Chemotherapy and national drug policy in malaria

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Indian national anti-malarial drug policy(revised-April

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Chemotherapy and national drug policy in malaria

  1. 1. CHEMOTHERAPY AND NATIONAL DRUG POLICY IN MALARIA. DR .G . C. SAHU ROH&FW; GoI; GoI; AHMEDABAD Dr.G.C Sahu/ROHFW/GoI/ABad 1
  2. 2. Infective vector mosq.bite Sporozoite inoculation Liver cycle Vec.mosq.picks up Gametocytes Mosquito cycleRepeatative RBC cycle …. IN THE …. IN THESEQUENCESEQUENCE LIFE CYCLE LIFE CYCLE OF OF OF MALARIA OF MALARIAEVENTS… EVENTS… PARASITE PARASITE Dr.G.C Sahu/ROHFW/GoI/ABad 2
  3. 3. 4 H U M A N M A L. P A R A S I T E SDr.G.C Sahu/ROHFW/GoI/ABad 3
  4. 4. An effective treatment policy should aim to: Reduce morbidity Prevent the progression of uncomplicated diseaseinto severe and potentially fatal disease and therebyreduce malaria mortality Reduce the impact of placental malaria infectionand maternal malaria-associated anaemia through malaria-associatedchemoprophylaxis or preventive intermittent therapy. Prevent or delay the development of antimalarialdrug resistance by correct diagnosis and rationaltreatment of all malaria positive cases. Dr.G.C Sahu/ROHFW/GoI/ABad 4
  5. 5. Treatment of Malaria --- Aims Of Treatment Aims Causation Therapy Drugs Chloroquine, Symptoms are Blood quinine, To alleviate caused by blood schizonticidal pyrimethamine/s symptoms forms of the drugs ulphadoxine, parasite artemisinin Relapses are due Tissue To prevent to hypnozoites of schizonticidal Primaquine relapses P. vivax/ P. ovale drugs Primaquine for P. Spread is through Gametocytocidal falciparum,To prevent spread the gametocytes drugs Chloroquine for all other Thus, in effect, a blood schizonticidal drug and primaquine should be Thus, in effect, a blood schizonticidal drug and primaquine should be administered to ALL types of malaria. administered to ALL types of malaria.
  6. 6. Principles Of TreatmentTreatment of malaria depends on the following factors: Type of infection. Severity of infection. Status of the host. Associated conditions/ diseases.
  7. 7. Associated conditions/ diseases:Treatment of malaria may have to be modified due to certain associated conditions/ diseases.Treatment of malaria may have to be modified due to certain associated conditions/ diseases. Therefore, all such should be carefully assessed before starting the patient on anti malarial Therefore, all such should be carefully assessed before starting the patient on anti malarial treatment. treatment. Pregnancy: Treatment of malaria in pregnancy may prove to be difficult due to contra indication for use of certain Pregnancy: Treatment of malaria in pregnancy may prove to be difficult due to contra indication for use of certain antimalarials. Chloroquine can be used safely in all trimesters of pregnancy. Artemisinin is not shown to have any antimalarials. Chloroquine can be used safely in all trimesters of pregnancy. Artemisinin is not shown to have any antimalarials. deleterious effects on the fetus in animal studies and therefore can be considered if the situation demands. Quinine deleterious effects on the fetus in animal studies and therefore can be considered if the situation demands. Quinine can be used in pregnancy, but one should be watchful about hypoglycemia. can be used in pregnancy, but one should be watchful about hypoglycemia. hypoglycemia. Epilepsy: Malaria as well as anti malarials can trigger convulsions. Mefloquine is better avoided in these patients. Epilepsy: Malaria as well as anti malarials can trigger convulsions. Mefloquine is better avoided in these patients. Cardiac disease: High-grade fever of malaria can exacerbate left ventricular failure and therefore, in all such Cardiac disease: High- High-grade fever of malaria can exacerbate left ventricular failure and therefore, in all such and patients energetic management of malaria is called for. Fever should be controlled with anti-pyretics and tepid patients energetic management of malaria is called for. Fever should be controlled with anti- should anti-pyretics and tepid sponging. Chloroquine, artemisinin, pyrimethamine/ sulphadoxine, tetracyclines and primaquine can be safely used in sponging. Chloroquine, artemisinin, pyrimethamine/ sulphadoxine, tetracyclines and primaquine can be safely used in Chloroquine, artemisinin, pyrimethamine/ sulphadoxine, these patients. Quinine can also be used carefully. Mefloquine and halofantrine are better avoided in patients with these patients. Quinine can also be used carefully. Mefloquine and halofantrine are better avoided in patients with known cardiac illness. known cardiac illness. Hepatic insufficiency: None of the antimalarial drugs have any direct hepatotoxic effect. However, Hepatic insufficiency: None of the antimalarial drugs have any direct hepatotoxic effect. However, chloroquine is not advisable in patients with severe hepatic insufficiency. chloroquine is not advisable in patients with severe hepatic insufficiency. Renal failure: The initial dose of antimalarial drugs need not be reduced in patients with renal failure. However, if Renal failure: The initial dose of antimalarial drugs need not be reduced in patients with renal failure. However, if However, the patient requires parenteral antimalarials even after three days and continues to be sick, then the dose can be can be the patient requires parenteral antimalarials even after three days and continues to be sick, then the dose can reduced by one third to half of usual dose. reduced by one third to half of usual dose. Dermatitis: Concomitant use of chloroquine with gold salts and phenyl butazone should be avoided because all Dermatitis: Concomitant use of chloroquine with gold salts and phenyl butazone should be avoided because all the three can cause dermatitis. the three can cause dermatitis. Anti-malarials contra-indicated in pregnancy. Anti- Anti-malarials contra- contra-indicated in pregnancy. × Mefloquine::- 11 trimester Mefloquine Mefloquine:- st st trimester × SS-P combination:-- 11 and last trimester -P combination: combination:- st st and last trimester × Halo,Tetra,Doxy::- All trimester Halo,Tetra,Doxy All trimester Halo,Tetra,Doxy:- × Primaquine::- All trimester. Primaquine All trimester. Primaquine:-
  8. 8. In an endemic area, malaria often presents with atypical manifestations Atypical features are more common in the following situations: Falciparum malaria Falciparum malaria Early infection Early infection Patients at extremes of age Patients at extremes of age Patients who are immune-compromised (extremes of age, malnourished, AIDS, Patients who are immune-compromised (extremes of age, malnourished, AIDS, tuberculosis, cancers, on immunosuppressive therapy etc.) tuberculosis, cancers, on immunosuppressive therapy etc.) Patients on chemoprophylaxis for malaria Patients on chemoprophylaxis for malaria Patients who have had recurrent attacks of malaria Patients who have had recurrent attacks of malaria Patients with end stage organ failure Patients with end stage organ failure Last but not the least, pregnancy. Last but not the least, pregnancy.
  9. 9. INFORMATIONS ONE MUST HAVE BEFORE TREATING A INFORMATIONS ONE MUST HAVE BEFORE TREATING A CASE OF MALARIA. CASE OF MALARIA.THE TYPE OF SPECIES YOU ARE TREATING i eP. VIVAX OR P. FALCIPARUMTHE STAGE OF PARASITES YOU ARE TREATING i.eASEXUAL STAGE(RING) OR SEXUAL STAGE(GAMETO) THE TYPE OF TREATEMENT YOU ARE GIVING i.e{PRESUMPTIVE TREATMENT OR RADICAL TREATMENT}Type of severity of infection i.e complicated or non complicated. THE TYPE OF AREA IN WHICH THE TREATMENT ISGIVEN i.e. LOW-RISK AREA OR HIGH RISK AREA. RESPONSE OF THE PARASITE TO THE DRUG GIVENi.e. SENSITIVE OR RESISTANT. Dr.G.C Sahu/ROHFW/GoI/ABad 9
  10. 10. SCHIZONTICIDAL DRUGS: CHLOROQUINE, AMODIAQUINE, QUININE,QUINIDINE,PYREMETHAMINE, TRIMETHOPRIM,PROGUANIL, SULFONAMIDES IN COMBN.WITHPYREMETHAMINE, MEFLOQUINE, HALOFANTRINE,ARTEMESININE. Dr.G.C Sahu/ROHFW/GoI/ABad 10
  11. 11. GAMETOCIDAL AND ANTI- RELAPSE DRUG(S) : PRIMAQUINE Dr.G.C Sahu/ROHFW/GoI/ABad 11
  12. 12. What would be the optimal anti- malaria compound?(1) The optimal anti-malaria compound must have such six advantages therapeutically as follows: • High efficacy The 28-day cure rate should be over 95% in multi-drugs resistant falciparum malaria endemic areas • Quick acting The development of parasites should be stopped after the initial dose, which is the key point to reduce the incidence of cerebral malaria , thereby, reduced the mortality of malaria Dr.G.C Sahu/ROHFW/GoI/ABad
  13. 13. What would be the optimal anti-malaria compound?(2)• Short treatment course The optimal treatment course with better patients compliance would be once daily for just two days.• Low toxicity The incidence of side effects should be less than 5%.
  14. 14. What would be the optimal anti-malaria compound?(3)• Preventing transmission It will be advantages to control the prevalence of malaria and very important for preventing from the disease to neutralize and kill quickly the gametocytes of falciparum malaria• Low cost It should be affordable for most of the patients in malaria endemic areas of the developing countries, so that those patients could take the drug to cure malaria.
  15. 15. Dr.G.C Sahu/ROHFW/GoI/ABad 15
  16. 16. Anti Malarial Drugs: ChloroquineMechanism of action:The mechanism of action of chloroquine is unclear. Beingalkaline, the drug reaches high concentration within the foodvacuoles of the parasite and raises its pH. It is found toinduce rapid clumping of the pigment. Chloroquine inhibitsthe parasitic enzyme heme polymerase that converts thetoxic heme into non-toxic hemazoin, thereby resulting in theaccumulation of toxic heme within the parasite. It may alsointerfere with the biosynthesis of nucleic acids. Othermechanisms suggested include formation of drug-hemecomplex, intercalation of the drug with the parasitic DNA etc. Dr.G.C Sahu/ROHFW/GoI/ABad 16
  17. 17. Anti Malarial Drugs: Quinine Food Heme Vacuo polyme le rase Non Toxic Hemo Toxic Hemazoin globin Heme (Malarial Pigment) Degradat ? Inhibited ion by QuinineMechanism of action:Quinine acts as a blood schizonticide although it also has gametocytocidalactivity against P. vivax and P. malariae. Because it is a weak base, it isconcentrated in the food vacuoles of P. falciparum. It is said to act by inhibitingheme polymerase, thereby allowing accumulation of its cytotoxic substrate,heme. As a schizonticidal drug, it is less effective and more toxic thanchloroquine. However, it has a special place in the management of severefalciparum malaria in areas with known resistance to chloroquine. Dr.G.C Sahu/ROHFW/GoI/ABad 17
  18. 18. Anti Malarial Drugs: Pyrimethamine/ SulphadoxinePyrimethamine and sulphadoxine are very useful adjuncts in the treatmentPyrimethamine and sulphadoxine are very useful adjuncts in the of uncomplicated, chloroquine resistant, P. falciparum malaria. resistant,Anti malarial activity:Pyrimethamine inhibits the dihydrofolate reductase of plasmodia andPyrimethamine inhibits the dihydrofolate reductasethereby blocks the biosynthesis of purines and pyrimidines, which are so the biosynthesis of purines and pyrimidines, which areessential for DNA synthesis and cell multiplication. This leads to failure ofnuclear division at the time of schizont formation in erythrocytes and liver.Availability: Pyrimethamine and sulphadoxine combined tablets areAvailability: Pyrimethamine and sulphadoxineavailable, containing 25 mg of pyrimethamine and 500 mg of sulphadoxine containing 25 mg of pyrimethamine and 500in each tablet. Dose of Pyrimethamine/sulfadoxine: Pyrimethamine/sulfadoxine: 3 tablets as per the WHO recommendations Dr.G.C Sahu/ROHFW/GoI/ABad 18
  19. 19. Anti Malarial Drugs:Mefloquine Mefloquine was born during the Vietnam war, as a result of research into Mefloquine was born war, newer anti malarials, to protect the American soldiers from the multi drug malarials, protect the American soldiers resistant falciparum malaria. Nothing much has happened after that and resistant falciparum malaria. Nothing hence this new drug should be restricted for use against multi drug resistant falciparum only. resistant falciparum only.Anti malarial activity:Mefloquine has been found to produce swelling of the P. falciparum foodMefloquine has been found to produce swelling of the P. falciparumvacuoles. It may act by forming toxic complexes with free heme that damage heme thatmembranes and interact with other plasmodial components. It is effectiveagainst the blood forms of falciparum malaria, including the chloroquine theresistant types. Availability: It is available as 250 mg tablets.Dose: 15 mg/kg in a single dose. If the dose exceeds 1000 mg, the second dose exceeds 1000 mg, the second dosecan be given after 4-8 hours to minimise gastric irritation. Total dose should 4-8 minimise Dr.G.C exceed 1500 mg. not Sahu/ROHFW/GoI/ABad 19
  20. 20. Artemesia annua Sweet AnnieSweet wormwoodAnnual wormwood Qinghao Dr.G.C Sahu/ROHFW/GoI/ABad
  21. 21. Anti Malarial Drugs:Anti Malarial Drugs: The Artemisinin DerivativesIt is the fastest acting anti malarial available.. It inhibits the development of theIt is the fastest acting anti malarial available It inhibits the development of thetrophozoites and thus prevents progression of the disease. It starts acting withintrophozoites and thus prevents progression of the disease. It starts acting within12 hours.. It is also effective against the chloroquine resistant strains of P. falciparum.12 hours It is also effective against the chloroquine resistant strains of P. falciparum.These properties of the drug are very useful in managing complicated P. falciparumThese properties of the drug are very useful in managing complicated P. falciparummalaria.malaria. Dose: Artemether: 3.2 mg/kg intra muscularly as a loading dose, followed by 1.6 mg/kg : 3.2 mg/kg intra muscularly as a loading dose, followed by 1.6 mg/kg daily until oral therapy or a maximum of 7 days. daily until oral therapy or a maximum of 7 days. Arteether: 3 mg/kg once a day for 3 days, as deep intra muscular injection. 3 mg/kg once a day for 3 days, as deep intra muscular injection.Artesunate: Oral- 5 mg/kg on the first day followed by 2.5 mg/kg on the second and Oral- 5 mg/kg on the first day followed by 2.5 mg/kg on the second and third days. Oral artesunate is not recommended in pregnancy. third days. Oral artesunate is not recommended in pregnancy.Parenteral- Loading dose of 2.4 mg/kg followed by 1mg/kg after 4 hours and 24 hours;Parenteral- Loading dose of 2.4 mg/kg followed by 1mg/kg after 4 hours and 24 hours; thereafter, 1.2 mg/kg daily for maximum of 7 days. For children, the recommended thereafter, 1.2 mg/kg daily for maximum of 7 days. For children, the recommended dose is 1.2 mg/kg/day for 5-7 days. dose is 1.2 mg/kg/day for 5-7 days. Dr.G.C Sahu/ROHFW/GoI/ABad 21
  22. 22. Site of Action Artemisinin Artemisinin Conventional Conventional Treatment Treatment Dr.G.C Sahu/ROHFW/GoI/ABad Artemisinin Artemisinin
  23. 23. ArtemisininsDr.G.C Sahu/ROHFW/GoI/ABad
  24. 24. Anti Malaria Drugs: PrimaquinePrimaquine is the essential co-drug with chloroquine in treating all is the essential co-drug treating allcases of malaria. It is highly effective against the gametocytes of all effective against the gametocytes of allplasmodia and thereby prevents spread of the disease to the mosquito mosquitofrom the patient. It is also effective against the dormant tissue forms of patient. It is also effective tissueP. vivax and P. ovale malaria, and thereby offers radical cure andprevents relapses. It has insignificant activity against the asexual blood the asexual bloodforms of the parasite and therefore it is always used in conjunction therefore conjunctionwith a blood schizonticide and never as a single agent.Mechanism of action is not well understood. It may be acting bygenerating reactive oxygen species or by interfering with theelectron transport in the parasite.Availability: Primaquine is available as tablets containing 2.5, 7.5 and Primaquine is available 15 mg of the salt. Dr.G.C Sahu/ROHFW/GoI/ABad 24
  25. 25. Drug DrugsClass Blood Chloroquine, Quinine, Quinidine, Mefloquine,Schizonto Halofantrine, Sulfonamides, Tetracyclines, cidal Atovaquone, Artemisinin compounds Tissue Primaquine, Proguanil, Pyrimethamine,Schizonto cidalGametocidal PrimaquineHypnozoit Primaquine ocidal Dr.G.C Sahu/ROHFW/GoI/ABad 25
  26. 26. What is presumptive treatment? **Presumption - In an area with high transmission of malaria, it shouldbe presumed that ALL cases of fever are due to malaria.Treatment - First loading dose of chloroquine should be administeredimmediately after collecting the blood specimen, even without waiting for after collecting the blood specimen, waiting forits report. If the fever is indeed malaria, this treatment alleviates symptoms early, alleviates symptoms early,may be well before the test result is available. If it is malaria, chloroquine also prevents the spread of malaria by is malaria,destroying the gametocytes of P. vivax (the more common malaria). If it is not malaria, nothing is lost, for chloroquine at this dose is safe this dose is safeand has no adverse effects. It cures early and more important, it prevents spread of P. vivax It cures early and more important, it prevents spread of P. vivaxmalaria.malaria. ** Till recently , it was recommended treatment under the National ** Till recently , it was recommended treatment under the National Malaria Eradication Programme(now NVBDCP) in India. Malaria Eradication Programme(now NVBDCP) in India. Dr.G.C Sahu/ROHFW/GoI/ABad 26
  27. 27. 1 0    ‐ 20 CY   LI OR  PO E F R UG AF  D D S IA AN AR Y   AL DA ” I  M   TO OW A NT OR RR L   E  F MO ON A I AT T O A TI PR  N PRO E  PT H “A
  28. 28. THE  NATIONAL  ANTI  MALARIA DRUG POLICY‐2010    THE  NATIONAL  ANTI  MALARIA DRUG POLICY‐2010    “APPROPRIATE  FOR  TODAY  AND SAFE FOR TOMORROW” “APPROPRIATE  FOR  TODAY  AND SAFE FOR TOMORROW”Effective treatment of malaria under the National Drug Policy aims at: treatment of malaria under the aims Providing complete cure (clinical and parasitological) ofmalaria cases Prevention of progression of uncomplicated malaria intosevere malaria and thereby reduce malaria mortality Prevention of relapses by administration of radicaltreatment Interruption of transmission of malaria by use ofgametocytocidal drugs Preventing development of drug resistance by rationaltreatment of malaria cases. Dr.G.C Sahu/ROHFW/GoI/ABad 28
  29. 29. Treatment of uncomplicated malaria All fever cases suspected to be malaria should be investigated by microscopy or All fever cases suspected to be malaria should be investigated by microscopy or RDT. RDT.1. P.vivax cases should be treated with chloroquine for three days and Primaquine1. P.vivax cases should be treated with chloroquine for three days and Primaquinefor 14 days. Primaquine is used to prevent relapse but is contraindicated infor 14 days. Primaquine is used to prevent relapse but is contraindicated inpregnant women, infants and individuals with G6PD deficiency.pregnant women, infants and individuals with G6PD deficiency.Note: Patients should be instructed to report back in case of haematuria or highNote: Patients should be instructed to report back in case of haematuria or highcolored urine /cyanosis or blue coloration of lips and Primaquine should becolored urine /cyanosis or blue coloration of lips and Primaquine should bestopped in such cases. Care should be taken in patients with anaemia.stopped in such cases. Care should be taken in patients with anaemia.2. P. falciparum cases should be treated with ACT (Artesunate 3 days +2. falciparum cases should be treated with ACT (Artesunate 3 days +Sulphadoxine-Pyrimethamine 1 day). This is to be accompanied by single doseSulphadoxine-Pyrimethamine 1 day). This is to be accompanied by single doseprimaquine preferably on day 2.primaquine preferably on day 2.3. Pregnant women with uncomplicated P. falciparum should be treated as3. with uncomplicated P. falciparum should be treated asfollows:follows: 1st Trimester: Quinine 1st Trimester: Quinine 2nd & 3rd Trimester: ACT 2nd & 3rd Trimester: ACT Note: Primaquine is contra indicated in pregnant woman Note: Primaquine is contra indicated in pregnant woman Dr.G.C Sahu/ROHFW/GoI/ABad 29
  30. 30. 5. In cases where parasitological diagnosis is not possible due to non-availability of5. In cases where parasitological diagnosis is not possible due to non-availability ofeither timely microscopy or RDT, suspected malaria cases will be treated with fulleither timely microscopy or RDT, suspected malaria cases will be treated with fullcourse of chloroquine, till the results of microscopy are received. Once thecourse of chloroquine, till the results of microscopy are received. Once theparasitological diagnosis is available, appropriate treatment as per the species, isparasitological diagnosis is available, appropriate treatment as per the species, isto be administered.to be administered.6. Presumptive treatment with chloroquine is no more recommended.6. Presumptive treatment with chloroquine is no more recommended.7. Resistance should be suspected if in spite of full treatment with no history of7. Resistance should be suspected if in spite of full treatment with no history ofvomiting, diarrhoea, patient does not respond within 72 hours, clinically andvomiting, diarrhoea, patient does not respond within 72 hours, clinically andparasitologically. Such cases not responding to ACT, should be treated with oralparasitologically. Such cases not responding to ACT, should be treated with oralquinine with Tetracycline // Doxycycline. These instances should be reported toquinine with Tetracycline Doxycycline. These instances should be reported toconcerned District Malaria /State Malaria Officer/ROHFW for initiation ofconcerned District Malaria /State Malaria Officer/ROHFW for initiation oftherapeutic efficacy studies.therapeutic efficacy studies. Dr.G.C Sahu/ROHFW/GoI/ABad 30
  31. 31. DRUG SCHEDULE FOR TREATMENT OF MALARIA UNDER NVBDCP 1. Chloroquine: 25 mg/kg body weight divided over Chloroquine:three days i.e. 10mg/kg on day 1, 10mg/kg on day 2and 5mg/kg on day 3.2. Primaquine: 0.25 mg/kg body weight daily for 14 Primaquine:days. * Primaquine is contraindicated in infants, pregnant women and individuals with G6PD deficiency. with 14 day regimen of Primaquine should be given under supervision. Dr.G.C Sahu/ROHFW/GoI/ABad 31
  32. 32. Treatment of uncomplicated P.falciparum casesArtemisinin based Combination Therapy (ACT)* Artesunate 4 mg/kg body weight daily for 3 days Plus Sulfadoxine (25 mg/kg body weight) . Pyrimethamine(1.25 mg/kg body weight) on first day.* ACT is not to be given in 1st trimester of pregnancy. Dr.G.C Sahu/ROHFW/GoI/ABad 32
  33. 33. Treatment of uncomplicated P.falciparum cases in pregnancy1st Trimester : Quinine salt 10mg/kg 3 times daily for 7 days.Note: Quinine may induce hypoglycemia; pregnant womenshould not start taking quinine on an empty stomach andshould eat regularly, while on quinine treatment.2nd and 3rd trimester: ACT as per dosage given above. Dr.G.C Sahu/ROHFW/GoI/ABad 33
  34. 34. Treatment of mixed infections (P.vivax + P.falciparum) (P.vivax P.falciparum) cases All mixed infections should be treated with full course of ACT andPrimaquine 0.25 mg per kg body weight daily for 14 days. Dr.G.C Sahu/ROHFW/GoI/ABad 34
  35. 35. Treatment of severe malaria cases:Treatment of severe malaria cases: Severe malaria is an emergency is an emergencyand treatment should be given as per severity and associated complications which canand treatment should be given as per severity and associated complications which canbest be decided by the treating physician.. The guidelines for specific antimalarialbest be decided by the treating physician The guidelines for specific antimalarialtherapy is as follows:therapy is as follows: Artesunate: 2.4 mg/kg body weight IV or IM given on admission (time = 0 : 2.4 mg/kg body weight IV or IM given on admission (time = 0h); then at 12 h and 24 h and then once a day.h); then at 12 h and 24 h and then once a day. (or) (or) Artemether: 3.2 mg/kg body weight IM given on admission and then 1.6 : 3.2 mg/kg body weight IM given on admission and then 1.6mg/kg body weight per day.mg/kg body weight per day.(or)(or) Arteether: 150 mg IM daily for 3 days in adults only (not recommended for Arteether: 150 mg IM daily for 3 days in adults only (not recommended forchildren).children). (or) (or) Quinine: 20 mg/kg* body weight on admission (IV infusion or divided IM : 20 mg/kg* body weight on admission (IV infusion or divided IMinjection) followed by maintenance dose of 10 mg/kg body weight 8 hourly.injection) followed by maintenance dose of 10 mg/kg body weight 8 hourly.The infusion rate should not exceed 5 mg salt/kg body weight per hour.The infusion rate should not exceed 5 mg salt/kg body weight per hour.(*loading dose of Quinine i.e. 20mg /kg body weight on admission may not be given if the patient has(*loading dose of Quinine i.e. 20mg /kg body weight on admission may not be given if the patient hasalready received quinine or if the clinician feels inappropriate).already received quinine or if the clinician feels inappropriate). Note:The parenteral treatment in severe malaria cases should be given for minimum of 24 hours once started (irrespective of the patient.s ability to tolerate oral medication earlier than 24 hours). 35
  36. 36. 1.. After parenteral artemisinin therapy, patients willreceive a full course of oral ACT for 3 days.2.. Those patients who received parenteral Quininetherapy should receive: receive:Oral Quinine 10 mg/kg body weight three times aday for 7 days (including the days when parenteralQuinine was administered) plus Doxycycline 3mg/kg body weight once a day or Clindamycin 10mg/kg body weight 12-hourly for 7 days 12-hourly (Doxycycline is contraindicated in pregnant women and children under 8 years of age). (Doxycycline is contraindicated in pregnant women and children under 8 years of age). Dr.G.C Sahu/ROHFW/GoI/ABad 36
  37. 37. Why injectable Arteether Over injectable Artesunate & injectable Artemether in the National Drug Policy ??? Inj.ARTEETHER:1. Immediate onset and rapid reduction of parasitaemia with complete clearance in most cases within 48 hours2. Clinical recovery of the patient, e.g. defervescence is faster than with other antimalarials.3. Therapeutically equivalent to quinine in cerebral malaria4. More lipophilic properties than artemether favouring accumulation in brain tissue and thus the treatment of cerebral malaria were regarded as advantages over the other compounds.5. Arteether has much slower elimination.[elimination half6. life:Arteether-20 hrs;Artemether-6hrs;Artesunate-1hr]
  38. 38. Comparative Efficacy : In Cerebral Malaria Parameter Arteether QuinineComa recovery time 24.33 38.87(hrs.) 6.67 27.27Mortality (%)
  39. 39. Important for Rx Most blood schizonticidal drugs prevent the development of the Most blood schizonticidal drugs prevent the development of theforthcoming erythrocytic cycle of parasitic development and henceforthcoming erythrocytic cycle of parasitic development and hencehave no or little effect on the ongoing cycle that is already causinghave no or little effect on the ongoing cycle that is already causingfever. Therefore, it would take at least 48 hours for the treatment tofever. Therefore, it would take at least 48 hours for the treatment tobe effective.be effective. In severe P. falciparum malaria, oral antimalarials should not be In severe P. falciparum malaria, oral antimalarials should not beused. Vomiting, poor general health, poor compliance, erratic G.I.used. Vomiting, poor general health, poor compliance, erratic G.I.absorption due to splanchnic vasculopathy etc. make oral therapyabsorption due to splanchnic vasculopathy etc. make oral therapyless reliable. Therefore, use only parenteral antimalarials. This alsoless reliable. Therefore, use only parenteral antimalarials. This alsomeans that oral only antimalarials like Mefloquine and Halofantrinemeans that oral only antimalarials like Mefloquine and Halofantrinehave no place in treating severe falciparum malaria.have no place in treating severe falciparum malaria. In all cases of P. falciparum malaria, the antimalarial drugs should In all cases of P. falciparum malaria, the antimalarial drugs shouldbe chosen depending on the severity of the illness and thebe chosen depending on the severity of the illness and thesensitivity pattern in the locality. Changing the drugs or adding thesensitivity pattern in the locality. Changing the drugs or adding thedrugs in between is not advisable.drugs in between is not advisable. Dr.G.C Sahu/ROHFW/GoI/ABad
  40. 40. Chloroquine + Quinine Chloroquine + Quinine…..Important for Rx…..Important Chloroquine + Mefloquine Chloroquine + Mefloquine Most antimalarial drugs have a long Most antimalarial drugs have a long Quinine + Mefloquine Quinine + Mefloquineplasma half-life. Therefore, addingplasma half-life. Therefore, addingsimilar drugs half way through thesimilar drugs half way through the Quinine + Primaquine Quinine + Primaquinetreatment will only add to thetreatment will only add to theadverse effects and not to theadverse effects and not to the Quinine + Halofantrine Quinine + Halofantrinetherapeutic benefit. The followingtherapeutic benefit. The followingcombinations should therefore becombinations should therefore be Mefloquine + Primaquine Mefloquine + Primaquineavoided, concurrently or within a shortavoided, concurrently or within a shortinterval:interval: Administration of Primaquine and Administration of Primaquine and Pyrimethamine/sulphadoxine on the Pyrimethamine/sulphadoxine on the Do not exceed the maximum Do not exceed the maximumrecommended dose of antimalarial same day is also not advisable. Both same day is also not advisable. Bothrecommended dose of antimalarialdrugs. All antimalarial drugs have adrugs. All antimalarial drugs have a sulpha and primaquine can sulpha and primaquine cannarrow safety range and excessnarrow safety range and excess precipitate hemolytic crisis in precipitate hemolytic crisis indose may lead to adverse effects..dose may lead to adverse effects patients with Glucose 6-phosphate patients with Glucose 6-phosphateMoreover, larger dose does not offerMoreover, larger dose does not offer dehydrogenase deficiency. dehydrogenase deficiency.any superior antimalarial effect.any superior antimalarial effect. Dr.G.C Sahu/ROHFW/GoI/ABad
  41. 41. Pregnancy and lactation Pregnancy and lactation Infants below one year of age. In these two Infants below one year of age. In these two ……..Important for Rx ……..Important categories, chloroquine should be given every week categories, chloroquine should be given every week as a suppressive chemoprophylaxis to prevent as a suppressive chemoprophylaxis to prevent relapse of vivax malaria. When these patients are fit relapse of vivax malaria. When these patients are fit for administration of primaquine, they should be for administration of primaquine, they should be primaquine, given full therapeutic dose of chloroquine as well as given full therapeutic dose of chloroquine as well as Primaquine should primaquine. primaquine. primaquine.be administered to ALL administered to ALL Patients with known Glucose 6-phosphate Patients with known Glucose 6- 6-phosphate dehydrogenase deficiency dehydrogenase deficiencycases of malaria as Concurrently with quinine, mefloquine and Concurrently with quinine, mefloquine andradical treatment except halofantrine into newer antimalarial drugs is scanty halofantrine into newer antimalarial drugs is scanty Research Researchin the following and the parasite is fast developing resistance even and the parasite is fast developing resistance even for newer drugs. be usedwe deplete the newer drugs for It should not Thus if we deplete the newer drugs newer drugs. be used on the same day with It should not Thus if on the same day withsituations where it is sulphadoxine. In such may not can be given the next sulphadoxine. In such cases it havebe given the next by misusing them, we may not can anything left for sulphadoxine. by misusing them, we cases it have anything left for day. day. treating ALL DRUG RESISTANT malaria in the not- treating ALL DRUG RESISTANT malaria in the not-contraindicated: too-far-future. too- far- too-far-future. not- Therefore, newer anti malarial drugs should be Therefore, newer anti malarial drugs should be used only when definitely indicated and not used only when definitely indicated and not indiscriminately. Do not misuse the indiscriminately. These drugs should be used ONLY whennewer antimalarial These drugs should be used ONLY when parasite index or other methods PROVE drug parasite index or other methods PROVE drug resistant malaria.drugs. We need to resistant malaria. In addition, artemisinin derivatives can be usedpreserve them for future. In addition, artemisinin derivatives can be used in cases of hyperparasitemia or life-threatening in cases of hyperparasitemia or life- life-threatening complications on account of their ability to clear the complications on account of their ability to clear the parasitemia earlier compared to other anti malarial parasitemia earlier compared to other anti malarial Dr.G.C Sahu/ROHFW/GoI/ABad drugs. drugs.
  42. 42. While most of the the clinical manifestationsof malaria are caused by the malarial are caused by the malarialinfection per se………………infection per se………………• High grade fever as well as the side effectsof anti malarial therapy can also contributeto the clinical manifestations.• All these may act in unison, furtherconfusing the picture.• In some cases, secondary infections likepneumonia or urinary tract infection can addto the woes. All the above facts should always be kept in mind. Dr.G.C Sahu/ROHFW/GoI/ABad
  43. 43. Artemisinin based combinations- 1 combinations- Artemisinin based combinations are known to improve cure rates, reduce the Artemisinin based combinations are known to improve cure rates, reduce the development of resistance and they might decrease transmission of drug-resistant development of resistance and they might decrease transmission of drug-resistant parasites. The total effect of artemisinin combinations (which can be simultaneous or parasites. The total effect of artemisinin combinations (which can be simultaneous orsequential) is to reduce the chance of parasite recrudescence, reduce the within-sequential) is to reduce the chance of parasite recrudescence, reduce the within- patient selection pressure, and prevent transmission.. patient selection pressure, and prevent transmission Artesunate + Chloroquine Very high chloroquine failure rates (>60%) and sub-optimal Efficacy efficacy of the combination (<85% cure rate) Not approved; Not a viable option in areas with pre- Status existing moderate to high levels of P. falciparum resistance to Chloroquine Dr.G.C Sahu/ROHFW/GoI/ABad
  44. 44. Artemisinin based combinations - 2Artesunate + Sulfadoxine/Pyrimethamine (SP) Efficacy and advantages Well tolerated; Efficacy dependent on the level of pre- existing resistance to SP Disadvantages Pharmacokinetic mismatch; adverse effects to SP Dose Artesunate 4mg/kg once daily for 3 days and SP single dose of 25mg/kg and 1.25mg/kg respectively Status Approved (in areas where SP efficacy is high); Resistance to SP limits the use Dr.G.C Sahu/ROHFW/GoI/ABad
  45. 45. Artemisinin based combinations - 3Artemether + Lumefantrine (Coartem,TM RiametTM) (Coartem,TM RiametTM) Efficacy and advantages As effective, and better tolerated, as artesunate plus mefloquine; No serious adverse reactions documented Disadvantages ?Irreversible hearing impairment Dose Artemether 1.5mg/kg and Lumifantrine 9mg/kg at 0, 8, 24, 36, 48 and 60 hours Status Approved; Not recommended for use in pregnancy and lactating women Dr.G.C Sahu/ROHFW/GoI/ABad
  46. 46. Combination therapies recommended by WHOFDC • Artemether/Lumefantrine • Artesunate + amodiaquine ACTs • Artesunate + SP • Artesunate + mefloquine Dr.G.C Sahu/ROHFW/GoI/ABad
  47. 47. How and when can Artemisinin drugsbe affordable for most malaria patients in the world?
  48. 48. Using compounds to replace the single- ingredient drugs should be recommended.Artemisinin drugs Alone:• High consuming of Artemisinin• High cost• Long treatment courseArtemisinin compounds(ACT):• Low consuming of artemisinin• Lower cost• Short treatment course• Low recrudescence, easy to finish the complete treatment course.
  49. 49. Parasitological rationale for combination treatment• If for example 1 of 106 parasites is resistant to treatment A and 1 of 106 parasites is resistant to treatment B, then 1 of 1012 will be resistant to both.• A typical malaria patient would have 1010 parasites
  50. 50. Practical rationale for combination therapy• Most of the artemisinin drug combination regimens last 3 days and are well tolerated• Hence high compliance• High compliance + high efficacy = high effectiveness• High effectiveness means long durability• Long durability means rarer policy changes with their inevitable costs and woes
  51. 51. Quick comparison between blood schizonticidal drugs schizonticidal drugs Chloroquine Sulpha/Pyri Quinine Mefloquine Quinghasu Efficacy ++++ ++ +++ +++ +++++ +++++Onset of action Rapid Slow Rapid Rapid Fastest Fastest Prototype drug, Only for Only for resistant Only for Reserved for drug resistant first choice for all uncomplicated, P. falciparum uncomplicated, multi P. falciparum. However, it falciparum. cases resistant drug resistant may be considered in life P. falciparum P. falciparum threatening complications Use of P. falciparum due to its rapid action Parenteral Not useful in acute Drug of choice for Not to be used in Useful in severe Use in severe preparation can be illness; can be co- co- severe malaria; it was acute illness; can be malaria; may be used in areas with prescribed with the only parenteral co-prescribed with co- more effective and P. falciparum sensitive strains other parenteral drug available for a artemisinin after better tolerated than malaria antimalarials long time until acute phase is over. quinine. parenteral chloroquine and artemisinin arrived Toxicity ++ +++ +++ +++ + Almost none, only Allergy to sulpha Prior hypersensitive Epilepsy, psychosis, NoneContra indications advanced liver reactions heart block, ß blocker disease use Use in pregnancy Yes Only in 2nd trimester Only if warranted, Not in first trimester Yes, if the situation Yes, if the situation if warranted watch for demands demands hypoglycemia Cost Cheapest Cheap Moderate Expensive Expensive 51 Dr.G.C Sahu/ROHFW/GoI/ABad
  52. 52. Malaria Parasite Resistance• Mechanism of resistance is due to genetic mutations in malaria parasite Resistance Resistance More Drug Used Delayed ResponseIncreased Clinical Cases Recurrence of Infection Increase Transmission Increased Gametocyte Dr.G.C Sahu/ROHFW/GoI/ABad
  53. 53. The Acts of Commissions And Omissions IN MALARIA. The Acts of Commissions And Omissions IN MALARIA. Mis-diagnosis Mis-diagnosis In an endemic area, there may be a tendency to diagnose all cases of In an endemic area, there may be a tendency to diagnose all cases of fever as malaria, forgetting to even consider other causes. Whereas fever as malaria, forgetting to even consider other causes. Whereas Over-diagnosis Over-diagnosis presumptive treatment with chloroquine in cases of fever is well presumptive treatment with chloroquine in cases of fever is well Obsession with malaria Obsession with malaria accepted, sometimes, doctors may go beyond that and indulge in accepted, sometimes, doctors may go beyond that and indulge inand forgetting the OTHER presumptive treatment with newer drugs, (reserved for multi drugand forgetting the OTHER presumptive treatment with newer drugs, (reserved for multi drug causes of fever causes of fever resistance falciparum malaria), even if the MP test is repeatedly resistance falciparum malaria), even if the MP test is repeatedly negative. Most often such cases turn out to be non-malarial fevers. negative. Most often such cases turn out to be non-malarial fevers. Therefore consider other causes of fever. Therefore consider other causes of fever. 1. Malaria may not be considered as a possibility in places where iit is 1. Malaria may not be considered as a possibility in places where t is not common-history of travel to malarious area should be elicited. not common-history of travel to malarious area should be elicited. 2. It may not be considered in patients on chemoprophylaxis for 2. It may not be considered in patients on chemoprophylaxis for Under-diagnosis Under-diagnosis malaria. Chemoprophylaxis does not offer 100% protection and malaria malaria. Chemoprophylaxis does not offer 100% protection and malaria Forgetting malaria Forgetting malaria should be therefore looked for in these patients. should be therefore looked for in these patients. 3. Malaria can always co-exist with other infections in an endemic area. 3. Malaria can always co-exist with other infections in an endemic area. Therefore, it should be considered even in patients with other obvious Therefore, it should be considered even in patients with other obvious infections causing fever. infections causing fever. Dr.G.C Sahu/ROHFW/GoI/ABad 53
  54. 54. Mis-report Mis-report Artifacts may be read as malarial parasites on peripheral smear as well as QBC test. DirtyFalse positive slides, contaminated stains, inexperienced microscopist, recycled QBC tubes may be the microscopist, causes. Malarial parasites may be missed and the test reported as negative. Inadequate smear, dirty stains, contaminated/deteriorated stains, wrong buffer pH, inexperienced technician,False negative incomplete examination of the slide, storage of blood in anticoagulant before preparing the smear etc. may contribute to this problem. Dr.G.C Sahu/ROHFW/GoI/ABad 54
  55. 55. Mis-judgement of severity Mis-judgement Panic reaction to P. falciparum malaria is common among Panic reaction to P. falciparum malaria is common among patients and not uncommon among doctors, resulting in patients and not uncommon among doctors, resulting in over-reaction to the situation and over-treatment. Mild over-reaction to the situation and over-treatment. Mild anemia, mild icterus, headache etc. are common in anemia, mild icterus, headache etc. are common in falciparum malaria and need not necessarily imply severe falciparum malaria and need not necessarily imply severeOver-estimationOver-estimation malaria. Such patients need not be treated with parenteral or malaria. Such patients need not be treated with parenteral or second line antimalarial drugs. Also it should not be second line antimalarial drugs. Also it should not be forgotten that some of the manifestations could be due to forgotten that some of the manifestations could be due to fever, drugs etc., and not necessarily due to severe malaria. fever, drugs etc., and not necessarily due to severe malaria. P. falciparum malaria can cause dramatic complications and P. falciparum malaria can cause dramatic complications and therefore one should be always looking for them. Patients therefore one should be always looking for them. Patients who are at for development of complications should be who are at for development of complications should beUnder-estimationUnder-estimation ideally admitted for observation. Any indication of ideally admitted for observation. Any indication of complication should be properly managed. Neglecting the complication should be properly managed. Neglecting the signs like high fever, prostration, significant pallor and signs like high fever, prostration, significant pallor and jaundice, dehydration etc. may prove costly. Hypoglycemia jaundice, dehydration etc. may prove costly. Hypoglycemia may be easily missed. may be easily missed. Dr.G.C Sahu/ROHFW/GoI/ABad 55
  56. 56. IT MUST ALWAYS BE REMEMBERED THAT MALARIA IS ALOCAL PHENOMENA AND ITS FOCAL NATURE IS DETERMINED BY ITS FOCAL THE FLIGHT RANGE OF THE LOCAL VECTOR(S)POPULATION . AS LONG AS MALARIA PARASITES REMAIN IN THE HUMANBODY, IT IS MORE OR LESS PROTECTED FROM THE ENVIRONMENTAND ITS DEVELOPMENT CONTINUES UNABATED EXCEPT FOR THE INFLUENCE OF THE IMMUNITY OR ADMINISTRATION OF APPRPRIATE ANTI-MALARIA DRUGS .. ANTI-MALARIA Dr.G.C Sahu/ROHFW/GoI/ABad 56
  57. 57. …..AndDr.G.C Sahu/ROHFW/GoI/ABad 57
  58. 58. ADDITIONAL INFORMATIONS
  59. 59. Level of parasitemia and clinical correlates Parasitemia Parasites ccm/ l ccm/ Remarks 0.0001-0.0004% 0.0001- 5-20 Sensitivity of thick blood film 0.002% 100 Patients may have symptoms below this level, where malaria is seasonal seasonal 0.2% 10,000 Level above which immunes show symptoms 2% 100,000 Maximum parasitemia of P.vivax. and P.ovale 2-5% 100,000-250,000 100,000- Hyperparasitemia/severe malaria*, increased mortality Hyperparasitemia/severe 10% 500,000 Exchange transfusion may be considered/high mortality* WHO criteria for severe malaria are parasitemia > 10,000 / l and severe anemia (Hb < 5 g/l). Prognosis (Hb g/l). is poor if > 20% parasites are pigment containing trophozoites and schizonts and/or if > 5% of neutrophils contain visible pigment. Dr.G.C Sahu/ROHFW/GoI/ABad
  60. 60. Examination of blood smear Demonstration of the parasite in a smear of the blood definitely establishes Demonstration of the parasite in a smear of the blood definitely establishesthe presence of malaria.the presence of malaria. A negative finding on examination does not rule out malaria.. Only 50% A negative finding on examination does not rule out malaria Only 50%of children with malaria are smear positive, even on repeated examination.of children with malaria are smear positive, even on repeated examination. A positive finding on examination does not confirm clinical malaria, A positive finding on examination does not confirm clinical malaria,especially in patients from an endemic area, in whom a symptomatic parasitemiaespecially in patients from an endemic area, in whom a symptomatic parasitemiaoften exists.often exists. Both thick and thin films are essential.. If the parasitemia is light, a thin film Both thick and thin films are essential If the parasitemia is light, a thin filmexamination may miss the diagnosis. Thick films save time in diagnosis of scantyexamination may miss the diagnosis. Thick films save time in diagnosis of scantyinfections but make species identification of the parasite difficult.infections but make species identification of the parasite difficult. At least 100-200 fields of a thick film should be scrutinized before a At least 100-200 fields of a thick film should be scrutinized before aslide is reported as negative for malaria. In doubtful cases, the examinationslide is reported as negative for malaria. In doubtful cases, the examinationcan be repeated after 4 hours.can be repeated after 4 hours. Various techniques to enhance the diagnostic utility of the peripheral blood smear Various techniques to enhance the diagnostic utility of the peripheral blood smearexamination are in use. Fluorescent staining and microscopy, centrifugation,examination are in use. Fluorescent staining and microscopy, centrifugation,selective magnetic separation techniques, and other techniques have been used butselective magnetic separation techniques, and other techniques have been used buthave only a moderate effect. Dr.G.C Sahu/ROHFW/GoI/ABadhave only a moderate effect. 60
  61. 61. Treatment of P. vivax malaria: A flow chart Chloroquine + Primaquine After 48 hours Clinical Recovery Status quo / worse Continue the treatment Suspect P. falciparum, repeat M.P. test at 48 Repeat the M.P. test on hrs. (A thin smear examination is better for species the 6th day identification and for assessing parasite count)NEGATIVE POSITIVE POSITIVE NEGATIVECured Consider other causes P. Falciparum P. Vivax of fever, may Treat as possibly If the patient has be in typical malarial association chloroquine resistant complications, treat as with malaria P. falciparum; otherwise, wait. Dr.G.C Sahu/ROHFW/GoI/ABad 61
  62. 62. Treatment of P. falciparum malaria -A flow chart -A Complicated and Uncomplicated and chloroquine chloroquine sensitive sensitive Tab. Chloroquine + Primaquine Inj. Chloroquine + Inj. single dose Primaquine single dose Status quo/ worse; Better; parasite count reduced by parasite count reduced > 75% by < 75% Continue Consider resistance Dr.G.C Sahu/ROHFW/GoI/ABad 62
  63. 63. Drugs for chloroquine resistant Pf malaria Complicated and Uncomplicated and ChloroquineChloroquine resistant resistant 1. Inj.Quinine + 1. Inj.Quinine + Pyrimethamine/Sulphadoxine Pyrimethamine/Sulphadoxine Use any one of the following combinations: Use any one of the following combinations: 2. Inj. Quinine + Tetracycline / 2. Inj. Quinine + Tetracycline /1. Tab.Quinine + Tab. Pyrimethamine/ Sulfa.1. Tab.Quinine + Tab. Pyrimethamine/ Sulfa. Doxycycline Doxycycline2. Tab. Quinine + Tetracycline /doxycycline 2. Tab. Quinine + Tetracycline /doxycycline 3. Inj. Artemether / Arteether / 3. Inj. Artemether / Arteether / 3. Tab. Artesunate + Tab. Mefloquine 3. Tab. Artesunate + Tab. Mefloquine Artesunate + Mefloquine. Artesunate + Mefloquine.4.Tab.Mefloquine + Pyrimethamine/Sulpha. 4.Tab.Mefloquine + Pyrimethamine/Sulpha. 63 Dr.G.C Sahu/ROHFW/GoI/ABad
  64. 64. Clinical approach to cases of recurrent malaria Recurrence Within 8-10 After 2 After 2 days weeks months 1st ?P. falciparum ?Re-infection ?Re-infection possibility 2nd ?Compliance ?P. falciparum ?Relapse possibility Dr.G.C Sahu/ROHFW/GoI/ABad 64
  65. 65. Established antimalarial drugs Drug Role Best features(s) Best features(s) Limitation Chloroquine TX of and CP against non-Pf TX of and CP against non-Pf Very safe; low cost; Very safe; low cost; Widespread R Widespread R and sensitive Pf parasites and sensitive Pf parasites long half-life long half-lifeQuinine/quinidineQuinine/quinidine Best TX for Pf malaria; low Best TX for Pf malaria; low Limited R; rapidly Limited R; rapidly Fairly toxic ((cinchonism, Fairly toxic cinchonism, cost cost acting acting cardiac) cardiac) Amodiaquine TX of R Pf malaria TX of R Pf malaria Low cost Low cost Toxicity (bone marrow, Toxicity (bone marrow, liver); R Common liver); R Common Mefloquine CP against R malaria; not CP against R malaria; not Relatively little R, Relatively little R, Moderately toxic (mostly Moderately toxic (mostly approved for TX in United approved for TX in United though increasing; though increasing; CNS); high cost; R in SE CNS); high cost; R in SE State State long half-life long half-life Asia Asia Fansidar TX of Pf malaria; no longer TX of Pf malaria; no longer Relatively low cost; Relatively low cost; Skin toxicity (can be fatal); Skin toxicity (can be fatal); recommended for CP recommended for CP long half-life long half-life increasing R increasing R Primaquine Eradication of chronic liver Eradication of chronic liver Only drug for this Only drug for this Hemolysis with G6Pd Hemolysis with G6Pd stage Pv,Po malaria stage Pv,Po malaria indication indication deficiency; increasing R deficiency; increasing R Progunil CP only (often with CP only (often with Low cost; nontoxic Low cost; nontoxic R common R common Chloroquine) Chloroquine)S-P CombinationsS-P Combinations CP only (often with CP only (often with Low cost Low cost R Common; skin rashes R Common; skin rashes Chloroquine) Chloroquine) Tetracycline Cp; TX of Pf malaria in Cp; TX of Pf malaria in Low cost Low cost Skin and gastrointestinal Skin and gastrointestinal Combination with quinine Combination with quinine Dr.G.C Sahu/ROHFW/GoI/ABad 65
  66. 66. New antimalarial drugs Drug Role Best Feature(s) Feature(s) Limitations Halofantriine TX of Pf malaria; not TX of Pf malaria; not Usually effective against R Usually effective against R Variable bioavailability, Variable bioavailability, approved for CP approved for CP Pf malaria Pf malaria cardiac toxicity cardiac toxicity Artemisinin and Artemisinin and TX of Pf malaria TX of Pf malaria Rapidly acting; effective Rapidly acting; effective Recurrence after TX fairly Recurrence after TX fairlyrelated compoundsrelated compounds against multidrug-R against multidrug-R common common Atovaquone ? TX of Pf malaria? ? TX of Pf malaria? Limited toxicity Limited toxicity Limited studies so far Limited studies so far CP (Probably in CP (Probably in show frequent recurrence show frequent recurrence combination with combination with after TX after TX proguanil proguanil Pyronaridine ? TX of malaria ? TX of malaria Effective against R strains Effective against R strains Studies limited to date Studies limited to dateDesferrioxamine ? TX of severe Pf ? TX of severe Pf Well tolerated when used Well tolerated when used Studies limited to date Studies limited to date malaria malaria for iron overload for iron overload Azithromycin ? CP ? CP Limited toxicity Limited toxicity Studies limited to date Studies limited to date Dr.G.C Sahu/ROHFW/GoI/ABad 66
  67. 67. Other Drugs for Chemotherapy of Malaria Many drugs have been tested for Many drugs have been tested for Clindamycin: It acts Clindamycin: It acts their potential anti malarial effects. their potential anti malarial effects. Fluoroquinolones: Fluoroquinolones: Fluoroquinolones: by inhibiting the protein by inhibiting the protein Research into newer anti malarials Research into newer anti malarials Both Both synthesis by binding to synthesis by binding to being scanty, such attempts might being scanty, such attempts might throw up one or two candidates for throw up one or two candidates for ciprofloxacin ciprofloxacin the 50s subunit of the 50s subunit of use in malaria, however, these use in malaria, however, these and norfloxacin and norfloxacin ribosomes. It can be ribosomes. It can be ribosomes. drugs are yet to find a place in drugs are yet to find a place in have been found to have been found to used for drug resistant used for drug resistant standard anti malarial regimen. standard anti malarial regimen. Clindamycin, fluoroquinolones Clindamycin, fluoroquinolones have anti malarial have anti malarial malaria along with malaria along with Clindamycin, like ciprofloxacin and like ciprofloxacin and activity both in activity both in quinine at a dose of 10 quinine at a dose of 10 Norfloxacin, azithromycin etc. Norfloxacin, azithromycin etc. Norfloxacin, vitro and in vivo. vitro and in vivo. mg/kg 8 hourly for 5 mg/kg 8 hourly for 5 have been found to be effective have been found to be effective However, results However, results days. Adverse effects days. Adverse effects against malarial parasites. against malarial parasites. include are not consistent. are not consistent. include Atovaquone; Atovaquone; Atovaquone; pseudomembrane colitis pseudomembrane colitis Desferrioxamine; Desferrioxamine; Desferrioxamine; and skin rashes. In one and skin rashes. In one Pyronaridine; Piperaquine; Pyronaridine; Piperaquine; Pyronaridine; Piperaquine; study, a cure rate of only study, a cure rate of only WR-288, 605; and 566C80 WR- WR-288, 605; and 566C80 50% was observed. (Hall Atovaquone plus Proguanil: Atovaquone plus Proguanil: Proguanil: 50% was observed. (Hall are drugs undergoing are drugs undergoing A fixed dose combination of A fixed dose combination of et al) et al) trials. trials. atovaquone and proguanil atovaquone and proguanil hydrochloride (Malarone™) is now Malarone™ hydrochloride (Malarone™) is now approved for both treatment and approved for both treatment and Pyronaridine: Structurally, it Pyronaridine: Structurally, it Pyronaridine: prophylaxis of malaria. It is available prophylaxis of malaria. It is available malaria. resembles amodiaquine and has been resembles amodiaquine and has been as 250 mg atovaquone + 100 mg found to be highly effective against found to be highly effective againstAzithromycin: AzithromycinAzithromycin: Azithromycin as 250 mg atovaquone + 100 mg chloroquine resistant strains in China. chloroquine resistant strains in China. proguanil per tablet for adults and proguanil per tablet for adults andis found to have anti malarialis found to have anti malarial 62.5 mg atovaquone + 25 mg Piperaquine: Its activity is similar to Piperaquine: Its activity is similar to Piperaquine: 62.5 mg atovaquone + 25 mg that of chloroquine. A combinationactivity and has been found toactivity and has been found to proguanil per tablet for children.. It that of chloroquine. A combination chloroquine. proguanil per tablet for children It with artimisinin is undergoing studies. with artimisinin is undergoing studies.be useful as a causalbe useful as a causal has been shown to be highly has been shown to be highly WR-288, 605: It is 7.4 times more WR- efficacious in the treatment of WR-288, 605: It is 7.4 times moreprophylactic agent. It wasprophylactic agent. It was efficacious in the treatment of uncomplicated malaria caused by active than primaquine as a tissue active than primaquine as a tissue uncomplicated malaria caused byfound to be effective at thefound to be effective at the Plasmodium falciparum, including Plasmodium falciparum, including falciparum, schizonticidal drug. It has lesser schizonticidal drug. It has lesserdose of 300 mg stat, followed malaria that has been acquired in toxicity, good oral bio-availability toxicity, good oral bio- bio-availabilitydose of 300 mg stat, followed malaria that has been acquired in areas with chloroquine-resistant or areas with chloroquine- chloroquine-resistant or and longer half-life. and longer half- half-life.by 250 mg daily for 7 days asby 250 mg daily for 7 days as multidrug-resistant strains. The daily multidrug- multidrug-resistant strains. The daily strains. Lumefantrine is an aryl alcohol Lumefantrine is an aryl alcohola prophylactic agent againsta prophylactic agent against dose should be taken at the same dose should be taken at the same related to quinine, mefloquine and related to quinine, mefloquine andchloroquine resistant P.chloroquine resistant P. time each day with food or milk. time each day with food or milk. halofantrine that is devoid of cardiac halofantrine that is devoid of cardiacfalciparum infection. toxicity of halofantrine. It is being toxicity of halofantrine. It is beingfalciparum infection. infection. halofantrine. tried in combination with artemether. tried in combination with artemether. artemether. Dr.G.C Sahu/ROHFW/GoI/ABad
  68. 68. The Primaquine Questions - Confusions in Primaquine Use In Malaria Often primaquine is not prescribed for falciparum malaria because it is not needed for attaining a cure of the infection. But it is required to prevent the spread of falciparum infection because unlike in case of vivax malaria, Chloroquine does not sterilize the To use or gametocytes of falciparum species. Therefore, if primaquine is not used in falciparum malaria, there will be a selective spread of P. falciparum malaria, which may be even resistant to drugs. Therefore, do not forget to use primaquine in P. falciparum malaria- not? prevent the spread of P. falciparum, prevent the spread of drug resistant strains! Primaquine is hence a must for both P.vivax and P.falciparum infections.What is the 0.25mg/kg/day (once a day) for 5 days in P. vivax; 0.75 mg/kg as single dose in P. dose? falciparum. In cases of P. vivax malaria, the National Malaria Eradication Programme (N.M.E.P.) in India recommends*5 days or 14 Primaquine therapy for 5 days, whereas the standard literature recommends for 14 days. 5 days therapy is adequate in most cases. In cases of relapse, a 14-day treatment is advisable. days? What is the At present, Primaquine is the only drug available for tissue schizonticidal activity in P. vivax malaria and gametocytocidal activity in P. falciparum infection. Therefore, it must be used in bothalternative to these infections. Therefore, at present there are no alternatives to primaquine. Newer antiprimaquine? malarials like mefloquine or artemisinin derivatives are NOT substitutes for primaquine! Is thereprimaquine Although resistance to primaquine has been reported from S. E. Asia and Africa, it is rare. Suchresistance? cases are managed with a higher dose of primaquine.Primaquine or ‘parda’? In some hospitals, patients with malaria are made to lie inside mosquito nets, with the idea of preventing the spread of the infection to the hospital mosquitoes and hence to other patients. (Mosquito Often these patients are not administered primaquine. Remember, mosquito nets may not prevent nets) the spread of falciparum malaria, but Primaquine WILL. Dr.G.C Sahu/ROHFW/GoI/ABad 68
  69. 69. G-6 P D Deficiency-Four most common variants out of 300+ known All WorldGdB Normal Activity Populations Normal Activity; Acetic acid substituted for asparagine at Africa (mostGdA position 126, Guanine for adenine at DNA position376 common variant) 8 - 20% Normal Activity; Methionine for Valine at position 67 and Aspartic Acid for Asparagine at position 126, Adenine forGdA- Guanine at position 202 and Guanine for Adenine at position Africa 376 Iran, Iraq, India, < 5% Normal Activity; Phenylalanine for Serine atGdMed Pakistan, Greece, position 188; Thiamine for Cytosine at position 563 Sardinia Dr.G.C Sahu/ROHFW/GoI/ABad 69
  70. 70. Primaquine Treatment Regimens 1 tablet* per day x 14 days G-6-PD NORMAL * The Indian programme recommends 5 days RT regime to all P.vivax cases. 3 tablets per week G-6-PD deficiency (Mild African form) for 8 weeks G-6-PD deficiency 2 tablets per week for (More severe 30 weeksMediterranean variety)- Indian strain •1 tablet consists of 26.3 mg pimaquine phosphate, 15 mg primaquine base. •…..So there is no absolute contraindication ! ! Dr.G.C Sahu/ROHFW/GoI/ABad 70
  71. 71. Potential Vaccines in Malaria. Target Protection Sporozoite anti-infection Merozoite anti-parasite Infected RBC anti-parasite Exo-antigens anti-disease Sexual stages anti-transmission Malaria is a preventable infection that can be fatal if left untreated.Currently, you cannot be vaccinated against malaria, but you can protect yourself 71 Dr.G.C Sahu/ROHFW/GoI/ABad

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