PowerPoint

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2009TED592

MicroSoftBill Gates

The Deadliest Animal in the World4

Plasmodium falciparumP. vivaxP. ovaleP. malariae

Malaria caused by P falciparum and P vivax

Prevalence and molecular characterization of Plasmodium inui among Formosan macaques (Macaca cyclopis ) in Taiwan.Huang CC1, Ji DD, Chiang YC, Teng HJ, Liu HJ, Chang CD, Wu YH.Author informationAbstractSince the 1970s, no information on simian malaria has been documented in Taiwan, an area that is free from human malaria. To update the prevalence of simian malaria, a molecular-based survey was performed. Blood samples from 286 Formosan macaques ( Macaca cyclopis ) were tested for Plasmodium species by microscopy and nested polymerase chain reaction. Furthermore, the field isolates were characterized by sequencing the 42-kDa fragment of the merozoite surface protein 1 (MSP-1(42)). Of the 286 blood samples analyzed, 7 (2.4%) were positive by microscopy and nested PCR. All malaria-infected Formosan macaques were those collected from southern Taiwan, whereas no evidence of malarial parasites was observed among monkeys from eastern and northern Taiwan. Molecular and phylogenetic analyses based on the asexual stage small subunit ribosomal RNA (SSU rRNA) gene clearly identified these samples as a single infection with Plasmodium inui . Furthermore, phylogenetic analysis of the MSP-1(42) gene showed that the 7 field isolates were closely related to P. inui strains Taiwan I and II, which were obtained from Formosan macaques in 1963. These findings indicate that P. inui is the only cause of simian malaria in Taiwan, has been circulating in Formosan macaques at least for 46 yr, and has a geographic preference for southern Taiwan.13

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::4-6236 Cerebral malariaSevere anaemia Metabolic acidosis Hypoglycemia bacterial coinfection

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, mortality of 1520%, and survivors may suffer from persistent neurological sequelae 28

Frontiers in Bioscience S4, 1424-1448, June 1, 2012 Protein trafficking pathways from the ER to the DV in P. falciparum. Most DV-targeted proteins enter the secretory pathway via the ER but it is not clear whether they traverse a post-ER compartment such as the Golgi apparatus. Several trafficking routes from the ER to the DV have been reported: direct vesicle-mediated transport (I, e.g. PfCRT) or trafficking via the hemoglobin ingestion pathway (II - V). The transport from the ER to the cytostomal system occurs either directly (II, e.g. PfPM2), via the parasite's plasma membrane (III, e.g. PfPM1), via the PV (IV, e.g. PfDPAP1) or via the host erythrocyte's cytosol (V, e.g. PfHRP2). PfPM1 and PfPM2 are cleaved and activated in the acidic environment of the DV. PM: parasite plasma membrane, PVM: parasitophorous vacuole membrane.29

Frontiers in Bioscience S4, 1424-1448, June 1, 2012

Frontiers in Bioscience S4, 1424-1448, June 1, 2012Figure 3. Generation of free amino acids from hemoglobin. Hemoglobin degradation involves initial cleavage by plasmepsins and falcipains into large fragments that are further digested into smaller peptides by falcilysin. The dipeptidyl aminopeptidase 1 (PfDPAP1) may release dipeptides from the N termini of these oligopeptides. Some of the generated small peptides might be transported out of the DV into the parasite's cytoplasm by an unknown transporter. The cleavage into amino acids might occur in the DV by the acidic aminopeptidase P (PfAPP) as well as in the cytoplasm by the aminopeptidases PfM1AAP, PfM17LAP and/or PfM18AAP.

Drugs that interfere with crystal formation have been some of the most successful in malaria therapy. Among these is chloroquine31

VerapamilFunction of transport proteins on the P. falciparum digestive vacuolar membrane. The P. falciparum chloroquine resistance transporter (PfCRT) transports drugs out of the DV, whereas the P-glycoprotein homolog 1 (Pgh-1) transports a range of compounds into the DV. The inwardly-acting proton pumps V-type H+-ATPase and the V-type H+-PPase contribute to the acidification of the DV lumen. Substrates and inhibitors of the transport proteins are indicated. AMDP: aminomethylenediphosphonate, AQ: amodiaquine, ART: artemisinin, CQ: chloroquine, HF: halofantrine, MQ: mefloquine, NaF: sodium fluoride, ONT-093: 4-(2-(4-((E)-3-ethoxyprop-1-enyl)phenyl)-4-(4-(propan-2-ylamino)phenyl)-1H-imidazol-5-yl)-N-propan-2-ylaniline, PQ: primaquine, QC: quinacrine, QD: quinidine, QN: quinine, XR-9576: tariquidar.

Drug efflux by the mutated molecule represents an expansion of the normal physiological function of PfCRT, which may include transport of amino acids or short polypeptides from the digested hemoglobin 32

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ACT, the currently recommended treatment for malaria, was discovered by a screen of Chinese herbal medicines used to treat fevers. 35

Daily mean percentage parasitemia levels in mice after administration of artemisinin combination therapies.

Pharmacology & PharmacyVol.3No.1(2012),36Artesunate60mg/vialQuinine100mg/tabHydroxychloroquine plaquenil200mg/tabPrimaquine7.5mg/tabArtequinartesunate 600mg+mefloquine 1500mg24Artesunate (60mg/amp, made in China) 2.4mg/kg stat and q12h*2 dose then qd *6 days artemisininQuinine: 20mg/kg stat then 10mg/kg q8h *7 days)Artesunate 2 amp st + q12h *2+ qd *6 = total 18 ample38HydroxychloroquineArtemisinin-based combination therapy (ACT)WHO: Artequin 600/1500Artesunate 3 tabs + mefloquine 6 tabsquinine + (doxycyline, tetracycline or clindamycin) x 7 daysHydroxychloroquine(1# 200mg) : 800mg4tab., 6-8 400mg2tab.,2 ,400mg, 2gm (total 10#)Artesunate 1# (200mg) + Mefloquine 2# (500mg) QD x 3 daysQuinine 10mg/kg (1# 100mg)39P. malariae : hydroxychloroquineP. vivax, P. ovale : hydroxychloroquineprimaquine (0.5 mg/kg) x 14 daysP. vivaxACT + primaquine ()Primaquine 30mg (4#; 1# 7.5mg) QD x 14 days40

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PentoxifyllinMonoclonal antibodies Seizure prophylaxisMannitolAdequate blood transfusionAdequate fluid resuscitationMaitland BMC Medicine (2015)13:42

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RTS,S?6-12RTS,S31%51One world, one health