Released August 2007 - The Indian Society for Parasitology

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18 Gupta and Singlafalciparum and is well tolerated (Olliaro and Trigg, tafenoquine, an 8-aminoquinoline, offers more activity1995; Vugt et al., 1999). against hepatic stages of malarial parasites than parentcompound primaquine. Similarly, lumefantrine wasC. Piperaquine is another resurgent antimalarial drug. It developed as an analogue of halofantrine, which hasis a bisquinoline that was first synthesized and used in more toxicity (Rosenthal, 2003).China in 1960's. Due to development of resistance, itsuse was abandoned. But now, it is being tried again Compounds active against newer targets: Whereasalong with artemisinin as artemisinin combination artemisinin derivatives, particularly in combinationtherapy (ACT) to provide inexpensive, short course with other drugs, offer the best hope for the treatment oftreatment regimen with a high cure rate. Piperaquine malaria, especially MDR parasite strains, there havebased ACT's are CV4 (China Vietnam 4) which has been a number of exciting new developments.dihydroartemisinin, trimethoprim, piperaquine Information gleaned from the malaria genomephosphate and primaquine phosphate, CV 8 same sequencing project has led to the identification of adrugs with increased concentration (this product is still number of novel drug targets in the parasite that can bea part of national policy in Vietnam), Artecom without exploited for the discovery of new antimalarial drugs.primaquine and ArtekinTM or Duo- Cotecxin, which This is the most innovative approach of antimalarialhas dihydroartemisinin and piperaquine phosphate only drug discovery. Many of the enzymatic pathways in(Denis et al., 2002; Davis et al., 2005).plasmodia are unique or differ significantly from thehuman host. Targets could be of various types viz.D. Artesunate-amodiaquine (ASAQ) and artesunate- among cytosolic targets folate metabolism, purinemefloquine. These are two non-fixed drug salvage and pyrimidine synthetic pathways arecombinations which are being tried in Thailand, some potential drug acting sites. A recent report showed that aregions of South East Asia, Brazil and France. These are number of aspartic protease inhibitors of HIV are alsohighly effective against MDR P. falciparum and are effective antimalarials (Skinner-Adams et al., 2004).well tolerated. Artesunate-sulphadoxinemetabolismSimilarly, in parasitic membrane targets, phospholipidpyrimethamine is another combination drug that isoffers a potential drug target site.available as blister pack using age-based dosing and is Phospholipid synthesis is important for producingcurrently used in clinical trials in Africa (von Seidlein et membranes for parasitophorous vacuoles, cytosol andal., 2000). The other drug combination under multiple sub-cellular compartments. A new compoundevaluation is artesunate, chlorproguanil and dapsone G25 has even been found to be effective in vitro (Calas(Lapad plus). It is being tried where sufadoxinewhichet al., 2000). Another site of action is food vacuoles,pyrimethamine has failed. It offers the advantage ofare acidic in malarial parasite. The food vacuolecombining rapid potency of artesunate with slow appears to be the site of action of a number of existingcurative efficacy of recovery of chlorproguanilagainstantimalarials and also offers opportunities for therapiesdapsone (Alloueche et al., 2004).newer targets. In the food vacuole, haemoglobinis degraded into haeme, which is polymerised intoE. Artesunate along with pyronaridine is in early stages insoluble haemozoin pigment and globin. Globin inof development. Pyronaridine is an antimalarial which turn, is hydrolysed to individual amino acids.was synthesized and developed in China and has proven Antimalarial drugs appear to act by preventingits efficacy against drug-resistant falciparum malaria haemozoin pigment, producing free radicals in the food(Ringwald et al., 1996).vacuole or, in the case of experimental compounds,preventing globin hydrolysis. Globin hydrolysis isF. Naphthoquine and dihydroartemisinin. Fewmediated by a number of proteases and these enzymespreliminary studies indicated a cure rate of 100%offer potential targets for chemotherapy (Rosentahl,obtainable with a two-dose, one-day regime, leading to 2001). Other targets could be mitochondrial pathwaysinterest in this product but lack of pre-clinical data, (e. g. atovaquone acts on electron transport system)especially toxicology data on naphthoquine, makes it and apicoplasts involved in fatty acid and amino aciddifficult to determine the future status of this product. metabolism. Most of the antibiotics like tetracyclines,Miscellaneousclindamycin, macrolides, chloramphenicol etc. act bytargeting only apicoplast or mitochondrial sitesDevelopment of analogue drugs: Research is in (Ringwald et al., 1996).progress to develop newer antimalarials by chemicalmodification of the existing compounds. For example,Fosmidomycin: It is another novel compound which
Antimalarial agents19inhibits 1-deoxy-D-xylulose 5-phosphate Iron chelators have also some antimalarial activityreductoisomerase, an enzyme of the nonmevalonate (Loyevsky and Gordeuk, 2001). Similarly, vitamin andpathway of isoprenoid biosynthesis, which is absent in mineral supplements have been found to reduce clinicalhumans but present in many pathogens and plants. attacks of malaria especially vitamin A and ZincFosmidomycin has been well tolerated but produced (Greenwood et al., 2005).modest cure rates when used alone (Missinou et al.,2002; Lell et al., 2003). However, it can be used Drug resistance reversers: These are the agents whicheffectively in combination with other antimalarials like can reverse the parasitic resistance to knownclindamycin (Olliaro and Taylor, 2004).antimalarials, rendering these antimalarials effectiveagain. Important example is antihypertensiveTrioxane antimalarials: Several structural analogues verapamil (Martin et al., 1987) and antidepressantof artemisinin with crucial 1, 2, 4 trioxane activity are desipramine (Bitonti et al., 1988), both of which canbeing synthesized and screened for antimalarial reverse the resistance of P. falciparum to chloroquineactivity. Ferozan-50F is one such compound and is when used in high concentrations. Antihistaminefound to be effective, orally, against P. berghei infection chlorpheniramine has also been found to reversein mice. It exerts some action against pre-erythrocytic resistance even at safe dosing levels (Sowunmi et al.,schizogony and has a potent gametocidal effect in 1997). Similarly, chlorpromazine helps in the reversalinfected mosquitoes. Synthetic trioxanes are of resistance to quinine, and penfluoridol inconsidered as effective as arteether against P. mefloquine-resistance reversal (Dutta, 1995).falciparum-resistant to chloroquine, pyrimethamineand quinine. These compounds are cheaper to The medicines for malaria venture (Gardiner et al.,synthesize and might prove to be a viable alternative to 2005), a non-profit organization, created to facilitateartemisinins (Posner et al., 1994).discovery, development, and delivery of new affordableantimalarial drugs, is currently supporting theBulaquine, a new drug that has been discovered by evaluation of the effectiveness of many new classes ofCentral Drug Research Institute, Lucknow, India potential antimalarial compounds. If or when these new(CDRI compound 80/53), is being marketed under the drugs will become widely available, is still far fromTMname Aablaquin by Nicholas Piramal India Limited certain; however, they do hold the promise that drug-(Kshirsagar, 2006). An analogue of primaquine, resistant malaria can be combated in a foreseeablebulaquine appears to be a relatively safer substitute for future. Unfortunately, as with all the other newlythe radical cure of relapsing form of vivax malaria. Its developed drugs, the cost per treatment may be theadvantage is that it is 8-times less toxic than primaquine important rate-limiting step to their general use.(Dutta et al., 1989; Puri et al., 1989).REFERENCESPlant molecules: From time to time, plant productsAlloueche A, Bailey W, Barton S, Bwika J, Chimpeni P, Faladehave been evaluated for antimalarial activity. CinchonaCO et al. 2004. Comparison of chlorproguanil-dapsone withand Artemisia are such plants providing quinine and sulfadoxine-pyrimethamine for the treatment ofartemisinins, respectively, which are presently the uncomplicated falciparum malaria in young African children:mainstay for treatment of malaria. Some other plants double-blind randomised controlled trial. Lancet 363:1843-also have key molecules, which exhibit antimalarial 1848.activity e. g. Alstonia plant with indole alkaloids, Baird JK, Basri H, Subianto B, Fryauff DJ, McElroy PD,Dichroa febrifuga with febrifugine, Simaba cedron Leksana B et al. 1995. Treatment of chloroquine-resistantwith cedronin and Brucea javanica with brucein. Out of Plasmodium vivax with chloroquine and primaquine orthese, febrifugine especially has been found to be halofantrine. J Infect Dis 171:1678-1682.effective. It is 50- to 100-times more active than quinine Bitonti AJ, Sjoerdsma A, McCann PP, Kyle DE, Oduola AM,against P. vivax, but its use is limited due to its side- Rossan RN, Milhous WK and Davidson DE Jr. 1988.effects (Guru et al., 1996).Reversal of chloroquine resistance in malaria parasiteDiamidines, which have been used asPlasmodium falciparum by desipramine. Science 242:1301-1303.antitrypanosomal and antileishmanial drugs, are alsoBloland PB, Kazembe PN, Watkins WM, Doumbo OK,being evaluated for their antimalarial actionNwanyanwn OC and Ruebush TK. 1997. Malarone-donation(Werbovetz, 2006). programme in Africa. Lancet 350:1624-1625.
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70 Ravindran and WilliamsTable I. C
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• Short communications: those rep
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journal does not follow floating nu
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The Indian Society for Parasitology
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Designed & Printed at :- Azad Offse
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