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Jounal clab 2


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Jounal clab 2

  1. 1. Abstract:Schistosomiasis is a water-born parasitic disease in humans caused by various species oftrematods of the genus Schistosoma. The effect of the infection causes impaired growth andcognitive development in children; and in adults, hyper tension of abdominal blood pressure,hepatospleenomegali, bladder cancer and kidney failure as a result of chronic infection. It is thesecond most devastating parasitic disease in tropical and sub-tropical areas after malaria. Morethan 200 million people worldwide have been infecting by the parasite. It is considered as aneglected tropical disease (Hotez, 2007). Poor socioeconomic conditions are mainly responsiblefor the transmission of the disease, the rate of which is increasing worldwide.Transmission of the disease mainly occurs by cercariae which is a larvae form of parasiteSchistosoma. The parasite performs a complex life cycle where snail is intermediate host andhuman is main host. The intermediate host- snail, releases the cercariae into fresh-water. Humanskin in contact with the contaminated fresh water results in penetration of the cercariae throughskin and transforms into larva which then migrates to the hepatic portal system as a part of its lifecycle. Control of the disease transmission mainly depends on the improvement in sanitation,health education, snail control as well as chemotherapy. As there are no vaccines for the parasiticdisease reported untill now, chemotherapy is the best way to control the disease. The currentlyavailable chemotherapeutic drugs for schistosomiasis are praziquantel (PZQ), Artemether, 2-(alkylamino)-1-phenyl-1-ethanethiosulfuric acids, all of which are now limited in application.PZQ is the most effective drug to the present time against all types of schistosomiasis andconsiderably less side effects. As the drug target voltage-gated Ca2+ channels of pathogen, it isable to induce contraction and therby paralyses but only in adult pathogens and it is believed Ihas no effect on immature schistosomes. The efficacy of PZQ not only depends on the differentdevelopmental stage of infection, but also on host’s immune system. As the paralyzedschistosome is destroyed by phagosistosis of the immune system, the efficacy of PZQ needsstrong host immune system. Even though PZQ is effective for almost all types ofschistosomiasis, the drug alone has partial-protective activity. However the activity of the drugbecome reduces due to the generation of resistant pathogen (Fallon, P.G. 1994). In the case ofother available drugs, Oxamniquine is mainly effective to treat intestinal schistosomiasis inAfrica and South America, whereas Metrifonate has been using to treat urinary schistosomiasis
  2. 2. worldwide, artemisisnin is significantly less effective against adult schistosome parasites. Due tolake of proper treatment and preventive therapy the rate of the disease occurrence is increasingrapidly worldwide and will become a remarkable threat to human populations in the near future.The eradication of the disease is completely impossible, as there are no vaccine for the parasiticdisease has reported untill now. Under the present circumstances, a safe, non-toxic but effectivedrug should be urgently introduced to control the schistosomiasis in novel way by targetingcommon biochemical mechanism. Thioredoxin glutathione reductase (TGR) is one of suchcommon pathway which present in all developmental stages as well as in all infectious pathogen.By quantitative high-throughput screen (qHTS) of NIH Molecular Libraries, followed byconfirmatory and target deconvolution assay, four promising series were identified (1. oxadiazole2-oxides, 2. phosphinic amides, 3. quinolinyl sulfonamides , 4. Phosphoramidite) as Thioredoxinglutathione reductase (TGR) inhibitors. The aim of this study was to analyse the activityphosphinic amides and oxadiazole 2-oxides against antioxidant pathway at all developmentalstages of parasite as well as all major species infecting humans, and S. mansoni–infected mice.Among the ten selected compound, 4-phenyl-1,2,5-oxadiazole-3-carbonitrile-2-oxide showedmost active against in-vitro adult pathogen as well as multiple parasitic stages and egg-associated pathologies by generating NO. The protective activity of the compound was alsoobserved against the three major species of schistosome pathogen infecting human. Thecytotoxic effect of the compound was lower as compared to the PZQ.Discussion:The level of activity of compound 9 was equal to or better than that of the currently used drug, PZQ, and surpassesall landmarks for new lead compounds for schistosomiasis control. The low cytotoxicity and high bioactivity andtolerance by mice of compound 9 support the potential of this compound as a highly effective lead compound forhuman the series of oxadiazole 2-oxides, 4-phenyl-1,2,5-oxadiazole-3-carbonitrile-2-oxide isidentified as the most active compound which showed a significant activity against almost allstages of the parasite life cycle. Therefore it might be a effective drug to treat both short-termand long-term schistosomiasis. Thus, the compound might be potential new drug which able totreat schistosomiasis more effectively at any point during the infection. Unlike PZQ, thecompound able to reduce the larval count in lung, it might be a promising prophylactic drug forschistosomiasis treatment. PZQ is much less effective against juvenile liver parasites than against adultparasites, producing only a 25–30% reduction in worm burdens. Although artemether affords B80% reduction ifjuvenile parasites are targeted, it is less effective against adult schistosome parasites, resulting in o50% reduction inworm burden 31. In addition, compound 9 was found to be active against adults…..
  3. 3. compound 9 was found to be active against adults of the other main schistosome species infecting humans, S.japonicum and S. haematobium. Therefore, compound 9, or its derivatives, could be useful……The almost completely dependence on PZQ for schistosomiasis treatment lead to the increase ofdeveloping resistant strains worldwide resulting in out-of-control of the disease effect. A thecompound have different mode of action than PZQ to kill the pathogen, might be a potential drugto treat PZQ-resistant strain. Apart from this, the compound might be a perfect choice forcombination therapy with PZQ or artemisnin to treat more effectively than alone.Future scope:The analysis is undoubtedly a prominence step forward, but the goal of new schistomatosis drugdevelopment is far from the point of view. Rather, it envisages an initiative point to develop newsafe but potential drug to control the divesting effect of sichtomatosis worldwide. Although thestudy conclude that the compound has a less cytotoxic effect with better tolerance by mouse incomparison to currently used drug PZQ, further study needs to confirm the protective activityagainst all developmental stage of the compound is more than the currently used drug, PZQ.Next goal would be to measure the efficiency of the compound against all developmental stagein a single in vivo experiment by using PZQ as a positive control.The compound act as TGR inhibitor lead to impairment of redox mechanism in pathogen,ultimately kill it. Like PZQ, the killed pathogen in host tissue may be target by the host’simmune system to eliminate by phagosytosis. Thus the efficacy of the drug might also bedepending on the host immunity; consequently sex, race or others. However the effect of thecompound on the host’s cell-enzyme: Thioredoxin Reductase (TrxR), Glutaredoxin (Grx) andGlutathione Reductase (GR) also needs to analyze. By using various derivatives of thecompound, the efficacy of the drug might possible to increase selectively. As the compoundgenerates toxic NO, the side effects also need to analyze more details before using as drug.It is important to conduct pharmacokinetic analysis of the compound for biological half life ,excretion or elimination rate constant for the compound before going to clinical trial.Ref:
  4. 4. 1. Hotez, P.J. et al. Control of neglected tropical diseases. N. Engl. J. Med. 357, 1018–1027(2007).2. Fallon, P.G. & Doenhoff, M.J. Drug-resistant schistosomiasis: resistance to praziquanteland oxamniquine induced in Schistosoma mansoni in mice is drug specific. Am. J. Trop.Med. Hyg. 51, 83–88 (1994).3. Herwaldt, B.L., Tao, L.F., van Pelt, W., Tsang, V.C. & Bruce, J.I. Persistence ofSchistosoma haematobium infection despite multiple courses of therapy withpraziquantel. Clin. Infect. Dis. 20, 309–315 (1995).4. Murray-Smith, S.Q., Scott, B.J., Barton, D.P. & Weinstein, P. A case of refractoryschistosomiasis. Med. J. Aust. 165, 458 (1996).5. Ismail, M. et al. Resistance to praziquantel: direct evidence from Schistosoma mansoniisolated from Egyptian villagers. Am. J. Trop. Med. Hyg. 60, 932–935 (1999).6. Simeonov, A. et al. Quantitative high-throughput screen identifies inhibitors of theSchistosoma mansoni redox cascade. PLoS Negl. Trop. Dis 2, e127 (2008).7.