1. Falciparum Malaria Dr.R.V.S.N.Sarma., M.D., M.Sc., Consultant Physician & Chest Specialist Ph: 93805 21221, 3760 9993 Visit us at : www.drsarma.in

2. Malaria Burden Malaria kills 1.5 to 2.7 m people world wide every year Malaria kills 1.5 to 2.7 m people world wide every year 95% are due to P.falciparum 95% are due to P.falciparum In India P.falciparum up to 34% In India P.falciparum up to 34% Case fatality rate is up to 9% Case fatality rate is up to 9% Chloroquine resistance is major concern Chloroquine resistance is major concern Multi drug resistance emerged in India Multi drug resistance emerged in India

3. The Plasmodium species P.falciparum 15% of Malaria in India P.falciparum 15% of Malaria in India P.vivax Commonest in India P.vivax Commonest in India P.malariae Africa & South America P.malariae Africa & South America P.ovale African continent P.ovale African continent

4. Falciparum Malaria

5. What is the cause ? Inappropriate use of anti-malarials Inappropriate use of anti-malarials Shot gun use of Chloroquine Shot gun use of Chloroquine Mass scale deployment of chloroquine Mass scale deployment of chloroquine Almost always as monotherapy Almost always as monotherapy Inadequate dose and duration Inadequate dose and duration Continued use in spite of drug resistance Continued use in spite of drug resistance

6. Malaria Resurgence Resistance of the parasite Resistance of the parasite Resistance of the vector Resistance of the vector Resistance of the people Resistance of the people Resistance of the community Resistance of the community Resistance of the government Resistance of the government

7. Current WHO Call WHO Facts on ACTs – Jan 2006 Update

8. Recent Recommendations International Conference on Malaria International Conference on Malaria (125 Years of Malaria Research ) New Delhi, November 4—6, 2005 New Delhi, November 4—6, 2005 Organized by Malaria Research Centre Malaria Research Centre Malaria Research Centre Malaria Research Centre (Indian Council of Medical Research) 22 Sham Nath Marg, Delhi-110054 (India)

9. Why is falciparum malignant ? Each cycle releases 20 times more merozoites than vivax Each cycle releases 20 times more merozoites than vivax Multiple infestation of RBC Multiple infestation of RBC Early hemolysis and endotoxin release, cerebral toxicity Early hemolysis and endotoxin release, cerebral toxicity Bilirubin load affects kidneys, liver Bilirubin load affects kidneys, liver Hypovolemia and shock occur Hypovolemia and shock occur Usually resistant to Chloroquine Usually resistant to Chloroquine

10. Differentiation of falciparum P.falciparum trophoziteP.vivax trophozite

11. Differentiation of falciparum P.falciparum shizontP.vivax shizont

12. Differentiation of falciparum P.falciparum gametocyteP.vivax gametocyte

13. Falciparum gametocytes MaleFemale

14. Electron Micrographs P.falciparum EMP.vivax EM

15. Falciparum invading RBC

16. Mangalore story

17. Drug Rx. of falciparum Chloroquine is not the drug of choice Chloroquine is not the drug of choice Should not be treated with single drug Should not be treated with single drug Combination therapy is a must Combination therapy is a must Weaker drugs like Proguanil are of no avail Weaker drugs like Proguanil are of no avail Artemisinin based CT – ACT is the Rx. of choice Artemisinin based CT – ACT is the Rx. of choice

18. The Anti-malarial Drugs Artesunate, Artether, Artemether Artesunate, Artether, Artemether Mefloquine, Amodiaquine Mefloquine, Amodiaquine Quinine, Chloroquine Quinine, Chloroquine Lumefantrine, Halofantrine, Lumefantrine, Halofantrine, Proguanilchlor (chlorguanide) Proguanilchlor (chlorguanide) Sulfadoxin+Pyrimethmine, Dapsone Sulfadoxin+Pyrimethmine, Dapsone Tetracyclines, Doxycyclin, Clindamycin Tetracyclines, Doxycyclin, Clindamycin

19. Today’s Watch Word Combination Therapy (CT) Artemisinin based Combination Therapy (ACT)

20. What is CT ? Anti-malarial combination therapy (CT) is the simultaneous use of two or more blood schizonticidal drugs with different biochemical targets in the parasites and independent modes of action. Anti-malarial combination therapy (CT) is the simultaneous use of two or more blood schizonticidal drugs with different biochemical targets in the parasites and independent modes of action.

21. What is ACT ? Artemisinin-based combination therapy (ACT) is an antimalarial combination therapy with an artemisinin derivative as one component of the combination given for at least 3 days. Artemisinin-based combination therapy (ACT) is an antimalarial combination therapy with an artemisinin derivative as one component of the combination given for at least 3 days.

22. Rationale for ACT Resistance to Chloroquine and SP Resistance to Chloroquine and SP Protect individual drug from resistance Protect individual drug from resistance To decrease rate of decline in efficacy To decrease rate of decline in efficacy To interrupt spread of resistant strains To interrupt spread of resistant strains To decrease transmission in a region To decrease transmission in a region The combination is often more effective In the rare event of resistance to one of the drugs during the course of the infection, the parasite will be killed by the other drug

23. What are Artemisinins ? Artemisinin derivatives Methyl Ether Hemisuccinate Ethyl Ether Arteether Artemether Artesunate Dihydroartemisin Qinghaosu ("ching-how-soo")

24. Why Artemisinins ? Short half-life; hence good for combination Short half-life; hence good for combination Rapid substantial reduction of the parasite biomass Rapid substantial reduction of the parasite biomass Rapid resolution of clinical symptoms Rapid resolution of clinical symptoms Effective action against multi-drug resistant P. falciparum Effective action against multi-drug resistant P. falciparum Reduction of gametocyte carriage Reduction of gametocyte carriage No documented parasite resistance yet No documented parasite resistance yet Few reported adverse effects. Few reported adverse effects.

25. No Monotherapy No Chloroquine for P.falcipatum No Chloroquine for P.falcipatum No Monotherapy with Artemisinin No Monotherapy with Artemisinin

26. ACT - WHO Guidelines Technical Consultation on Anti-malarial Combination Therapy: Geneva, April 2001 Technical Consultation on Anti-malarial Combination Therapy: Geneva, April 2001 Guidelines for the treatment of Malaria Guidelines for the treatment of Malaria WHO document – 266 page book – February 2006 WHO document – 266 page book – February 2006

27. Treatment of uncomplicated P.falciparum malaria

28. Recommended Combinations 1. Artemether + Lumefantrine (Lumether) 2. Artesunate (3 days) + Amodiaquine 3. Artesunate (3 days) + Mefloquine 4. Artesunate (3 days) + SP 5. Amodiaquine + SP (as interim option)

29. WHO Recommendations Upto 1 st Nov 2005 – ACT is adopted by total of 56 countries Upto 1 st Nov 2005 – ACT is adopted by total of 56 countries 34 Countries in Africa 34 Countries in Africa 22 Countries outside Africa 22 Countries outside Africa India has adopted in 2005 India has adopted in 2005 14 countries AL as first line Rx. 14 countries AL as first line Rx. Indian Govt. chosen AS + SP – 1 st line Indian Govt. chosen AS + SP – 1 st line In five states it is available in NAMP In five states it is available in NAMP

30. β Artemether Methyl ether of Artemisinin Methyl ether of Artemisinin Effective Schizonticidal and gametocidal drug Effective Schizonticidal and gametocidal drug Short half life 2 - 6 hours Short half life 2 - 6 hours Interferes with the conversion of Haem to non toxic hemozoin in the parasite Interferes with the conversion of Haem to non toxic hemozoin in the parasite Not indicated in 1 st trimester of preg. Not indicated in 1 st trimester of preg.

31. β Artemether side effects Very few and less troublesome Very few and less troublesome Cough Cough Body aches Body aches Abd pain, Nausea, Vomiting, Anorexia Abd pain, Nausea, Vomiting, Anorexia Palpitations Palpitations Dizziness, weakness Dizziness, weakness Skin rash, itching Skin rash, itching

32. Lumefantrine Schizonticidal; Safe in pregnancy Schizonticidal; Safe in pregnancy AMMS – China discovered it 1970 AMMS – China discovered it 1970 Registered for use in 1987 Registered for use in 1987 Half life 3-6 days Half life 3-6 days Acts on the food vacuole of parasite Acts on the food vacuole of parasite Inhibition of Nucleic acid and Protein synthesis in the parasite Inhibition of Nucleic acid and Protein synthesis in the parasite

33. AL Peak Plasma concentrations

34. Artemether-Lumefantrine - AL (Coartem, Lumether, Riamet) 6 dose regimen of Lumether

35. AL Dosage Schedule

36. Low Resistance areas

37. Course of Rx blister packs

38. PUBLIC SECTOR PRIVATE SECTOR COARTEM® PREFERENTIAL PRICING FOR PUBLIC SECTOR: PRICE CHANGES BY 2005

39. FCT in hours with AL FCT (Hours)

40. PCT in days with AL

41. Artesunate + Mefloquine AS + MQ

42. Artesunate + Amodiaquine AS + AQ

43. Artesunate + sulfadoxine – pyrimethamine – AS + SP

44. ACT trend worldwide

45. Comparative Efficacy

46. AL v/s Q+DC – 3 rd Day

47. AL v/s Q+DC – 28 th Day

48. Second line Combinations 1. Artesunate (7 days) + Tetracycline (7) 2. Artesunate (7 days) + Doxycycline (7) 3. Artesunate (7 days) + Clindamycin (7) or 4. Quinine in place of AS + any of the above antibiotics for 7 days

49. What to give in pregnancy ? In 1st trimester In 1st trimester –Quinine + Clindamycin 7 days In 2 nd and 3 rd trimesters In 2 nd and 3 rd trimesters –Any ACT combination as per rec. or –Artesunate + Clindamycin 7 days or –Quinine + Clindamycin 7 days Lactating women same ACT Lactating women same ACT

50. Warning Artemisinins should never be used as monotherapy Artemisinins should never be used as monotherapy Artesunate combinations always given for 3 days; never single dose of AS. Artesunate combinations always given for 3 days; never single dose of AS. For AL six doses must be over 3 days For AL six doses must be over 3 days AQ or MQ or SP should never be used alone - lest drug resistance occurs AQ or MQ or SP should never be used alone - lest drug resistance occurs

51. Combinations not recommended 1. Chloroquine based combinations (e.g CQ + SP; CQ + Artesunate) 2. Artesunate (single dose) + SP 3. Chloproguanil-Dapsone (LapDap)

52. Treatment of severe P.falciparum malaria Severe malaria is a medical emergency

53. Complications of falciparum malaria Coma - cerebral malaria, convulsions Coma - cerebral malaria, convulsions Renal failure – black water fever Renal failure – black water fever Hyperpyrexia, acute pulmonary edema Hyperpyrexia, acute pulmonary edema Hemolytic Jaundice, severe bleeding Hemolytic Jaundice, severe bleeding Hypovolemic shock, Hypoglycemia Hypovolemic shock, Hypoglycemia Metabolic acidosis, Coagulopathy, Metabolic acidosis, Coagulopathy, Severe anaemia, hyperparasitemia Severe anaemia, hyperparasitemia

54. Artemisinins parenteral αβ Arteether – 150 mg (2ml) i.m od x 3 days or 3 mg/kg od i.m. x 3 days Artesunate 2.4 mg/kg i.v. or i.m. given on admission (time = 0), then at 12 h and 24 h, then once a day Artemether 3.2 mg/kg i.m. given on admission then 1.6 mg/kg per day is an acceptable alternative to quinine i.v infusions Rectal artemisinins are not as effective

55. Quinine parenteral A loading dose of quinine of 20 mg salt/kg bw. 10 mg/kg 8 th hrly i.v infusion A loading dose of quinine of 20 mg salt/kg bw. 10 mg/kg 8 th hrly i.v infusion Rate-controlled i.v. infusion is the preferred route of quinine admin. If this cannot be given safely, then i.m. injection is a satisfactory alternative. Rectal admin. is not effective Quinidine can substitute quinine

56. Some brand names ArteetherE Mal inj, Falcy inj ArteetherE Mal inj, Falcy inj ArtemetherLarether caps, inj ArtemetherLarether caps, inj ArtesunateFalcigo, Falcynate tab, inj ArtesunateFalcigo, Falcynate tab, inj MefloquineMQF, Meflotas, Mefque –tab MefloquineMQF, Meflotas, Mefque –tab QuinineQuinarsol, Cinkona inj, tab QuinineQuinarsol, Cinkona inj, tab SPPyralfin, Laridox, Amalar SPPyralfin, Laridox, Amalar PrimaquineMalirid, Primacip, PMQinga PrimaquineMalirid, Primacip, PMQinga

57. AM

58. 1. The costs of estimated global ACT requirements far exceeds the current level of ACT financing by the GFA. 2. An enhancement of the financial resources for purchasing ACTs is, therefore, urgently required to both encourage endemic countries to adopt these effective treatment policies and to control malaria mortality 3. Malaria is a highly treatable disease, and very effective treatment is available in the form of ACTs. WHO calls on all member countries to unite in a global coalition to enable countries accelerate access to ACTs and make these life- saving medicines affordable to the people in need. Momentum is high to ensure access to effective antimalarial treatment

61. αβ ARTEETHER 150 mg (2 ml amp.) O.D. intramuscular x 3 days = Total 3 ampoules in a box To be given I.M

62. Let us give Colour to their Lives

63. www.drsarma.in Points Ponder If we find a person’s Hb is say 8 g% - What shall we do ? It is imperative to identify the type of anaemia and treat ! In middle age or elderly – anemia is the clue to Ca !! Thorough examination for occult or chronic bleeding- a must All cases of anaemia are not IDA – Tonics aren’t the answer Anaemia – 1. Under production 2. Hemolytic 3. Hemorrhagic Reticulocyte count is the first test that is needed RDW – RBC indices will classify the type of anaemia Peripheral smear examination is invaluable in the Dx.

64. A Practical Approach to Anemia This session will be after tea break How to efficiently and accurately work up an anemic patient ?

65. www.drsarma.in This is time for Tea The Next part our CME is on Anaemia Let us quickly come back after Tea