Recent advances in treatment of malaria


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  • Reference and add a note of need of drugs
  • New dosing regimens or formulations may optimize activity In case of both artemisinin derivatives and atovaquone, the new agents have had unacceptable failure rates when used as single drugs to treat falciparum malaria, but they have been highly sucessful in combination with other established antimalarials. The second advantage use of combination therapy slows the progression of parasite resistance to new agents. The combination of short acting highly potent compund and a long acting agent may prove effective, if the initial decrease in parasite burden is so greatas to limit subsequent resistance development to the long acting agente.gartesunate/ mefloquine. As other alternative two drugs with similar pharmacokinetics may prove effective even if resistance to each other is present in the community eg (Amodiaquine/s-p). Although a combination regimen sulfadoxine-pyrimethamine looses efficacy once resistance is seen but when combined with amodiaquine excellent antimalarial efficacy in regions of east africa where fairly high levels of resistance to ondividual drug.
  • Artemisinin is the active principle of the plant artimisiaannuaSesquiterpinelactone derivative Most potent and rapid acting blood schizonticides . Short duration of action. high recrudescence rate ,Poorly soluble in water & oil Artimisiaannua is used in chinese traditional medicine as quinghauso as Elicit quicker defervescence and clearing of parasitemia in 48 hours Artemisinin is poorly soluble in water and oil several derivatives have been produced of which 3 are marketed in India Do not kill hypnozoites but have some action on gametocytes of falciparum Adults and children: 25mg/Kg on the first day followed by 12.5mg/Kg on the second and third day in combination with mefloquine (15mg/Kg) in a single dose on the second day. In some areas, a higher dose (25mg/Kg) of mefloquine may be required for a cure to be obtained.
  • Ethyl ether of dihydroartemisininTherapeutically equivalent to quinine in cerebral malaria Available as  arteether and /arteetherARTEMETHER & ARTESUNATE ARE PRODRUGS CONVERTED TO DIHYDROARTEMISININ RESPONSIBLE FOR ACTIVITY
  • Intraparasitic ferrous protoporphyrinIV catalyses breakdown of endoperoxide bridge Chloroquine antagonizes the antimalarial activityIron chelators antagonize antiparasitic effect of artemisinin
  • Artemisinin compounds rapidly kill more than > 95 % of the plasmodia and only leave small biomass of the parasites to be killed by long t1/2 drugsShort half-life; hence good for combinationRapid substantial reduction of the parasite biomassRapid resolution of clinical symptomsEffective action against multi-drug resistant P. falciparumReduction of gametocyte carriageNo documented parasite resistance yetFew reported adverse effects.
  • TetracyclinesSlow but potent action on erythrocytic stage of all MP & Pre-erythrocytic stage of falciparum Always used in combination with quinine or S-P for treatment of chloroquine resistant malaria
  • Most advanced non artemisinin combination in development Dunne, M.W. et al. A multicenter study of azithromycin, alone and in combination with chloroquine, for the treatment of acute uncomplicated Plasmodium falciparum malaria in India. J. Infect. Dis. 191, 1582–1588.
  • In India total 117 districts, 256 PHCs in 48 districts
  • Since halofantrine use is limited by toxicity, the analog lumefantrine was developed and is now component of a new combination co-artemether, new antifolates and endoperoxides related to artemisinin are also under study
  • PfCRT, which actively pumps drug molecules out of the target area, rendering them ineffective.
  • Most innovative approach Purine salvage pathway Francis W. Muregi1,2*, Isao Ohta3, Uchijima Masato1,Hideto Kino4, Akira Ishih1. Resistance of a Rodent Malaria Parasite to a ThymidylateSynthase Inhibitor Induces an Apoptotic Parasite Death and Imposes a Huge Cost of FitnessMuregi FW, Ohta I, Masato U, Kino H, Ishih A (2011) Resistance of a Rodent Malaria Parasite to a ThymidylateSynthase Inhibitor Induces an Apoptotic Parasite Death and Imposes a Huge Cost of Fitness. PLoS ONE 6(6): e21251. doi:10.1371/journal.pone.0021251Penna-Coutinho J, Cortopassi WA, Oliveira AA, França TCC, Krettli AU (2011) Antimalarial Activity of Potential Inhibitors of Plasmodium falciparum Lactate Dehydrogenase Enzyme Selected by Docking Studies. PLoS ONE 6(7): e21237. doi:10.1371/journal.pone.0021237
  • Unraveling the Mode of Action of the AntimalarialCholine Analog G25 in Plasmodium falciparum and SaccharomycescerevisiaeRodolpheRoggero, Rachel Zufferey, MihaelaMinca, Eric Richier, Michele Calas, Henri Vial, Choukri Ben MamounAntimicrob Agents Chemother. 2004 August; 48(8): 2816–2824.
  • Type II fatty acid biosynthesis is absent in humans Fabh: Beta ketoacyl carrier protein synthase is tEnoylacyl carrier protein reductaseDOXP : D oxy d xylulose pathway
  • This is the protein coat of the sporozoite, the parasite stage that is inoculated by feeding anopheline mosquito which then invades liver cells and multiplies there before entering the blood stream
  • Recent advances in treatment of malaria

    1. 1. Recent advances intreatment of Malaria Dr Naser Tadvi Associate Professor, Pharmacology Kamineni Institute of Medical Sciences, Narketpally
    2. 2. Objectives• Life cycle of Malarial Parasite• Currently used drugs• Chloroquine resistant and multidrug resistant malaria• Recent advances in antimalarial drug therapy – Used of combination therapies – analogs of existing agents – Natural products – Compounds active against other diseases – Drug resistance reversers – Compounds active against newer targets
    3. 3. Malaria• Malaria is a protozoal disease caused by infection with parasites of genus Plasmodium and transmitted to man by certain species of infected female Anopheline mosquito• In 2008 there were an estimated 243 million cases of malaria worldwide and it accounted for an estimated 8.63 lac deaths• In 2008 total cases of malaria in India were 1.52 million of these 49.56% (0.76 million) were P.falciparum cases
    4. 4. Life cycle of malarial parasite Oocyst Sporogony Sporozoites Mosquito Salivary Zygote Gland Hypnozoites Exo- (for P. vivax and P. ovale) erythrocytic (hepatic) cycle Gametocytes Erythrocytic CycleSchizogony
    5. 5. Drugs used in treatment of Malaria• Cinchona alkaloids: quinine,quinidine• 4 aminoquinolines: chloroquine, hydroxychloroquine, amodiaquine,• 8 aminoquinolines: primaquine, tafenoquine, bulaquine• quinoline methanol: mefloquine, halofantrine, lumefantrine• Antifolates: – pyrimethamine , proguanil, sulfadoxine• Antibiotics: tetracycline, doxycycline, clindamycin• Hydronaphthoquinone: Atovaquone• Qinghaosu compounds: Artesunate, artemether, arteether
    6. 6. Drug resistant malaria• Definition: – Ability of the parasite species to survive and/or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended• MDR Malaria: – Resistance to 3 or more antimalarials of different chemical classes of which two are 4-aminoquinolines and diaminopyridine
    7. 7. Mechanism of resistance• Efflux of drug by active pump mechanism• ↓ concentration of drug in vacuoles• Crt- Chloroquine resistant transporter & mutations in Pfmdr transporter• Binding of chloroquine with haemoglobin breakdown product to form toxic complexes prevented
    8. 8. Problem status in India• Chloroquine resistance status in India was earlier assessed following the WHO in-vivo protocol. 16,833 P. falciparum cases had been subjected to the protocol till 2002, out of which 77.5% were sensitive to chloroquine, 14.0% resistant at RI level, 4.8% at RII and 3.7% at RIII level.• From 2002-03 onwards, the new WHO protocol on therapeutic efficacy is being followed to assess the efficacy of antimalarial drugs. 4,287 Pf cases have been tested against chloroquine so far, out of which 60.9% have shown Adequate Clinical and Parasitological Response (ACPR), and 39.1% treatment failure have shown either Early Treatment Failure (ETF) or Late treatment Failure (LTF).
    9. 9. Recent advances• Use of existing drugs in combination• Development of analogs of existing drugs• Natural analogs• Compounds active against other diseases• Drug resistance reversers• Compounds active against new targets• Vaccine for malaria
    10. 10. Combination therapies• Artemisinin based combination therapy• Atovaquone/ proguanil• Amodiaquine/ sulfadoxine/ pyremethamine• Chlorproguanil / dapsone
    11. 11. Artemisinin based combination therapy (ACT)• Artemisinin compounds are shorter acting drugs• Monotherapy needs to be extended beyond disappearance of parasite to prevent recrudescence• This can be prevented by combining 3-5 day regimen of artemisin compounds with one long acting drug like mefloquine 15 mg/kg single dose• Indicated by WHO in acute uncomplicated resistant falciparum malaria
    12. 12. Artemisinin derivatives Artemisinin derivatives Dihydroartemisin Ethyl Ether Methyl Ether Arteether Artemether Qinghaosu Hemisuccinate("ching-how-soo") Artesunate
    13. 13. Artemisinin derivatives• Artesunate : Water soluble ester of dihydroartemisinin – can be given oral, IM,IV, rectal Oral Parenteral 100 mg BD on day 1 120 mg on day 1 50 mg BD day 2 to day 5 60 mg OD day 2 to day 5• Artemether: Methyl ether of dihydroartemisinin – Dose: Oral & IM •80 mg BD on day 1 , 80 mg OD day 2 to day 5•Arteether : • A longer t1/2 & more lipophilic than artemether favouring accumulation in brain 150 mg (2 ml amp.) O.D. i.m x 3 days
    14. 14. Mechanism of action• These compounds have presence of endoperoxide bridge• Endoperoxide bridge interacts with heme in parasite• Heme iron cleaves this endoperoxide bridge• There is generation of highly reactive free radicals which damage parasite membrane by covalently binding to membrane proteins
    15. 15. Why combination therapy• Rapid clinical & parasitological cure• High cure rates and low relapse rates• Absence of resistance• Good tolerability profile
    16. 16. ACT Regimens in use• Artesunate – Sulfadoxine, pyrimethamine: – Adopted as first line in india under NMP – ARTESUNATE 100 mg BD for 3 days with S-P, 3 tablets• Artesunate Mefloquine: – By combining artesunate further spread of mefloquine resistance can be prevented – Artesunate 100 mg BD for 3 days, + mefloquine 750 mg on second day & 500 mg on third day
    17. 17. Artemether & lumefantrine• Lumefantrine is highly effective , long acting oral erythrocytic schizonticide related to mefloquine• Highly lipophilic onset delayed , peak 6 hrs• Available as fixed dose combination• 80 mg artemether BD WITH 480 mg lumefantrine BD for 3 daysOther ACTs: – DHA – Piperaquine, Artesunate- pyronaridine
    18. 18. Azithromycin + Chloroquine• Azithromycin 250 + Chloroquine 150 mg – Fixed dose combination for prophylactic use during pregnancy has been developed by Pfizer currently in phase III – 4 tablets should be taken – Phase III data in adults shows high efficacy even in areas where chloroquine resistance is high – Clinical evidence of synergy Ollioro P, Wells TNC. The global portfolio of new antimalarial medicines under development. Nature 2009 ; 85(6):584-95.
    19. 19. Current drug policy in india• According to revised drug policy there is no scope of presumptive treatment in malaria control• The drug policy is changed in areas/block PHCs having 10% or more treatment failure (ETF+LTF) to the currently used antimalarial drug in therapeutic efficacy studies in a minimum sample of 30 patients.• The current National Drug Policy recommends the use of ACT (Artesunate plus Sulfadoxine Pyrimethamine) for treatment of P.falcipuram cases in chloroquine resistant areas/block PHCs.• ACT use is now implemented in 117 high endemic districts of Andhra Pradesh, Chhattisgarh, Jharkhand, Madhya Pradesh, Orissa, Arunachal Pradesh, Assam, Manipur, Meghalaya, Mizoram, Nagaland and Tripura and 256 block PHCs in 48 districts which have reported resistance to chloroquine.
    20. 20. Districts in Andhra Pradesh identified for use of ACT for treatment of pf malaria• Vizianagaram,• Vishakapatnam,• Srikakulam,• East Godavari• KhammamAnonymous: Strategic Action Plan for Malaria in India 2007--2012. Directorate of National Vector BorneDisease Control Programme (NVBDCP) 22, Sham Nath Marg , Delhi-110054; India
    21. 21. Development of analogs of existing drugs• Pyronaridine: – Related to chloroquine developed in china• Tafenoquine: – More active slowly metabolized analog of primaquine, has advantage that it can be given on weekly basis.• Bulaquine: – Congener of primaquine developed in india – Comparable antirelapse activity when used for 5 days – Partly metabolized to primaquine – Better tolerated in G6PD deficiency
    22. 22. Natural products• 68 plant species belonging to 33 families used by people in North East India for treatment of Malaria• Six plant species : Alstonia scholaris, Coptis teeta, Crotolaria occulta, Ocimum sanctum, Polygala persicariaefolia, and Vitex peduncularis, have been reported by more than one worker• The extract of Azadirachta. Indica also used in malaria, Charaka 300 BC and Sushruta 200 BC reported antimalarial and antipyretic activity of these species• Main drugs developed for malaria and used until now (quina alkaloid derived drugs and artemisinin) were discovered based on traditional use and ethnomedical data.Shankar R, Deb S, Sharma BK. Antimalarial plants of northeast India: An overview. JAyurveda Integr Med 2012;3:10-6
    23. 23. Plants with antimalarial activityPlant name Family Part MethodologyAcacia farnesiana Tarua kadam (Ass) Bark With quinine stops remittent feverCarica Papaya L. Papeya (Beng) LeafCinnamonium Tezpatta Bark and Boiled in waterbejolghota leaf used for bathing , also internal useCitrus medica L. Baranimbu Fruit Juice is usedCitrus sinensis L. Musambi Leaf Decoction is takenCroton tiglium L. Jaiphal Leaf, Powder taken with flower glass of waterDatura metel L. Dhatura Seed, leaf, rootShankar R, Deb S, Sharma BK. Antimalarial plants of northeast India: An overview. JAyurveda Integr Med 2012;3:10-6
    24. 24. Compounds active against other diseases• Folate antagonists• Tetracyclines• Atovaquone• Iron chelators Rosenthal PJ. Antimalarial drug discovery: old and new approaches. The Journal of Experimental Biology , 2003. 206:3735-44.
    25. 25. Drug resistance reversers• Combining previously effective drugs with compounds that reverse parasite resistance – Verapamil – Desipramine – Trifluoperazine – ChlorpheniramineHobbs C, Duffy P. Drugs for malaria: something old, something new, somethingBorrowed. F1000 Biology Reports 2011, 3:24
    26. 26. New chemosensitizing agent• Tricyclic acridone molecules with a short alkyl amine chain attached to the central nitrogen atom could make chloroquine-resistant parasites susceptible to the drug again. (Chemo sensitizing action) This action is attributed to blocking the PfCRT pump protein, meaning that the chloroquine can reach its target.• This new class of antimalarial drug have dual role t can reverse the malaria parasites resistance to existing drugs and also have antimalarial action J X Kelly et al, Nature, 2009. DOI: 10.1038/nature07937
    27. 27. Compounds active against new targetsA. Cytosolic targetsMechanism Target molecule Examples/pathway Existing New drugsFolate Dihydrofolate Pyrimethamine Chlorproguanilmetabolism reductase Clociguanil Dihydropteroate Sulfadoxine synthetasePyrimidine Thymidilate - 5-fluorooraote*pathway synthetaseGlycolysis Lactate Gossypol dehydrogenase derivativesMuregi FW, (2011) PLoS ONE 6(6): e21251. doi:10.1371/journal.pone.0021251
    28. 28. Compounds active against new targetsB. Parasite membrane targetsMechanism Target Examples/pathway molecule Existing New drugsPhospholipid Choline - G25synthesis transporterMembrane Unique - Dinucleosidetransport channels phosphate dimers Rodolphe R et al 2004. Antimicrob Agents Chemother. 2004 August; 48(8): 2816–24.
    29. 29. Compounds active against new targetsC. Food Vacuole targetsMechanism Target Examples/pathway molecule Existing New drugsHeme Hemozoin Quinolines New quinolinespolymerizationGlobin Plasmepsins - Proteasehydrolysis (proteases) inhibitorsFree radical Unknown Artemisinins Artemisidegeneration Artemisone OZ439
    30. 30. Compounds active against new targetsD. Mitochondrial targetsMechanism Target Examples/pathway molecule Existing New drugsElectron Cytochrome c Atovaquone -transport oxidoreducatse
    31. 31. Compounds active against new targets Chloroplast like organelle in plasmodia functions includeE. Apicoplast fatty acid, heme and amino acid metabolismMechanism Target molecule Examples/pathway Existing New drugsProtein synthesis Apicoplast Antibiotics - ribosomeDNA synthesis DNA gyrase QuinolonesTranscription RNA polymerase RifampinType II Fatty acid Fabh ThiolactomycinBiosynthesis Fabl TriclosanIsoprenoid DOXP Fosmidomycinsynthesis reductoisomerase
    32. 32. Vaccine for malaria• RTS,S/ASO1 Vaccine – Hybrid construct of the hepatitis B surface antigen fused with a recombinant antigen derived from part of circum sporozoite protein – Primarily for use in infants and ypung children in sub saharan Africa – WHO has already taken the unusual step of indicating that it would recommend this first malaria vaccine for use in some african countries as early as 2015
    33. 33. THANK YOU