Novartis Malaria Initiative: best practice example of pharmaceutical industry's engagement in the fight against malaria

Lefèvre, Gilbert; Marrast, Anne Claire; Grueninger, Heiner

doi:10.1111/j.1749-6632.2011.05973.x

Cited by 7 publications

(5 citation statements)

References 69 publications

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“…Artemether-lumefantrine (AL) (20 mg and 120 mg, respectively) (Coartem©, Novartis Pharm AG) is one of the most popular and efficacious fixed dose of ACT which is currently available [10]. AL was introduced in Tanzania as a first-line therapy for malaria in 2006 to replace sulphadoxine-pyrimethamine (SP) [11].…”

Section: Introductionmentioning

confidence: 99%

Safety of artemether-lumefantrine exposure in first trimester of pregnancy: an observational cohort

Mosha

Mazuguni

Mrema

et al. 2014

Malar J

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BackgroundThere is limited data available regarding safety profile of artemisinins in early pregnancy. They are, therefore, not recommended by WHO as a first-line treatment for malaria in first trimester due to associated embryo-foetal toxicity in animal studies. The study assessed birth outcome among pregnant women inadvertently exposed to artemether-lumefantrine (AL) during first trimester in comparison to those of women exposed to other anti-malarial drugs or no drug at all during the same period of pregnancy.MethodsPregnant women with gestational age <20 weeks were recruited from Maternal Health clinics or from monthly house visits (demographic surveillance), and followed prospectively until delivery.Results2167 pregnant women were recruited and 1783 (82.3%) completed the study until delivery. 319 (17.9%) used anti-malarials in first trimester, of whom 172 (53.9%) used (AL), 78 (24.4%) quinine, 66 (20.7%) sulphadoxine-pyrimethamine (SP) and 11 (3.4%) amodiaquine. Quinine exposure in first trimester was associated with an increased risk of miscarriage/stillbirth (OR 2.5; 1.3–5.1) and premature birth (OR 2.6; 1.3–5.3) as opposed to AL with (OR 1.4; 0.8–2.5) for miscarriage/stillbirth and (OR 0.9; 0.5–1.8) for preterm birth. Congenital anomalies were identified in 4 exposure groups namely AL only (1/164[0.6%]), quinine only (1/70[1.4%]), SP (2/66[3.0%]), and non-anti-malarial exposure group (19/1464[1.3%]).ConclusionExposure to AL in first trimester was more common than to any other anti-malarial drugs. Quinine exposure was associated with adverse pregnancy outcomes which was not the case following other anti-malarial intake. Since AL and quinine were used according to their availability rather than to disease severity, it is likely that the effect observed was related to the drug and not to the disease itself. Even with this caveat, a change of policy from quinine to AL for the treatment of uncomplicated malaria during the whole pregnancy period could be already envisaged.

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Section: Introductionmentioning

confidence: 99%

Safety of artemether-lumefantrine exposure in first trimester of pregnancy: an observational cohort

Mosha

Mazuguni

Mrema

et al. 2014

Malar J

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“…Thankfully, with the investment of funds from organizations such as the Bill and Melinda Gates Foundation, Medicines for Malaria Venture (MMV), the Drugs for Neglected Diseases initiative (DNDi), and the Institute for One World Health (IOWH) this scenario is changing [47], [48]. Now, pharmaceutical giants such as Novartis [49], GSK [50], Pfizer (just to name a few) investing great efforts in the development of novel antimalarials (www.mmv.org/research-development/science-portfolio). However, due to the diversity of parasite species and their complex life cycles, the development of inexpensive and rapid drug screening methods is a constant challenge.…”

Section: Introductionmentioning

confidence: 99%

Functional Expression of Parasite Drug Targets and Their Human Orthologs in Yeast

et al. 2011

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BackgroundThe exacting nutritional requirements and complicated life cycles of parasites mean that they are not always amenable to high-throughput drug screening using automated procedures. Therefore, we have engineered the yeast Saccharomyces cerevisiae to act as a surrogate for expressing anti-parasitic targets from a range of biomedically important pathogens, to facilitate the rapid identification of new therapeutic agents.Methodology/Principal FindingsUsing pyrimethamine/dihydrofolate reductase (DHFR) as a model parasite drug/drug target system, we explore the potential of engineered yeast strains (expressing DHFR enzymes from Plasmodium falciparum, P. vivax, Homo sapiens, Schistosoma mansoni, Leishmania major, Trypanosoma brucei and T. cruzi) to exhibit appropriate differential sensitivity to pyrimethamine. Here, we demonstrate that yeast strains (lacking the major drug efflux pump, Pdr5p) expressing yeast (ScDFR1), human (HsDHFR), Schistosoma (SmDHFR), and Trypanosoma (TbDHFR and TcDHFR) DHFRs are insensitive to pyrimethamine treatment, whereas yeast strains producing Plasmodium (PfDHFR and PvDHFR) DHFRs are hypersensitive. Reassuringly, yeast strains expressing field-verified, drug-resistant mutants of P. falciparum DHFR (Pfdhfr 51I,59R,108N) are completely insensitive to pyrimethamine, further validating our approach to drug screening. We further show the versatility of the approach by replacing yeast essential genes with other potential drug targets, namely phosphoglycerate kinases (PGKs) and N-myristoyl transferases (NMTs).Conclusions/SignificanceWe have generated a number of yeast strains that can be successfully harnessed for the rapid and selective identification of urgently needed anti-parasitic agents.

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“…However, this is changing with the investment of funds from organizations such as the Gates Foundation, Medicines for Malaria Venture, the Drugs for Neglected Diseases initiative and the Institute for One World Health [5,6], and companies such as Novartis [7], GSK [8] and Pfizer. Various groups have developed efficient high-throughput drug-screening methods based on intact parasites [9–12].…”

Section: Introductionmentioning

confidence: 99%

“…There is a pressing need for new treatments targeting these diseases, which have often been neglected because they overwhelmingly or exclusively affect the inhabitants of developing countries [3,4]. However, this is changing with the investment of funds from organizations such as the Gates Foundation, Medicines for Malaria Venture, the Drugs for Neglected Diseases initiative and the Institute for One World Health [5,6], and companies such as Novartis [7], GSK [8] and Pfizer. Various groups have developed efficient high-throughput drug-screening methods based on intact parasites [9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Yeast-based automated high-throughput screens to identify anti-parasitic lead compounds

et al. 2013

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We have developed a robust, fully automated anti-parasitic drug-screening method that selects compounds specifically targeting parasite enzymes and not their host counterparts, thus allowing the early elimination of compounds with potential side effects. Our yeast system permits multiple parasite targets to be assayed in parallel owing to the strains’ expression of different fluorescent proteins. A strain expressing the human target is included in the multiplexed screen to exclude compounds that do not discriminate between host and parasite enzymes. This form of assay has the advantages of using known targets and not requiring the in vitro culture of parasites. We performed automated screens for inhibitors of parasite dihydrofolate reductases, N-myristoyltransferases and phosphoglycerate kinases, finding specific inhibitors of parasite targets. We found that our ‘hits’ have significant structural similarities to compounds with in vitro anti-parasitic activity, validating our screens and suggesting targets for hits identified in parasite-based assays. Finally, we demonstrate a 60 per cent success rate for our hit compounds in killing or severely inhibiting the growth of Trypanosoma brucei, the causative agent of African sleeping sickness.

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Novartis Malaria Initiative: best practice example of pharmaceutical industry's engagement in the fight against malaria

Cited by 7 publications

References 69 publications

Safety of artemether-lumefantrine exposure in first trimester of pregnancy: an observational cohort

Safety of artemether-lumefantrine exposure in first trimester of pregnancy: an observational cohort

Functional Expression of Parasite Drug Targets and Their Human Orthologs in Yeast

Yeast-based automated high-throughput screens to identify anti-parasitic lead compounds

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