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Anti malarial models
- 1. EVALUATION OF NEWER ANTIMALARIALS Dr Pruthvi D Final Year PG MD Pharmacology
- 2. History Life cycle Drug development strategy New drugs in pipeline Malaria vaccine
- 3. HISTORY
- 6. CELL BASED SCREENS Blood stage screens: Liver stage screens: Transmission screens SYBR YOYO THE SYTO SERIES PRO- PIDIUM IODIDE ACRIDINE ORANGE THE HOECHST DYE SERIES PICOGREEN
- 8. TRANSMISSION ASSAY Direct feeding assay Membrane feeding assay
- 10. IC 50 of P falciparum blood stages- parasite proliferation assay P vivax blood stage sensitivity- schizont maturation assay Transmission blocking activity- viability of purified gametocytes or ookinetes Ability of gametocytes to infect mosquitoes- standard membrane feeding assay & direct feeding from infected mice assay
- 11. NEW DRUGS IN PIPELINE
- 13. MALARIA VACCINE No human vaccine against protozoal diseases. Species specific. Main targets are P falciparum & P vivax. First vaccine is RTS,S Alternative strategies Attenuated P falciparum sporozoits
- 14. REFERENCES Review Of Antimalarial Drug Discovery ,Anna Caroline C Aguiar Et Al, Mem Inst Oswaldo Cruz, Rio De Janeiro, Vol. 107(7): 831-845, November 2012 . Antimalarial Drug Discovery — Approaches And Progress Towards New Medicines, Erika L. Flannery1, Arnab K. Chatterjee2 And Elizabeth A. Winzeler1 , Nature Reviews , Microbiology ,Volume 11, December 2013 Malaria medicines: a glass half full? , Timothy N. C. Wells1, Rob Hooft van Huijsduijnen1 and Wesley C. Van Voorhis1,2 , Nature Reviews Drug Discovery , May 2015; doi:10.1038/nrd4573 .
Editor's Notes
- 85% of deaths occuring in children below 5 years…highest mortality in africa drastic impact on health care systems n economic growth///WHO global malaria action plan aims at tenfold decrease in malarial deaths by 2030… p knowlesi….infects humans..which is a simian parasite…
- P vivax and ovale- relapses due to hypnozoits.(exo-erythrocytic cycle) P falciparum----cerebral malaria and respiratory distress life-threatening manifestations that are related to iRBC cytoadherence on microvascular endothelial cells), blockage of deep capillaries with neurological symptoms and death.
- the discovery of antimalarials from natural sources, & chemical modifications of existing antimalarials, the development of hybrid compounds, testing of commercially available drugs that have been approved for human use for other diseases & molecular modelling using virtual screening technology and docking targets are proteins essential for the parasite survival n propogation SAR analysis to identify lead compounds
- Incorporation of radioactive hypoxanthine into live parasite DNA……ELISA----to detect LDH& HRP…SYBR- invitro & invivo- less expensive // YOYO– most sensitive detects low levels of parasitemia// SYTO--- binding affinities , Hoescht ---most expensive, Transfected parasited detected by flow cytometry or fluorescence microscopy// green fluorescent protein (GFP)-recombinant Plasmodium berghei and P. falciparum parasites have been successfully used .inhibition of haemozoin----in p falciparum(( cyanine dyes with high affinity to nucleic acids))) first blood stage screens --2008---high throughput screening, 384 or 1536 well format....increase in nucleic acid content...identified by flourescent dna binding dyes 4 million compounds screened through this method till now... 0.1 % showed activity against falciparum facilities for HTS....Malaria box from MMV (medicines for malaria venture) drugs discoved were class of spiroindolones( KAE609)MMv 390048, Ketotifen liver screen----compounds identified were GNF179(imidazolopiperazine class), KAF 156----low throughput assay p cynomolgi Transmission screens: identify the overall atp hydrolysis to measure viability( Gametocyte stage specific GFP tag flow cytometry)
- Involves biochemical assays ex to detect ATP hydrolysis in kinase activity assay…. Disappointing results through this method….target molecules identified using chemical inhibition studies….or by knock down models,…once target selected recombinant protein produced n biochemical assay developed to identify the compounds that inhibit targets function….pyrimithamine proguanil
- ----- Meeting Notes (22/07/15 23:29) ----- severe combined immunodeficient mice ----- Meeting Notes (23/07/15 08:43) ----- gametocyte stage specific GFP tag...detected by flow cytometry
- Primaquine was identified in 1950’s by dosing hundreds of p cynomolgi( hypnozoite producing strains)infected monkeys….vivax cannot be maintained in cell culture…low throughput assayusing p cynomolgi sporozoits from infected monkeys used to infect monkey hepatocytes
- dihydro orotate dehydrogenase....DSM 265...human model.PCR based parasite detection methods....
- Di hydroartemisinin- piperaquine // pyronaridine-artesunate // artesunate- mefloquine // Chemoprophylaxis-----atovaquone-proguanil // mefloquine DSM 265:: human experimentally induced infection model: KAE609: radical cure
- Single exposure radical cure n prophylaxis