AVELE in a P. berghei ANKA murine malaria model that elicits pathogenesis similar to falciparum malaria. Methods: A 4-day suppressive and the curative assays determined the antiparasitic activity of AVELE using four doses (250, 500, 750 and 1000 mg/kg, Coartem® as the positive control and 5% ethanol as the negative control in male ICR mice infected with P. berghei. Results: The 500, 750 and 1000 mg/kg doses of AVELE significantly (p ≤0.01 inhibited parasitaemia by 79.3, 79.6 and 87.3% respectively, in the 4-day suppressive assay, but not in the curative assay. Chronic administration of the high dose of AVELE ruled out overt signs of toxicity and stress as well as hepatotoxicity, renotoxicity and haematotoxicity. Interpretation & conclusion: The oral administration of a crude ethonolic leaf extract of A. vulgaris is non-toxic and possesses potent antimalarial properties in terms of antiparasitic activity.

  12. Antimalarial drug targets in Plasmodium falciparum predicted by stage-specific metabolic network analysis

    Huthmacher Carola

    2010-08-01

    Full Text Available Abstract Background Despite enormous efforts to combat malaria the disease still afflicts up to half a billion people each year of which more than one million die. Currently no approved vaccine is available and resistances to antimalarials are widely spread. Hence, new antimalarial drugs are urgently needed. Results Here, we present a computational analysis of the metabolism of Plasmodium falciparum, the deadliest malaria pathogen. We assembled a compartmentalized metabolic model and predicted life cycle stage specific metabolism with the help of a flux balance approach that integrates gene expression data. Predicted metabolite exchanges between parasite and host were found to be in good accordance with experimental findings when the parasite's metabolic network was embedded into that of its host (erythrocyte. Knock-out simulations identified 307 indispensable metabolic reactions within the parasite. 35 out of 57 experimentally demonstrated essential enzymes were recovered and another 16 enzymes, if additionally the assumption was made that nutrient uptake from the host cell is limited and all reactions catalyzed by the inhibited enzyme are blocked. This predicted set of putative drug targets, shown to be enriched with true targets by a factor of at least 2.75, was further analyzed with respect to homology to human enzymes, functional similarity to therapeutic targets in other organisms and their predicted potency for prophylaxis and disease treatment. Conclusions The results suggest that the set of essential enzymes predicted by our flux balance approach represents a promising starting point for further drug development.

  13. An Alternative Paradigm for the Role of Antimalarial Plants in Africa

    Steven Maranz

    2012-01-01

    Full Text Available Most investigations into the antimalarial activity of African plants are centered on finding an indigenous equivalent to artemisinin, the compound from which current frontline antimalarial drugs are synthesized. As a consequence, the standard practice in ethnopharmacological research is to use in vitro assays to identify compounds that inhibit parasites at nanomolar concentrations. This approach fails to take into consideration the high probability of acquisition of resistance to parasiticidal compounds since parasite populations are placed under direct selection for genetic that confers a survival advantage. Bearing in mind Africa's long exposure to malaria and extensive ethnobotanical experimentation with both therapies and diet, it is more likely that compounds not readily overcome by Plasmodium parasites would have been retained in the pharmacopeia and cuisine. Such compounds are characterized by acting primarily on the host rather than directly targeting the parasite and thus cannot be adequately explored in vitro. If Africa's long history with malaria has in fact produced effective plant therapies, their scientific elucidation will require a major emphasis on in vivo investigation.

  14. Antimicrobial and antimalarial properties of medicinal plants used by the indigenous tribes of Andaman and Nicobar Islands, India.

    Chander, M Punnam; Pillai, C R; Sunish, I P; Vijayachari, P

    2016-07-01

    In this study, methanol extracts of six medicinal plants (Alstonia macrophylla, Claoxylon indicum, Dillenia andamanica, Jasminum syringifolium, Miliusia andamanica and Pedilanthus tithymaloides) traditionally used by Nicobarese tribes of Andaman and Nicobar Islands were studied for antimicrobial and antimalarial activities as well as preliminary photochemical analysis. Plants were collected from Car Nicobar of Andaman and Nicobar Islands and the ethnobotanical data were gathered from traditional healers who inhabit the study area. The methanol extracts were obtained by cold percolation method and the antimicrobial activity was found using agar well diffusion method. Among the plants tested, J. syringifolium, D. andamanica, C. indicum were most active. The antimalarial activity was evaluated against Plasmodium falciparum chloroquine-sensitive MRC-2 isolate. The crude extract of M. andamanica showed excellent antimalarial activity followed by extracts of P. tithymaloides, J. syringifolium and D. andamanica. The chemical injury to erythrocytes was also carried out and it showed that, there were no morphological changes in erythrocytes by the methanol crude extracts. The in vitro antimicrobial and antimalarial activity might be due to the presence of alkaloids, flavonoids, triterpenes, sterols, tannins and saponins in the methanol extracts of tested plants. PMID:27174207

  15. A new class of anti-malarial therapeutics that inhibit nucleotide synthesis in Plasmodium falciparum and vivax

    Keough, D. T.; Hocková, Dana; Holý, Antonín; Naesens, L.; Skinner-Adams, T. S.; de Jersey, J.; Guddat, L. W.

    Lorne : The University of Queensland, 2009. -. [Lorne Conference on Protein Structure and Function /34./. 08.02.2009-12.02.2009, Lorne] Institutional research plan: CEZ:AV0Z40550506 Keywords : Plasmodium falciparum * anti-malarial therapeutics * nucleotide synthesis Subject RIV: CC - Organic Chemistry

  16. Effect of antimalarial drug primaquine and its derivatives on the ionization potential of hemoglobin: A QM/MM study

    Liu, Haining; Ding, Yuanqing; Walker, Larry A.; Doerksen, Robert J

    2013-01-01

    We used quantum mechanics/molecular mechanics calculations to test if antimalarial primaquine (PQ) and its derivatives aid the conversion of hemoglobin to methemoglobin by binding to hemoglobin and merely lowering hemoglobin’s ionization potential (IP). Our results showed that PQ and its derivatives do not significantly lower the hemoglobin IP, disproving the hypothesis.

  17. Plasmodium falciparum Thioredoxin Reductase (PfTrxR) and Its Role as a Target for New Antimalarial Discovery.

    McCarty, Sara E; Schellenberger, Amanda; Goodwin, Douglas C; Fuanta, Ngolui Rene; Tekwani, Babu L; Calderón, Angela I

    2015-01-01

    The growing resistance to current antimalarial drugs is a major concern for global public health. The pressing need for new antimalarials has led to an increase in research focused on the Plasmodium parasites that cause human malaria. Thioredoxin reductase (TrxR), an enzyme needed to maintain redox equilibrium in Plasmodium species, is a promising target for new antimalarials. This review paper provides an overview of the structure and function of TrxR, discusses similarities and differences between the thioredoxin reductases (TrxRs) of different Plasmodium species and the human forms of the enzyme, gives an overview of modeling Plasmodium infections in animals, and suggests the role of Trx functions in antimalarial drug resistance. TrxR of Plasmodium falciparum is a central focus of this paper since it is the only Plasmodium TrxR that has been crystallized and P. falciparum is the species that causes most malaria cases. It is anticipated that the information summarized here will give insight and stimulate new directions in which research might be most beneficial. PMID:26111176

  18. Plasmodium falciparum Thioredoxin Reductase (PfTrxR and Its Role as a Target for New Antimalarial Discovery

    Sara E. McCarty

    2015-06-01

    Full Text Available The growing resistance to current antimalarial drugs is a major concern for global public health. The pressing need for new antimalarials has led to an increase in research focused on the Plasmodium parasites that cause human malaria. Thioredoxin reductase (TrxR, an enzyme needed to maintain redox equilibrium in Plasmodium species, is a promising target for new antimalarials. This review paper provides an overview of the structure and function of TrxR, discusses similarities and differences between the thioredoxin reductases (TrxRs of different Plasmodium species and the human forms of the enzyme, gives an overview of modeling Plasmodium infections in animals, and suggests the role of Trx functions in antimalarial drug resistance. TrxR of Plasmodium falciparum is a central focus of this paper since it is the only Plasmodium TrxR that has been crystallized and P. falciparum is the species that causes most malaria cases. It is anticipated that the information summarized here will give insight and stimulate new directions in which research might be most beneficial.

  19. Plant-Derived Antimalarial Agents: New Leads and Efficient Phytomedicines. Part II. Non-Alkaloidal Natural Products

    Alaíde Braga de Oliveira

    2009-08-01

    Full Text Available Malaria is still the most destructive and dangerous parasitic infection in many tropical and subtropical countries. The burden of this disease is getting worse, mainly due to the increasing resistance of Plasmodium falciparum against the widely available antimalarial drugs. There is an urgent need for new, more affordable and accessible antimalarial agents possessing original modes of action. Natural products have played a dominant role in the discovery of leads for the development of drugs to treat human diseases, and this fact anticipates that new antimalarial leads may certainly emerge from tropical plant sources. This present review covers most of the recently-published non-alkaloidal natural compounds from plants with antiplasmodial and antimalarial properties, belonging to the classes of terpenes, limonoids, flavonoids, chromones, xanthones, anthraquinones, miscellaneous and related compounds, besides the majority of papers describing antiplasmodial crude extracts published in the last five years not reviewed before. In addition, some perspectives and remarks on the development of new drugs and phytomedicines for malaria are succinctly discussed.

  20. Why Hospital Pharmacists Have Failed to Manage Antimalarial Drugs Stock-Outs in Pakistan? A Qualitative Insight

    Madeeha Malik

    2013-01-01

    Full Text Available Purpose. This study aimed to explore the perceptions of hospital pharmacists towards drug management and reasons underlying stock-outs of antimalarial drugs in Pakistan. Methods. A qualitative study was designed to explore the perceptions of hospital pharmacists regarding drug management and irrational use of antimalarial drugs in two major cities of Pakistan, namely, Islamabad (national capital and Rawalpindi (twin city. Semistructured interviews were conducted with 16 hospital pharmacists using indepth interview guides at a place and time convenient for the respondents. Interviews, which were audiotaped and transcribed verbatim, were evaluated by thematic content analysis and by other authors’ analysis. Results. Most of the respondents were of the view that financial constraints, inappropriate drug management, and inadequate funding were the factors contributing toward the problem of antimalarial drug stock-outs in healthcare facilities of Pakistan. The pharmacists anticipated that prescribing by nonproprietary names, training of health professionals, accepted role of hospital pharmacist in drug management, implementation of essential drug list and standard treatment guidelines for malaria in the healthcare system can minimize the problem of drug stock outs in healthcare system of Pakistan. Conclusion. The current study showed that all the respondents in the two cities agreed that hospital pharmacist has failed to play an effective role in efficient management of anti-malarial drugs stock-outs.

  1. Acceptability by community health workers in Senegal of combining community case management of malaria and seasonal malaria chemoprevention

    Tine, Roger Ck; Ndiaye, Pascal; Ndour, Cheikh T;

    2013-01-01

    Community case management of malaria (CCMm) and seasonal malaria chemoprevention (SMC) are anti-malarial interventions that can lead to substantial reduction in malaria burden acting in synergy. However, little is known about the social acceptability of these interventions. A study was undertaken...... to assess whether combining the interventions would be an acceptable approach to malaria control for community health workers (CHWs)....

  2. Antimalarial drug quality in the most severely malarious parts of Africa - a six country study.

    Roger Bate

    Full Text Available A range of antimalarial drugs were procured from private pharmacies in urban and peri-urban areas in the major cities of six African countries, situated in the part of that continent and the world that is most highly endemic for malaria. Semi-quantitative thin-layer chromatography (TLC and dissolution testing were used to measure active pharmaceutical ingredient content against internationally acceptable standards. 35% of all samples tested failed either or both tests, and were substandard. Further, 33% of treatments collected were artemisinin monotherapies, most of which (78% were manufactured in disobservance of an appeal by the World Health Organisation (WHO to withdraw these clinically inappropriate medicines from the market. The high persistence of substandard drugs and clinically inappropriate artemisinin monotherapies in the private sector risks patient safety and, through drug resistance, places the future of malaria treatment at risk globally.

  3. Structural Basis for Binding and Selectivity of Antimalarial and Anticancer Ethylenediamine Inhibitors to Protein Farnesyltransferase

    Hast, Michael A.; Fletcher, Steven; Cummings, Christopher G.; Pusateri, Erin E.; Blaskovich, Michelle A.; Rivas, Kasey; Gelb, Michael H.; Voorhis, Wesley C.Van; Sebti, Said M.; Hamilton, Andrew D.; Beese, Lorena S. ((Yale)); ((USF)); ((UWASH)); ((Duke))

    2009-03-20

    Protein farnesyltransferase (FTase) catalyzes an essential posttranslational lipid modification of more than 60 proteins involved in intracellular signal transduction networks. FTase inhibitors have emerged as a significant target for development of anticancer therapeutics and, more recently, for the treatment of parasitic diseases caused by protozoan pathogens, including malaria (Plasmodium falciparum). We present the X-ray crystallographic structures of complexes of mammalian FTase with five inhibitors based on an ethylenediamine scaffold, two of which exhibit over 1000-fold selective inhibition of P. falciparum FTase. These structures reveal the dominant determinants in both the inhibitor and enzyme that control binding and selectivity. Comparison to a homology model constructed for the P. falciparum FTase suggests opportunities for further improving selectivity of a new generation of antimalarial inhibitors.

  4. Holographic analysis on deformation and restoration of malaria-infected red blood cells by antimalarial drug

    Byeon, Hyeokjun; Ha, Young-Ran; Lee, Sang Joon

    2015-11-01

    Malaria parasites induce morphological, biochemical, and mechanical changes in red blood cells (RBCs). Mechanical variations are closely related to the deformability of individual RBCs. The deformation of various RBCs, including healthy and malaria-infected RBCs (iRBCs), can be directly observed through quantitative phase imaging (QPI). The effects of chloroquine treatment on the mechanical property variation of iRBCs were investigated using time-resolved holographic QPI of single live cells on a millisecond time scale. The deformabilities of healthy RBCs, iRBCs, and drug-treated iRBCs were compared, and the effect of chloroquine on iRBC restoration was experimentally examined. The present results are beneficial to elucidate the dynamic characteristics of iRBCs and the effect of the antimalarial drug on iRBCs.

  5. Parasites resistant to the antimalarial atovaquone fail to transmit by mosquitoes.

    Goodman, Christopher D; Siregar, Josephine E; Mollard, Vanessa; Vega-Rodríguez, Joel; Syafruddin, Din; Matsuoka, Hiroyuki; Matsuzaki, Motomichi; Toyama, Tomoko; Sturm, Angelika; Cozijnsen, Anton; Jacobs-Lorena, Marcelo; Kita, Kiyoshi; Marzuki, Sangkot; McFadden, Geoffrey I

    2016-04-15

    Drug resistance compromises control of malaria. Here, we show that resistance to a commonly used antimalarial medication, atovaquone, is apparently unable to spread. Atovaquone pressure selects parasites with mutations in cytochrome b, a respiratory protein with low but essential activity in the mammalian blood phase of the parasite life cycle. Resistance mutations rescue parasites from the drug but later prove lethal in the mosquito phase, where parasites require full respiration. Unable to respire efficiently, resistant parasites fail to complete mosquito development, arresting their life cycle. Because cytochrome b is encoded by the maternally inherited parasite mitochondrion, even outcrossing with wild-type strains cannot facilitate spread of resistance. Lack of transmission suggests that resistance will be unable to spread in the field, greatly enhancing the utility of atovaquone in malaria control. PMID:27081071

  6. Distillation Time as Tool for Improved Antimalarial Activity and Differential Oil Composition of Cumin Seed Oil.

    Zheljazkov, Valtcho D; Gawde, Archana; Cantrell, Charles L; Astatkie, Tess; Schlegel, Vicki

    2015-01-01

    A steam distillation extraction kinetics experiment was conducted to estimate essential oil yield, composition, antimalarial, and antioxidant capacity of cumin (Cuminum cyminum L.) seed (fruits). Furthermore, regression models were developed to predict essential oil yield and composition for a given duration of the steam distillation time (DT). Ten DT durations were tested in this study: 5, 7.5, 15, 30, 60, 120, 240, 360, 480, and 600 min. Oil yields increased with an increase in the DT. Maximum oil yield (content, 2.3 g/100 seed), was achieved at 480 min; longer DT did not increase oil yields. The concentrations of the major oil constituents α-pinene (0.14-0.5% concentration range), β-pinene (3.7-10.3% range), γ-cymene (5-7.3% range), γ-terpinene (1.8-7.2% range), cumin aldehyde (50-66% range), α-terpinen-7-al (3.8-16% range), and β-terpinen-7-al (12-20% range) varied as a function of the DT. The concentrations of α-pinene, β-pinene, γ-cymene, γ-terpinene in the oil increased with the increase of the duration of the DT; α-pinene was highest in the oil obtained at 600 min DT, β-pinene and γ-terpinene reached maximum concentrations in the oil at 360 min DT; γ-cymene reached a maximum in the oil at 60 min DT, cumin aldehyde was high in the oils obtained at 5-60 min DT, and low in the oils obtained at 240-600 min DT, α-terpinen-7-al reached maximum in the oils obtained at 480 or 600 min DT, whereas β-terpinen-7-al reached a maximum concentration in the oil at 60 min DT. The yield of individual oil constituents (calculated from the oil yields and the concentration of a given compound at a particular DT) increased and reached a maximum at 480 or 600 min DT. The antimalarial activity of the cumin seed oil obtained during the 0-5 and at 5-7.5 min DT timeframes was twice higher than the antimalarial activity of the oils obtained at the other DT. This study opens the possibility for distinct marketing and utilization for these improved oils. The antioxidant

  7. Combating poor-quality anti-malarial medicines: a call to action.

    Bassat, Quique; Tanner, Marcel; Guerin, Philippe J; Stricker, Kirstin; Hamed, Kamal

    2016-01-01

    The circulation of poor-quality medicines continues to undermine the fight against many life-threatening diseases. Anti-malarial medicines appear to have been particularly compromised and present a major public health threat in malaria-endemic countries, negatively affecting individuals and their communities. Concerted collaborative efforts are required from global, regional and national organizations, involving the public and private sectors, to address the problem. While many initiatives are underway, a number of unmet needs deserve urgent and increased multisector attention. At the global level, there is a need for an international public health legal framework or treaty on poor-quality medicines, with statutes suitable for integration into national laws. In addition, increased international efforts are required to strengthen the governance of global supply chains and enhance cooperation between national medicine regulation authorities and law enforcement bodies. Increased investment is needed in innovative technologies that will enable healthcare teams to detect poor-quality medicines at all levels of the supply chain. At the regional level, a number of initiatives would be beneficial-key areas are standardization, simplification, and reciprocal recognition of registration processes and development of quality control capacity in regional centres of excellence that are better aligned with public health needs; improved surveillance methods and creation of a framework for compulsory and transparent reporting of poor-quality medicines; additional support for national medicine regulation authorities and other national partner authorities; and an increase in support for regional laboratories to boost their capabilities in detecting poor-quality medicines. It is vital that all stakeholders involved in efforts against poor-quality anti-malarial medicines extend and strengthen their actions in these critical areas and thus effectively support global health development

  8. Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance.

    Warhurst, David C; Craig, John C; Raheem, K Saki

    2016-01-01

    Antimalarial chloroquine (CQ) prevents haematin detoxication when CQ-base concentrates in the acidic digestive vacuole through protonation of its p-aminopyridine (pAP) basic aromatic nitrogen and sidechain diethyl-N. CQ export through the variant vacuolar membrane export channel, PFCRT, causes CQ-resistance in Plasmodium falciparum but 3-methyl CQ (sontochin SC), des-ethyl amodiaquine (DAQ) and bis 4-aminoquinoline piperaquine (PQ) are still active. This is determined by changes in drug accumulation ratios in parasite lipid (LAR) and in vacuolar water (VAR). Higher LAR may facilitate drug binding to and blocking PFCRT and also aid haematin in lipid to bind drug. LAR for CQ is only 8.3; VAR is 143,482. More hydrophobic SC has LAR 143; VAR remains 68,523. Similarly DAQ with a phenol substituent has LAR of 40.8, with VAR 89,366. In PQ, basicity of each pAP is reduced by distal piperazine N, allowing very high LAR of 973,492, retaining VAR of 104,378. In another bis quinoline, dichlorquinazine (DCQ), also active but clinically unsatisfactory, each pAP retains basicity, being insulated by a 2-carbon chain from a proximal nitrogen of the single linking piperazine. While LAR of 15,488 is still high, the lowest estimate of VAR approaches 4.9 million. DCQ may be expected to be very highly lysosomotropic and therefore potentially hepatotoxic. In 11 pAP antimalarials a quadratic relationship between logLAR and logResistance Index (RI) was confirmed, while log (LAR/VAR) vs logRI for 12 was linear. Both might be used to predict the utility of structural modifications. PMID:27483471

  9. Medicines informal market in Congo, Burundi and Angola: counterfeit and sub-standard antimalarials

    Bertocchi Paola

    2007-02-01

    Full Text Available Abstract Background The presence of counterfeits and sub-standards in African medicines market is a dramatic problem that causes many deaths each year. The increase of the phenomenon of pharmaceutical counterfeiting is due to the rise of the illegal market and to the impossibility to purchase branded high cost medicines. Methods In this paper the results of a quality control on antimalarial tablet samples purchased in the informal market in Congo, Burundi and Angola are reported. The quality control consisted in the assay of active substance by means of validated liquid chromatographic methods, uniformity of mass determination, disintegration and dissolution tests. Moreover, a general evaluation on label and packaging characteristics was performed. Results The results obtained on thirty antimalarial tablet samples containing chloroquine, quinine, mefloquine, sulphadoxine and pyrimethamine showed the presence of different kinds of problems: a general problem concerning the packaging (loose tablets, packaging without Producer name, Producer Country and sometimes without expiry date; low content of active substance (in one sample; different, non-declared, active substance (in one sample; sub-standard technological properties and very low dissolution profiles (in about 50% of samples. This last property could affect the bioavailability and bioequivalence in comparison with branded products and could be related to the use of different excipients in formulation or bad storage conditions. Conclusion This paper evidences that the most common quality problem in the analysed samples appears to be the low dissolution profile. Here it is remarked that the presence of the right active substance in the right quantity is not a sufficient condition for a good quality drug. Dissolution test is not less important in a quality control and often evidences in vitro possible differences in therapeutic efficacy among drugs with the same active content. Dissolution

  10. Diversity and utilization of antimalarial ethnophytotherapeutic remedies among the Kikuyus (Central Kenya

    Bussmann Rainer W

    2006-02-01

    Full Text Available Abstract Plants in Kenya are becoming increasingly important as sources of traditional medicines. The World Health Organization (WHO has estimated that malaria kills about 2.7 million people every year, 90% of who are from Africa. Malaria continues to be a national concern in Kenya as it plays a major role in the high mortality rates being experienced currently. The use and miss-use of chloroquine to prevent and treat falciparium malaria has led to widespread appearance of chloroquine resistant parasites in Kenya and other tropical countries. These factors and the rising costs of non-chloroquine drugs have made the local people to turn to traditional remedies for management of this menace. This paper examines the current utilization of traditional plant medicines in managing malaria menace in Central Kenya. The results show both indigenous and introduced species are in use indicating traditional medicinal practices in this region are dynamic. In total 58 species in 54 genera and 33 families were identified. The family Rubiaceae was found to have the highest number of reported species. Use of the various taxa is compared between five districts within Central Province of Kenya. The commonest species in this pharmacopoeia are: Caesalpinia volkensii Harms, Strychnos henningsii Gilg, Ajuga remota Benth., Warbugia ugandensis Sprague and Olea europaea L. The first three species are used in all the five districts while the others are restricted in some of the districts. In 74% of the anti-malarial plant species reported in this study, the remedies are obtained in destructive manner and may need conservation measures to ensure sustainable utilization. The results of this study become a basis for selecting plants for further pharmacological and phytochemical studies in developing new and locally relevant anti-malarial agents.

  11. Malaria healthcare policy change in Kenya: Implications on sales and marketing of antimalarials

    Peter K. Ngure , Lorraine Nyaoke & David Minja

    2012-03-01

    Full Text Available Background & objectives: Malaria healthcare policy change in Kenya aimed at improving the control of malariabut faced a number of challenges in implementation related to marketing of the drugs. This research investigatedthe effect of the change of the national malaria policy on drug sales and strategic marketing responses ofantimalarial pharmaceutical companies in Kenya.Study design: A descriptive cross-sectional design was employed to describe the existing state of antimalarialsmarket in Kenya after the change of the malaria healthcare policy.Results & conclusion: Policy change did result in an increase in the sales of Coartem®. Novartis Pharma recordeda 97% growth in sales of Coartem® between 2003 and 2004. However, this increase was not experienced by allthe companies. Further, SPs (which had been replaced as first-line therapy for malaria registered good sales. Inmost cases, these sales were higher than the sales of Coartem®. Generally, the sales contribution of SPs andgeneric antimalarial medicines exceeded that of Coartem® for most distributors. The most common changemade to marketing strategies by distributors (62.5% was to increase imports of antimalarials. A total of 40% ofthe manufacturers preferred to increase their budgetary allocation for marketing activities. In view of the factthat continued sale of SP drugs and limited availability of AL poses the risk of increasing the incidence ofmalaria in Kenya, it is therefore, recommended that pharmacy surveillance systems be strengthened to ensuredrugs that have been rendered non-viable or that prescription-only medicines are not sold contrary to the nationalguidelines.

  12. In Vivo Antimalarial Activity of Annona muricata Leaf Extract in Mice Infected with Plasmodium berghei.

    Somsak, Voravuth; Polwiang, Natsuda; Chachiyo, Sukanya

    2016-01-01

    Malaria is one of the most important infectious diseases in the world. The choice for the treatment is highly limited due to drug resistance. Hence, finding the new compounds to treat malaria is urgently needed. The present study was attempted to evaluate the antimalarial activity of the Annona muricata aqueous leaf extract in Plasmodium berghei infected mice. Aqueous leaf extract of A. muricata was prepared and tested for acute toxicity in mice. For efficacy test in vivo, standard 4-day suppressive test was carried out. ICR mice were inoculated with 10(7) parasitized erythrocytes of P. berghei ANKA by intraperitoneal injection. The extracts (100, 500, and 1000 mg/kg) were then given orally by gavage once a day for 4 consecutive days. Parasitemia, percentage of inhibition, and packed cell volume were subsequently calculated. Chloroquine (10 mg/kg) was given to infected mice as positive control while untreated control was given only distilled water. It was found that A. muricata aqueous leaf extract at doses of 100, 500, and 1000 mg/kg resulted in dose dependent parasitemia inhibition of 38.03%, 75.25%, and 85.61%, respectively. Survival time was prolonged in infected mice treated with the extract. Moreover, no mortality to mice was observed with this extract up to a dose of 4000 mg/kg. In conclusion, the A. muricata aqueous leaf extract exerted significant antimalarial activity with no toxicity and prolonged survival time. Therefore, this extract might contain potential lead molecule for the development of a new drug for malaria treatment. PMID:27092277

  13. Ligand based validated comparative chemometric modeling and pharmacophore mapping of aurone derivatives as antimalarial agents.

    Adhikari, Nilanjan; Halder, Amit Kumar; Mondal, Chanchal; Jha, Tarun

    2013-09-01

    Chloroquine resistance is nowadays a great problem. Aurone derivatives are effective against chloroquine resistant parasite. Ligand based validated comparative chemometric modeling through 2D-QSAR and kNN-MFA 3DQSAR studies as well as common feature 3D pharmacophore mapping were done on thirtyfive aurone derivatives having antimalarial activity. Statistically significant 2D-QSAR models were generated on unsplitted as well as splitted dataset by MLR and PLS technique. The MLR model of the unsplitted method was validated by two-deep cross validation and 10 fold cross validation for determining the predictive ability. The PLS technique of the unsplitted method was done to compare the significance of these methods. In the splitted method, model was developed on the training set by Y-based ranking method by using the same descriptors and was validated on fifty pairs of the test and the training sets by k-MCA technique. These models generated by using the same descriptors were well validated irrespective of MLR as well as PLS analysis of unsplitted as well as splitted methods and are showing similar results. Therefore, these descriptors and model generated were reliable and robust. The kNN-MFA 3D-QSAR models were generated by three variable selection methods: genetic algorithm, simulated annealing and stepwise regression. The kNN-MFA 3D-QSAR results support the 2D QSAR data and in turn validate the earlier observed SAR results. Common feature 3D-pharmacophore generation was performed on these compounds to validate both 2D and 3D-QSAR studies as well as the earlier observed SAR data. The work highlights the required structural features for the higher antimalarial activity. PMID:24010937

  14. The popular herbal antimalarial, extract of Cryptolepis sanguinolenta, is potently cytotoxic.

    Ansah, Charles; Gooderham, Nigel J

    2002-12-01

    The aqueous root extract of Cryptolepis sanguinolenta (CSE) is a popular antimalarial in West African ethnomedicine. Cryptolepine (CLP), the major alkaloid of the plant, is a cytotoxic DNA intercalator that has promise as an anticancer agent. To date the aqueous root extract, the traditional antimalarial formulation, has not been evaluated for toxicity. In this study, we have examined the in vitro toxicity of CSE and CLP using V79 cells, a Chinese hamster lung fibroblast frequently used to assess genetic toxicity, and a number of organ-specific human cancer cell lines. CSE and CLP caused a dose- and time-dependent reduction in viability of the V79 cell line. Flow cytometric analysis of CSE- and CLP-treated (24 h) asynchronously growing V79 cells using propidium iodide (PI) staining revealed an accumulation of cells (up to 55%) in the sub-G1 phase of the cell cycle, indicative of cell death. The V79 cells and almost all the organ-specific human cancer cell lines exposed to CSE and CLP were profoundly growth inhibited, as measured in a clonogenicity assay. In a V79 cell mutation assay (hprt gene), CSE (5-50 microg/ml) only induced mutation at the highest dose employed (mutation frequency approximately 4 and 38 mutant clones per 10(6) cells for control and CSE, respectively), but CLP (0.5-5.0 microM) was not mutagenic. These results indicate that CSE and CLP are very cytotoxic and may be weak mammalian mutagens and/or clastogens. The poor genotoxicity of CSE and CLP coupled with their potent cytotoxic action support their anticancer potential. PMID:12441369

  15. Adherence of community caretakers of children to pre-packaged antimalarial medicines (HOMAPAK® among internally displaced people in Gulu district, Uganda

    Opwonya John

    2006-05-01

    Full Text Available Abstract Background In 2002, home-based management of fever (HBMF was introduced in Uganda, to improve access to prompt, effective antimalarial treatment of all fevers in children under 5 years. Implementation is through community drug distributors (CDDs who distribute pre-packaged chloroquine plus sulfadoxine-pyrimethamine (HOMAPAK® free of charge to caretakers of febrile children. Adherence of caretakers to this regimen has not been studied. Methods A questionnaire-based survey combined with inspection of blister packaging was conducted to investigate caretakers' adherence to HOMAPAK®. The population surveyed consisted of internally displaced people (IDPs from eight camps. Results A total of 241 caretakers were interviewed. 95.0% (CI: 93.3% – 98.4% of their children had received the correct dose for their age and 52.3% of caretakers had retained the blister pack. Assuming correct self-reporting, the overall adherence was 96.3% (CI: 93.9% – 98.7%. The nine caretakers who had not adhered had done so because the child had improved, had vomited, did not like the taste of the tablets, or because they forgot to administer the treatment. For 85.5% of cases treatment had been sought within 24 hours. Blister packaging was considered useful by virtually all respondents, mainly because it kept the drugs clean and dry. Information provided on, and inside, the package was of limited use, because most respondents were illiterate. However, CDDs had often told caretakers how to administer the treatment. For 39.4% of respondents consultation with the CDD was their reported first action when their child has fever and 52.7% stated that they consult her/him if the child does not get better. Conclusion In IDP camps, the HBMF strategy forms an important component of medical care for young children. In case of febrile illness, most caretakers obtain prompt and adequate antimalarial treatment, and adhere to it. A large proportion of malaria episodes are thus

  16. A Chemical Proteomics Approach for the Search of Pharmacological Targets of the Antimalarial Clinical Candidate Albitiazolium in Plasmodium falciparum Using Photocrosslinking and Click Chemistry

    Diana Marcela Penarete-Vargas; Anaïs Boisson; Serge Urbach; Hervé Chantelauze; Suzanne Peyrottes; Laurent Fraisse; Vial, Henri J

    2014-01-01

    Plasmodium falciparum is responsible for severe malaria which is one of the most prevalent and deadly infectious diseases in the world. The antimalarial therapeutic arsenal is hampered by the onset of resistance to all known pharmacological classes of compounds, so new drugs with novel mechanisms of action are critically needed. Albitiazolium is a clinical antimalarial candidate from a series of choline analogs designed to inhibit plasmodial phospholipid metabolism. Here we developed an origi...

  17. Development of a TaqMan Allelic Discrimination Assay for detection of Single Nucleotides Polymorphisms associated with anti-malarial drug resistance

    Kamau Edwin

    2012-01-01

    Full Text Available Abstract Background Anti-malarial drug resistance poses a threat to current global efforts towards control and elimination of malaria. Several methods are used in monitoring anti-malarial drug resistance. Molecular markers such as single nucleotide polymorphism (SNP for example are increasingly being used to identify genetic mutations related to anti-malarial drug resistance. Several methods are currently being used in analysis of SNP associated with anti-malarial drug resistance and although each one of these methods has unique strengths and shortcoming, there is still need to improve and/or develop new methods that will close the gap found in the current methods. Methods TaqMan Allelic Discrimination assays for detection of SNPs associated with anti-malarial drug resistance were designed for analysis on Applied Biosystems PCR platform. These assays were designed by submitting SNP sequences associated with anti-malarial drug resistance to Applied Biosystems website. Eleven SNPs associated with resistance to anti-malarial drugs were selected and tested. The performance of each SNP assay was tested by creating plasmid DNAs carrying codons of interests and analysing them for analysis. To test the sensitivity and specificity of each SNP assay, 12 clinical samples were sequenced at codons of interest and used in the analysis. Plasmid DNAs were used to establish the Limit of Detection (LoD for each assay. Results Data from genetic profiles of the Plasmodium falciparum laboratory strains and sequence data from 12 clinical samples was used as the reference method with which the performance of the SNP assays were compared to. The sensitivity and specificity of each SNP assay was establish at 100%. LoD for each assay was established at 2 GE, equivalent to less than 1 parasite/μL. SNP assays performed well in detecting mixed infection and analysis of clinical samples. Conclusion TaqMan Allelic Discrimination assay provides a good alternative tool in

  18. Vector incrimination and effects of antimalarial drugs on malaria transmission and control in the Amazon Basin of Brazil

    T. A. Klein

    1992-01-01

    Full Text Available World ecosystems differ significantly and a multidisciplinary malaria control approach must be adjusted to meet these requirements. These include a comprehensive understanding of the malaria vectors, their behavior, seasonal distribution and abundance, susceptibility to insecticides (physiological and behavioral, methods to reduce the numbers of human gametocyte carriers through effective health care systems and antimalarial drug treatment, urban malaria transmission versus rural or forest malaria transmission, and the impact of vaccine development. Many malaria vectors are members of species complexes and individual relationship to malaria transmission, seasonal distribution, bitting behavior, etc. is poorly understood. Additionaly, malaria patients are not examined for circulating gametocytes and both falciparum and vivax malaria patients may be highly infective to mosquitoes after treatment with currently used antimalarial drugs. Studies on the physiological and behavioral effects of DDT and other insecticides are inconclusive and need to be evalusted.

  19. Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in African Children with Malaria

    Salman, Sam; Bendel, Daryl; Lee, Toong C.; Templeton, David; Davis, Timothy M. E.

    2015-01-01

    The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in 91 young African children with severe malaria or who could not tolerate oral antimalarial therapy. Each received 3.0 mg/kg of body weight of artemether at 0, 8, 24, 36, 48, and 60 h or until the initiation of oral treatment. Few blood samples were drawn postdose. Plasma artemether and dihydroartemisinin (DHA) levels were measured using liquid chromatography-mass spectrometry, and the data were analyzed using establis...

  20. Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs

    Mu, Jianbing; Myers, Rachel A.; Jiang, Hongying; Liu, Shengfa; Ricklefs, Stacy; Waisberg, Michael; Chotivanich, Kesinee; Wilairata, Polrat; Krudsood, Srivicha; White, Nicholas J; Udomsangpetch, Rachanee; Cui, Liwang; Ho, May; Ou, Fengzheng; Li, Haibo

    2010-01-01

    Antimalarial drugs impose strong pressure on Plasmodium falciparum parasites and leave signatures of selection in the parasite genome 1,2. Search for signals of selection may lead to genes encoding drug or immune targets 3. The lack of high-throughput genotyping methods, inadequate knowledge of parasite population history, and time-consuming adaptations of parasites to in vitro culture have hampered genome-wide association studies (GWAS) of parasite traits. Here we report genotyping of DNA fr...

  1. Activity of clinically relevant antimalarial drugs on Plasmodium falciparum mature gametocytes in an ATP bioluminescence "transmission blocking" assay.

    Joël Lelièvre

    Full Text Available BACKGROUND: Current anti-malarial drugs have been selected on the basis of their activity against the symptom-causing asexual blood stage of the parasite. Which of these drugs also target gametocytes, in the sexual stage responsible for disease transmission, remains unknown. Blocking transmission is one of the main strategies in the eradication agenda and requires the identification of new molecules that are active against gametocytes. However, to date, the main limitation for measuring the effect of molecules against mature gametocytes on a large scale is the lack of a standardized and reliable method. Here we provide an efficient method to produce and purify mature gametocytes in vitro. Based on this new procedure, we developed a robust, affordable, and sensitive ATP bioluminescence-based assay. We then assessed the activity of 17 gold-standard anti-malarial drugs on Plasmodium late stage gametocytes. METHODS AND FINDINGS: Difficulties in producing large amounts of gametocytes have limited progress in the development of malaria transmission blocking assays. We improved the method established by Ifediba and Vanderberg to obtain viable, mature gametocytes en masse, whatever the strain used. We designed an assay to determine the activity of antimalarial drugs based on the intracellular ATP content of purified stage IV-V gametocytes after 48 h of drug exposure in 96/384-well microplates. Measurements of drug activity on asexual stages and cytotoxicity on HepG2 cells were also obtained to estimate the specificity of the active drugs. CONCLUSIONS: The work described here represents another significant step towards determination of the activity of new molecules on mature gametocytes of any strain with an automated assay suitable for medium/high-throughput screening. Considering that the biology of the forms involved in the sexual and asexual stages is very different, a screen of our 2 million-compound library may allow us to discover novel anti-malarial

  2. Differences in anti-malarial activity of 4-aminoalcohol quinoline enantiomers and investigation of the presumed underlying mechanism of action

    Mullié Catherine

    2012-03-01

    Full Text Available Abstract Background A better anti-malarial efficiency and lower neurotoxicity have been reported for mefloquine (MQ (+- enantiomer. However, the importance of stereoselectivity remains poorly understood as the anti-malarial activity of pure enantiomer MQ analogues has never been described. Building on these observations, a series of enantiopure 4-aminoalcohol quinoline derivatives has previously been synthesized to optimize the efficiency and reduce possible adverse effects. Their in vitro activity on Plasmodium falciparum W2 and 3D7 strains is reported here along with their inhibition of β-haematin formation and peroxidative degradation of haemin, two possible mechanisms of action of anti-malarial drugs. Results The (S-enantiomers of this series of 4-aminoalcohol quinoline derivatives were found to be at least as effective as both chloroquine (CQ and MQ. The derivative with a 5-carbon side-chain length was the more efficient on both P. falciparum strains. (R -enantiomers displayed an activity decreased by 2 to 15-fold as compared to their (S counterparts. The inhibition of β-haematin formation was significantly stronger with all tested compounds than with MQ, irrespective of the stereochemistry. Similarly, the inhibition of haemin peroxidation was significantly higher for both (S and (R-enantiomers of derivatives with a side-chain length of five or six carbons than for MQ and CQ. Conclusions The prominence of stereochemistry in the anti-malarial activity of 4-aminoalcohol quinoline derivatives is confirmed. The inhibition of β-haematin formation and haemin peroxidation can be put forward as presumed mechanisms of action but do not account for the stereoselectivity of action witnessed in vitro.

  3. Anti-malarial activity and toxicity assessment of Himatanthus articulatus, a plant used to treat malaria in the Brazilian Amazon

    Vale, Valdicley V; Thyago C. Vilhena; Trindade, Rafaela C Santos; Ferreira, Márlia Regina C; Percário, Sandro; Soares, Luciana F; Pereira, Washington Luiz A; Geraldo C. Brandão; Oliveira, Alaíde B; Dolabela, Maria F; De Vasconcelos, Flávio

    2015-01-01

    Background Plasmodium falciparum has become resistant to some of the available drugs. Several plant species are used for the treatment of malaria, such as Himatanthus articulatus in parts of Brazil. The present paper reports the phyto-chemistry, the anti-plasmodial and anti-malarial activity, as well as the toxicity of H. articulatus. Methods Ethanol and dichloromethane extracts were obtained from the powder of stem barks of H. articulatus and later fractionated and analysed. The anti-plasmod...

  4. Development of a specific monoclonal antibody-based ELISA to measure the artemether content of antimalarial drugs.

    Suqin Guo

    Full Text Available Artemether is one of the artemisinin derivatives that are active ingredients in antimalarial drugs. Counterfeit and substandard antimalarial drugs have become a serious problem, which demands reliable analytical tools and implementation of strict regulation of drug quality. Structural similarity among artemisinin analogs is a challenge to develop immunoassays that are specific to artemisinin derivatives. To produce specific antibodies to artemether, we used microbial fermentation of artemether to obtain 9-hydroxyartemether, which was subsequently used to prepare a 9-O-succinylartemether hapten for conjugation with ovalbumin as the immunogen. A monoclonal antibody (mAb, designated as 2G12E1, was produced with high specificity to artemether. 2G12E1 showed low cross reactivities to dihydroartemisinin, artemisinin, artesunate and other major antimalarial drugs. An indirect competitive enzyme linked immunosorbent assay (icELISA developed showed a concentration causing 50% of inhibition for artemether as 3.7 ng mL⁻¹ and a working range of 0.7-19 ng mL⁻¹. The icELISA was applied for determination of artemether content in different commercial drugs and the results were comparable to those determined by high-performance liquid chromatography analysis. In comparison with reported broad cross activity of anti-artemisinin mAbs, the most notable advantage of the 2G12E1-based ELISA is its high specificity to artemether only.

  5. The use of genotyping in antimalarial clinical trials: a systematic review of published studies from 1995–2005

    Rosenthal Philip J

    2006-12-01

    Full Text Available Abstract Background The use of genotyping to distinguish recrudescent from new infections is currently recommended for all clinical antimalarial efficacy trials by the World Health Organization. However, genotyping-adjusted drug efficacy estimates may vary between trials due to the use of different genotyping methods and to the different settings in which these methods are applied. Methods A systematic review of all clinical antimalarial efficacy trials published from 1995–2005 was performed to characterize the use of genotyping, including the methods used and the effect of these methods on estimates of drug efficacy. Results In a multivariate analysis, the method of interpretation of genotyping results, the studied therapy, the location of the trial, and the duration of study follow-up all had statistically significant effects on the percent of genotyped outcomes classified as new infections. Conclusion Criteria for defining appropriate, standardized genotyping methods for use in different settings are needed to enable more accurate estimates of antimalarial drug efficacy and better comparison between trials. The advantages and disadvantages of different genotyping methods and their potential impact in various settings are discussed.

  6. Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum.

    Daria Van Tyne

    2011-04-01

    Full Text Available The Plasmodium falciparum parasite's ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (∼ 1 SNP/kb, and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS, searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome.

  7. Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor.

    Goldgof, Gregory M; Durrant, Jacob D; Ottilie, Sabine; Vigil, Edgar; Allen, Kenneth E; Gunawan, Felicia; Kostylev, Maxim; Henderson, Kiersten A; Yang, Jennifer; Schenken, Jake; LaMonte, Gregory M; Manary, Micah J; Murao, Ayako; Nachon, Marie; Stanhope, Rebecca; Prescott, Maximo; McNamara, Case W; Slayman, Carolyn W; Amaro, Rommie E; Suzuki, Yo; Winzeler, Elizabeth A

    2016-01-01

    The spiroindolones, a new class of antimalarial medicines discovered in a cellular screen, are rendered less active by mutations in a parasite P-type ATPase, PfATP4. We show here that S. cerevisiae also acquires mutations in a gene encoding a P-type ATPase (ScPMA1) after exposure to spiroindolones and that these mutations are sufficient for resistance. KAE609 resistance mutations in ScPMA1 do not confer resistance to unrelated antimicrobials, but do confer cross sensitivity to the alkyl-lysophospholipid edelfosine, which is known to displace ScPma1p from the plasma membrane. Using an in vitro cell-free assay, we demonstrate that KAE609 directly inhibits ScPma1p ATPase activity. KAE609 also increases cytoplasmic hydrogen ion concentrations in yeast cells. Computer docking into a ScPma1p homology model identifies a binding mode that supports genetic resistance determinants and in vitro experimental structure-activity relationships in both P. falciparum and S. cerevisiae. This model also suggests a shared binding site with the dihydroisoquinolones antimalarials. Our data support a model in which KAE609 exerts its antimalarial activity by directly interfering with P-type ATPase activity. PMID:27291296

  8. G6PD Deficiency and Antimalarial Efficacy for Uncomplicated Malaria in Bangladesh: A Prospective Observational Study

    Ley, Benedikt; Alam, Mohammad Shafiul; Thriemer, Kamala; Hossain, Mohammad Sharif; Kibria, Mohammad Golam; Auburn, Sarah; Poirot, Eugenie; Price, Ric N.; Khan, Wasif Ali

    2016-01-01

    Background The Bangladeshi national treatment guidelines for uncomplicated malaria follow WHO recommendations but without G6PD testing prior to primaquine administration. A prospective observational study was conducted to assess the efficacy of the current antimalarial policy. Methods Patients with uncomplicated malaria, confirmed by microscopy, attending a health care facility in the Chittagong Hill Tracts, Bangladesh, were treated with artemether-lumefantrine (days 0–2) plus single dose primaquine (0.75mg/kg on day2) for P. falciparum infections, or with chloroquine (days 0–2) plus 14 days primaquine (3.5mg/kg total over 14 days) for P. vivax infections. Hb was measured on days 0, 2 and 9 in all patients and also on days 16 and 30 in patients with P. vivax infection. Participants were followed for 30 days. The study was registered with the clinical trials website (NCT02389374). Results Between September 2014 and February 2015 a total of 181 patients were enrolled (64% P. falciparum, 30% P. vivax and 6% mixed infections). Median parasite clearance times were 22.0 (Interquartile Range, IQR: 15.2–27.3) hours for P. falciparum, 20.0 (IQR: 9.5–22.7) hours for P. vivax and 16.6 (IQR: 10.0–46.0) hours for mixed infections. All participants were afebrile within 48 hours, two patients with P. falciparum infection remained parasitemic at 48 hours. No patient had recurrent parasitaemia within 30 days. Adjusted male median G6PD activity was 7.82U/gHb. One male participant (1/174) had severe G6PD deficiency (<10% activity), five participants (5/174) had mild G6PD deficiency (10–60% activity). The Hb nadir occurred on day 2 prior to primaquine treatment in P. falciparum and P. vivax infected patients; mean fractional fall in Hb was -8.8% (95%CI -6.7% to -11.0%) and -7.4% (95%CI: -4.5 to -10.4%) respectively. Conclusion The current antimalarial policy remains effective. The prevalence of G6PD deficiency was low. Main contribution to haemolysis in G6PD normal

  9. G6PD Deficiency and Antimalarial Efficacy for Uncomplicated Malaria in Bangladesh: A Prospective Observational Study.

    Benedikt Ley

    Full Text Available The Bangladeshi national treatment guidelines for uncomplicated malaria follow WHO recommendations but without G6PD testing prior to primaquine administration. A prospective observational study was conducted to assess the efficacy of the current antimalarial policy.Patients with uncomplicated malaria, confirmed by microscopy, attending a health care facility in the Chittagong Hill Tracts, Bangladesh, were treated with artemether-lumefantrine (days 0-2 plus single dose primaquine (0.75mg/kg on day2 for P. falciparum infections, or with chloroquine (days 0-2 plus 14 days primaquine (3.5mg/kg total over 14 days for P. vivax infections. Hb was measured on days 0, 2 and 9 in all patients and also on days 16 and 30 in patients with P. vivax infection. Participants were followed for 30 days. The study was registered with the clinical trials website (NCT02389374.Between September 2014 and February 2015 a total of 181 patients were enrolled (64% P. falciparum, 30% P. vivax and 6% mixed infections. Median parasite clearance times were 22.0 (Interquartile Range, IQR: 15.2-27.3 hours for P. falciparum, 20.0 (IQR: 9.5-22.7 hours for P. vivax and 16.6 (IQR: 10.0-46.0 hours for mixed infections. All participants were afebrile within 48 hours, two patients with P. falciparum infection remained parasitemic at 48 hours. No patient had recurrent parasitaemia within 30 days. Adjusted male median G6PD activity was 7.82U/gHb. One male participant (1/174 had severe G6PD deficiency (<10% activity, five participants (5/174 had mild G6PD deficiency (10-60% activity. The Hb nadir occurred on day 2 prior to primaquine treatment in P. falciparum and P. vivax infected patients; mean fractional fall in Hb was -8.8% (95%CI -6.7% to -11.0% and -7.4% (95%CI: -4.5 to -10.4% respectively.The current antimalarial policy remains effective. The prevalence of G6PD deficiency was low. Main contribution to haemolysis in G6PD normal individuals was attributable to acute malaria rather

  10. A retrospective analysis of the change in anti-malarial treatment policy: Peru

    Vincent-Mark Arlene

    2009-04-01

    Full Text Available Abstract Background National malaria control programmes must deal with the complex process of changing national malaria treatment guidelines, often without guidance on the process of change. Selecting a replacement drug is only one issue in this process. There is a paucity of literature describing successful malaria treatment policy changes to help guide control programs through this process. Objectives To understand the wider context in which national malaria treatment guidelines were formulated in a specific country (Peru. Methods Using qualitative methods (individual and focus group interviews, stakeholder analysis and a review of documents, a retrospective analysis of the process of change in Peru's anti-malarial treatment policy from the early 1990's to 2003 was completed. Results The decision to change Peru's policies resulted from increasing levels of anti-malarial drug resistance, as well as complaints from providers that the drugs were no longer working. The context of the change occurred in a time in which Peru was changing national governments, which created extreme challenges in moving the change process forward. Peru utilized a number of key strategies successfully to ensure that policy change would occur. This included a having the process directed by a group who shared a common interest in malaria and who had long-established social and professional networks among themselves, b engaging in collaborative teamwork among nationals and between nationals and international collaborators, c respect for and inclusion of district-level staff in all phases of the process, d reliance on high levels of technical and scientific knowledge, e use of standardized protocols to collect data, and f transparency. Conclusion Although not perfectly or fully implemented by 2003, the change in malaria treatment policy in Peru occurred very quickly, as compared to other countries. They identified a problem, collected the data necessary to justify the

  11. Cytotoxicity of antimalarial plant extracts from Kenyan biodiversity to the brine shrimp, Artemia salina L. (Artemiidae

    Joseph Mwanzia Nguta

    2012-07-01

    Full Text Available Artemia salina (Artemiidae, the brine shrimp larva, is an invertebrate used in the alternative test to determine toxicity of chemicals and natural products. In this study the medium lethal concentration fifty (LC50 values of 45 antimalarial plant extracts and positive controls, cyclophosphamide and etoposide were determined using Artemia salina (Artemiidae. Out of the 45 organic extracts screened for activity against Artemia salina larvae, 23 (51% of the crude extracts demonstrated activity at or below 100 μg/mL, and were categorized as having strong cytotoxic activity, 18 (40% of the crude extracts had LC50 values between 100 μg/mL and 500 μg/mL, and were categorized as having moderate cytotoxicity, 2 (4.5% of the crude extracts had LC50 values between 500 μg/mL and 1000 μg/mL, and were considered to have weak cytotoxic activity, while 2 (4.5% of the crude extracts had LC50 values greater than 1000 μg/mL and were considered to be non toxic. Approximately 20% (9 of the aqueous extracts demonstrated activity at or below 100 g/mL and were considered to have strong cytotoxic activity, 40% (18 of the screened aqueous crude extracts had LC50 values between 100 μg/mL and 500 μg/mL and were considered to be moderately cytotoxic, 16% (7 of the crude extracts had LC50 values between 500 μg/mL and 1000 μg/mL and were considered to have weak cytotoxic activity while 24% (11 of the aqueous extracts had LC50 values greater than 1000μg/mL and were categorized as non toxic The positive controls, cyclophosphamide and etoposide exhibited strong cytotoxicity with LC50 values of 95 μg/mL and 6 μg/mL respectively in a 24 hour lethality study, validating their use as anticancer agents. In the current study, 95.5% of all the screened organic extracts and 76% of the investigated aqueous extracts demonstrated LC50 values <1000 g/mL, indicating that these plants could not make safe anti-malarial treatments. This calls for dose adjustment amongst the

  12. SMS for Life: a pilot project to improve anti-malarial drug supply management in rural Tanzania using standard technology

    Mwafongo Winfred

    2010-10-01

    Full Text Available Abstract Background Maintaining adequate supplies of anti-malarial medicines at the health facility level in rural sub-Saharan Africa is a major barrier to effective management of the disease. Lack of visibility of anti-malarial stock levels at the health facility level is an important contributor to this problem. Methods A 21-week pilot study, 'SMS for Life', was undertaken during 2009-2010 in three districts of rural Tanzania, involving 129 health facilities. Undertaken through a collaborative partnership of public and private institutions, SMS for Life used mobile telephones, SMS messages and electronic mapping technology to facilitate provision of comprehensive and accurate stock counts from all health facilities to each district management team on a weekly basis. The system covered stocks of the four different dosage packs of artemether-lumefantrine (AL and quinine injectable. Results Stock count data was provided in 95% of cases, on average. A high response rate (≥ 93% was maintained throughout the pilot. The error rate for composition of SMS responses averaged 7.5% throughout the study; almost all errors were corrected and messages re-sent. Data accuracy, based on surveillance visits to health facilities, was 94%. District stock reports were accessed on average once a day. The proportion of health facilities with no stock of one or more anti-malarial medicine (i.e. any of the four dosages of AL or quinine injectable fell from 78% at week 1 to 26% at week 21. In Lindi Rural district, stock-outs were eliminated by week 8 with virtually no stock-outs thereafter. During the study, AL stocks increased by 64% and quinine stock increased 36% across the three districts. Conclusions The SMS for Life pilot provided visibility of anti-malarial stock levels to support more efficient stock management using simple and widely available SMS technology, via a public-private partnership model that worked highly effectively. The SMS for Life system has

  13. Novel morpholinoquinoline nucleus clubbed with pyrazoline scaffolds: Synthesis, antibacterial, antitubercular and antimalarial activities.

    Karad, Sharad C; Purohit, Vishal B; Thakor, Parth; Thakkar, Vasudev R; Raval, Dipak K

    2016-04-13

    A series of novel morpholinoquinoline based conjugates with pyrazoline moiety were synthesized under microwave irradiation. The newly synthesized compounds were screened for their preliminary in vitro antibacterial activity against a panel of pathogenic strains of bacteria and fungi, antituberculosis activity against Mycobacterium tuberculosis H37Rv and antimalarial activity against Plasmodium falciparum. Most of them exhibited significant antibacterial activity as compared to the first line drugs. Compounds 6a and 9d were found to possess excellent antibacterial activity potency as compared to ampicillin (286 μM), chloramphenicol (154 μM) and ciprofloxacin (150 μM). In antifungal screening, against Candida albicans, compounds 6c, 7c, 8a, 8b, 8c and 9b showed significant activity as compared to griseofulvin (1147 μM). Compounds 8b, 6b, 9d, 6a, 9b, 7b and 8a displayed brilliant activity against P. falciparum strain as compared to chloroquine (IC50 0.062 μM) as well as quinine (IC50 0.826 μM). Compounds 6d, 7b, 8b, 9c and 9d exhibited superior antitubercular activity. Among them 8b was found to be equipotent to rifampicin with 95% inhibition. The cytotoxicity of the synthesized compounds was tested using bioassay of Schizosaccharomyces pombe cells at cellular level. PMID:26900659

  14. Reverse pharmacology for developing an anti-malarial phytomedicine. The example of Argemone mexicana

    Claudia Simoes-Pires

    2014-12-01

    Reverse pharmacology, also called bedside-to-bench, is a research approach based on the traditional knowledge and relates to reversing the classical laboratory to clinic pathway to a clinic to laboratory practice. It is a trans-disciplinary approach focused on traditional knowledge, experimental observations and clinical experiences. This paper is an overview of the reverse pharmacology approach applied to the decoction of Argemone mexicana, used as an antimalarial traditional medicine in Mali. A. mexicana appeared as the most effective traditional medicine for the treatment of uncomplicated falciparum malaria in Mali, and the clinical efficacy of the decoction was comparable to artesunate–amodiaquine as previously published. Four stages of the reverse pharmacology process will be described here with a special emphasis on the results for stage 4. Briefly, allocryptopine, protopine and berberine were isolated through bioguided fractionation, and had their identity confirmed by spectroscopic analysis. The three alkaloids showed antiparasitic activity in vitro, of which allocryptopine and protopine were selective towards Plasmodium falciparum. Furthermore, the amount of the three active alkaloids in the decoction was determined by quantitative NMR, and preliminary in vivo assays were conducted. On the basis of these results, the reverse pharmacology approach is discussed and further pharmacokinetic studies appear to be necessary in order to determine whether these alkaloids can be considered as phytochemical markers for quality control and standardization of an improved traditional medicine made with this plant.

  15. Inhibition of Plasmodium falciparum Hsp90 Contributes to the Antimalarial Activities of Aminoalcohol-carbazoles.

    Wang, Tai; Mäser, Pascal; Picard, Didier

    2016-07-14

    Malaria caused by the protozoan parasite Plasmodium falciparum (Pf) remains a major public health problem throughout the developing world. One molecular target that should receive more attention is the molecular chaperone Hsp90. It is essential and highly conserved in all eukaryotes, including in protozoan parasites. We have identified an amino-alcohol carbazole (N-CBZ) as a PfHsp90-selective inhibitor by virtually docking a large set of antimalarial compounds, previously found in a phenotypic screen, into a PfHsp90-specific pocket. By correlating the ability of 30 additional N-CBZ derivatives to bind directly to PfHsp90 with their Pf-inhibitory activity, we found that these types of compounds are more likely to inhibit Pf growth if they bind PfHsp90. For plausible targets such as PfHsp90, our workflow may help identifying the molecular target for compounds found by screening large chemical libraries for a desired biological effect and, conversely, ensuring biological effectiveness for compounds affecting a particular target. PMID:27312008

  16. Assessment of Antimalarial Activity against Plasmodium falciparum and Phytochemical Screening of Some Yemeni Medicinal Plants

    Mohammed A. Alshawsh

    2009-01-01

    Full Text Available Developing countries, where malaria is one of the most prevalent diseases, still rely on traditional medicine as a source for the treatment of this disease. In the present study, six selected plants (Acalypha fruticosa, Azadirachta indica, Cissus rotundifolia, Echium rauwalfii, Dendrosicyos socotrana and Boswellia elongata commonly used in Yemen by traditional healers for the treatment of malaria as well as other diseases, were collected from different localities of Yemen, dried and extracted with methanol and water successfully. The antiplasmodial activity of the extracts was evaluated against fresh clinical isolates of Plasmodium falciparum. The selectivity parameters to evaluate the efficacy of these medicinal plants were measured by in vitro micro test (Mark III according to World Health Organization (WHO 1996 & WHO 2001 protocols of antimalarial drug tests. Among the investigated 12 extracts, three were found to have significant antiplasmodial activity with IC50 values less than 4 µg/ml, namely the water extracts of A. fruticosa, A. indica and D. socotrana. Six extracts showed moderate activity with IC50 values ranging from 10 to 30 µg/ml and three appeared to be inactive with IC50 values more than 30 µg/ml. In addition, preliminary phytochemical screening of the methanolic and aqueous extracts indicated the presence of saponins, tannins, flavonoids, terpenoids, polysaccharides and peptides.

  17. Antimalarial activity of selected Sudanese medicinal plants with emphasis to Maytenus senegalensis

    The aim of the present study is to identify and characterize the antimalrial agents from traitional Sudanese medicinal plants. 49 plants parts representing 26 species from 15 families were extracted and screened for their in vitro antimalrial activity using P. falciparum strain 3D7 which is chloroquine sensitive and Dd2 strain which is chloroquine resistant and pyrimethamine sensitive.The plant species investigated exhibited diverse botanical families. They includes Annonaceae, Aristolochiaceae, Asteraceae, Balantiaceae, Caesalpiniceae, Celasteraceae, Cucurbitaceae, Fabaceae, Graminae, Meliaceae, Myrtaceae, Polygonaceae, Rubiaceae, Rutaceae, and simaroubaceae. The evaluation of these plants for their antimalarial activity and their effect on lymphocyte proliferation was carried out. 57 extracts were tested on the chloroquine sensitive strain (3D7). Where 34 extracts (59%) exhibited significant activity against 3D7 with IC50 values ≤ 50 μ g/ml. While 21 extracts (57%) showed antimalrial activities with IC50 values ≤ 50 μ g/ml on Dd2. 13 extracts (22%) and ten extracts (18%) only showed an activity with IC50 values ≤ 5 μ g/ml on 3 D7 and Dd2, respectively. The activities of some plant extracts, which affected 3D7 strain, were measured using the radiolabelled (3H) hypoxanthine method and microscopical count. 15 plant extracts (48%) from 32 showed IC50 values ≤ 50 μ g/ml against 3D7 strain using the radiolabelled hypoxanthine methods and only 5 extracts (16%) showed IC50 values ≤ 5 μ g/ml against 3D7. Most of the extracts screened had a low effect on lymphocyte proliferation (IC50 values >100 μ g/ml), where as Sonochous cornatus, Balanites aegyptiaca, Tamarindus indica, Acacia nilotica, Annona squamosa, Eucalyptus globulus and Cassia tora enhanced lymphocyte proliferation. liquid-liquid partition of methanolic preparation of Acacia nilotica seeds and husk showed that the ethylacetate phase possessed the highest activity against both 3D7 and Dd2 strains

  18. Chemogenomic profiling of Plasmodium falciparum as a tool to aid antimalarial drug discovery

    Pradhan, Anupam; Siwo, Geoffrey H.; Singh, Naresh; Martens, Brian; Balu, Bharath; Button-Simons, Katrina A.; Tan, Asako; Zhang, Min; Udenze, Kenneth O.; Jiang, Rays H.Y.; Ferdig, Michael T.; Adams, John H.; Kyle, Dennis E.

    2015-01-01

    The spread of Plasmodium falciparum multidrug resistance highlights the urgency to discover new targets and chemical scaffolds. Unfortunately, lack of experimentally validated functional information about most P. falciparum genes remains a strategic hurdle. Chemogenomic profiling is an established tool for classification of drugs with similar mechanisms of action by comparing drug fitness profiles in a collection of mutants. Inferences of drug mechanisms of action and targets can be obtained by associations between shifts in drug fitness and specific genetic changes in the mutants. In this screen, P. falciparum, piggyBac single insertion mutants were profiled for altered responses to antimalarial drugs and metabolic inhibitors to create chemogenomic profiles. Drugs targeting the same pathway shared similar response profiles and multiple pairwise correlations of the chemogenomic profiles revealed novel insights into drugs’ mechanisms of action. A mutant of the artemisinin resistance candidate gene - “K13-propeller” gene (PF3D7_1343700) exhibited increased susceptibility to artemisinin drugs and identified a cluster of 7 mutants based on similar enhanced responses to the drugs tested. Our approach of chemogenomic profiling reveals artemisinin functional activity, linked by the unexpected drug-gene relationships of these mutants, to signal transduction and cell cycle regulation pathways. PMID:26541648

  19. Novel Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Anti-malarial Activity in the Mouse Model

    Booker, Michael L.; Bastos, Cecilia M.; Kramer, Martin L.; Barker, Jr., Robert H.; Skerlj, Renato; Sidhu, Amar Bir; Deng, Xiaoyi; Celatka, Cassandra; Cortese, Joseph F.; Guerrero Bravo, Jose E.; Crespo Llado, Keila N.; Serrano, Adelfa E.; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Viera, Sara; Garuti, Helen; Wittlin, Sergio; Papastogiannidis, Petros; Lin, Jing-wen; Janse, Chris J.; Khan, Shahid M.; Duraisingh, Manoj; Coleman, Bradley; Goldsmith, Elizabeth J.; Phillips, Margaret A.; Munoz, Benito; Wirth, Dyann F.; Klinger, Jeffrey D.; Wiegand, Roger; Sybertz, Edmund (Leiden-MC); (Puerto Rico); (STPHI); (Harvard); (GSK); (Genzyme); (UTSMC)

    2010-11-22

    Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. A high throughput screen and subsequent medicinal chemistry program identified a series of N-alkyl-5-(1H-benzimidazol-1-yl)thiophene-2-carboxamides with low nanomolar in vitro potency against DHODH from P. falciparum, P. vivax, and P. berghei. The compounds were selective for the parasite enzymes over human DHODH, and x-ray structural data on the analog Genz-667348, demonstrated that species selectivity could be attributed to amino acid differences in the inhibitor-binding site. Compounds from this series demonstrated in vitro potency against the 3D7 and Dd2 strains of P. falciparum, good tolerability and oral exposure in the mouse, and ED{sub 50} values in the 4-day murine P. berghei efficacy model of 13-21 mg/kg/day with oral twice-daily dosing. In particular, treatment with Genz-667348 at 100 mg/kg/day resulted in sterile cure. Two recent analogs of Genz-667348 are currently undergoing pilot toxicity testing to determine suitability as clinical development candidates.

  20. Antimalarial Evaluation of the Chemical Constituents of Hairy Root Culture of Bixa orellana L.

    Bo Zhai

    2014-01-01

    Full Text Available Over 216 million malaria cases are reported annually worldwide and about a third of these cases, primarily children under the age of five years old, will not survive the infection. Despite this significant world health impact, only a limited number of therapeutic agents are currently available. The lack of scaffold diversity poses a threat in the event that multi-drug–resistant strains emerge. Terrestrial natural products have provided a major source of chemical diversity for starting materials in many FDA approved drugs over the past century. Bixa orellana L. is a popular plant used in South America for the treatment of malaria. In search of new potential therapeutic agents, the chemical constituents of a selected hairy root culture line of Bixa orellana L. were characterized utilizing NMR and mass spectrometry methods, followed by its biological evaluation against malaria strains 3D7 and K1. The crude extract and its isolated compounds demonstrated EC50 values in the micromolar range. Herein, we report our findings on the chemical constituents of Bixa orellana L. from hairy roots responsible for the observed antimalarial activity.

  1. Thermodynamic Studies of Antimalarial Drugs and Their Interaction with Myoglobin, Hemoglobin and Phospholipid Model Membranes

    Samira A. Barghouthi

    2005-01-01

    Full Text Available In this research we present binding studies of some selected antimalarial drugs such as primaquine and quinacrine with biomolecules. Ultraviolet-visible spectrophotometry and fluorescence spectrophotometry along with equilibrium dialysis techniques were used to monitor the interaction of these drugs with myoglobin, hemoglobin albumin and with phospholipid unilamellar vesicles. Fluorescence spectrophotometry, UV-visible difference spectrophotometry and equilibrium dialysis showed no evidence of any binding of these drugs to myoglobin or hemoglobin. However, binding to albumin was evident from a blue shift in UV-Vis absorption spectra. Both primaquine and quinacrine were found to bind to phospholipid vesicles with binding constants of 2.7 ± 0.4x102 and 8.1 ± 0.8x104, respectively. As for the number of molecules per binding site, we found that eight molecules of primaquine occupies ten binding sites and in case of quinacrine two drug molecule for each ten binding sites. Physical parameters for primaquine are determined via UV-Vis absorption at a wavelength of 350 nm. In case of quinacrine fluorescence intensity was employed to measure concentrations with an excitation wavelength of 425 nm and an emission wavelength at 497 nm.

  2. Resistance of Plamodium falciparum to Antimalarial Drugs in Zaragoza (Antioquia, Colombia, 1998

    Silvia Blair-Trujillo

    2002-04-01

    Full Text Available Plasmodium falciparum sensitivity to chloroquine (CHL, amodiaquine (AMO and sulfadoxine/pyrimethamine (SDX/PYR was assessed in vivo and in vitro in a representative sample from the population of Zaragoza in El Bajo Cauca region (Antioquia-Colombia. There were 94 patients with P. falciparum evaluated. For the in vivo test the patients were followed by clinical examination and microscopy, during 7 days. The in vitro test was performed following the recommendations of the World Health Organization. The in vivo prevalence of resistance to CHL was 67%, to AMO 3% and to SDX/PYR 9%. The in vitro test showed sensitivity to all antimalarials evaluated. Concordance for CHL between the in vivo and in vitro tests was 33%. For AMO and SDX/PYR, the concordance was 100%. We conclude that a high percentage of patients are resistant to CHL (in vivo. A high rate of intestinal parasitism might explain in part, the differences observed between the in vivo and the in vitro results. Therefore, new policies and treatment regimens should be proposed for the treatment of the infection in the region. Nationwide studies assessing the degree of resistance are needed.

  3. Cytotoxic and Antimalarial Amaryllidaceae Alkaloids from the Bulbs of Lycoris radiata

    Bin Hao

    2013-02-01

    Full Text Available Phytochemical investigation of the 80% ethanol extract of the bulbs of Lycoris radiata resulted in the isolation of five new Amaryllidaceae alkaloids: (+-5,6-dehydrolycorine (1, (+-3α,6β-diacetyl-bulbispermine (2, (+-3α-hydroxy-6β-acetyl- bulbispermine (3, (+-8,9-methylenedioxylhomolycorine-N-oxide (5, and 5,6-dihydro-5- methyl-2-hydroxyphenanthridine (7, together with two known compounds, (+-3α-methoxy- 6β-acetylbulbispermine (4 and (+-homolycorine- N-oxide (6. Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC NMR spectroscopy, in addition to high resolution mass spectrometry. Alkaloid 1 showed potent cytotoxicity against astrocytoma and glioma cell lines (CCF-STTG1, CHG-5, SHG-44, and U251, as well as HL-60, SMMC-7721, and W480 cell lines with IC50 values of 9.4–11.6 μM. Additonally, compound 1 exhibited antimalarial activity with IC50 values of 2.3 μM for D-6 strain and 1.9 μM for W-2 strain of Plasmodium falciparum.

  4. Antimalarial Drug Resistance: Surveillance and Molecular Methods for National Malaria Control Programmes

    Umberto D'Alessandro

    1998-09-01

    Full Text Available National malaria control programmes have the responsibility to develop a policy for malaria disease management based on a set of defined criteria as efficacy, side effects, costs and compliance. These will fluctuate over time and national guidelines will require periodic re-assessment and revision. Changing a drug policy is a major undertaking that can take several years before being fully operational. The standard methods on which a decision can be taken are the in vivo and the in vitro tests. The latter allow a quantitative measurement of the drug response and the assessment of several drugs at once. However, in terms of drug policy change its results might be difficult to interpret although they may be used as an early warning system for 2nd or 3rd line drugs. The new WHO 14-days in vivo test addresses mainly the problem of treatment failure and of haematological parameters changes in sick children. It gives valuable information on whether a drug still `works'. None of these methods are well suited for large-scale studies. Molecular methods based on detection of mutations in parasite molecules targeted by antimalarial drugs could be attractive tools for surveillance. However, their relationship with in vivo test results needs to be established

  5. Combination Therapy Counteracts the Enhanced Transmission of Drug-Resistant Malaria Parasites to Mosquitoes

    Hallett, Rachel L; Colin J Sutherland; Alexander, Neal; Ord, Rosalynn; Jawara, Musa; Drakeley, Chris J.; Pinder, Margaret; Walraven, Gijs; Geoffrey A T Targett; Alloueche, Ali

    2004-01-01

    Malaria parasites carrying genes conferring resistance to antimalarials are thought to have a selective advantage which leads to higher rates of transmissibility from the drug-treated host. This is a likely mechanism for the increasing prevalence of parasites with resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine in sub-Saharan Africa. Combination therapy is the key strategy being implemented to reduce the impact of resistance, but its effect on the transmission of genetically resi...

  6. A review of age-old antimalarial drug to combat malaria:efficacy up-gradation by nanotechnology based drug delivery

    Satyajit Tripathy; Somenath Roy

    2014-01-01

    Malaria is uncontrolled burden in the world till now.Despite of different efforts to develop antimalarial drug for decades, any anti-malarial drug can able to eradicate completely till now. Many anti-malarial substances are practically ineffectual because of their physicochemical limitations, cytotoxicity, chemical instability and degradation, and limited activities against intracellular parasites.Taking into consideration, the amount of research is going to conduct in the field of nanoparticle based drug delivery systems, lead to new ways of improving the treatment of infectious diseases.The study has focused on the progress and advancement of research on nanotechnology based drug delivery to eradicate the malaria.We like to focus the efficacy of nanotechnology based drug applicationfor the opening out of novel chemotherapeutics in laboratory research, which may show the way to better use with age-old antimalarial drug and may draw the attention of pharmaceutical industries for the improvement and designing of effective anti-malarial drugs in future.

  7. Feasibility, safety and effectiveness of combining home based malaria management and seasonal malaria chemoprevention in children less than 10 years in Senegal

    Tine, Roger C K; Ndour, Cheikh T; Faye, Babacar;

    2014-01-01

    Home-based management of malaria (HMM) may improve access to diagnostic testing and treatment with artemisinin combination therapy (ACT). In the Sahel region, seasonal malaria chemoprevention (SMC) is now recommended for the prevention of malaria in children. It is likely that combinations of...... antimalarial interventions can reduce the malaria burden. This study assessed the feasibility, effectiveness and safety of combining SMC and HMM delivered by community health workers (CHWs)....

  8. PENGOBATAN MALARIA DENGAN KOMBINASI ARTEMISININ

    Emilianan Tjitra

    2012-09-01

    Full Text Available Previous approaches in malaria treatment fail to reduce the morbidity and mortality of malaria. Widespread overuse of antimalarial treatment of clinical malaria may have contributed to increase drug resistance. Moreover, poor compliance or inadequate dosage also selects for parasite resistance. The paradigm of radical treatment using drug combinations may improve the cure rate and compliance, thereby preventing or delaying the emergence of parasites resistant to antimalarial drugs. The ideal combined antimalarial regimen in Indonesia should be safe and tolerated by all age groups, effective and rapidly acting for both P.falciparum and P.vivax malaria, short course, good compliance and acceptable, without resistance and/or cross-resistance or , not widely spread use, cost-effective and affordable. Artemisinin derivatives are the best partner drug for combination, with advantages that include: well absorbed, safe and well tolerated, rapidly converted to active metabolite, having very short half-life, broad specificity of action, and extremely potent. Current artemisinin-based combinations which are suitable for Indonesia include: amodiaquine plus artesunate given as single daily dose for 3 days (AQ3+ATS3, mefloquine plus artesunate given as single daily dose for 3 days (MQ3+ATS3, lumefantrine/benflumetol plus artemether given as twice daily dose for 3 days (COARTEMETHER, piperaquine plus dihydroartemisinin given as single daily dose for 2-3 days (PPQ2-3+DHA2-3, and piperaquine plus artemisinin given as single daily dose for 2 days (PPQ2+ATM2. Given the imbalance between rapid development of parasite resistance and slow availability of new effective antimalarial drugs, research and development of antimalarial drugs must be encouraged.

  9. Screening of Kenyan medicinal plants for antimalarial effects on Plasmodium falciparum in vitror. Final report for the period 15 December 1993 - 31 December 1994

    The antimalarial activities of extracts of Albizia gummifera and Aspilia mossambicensis against culture adapted isolates of Plasmodium falciparum were evaluated using an in citro 3H-hypoxanthine uptake technique. Chloroquine was used as a standard antimalarial drug for comparison with the plant extracts. The plant extracts showed various levels of activities (expressed as 50% inhibitory concentration (IC50s) in ug/ml of test culture) against P. falciparum in vitro, with Al gummifera showing the highest activity (eman IC50 of 5.98 ± 2.9 SD, n=6), followed by A. mossambicensis (mean IC50 73.36 ± 59.3 SD, n=18). The mean antimalarial activity of chloroquine (in ug/ml) was 0.037 (± 0.04 SD, n=10), far higher than that of the plant extracts. (author). 5 refs, 2 tabs

  10. In Vivo Antimalarial Effects of Iranian Flora Artemisia khorassanica against Plasmodium berghei and Pharmacochemistry of its Natural Components

    M Amini

    2010-02-01

    Full Text Available "nBackground: The aim of this study was to evaluate the antimalarial effects of Iranian flora Artemisia khorassanica against Plasmodium berghei in vivo and pharmacochemistry of its natural components."nMethods: The aerial parts of Iranian flora A. khorasanica were collected at flowering stage from Khorassan Province, northeastern Iran in 2008. They were air-dried at room temperature; powder was macerated in methanol and the extract defatted in refrigerator, filtered, diluted with water, then eluted with n-hexane and finally non-polar components were identified through Gas Chromatography and Mass Spectroscopy (GC-MS. Toxicity of herbal extracts was assessed on naïve NMRI mice, and its anti-malarial efficacy was investigated on infected Plasmodium berghei animals. This is the first ap­plication on A. khorssanica extract for treatment of murine malaria. The significance of differences was determined by Analysis of Variances (ANOVA and Student's t-test using Graph Pad Prism Software."nResults: The herbal extract was successfully tested in vivo for its anti-plasmodial activity through ar­temisin composition, which is widely used as a standard malaria treatment."nConclusion: Although, this study confirmed less anti-malarial effects of A. khorssanica against mur­ine malaria in vivo, how­ever there are some evidences on reducing pathophysiology by this medica­tion. In complementary assay, major components were detected by GC-MS analysis in herbal extract including chrysanthe­none (7.8%, palmitic acid (7.4% and cis-thujone (5.8%.  The most retention indices of the compo­nent are given as n-eicosane, palmitic acid and n-octadecane.

  11. Gel versus capillary electrophoresis genotyping for categorizing treatment outcomes in two anti-malarial trials in Uganda

    Hubbard Alan E

    2010-01-01

    Full Text Available Abstract Background Molecular genotyping is performed in anti-malarial trials to determine whether recurrent parasitaemia after therapy represents a recrudescence (treatment failure or new infection. The use of capillary instead of agarose gel electrophoresis for genotyping offers technical advantages, but it is unclear whether capillary electrophoresis will result in improved classification of anti-malarial treatment outcomes. Methods Samples were genotyped using both gel and capillary electrophoresis from randomized trials of artemether-lumefantrine (AL vs. dihydroartemisinin-piperaquine (DP performed in two areas of Uganda: Kanungu, where transmission is moderate, and Apac, where transmission is very high. Both gel and capillary methods evaluated polymorphic regions of the merozoite surface protein 1 and 2 and glutamine rich protein genes. Results Capillary electrophoresis detected more alleles and provided higher discriminatory power than agarose gel electrophoresis at both study sites. There was only moderate agreement between classification of outcomes with the two methods in Kanungu (kappa = 0.66 and poor agreement in Apac (kappa = 0.24. Overall efficacy results were similar when using gel vs. capillary methods in Kanungu (42-day risk of treatment failure for AL: 6.9% vs. 5.5%, p = 0.4; DP 2.4% vs. 2.9%, p = 0.5. However, the measured risk of recrudescence was significantly higher when using gel vs. capillary electrophoresis in Apac (risk of treatment failure for AL: 17.0% vs. 10.7%, p = 0.02; DP: 8.5% vs. 3.4%, p = 0.03. Risk differences between AL and DP were not significantly different whether gel or capillary methods were used. Conclusions Genotyping with gel electrophoresis overestimates the risk of recrudescence in anti-malarial trials performed in areas of high transmission intensity. Capillary electrophoresis provides more accurate outcomes for such trials and should be performed when possible. In areas of moderate transmission

  12. Identification of β-hematin inhibitors in a high-throughput screening effort reveals scaffolds with in vitro antimalarial activity

    Rebecca D. Sandlin

    2014-12-01

    Full Text Available The emergence of drug resistant strains of Plasmodium spp. creates a critical need for the development of novel antimalarials. Formation of hemozoin, a crystalline heme detoxification process vital to parasite survival serves as an important drug target. The quinoline antimalarials including chloroquine and amodiaquine owe their antimalarial activity to inhibition of hemozoin formation. Though in vivo formation of hemozoin occurs within the presence of neutral lipids, the lipophilic detergent NP-40 was previously shown to serve as a surrogate in the β-hematin (synthetic hemozoin formation process. Consequently, an NP-40 mediated β-hematin formation assay was developed for use in high-throughput screening. Here, the assay was utilized to screen 144,330 compounds for the identification of inhibitors of crystallization, resulting in 530 hits. To establish the effectiveness of these target-based β-hematin inhibitors against Plasmodium falciparum, each hit was further tested in cultures of parasitized red blood cells. This effort revealed that 171 of the β-hematin inhibitors are also active against the parasite. Dose–response data identified 73 of these β-hematin inhibitors have IC50 values ⩽5 μM, including 25 compounds with nanomolar activity against P. falciparum. A scaffold-based analysis of this data identified 14 primary scaffolds that represent 46% of the 530 total hits. Representative compounds from each of the classes were further assessed for hemozoin inhibitory activity in P. falciparum infected human erythrocytes. Each of the hit compounds tested were found to be positive inhibitors, while a negative control did not perturb this biological pathway in culture.

  13. A new double-antibody sandwich ELISA targeting Plasmodium falciparum aldolase to evaluate anti-malarial drug sensitivity

    Brun Reto

    2009-10-01

    Full Text Available Abstract Background The standard in vitro test to assess anti-malarial activity of chemical compounds is the [3H]hypoxanthine incorporation assay. It is a radioactivity-based method to measure DNA replication of Plasmodium in red blood cells. The method is highly reproducible, however, the handling of radioactive material is costly, hazardous and requires the availability of appropriate technology and trained staff. Several other ways to evaluate in vitro anti-malarial activity do exist, all with their own assets and limitations. Methods The newly developed double-antibody sandwich ELISA described here is based on the properties of a non-overlapping pair of monoclonal antibodies directed against Plasmodium falciparum aldolase. This glycolytic enzyme possesses some unique nucleotide sequences compared to the human isoenzymes and has been highly conserved through evolution. Out of twenty possibilities, the most sensitive antibody pair was selected and used to quantitatively detect parasite aldolase in infected blood lysates. Results A total of 34 compounds with anti-malarial activity were tested side-by-side by ELISA and the [3H]hypoxanthine incorporation assay. The novel ELISA provided IC50s closely paralleling those from the radioactivity-based assay (R = 0.99, p Conclusion The newly developed ELISA presents several advantages over the comparative method, the [3H]hypoxanthine incorporation assay. The assay is highly reproducible, less hazardous (involves no radioactivity and requires little and cheap technical equipment. Relatively unskilled personnel can conduct this user-friendly assay. All this makes it attractive to be employed in resource-poor laboratories.

  14. Molecular screening of S769N mutation for PFATPASE in subjects with plasmodiasis in Owo

    Hassan A.O

    2016-03-01

    Full Text Available Background: The emergence and spread of drug-resistant Plasmodium falciparum is a major problem of public health concern. Due to the high incidence of parasite resistance to antimalarial drugs, artemisinin-based combination therapies (ACTs have now replaced those failing drugs in order to combat the growing drug resistance. Aim: This study is undertaken to detect resistant strains of P. falciparum to artemisinin in infected human blood in Owo. Methods: A total of 1000 participants took part in the study. Falciparum malaria was confirmed by microscopic examination of Giemsastained blood samples from patients who presented with fever at Federal Medical Centre, Owo, Ondo state, Nigeria. Molecular methods were employed to detect a marker of resistance of P. falciparum to artemisinins: Parasite DNA was extracted from patient blood using Tris-EDTA buffer-based extraction method. Amplification was carried out by Nested Polymerase Chain Reaction followed by Restriction Fragment Length Polymorphisms (PCR/RFLP for the detection of falciparum sarco/endoplasmic reticulum calcium-dependent ATPase (SERCA PfATPase6 gene mutation. Results: The result showed that resistant PfATPase6 gene which codes for artemisinin resistance was not present in the population studied. Conclusion: Since there was no resistant gene detected in the population studied, it could be said that artemisinin resistance has not yet developed in this area and subsequent monitoring of resistance pattern to artemisinin based therapy is advised in order to detect and prevent its spread.

  15. Global gene expression profiling of Plasmodium falciparum in response to the anti-malarial drug pyronaridine

    Chavalitshewinkoon-Petmitr Porntip

    2011-08-01

    Full Text Available Abstract Background Pyronaridine (PN and chloroquine (CQ are structurally related anti-malarial drugs with primarily the same mode of action. However, PN is effective against several multidrug-resistant lines of Plasmodium falciparum, including CQ resistant lines, suggestive of important operational differences between the two drugs. Methods Synchronized trophozoite stage cultures of P. falciparum strain K1 (CQ resistant were exposed to 50% inhibitory concentrations (IC50 of PN and CQ, and parasites were harvested from culture after 4 and 24 hours exposure. Global transcriptional changes effected by drug treatment were investigated using DNA microarrays. Results After a 4 h drug exposure, PN induced a greater degree of transcriptional perturbation (61 differentially expressed features than CQ (10 features. More genes were found to respond to 24 h treatments with both drugs, and 461 features were found to be significantly responsive to one or both drugs across all treatment conditions. Filtering was employed to remove features unrelated to primary drug action, specifically features representing genes developmentally regulated, secondary stress/death related processes and sexual stage development. The only significant gene ontologies represented among the 46 remaining features after filtering relate to host exported proteins from multi-gene families. Conclusions The malaria parasite's molecular responses to PN and CQ treatment are similar in terms of the genes and pathways affected. However, PN appears to exert a more rapid response than CQ. The faster action of PN may explain why PN is more efficacious than CQ, particularly against CQ resistant isolates. In agreement with several other microarray studies of drug action on the parasite, it is not possible, however, to discern mechanism of drug action from the drug-responsive genes.

  16. Competing intermolecular interactions of artemisinin-type agents and aspirin with membrane phospholipids: Combined model mass spectrometry and quantum-chemical study

    Highlights: • Competitive binding of artemisinin agents and aspirin with phospholipids is shown. • Complexation between the antimalarial drugs and aspirin molecules is also found. • Energetically favorable structures of the model complexes are identified by DFT. • Membranotropic activity of the studied drugs can be modified under joint usage. - Abstract: Study of intermolecular interactions of antimalarial artemisinin-type drugs and aspirin with membrane phospholipids is important in term of elucidation of the drugs activity modification under their joint usage. Combined experimental and computational study of the interaction of dihydroartemisinin, α-artemether, and artesunate with aspirin (ASP) and dipalmitoylphosphatidylcholine (DPPC) is performed by electrospray ionization (ESI) mass spectrometry and by DFT B3LYP/aug-cc-pVDZ methods. The results of the ESI investigation of systems containing artemisinin-type agent, ASP and DPPC, reveal a competition between the antimalarial agents and ASP for binding with DPPC molecules. The complexation between the antimalarial drugs and ASP is also found. Observed phenomena suggest that membranotropic activity of artemisin-type agents and aspirin is modified under their combined usage. To elucidate structure-energy characteristics of the non-covalent complexes studied the model DFT calculations are performed for dihydroartemisinin · ASP complex and complexes of the each drug with phosphatidylcholine head of DPPC in neutral and cationized forms

  17. Competing intermolecular interactions of artemisinin-type agents and aspirin with membrane phospholipids: Combined model mass spectrometry and quantum-chemical study

    Pashynska, Vlada, E-mail: vlada@vl.kharkov.ua [B.Verkin Institute for Low Temperature Physics and Engineering of the National Academy of Sciences of Ukraine, Lenin Ave., 47, 61103 Kharkov (Ukraine); Stepanian, Stepan [B.Verkin Institute for Low Temperature Physics and Engineering of the National Academy of Sciences of Ukraine, Lenin Ave., 47, 61103 Kharkov (Ukraine); Gömöry, Agnes; Vekey, Karoly [Institute of Organic Chemistry of Research Centre for Natural Sciences of the Hungarian Academy of Sciences, Magyar tudosok korutja, 2, Budapest H-1117 (Hungary); Adamowicz, Ludwik [University of Arizona, Department of Chemistry and Biochemistry, Tucson, AZ 85721 (United States)

    2015-07-09

    Highlights: • Competitive binding of artemisinin agents and aspirin with phospholipids is shown. • Complexation between the antimalarial drugs and aspirin molecules is also found. • Energetically favorable structures of the model complexes are identified by DFT. • Membranotropic activity of the studied drugs can be modified under joint usage. - Abstract: Study of intermolecular interactions of antimalarial artemisinin-type drugs and aspirin with membrane phospholipids is important in term of elucidation of the drugs activity modification under their joint usage. Combined experimental and computational study of the interaction of dihydroartemisinin, α-artemether, and artesunate with aspirin (ASP) and dipalmitoylphosphatidylcholine (DPPC) is performed by electrospray ionization (ESI) mass spectrometry and by DFT B3LYP/aug-cc-pVDZ methods. The results of the ESI investigation of systems containing artemisinin-type agent, ASP and DPPC, reveal a competition between the antimalarial agents and ASP for binding with DPPC molecules. The complexation between the antimalarial drugs and ASP is also found. Observed phenomena suggest that membranotropic activity of artemisin-type agents and aspirin is modified under their combined usage. To elucidate structure-energy characteristics of the non-covalent complexes studied the model DFT calculations are performed for dihydroartemisinin · ASP complex and complexes of the each drug with phosphatidylcholine head of DPPC in neutral and cationized forms.

  18. Mestizos with Systemic Lupus Erythematosus Develop Renal Disease Early while Antimalarials Retard its Appearance: Data from a Latin American Cohort

    Pons-Estel, Guillermo J.; Alarcón, Graciela S.; Burgos, Paula I.; Hachuel, Leticia; Boggio, Gabriela; Wojdyla, Daniel; Nieto, Romina; Alvarellos, Alejandro; Catoggio, Luis J.; Guibert-Toledano, Marlene; Sarano, Judith; Massardo, Loreto; Vásquez, Gloria M.; Iglesias-Gamarra, Antonio; Lavras Costallat, Lilian T.; Da Silva, Nilzio A.; Alfaro, José L.; Abadi, Isaac; Segami, María I.; Huerta, Guillermo; Cardiel, Mario H.; Pons-Estel, Bernardo A.

    2014-01-01

    Objectives To assess the predictors of time-to-lupus renal disease in Latin American patients. Methods SLE patients (n=1480) from GLADEL’s (Grupo Latino Americano De Estudio de Lupus) longitudinal inception cohort were studied. Endpoint was ACR renal criterion development after SLE diagnosis (prevalent cases excluded). Renal disease predictors were examined by univariable and multivariable Cox proportional hazards regression analyses. Antimalarials were considered time-dependent in alternative analyses. Results Of the entire cohort, 265 patients (17.9%) developed renal disease after entering the cohort. Of them, 88 (33.2%) developed persistent proteinuria, 44 (16.6%) cellular casts and 133 (50.2%) both; 233 patients (87.9%) were women; mean (± SD) age at diagnosis was 28.0 (11.9) years; 12.8% were African-Latin Americans, 52.5% Mestizos, 34.7% Caucasians (p=0.0016). Mestizo ethnicity (HR 1.61, 95% CI 1.19–2.17), hypertension (HR 3.99, 95% CI 3.02–5.26) and SLEDAI at diagnosis (HR 1.04, 95% CI 1.01–1.06) were associated with a shorter time-to-renal disease occurrence; antimalarial use (HR 0.57, 95% CI 0.43–0.77), older age at onset (HR 0.90, 95% CI 0.85–0.95, for every 5 years) and photosensitivity (HR 0.74, 95% CI 0.56–0.98) were associated with a longer time. Alternative model results were consistent with the antimalarial protective effect (HR 0.70, 95% CI 0.50–0.99). Conclusions Our data strongly support the fact that Mestizo patients are at increased risk of developing renal disease early while antimalarials seem to delay the appearance of this SLE manifestation. These data have important implications for the treatment of these patients regardless of their geographic location. PMID:23857989

  19. Acyclic Nucleoside Phosphonates as Inhibitors of Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase: New Anti-Malarial Chemotherapy Leads

    Hocková, Dana; Holý, Antonín; Česnek, Michal; Baszczyňski, Ondřej; Tichý, Tomáš; Krečmerová, Marcela; Janeba, Zlatko; Skinner-Adams, T. S.; Naesens, L.; Keough, D. T.; de Jersey, J.; Guddat, L. W.

    Praha : Institute of Organic Chemistry and Biochemistry AS CR, v. v. i., 2011 - (Hocek, M.), s. 171-174 ISBN 978-80-86241-37-1. - (Collection Symposium Series. 12). [Chemistry of Nucleic Acid Components /15./. Český Krumlov (CZ), 05.06.2011-10.06.2011] R&D Projects: GA MŠk 1M0508; GA ČR GAP207/11/0108 Institutional research plan: CEZ:AV0Z40550506 Keywords : ANPs * acyclic nucleoside phosphonates * anti-malarial * Plasmodium * HGXPRTase Subject RIV: CC - Organic Chemistry

  20. Reduction of anti-malarial consumption after rapid diagnostic tests implementation in Dar es Salaam: a before-after and cluster randomized controlled study

    Swai Ndeniria

    2011-04-01

    Full Text Available Abstract Background Presumptive treatment of all febrile patients with anti-malarials leads to massive over-treatment. The aim was to assess the effect of implementing malaria rapid diagnostic tests (mRDTs on prescription of anti-malarials in urban Tanzania. Methods The design was a prospective collection of routine statistics from ledger books and cross-sectional surveys before and after intervention in randomly selected health facilities (HF in Dar es Salaam, Tanzania. The participants were all clinicians and their patients in the above health facilities. The intervention consisted of training and introduction of mRDTs in all three hospitals and in six HF. Three HF without mRDTs were selected as matched controls. The use of routine mRDT and treatment upon result was advised for all patients complaining of fever, including children under five years of age. The main outcome measures were: (1 anti-malarial consumption recorded from routine statistics in ledger books of all HF before and after intervention; (2 anti-malarial prescription recorded during observed consultations in cross-sectional surveys conducted in all HF before and 18 months after mRDT implementation. Results Based on routine statistics, the amount of artemether-lumefantrine blisters used post-intervention was reduced by 68% (95%CI 57-80 in intervention and 32% (9-54 in control HF. For quinine vials, the reduction was 63% (54-72 in intervention and an increase of 2.49 times (1.62-3.35 in control HF. Before-and-after cross-sectional surveys showed a similar decrease from 75% to 20% in the proportion of patients receiving anti-malarial treatment (Risk ratio 0.23, 95%CI 0.20-0.26. The cluster randomized analysis showed a considerable difference of anti-malarial prescription between intervention HF (22% and control HF (60% (Risk ratio 0.30, 95%CI 0.14-0.70. Adherence to test result was excellent since only 7% of negative patients received an anti-malarial. However, antibiotic

  1. Plasmodium falciparum drug resistance in Angola.

    Fançony, Cláudia; Brito, Miguel; Gil, Jose Pedro

    2016-01-01

    Facing chloroquine drug resistance, Angola promptly adopted artemisinin-based combination therapy as the first-line to treat malaria. Currently, the country aims to consolidate malaria control, while preparing for the elimination of the disease, along with others African countries in the region. However, the remarkable capacity of Plasmodium to develop drug resistance represents an alarming threat for those achievements. Herein, the available, but relatively scarce and dispersed, information on malaria drug resistance in Angola, is reviewed and discussed. The review aims to inform but also to encourage future research studies that monitor and update the information on anti-malarial drug efficacy and prevalence of molecular markers of drug resistance, key fields in the context and objectives of elimination. PMID:26858018

  2. A cluster randomised trial introducing rapid diagnostic tests into registered drug shops in Uganda

    Mbonye, Anthony K; Magnussen, Pascal; Lal, Sham; Hansen, Kristian S; Cundill, Bonnie; Chandler, Clare; Clarke, Siân E

    2015-01-01

    introducing mRDTs in registered drug shops was implemented in 20 geographical clusters of drug shops in Mukono district, central Uganda. Ten clusters were randomly allocated to the intervention (diagnostic confirmation of malaria by mRDT followed by ACT) and ten clusters to the control arm (presumptive......BACKGROUND: Inappropriate treatment of malaria is widely reported particularly in areas where there is poor access to health facilities and self-treatment of fevers with anti-malarial drugs bought in shops is the most common form of care-seeking. The main objective of the study was to examine the...... impact of introducing rapid diagnostic tests for malaria (mRDTs) in registered drug shops in Uganda, with the aim to increase appropriate treatment of malaria with artemisinin-based combination therapy (ACT) in patients seeking treatment for fever in drug shops. METHODS: A cluster-randomized trial of...

  3. Surveillance of artemether-lumefantrine associated Plasmodium falciparum multidrug resistance protein-1 gene polymorphisms in Tanzania

    Kavishe, Reginald A; Paulo, Petro; Kaaya, Robert D;

    2014-01-01

    recommended first-line drug in treatment of uncomplicated malaria. This study surveyed the distribution of the Plasmodium falciparum multidrug resistance protein-1 single nucleotide polymorphisms (SNPs) associated with increased parasite tolerance to ALu, in Tanzania. METHODS: A total of 687 Plasmodium......BACKGROUND: Resistance to anti-malarials is a major public health problem worldwide. After deployment of artemisinin-based combination therapy (ACT) there have been reports of reduced sensitivity to ACT by malarial parasites in South-East Asia. In Tanzania, artemether-lumefantrine (ALu) is the...... in all regions, ranging from 17% - 26%. CONCLUSION: This is the first country-wide survey on Pfmdr1 mutations associated with ACT resistance. Distribution of individual Pfmdr1 mutations at codons 86, 184 and 1246 varies throughout Tanzanian regions. There is a general homogeneity in distribution of...

  4. Eradication of malaria through genetic engineering:the current situation

    Wing-Chui Chong; Rusliza Basir; Yam Mun Fei

    2013-01-01

    Malaria is an intra-cellular parasitic protozoon responsible for millions of deaths annually.Host and parasite genetic factors are crucial in affecting susceptibility to malaria and progression of the disease.Recent increased deployment of vector controls and new artemisinin combination therapies have dramatically reduced the mortality and morbidity of malaria worldwide.However, the gradual emergence of parasite and mosquito resistance has raised alarm regarding the effectiveness of current artemisinin-based therapies.In this review, mechanisms of anti-malarial drug resistance in thePlasmodium parasite and new genetically engineered tools of research priorities are discussed.The complexity of the parasite lifecycle demands novel interventions to achieve global eradication.However, turning laboratory discovered transgenic interventions into functional products entails multiple experimental phases in addition to ethical and safety hurdles.Uncertainty over the regulatory status and public acceptance further discourage the implementation of genetically modified organisms.

  5. [Multiple and successive treatment failures in a patient infected by Plasmodium falciparum in Cambodia and treated by dihydroartemisinin-piperaquine].

    Witkowski, B; Khim, N; Kim, S; Domergue, A; Duru, V; Menard, D

    2016-05-01

    Cases of treatment failures following administration of artemisinin-based combination therapies (ACT) remain rare in malaria endemic areas. In Cambodia, however, failures of these treatments are now commonly observed. Usually, these post-treatment recurrences occur only once and a second course of the same treatment is sufficient to cure patients.We describe here an atypical case of a Plasmodium falciparum-infected patient manifesting several malaria recrudescence episodes following dihydroartemisinin-piperaquine (Eurartesim®) treatment. This case report illustrates the current issue of resistance to the latest generation of antimalarial drugs in Southeast Asia and highlights the difficulty in efficaciously fighting malaria in this region if new therapy remains unimplemented. PMID:27100863

  6. Overcoming chloroquine resistance in malaria: Design, synthesis and structure-activity relationships of novel chemoreversal agents.

    Boudhar, Aicha; Ng, Xiao Wei; Loh, Chiew Yee; Chia, Wan Ni; Tan, Zhi Ming; Nosten, Francois; Dymock, Brian W; Tan, Kevin S W

    2016-08-25

    Malaria remains a significant infectious disease with even artemisinin-based therapies now facing resistance in the field. Development of new therapies is urgently needed, either by finding new compounds with unique modes of action, or by reversing resistance towards known drugs with 'chemosensitizers' or 'chemoreversal' agents (CRA). Concerning the latter, we have focused on the resistance mechanisms developed against chloroquine (CQ). We have synthesized a series of compounds related to previously identified CRAs, and found promising novel compounds. These compounds show encouraging results in a coumarin labeled chloroquine uptake assay, exhibiting a dose response in resensitising parasites to the antimalarial effects of chloroquine. Selected compounds show consistent potency across a panel of chloroquine and artemisinin sensitive and resistant parasites, and a wide therapeutic window. This data supports further study of CRAs in the treatment of malaria and, ultimately, their use in chloroquine-based combination therapies. PMID:27173385

  7. Safety, efficacy and population pharmacokinetics of fixed-dose combination of artesunate-mefloquine in the treatment of acute uncomplicated Plasmodium falciparum malaria in India

    Neena Valecha

    2013-12-01

    Full Text Available Background & objectives: India has switched over to artemisinin-based combination therapy (ACT for the treatment of acute uncomplicated Plasmodium falciparum malaria and the ACT used in the national programme is artesunate + sulphadoxine-pyrimethamine. Since the efficacy of ACT is dependent also on the partner drug, there is a need to evaluate and deploy multiple ACTs. Methods: This multicentre, single-arm, open-label clinical trial was carried out to assess the efficacy, safety and population pharmacokinetics of a fixed dose combination (FDC artesunate mefloquine (ASMQ in P. falciparum infected, Indian adults at Panjim, Goa, and Mangalore, Karnataka between December 2007 and November 2008. Results: A total of 77 patients (males 74 were screened and enrolled: 42 at Goa and 35 at Mangalore with a median age of 25 yr (range 18-55 yr. One patient failed in treatment on D53, a PCR proven new infection, seven developed recurrent vivax parasitaemia and 11 did not have a parasitological endpoint. By per protocol analysis, the D63 cure rate was 58/59 (98.3; 95% C.I. 90.9-99.9%, and 58/58, with PCR correction. ASMQ was welltolerated and no serious adverse events were reported. Interpretation & conclusion: The study showed that the ASMQ FDC was efficacious and well-tolerated for the treatment of acute, uncomplicated P. falciparum malaria in highly endemic, chloroquine resistant areas of Goa and Mangalore. It is a viable option for India.

  8. Development of hot melt co-formulated antimalarial solid dispersion system in fixed dose form (ARLUMELT): Evaluating amorphous state and in vivo performance.

    Fule, Ritesh; Dhamecha, Dinesh; Maniruzzaman, Mohammed; Khale, Anubha; Amin, Purnima

    2015-12-30

    The aim of this study was to investigate the industrial feasibility of developing a co-formulated solid dispersion (SD) containing two antimalarial drugs artemether (ARTM) and lumefantrine (LUMF). Soluplus(®) (polyethyleneglycol-polyvinyl caprolactam-polyvinyl acetate grafted copolymer) was used as primary carrier matrices via hot-melt extrusion processing to improve solubility profile and the oral bioavailability of the combination. Based on the preliminary screening, the optimized quantities of PEG 400, Lutrol F127 and Lutrol F68 were incorporated as surfactant with soluplus in different ratios to improve extrudability, increase wettability and the melt viscosity of the HME process. Soluplus(®) was proved to successfully stabilize both the drugs inside its polymeric network during extrusion via forming a stable solid dispersion. Physicochemical properties of the APIs and the SDs characterized by thermo-gravimetric analysis (TGA), differential scanning calorimetry (DSC), MDSC, FTIR spectroscopy and X-ray diffractometry (XRD) revealed the amorphous existence of the drug in all SDs developed. Molecular level morphology of solid dispersion characterized by using advanced physicochemical characterization techniques such as Raman spectroscopy, atomic force microscopy (AFM) and 2D NMR showed the transformation of the crystalline drugs to its stable amorphous state. All manufactured SDs retained their amorphicity even after a stability study conducted in accelerated condition over 6 months. The solubility and in vitro dissolution performance of both drugs in SD formulations was improved significantly when compared with pure drugs and marketed product while the in vivo studies revealed the same.The pharmacokinetic studies in rats revealed that the SD (AL1) shows a 44.12-65.24 folds increase in the AUC(0-72) and 42.87-172.61 folds increase in Cmax compared to that of pure drugs and a better bioavailability than that of commercial product. PMID:26471056

  9. In-silico studies on DegP protein of Plasmodium falciparum in search of anti-malarials.

    Sharma, Drista; Soni, Rani; Patel, Sachin; Joshi, Deepti; Bhatt, Tarun Kumar

    2016-09-01

    Despite encouraging progress over the past decade, malaria caused by the Plasmodium parasite continues to pose an enormous disease burden and is one of the major global health problems. The extreme challenge in malaria management is the resistance of parasites to traditional monochemotherapies like chloroquine and sulfadoxine-pyrimethamine. No vaccine is yet in sight, and the foregoing effective drugs are also losing ground against the disease due to the resistivity of parasites. New antimalarials with novel mechanisms of action are needed to circumvent existing or emerging drug resistance. DegP protein, secretory in nature has been shown to be involved in regulation of thermo-oxidative stress generated during asexual life cycle of Plasmodium, probably required for survival of parasite in host. Considering the significance of protein, in this study, we have generated a three-dimensional structure of PfDegP followed by validation of the modeled structure using several tools like RAMPAGE, ERRAT, and others. We also performed an in-silico screening of small molecule database against PfDegP using Glide. Furthermore, molecular dynamics simulation of protein and protein-ligand complex was carried out using GROMACS. This study substantiated potential drug-like molecules and provides the scope for development of novel antimalarial drugs. PMID:27491850

  10. De Novo transcriptome assembly (NGS of Curcuma longa L. rhizome reveals novel transcripts related to anticancer and antimalarial terpenoids.

    Ramasamy S Annadurai

    Full Text Available Herbal remedies are increasingly being recognised in recent years as alternative medicine for a number of diseases including cancer. Curcuma longa L., commonly known as turmeric is used as a culinary spice in India and in many Asian countries has been attributed to lower incidences of gastrointestinal cancers. Curcumin, a secondary metabolite isolated from the rhizomes of this plant has been shown to have significant anticancer properties, in addition to antimalarial and antioxidant effects. We sequenced the transcriptome of the rhizome of the 3 varieties of Curcuma longa L. using Illumina reversible dye terminator sequencing followed by de novo transcriptome assembly. Multiple databases were used to obtain a comprehensive annotation and the transcripts were functionally classified using GO, KOG and PlantCyc. Special emphasis was given for annotating the secondary metabolite pathways and terpenoid biosynthesis pathways. We report for the first time, the presence of transcripts related to biosynthetic pathways of several anti-cancer compounds like taxol, curcumin, and vinblastine in addition to anti-malarial compounds like artemisinin and acridone alkaloids, emphasizing turmeric's importance as a highly potent phytochemical. Our data not only provides molecular signatures for several terpenoids but also a comprehensive molecular resource for facilitating deeper insights into the transcriptome of C. longa.

  11. Temporal trends in prevalence of Plasmodium falciparum drug resistance alleles over two decades of changing antimalarial policy in coastal Kenya.

    Okombo, John; Kamau, Alice W; Marsh, Kevin; Sutherland, Colin J; Ochola-Oyier, Lynette Isabella

    2014-12-01

    Molecular surveillance of drug resistance markers through time provides crucial information on genomic adaptations, especially in parasite populations exposed to changing drug pressures. To assess temporal trends of established genotypes associated with tolerance to clinically important antimalarials used in Kenya over the last two decades, we sequenced a region of the pfcrt locus encompassing codons 72-76 of the Plasmodium falciparum chloroquine resistance transporter, full-length pfmdr1 - encoding multi-drug resistance protein, P-glycoprotein homolog (Pgh1) and pfdhfr encoding dihydrofolate reductase, in 485 archived Plasmodium falciparum positive blood samples collected in coastal Kenya at four different time points between 1995 and 2013. Microsatellite loci were also analyzed to compare the genetic backgrounds of parasite populations circulating before and after the withdrawal of chloroquine and sulfadoxine/pyrimethamine. Our results reveal a significant increase in the prevalence of the pfcrt K76 wild-type allele between 1995 and 2013 from 38% to 81.7% (p drug in contrast to a selective sweep around the triple mutant pfdhfr allele, leading to a mono-allelic population at this locus. These findings highlight the importance of continual surveillance and characterization of parasite genotypes as indicators of the therapeutic efficacy of antimalarials, particularly in the context of changes in malaria treatment policy. PMID:25516825

  12. Site-specific integration and expression of an anti-malarial gene in transgenic Anopheles gambiae significantly reduces Plasmodium infections.

    Janet M Meredith

    Full Text Available Diseases transmitted by mosquitoes have a devastating impact on global health and this is worsening due to difficulties with existing control measures and climate change. Genetically modified mosquitoes that are refractory to disease transmission are seen as having great potential in the delivery of novel control strategies. Historically the genetic modification of insects has relied upon transposable elements which have many limitations despite their successful use. To circumvent these limitations the Streptomyces phage phiC31 integrase system has been successfully adapted for site-specific transgene integration in insects. Here, we present the first site-specific transformation of Anopheles gambiae, the principal vector of human malaria. Mosquitoes were initially engineered to incorporate the phiC31 targeting site at a defined genomic location. A second phase of genetic modification then achieved site-specific integration of Vida3, a synthetic anti-malarial gene. Expression of Vida3, specifically in the midgut of bloodfed females, offered consistent and significant protection against Plasmodium yoelii nigeriensis, reducing average parasite intensity by 85%. Similar protection was observed against Plasmodium falciparum in some experiments, although protection was inconsistent. In the fight against malaria, it is imperative to establish a broad repertoire of both anti-malarial effector genes and tissue-specific promoters for their expression, enabling those offering maximum effect with minimum fitness cost to be identified. In the future, this technology will allow effective comparisons and informed choices to be made, potentially leading to complete transmission blockade.

  13. The search for new antimalarial drugs from plants used to treat fever and malaria or plants ramdomly selected: a review

    Krettli Antoniana U

    2001-01-01

    Full Text Available In this review we discuss the ongoing situation of human malaria in the Brazilian Amazon, where it is endemic causing over 610,000 new acute cases yearly, a number which is on the increase. This is partly a result of drug resistant parasites and new antimalarial drugs are urgently needed. The approaches we have used in the search of new drugs during decades are now reviewed and include ethnopharmocology, plants randomly selected, extracts or isolated substances from plants shown to be active against the blood stage parasites in our previous studies. Emphasis is given on the medicinal plant Bidens pilosa, proven to be active against the parasite blood stages in tests using freshly prepared plant extracts. The anti-sporozoite activity of one plant used in the Brazilian endemic area to prevent malaria is also described, the so called "Indian beer" (Ampelozizyphus amazonicus, Rhamnaceae. Freshly prepared extracts from the roots of this plant were totally inactive against blood stage parasites, but active against sporozoites of Plasmodium gallinaceum or the primary exoerythrocytic stages reducing tissue parasitism in inoculated chickens. This result will be of practical importance if confirmed in mammalian malaria. Problems and perspectives in the search for antimalarial drugs are discussed as well as the toxicological and clinical trials to validate some of the active plants for public health use in Brazil.

  14. Phytochemical screening and in vivo antimalarial activity of extracts from three medicinal plants used in malaria treatment in Nigeria.

    Bankole, A E; Adekunle, A A; Sowemimo, A A; Umebese, C E; Abiodun, O; Gbotosho, G O

    2016-01-01

    The use of plant to meet health-care needs has greatly increased worldwide in the recent times. The search for new plant-derived bioactive agents that can be explored for the treatment of drug-resistant malaria infection is urgently needed. Thus, we evaluated the antimalarial activity of three medicinal plants used in Nigerian folklore for the treatment of malaria infection. A modified Peter's 4-day suppressive test was used to evaluate the antimalarial activity of the plant extracts in a mouse model of chloroquine-resistant Plasmodium berghei ANKA strain. Animals were treated with 250, 500, or 800 mg/kg of aqueous extract. It was observed that of all the three plants studied, Markhamia tomentosa showed the highest chemosuppression of parasites of 73 % followed by Polyalthia longifolia (53 %) at day 4. All the doses tested were well tolerated. Percentage suppression of parasite growth on day 4 post-infection ranged from 1 to 73 % in mice infected with P. berghei and treated with extracts when compared with chloroquine diphosphate, the standard reference drug which had a chemosuppression of 90 %. The percentage survival of mice that received extract ranged from 0 to 60 % (increased as the dose increases to 800 mg/kg). Phytochemical analysis revealed the presence of tannins, saponins, and phenolic compounds in all the three plants tested. PMID:26391173

  15. Antimalarial potential of homeopathic medicines against schizont maturation of Plasmodium berghei in short-term in vitro culture

    Upma Bagai

    2012-12-01

    Full Text Available In vitro assessment of antimalarial drug susceptibility of Plasmodium has been a major research success, which has paved the way for the understanding of parasite and rapid screening of antimalarial drugs for their effectiveness. In the present study a preliminary screening to check the antiplasmodial activity of mother tincture (ϕ and various potencies (6C, 30C, 200C of homeopathic medicines Cinchona officinalis/china (Chin., Chelidonium majus (Chel. and Arsenicum album (Ars. were done by assessing the in vitro schizont maturation inhibition assay. A significant reduction in the growth of intraerythrocytic stages of P. berghei was observed with decreasing dilution of ϕ and various potencies of Chin., Chel. and Ars. exhibiting a dose dependent effect. Maximum schizont maturation inhibition was observed by Chin. ϕ (1:1, Chin. 30 (1:1, 1:2 and Chel. 30 (1:1 i.e. 80%. The standard drug CQ at 10 µM concentration exhibited 95.4±1.6% inhibition of schizont maturation. Ars. 30 (1:1 also have been found to possess strong antiplasmodial efficacy with 75.5±2.6% schizont inhibition. The presence of free merozoites in Ars. 200 with weak schizonticidal inhibition activity (40-45% also pointed towards the ability of parasite to survive in the given drug pressure.

  16. Artemisinin resistance or tolerance in human malaria patients

    Jerapan Krungkrai; Waranya Imprasittichai; Sumintra Otjungreed; Sawirasagee Pongsabut; Sudaratana R Krungkrai

    2010-01-01

    Malaria is a major cause of morbidity and mortality in the developing world. This situation is mainly due to emergence of resistance to most antimalarial drugs currently available. Artemisinin-based combination treatments are now first-line drugs forPlasmodium falciparum (P. falciparum) malaria. Artemisinin (qinghaosu) and its derivatives are the most rapid acting and efficacious antimalarial drugs. This review highlights most recent investigations into the emergence of artemisinin resistance in falciparum malaria patients on the Thai-Cambodian border, a historical epicenter for multidrug resistance spread spanning over50 years. The study presents the first evidence that highlights the parasites reduced susceptibility to artemisinin treatment by prolonged parasite-clearance times, raising considerable concern on resistance development. Although the exact mechanism of action remains unresolved, development of resistance was proposed based from bothin vitro experiments and human patients. Lines of evidence suggested that the parasites in the patients are in dormant forms, presumably tolerate to the drug pressure. The World Health Organization has launched for prevention and/or containment of the artemisinin-resistant malaria parasites. Taken together, the emergence of artemisinin resistance to the most potent antidote for falciparum malaria, poses a serious threat to global malaria control and prompts renewed efforts for urgent development of new antimalarial weapons.

  17. 7,8,15,16-tetraoxa-dispiro[5.2.5.2]hexadecane-3-carboxylic acid derivatives and their antimalarial activity

    BOGDAN SOLAJA; Milhous, Wilbur K.; DEJAN OPSENICA; NATASA TERZIC; IGOR OPSENICA

    2004-01-01

    Several C2 symmetrical mixed tetraoxanes were prepared starting from a gemdihydroperoxide and a ketone. The obtained tetraoxanes showed pronounced antimalarial activity against P. falciparum chloroquine resistant W2 and chloroquine susceptible D6 strains, with N-(2-dimethylamino)ethyl-7,8,15,16-tetraoxa-dispiro[5.2.5.2] hexadecane-3-carboxamide being as active as artemisinin.

  18. 7,8,15,16-tetraoxa-dispiro[5.2.5.2]hexadecane-3-carboxylic acid derivatives and their antimalarial activity

    BOGDAN SOLAJA

    2004-11-01

    Full Text Available Several C2 symmetrical mixed tetraoxanes were prepared starting from a gemdihydroperoxide and a ketone. The obtained tetraoxanes showed pronounced antimalarial activity against P. falciparum chloroquine resistant W2 and chloroquine susceptible D6 strains, with N-(2-dimethylaminoethyl-7,8,15,16-tetraoxa-dispiro[5.2.5.2] hexadecane-3-carboxamide being as active as artemisinin.

  19. The malaria parasite cation ATPase PfATP4 and its role in the mechanism of action of a new arsenal of antimalarial drugs

    Natalie Jane Spillman

    2015-12-01

    Full Text Available The intraerythrocytic malaria parasite, Plasmodium falciparum, maintains a low cytosolic Na+ concentration and the plasma membrane P-type cation translocating ATPase ‘PfATP4’ has been implicated as playing a key role in this process. PfATP4 has been the subject of significant attention in recent years as mutations in this protein confer resistance to a growing number of new antimalarial compounds, including the spiroindolones, the pyrazoles, the dihydroisoquinolones, and a number of the antimalarial agents in the Medicines for Malaria Venture's ‘Malaria Box’. On exposure of parasites to these compounds there is a rapid disruption of cytosolic Na+. Whether, and if so how, such chemically distinct compounds interact with PfATP4, and how such interactions lead to parasite death, is not yet clear. The fact that multiple different chemical classes have converged upon PfATP4 highlights its significance as a potential target for new generation antimalarial agents. A spiroindolone (KAE609, now known as cipargamin has progressed through Phase I and IIa clinical trials with favourable results. In this review we consider the physiological role of PfATP4, summarise the current repertoire of antimalarial compounds for which PfATP4 is implicated in their mechanism of action, and provide an outlook on translation from target identification in the laboratory to patient treatment in the field.

  20. The malaria parasite cation ATPase PfATP4 and its role in the mechanism of action of a new arsenal of antimalarial drugs.

    Spillman, Natalie Jane; Kirk, Kiaran

    2015-12-01

    The intraerythrocytic malaria parasite, Plasmodium falciparum, maintains a low cytosolic Na(+) concentration and the plasma membrane P-type cation translocating ATPase 'PfATP4' has been implicated as playing a key role in this process. PfATP4 has been the subject of significant attention in recent years as mutations in this protein confer resistance to a growing number of new antimalarial compounds, including the spiroindolones, the pyrazoles, the dihydroisoquinolones, and a number of the antimalarial agents in the Medicines for Malaria Venture's 'Malaria Box'. On exposure of parasites to these compounds there is a rapid disruption of cytosolic Na(+). Whether, and if so how, such chemically distinct compounds interact with PfATP4, and how such interactions lead to parasite death, is not yet clear. The fact that multiple different chemical classes have converged upon PfATP4 highlights its significance as a potential target for new generation antimalarial agents. A spiroindolone (KAE609, now known as cipargamin) has progressed through Phase I and IIa clinical trials with favourable results. In this review we consider the physiological role of PfATP4, summarise the current repertoire of antimalarial compounds for which PfATP4 is implicated in their mechanism of action, and provide an outlook on translation from target identification in the laboratory to patient treatment in the field. PMID:26401486

  1. The malaria parasite cation ATPase PfATP4 and its role in the mechanism of action of a new arsenal of antimalarial drugs

    Spillman, Natalie Jane; Kirk, Kiaran

    2015-01-01

    The intraerythrocytic malaria parasite, Plasmodium falciparum, maintains a low cytosolic Na+ concentration and the plasma membrane P-type cation translocating ATPase ‘PfATP4’ has been implicated as playing a key role in this process. PfATP4 has been the subject of significant attention in recent years as mutations in this protein confer resistance to a growing number of new antimalarial compounds, including the spiroindolones, the pyrazoles, the dihydroisoquinolones, and a number of the antimalarial agents in the Medicines for Malaria Venture's ‘Malaria Box’. On exposure of parasites to these compounds there is a rapid disruption of cytosolic Na+. Whether, and if so how, such chemically distinct compounds interact with PfATP4, and how such interactions lead to parasite death, is not yet clear. The fact that multiple different chemical classes have converged upon PfATP4 highlights its significance as a potential target for new generation antimalarial agents. A spiroindolone (KAE609, now known as cipargamin) has progressed through Phase I and IIa clinical trials with favourable results. In this review we consider the physiological role of PfATP4, summarise the current repertoire of antimalarial compounds for which PfATP4 is implicated in their mechanism of action, and provide an outlook on translation from target identification in the laboratory to patient treatment in the field. PMID:26401486

  2. Ligand-based virtual screening and in silico design of new antimalarial compounds using nonstochastic and stochastic total and atom-type quadratic maps.

    Marrero-Ponce, Yovani; Iyarreta-Veitía, Maité; Montero-Torres, Alina; Romero-Zaldivar, Carlos; Brandt, Carlos A; Avila, Priscilla E; Kirchgatter, Karin; Machado, Yanetsy

    2005-01-01

    Malaria has been one of the most significant public health problems for centuries. It affects many tropical and subtropical regions of the world. The increasing resistance of Plasmodium spp. to existing therapies has heightened alarms about malaria in the international health community. Nowadays, there is a pressing need for identifying and developing new drug-based antimalarial therapies. In an effort to overcome this problem, the main purpose of this study is to develop simple linear discriminant-based quantitative structure-activity relationship (QSAR) models for the classification and prediction of antimalarial activity using some of the TOMOCOMD-CARDD (TOpological MOlecular COMputer Design-Computer Aided "Rational" Drug Design) fingerprints, so as to enable computational screening from virtual combinatorial datasets. In this sense, a database of 1562 organic chemicals having great structural variability, 597 of them antimalarial agents and 965 compounds having other clinical uses, was analyzed and presented as a helpful tool, not only for theoretical chemists but also for other researchers in this area. This series of compounds was processed by a k-means cluster analysis in order to design training and predicting sets. Afterward, two linear classification functions were derived in order to discriminate between antimalarial and nonantimalarial compounds. The models (including nonstochastic and stochastic indices) correctly classify more than 93% of the compound set, in both training and external prediction datasets. They showed high Matthews' correlation coefficients, 0.889 and 0.866 for the training set and 0.855 and 0.857 for the test one. The models' predictivity was also assessed and validated by the random removal of 10% of the compounds to form a new test set, for which predictions were made using the models. The overall means of the correct classification for this process (leave group 10% full-out cross validation) using the equations with nonstochastic

  3. Antimalarial activity of ruthenium(II) and osmium(II) arene complexes with mono- and bidentate chloroquine analogue ligands.

    Ekengard, Erik; Glans, Lotta; Cassells, Irwin; Fogeron, Thibault; Govender, Preshendren; Stringer, Tameryn; Chellan, Prinessa; Lisensky, George C; Hersh, William H; Doverbratt, Isa; Lidin, Sven; de Kock, Carmen; Smith, Peter J; Smith, Gregory S; Nordlander, Ebbe

    2015-11-28

    Eight new ruthenium and five new osmium p-cymene half-sandwich complexes have been synthesized, characterized and evaluated for antimalarial activity. All complexes contain ligands that are based on a 4-chloroquinoline framework related to the antimalarial drug chloroquine. Ligands HL(1-8) are salicylaldimine derivatives, where HL(1) = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine, and HL(2-8) contain non-hydrogen substituents in the 3-position of the salicylaldimine ring, viz. F, Cl, Br, I, NO2, OMe and (t)Bu for HL(2-8), respectively. Ligand HL(9) is also a salicylaldimine-containing ligand with substitutions in both 3- and 5-positions of the salicylaldimine moiety, i.e. N-(2-((2-hydroxy-3,5-di-tert-butylphenyl)methyl-imino)ethyl)-7-chloroquinolin-4-amine, while HL(10) is N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) The half sandwich metal complexes that have been investigated are [Ru(η(6)-cym)(L(1-8))Cl] (Ru-1-Ru-8, cym = p-cymene), [Os(η(6)-cym)(L(1-3,5,7))Cl] (Os-1-Os-3, Os-5, and Os-7), [M(η(6)-cym)(HL(9))Cl2] (M = Ru, Ru-HL(9); M = Os, Os-HL(9)) and [M(η(6)-cym)(L(10))Cl]Cl (M = Ru, Ru-10; M = Os, Os-10). In complexes Ru-1-Ru-8 and Ru-10, Os-1-Os-3, Os-5 and Os-7 and Os-10, the ligands were found to coordinate as bidentate N,O- and N,N-chelates, while in complexes Ru-HL(9) and Os-HL(9), monodentate coordination of the ligands through the quinoline nitrogen was established. The antimalarial activity of the new ligands and complexes was evaluated against chloroquine sensitive (NF54 and D10) and chloroquine resistant (Dd2) Plasmodium falciparum malaria parasite strains. Coordination of ruthenium and osmium arene moieties to the ligands resulted in lower antiplasmodial activities relative to the free ligands, but the resistance index is better for the ruthenium complexes compared to chloroquine. Overall, osmium complexes appeared to be less active than the corresponding ruthenium complexes. PMID:26491831

  4. Apicoplast Biosynthetic Pathways as Possible Targetsfor Combination Therapy of Malaria

    Solomon Tesfaye; Bhanu Prakash; Prati Pal Singh

    2015-01-01

    The emergence of malaria parasite strains resistant to practically all the antimalarial drugs in clinical use is now making itnecessary to discover and develop both new antimalarial drugs and treatments. Recent advances in molecular techniques along withthe availability of genome sequence ofPlasmodiumfalciparum may provide a wide range of novel targets in metabolic pathways likeisoprenoid biosynthesis, fatty acid biosynthesis and heme biosynthesis in the apicoplast of Plasmodiurn. On the other hand, thecombination therapy approach (currently used to retard the selection of parasite strains resistant to individual components of acombination of drugs) has proved to be a success in the combination of sulphadoxine and pyrimethamine, which targets two differentsteps in the folate pathway of malaria parasite. However, after the success of this therapeutic combination, the efficacy of othercombinations of drugs which target different enzymes in a particular metabolic pathway has, apparently, not been reported. Therefore,herein, we review various drug targets so far discovered in apicoplast-related anabolic pathways, especially, with a sharper focus onthe possibility to target more than one enzyme at a time in a particular metabolic pathway of malaria parasites.

  5. Design and Synthesis of Some New Quinoline Based 1,2,3-Triazoles as Antimicrobial and Antimalarial Agents

    Parthasaradhi Y.

    2015-09-01

    Full Text Available A series of novel 6-bromo-2-chloro-3-(4-phenyl-[1,2,3]triazol-1-ylmethyl-quinoline and its derivatives (5a-j were synthesized in good yields from the intermediates (6-bromo-2-chloro-quinolin-3-yl-methanol (2, methanesulfonic acid (6-bromo-2-chloroquinolin-3-ylmethyl methanesulfonate (3 and 3-azidomethyl-6-bromo-2-chloro-quinoline (4. The synthetic route leading to the title compounds is commenced from commercially available 6-bromo-2-chloro-quinolin-3-carbaldehyde (1. The chemical structures of the newly synthesized compounds were elucidated by their IR, 1H and 13C NMR, mass spectral data and elemental analysis. Further, all the target compounds were screened for their antimicrobial activity against various microorganisms and antimalarial activity towards P. falciparum. DOI: http://dx.doi.org/10.17807/orbital.v7i3.692 

  6. An amphiphilic graft copolymer-based nanoparticle platform for reduction-responsive anticancer and antimalarial drug delivery

    Najer, Adrian; Wu, Dalin; Nussbaumer, Martin G.; Schwertz, Geoffrey; Schwab, Anatol; Witschel, Matthias C.; Schäfer, Anja; Diederich, François; Rottmann, Matthias; Palivan, Cornelia G.; Beck, Hans-Peter; Meier, Wolfgang

    2016-08-01

    Medical applications of anticancer and antimalarial drugs often suffer from low aqueous solubility, high systemic toxicity, and metabolic instability. Smart nanocarrier-based drug delivery systems provide means of solving these problems at once. Herein, we present such a smart nanoparticle platform based on self-assembled, reduction-responsive amphiphilic graft copolymers, which were successfully synthesized through thiol-disulfide exchange reaction between thiolated hydrophilic block and pyridyl disulfide functionalized hydrophobic block. These amphiphilic graft copolymers self-assembled into nanoparticles with mean diameters of about 30-50 nm and readily incorporated hydrophobic guest molecules. Fluorescence correlation spectroscopy (FCS) was used to study nanoparticle stability and triggered release of a model compound in detail. Long-term colloidal stability and model compound retention within the nanoparticles was found when analyzed in cell media at body temperature. In contrast, rapid, complete reduction-triggered disassembly and model compound release was achieved within a physiological reducing environment. The synthesized copolymers revealed no intrinsic cellular toxicity up to 1 mg mL-1. Drug-loaded reduction-sensitive nanoparticles delivered a hydrophobic model anticancer drug (doxorubicin, DOX) to cancer cells (HeLa cells) and an experimental, metabolically unstable antimalarial drug (the serine hydroxymethyltransferase (SHMT) inhibitor (+/-)-1) to Plasmodium falciparum-infected red blood cells (iRBCs), with higher efficacy compared to similar, non-sensitive drug-loaded nanoparticles. These responsive copolymer-based nanoparticles represent a promising candidate as smart nanocarrier platform for various drugs to be applied to different diseases, due to the biocompatibility and biodegradability of the hydrophobic block, and the protein-repellent hydrophilic block.Medical applications of anticancer and antimalarial drugs often suffer from low aqueous

  7. Antimalarial potential of kolaviron, a biflavonoid fromGarcinia kola seeds, againstPlasmodium bergheiinfection in Swiss albino mice

    Adaramoye Oluwatosin; Akinpelu Tolulope; Kosoko Ayokulehin; Okorie Patricia; Kehinde Aderemi; Falade Catherine; Ademowo Olusegun

    2014-01-01

    Objective:To investigate the antimalarial potential of kolaviron(KV), a biflavonoid fraction from Garcinia kolaseeds, againstPlasmodium berghei(P. berghei) infection inSwiss albino mice. Methods:The study consists of seven groups of ten mice each.GroupsⅠ,Ⅱ and Ⅲ were normal mice that received corn oil,KV1 and chloroquine(CQ), respectively.GroupsⅣ,Ⅴ,Ⅵ and Ⅶ were infected mice that received corn oil,CQ,KV1 andKV2, respectively.CQ,KV1 andKV2 were given at10-,100- and200-mg/kg daily, respectively for three consecutive days.Results:Administration ofKV1 andKV2 significantly(P<0.05) suppressedP. berghei-infection in the mice by85% and90%, respectively, whileCQ produced87% suppression relative to untreated infected group after the fifth day of treatment.Also,KV2 significantly(P<0.05) increased the mean survival time of the infected mice by175%.The biflavonoid prevented a drastic reduction inPCV from day 4 of treatment, indicating its efficacy in ameliorating anaemia.Significant(P<0.05) oxidative stress assessed by the elevation of serum and hepatic malondialdehydewere observed in untreatedP. berghei-infected mice.Specifically, serum and hepatic malondialdehyde levels increased by 93% and78%, respectively in the untreated infected mice.Furthermore, antioxidant indices, viz; superoxide dismutase, catalase, glutathione-s-transferase, gluathione peroxidase and reduced gluathione decreased significantly(P<0.05) in the tissues of untreatedP. berghei-infected mice. KV significantly(P<0.05) ameliorated theP. berghei-induced decrease in antioxidant status of the infected mice.Conclusions:This study shows that kolaviron, especially at200 mg/kg, has high antimalarial activities inP. berghei-infected mice, in addition to its known antioxidant properties.

  8. Quality of anti-malarial drugs provided by public and private healthcare providers in south-east Nigeria

    Uzochukwu Benjamin

    2009-02-01

    Full Text Available Abstract Background There is little existing knowledge about actual quality of drugs provided by different providers in Nigeria and in many sub-Saharan African countries. Such information is important for improving malaria treatment that will help in the development and implementation of actions designed to improve the quality of treatment. The objective of the study was to determine the quality of drugs used for the treatment of malaria in a broad spectrum of public and private healthcare providers. Methods The study was undertaken in six towns (three urban and three rural in Anambra state, south-east Nigeria. Anti-malarials (225 samples, which included artesunate, dihydroartemisinin, sulphadoxine-pyrimethamine (SP, quinine, and chloroquine, were either purchased or collected from randomly selected providers. The quality of these drugs was assessed by laboratory analysis of the dissolution profile using published pharmacopoeial monograms and measuring the amount of active ingredient using high performance liquid chromatography (HPLC. Findings It was found that 60 (37% of the anti-malarials tested did not meet the United States Pharmacopoeia (USP specifications for the amount of active ingredients, with the suspect drugs either lacking the active ingredients or containing suboptimal quantities of the active ingredients. Quinine (46% and SP formulations (39% were among drugs that did not satisfy the tolerance limits published in USP monograms. A total of 78% of the suspect drugs were from private facilities, mostly low-level providers, such as patent medicine dealers (vendors. Conclusion This study found that there was a high prevalence of poor quality drugs. The findings provide areas for public intervention to improve the quality of malaria treatment services. There should be enforced checks and regulation of drug supply management as well as stiffer penalties for people stocking substandard and counterfeit drugs.

  9. Effect of transmission reduction by insecticide-treated bednets (ITNs on antimalarial drug resistance in western Kenya.

    Monica Shah

    Full Text Available Despite the clear public health benefit of insecticide-treated bednets (ITNs, the impact of malaria transmission-reduction by vector control on the spread of drug resistance is not well understood. In the present study, the effect of sustained transmission reduction by ITNs on the prevalence of Plasmodium falciparum gene mutations associated with resistance to the antimalarial drugs sulfadoxine-pyrimethamine (SP and chloroquine (CQ in children under the age of five years was investigated during an ITN trial in Asembo area, western Kenya. During the ITN trial, the national first line antimalarial treatment changed from CQ to SP. Smear-positive samples collected from cross sectional surveys prior to ITN introduction (baseline, n = 250 and five years post-ITN intervention (year 5 survey, n = 242 were genotyped for single nucleotide polymorphisms (SNPs at dhfr-51, 59, 108, 164 and dhps-437, 540 (SP resistance, and pfcrt-76 and pfmdr1-86 (CQ resistance. The association between the drug resistance mutations and epidemiological variables was evaluated. There were significant increases in the prevalence of SP dhps mutations and the dhfr/dhps quintuple mutant, and a significant reduction in the proportion of mixed infections detected at dhfr-51, 59 and dhps-437, 540 SNPs from baseline to the year 5 survey. There was no change in the high prevalence of pfcrt-76 and pfmdr1-86 mutations. Multivariable regression analysis further showed that current antifolate use and year of survey were significantly associated with more SP drug resistance mutations. These results suggest that increased antifolate drug use due to drug policy change likely led to the high prevalence of SP mutations 5 years post-ITN intervention and reduced transmission had no apparent effect on the existing high prevalence of CQ mutations. There is no evidence from the current study that sustained transmission reduction by ITNs reduces the prevalence of genes associated with malaria

  10. DETECTION OF PUTATIVE ANTIMALARIAL-RESISTANT PLASMODIUM VIVAX IN ANOPHELES VECTORS AT THAILAND-CAMBODIA AND THAILAND-MYANMAR BORDERS.

    Rattaprasert, Pongruj; Chaksangchaichot, Panee; Wihokhoen, Benchawan; Suparach, Nutjaree; Sorosjinda-Nunthawarasilp, Prapa

    2016-03-01

    Monitoring of multidrug-resistant (MDR)falciparum and vivax malaria has recently been included in the Global Plan for Artemisinin Resistance Containment (GPARC) of the Greater Mekong Sub-region, particularly at the Thailand-Cambodia and Thailand-Myanmar borders. In parallel to GPARC, monitoring MDR malaria parasites in anopheline vectors is an ideal augment to entomological surveillance. Employing Plasmodium- and species-specific nested PCR techniques, only P. vivax was detected in 3/109 salivary gland DNA extracts of anopheline vectors collected during a rainy season between 24-26 August 2009 and 22-24 September 2009 and a dry season between 29-31 December 2009 and 16-18 January 2010. Indoor and out- door resting mosquitoes were collected in Thong Pha Phum District, Kanchanaburi Province (border of Thailand-Myanmar) and Bo Rai District, Trat Province (border of Thailand-Cambodia): one sample from Anopheles dirus at the Thailand-Cambodia border and two samples from An. aconitus from Thailand-Myanmar border isolate. Nucleotide sequencing of dihydrofolate reductase gene revealed the presence in all three samples of four mutations known to cause high resistance to antifolate pyrimethamine, but no mutations were found in multidrug resistance transporter 1 gene that are associated with (falciparum) resistance to quinoline antimalarials. Such findings indicate the potential usefulness of this approach in monitoring the prevalence of drug-resistant malaria parasites in geographically regions prone to the development of drug resistance and where screening of human population at risk poses logistical and ethical problems. Keywords: Anopheles spp, Plasmodium vivax, antimalarial resistance, Greater Mekong Sub-region, nested PCR, vector surveillance PMID:27244954

  11. In vitro genotoxicity of the West African anti-malarial herbal Cryptolepis sanguinolenta and its major alkaloid cryptolepine.

    Ansah, Charles; Khan, Ayesha; Gooderham, Nigel J

    2005-03-01

    Cryptolepine (CLP), the major alkaloid of the West African anti-malarial herbal Cryptolepis sanguinolenta (Periplocaceae) is a DNA intercalator that exhibits potent toxicity to a variety of mammalian cells in vitro. We have hypothesized that the DNA intercalating properties of cryptolepine could trigger genetic damage in mammalian cells. The objective of the present study was therefore to assess the ability of both cryptolepine (CLP) and the traditional anti-malarial formulation, the aqueous extract from the roots (CSE) to induce mutation at the hprt locus and micronuclei (MN) formation in V79, a Chinese hamster fibroblast cell line commonly used in genetic toxicity studies. CSE at a high concentration (50 microg/ml) induced an apparent significant ten fold increase in mutant frequency compared to vehicle control (mean of 38 versus 4 mutant clones/10(6) surviving cells) but, this concentration of CSE was very toxic (<15% cell survival). CLP did not appear to be mutagenic in the dosage range used (up to 2.5 microM, equivalent to 1.1 microg/ml). However, after 24h treatment of V79 cells both CSE and CLP induced a dose-dependent increase in micronuclei of 4.15% and 6.43% (25 microg/ml CSE and 2.5 microM, equivalent to 1.1 microg/ml CLP, respectively) compared to 0.36% in vehicle control. These results show that treatment of mammalian cells with CSE and CLP can lead to DNA damage and we suggest that the routine use of CSE and the potential use of CLP derivatives in malaria chemotherapy could carry a genotoxic risk. PMID:15664441

  12. High dose artesunate in combination with mefloquine: pharmacovigilance in the Venezuelan Amazon.

    Metzger, W G; Magris, M; Vivas-Martínez, S; Giron, A; Brooms, J D; Villalobos, N; Cruz, L; Peña Pimentel, F N; Perez, L; España, R

    2012-03-01

    Forty-six patients in a remote health post of Amazonas, Venezuela, accidentally received artesunate in a dose of 10 mg/kg/day combined with mefloquine. This corresponds to the upper limit of the therapeutic range recommended by the WHO (2-10 mg/kg/day). Side effects were retrospectively investigated and a pharmacovigilance report was written. The main side effects were vomiting and diarrhea. Four patients developed complications with signs of dehydration. It is suggested to re-assess the therapeutic range of artesunate when given in combination with mefloquine and to establish a worldwide centralized antimalarial toxicity reporting system. PMID:22153748

  13. Comparative antimalarial activities and ADME profiles of ozonides (1,2,4-trioxolanes) OZ277, OZ439, and their 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres.

    Wang, Xiaofang; Dong, Yuxiang; Wittlin, Sergio; Charman, Susan A; Chiu, Francis C K; Chollet, Jacques; Katneni, Kasiram; Mannila, Janne; Morizzi, Julia; Ryan, Eileen; Scheurer, Christian; Steuten, Jessica; Santo Tomas, Josefina; Snyder, Christopher; Vennerstrom, Jonathan L

    2013-03-28

    To ascertain the structure-activity relationship of the core 1,2,4-trioxolane substructure of dispiro ozonides OZ277 and OZ439, we compared the antimalarial activities and ADME profiles of the 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. Consistent with previous data, both dioxolanes had very weak antimalarial properties. For the OZ277 series, the trioxane isostere had the best ADME profile, but its overall antimalarial efficacy was not superior to that of the trioxolane or tetraoxane isosteres. For the OZ439 series, there was a good correlation between the antimalarial efficacy and ADME profiles in the rank order trioxolane > trioxane > tetraoxane. As we have previously observed for OZ439 versus OZ277, the OZ439 series peroxides had superior exposure and efficacy in mice compared to the corresponding OZ277 series peroxides. PMID:23489135

  14. Licochalcone A, a new antimalarial agent, inhibits in vitro growth of the human malaria parasite Plasmodium falciparum and protects mice from P. yoelii infection

    Chen, M; Theander, T G; Christensen, S B;

    1994-01-01

    Licochalcone A, isolated from Chinese licorice roots, inhibited the in vitro growth of both chloroquine-susceptible (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains in a [3H]hypoxanthine uptake assay. The growth inhibition of the chloroquine-resistant strain by licochalcone A was...... licochalcone A exhibits potent antimalarial activity and might be developed into a new antimalarial drug....

  15. A comparative, randomized clinical trial of artemisinin/naphtoquine twice daily one day versus artemether/lumefantrine six doses regimen in children and adults with uncomplicated falciparum malaria in Côte d'Ivoire

    Toure Walamtchin

    2009-07-01

    Full Text Available Abstract Background Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination anti-malarial therapy, including artemisinins, has been advocated to improve efficacy and limit the spread of resistance. The fixed combination of oral artemether-lumefantrine (AL is highly effective and well-tolerated. Artemisinin/naphtoquine (AN is a fixed-dose ACT that has recently become available in Africa. The objectives of the study were to compare the efficacy and safety of AN and AL for the treatment of uncomplicated falciparum malaria in a high transmission-intensity site in Ivory Coast. Methods We enrolled 122 participants aged 6 months or more with uncomplicated falciparum malaria. Participants were randomized to receive either artemisinin/naphtoquine or artemether/lumefantrine with variable dose according to their weight. Primary endpoints were the risks of treatment failure within 28 days, either unadjusted or adjusted by genotyping to distinguish recrudescence from new infection. Results Among 125 participants enrolled, 123 (98.4% completed follow-up. Clinical evaluation of the 123 participants showed that cumulative PCR-uncorrected cure rate on day 28 was 100% for artemisinin/naphtoquine and 98.4% for artemether/lumefantrine. Both artemisinin-based combinations effected rapid fever and parasite clearance. Interpretation These data suggest that Arco® could prove to be suitable for use as combination antimalarial therapy. Meanwhile, pharmacokinetic studies and further efficacy assessment should be conducted before its widespread use can be supported.

  16. Is primaquine useful and safe as true exo-erythrocytic merontocidal, hypnozoitocidal and gametocidal antimalarial drug?

    Francisco Javier López-Antuñano

    1999-10-01

    Full Text Available The main objective of this paper is to make available in a single document, a sequence of events that have been published on the biology of malaria parasites and their interaction with the human host, looking for arguments for effective and save treatment: what we know and what we would like to know about the effects of primaquine in order to justify its use in clinical and public health practice. The practicioner should be aware that the antimalarial activity, hemolytic and methemoglobinemic side effects, and detoxification of primaquine are all thought to depend on various biotransformation products of the drug. In spite of the universal use during over six decades, their site and mechanism of formation and degradation and their specific biologic effects remain very poorly understood in human beings. The mature gametocytes of P. falciparum are naturally resistant to chloroquine and other blood merontocides, but they are usually eliminated with a single dose of 1.315 mg/kg per os (p.o. of primaquine phosphate (equivalent to 0.75 mg-base. Rather than empirically, related with relapses frequency, dosage schedules should only be determined through consideration of the kinetics and dynamics of the drug and its effect on sporozoites, pre and exo-erythrocytic merontes, hypnozoites and gametocytes of P. vivax. Where medical care services are not available or not capable to detect glucose -6- phosphate dehydrogenese- (G-6-PD deficiencies and deleterious effects of the drug, we recommend not to use primaquine. Both, P. vivax primary clinical attack and P. vivax relapses, as and when they occur should be treated with a course of 10 mg/kg chloroquine-base p.o. Prevention of relapses is probably related to strain characteristics of P. vivax hypnozoites populations envolved. If well informed and qualified medical care workers decide to use primaquine in the absence of enzime defficiencies and are able to follow-up the clinical, toxicological and parasitic

  17. Genotyping of Plasmodium falciparum using antigenic polymorphic markers and to study anti-malarial drug resistance markers in malaria endemic areas of Bangladesh

    Akter Jasmin

    2012-11-01

    Full Text Available Abstract Background In the past many regions of Bangladesh were hyperendemic for malaria. Malaria control in the 1960s to 1970s eliminated malaria from the plains but in the Chittagong Hill Tracts remained a difficult to control reservoir. The Chittagong Hill Tracts have areas with between 1 and 10% annual malaria rates, predominately 90-95% Plasmodium falciparum. In Southeast Asia, multiplicity of infection for hypo-endemic regions has been approximately 1.5. Few studies on the genetic diversity of P. falciparum have been performed in Bangladesh. Anderson et al. performed a study in Khagrachari, northern Chittagong Hill Tracts in 2002 on 203 patients and found that parasites had a multiplicity of infection of 1.3 by MSP-1, MSP-2 and GLURP genotyping. A total of 94% of the isolates had the K76T Pfcrt chloroquine resistant genotype, and 70% showed the N86Y Pfmdr1 genotype. Antifolate drug resistant genotypes were high with 99% and 73% of parasites having two or more mutations at the dhfr or dhps loci. Methods Nested and real-time polymerase chain reaction (PCR methods were used to genotype P. falciparum using antigenic polymorphic markers and to study anti-malarial drug resistance markers in malaria endemic areas of Bangladesh. Results The analysis of polymorphic and drug resistant genotype on 33 paired recrudescent infections after drug treatment in the period 2004 to 2008 in the Chittagong Hill Tracts, which is just prior to countrywide provision of artemisinin combination therapy. Overall the multiplicity of infection for MSP-1 was 2.7 with a slightly smaller parasite diversity post-treatment. The 13 monoclonal infections by both GLURP and MSP-1 were evenly divided between pre- and post-treatment. The MSP-1 MAD block was most frequent in 66 of the samples. The prevalence of the K76T PfCRT chloroquine resistant allele was approximately 82% of the samples, while the resistant Pfmdr1 N86Y was present in 33% of the samples. Interestingly, the post

  18. Assessment of the efficacy of first-line antimalarial drugs after 5 years of deployment by the National Malaria Control Programme in Côte d'Ivoire

    Offianan AT

    2011-11-01

    Full Text Available Andre T Offianan1, Serge B Assi2, Aristide MA Coulibaly1, Landry T N'guessan1, Aristide A Ako1, Florence K Kadjo2, Moïse K San2, Louis K Penali2 1Malariology Department, Institut Pasteur de Côte d'Ivoire, Abidjan, Côte d'Ivoire; 2National Malaria Control Programme, Abidjan, Côte d'Ivoire Background: The emergence of artemisinin resistance has raised concerns that the most potent antimalarial drug may be under threat. Artesunate + amodiaquine (ASAQ and artemether-lumefantrine (AL are respectively the first- and second-line treatments for uncomplicated falciparum malaria in Côte d'Ivoire. A comparison of the efficacy and safety of these two drug combinations was necessary to make evidence-based drug treatment policies. Methods: In an open-label, non inferiority, randomized, controlled clinical trial, children aged 6–59 months were randomized to receive ASAQ or AL. Both drug regimens were given for 3 days, and follow-up was for 28 days. The primary endpoint was the 28-day cure rates and was defined as proportion of patients with polymerase chain reaction (PCR-corrected cure rate after 28 days of follow-up. Findings: A total of 251 patients who were attending the Ayame and Dabakala hospitals and presenting with symptomatic acute uncomplicated falciparum malaria were randomized to receive ASAQ (128 and AL (123. The intention-to-treat analysis showed effectiveness rates of 94.5% and 93.5% for ASAQ and AL, respectively on day 28. After adjustment for PCR results, these rates were 96.1% and 96.8%, respectively. On day 28, the per-protocol analysis showed effectiveness rates of 98.4% and 96.6% for ASAQ and AL, respectively. After adjustment by PCR for reinfection, these rates were 100% for each drug, and both regimens were well tolerated. Conclusion: ASAQ and AL remain efficacious treatments of uncomplicated falciparum malaria in Ivorian children 5 years after adoption. The efficacy of ASAQ and AL in Côte d'Ivoire requires, therefore, continuous

  19. Synthesis, Docking, In Vitro and In Vivo Antimalarial Activity of Hybrid 4-aminoquinoline-1,3,5-triazine Derivatives Against Wild and Mutant Malaria Parasites.

    Bhat, Hans Raj; Singh, Udaya Pratap; Gahtori, Prashant; Ghosh, Surajit Kumar; Gogoi, Kabita; Prakash, Anil; Singh, Ramendra K

    2015-09-01

    A new series of hybrid 4-aminoquinoline-1,3,5-triazine derivatives was synthesized by a four-step reaction. Target compounds were screened for in vitro antimalarial activity against chloroquine-sensitive (3D-7) and chloroquine-resistant (RKL-2) strains of Plasmodium falciparum. Compounds exhibited, by and large, good antimalarial activity against the resistant strain, while two of them, that is 8g and 8a, displayed higher activity against both the strains of P. falciparum. Additionally, docking study was performed on both wild (1J3I.pdb) and quadruple mutant (N51I, C59R, S108 N, I164L, 3QG2.pdb) type pf-DHFR-TS to highlight the structural features of hybrid molecules. PMID:25487527

  20. Use of the atmospheric generators for capnophilic bacteria Genbag-CO2 for the evaluation of in vitro Plasmodium falciparum susceptibility to standard anti-malarial drugs

    Travers Dominique; Amalvict Rémy; Baret Eric; Basco Leonardo K; Pascual Aurélie; Rogier Christophe; Pradines Bruno

    2011-01-01

    Abstract Background The aim of this study was to evaluate the cultivation system in which the proper atmospheric conditions for growing Plasmodium falciparum parasites were maintained in a sealed bag. The Genbag® system associated with the atmospheric generators for capnophilic bacteria Genbag CO2® was used for in vitro susceptibility test of nine standard anti-malarial drugs and compared to standard incubator conditions. Methods The susceptibility of 36 pre-identified parasite strains from a...

  1. A novel way to grow hemozoin-like crystals in vitro and its use to screen for hemozoin inhibiting antimalarial compounds.

    Vincent Thomas

    Full Text Available BACKGROUND: Hemozoin crystals are normally formed in vivo by Plasmodium parasites to detoxify free heme released after hemoglobin digestion during its intraerythrocytic stage. Inhibition of hemozoin formation by various drugs results in free heme concentration toxic for the parasites. As a consequence, in vitro assays have been developed to screen and select candidate antimalarial drugs based on their capacity to inhibit hemozoin formation. In this report we describe new ways to form hemozoin-like crystals that were incidentally discovered during research in the field of prion inactivation. METHODS: We investigated the use of a new assay based on naturally occurring "self-replicating" particles and previously described as presenting resistance to decontamination comparable to prions. The nature of these particles was determined using electron microscopy, Maldi-Tof analysis and X-ray diffraction. They were compared to synthetic hemozoin and to hemozoin obtained from Plasmodium falciparum. We then used the assay to evaluate the capacity of various antimalarial and anti-prion compounds to inhibit "self-replication" (crystallisation of these particles. RESULTS: We identified these particles as being similar to ferriprotoporphyrin IX crystal and confirmed the ability of these particles to serve as nuclei for growth of new hemozoin-like crystals (HLC. HLC are morphologically similar to natural and synthetic hemozoin. Growth of HLC in a simple assay format confirmed inhibition by quinolines antimalarials at potencies described in the literature. Interestingly, artemisinins and tetracyclines also seemed to inhibit HLC growth. CONCLUSIONS: The described HLC assay is simple and easy to perform and may have the potential to be used as an additional tool to screen antimalarial drugs for their hemozoin inhibiting activity. As already described by others, drugs that inhibit hemozoin crystal formation have also the potential to inhibit misfolded proteins

  2. A Repeat Random Survey of the Prevalence of Falsified and Substandard Antimalarials in the Lao PDR: A Change for the Better

    Tabernero, Patricia; Mayxay, Mayfong; Culzoni, María Julia; Dwivedi, Prabha; Swamidoss, Isabel; Allan, Elizabeth Louise; Khanthavong, Maniphone; Phonlavong, Chindaphone; Vilayhong, Chantala; Yeuchaixiong, Sengchanh; Sichanh, Chanvilay; Sengaloundeth, Sivong; Kaur, Harparkash; Facundo M Fernández; Green, Michael D.

    2015-01-01

    In 2003, a stratified random sample survey was conducted in the Lao People's Democratic Republic (Laos) to study the availability and quality of antimalarials in the private sector. In 2012, this survey was repeated to allow a statistically valid analysis of change through time. The counterfeit detection device 3 (CD-3) was used to assess packaging quality in the field and HPLC and mass spectroscopy analysis chemical analysis performed. The availability of oral artesunate monotherapies had si...

  3. Self-medication with anti-malarials is a common practice in rural communities of Kilosa district in Tanzania despite the reported decline of malaria

    Chipwaza, Beatrice; Joseph P Mugasa; Mayumana, Iddy; Amuri, Mbaraka; Makungu, Christina; Gwakisa, Paul S.

    2014-01-01

    Background Self-medication has been widely practiced worldwide particularly in developing countries including Tanzania. In sub-Saharan Africa high incidences of malaria have contributed to self-medication with anti-malarial drugs. In recent years, there has been a gain in malaria control, which has led to decreased malaria transmission, morbidity and mortality. Therefore, understanding the patterns of self-medication during this period when most instances of fever are presumed to be due to no...

  4. First Assessment in Humans of the Safety, Tolerability, Pharmacokinetics, and Ex Vivo Pharmacodynamic Antimalarial Activity of the New Artemisinin Derivative Artemisone▿

    Nagelschmitz, Johannes; Voith, Barbara; Wensing, Georg; Roemer, Axel; Fugmann, Burkhard; Haynes, Richard K.; Kotecka, Barbara M.; Karl H Rieckmann; Edstein, Michael D.

    2008-01-01

    In preclinical studies, artemisone (BAY 44-9585), a new artemisinin derivative, was shown to possess enhanced efficacy over artesunate, and it does not possess the neurotoxicity characteristic of the current artemisinins. In a phase I program with double-blind, randomized, placebo-controlled, single and multiple ascending oral-dose studies, we evaluated the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of artemisone. Single doses (10, 20, 30, 40, an...

  5. The malaria parasite cation ATPase PfATP4 and its role in the mechanism of action of a new arsenal of antimalarial drugs

    Natalie Jane Spillman; Kiaran Kirk

    2015-01-01

    The intraerythrocytic malaria parasite, Plasmodium falciparum, maintains a low cytosolic Na+ concentration and the plasma membrane P-type cation translocating ATPase ‘PfATP4’ has been implicated as playing a key role in this process. PfATP4 has been the subject of significant attention in recent years as mutations in this protein confer resistance to a growing number of new antimalarial compounds, including the spiroindolones, the pyrazoles, the dihydroisoquinolones, and a number of the antim...

  6. Genetic polymorphisms associated with anti-malarial antibody levels in a low and unstable malaria transmission area in southern Sri Lanka

    Dewasurendra Rajika L; Suriyaphol Prapat; Fernando Sumadhya D; Carter Richard; Rockett Kirk; Corran Patrick; Kwiatkowski Dominic; Karunaweera Nadira D

    2012-01-01

    Abstract Background The incidence of malaria in Sri Lanka has significantly declined in recent years. Similar trends were seen in Kataragama, a known malaria endemic location within the southern province of the country, over the past five years. This is a descriptive study of anti-malarial antibody levels and selected host genetic mutations in residents of Kataragama, under low malaria transmission conditions. Methods Sera were collected from 1,011 individuals residing in Kataragama and anti-...

  7. Highly potent anti-proliferative effects of a gallium(III) complex with 7-chloroquinoline thiosemicarbazone as a ligand: synthesis, cytotoxic and antimalarial evaluation.

    Kumar, Kewal; Schniper, Sarah; González-Sarrías, Antonio; Holder, Alvin A; Sanders, Natalie; Sullivan, David; Jarrett, William L; Davis, Krystyn; Bai, Fengwei; Seeram, Navindra P; Kumar, Vipan

    2014-10-30

    A gallium(III) complex with 7-chloroquinoline thiosemicarbazone was synthesized and characterized. The complex proved to be thirty-one times more potent on colon cancer cell line, HCT-116, with considerably less cytotoxicity on non-cancerous colon fibroblast, CCD-18Co, when compared to etoposide. Its anti-malarial potential on 3D7 isolate of Plasmodium falciparum was better than lumefantrine. PMID:25147149

  8. In vitro and in vivo anti-malarial activity of limonoids isolated from the residual seed biomass from Carapa guianensis (andiroba) oil production

    Pereira, Tiago B; Rocha e Silva, Luiz F.; Amorim, Rodrigo CN; Melo, Márcia RS; Zacardi de Souza, Rita C; Marcos N. Eberlin; Emerson S. Lima; Vasconcellos, Marne C.; Pohlit, Adrian M.

    2014-01-01

    Background Carapa guianensis is a cultivable tree used by traditional health practitioners in the Amazon region to treat several diseases and particularly symptoms related to malaria. Abundant residual pressed seed material (RPSM) results as a by-product of carapa or andiroba oil production. The objective of this study was to evaluate the in vitro and in vivo anti-malarial activity and cytotoxicity of limonoids isolated from C. guaianensis RPSM. Methods 6α-acetoxyepoxyazadiradione (1), andiro...

  9. Comparison of the Exposure Time Dependence of the Activities of Synthetic Ozonide Antimalarials and Dihydroartemisinin against K13 Wild-Type and Mutant Plasmodium falciparum Strains

    Yang, Tuo; Xie, Stanley C.; Cao, Pengxing; Giannangelo, Carlo; McCaw, James; Creek, Darren J.; Charman, Susan A.; Klonis, Nectarios

    2016-01-01

    Fully synthetic endoperoxide antimalarials, namely, OZ277 (RBx11160; also known as arterolane) and OZ439 (artefenomel), have been approved for marketing or are currently in clinical development. We undertook an analysis of the kinetics of the in vitro responses of Plasmodium falciparum to the new ozonide antimalarials. For these studies we used a K13 mutant (artemisinin resistant) isolate from a region in Cambodia and a genetically matched (artemisinin sensitive) K13 revertant. We used a pulsed-exposure assay format to interrogate the time dependence of the response. Because the ozonides have physicochemical properties different from those of the artemisinins, assay optimization was required to ensure that the drugs were completely removed following the pulsed exposure. Like that of artemisinins, ozonide activity requires active hemoglobin degradation. Short pulses of the ozonides were less effective than short pulses of dihydroartemisinin; however, when early-ring-stage parasites were exposed to drugs for periods relevant to their in vivo exposure, the ozonide antimalarials were markedly more effective. PMID:27161632

  10. Discovery of carbohybrid-based 2-aminopyrimidine analogues as a new class of rapid-acting antimalarial agents using image-based cytological profiling assay.

    Lee, Sukjun; Lim, Donghyun; Lee, Eunyoung; Lee, Nakyung; Lee, Hong-Gun; Cechetto, Jonathan; Liuzzi, Michel; Freitas-Junior, Lucio H; Song, Jin Sook; Bae, Myung Ae; Oh, Sangmi; Ayong, Lawrence; Park, Seung Bum

    2014-09-11

    New antimalarial agents that exhibit multistage activities against drug-resistant strains of malaria parasites represent good starting points for developing next-generation antimalarial therapies. To facilitate the progression of such agents into the development phase, we developed an image-based parasitological screening method for defining drug effects on different asexual life cycle stages of Plasmodium falciparum. High-throughput screening of a newly assembled diversity-oriented synthetic library using this approach led to the identification of carbohybrid-based 2-aminopyrimidine compounds with fast-acting growth inhibitory activities against three laboratory strains of multidrug-resistant P. falciparum. Our structure-activity relationship study led to the identification of two derivatives (8aA and 11aA) as the most promising antimalarial candidates (mean EC50 of 0.130 and 0.096 μM against all three P. falciparum strains, selectivity indices >600, microsomal stabilities >80%, and mouse malaria ED50 values of 0.32 and 0.12 mg/kg/day, respectively), targeting all major blood stages of multidrug-resistant P. falciparum parasites. PMID:25137549

  11. Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in African Children with Malaria

    Salman, Sam; Bendel, Daryl; Lee, Toong C.; Templeton, David

    2015-01-01

    The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in 91 young African children with severe malaria or who could not tolerate oral antimalarial therapy. Each received 3.0 mg/kg of body weight of artemether at 0, 8, 24, 36, 48, and 60 h or until the initiation of oral treatment. Few blood samples were drawn postdose. Plasma artemether and dihydroartemisinin (DHA) levels were measured using liquid chromatography-mass spectrometry, and the data were analyzed using established population compartmental pharmacokinetic models. Parasite clearance was prompt (median parasite clearance time, 24 h), and there were no serious adverse events. Consistent with studies in healthy adults (S. Salman, D. Bendel, T. C. Lee, D. Templeton, and T. M. E. Davis, Antimicrob Agents Chemother 59:3197–3207, 2015, http://dx.doi.org/10.1128/AAC.05013-14), the absorption of sublingual artemether was biphasic, and multiple dosing was associated with the autoinduction of the metabolism of artemether to DHA (which itself has potent antimalarial activity). In contrast to studies using healthy volunteers, pharmacokinetic modeling indicated that the first absorption phase did not avoid first-pass metabolism, suggesting that the drug is transferred to the upper intestine through postdose fluid/food intake. Simulations using the present data and those from an earlier study in older Melanesian children with uncomplicated malaria treated with artemether-lumefantrine tablets suggested that the bioavailability of sublingual artemether was at least equivalent to that after conventional oral artemether-lumefantrine (median [interquartile range] areas under the concentration-time curve for artemether, 3,403 [2,471 to 4,771] versus 3,063 [2,358 to 4,514] μg · h/liter, respectively; and for DHA, 2,958 [2,146 to 4,278] versus 2,839 [1,812 to 3,488] μg · h/liter, respectively; P ≥ 0.42). These findings suggest that sublingual artemether could be used as prereferral treatment for sick

  12. The detection and treatment of Plasmodium falciparum malaria: Time for change

    Nosten F

    2004-01-01

    Full Text Available In most countries where malaria is endemic, P. falciparum malaria is on the rise. This is primarily due to the spread of drug-resistant strains. Drug resistance is mediated by spontaneous changes in the parasite genome that allow resistant parasites to escape the action of the drugs. The spread of drug resistance increases the transmission of malaria parasites. The consequences for the populations at risk are profound both in terms of consequences for health and economy. In order to halt the progression of drug resistance, we need to change the way antimalarials are used. As in tuberculosis and HIV/AIDS, we must use a combination of drugs for the treatment of malaria. Taking into account the pharmacokinetic and pharmacodynamic properties of the various anti-malarial agents, artemisinin-based combination therapy (ACT seems to be the best option. This strategy should be used in conjunction with early diagnosis and appropriate vector control measures to achieve reduction in the emergence and spread of drug resistance.

  13. Surveillance of the efficacy of artemether-lumefantrine and artesunate-amodiaquine for the treatment of uncomplicated Plasmodium falciparum among children under five in Togo, 2005-2009

    Dorkenoo Monique A

    2012-10-01

    Full Text Available Abstract Background Malaria remains a major public health problem in Togo. The national malaria control programme in Togo changed the anti-malarial treatment policy from monotherapy to artemisinin combination therapy in 2004. This study reports the results of therapeutic efficacy studies conducted on artemether-lumefantrine and artesunate-amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Togo, between 2005 and 2009. Methods Children between 6 and 59 months of age, who were symptomatically infected with P. falciparum, were treated with either artemether-lumefantrine or artesunate-amodiaquine. The primary end-point was the 28-day cure rate, PCR-corrected for reinfection and recrudescence. Studies were conducted according to the standardized WHO protocol for the assessment of the efficacy of anti-malarial treatment. Differences between categorical data were compared using the chi-square test or the Fisher’s exact test where cell counts were ≤ 5. Differences in continuous data were compared using a t-test. Results A total of 16 studies were conducted in five sentinel sites, with 459, 505 and 332 children included in 2005, 2007 and 2009, respectively. The PCR-corrected 28-day cure rates using the per-protocol analysis were between 96%-100% for artemether-lumefantrine and 94%-100% for artesunate-amodiaquine. Conclusions Both formulations of artemisinin-based combination therapy were effective over time and no severe adverse events related to the treatment were reported during the studies.

  14. Are patent medicine vendors effective agents in malaria control? Using lot quality assurance sampling to assess quality of practice in Jigawa, Nigeria.

    Sima Berendes

    Full Text Available BACKGROUND: Patent medicine vendors (PMV provide antimalarial treatment and care throughout Sub-Saharan Africa, and can play an important role in the fight against malaria. Their close-to-client infrastructure could enable lifesaving artemisinin-based combination therapy (ACT to reach patients in time. However, systematic assessments of drug sellers' performance quality are crucial if their role is to be managed within the health system. Lot quality assurance sampling (LQAS could be an efficient method to monitor and evaluate PMV practice, but has so far never been used for this purpose. METHODS: In support of the Nigeria Malaria Booster Program we assessed PMV practices in three Senatorial Districts (SDs of Jigawa, Nigeria. A two-stage LQAS assessed whether at least 80% of PMV stores in SDs used national treatment guidelines. Acceptable sampling errors were set in consultation with government officials (alpha and beta <0.10. The hypergeometric formula determined sample sizes and cut-off values for SDs. A structured assessment tool identified high and low performing SDs for quality of care indicators. FINDINGS: Drug vendors performed poorly in all SDs of Jigawa for all indicators. For example, all SDs failed for stocking and selling first-line antimalarials. PMV sold no longer recommended antimalarials, such as Chloroquine, Sulfadoxine-Pyrimethamine and oral Artesunate monotherapy. Most PMV were ignorant of and lacked training about new treatment guidelines that had endorsed ACTs as first-line treatment for uncomplicated malaria. CONCLUSION: There is urgent need to regularly monitor and improve the availability and quality of malaria treatment provided by medicine sellers in Nigeria; the irrational use of antimalarials in the ACT era revealed in this study bears a high risk of economic loss, death and development of drug resistance. LQAS has been shown to be a suitable method for monitoring malaria-related indicators among PMV, and should be

  15. Design and evaluation of antimalarial peptides derived from prediction of short linear motifs in proteins related to erythrocyte invasion.

    Alessandra Bianchin

    Full Text Available The purpose of this study was to investigate the blood stage of the malaria causing parasite, Plasmodium falciparum, to predict potential protein interactions between the parasite merozoite and the host erythrocyte and design peptides that could interrupt these predicted interactions. We screened the P. falciparum and human proteomes for computationally predicted short linear motifs (SLiMs in cytoplasmic portions of transmembrane proteins that could play roles in the invasion of the erythrocyte by the merozoite, an essential step in malarial pathogenesis. We tested thirteen peptides predicted to contain SLiMs, twelve of them palmitoylated to enhance membrane targeting, and found three that blocked parasite growth in culture by inhibiting the initiation of new infections in erythrocytes. Scrambled peptides for two of the most promising peptides suggested that their activity may be reflective of amino acid properties, in particular, positive charge. However, one peptide showed effects which were stronger than those of scrambled peptides. This was derived from human red blood cell glycophorin-B. We concluded that proteome-wide computational screening of the intracellular regions of both host and pathogen adhesion proteins provides potential lead peptides for the development of anti-malarial compounds.

  16. Antimalarial activity of novel 4-cyano-3-methylisoquinoline inhibitors against Plasmodium falciparum: design, synthesis and biological evaluation.

    Buskes, Melissa J; Harvey, Katherine L; Richards, Benjamin J; Kalhor, Robabeh; Christoff, Rebecca M; Gardhi, Chamodi K; Littler, Dene R; Cope, Elliott D; Prinz, Boris; Weiss, Greta E; O'Brien, Nathan J; Crabb, Brendan S; Deady, Leslie W; Gilson, Paul R; Abbott, Belinda M

    2016-05-18

    Central to malaria pathogenesis is the invasion of human red blood cells by Plasmodium falciparum parasites. Following each cycle of intracellular development and replication, parasites activate a cellular program to egress from their current host cell and invade a new one. The orchestration of this process critically relies upon numerous organised phospho-signaling cascades, which are mediated by a number of central kinases. Parasite kinases are emerging as novel antimalarial targets as they have diverged sufficiently from their mammalian counterparts to allow selectable therapeutic action. Parasite protein kinase A (PfPKA) is highly expressed late in the cell cycle of the parasite blood stage and has been shown to phosphorylate a critical invasion protein, Apical Membrane Antigen 1. This enzyme could therefore be a valuable drug target so we have repurposed a substituted 4-cyano-3-methylisoquinoline that has been shown to inhibit rat PKA with the goal of targeting PfPKA. We synthesised a novel series of compounds and, although many potently inhibit the growth of chloroquine sensitive and resistant strains of P. falciparum, they were found to have minimal activity against PfPKA, indicating that they likely have another target important to parasite cytokinesis and invasion. PMID:27105169

  17. Assay method for quality control and stability studies of a new antimalarial agent (CDRI 99/411)$

    Kiran Khandelwal; Shakti Deep Pachauri; Sofia Zaidi; Pankaj Dwivedi; Ashok Kumar Sharma; Chandan Singh; Anil Kumar Dwivedi

    2013-01-01

    CDRI compound no. 99/411 is a potent 1,2,4-trioxane antimalarial candidate drug under development at our Institute. An HPLC method for determination of CDRI 99/411 with its starting material and intermediates has been developed and validated for in process quality control and stability studies. The analytical performance parameters such as linearity, precision, accuracy, specificity, limit of detection (LOD) and lower limit of quantification (LLOQ) were determined according to International Conference on Harmonization ICH Q2(R1) guidelines. HPLC separation was achieved on a RP-select B Lichrospheres column (250 mm  4 mm, 5μm, Merck) using water containing 0.1%glacial acetic acid and acetonitrile as the mobile phase in a gradient elution. The eluents were monitored by a photo diode array detector at 245 and 275 nm. Based on signal to noise ratio of 3 and 10 the LOD of CDRI 99/411 was 0.55 mg/mL, while the LLOQ was 1.05 mg/mL. The calibration curves were linear in the range of 1.05-68 mg/mL. Precision of the method was determined by inter- and intra-assay variations within the acceptable range.

  18. Solution NMR characterization of apical membrane antigen 1 and small molecule interactions as a basis for designing new antimalarials.

    Krishnarjuna, Bankala; Lim, San Sui; Devine, Shane M; Debono, Cael O; Lam, Raymond; Chandrashekaran, Indu R; Jaipuria, Garima; Yagi, Hiromasa; Atreya, Hanudatta S; Scanlon, Martin J; MacRaild, Christopher A; Scammells, Peter J; Norton, Raymond S

    2016-06-01

    Plasmodium falciparum apical membrane antigen 1 (PfAMA1) plays an important role in the invasion by merozoites of human red blood cells during a malaria infection. A key region of PfAMA1 is a conserved hydrophobic cleft formed by 12 hydrophobic residues. As anti-apical membrane antigen 1 antibodies and other inhibitory molecules that target this hydrophobic cleft are able to block the invasion process, PfAMA1 is an attractive target for the development of strain-transcending antimalarial agents. As solution nuclear magnetic resonance spectroscopy is a valuable technique for the rapid characterization of protein-ligand interactions, we have determined the sequence-specific backbone assignments for PfAMA1 from two P. falciparum strains, FVO and 3D7. Both selective labelling and unlabelling strategies were used to complement triple-resonance experiments in order to facilitate the assignment process. We have then used these assignments for mapping the binding sites for small molecules, including benzimidazoles, pyrazoles and 2-aminothiazoles, which were selected on the basis of their affinities measured from surface plasmon resonance binding experiments. Among the compounds tested, benzimidazoles showed binding to a similar region on both FVO and 3D7 PfAMA1, suggesting that these compounds are promising scaffolds for the development of novel PfAMA1 inhibitors. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26804042

  19. 1,2-Substituted 4-(1H-Quinolones: Synthesis, Antimalarial and Antitrypanosomal Activities in Vitro

    Abraham Wube

    2014-09-01

    Full Text Available A diverse array of 4-(1H-quinolone derivatives bearing substituents at positions 1 and 2 were synthesized and evaluated for antiprotozoal activities against Plasmodium falciparum and Trypanosoma brucei rhodesiense, and cytotoxicity against L-6 cells in vitro. Furthermore, selectivity indices were also determined for both parasites. All compounds tested showed antimalarial activity at low micromolar concentrations, with varied degrees of selectivity against L-6 cells. Compound 5a was found to be the most active against P. falciparum, with an IC50 value of 90 nM and good selectivity for the malarial parasite compared to the L-6 cells. Compound 10a, on the other hand, showed a strong antitrypanosomal effect with an IC50 value of 1.25 µM. In this study side chain diversity was explored by varying the side chain length and substitution pattern on the aliphatic group at position-2 and a structure-antiprotozoal activity study revealed that the aromatic ring introduced at C-2 contributed significantly to the antiprotozoal activities.

  20. Quantitative structure-activity relationships of the antimalarial agent artemisinin and some of its derivatives - a DFT approach.

    Rajkhowa, Sanchaita; Hussain, Iftikar; Hazarika, Kalyan K; Sarmah, Pubalee; Deka, Ramesh Chandra

    2013-09-01

    Artemisinin form the most important class of antimalarial agents currently available, and is a unique sesquiterpene peroxide occurring as a constituent of Artemisia annua. Artemisinin is effectively used in the treatment of drug-resistant Plasmodium falciparum and because of its rapid clearance of cerebral malaria, many clinically useful semisynthetic drugs for severe and complicated malaria have been developed. However, one of the major disadvantages of using artemisinins is their poor solubility either in oil or water and therefore, in order to overcome this difficulty many derivatives of artemisinin were prepared. A comparative study on the chemical reactivity of artemisinin and some of its derivatives is performed using density functional theory (DFT) calculations. DFT based global and local reactivity descriptors, such as hardness, chemical potential, electrophilicity index, Fukui function, and local philicity calculated at the optimized geometries are used to investigate the usefulness of these descriptors for understanding the reactive nature and reactive sites of the molecules. Multiple regression analysis is applied to build up a quantitative structure-activity relationship (QSAR) model based on the DFT based descriptors against the chloroquine-resistant, mefloquine-sensitive Plasmodium falciparum W-2 clone. PMID:23597248

  1. Aqueous Root Extract of the Anti-Malarial Herbal Cryptolepis sangunolenta (Lindl Schltr Inhibits Ovulation in Rabbits

    Charles Ansah

    2012-10-01

    Full Text Available The objective of the present study was to assess the effect of the aqueous root extract of Cryptolepis sanguinolenta (cryptolepis, a popular West Africa antimalarial agent on ovulation in rabbits. We demonstrated previously that the aqueous root extract of the plant inhibits reproduction and foetal development in mice. The possible mechanism involved in this reproductive effect and whether the effect is species dependent has yet to be elucidated. Using the rabbit, the present study examined the effect of cryptolepis on pre and post ovulatory events to explore further the mechanism of the reproductive toxicity of cryptolepis. Cryptolepis (62.5-500 mg/kg; p.o administered five hours before ovulation inhibited ovulation in rabbits as ovarian histology showed dilated but unraptured ovum. The effects of cryptolepis were similar to diclofenac, an NSAID used as a reference drug. Post ovulatory treatment with cryptolepis (62.5-500 mg/kg; p.o had little effect on ovarian histology but decreased the implantation index. This study shows that the anti-conceptive effects of cryptolepis involve inhibition of ovulation and early post ovulatory events in the rabbit.

  2. How is childhood development of immunity to Plasmodium falciparum enhanced by certain antimalarial interventions?

    Schellenberg David

    2007-12-01

    Full Text Available Abstract The development of acquired protective immunity to Plasmodium falciparum infection in young African children is considered in the context of three current strategies for malaria prevention: insecticide-impregnated bed nets or curtains, anti-sporozoite vaccines and intermittent preventive therapy. Evidence is presented that each of these measures may permit attenuated P. falciparum blood-stage infections, which do not cause clinical malaria but can act as an effective blood-stage "vaccine". It is proposed that the extended serum half-life, and rarely considered liver-stage prophylaxis provided by the anti-folate combination sulphadoxine-pyrimethamine frequently lead to such attenuated infections in high transmission areas, and thus contribute to the sustained protection from malaria observed among children receiving the combination as intermittent preventative therapy or for parasite clearance in vaccine trials.

  3. Enhanced Antimalarial Activity by a Novel Artemether-Lumefantrine Lipid Emulsion for Parenteral Administration

    Ma, Yufan; Lu, Tingli; Zhao, Wen; Wang, Ying(School of Physics, Shandong University, Jinan, 250100, PR China); Chen, Ting; Mei, Qibing; Chen, Tao

    2014-01-01

    Artemether and lumefantrine (also known as benflumetol) are difficult to formulate for parenteral administration because of their low aqueous solubility. Cremophor EL as an emulsion excipient has been shown to cause serious side effects. This study reports a method of preparation and the therapeutic efficacies of novel lipid emulsion (LE) delivery systems with artemether, lumefantrine, or artemether in combination with lumefantrine, for parenteral administration. Their physical and chemical s...

  4. Research influence on antimalarial drug policy change in Tanzania: case study of replacing chloroquine with sulfadoxine-pyrimethamine as the first-line drug

    Gonzalez-Block Miguel A

    2005-10-01

    Full Text Available Abstract Introduction Research is an essential tool in facing the challenges of scaling up interventions and improving access to services. As in many other countries, the translation of research evidence into drug policy action in Tanzania is often constrained by poor communication between researchers and policy decision-makers, individual perceptions or attitudes towards the drug and hesitation by some policy decision-makers to approve change when they anticipate possible undesirable repercussions should the policy change as proposed. Internationally, literature on the role of researchers on national antimalarial drug policy change is limited. Objectives To describe the (a role of researchers in producing evidence that influenced the Tanzanian government replace chloroquine (CQ with sulfadoxine-pyrimethamine (SP as the first-line drug and the challenges faced in convincing policy-makers, general practitioners, pharmaceutical industry and the general public on the need for change (b challenges ahead before a new drug combination treatment policy is introduced in Tanzania. Methods In-depth interviews were held with national-level policy-makers, malaria control programme managers, pharmaceutical officers, general medical practitioners, medical research library and publications officers, university academicians, heads of medical research institutions and district and regional medical officers. Additional data were obtained through a review of malaria drug policy documents and participant observations were also done. Results In year 2001, the Tanzanian Government officially changed its malaria treatment policy guidelines whereby CQ – the first-line drug for a long time was replaced with SP. This policy decision was supported by research evidence indicating parasite resistance to CQ and clinical CQ treatment failure rates to have reached intolerable levels as compared to SP and amodiaquine (AQ. Research also indicated that since SP was also facing

  5. Cheminformatics Based Machine Learning Models for AMA1-RON2 Abrogators for Inhibiting Plasmodium falciparum Erythrocyte Invasion.

    Maindola, Priyank; Jamal, Salma; Grover, Abhinav

    2015-10-01

    Malaria remains a dreadful disease by putting every year about 3.4 billion people at risk and resulting into mortality of 627 thousand people worldwide. Existing therapies based upon Quinines and Artemisinin-based combination therapies have started showing resistance, pressing the need for search of anti-malarials with different mechanisms of action. In this respect erythrocyte invasion by Plasmodium is immensely crucial, as being obligate intracellular parasite it must invade host cells. This process is mediated by interaction between conserved Apical Membrane Antigen (AMA1) and Rhoptry Neck (RON2) protein, which is compulsory for successful invasion of erythrocyte by Plasmodium and manifestation of the disease Malaria. Here, using the physicochemical properties of the compounds available from a confirmatory high throughput screening, which were tested for their disruption capability of this crucial molecular interaction, we trained supervised classifiers and validated their robustness by various statistical parameters. Best model was used for screening new compounds from Traditional Chinese Medicine Database. Some of the best hits already find their use as anti-malarials and the model predicts that an essential part of their effectiveness is likely due to inhibition of AMA1-RON2 interaction. Pharmacophoric features have also been identified to ease further designing of possible leads in an effective way. PMID:27490966

  6. MALARIA AND HIV IN ADULTS: When The Parasite runs into The Virus

    Emanuele Focà

    2012-05-01

    Full Text Available Malaria and HIV/AIDS are among the principal causes of morbidity and mortality worldwide, particularly in resource-limited settings such as sub-Saharan Africa. Despite the international community’s efforts to reduce incidence and prevalence of these diseases, they remain a global public health problem. Clinical manifestations of malaria may be more severe in HIV infected patients, which have higher risks of severe malaria and malaria related death. Co-infected pregnant women, children and international travelers from non-malaria endemic countries are at higher risk of clinical complications. However, there is a paucity and conflicting data regarding malaria and HIV co-infection, particularly on how HIV infection can modify the response to antimalarial drugs and about drug-interactions between antiretroviral agents and artemisinin-based combined regimens. Moreover, consulting HIV-infected international travelers and physicians specialized in HIV care and travel medicine should prescribe an adequate chemoprophylaxis in patients travelling towards malaria endemic areas and pay attention on interactions between antiretrovirals and antimalarial prophylaxis drugs in order to prevent clinical complications of this co-infection. This review aims to evaluate the available international literature on malaria and HIV co-infection in adults providing a critical comprehensive review of nowadays knowledge.

  7. MALARIA AND HIV IN ADULTS: When The Parasite runs into The Virus

    Emanuele Focà

    2012-01-01

    Full Text Available

    Malaria and HIV/AIDS are among the principal causes of morbidity and mortality worldwide, particularly in resource-limited settings such as sub-Saharan Africa. Despite the international community’s efforts to reduce incidence and prevalence of these diseases, they remain a global public health problem. Clinical manifestations of malaria may be more severe in HIV infected patients, which have higher risks of severe malaria and malaria related death. Co-infected pregnant women, children and international travelers from non-malaria endemic countries are at higher risk of clinical complications. However, there is a paucity and conflicting data regarding malaria and HIV co-infection, particularly on how HIV infection can modify the response to antimalarial drugs and about drug-interactions between antiretroviral agents and artemisinin-based combined regimens. Moreover, consulting HIV-infected international travelers and physicians specialized in HIV care and travel medicine should prescribe an adequate chemoprophylaxis in patients travelling towards malaria endemic areas and pay attention on interactions between antiretrovirals and antimalarial prophylaxis drugs in order to prevent clinical complications of this co-infection.

    This review aims to evaluate the available international literature on malaria and HIV co-infection in adults providing a critical comprehensive review of nowadays knowledge.

  8. Helichrysum gymnocephalum Essential Oil: Chemical Composition and Cytotoxic, Antimalarial and Antioxidant Activities, Attribution of the Activity Origin by Correlations

    François Couderc

    2011-09-01

    Full Text Available Helichrysum gymnocephalum essential oil (EO was prepared by hydrodistillation of its leaves and characterized by GC-MS and quantified by GC-FID. Twenty three compounds were identified. 1,8-Cineole (47.4%, bicyclosesquiphellandrene (5.6%, γ-curcumene (5.6%, α-amorphene (5.1% and bicyclogermacrene (5% were the main components. Our results confirmed the important chemical variability of H. gymnocephalum. The essential oil was tested in vitro for cytotoxic (on human breast cancer cells MCF-7, antimalarial (Plasmodium falciparum: FcB1-Columbia strain, chloroquine-resistant and antioxidant (ABTS and DPPH assays activities. H. gymnocephalum EO was found to be active against MCF-7 cells, with an IC50 of 16 ± 2 mg/L. The essential oil was active against P. falciparum (IC50 = 25 ± 1 mg/L. However, the essential oil exhibited a poor antioxidant activity in the DPPH (IC50 value > 1,000 mg/L and ABTS (IC50 value = 1,487.67 ± 47.70 mg/L assays. We have reviewed the existing results on the anticancer activity of essential oils on MCF-7 cell line and on their antiplasmodial activity against the P. falciparum. The aim was to establish correlations between the identified compounds and their biological activities (antiplasmodial and anticancer. β-Selinene (R² = 0.76, α-terpinolene (R² = 0.88 and aromadendrene (R² = 0.90 presented a higher relationship with the anti-cancer activity. However, only calamenene (R² = 0.70 showed a significant correlation for the antiplasmodial activity.

  9. Na+ Influx Induced by New Antimalarials Causes Rapid Alterations in the Cholesterol Content and Morphology of Plasmodium falciparum.

    Sudipta Das

    2016-05-01

    Full Text Available Among the several new antimalarials discovered over the past decade are at least three clinical candidate drugs, each with a distinct chemical structure, that disrupt Na+ homeostasis resulting in a rapid increase in intracellular Na+ concentration ([Na+]i within the erythrocytic stages of Plasmodium falciparum. At present, events triggered by Na+ influx that result in parasite demise are not well-understood. Here we report effects of two such drugs, a pyrazoleamide and a spiroindolone, on intraerythrocytic P. falciparum. Within minutes following the exposure to these drugs, the trophozoite stage parasite, which normally contains little cholesterol, was made permeant by cholesterol-dependent detergents, suggesting it acquired a substantial amount of the lipid. Consistently, the merozoite surface protein 1 and 2 (MSP1 and MSP2, glycosylphosphotidylinositol (GPI-anchored proteins normally uniformly distributed in the parasite plasma membrane, coalesced into clusters. These alterations were not observed following drug treatment of P. falciparum parasites adapted to grow in a low [Na+] growth medium. Both cholesterol acquisition and MSP1 coalescence were reversible upon the removal of the drugs, implicating an active process of cholesterol exclusion from trophozoites that we hypothesize is inhibited by high [Na+]i. Electron microscopy of drug-treated trophozoites revealed substantial morphological changes normally seen at the later schizont stage including the appearance of partial inner membrane complexes, dense organelles that resemble "rhoptries" and apparent nuclear division. Together these results suggest that [Na+]i disruptor drugs by altering levels of cholesterol in the parasite, dysregulate trophozoite to schizont development and cause parasite demise.

  10. Post-marketing assessment of content and efficacy of preservatives in artemisinin-derived antimalarial dry suspensions for paediatric use

    Plaizier-Vercammen Jacqueline

    2007-01-01

    Full Text Available Abstract Background Artemisinin-derivative formulations are now widely used to treat falciparum malaria. However, the dry powder suspensions developed for children are few and/or are of poor quality. In addition to the active compound, the presence of a suitable preservative in these medicines is essential. In this study, an evaluation of the preservative content and efficacy in some dry suspensions available on the Kenyan market was performed. Method UV spectrophotometry was used to identify the preservatives in each sample while HPLC-UV was used for quantification. After reconstitution of the powders in water, the dissolution of the preservatives was followed for 7 days. Antimicrobial efficacy of the preservatives was assessed by conducting a preservative efficacy test (PET following the European pharmacopoeia standards. Results Four different preservatives were identified namely methylparahydroxybenzoate (MP, propylparahydroxybenzoate (PP, benzoic acid and sorbic acid. MP and PP were identified in Artesiane® (artemether 300 mg/100 ml, Alaxin® (dihydroartemisinin 160 mg/80 ml andGvither ® (artemether 300 mg/100 ml respectively. Sorbic acid was presentin Artenam® (artemether 180 mg/60 ml while benzoic acid was identified in Santecxin® (dihydroartemisinin 160 mg/80 ml andArtexin® (dihydroartemisinin 160 mg/80 ml respectively. Cotecxin® (dihydroartemisinin 160 mg/80 ml did not contain any of the above preservatives. After reconstitution in water, preservativesin 50%(3/6 of the products did not completely dissolve and the PET results revealed that only Artenam® and Gvither® met the requirements for antimicrobial efficacy. The other products did not conform. Conclusion These results show that paediatric antimalarial dry powder formulations on the market may contain ineffective or incorrect amounts of preservatives. This is a potential risk to the patient. Studies conducted on the dry powder suspensions should include the analysis of both

  11. A Quantitative Documentation of the Composition of Two Powdered Herbal Formulations (Antimalarial and Haematinic Using Ethnomedicinal Information from Ogbomoso, Nigeria

    Adepoju Tunde Joseph Ogunkunle

    2014-01-01

    Full Text Available The safety of many African traditional herbal remedies is doubtful due to lack of standardization. This study therefore attempted to standardize two polyherbal formulations from Ogbomoso, Oyo State, Nigeria, with respect to the relative proportions (weight-for-weight of their botanical constituents. Information supplied by 41 local herbal practitioners was statistically screened for consistency and then used to quantify the composition of antimalarial (Maloff-HB and haematinic (Haematol-B powdered herbal formulations with nine and ten herbs, respectively. Maloff-HB contained the stem bark of Enantia chlorantha Oliv. (30.0, Alstonia boonei De Wild (20.0, Mangifera indica L. (10.0, Okoubaka aubrevillei Phelleg & Nomand (8.0, Pterocarpus osun Craib (4.0, root bark of Calliandra haematocephala Hassk (10.0, Sarcocephalus latifolius (J. E. Smith E. A. Bruce (8.0, Parquetina nigrescens (Afz. Bullock (6.0, and the vines of Cassytha filiformis L. (4.0, while Haematol-B was composed of the leaf sheath of Sorghum bicolor Moench (30.0, fruit calyx of Hibiscus sabdariffa L. (20.0, stem bark of Theobroma cacao L. (10.0, Khaya senegalensis (Desr. A. Juss (5.5, Mangifera indica (5.5, root of Aristolochia ringens Vahl. (7.0, root bark of Sarcocephalus latifolius (5.5, Uvaria chamae P. Beauv. (5.5, Zanthoxylum zanthoxyloides (Lam. Zepern & Timler (5.5, and seed of Garcinia kola Heckel (5.5. In pursuance of their general acceptability, the two herbal formulations are recommended for their pharmaceutical, phytochemical, and microbial qualities.

  12. A quantitative documentation of the composition of two powdered herbal formulations (antimalarial and haematinic) using ethnomedicinal information from ogbomoso, Nigeria.

    Ogunkunle, Adepoju Tunde Joseph; Oyelakin, Tosin Mathew; Enitan, Abosede Oluwaseyi; Oyewole, Funmilayo Elizabeth

    2014-01-01

    The safety of many African traditional herbal remedies is doubtful due to lack of standardization. This study therefore attempted to standardize two polyherbal formulations from Ogbomoso, Oyo State, Nigeria, with respect to the relative proportions (weight-for-weight) of their botanical constituents. Information supplied by 41 local herbal practitioners was statistically screened for consistency and then used to quantify the composition of antimalarial (Maloff-HB) and haematinic (Haematol-B) powdered herbal formulations with nine and ten herbs, respectively. Maloff-HB contained the stem bark of Enantia chlorantha Oliv. (30.0), Alstonia boonei De Wild (20.0), Mangifera indica L. (10.0), Okoubaka aubrevillei Phelleg & Nomand (8.0), Pterocarpus osun Craib (4.0), root bark of Calliandra haematocephala Hassk (10.0), Sarcocephalus latifolius (J. E. Smith) E. A. Bruce (8.0), Parquetina nigrescens (Afz.) Bullock (6.0), and the vines of Cassytha filiformis L. (4.0), while Haematol-B was composed of the leaf sheath of Sorghum bicolor Moench (30.0), fruit calyx of Hibiscus sabdariffa L. (20.0), stem bark of Theobroma cacao L. (10.0), Khaya senegalensis (Desr.) A. Juss (5.5), Mangifera indica (5.5), root of Aristolochia ringens Vahl. (7.0), root bark of Sarcocephalus latifolius (5.5), Uvaria chamae P. Beauv. (5.5), Zanthoxylum zanthoxyloides (Lam.) Zepern & Timler (5.5), and seed of Garcinia kola Heckel (5.5). In pursuance of their general acceptability, the two herbal formulations are recommended for their pharmaceutical, phytochemical, and microbial qualities. PMID:24701246

  13. Structural mapping of the ClpB ATPases of Plasmodium falciparum: Targeting protein folding and secretion for antimalarial drug design.

    AhYoung, Andrew P; Koehl, Antoine; Cascio, Duilio; Egea, Pascal F

    2015-09-01

    Caseinolytic chaperones and proteases (Clp) belong to the AAA+ protein superfamily and are part of the protein quality control machinery in cells. The eukaryotic parasite Plasmodium falciparum, the causative agent of malaria, has evolved an elaborate network of Clp proteins including two distinct ClpB ATPases. ClpB1 and ClpB2 are involved in different aspects of parasitic proteostasis. ClpB1 is present in the apicoplast, a parasite-specific and plastid-like organelle hosting various metabolic pathways necessary for parasite growth. ClpB2 localizes to the parasitophorous vacuole membrane where it drives protein export as core subunit of a parasite-derived protein secretion complex, the Plasmodium Translocon of Exported proteins (PTEX); this process is central to parasite virulence and survival in the human host. The functional associations of these two chaperones with parasite-specific metabolism and protein secretion make them prime drug targets. ClpB proteins function as unfoldases and disaggregases and share a common architecture consisting of four domains-a variable N-terminal domain that binds different protein substrates, followed by two highly conserved catalytic ATPase domains, and a C-terminal domain. Here, we report and compare the first crystal structures of the N terminal domains of ClpB1 and ClpB2 from Plasmodium and analyze their molecular surfaces. Solution scattering analysis of the N domain of ClpB2 shows that the average solution conformation is similar to the crystalline structure. These structures represent the first step towards the characterization of these two malarial chaperones and the reconstitution of the entire PTEX to aid structure-based design of novel anti-malarial drugs. PMID:26130467

  14. Helichrysum gymnocephalum essential oil: chemical composition and cytotoxic, antimalarial and antioxidant activities, attribution of the activity origin by correlations.

    Afoulous, Samia; Ferhout, Hicham; Raoelison, Emmanuel Guy; Valentin, Alexis; Moukarzel, Béatrice; Couderc, François; Bouajila, Jalloul

    2011-01-01

    Helichrysum gymnocephalum essential oil (EO) was prepared by hydrodistillation of its leaves and characterized by GC-MS and quantified by GC-FID. Twenty three compounds were identified. 1,8-Cineole (47.4%), bicyclosesquiphellandrene (5.6%), γ-curcumene (5.6%), α-amorphene (5.1%) and bicyclogermacrene (5%) were the main components. Our results confirmed the important chemical variability of H. gymnocephalum. The essential oil was tested in vitro for cytotoxic (on human breast cancer cells MCF-7), antimalarial (Plasmodium falciparum: FcB1-Columbia strain, chloroquine-resistant) and antioxidant (ABTS and DPPH assays) activities. H. gymnocephalum EO was found to be active against MCF-7 cells, with an IC(50) of 16 ± 2 mg/L. The essential oil was active against P. falciparum (IC(50) = 25 ± 1 mg/L). However, the essential oil exhibited a poor antioxidant activity in the DPPH (IC(50) value > 1,000 mg/L) and ABTS (IC(50) value = 1,487.67 ± 47.70 mg/L) assays. We have reviewed the existing results on the anticancer activity of essential oils on MCF-7 cell line and on their antiplasmodial activity against the P. falciparum. The aim was to establish correlations between the identified compounds and their biological activities (antiplasmodial and anticancer). β-Selinene (R² = 0.76), α-terpinolene (R² = 0.88) and aromadendrene (R² = 0.90) presented a higher relationship with the anti-cancer activity. However, only calamenene (R² = 0.70) showed a significant correlation for the antiplasmodial activity. PMID:21959299

  15. Gametocyte clearance dynamics following oral artesunate treatment of uncomplicated falciparum malaria in Malian children

    Djimde, Abdoulaye A.; Maiga, Amelia W.; Ouologuem, Dinkorma; Fofana, Bakary; Sagara, Issaka; Dembele, Demba; Toure, Sekou; Sanogo, Kassim; Dama, Souleymane; Sidibe, Bakary; Doumbo, Ogobara K.

    2016-01-01

    Artemisinin-based combination therapies decrease Plasmodium gametocyte carriage. However, the role of artesunate in monotherapy in vivo, the mechanisms involved, and the utility of gametocyte carriage as a potential tool for the surveillance of antimalarial resistance are poorly understood. In 2010–2011, we conducted an open-label, prospective efficacy study of artesunate as monotherapy in children 1–10 years of age with uncomplicated falciparum malaria in Bougoula-Hameau, Mali. Standard oral doses of artesunate were administered for 7 days and patients were followed up for 28 days. The data were compared to a similar study conducted in 2002–2004. Of 100 children enrolled in the 2010–2011 study, 92 were analyzed and compared to 217 children enrolled in the 2002–2004 study. The proportion of gametocyte carriers was unchanged at the end of treatment (23% at baseline vs. 24% on day 7, p = 1.0) and did not significantly decline until day 21 of follow-up (23% vs. 6%, p = 0.003). The mean gametocyte density at inclusion remained unchanged at the end of treatment (12 gametocytes/μL vs. 16 gametocytes/μL, p = 0.6). Overall, 46% of the 71 initial non-carriers had gametocytes detected by day 7. Similar results were found in the 2002–2004 study. In both studies, although gametocyte carriage significantly decreased by the end of the 28-day follow-up, artesunate did not clear mature gametocytes during treatment and did not prevent the appearance of new stage V gametocytes as assessed by light microscopy. Baseline gametocyte carriage was significantly higher 6 years after the deployment of artemisinin-based combination therapies in this setting. PMID:26839003

  16. Gametocyte clearance dynamics following oral artesunate treatment of uncomplicated falciparum malaria in Malian children

    Djimde Abdoulaye A.

    2016-01-01

    Full Text Available Artemisinin-based combination therapies decrease Plasmodium gametocyte carriage. However, the role of artesunate in monotherapy in vivo, the mechanisms involved, and the utility of gametocyte carriage as a potential tool for the surveillance of antimalarial resistance are poorly understood. In 2010–2011, we conducted an open-label, prospective efficacy study of artesunate as monotherapy in children 1–10 years of age with uncomplicated falciparum malaria in Bougoula-Hameau, Mali. Standard oral doses of artesunate were administered for 7 days and patients were followed up for 28 days. The data were compared to a similar study conducted in 2002–2004. Of 100 children enrolled in the 2010–2011 study, 92 were analyzed and compared to 217 children enrolled in the 2002–2004 study. The proportion of gametocyte carriers was unchanged at the end of treatment (23% at baseline vs. 24% on day 7, p = 1.0 and did not significantly decline until day 21 of follow-up (23% vs. 6%, p = 0.003. The mean gametocyte density at inclusion remained unchanged at the end of treatment (12 gametocytes/μL vs. 16 gametocytes/μL, p = 0.6. Overall, 46% of the 71 initial non-carriers had gametocytes detected by day 7. Similar results were found in the 2002–2004 study. In both studies, although gametocyte carriage significantly decreased by the end of the 28-day follow-up, artesunate did not clear mature gametocytes during treatment and did not prevent the appearance of new stage V gametocytes as assessed by light microscopy. Baseline gametocyte carriage was significantly higher 6 years after the deployment of artemisinin-based combination therapies in this setting.

  17. Use of the atmospheric generators for capnophilic bacteria Genbag-CO2 for the evaluation of in vitro Plasmodium falciparum susceptibility to standard anti-malarial drugs

    Travers Dominique

    2011-01-01

    Full Text Available Abstract Background The aim of this study was to evaluate the cultivation system in which the proper atmospheric conditions for growing Plasmodium falciparum parasites were maintained in a sealed bag. The Genbag® system associated with the atmospheric generators for capnophilic bacteria Genbag CO2® was used for in vitro susceptibility test of nine standard anti-malarial drugs and compared to standard incubator conditions. Methods The susceptibility of 36 pre-identified parasite strains from a wide panel of countries was assessed for nine standard anti-malarial drugs (chloroquine, quinine, mefloquine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone and pyrimethamine by the standard 42-hour 3H-hypoxanthine uptake inhibition method using the Genbag CO2® system and compared to controlled incubator conditions (5% CO2 and 10% O2. Results The counts per minute values in the control wells in incubator atmospheric conditions (5% CO2 and 10% O2 were significantly higher than those of Genbag® conditions (2738 cpm vs 2282 cpm, p 50 estimated under the incubator atmospheric conditions was significantly lower for atovaquone (1.2 vs 2.1 nM, p = 0.0011 and higher for the quinolines: chloroquine (127 vs 94 nM, p 50 between the 2 conditions for dihydroartemisinin, doxycycline and pyrimethamine. To reduce this difference in term of anti-malarial susceptibility, a specific cut-off was estimated for each drug under Genbag® conditions by regression. The cut-off was estimated at 77 nM for chloroquine (vs 100 nM in 10% O2, 611 nM for quinine (vs 800 nM, 30 nM for mefloquine (vs 30 nM, 61 nM for monodesethylamodiaquine (vs 80 nM and 1729 nM for pyrimethamine (vs 2000 nM. Conclusions The atmospheric generators for capnophilic bacteria Genbag CO2® is an appropriate technology that can be transferred to the field for epidemiological surveys of drug-resistant malaria. The present data suggest the importance of the gas mixture on in vitro

  18. First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials

    Moehrle, Joerg J; Duparc, Stephan; Siethoff, Christoph; van Giersbergen, Paul L M; Craft, J Carl; Arbe-Barnes, Sarah; Charman, Susan A; Gutierrez, Maria; Wittlin, Sergio; Vennerstrom, Jonathan L.

    2012-01-01

    Aims To assess the safety and pharmacokinetics of a new synthetic ozonide antimalarial, OZ439, in a first-in-man, double-blind study in healthy volunteers. Methods OZ439 was administered as single oral daily doses of a capsule formulation (50–1200 mg) or an oral dispersion (400–1600 mg, fed and fasted states) and for up to 3 days as an oral dispersion (200–800 mg day−1). Plasma concentrations of OZ439 and its metabolites were measured by LC-MS. Results The pharmacokinetic (PK) profile of OZ43...

  19. Exploring QSAR for Antimalarial Activities and Drug Distribution within Blood of a Series of 4-Aminoquinoline Drugs Using Genetic-MLR

    Amir Najafi

    2013-01-01

    Full Text Available Malaria has been one of the most significant public health problems for centuries. QSAR modeling of the antimalarial activity and blood-to-plasma concentration ratio of Chloroquine and a new series of 4-aminoquinoline derivatives were developed using genetic algorithms with multiple linear regression (GA-MLR method. We obtained two different models against Chloroquine-sensitive (3D7 and Chloroquine-resistant (W2 strains of Plasmodium falciparum with good adjustment levels. Drug distribution in blood, defined as drug blood-to-plasma concentration ratio (Rb, is related to molecular descriptors. Leave-many-out (LMO and Y-randomization methods confirmed the models' robustness.

  20. Radical Beckmann Rearrangement and Its Application in the Formal Total Synthesis of Antimalarial Natural Product Isocryptolepine via C-H Activation.

    Mahajan, Pankaj S; Humne, Vivek T; Tanpure, Subhash D; Mhaske, Santosh B

    2016-07-15

    The Beckmann rearrangement of ketoximes, mediated by ammonium persulfate-dimethyl sulfoxide as a reagent, has been achieved under neutral conditions. Based on the radical trapping and (18)O-labeling experiments, the transformation follows a mechanism involving a radical pathway. The scope and generality of the developed protocol has been demonstrated by 19 examples. The developed protocol and Pd-catalyzed intramolecular double C-H activation were used as key steps in the formal total synthesis of antimalarial natural product isocryptolepine. PMID:27377995