1. Dr. Ramamoorthy Hon. Prof. of Medicine & Head Dept. of Medicine Bombay Hospital Institute of Medical Sciences Mumbai Dr. Ramamoorthy Hon. Prof. of Medicine & Head Dept. of Medicine Bombay Hospital Institute of Medical Sciences Mumbai UPDATE ON MALARIA

2. MALARIA Incidence  200 to 300 million worldwide  1 to 2 million deaths Resurgence  Resistance of anopheline vector to DDT  Increasing resistance of PI. Falciparum to chloroquine & other drugs Incidence  200 to 300 million worldwide  1 to 2 million deaths Resurgence  Resistance of anopheline vector to DDT  Increasing resistance of PI. Falciparum to chloroquine & other drugs

3. TYPES OF RESISTANCE IN MALARIA  SSensitive. Parasite clearance in 7 days no recurrence in 28 days  R 1 Parasite clearance in 7 days. Recurrence in 28 days  R 2 > 75% clearance in 48 hrs. Recurrence in 7 days  R 3 < 75% clearance in 48 hrs. Recurrence in 7 days  SSensitive. Parasite clearance in 7 days no recurrence in 28 days  R 1 Parasite clearance in 7 days. Recurrence in 28 days  R 2 > 75% clearance in 48 hrs. Recurrence in 7 days  R 3 < 75% clearance in 48 hrs. Recurrence in 7 days

4. DISTRIBUTION OF RESISTANCE IN INDIA R 3 seen in Assam, Gujarat, Orissa & Rajasthan

5. MALARIA  Staining & identification  Giemsa’s stain preferable to Wright’s stain thick smears about 20 times more sensitive than thin smears because red cells have been lysed (in thick smear identification of species is difficult.)  Effect of parasite on red cell size or positive of parasite within RBC cannot be judged  Hence thin smear is for species identification of the parasite and thick smear is for the presence of the parasite  Staining & identification  Giemsa’s stain preferable to Wright’s stain thick smears about 20 times more sensitive than thin smears because red cells have been lysed (in thick smear identification of species is difficult.)  Effect of parasite on red cell size or positive of parasite within RBC cannot be judged  Hence thin smear is for species identification of the parasite and thick smear is for the presence of the parasite

6.  Gametocytes take 7 to 10 days to develop and hence to rely on the type of gametocyte to diagnose the species of malaria is not advisable  Gametocytes frequently present in blood of semi-immune residents in an endemic area  Double infection with PI. Vivax & PI. Falciparum common  Parasitized red cells are lighter than non parasitized cells and hence on centrifuging a sample of blood in a capillary tube parasitized cells are seen just below the buffy coat  DNA probes have also been used  Gametocytes take 7 to 10 days to develop and hence to rely on the type of gametocyte to diagnose the species of malaria is not advisable  Gametocytes frequently present in blood of semi-immune residents in an endemic area  Double infection with PI. Vivax & PI. Falciparum common  Parasitized red cells are lighter than non parasitized cells and hence on centrifuging a sample of blood in a capillary tube parasitized cells are seen just below the buffy coat  DNA probes have also been used

7. MORTALITY IN MALARIA  Vivax malaria  Rupture of spleen, immunocompromised state, repeated attacks in malnourished patient  Falciparum malaria  Pathogenesis budding, rosette formation, cytoadherence and sequestration  Cerebral malaria, renal involvement, hepatic involvement, pulmonary involvement, severe anemia, shock, hyperthermia, gram negative sepsis, pregnancy, metabolic acidosis, more than 3% parasitemia, DIC, severe vomiting and diarrhoea, infants and non immune subjects  Presence of trophozoites and schizonts in peripheral blood smear  Vivax malaria  Rupture of spleen, immunocompromised state, repeated attacks in malnourished patient  Falciparum malaria  Pathogenesis budding, rosette formation, cytoadherence and sequestration  Cerebral malaria, renal involvement, hepatic involvement, pulmonary involvement, severe anemia, shock, hyperthermia, gram negative sepsis, pregnancy, metabolic acidosis, more than 3% parasitemia, DIC, severe vomiting and diarrhoea, infants and non immune subjects  Presence of trophozoites and schizonts in peripheral blood smear

8. CYTOKINES  TNF alpha increased in severe falciparum malaria  Good correlation of increased TNF alpha levels with incidence of cerebral malaria, pulmonary involvement and sepsis  TNF alpha increased in severe falciparum malaria  Good correlation of increased TNF alpha levels with incidence of cerebral malaria, pulmonary involvement and sepsis

9. ANTIMALARIA DRUGS  Chloroquine – Amodiaquine  Quinine & Quinidine  Sulphonamides & Pyrimethamine  Primaquine  Tetracycline, Doxycycline, Clindamycin, Azithromycin & Quinolones  Chloroquine – Amodiaquine  Quinine & Quinidine  Sulphonamides & Pyrimethamine  Primaquine  Tetracycline, Doxycycline, Clindamycin, Azithromycin & Quinolones  Proguanil  Halofantrine & Mefloquine  Artemisinin  Atovaquone  Benflumentol / Hydroxypiperaquine  Desferixoamine  Proguanil  Halofantrine & Mefloquine  Artemisinin  Atovaquone  Benflumentol / Hydroxypiperaquine  Desferixoamine

10. PRECAUTIONS  Prolonged QT  Mefloquine  Quinine / Quinidine  Halofantrine  Hypokaemia due to vomiting – dangerous arrhythmias including Torsade Prolonged QT also seen in B 1 deficiency (vomiting in 1 st trimester)  Prolonged QT  Mefloquine  Quinine / Quinidine  Halofantrine  Hypokaemia due to vomiting – dangerous arrhythmias including Torsade Prolonged QT also seen in B 1 deficiency (vomiting in 1 st trimester)

11. Artemisin  Action rapid  Prevents parasite development  Prevents rosetting cytoadherance and sequestration  Reduction in gametocyte counts Atovoquone  Against MDR falciparum  High recrudescense rate rapid resistance  Combination with tetracycline / proguanil prevents the problem Artemisin  Action rapid  Prevents parasite development  Prevents rosetting cytoadherance and sequestration  Reduction in gametocyte counts Atovoquone  Against MDR falciparum  High recrudescense rate rapid resistance  Combination with tetracycline / proguanil prevents the problem

12. R 1 = Width of cytoplasm / diameter of nucleus  ½ R 2 = Width of cytoplasm / diameter of nucleus > ½ < 1 R 3 = Width of cytoplasm / diameter of nucleus  1 FSD = ‘Fansidar’ QN = Quinine MEF = Mefloquine ART = Artesunate 1.FSD 3 tab 2.QN or MEF 1000 mg 1500 mg IV in 12 hrs Even though R 1  6%, T coma is avoidable If R 2  6%, T coma may occur 3.ART Oral / TM Even though high density of R 1 or R 2, T coma is avoidable RING FORMSEQUESTRATION R1R1 Late TrophozoiteSchizont Hours Estimated Stage Specificity of Antimalarial Action of Artesunate & Other Antimalarials

13. Artemisinin  3.2 mgm / kgm stat. I.M.  1.6 mgm / kgm day Artesunate  Unstable in aqueous soln.  Stable in 5% Na bicarb  2 mgm / kgm stat  1 mgm / kgm after 12 hrs  1 mgm / kgm subsequently  Total 8-12 mgm / kgm Artemisinin  3.2 mgm / kgm stat. I.M.  1.6 mgm / kgm day Artesunate  Unstable in aqueous soln.  Stable in 5% Na bicarb  2 mgm / kgm stat  1 mgm / kgm after 12 hrs  1 mgm / kgm subsequently  Total 8-12 mgm / kgm

14. TETRACYCLINES, CLINDAMYCIN & COTRIMAXAZOLE  Limited antimalarial activity  Two slow when used alone  Usually with quinine, mefloquine etc.  Limited antimalarial activity  Two slow when used alone  Usually with quinine, mefloquine etc.

15. DESFERRIOXAMINE  In uncomplicated falciparum  Decrease in duration of coma & parasite  Clearance time when added to quinine  Acts by deprivation of iron to the parasite and also as a free oxygen radical scavenger  In uncomplicated falciparum  Decrease in duration of coma & parasite  Clearance time when added to quinine  Acts by deprivation of iron to the parasite and also as a free oxygen radical scavenger

16. PROPHYLAXIS  Mefloquine weekly 250 mgms in 1 trial found to be safe in pregnancy  At present not recommended in pregnancy  Doxycline daily – not safe in children & pregnancy  Chloroquine 300 mgm base weekly + Proguanil 100-200 mgm daily  Found to be safe even in pregnancy  Mefloquine weekly 250 mgms in 1 trial found to be safe in pregnancy  At present not recommended in pregnancy  Doxycline daily – not safe in children & pregnancy  Chloroquine 300 mgm base weekly + Proguanil 100-200 mgm daily  Found to be safe even in pregnancy

17.  Vaccine immunity is species specific and stage specific  Sporozoite vaccine to prevent infection & development of liver stages  Vaccines against asexual stages to block transmission  Vaccine immunity is species specific and stage specific  Sporozoite vaccine to prevent infection & development of liver stages  Vaccines against asexual stages to block transmission

18. THE FUTURE  Mother nature gave us the cinchona alkaloids and Qing Hao Su  World war II led to the discovery of Chloroquine, Chloroguanide, Amodiaquine and Pyrimethamine  The Vietnam war brought Mefloquine and Halofantine  Little pharmaceutical industry interest are low. Much of the malaria occurs in the developing countries.  Do we need another world war for developing newer antimalarials ? Even now malaria is a challenging problem and this may get out of control in the next millenium  Mother nature gave us the cinchona alkaloids and Qing Hao Su  World war II led to the discovery of Chloroquine, Chloroguanide, Amodiaquine and Pyrimethamine  The Vietnam war brought Mefloquine and Halofantine  Little pharmaceutical industry interest are low. Much of the malaria occurs in the developing countries.  Do we need another world war for developing newer antimalarials ? Even now malaria is a challenging problem and this may get out of control in the next millenium

19. THANK YOU