The recent advances in drug therapy of malaria are presented here

1. Recent advances in
treatment of Malaria
Dr Naser Tadvi
Associate
Professor, Pharmacology
Kamineni Institute of Medical
Sciences, Narketpally

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. 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. 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
Cycle
Schizogony

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. 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. 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. 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. 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. Combination therapies
• Artemisinin based combination therapy
• Atovaquone/ proguanil
• Amodiaquine/ sulfadoxine/ pyremethamine
• Chlorproguanil / dapsone

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. Artemisinin derivatives
Artemisinin derivatives
Dihydroartemisin
Ethyl Ether Methyl Ether
Arteether Artemether
Qinghaosu
Hemisuccinate
("ching-how-soo") Artesunate

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. 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. Why combination therapy
• Rapid clinical & parasitological cure
• High cure rates and low relapse rates
• Absence of resistance
• Good tolerability profile

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. 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
days
Other ACTs:
– DHA – Piperaquine, Artesunate- pyronaridine

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. 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. Districts in Andhra Pradesh identified for use
of ACT for treatment of pf malaria
• Vizianagaram,
• Vishakapatnam,
• Srikakulam,
• East Godavari
• Khammam
Anonymous: Strategic Action Plan for Malaria in India 2007--2012. Directorate of National Vector Borne
Disease Control Programme (NVBDCP) 22, Sham Nath Marg , Delhi-110054; India

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. 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. J
Ayurveda Integr Med 2012;3:10-6

23. Plants with antimalarial activity
Plant name Family Part Methodology
Acacia farnesiana Tarua kadam (Ass) Bark With quinine stops
remittent fever
Carica Papaya L. Papeya (Beng) Leaf
Cinnamonium Tezpatta Bark and Boiled in water
bejolghota leaf used for bathing ,
also internal use
Citrus medica L. Baranimbu Fruit Juice is used
Citrus sinensis L. Musambi Leaf Decoction is taken
Croton tiglium L. Jaiphal Leaf, Powder taken with
flower glass of water
Datura metel L. Dhatura Seed,
leaf, root
Shankar R, Deb S, Sharma BK. Antimalarial plants of northeast India: An overview. J
Ayurveda Integr Med 2012;3:10-6

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. Drug resistance reversers
• Combining previously effective drugs with
compounds that reverse parasite resistance
– Verapamil
– Desipramine
– Trifluoperazine
– Chlorpheniramine
Hobbs C, Duffy P. Drugs for malaria: something old, something new, something
Borrowed. F1000 Biology Reports 2011, 3:24

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
parasite's resistance to existing drugs and also have antimalarial action
J X Kelly et al, Nature, 2009. DOI: 10.1038/nature07937

27. Compounds active against new
targets
A. Cytosolic targets
Mechanism Target molecule Examples
/pathway Existing New drugs
Folate Dihydrofolate Pyrimethamine Chlorproguanil
metabolism reductase Clociguanil
Dihydropteroate Sulfadoxine
synthetase
Pyrimidine Thymidilate - 5-fluorooraote*
pathway synthetase
Glycolysis Lactate Gossypol
dehydrogenase derivatives
Muregi FW, et.al (2011) PLoS ONE 6(6): e21251. doi:10.1371/journal.pone.0021251

28. Compounds active against new
targets
B. Parasite membrane targets
Mechanism Target Examples
/pathway molecule Existing New drugs
Phospholipid Choline - G25
synthesis transporter
Membrane Unique - Dinucleoside
transport channels phosphate
dimers
Rodolphe R et al 2004. Antimicrob Agents Chemother. 2004 August; 48(8): 2816–24.

29. Compounds active against new
targets
C. Food Vacuole targets
Mechanism Target Examples
/pathway molecule Existing New drugs
Heme Hemozoin Quinolines New quinolines
polymerization
Globin Plasmepsins - Protease
hydrolysis (proteases) inhibitors
Free radical Unknown Artemisinins Artemiside
generation Artemisone
OZ439

30. Compounds active against new
targets
D. Mitochondrial targets
Mechanism Target Examples
/pathway molecule Existing New drugs
Electron Cytochrome c Atovaquone -
transport oxidoreducatse

31. Compounds active against new targets
Chloroplast like organelle in plasmodia functions include
E. Apicoplast
fatty acid, heme and amino acid metabolism
Mechanism Target molecule Examples
/pathway Existing New drugs
Protein synthesis Apicoplast Antibiotics -
ribosome
DNA synthesis DNA gyrase Quinolones
Transcription RNA polymerase Rifampin
Type II Fatty acid Fabh Thiolactomycin
Biosynthesis Fabl Triclosan
Isoprenoid DOXP Fosmidomycin
synthesis reductoisomerase

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. THANK YOU