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3 MALARIA Basic considerations and clinical features Malaria in man is caused by four distinct speciesofmalaria parasite: * P.vivax,P.falciparum,P.malariae,P.ovale * P.Vivax & P.falciparum are resposible for most of the infections found throughout the malarial belt. *P.malariae is widely distributed but is less common. *P.ovale is rare but in West Africa it seems to have replaced P.vivax. *Malaria is estimated to kill between 1.5 and 2.7 million people each year. *In an average one person, often a child below 5yrs. Of age die in every 12 seconds. *Additional 300-500 million people contact the disease each year(Butlon,1997)

4 MALARIA MILESTONES 1600 B.C. References can be found in the writings 400 Hippocrates’ description of malaria.Charaka and Sushrutha gave vivid descriptions of malaria & even associated it with the bites of the mosquitoes. 1640 A.D. Huan del Vego – Cinchona bark for malaria treatment 1696 Morton first detailed picture of Malaria. 1717 Lanicsi Links malaria to bad air in swamps and thus originates the name malaria. 1816 Gize-Extraction of quinine from cinchona bark 1820 Pelletier and Caventou – extraction of pure quinine alkaloids 1880 Laveran identifies malarial parasite under microscope. 1895 Golgi-Identification of P.vivax & P.malariae 1889-90 Sakharov,Marchiafava,Celli-identification of P.falciparum cont…….

5 1897 Ronald Ross–Demonstration on malarial oocysts in gut of female anopheles mosquito 1934 Chloroquine synthesized by Germans. 1939 Paul Miller – Insecticidal properties of DDT 1944 Curd, Davey, Rose – Synthesis of Proguanil for treatment. 1950 Elderfield– Synthesis of primaquine. 1967 WHO- emphasis on control of malaria rather than global eradication of the disease. 1990’s Synthesis of quinine analogue mefloquine. Artemesinins obtained from Quinghaosu introduced for resistant malaria. 1994 Sequencing of P.Falciparum Genome begun 1999 WHO Recommends – Combined therapy to delay resistance development to anti-malarials Including Artemesinin. 2000 Chloroquine resistance gene identified as PfeRTK767

6 PLASMODIUM VIVAX 1. Red cells containing parasites are usually enlarged. 2. Schuffner”s dots are frequently present in the red cells as shown. 3. The mature ring forms tend to be large and coarse. 4. Developing forms are frequently present. PLASMODIUM FALCIPARUM 1. Red cells are not enlarged. 2. Rings appear fine and delicate & there maybe several in one cell. 3. It is unusual to see developing forms in peripheral blood films. 4. Gametocytes have a characteristic crescent shape appearance.

7 PLASMODIUM MALARIAE 1.Ring forms may have a squarish appearance. 2.Band forms are a characteristic of this species. 3.Mature schizonts may have a typical daisy head appearance with up to ten merozoites. PLASMODIUM OVALE 1. Only found in Africa. 2. Red cells enlarged. 3. Comet forms common. 4. Rings large and coarser.

8 MALARIA PATHOLOGY * * Pigmentation of various organs with haemozoin giving a characteristic “SLATE GREY” Or “BLACK COLOUR”. * * Hyperplasia of the Reticulo-Endothelial system resulting from increased activity in order to deal with parasite and their product. * * Parasitized erythrocytes filling the Lumina of the capillaries of the internal organs. This is particularly seen in P.falciparum infection. * * Vascular changes-dilatation of sinusoidal vessels, perivascular haemorrhages are seen in falciparum malaria. * * Degenerative changes of parenchyma cells due to hypoxia [ seen in falciparum malaria]. * * Effects of anaemia. * * Immunosupression has been observed in malarial infection and this may lead to secondary bacterial infection.

9 THE SPLEEN Spleen is enlarged,colour varies from slate gray to black, capsule is thin & stretched, consistency soft in acute cases while firm in chronic cases. “ AGUE CAKE SPLEEN ” THE LIVER The Liver is uniformly enlarged due to vascular congestion and proliferation of reticuloendothelial cells. The colour varies from chocolate red to slate gray or even black depending upon the stage of congestion and deposition of the haemozoin pigment. BONE MARROW KIDNEYS

10 Does the Patient Need Hospitalization ? Seriously ill patients needing Hospitalization- Include:- Continuous vomiting andinability to retain oval drugs. Increasing Headache. Severe Dehydration. Poor general condition. Alteration of sensorium. Suspected cerebral malaria with unarousable Coma. Hyper pyrexia, convulsion. Pregnancy Oedema. Bleeding disorders.

11 COMPLICATIONS : Cerebral malaria and coma. Hyperpyrexia. Haemolytic Anaemia. Non cardiogenic pulmonary oedema (ARDS ) ; Acute tubular necrosis and renal failure ; Acute Hepatomegaly and centrilobular necrosis ; Hypoglycaemia ; An adrenal insufficiency like syndrome ; Cardiac dysrhythmias ; Lactic acidosis.

12 Pathophysiology : of complicated malaria Pathology associated with all malarial species is related to the rupture of the infected RBC and release of haemozoin (Malarial pigment). An increased in reticulo-endothelial system is fond causing hepato-splenomegaly. Cytoadhence of infected red cells to the vascular endothelium & RBC’s causing rossetting-compromises microcirculatory flow. In cerebral malaria-due to sequestration of the infected erythrocyles in the cerebral microcirculation. Sequestration in cytiadherence of trophozoite and schizont infected erythrocytes to the endothelial cells of the deeper vascular beds of the vital organs-specially the brain,liver,gut,heart & placenta,

13 Table 1= Anti-malarial Drug DRUG Indications Dosage Side effects/ Precautions C hloroquine Tabs: 150/300mg Syp: 50mg/ml Inj.:50mg/ml Treatment Prophylaxis Adults: Oral : Day 1=600mg stat 300mg after 6 hrs Day 2 = 300mg OD Day 3 = 300mg OD Injectable IM = 10ml stat, 5ml after 6 hrs., 5ml daily for 2 days Children: Oral : 10mg/kg stat, 5mg/kg after 6 hrs. Then 5mg/kg/day for 2 days 300 mg OD weekly,2 wks Before entering endemic Area continue for 4 wks after leaving Hepatic and/or renal dysfunction, Vision problems, Psoriasis, Epilepsy, Porphyria.

14 Contd…. Table 1:- Anti-malarial Drugs Drug Indications Dosage Side effects/ precautions Sulphadoxine Pyrimethamine Tablets 500mg sulphadoxine+ 25mg pyrimethamine Liquid: 250mg sulphadoxine+ 12.5mg pyrimethamine/5ml. Treatment Prophylaxis Adults :<50 kg 2 tabs. >50 kg 2 tabs. Children 0.5-0.75 mg/kg per dose. Adults : 1 tab. Once wkly. Unusual bleeding, Bruising rash, Fever, sore throat Quinine 300mg,600mg tabs, 300mg/ml inj. Adults : 300-600mg TID 5-7 days Children : 25mg/kg/day div. Every 8 hrs for 7 days, Disturbed vision, tinnitus,nausea, headache, rash, Special Precaution Renal dysfunction, optic neuritis, myasthenia gravis, cardiac dysfunction

15 Contd. Drug Indications Dosage Side effects/ precautions Primaquine 2.5,7.5,15mg tabs. Radical cure of vivax malaria Adults : 15mg/day x 14 days Along with standard Chloroquine treatment Children : 25mg/kg/day div. Every 8 hrs for 7 days Nausea,vomiting,weakness abd.pain, Methhaemoglobinaemia, Anemia, Leucopaemia, G6PD test Mefloquine 250 mg tabs. Resistant malaria Adults : 15mg/kg single dose Max.1259-1500mg or 750mg stat followed by another 250mg 6-8 hrs. Later Children : 15-25mg/kg, single oral dose Prophylaxis 5mg/kg/wk Nausea,vomiting,diarrhoe a,dizziness,rash, Somnolescence, Neuro-psychiatric symdrome, neuropathy, vestibulopathy, circulatory disease

16 Contd…. Artemether 40mg tabs. 80mg/ml inj. Resistant falciparum malaria, Severe falciparum malaria IM 3.2mg/kg initially then 1.6mg/kg 12-24 hrs. for 3-7 days Adults : Oral tab.Day 1=80mg BD Then, 80mg OD for 2-5 days. Children : Day 1=1.6mg/kg BD 1.6 mg/kg OD for 2-5 days Cardio toxicity, Blood changes, Raised liver Enzymes, Neurotoxicity. A rtesunate 50mg tab. 60mg inj. Resistant Falciparum Malaria, Severe malaria. Oral:Day 1 : 100mg BD Day2-5 : 50mg BD Parenteral : 2mg/kg stat, 1mg/kg 12 hrly. Till oral treatment possible Drug fever,rash Cardio toxicity, Raised liver enzymes, Arteether 150mg in 2ml amp. Resistant Falciparum malaria Adult : 150mg inj. IM once daily for 3 days. Children : 3mg/kg/day IM x 3 days. Neurotoxicity Nausea, Dizziness, Depressed GIT activity

17 Treatment of Resistant Malaria (Uncomplicated Resistant) 1.S ulphadoxine- P yrimethamine :- patients weighing >50kg. 3 tablets stat, patients weighing <50kg. 2 tablets stat, (provided patient has no sulpha allergy) + quinine 600mg TDS for 2 days. 2.Q uinine 600mg TDS or Quinine sulphate 10mg/kg/8 hrly for 7 days + Doxycycline 100mg BD or Tetracycline 500 mg BD for 7 days. 3.M efloquine 750 mg stat, followed by 750 mg after 6 hrs. (Pts. Weighing > 50 kg) or 500mg stat followed by 500mg after 6hrs. (Pts. Weighing < 50 kg.)

18 Treatment of Resistant Malaria (Complicated Resistant) Ideally all patients with complicated should be hospitalized. Inj. Quinine IV slowly in Dextrose. Higher loading dose is preferred relative to maintenance dose. In patients requiring more than 48 hours parenteral therapy, reduce the maintenance dose by ½ rd. In presence of renal failure; quinine dose should be halved after 48 hours. Inj. Artemether 160mg IM, then 80mg daily for 4 days

19 Artemether Dosage regimen RezartRoute Adults Pediatric Day 1Days 2-5 Day 1Days 2-5 80 mg/ Ampoule 60mg cap IM Oral 1.6mg/kg twice 1.6mg/kg twice 1.6 mg/kg once 1.6mg/kg once 1.6 mg/kg twice 1.6 mg/kg twice 1.6 mg/kg Once 1.6mg/kg once

20 Comparative Efficacy : In Cerebral Malaria Parameter Arteether Quinine Coma recovery time (hrs.) Mortality (%) 24.33 6.67 38.87 27.27

21 Arteether Dosage Regimen Rezart-ERoute Adults Pediatric 150 mg/ ampoule IM Day 1 150 mg Days 2 –3 150mg/ day Day 1 3mg/kg Days 2-3 3mg/kg/ day

22 Bulaquine : A New generation Anti-malarial drug Bulaquine a derivative of primaquine developed by the Central Drug research Institute in collaboration with W.H.O., Advantage :- Bulaquine has a biological activity against the tissue schizont forms of Plasmodium Vivax having :- a. A better therapeutic window. b. Lesser side effects, c. A better therapeutic index as compared to current treatment available.

23 Mechanism of action of : Bulaquine In contrast to current Drugs, 8-Aminoquinolones are the only drug which act on the liver stage and prevent infection by killing liver stages of the parasite before merozoites reach blood Stream. Thus prevents emergence of either primary or secondary attacks. Bulaquine Inhibits protein synthesis in protozoa and indirectly inhibits Polymerisation of Amino acids by the Plasmodia. It has also high gametocidal action.

24 Dosage of Bulaquine :- ** 25 mg once daily for 5 days. ** Should be given with chloroquine for complete cure of Vivax malaria. INDICATION : For the treatment of Vivax malaria Contra-indications: 1. Rheumatoid Arthritis. 2. Systematic Lupus erythematosus. C oncurrent use of D rugs known to cause Haemolysis

25 Future of Malarial Treatment I. Gene Therapy. II. Malarial Vaccine. III. Genetic Mapping Plasmodium falciparum. IV. Low Interleukin-12 Activity in severe Plasmodium falciparum malaria.



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