UPDATE ON MALARIA

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

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

3. TYPES OF RESISTANCE IN MALARIA • S Sensitive. Parasite clearance in 7 days no recurrence in 28 days • R1 Parasite clearance in 7 days. Recurrence in 28 days • R2 > 75% clearance in 48 hrs. Recurrence in 7 days • R3 < 75% clearance in 48 hrs. Recurrence in 7 days

4. DISTRIBUTION OF RESISTANCE IN INDIA R3 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

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

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

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

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

10. PRECAUTIONS • Prolonged QT • Mefloquine • Quinine / Quinidine • Halofantrine • Hypokaemia due to vomiting – dangerous arrhythmias including Torsade Prolonged QT also seen in B1 deficiency (vomiting in 1st 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

12. RING FORM SEQUESTRATION R1 Late Trophozoite Schizont Hours • FSD 3 tab 1500 mg IV in 12 hrs • QN or MEF 1000 mg Even though R1 6%, T coma is avoidable If R2 6%, T coma may occur • ART Oral / TM Even though high density of R1 or R2, T coma is avoidable Estimated Stage Specificity of Antimalarial Action of Artesunate & Other Antimalarials FSD = ‘Fansidar’ QN = Quinine MEF = Mefloquine ART = Artesunate R1 = Width of cytoplasm / diameter of nucleus  ½ R2 = Width of cytoplasm / diameter of nucleus > ½ < 1 R3 = Width of cytoplasm / diameter of nucleus  1

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

14. TETRACYCLINES, CLINDAMYCIN & COTRIMAXAZOLE • 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

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

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

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

19. THANK YOU