Upload
camilla-cristina
View
3
Download
2
Embed Size (px)
DESCRIPTION
Drogas Antihelmínticas
Citation preview
ReviewArticle
AREVIEWONANTHELMINTICDRUGSANDTHEIRFUTURESCOPE
PIYUSHYADAV*,RUPALISINGH
*DepartmentofPharmacy,PrasadInstituteofTechnology,Punchatia,Jaunpur222001(U.P.)India.Email:[email protected]
Received:23Feb2011,RevisedandAccepted:24March2011
ABSTRACT
Theanthelminticdrugsshowtheireffectsonthehumanbodyandtheirregularactivitiesbycausinghelminthiasiswhichisaverysevereparasiticdisease.Mostlypopulationandthelivestockparasitesproducetheresistanceagainstthehelminthsparasiteswhichcausesmorbidityandmortality.Thisreviewdealswiththeactivitiesoftheanthelminticdrugsonthedifferenttypesofspeciesandonhumanbodyalso.Theprevalenceofparasiticworms,anthelminticdrugdiscoveryismoreimportantinthepharmaceuticalindustry.Whentheefficacyofavailableanthelminticdrugsproducesthebetterresultsoverthediscoveryofnewdrugsitishinderedbythelackofhighthroughputscreeningmethodsanddrugeffectisassessedbyobservingmotilityormortalityofparasitesusinglaborious,subjectiveandlowthroughputbyusingthedifferentgenesandmutants.Thepurposeofthisreviewistofocusondrugswhichareusedinhumanandveterinarymedicinetotreatparasiticnematodeinfection.
Keywords:Anthelminticdrugs,Herbaldrugs,Helminthiasis,Mutants.
INTRODUCTION
Naturehasprovidedacompletestorehouseofremediestocureallailments of mankind and its related diseases. The human beingappears to be affected with more diseases than any other animalspecies.Therecanbelittledoubtthenthatissoughtouttoalleviatehissuffering from injuryanddiseasebytakingadvantageofplantsgrowingaroundhim.Inthepast,almostallthemedicinesusedwereextracted from the plants and the plant being mans chemist forages.
Thehistoryofherbalmedicinesisasoldashumancivilization.TheplantswereusedmedicinallyinChina,India,EgyptandGreecelongbefore the beginning of the Christian era. One of themost famoussurvivingremnantsisPapyrusEbers,ascrollsome60feetlonganda foot wide, sixteenth century before Christ. The drugs such asacacia, castor oil and fennel are mentioned along with apparentreferences to such compounds as iron oxide, sodium chloride,sodium carbonate and sulphur. Charaka made fifty groups of tenherbs each of them sufficient for an ordinary physicians need.Sushruta arranged 760 herbs in 7 distinct sets based on some oftheircommonproperties1.
MedicinalplantsarethesourceofgreateconomicvalueintheIndiansubcontinent.Herbalmedicine is still themain source ofmedicineand about 7580% of the whole population, mainly in developingcountries for primary health care because of better culturalacceptability,bettercompatibility,with thehumanbodyand fewersideeffects.
Nowadaysmultipledrug resistancehasbeendevelopeddue to theindiscriminate use of commercial antimicrobial drugs commonlyused in the treatment of infectious disease. In addition to thisproblem, theusesofantibioticsareassociatedwithadverseeffectson the host including hypersensitivity, immunosuppression andallergic reaction. Therefore, there is a need to develop alternativeantimicrobial drugs for the treatment of infectious diseases frommedicinalplants.Severalscreeningstudieshavebeencarriedoutindifferentpartsof theworld.Bacterialresistance isamajormedicalproblem, because it seriously limits the usefulness of manyantibiotics. Cross resistance is phenomenon in which bacteria,resistant to one drug are found to be resistant to a second drugwithoutbeenexposed2.
Bacterial resistance to antimicrobial drug is either natural oracquiredphenomenon.Naturalresistanceisgeneticallydeterminedanddependsupontheabsenceofmetabolicprocessorpathway inbacteria which is affected by the antibiotics. Acquired resistancerefers to the resistance developed in previously sensitive bacterialspecies 3. The biologically active compounds isolated from plantspeciesandusedasherbalmedicineandplantbasedantimicrobialsrepresentavastsourceofmedicinesandfurtherexplorationofplant
antimicrobialsneed tobedone.Antimicrobialsofplantorigin haveenormoustherapeuticpotentialandareeffectiveinthetreatmentofinfectiousdiseaseswhilesimultaneouslymitigatingmanyofthesideeffectsthatareoftenassociatedwithsyntheticantimicrobials.Mostdiseases caused by helminths are chronic, debilitating in nature,they probably cause more morbidity, greater economic and socialdeprivationamonghumansandanimalsthananyotherparasites.IthasbeenestimatedthatabouthalfoftheworldspopulationsuffersfromHelminthiasisandthenumberisincreasingdaybyday.Itisnotonly limited to tropical and subtropical countries but is also toendemic in many regions because of poor sanitation, poor familyhygiene, malnutrition and crowded living condition 4. Potentanthelminiticsareavailabletoday,andtreatmentisfrequentlydonebyusingdifferenttypesofdrugs.Howeverthehighcostsofmodernanthelminticshavelimitedeffectivecontroloftheparasites.Insomecases,widespreaduseoflowqualityanthelminticsareusedforthedevelopment of resistance and hence causes reduction in use ofanthelmintics 5. Only few of plants are being used traditionally asanthelmintics e.g. Aloe barberi, Trachyspermum ammi, Annonasenegalensis6.
Herbaldrugsanditsimportance
Intherecentyears,theimportanceofHerbaldrugsinMedicinehastremendously increased because of their fewer side effects.Consequently, thedemand for theherbal formulation is increasingday by day. The phytochemical constituents and theirstandardization are accelerated with the development ofinstrumentalanalysisandthisfieldbecomesimportantandnewforinvestigation.
As the half of world suffering from bacterial and Helminthesinfection, the source of infection being very common due to poorsanitation, poor family hygiene, malnutrition, and crowded livingconditions7.Thesourcesofinfectionsare:
1) Human being: The commonest source of infection is humanbeingthemselves.
2) Animals:Manypathogensareabletoinfectbothhumanbeingandanimals.Animalsactassourceofhumaninfection.
3) Insects:Bloodsuckinginsectmaytransmitpathogentohumanbeings.Besidesactingasvector,someinsectmayalsoactasareservoirforhosts.
4) Soilandwater:Somepathogenscansurviveinthesoilforverylong periods.Watermay act as the source of infection eitherduetocontaminationwithpathogenicmicroorganismorduetopresenceofaquaticvector.
5) Food:Contaminatedfoodactasasourceofinfection8.So there is a need to develop antibacterial and anthelmintics drugfrom herbal source. Anthelmintic activity was carried out bymeasuringthetimeforparalysisofworm9.
International Journal of Pharmacy and Pharmaceutical Sciences
ISSN- 0975-1491 Vol 3, Issue 3, 2011
Yadavetal.IntJPharmPharmSci,Vol3,Issue3,2011,1721
18
Anthelminticdrugs
Helminthesinfectionsarethemostcommoninfectionsinmanwhichaffects the large proportions of the worlds population. In thetreatment of parasitic diseases, the anthelmintics drugs are usedindiscriminately.Recentlytheuseofanthelminticsproducestoxicityin human beings. Hence the development and discovery of newsubstancesactingasanthelminticsarebeingderivedthroughplantswhichareconsideredtobethebestsourceofbioactivesubstances.Variousplantswereusedinveneraldiseases,topromotehealingofwounds, swellings, abscesses, rheumatism and treating pain inlower extremities, skin diseases, leucorrhoea, dysentery, dysuriaand fever 10, 11. Anthelmintics are those drugs that are used inexpelling out the worms that are parasitic in nature by eitherstunning them or by killing them. They are also known asvermifuges or vermicides. Natural anthelmintic includes thefollowinglistofcomponents:
Tobbacco Walnut Wormwood Clove Kalonjiseeds Garlic Malefern Pineapple Diatomaceousearth Soyaandotherlegumes Honey,water and vinegar aremixedwithwarmwater act as
vermifuges.
In other words, anthelmintics are drugs that are used for thetreatment of infections caused by the worms, flukes, nematodes,round worms, tapeworms etc. Anthelmintics are the tropical andveterinary types of medicines which are of huge importance.Parasiticwormsalsoinfectthelivestockandcropsthusaffectingthefood productionwith a resultant economic impact. It comes as nosurprise, that the drugs available for human treatment were firstdevelopedasveterinarymedicines.Insomecases,thissituationhasbeenexacerbatedbytheremarkablesuccessofivermectinoverthelast twenty years 12, which has decreased motivation foranthelmintic drug discovery programmes 13. Broad spectrumanthelmintics are effective against parasitic flat worms andnematodes.However,themajorityofdrugsaremorelimitedintheiraction, e.g., praziquantel a drug used in the treatment ofschistosomiasis and act by disrupting the calcium homeostasis 14andhasnoactivityagainstnematodes.
Pharmacologyofanthelmintics
Throughouttheworld,theparasitichelminticinfectionincreasesthemortality and morbidity day by day. This includes the intestinalnematodes (roundworms), trematodes (flukes) and cestodes(tapeworms). It is unevenly distributed disease in low incomecountries which affected worstly and highest risk of morbiditybecauseit is themajorsourceofenvironmentalcontaminationandtransmission. Albendazole, mebendazole and praziquantel are thecommonly used drugs acting as anthelmintics having broadspectrumactivityandhighcureratesduetothesustainabilityoftheperiodicemergenceofresistance.
Roundworms
The migration of the larval forms and eggs transmission throughskin contact in moist soil and in tropical areas causes migraine,eosinophiliaandpulmonaryrelatedproblems.
The common infections occurring with intestinal worms includeAscaris lumbricoides, Trichuris trichiura, Necator americanus andAncylostomaduodenalwith thehousehold aggregation of infection.Theeggsaredepositedonperianalareathatisduetoselfinfection.These infections also occur due to the contaminated surfaces likecarpets, curtains etc. The airborne and inhalation of the smallnumber of eggs are transmitted through ingestion of the infectedfood because the humans are the accidental hosts. After theingestionoftheinfectedproductstheimmunologicallungs,liverandcentralnervoussystemdamagesoccur.
Flukes
Flukes are the parasitic trematodes of Schistosoma specieswhichare transmitted through direct contact with fresh water. Theypenetrate into the intact human skin and enter the capillaries andthenmigrate to the central and portal systemwhere theymature.Acute schistosomiasis also known as Katayama fever, which is aform of visceral larvalmigraines. The adultmale and female pairsultimately migrate to the superior mesenteric veins and uretericvesicles.Theeggsarethenshedinthefaecesandurine.
Tapeworms
Humans are the intermediate host for the Taenia solium with thedevelopmentofthetissuecysts.Aftertheingestionoftheuncookedbeef(T.saginata)orporkitdevelopsthecystsanditcausesthemildabdominal symptoms. The infestations of the central nervoussystems caused due to thepork tapewormor flukes are knownasneurocysticercosis which is treated through albendazole andpraziquantel.
Classesofanthelminticdrugs
Anthelmintics are the broad and wide range of drugs and areseparatedintoclassesonthebasisofsimilarchemicalstructureandmode of action. The physiological and pharmacological actions ofanthelminticshavebeenobtainedfromstudiesonthelargeparasiticnematodesA.suum,C.elegans,hasbeenusedindefiningmoleculartargets.
Piperazine
It is themost popular and readily used drug for the treatment ofparasitic infection. Piperazinewas first used as an anthelmintic in1950sand it is still theactiveconstituentasover thecounterdrugandisusedintheremediesforthreadworminfectioninchildren.ItsmodeofactionhasbeenstudiedinA.suumandthereisnoliteraturesurveyonitsactioninC.elegansbecausethereisnoindicationthatitactsdifferently fromitseffects inA.suum. InA.suum itactsasaweak GABAmimetic agents and this will causes a flaccid orreversibleparalysisofbodywallmuscle.
Benzimidazole
The first thiabendazole was discovered in 1961 and it is a broadspectrum anthelmintics. There is an extensive literature onbenzimidazole compounds which showed a number of differentbiochemical effects. The anthelmintic efficacy of benzimidazoles isdue to the ability of compromising the cytoskeleton through aselectiveinteractionwithtubulinfactor15.Thisshowedtheeffectsof benzimidazoles on the species of C. elegans, which includes thelocomotion impairment, reproduction and detrimental effects onoocyteswith thedisruptionofprocesses thus requires the integralmicrotubules. Thus the sensitivity of C. elegans species gives theresponse to benzimidazole mediated through a single gene, andencodedbytubulin factor 16.Through this themolecularbasisofbenzimidazole molecule resistance has been investigated in theparasitic nematodes. The benzimidazole molecule showedresistanceindifferentnematodes likeHaemonchuscontortuswhichisassociatedwiththepresenceofspecificallelesoftubulininthedrug 17.Thespecifictubulin isoformcould confers the resistanceforthedrugwhichwastestedthroughexperimentsbutthisshowedthat the sensitivity of C. elegans mutants of benzimidazole can berescued by expressing the H. contortus alleles of tubulin frombenzimidazolethroughwhichisolationwasdone18.Throughthiswedemonstrate that a single amino acid substitution, Y for F, in tubulin confers the anthelmintic resistance and this is the firstexampleofa'modelhopping'approach.
Levamisole,PyrantelandMorantel
These anthelmintics are the nicotinic receptor agonist 19 whichcauses spastic muscle paralysis due to which the prolongedactivationoftheexcitatorynicotinicacetylcholine(nACh)receptorsonmuscleoccurs.Theprecisemodeofactionofthesereceptorshasbeen carefully studied at the single channel level on thebodywallmuscle preparation of A. suum 20. So the pharmacological analysishasprovidedevidenceforthesubtypesofnAChreceptors21.Ntype
Yadavetal.IntJPharmPharmSci,Vol3,Issue3,2011,1721
19
receptorsareactivatedbynicotine,Btypeofnicotinic receptors isactivatedbybepheniumandanLtypeisactivatedbylevamisoleandit is associated with levamisole resistance. Levamisole relatedcompounds also causes spastic paralysis in egglaying C. elegans.Recordings fromC.elegans bodywallmuscleusing levamisole andnicotineasagonisthasprovidedtheevidencethattherearemusclesubtypes of nACh receptor and these subtypes have differentreceptors subunit compositions. The levimasole receptor subunitsare unc38, unc29, unc63 22. These anthelmintics provide thepharmacologicaltoolstodissectthesubtypesandstoichiometriesofnativenematodenicotinicreceptors.Levamisolehas foundtobeenproductive in forward genetic screens. The levimasole haveprovided a resource of mutants that have been used to assignfunctionofgenesexpressedattheneuromuscularjunction.Someofthese are nACh (non acetylcholine) receptor subunits, but othersinterestinglyarenotandservetoeitherregulatenicotinicreceptorsormusclefunction.
Paraherquamide
Paraherquamide is a drug of oxindole alkaloid family andmarcfortine A are isolated from Penicillium paraherquei andPenicilliumroqueforti,respectively23.MarcfortineAwasfoundtobeactiveagainstC.Elegans24.TheC.eleganshavehighaffinitybindingsite for paraherquamidewhich has been identified in amembranepreparation which is isolated from C. elegans. 25. Paraherquamideand its derivative, 2deoxyparaherquamide, induces flaccidparalysis in parasitic nematodes. Pharmacological analysis is donethrough in vitro tests that showed the effects of these drugs onacetylcholinestimulatedbodywallmusclecontractionsinA.suuminwhich they act as typical competitive antagonists, shifting theconcentrationresponsecurvestotherightbut inaparallel fashion26.Paraherquamidealsoblocktheactionofnicotinicagonistsbutnotequipotently27.Thisantagonisthasgreateraffinitytodistinguishthenicotinic receptor subtypes on the muscle but for the receptorsmediatingtheresponsetolevamisoleandpyrantel.Paraherquamidewas found to be an effective antagonist of the levamisoleselectivereceptoronC.elegans bodywallmuscleand themodeofactionofthisdrugwastointerferewithcholinergictransmission,levamisole,isactascompetitiveantagonistsratherthancholinomimetics.Itisacompetitive inhibitor of the body wall nACh receptor as it wouldincreasetransmitterrelease.
Ivermectin
Ivermectin is a semisynthetic derivative of avermectin which isintroduced as anthelmintic in the 1980s by Merck contains largemacrocyclic lactone fermented product of the microorganismStreptomycesavermitilis. It isapotentdruganditsdiscoveryledtothedevelopmentofivermectinanalogueswhichincludemoxidectin,milbemycin oxime, doramectin, selamectin, abamectin andeprinomectin. 28. Ivermectincausestheparalysisofpharyngealandbodywallmusculature29.Ithasbeenshowntointeractwitharangeof ligandgated ion channels 30, acetylcholinegated chloridechannels,GABAgatedchloridechannels31,histaminegatedchloridechannels 32 and glycine receptors 33. Nematode glutamategatedchloridechannels(GluCl)hashighaffinitywhich iscorrelatedwithits potent anthelmintic activity. TheMerck teamwas succeeded inexpressing the cloningofGluClandGluCl ion channel subunitsin C. elegans 34 but both subunits were expressed either singly ortogether. GluCl responds to micromolar quantity of ivermectin,butnottoglutamatewhileGluClrespondstoglutamatebutnottoivermectin because coexpression of GluCl and GluCl yields achannel which responds to glutamate and it is positively butallosterically modulated by nanomolar quantity of ivermectin 35.EssentiallytherearefourgenesofC.eleganswhichareencodedbyGluCl subunits, two of which are alternately spliced the GluClchannels. Thepharyngealmuscleofmutants of avermectin speciesdoesnot respond to ivermectin 36. Ivermectinanthelmintic activityagainst Ascaridia galli and the pharynx of this species is notinhibitedbythisdrug37.TheroleofGluClchannelsinmediatingtheparalytic actions of ivermectin is playing an important role in themotornervoussystem.ThereisanimmunostainingroleofGluCl3AandBinmotorneuronsoftheparasiticnematodeH.contortus38.TheroleoftheseGluClchannelsinC.elegansinvolvestheregulation
of the duration of forwardmovement and glutamatergic regulatedbehaviour 39. The paralytic action of ivermectin derives fromactivationofGluCl in themotornervoussystemofnematodes.Themechanism of ivermectin resistance has been well studied in C.Elegansbecausehigh levelofresistanceisrequiredinmutationsofthese species. These genes further regulate the membranepermeability and gap junctions 40. The role of GluCl mutations inconferringivermectinresistanceofparasiticnematodes inthe fieldisalesstractableandmorecontroversial41.
Emodepside
Emodepside is cyclodepsipeptide molecule and semisyntheticderivative. A product obtained through fermentation from thefungus,Mycelia sterilia. Its discovery and anthelmintic activity hasrecently been discovered 42. It is effective against isolates ofparasites that are resistant to the molecule having poreformingproperties. Planar lipids does not appear to be an important inanthelmintic potency, as an optical isomer of emodepside withsimilarporeformingpropertiesdoesnotshowsanthelminticaction.Thusitmayactthroughthestereospecificbindingtoareceptor.A.suum causes themuscleparalysis andhave calciumandpotassiumdependent mechanism of action 43.The receptors for thecyclodepsipeptides have been cloned from a H. contortus cDNAlibrary by immuno screening with an antibody. This receptor hasbeen designated in the cells and showed gate calcium flux in adependentmanner 44. Itshomology is likemammalian latrophilins,which is a class of G proteincoupled receptors which bind to theneurotoxin, latrotoxin. Latrotoxin paralyze the mammals bytriggering neurotransmitter release and thus the identification oflatrophilin as an emodepside receptor raised the possibility thatemodepside causes paralysis by stimulating excessiveneurotransmitter release at neuromuscular sites thus showingeffects such as slowed development, inhibition of pharyngealpumping,decreasedlocomotionandinhibitionofegglayinginadulthermaphrodites which showed that emodepside exerts itspleiotropic actions. The use of the latrophilins in mediating theinhibitory effects of emodepside showed its effects on feeding andlocomotion using RNA and genes 45. The pharyngeal system ofmutants showed a reduced sensitivity in the favor of emodepsidebutitslocomotorsactivityisinhibited46.Emodepsidedoesnotshowits inhibitory effect on locomotion through the other latrophilinsmutants which respond just like wild animals. There is noredundancy function in terms of effect of emodepside onlocomotion, as the double mutants responds to emodepside in asimilar fashion 47 because emodepside has latrophilinindependentactions. Twenty thousand genomes for mutants are moved andpropagates in micromolar quantity of emodepside recovered thenineallelesofthegenenamedslo1.Thereisaninhibitoryeffectonthelocomotionandfeedingbyemodepsidecarryingthenullalleles.Emodepside activates the slo1 gene which behaves in the samemannerasthetreatedanimalsthusbringabouttheneuromuscularinhibition.
Nitazoxanide
Nitazoxanide is a pyruvate ferredoxin oxidoreductase inhibitorwhich acts against broad spectrumofprotozoaandhelminths thatoccurintheintestinaltract.Itiscurrentlyusedforthetreatmentofprotozoalinfections.Themechanismofactionofthiscompoundhasnotbeenfoundinnematodesbecauseanaerobicelectrontransportenzymes are the potential target 48. After seven days of culture,nitazoxanide reduces population growth by 33%. In contrastmebendazole and albendazole reduced the growth by over 90%.Nitazoxanide had no effect on either embryonation or hatching inHeligmosomoidespolygyrus.Thereforetheefficacyofthiscompoundisrelativelylowascomparedtootheranthelminticagents.
FUTURESCOPEOFTHEANTHELMINTICDRUGS
The challenges for thecompanies thatareengaged inanthelminticbehavior of the drugs are not shared by wealthy phase in thepharmaceuticalindustrybecauseanthelminticdrugsmarketiscosteffective and it is a prime concern. For mostly tropical medicineanthelminticsmustbeused inchemotherapyprogrammes inthoseregionswhereclinicalsupport issparseand thendrugsneedtobe
Yadavetal.IntJPharmPharmSci,Vol3,Issue3,2011,1721
20
very well tolerated in humans. For the last twenty years a smallquantity of drugs, especially ivermectin has addressed the needwhereas ivermectin has been hugely successful both in veterinaryand tropical medicine. The widest concern for the future is theemergence of resistance to all the anthelmintics that are usedcurrently including ivermectin a pivotal in defining the mode ofaction for the majority of these drugs and can also contribute inunderstanding mechanisms of resistance especially through themodelhopping approach. In future it is to be hoped that newanthelminticsthathavenovelmodesofactionwillsolvetheproblemof anthelmintic resistance. More targeted approaches toanthelminticdrugdiscoveryarealsoongoingandthusprovidingthefundamental information with the aim not to target peptidergicsignaling pathways which translated a marketable drug 49. ThefutureholdsthepromisethatC.elegansmayalsodirectlycontributeto drug discovery and efforts are of utmost importance in view ofthe increasing threat to livestock and humans from anthelminticresistance.
CONCLUSION
Fromthisreviewitisconcludedthatanthelminiticactivityofsomedrugswasbasedon its resistantactivityandhelminthiasis causingconsiderablehardhipandstuntedgrowth.MostlydiseasecausedbyHelminthiasis is of chronic debilitatingandof severenaturewhichcausesmoremorbidity.Itisconcludedthattheanthelminticefficacyof certain drugs might be attributed in the presence of genes,phytochemicals and mutants. The tropical medicines are mainlyusedinthetreatmentofthisseveredisease.TheAnthelminticsdrugtreatment must be used in chemotherapy programmes in thoseregionswhere clinical support is sparse andwheredrugsare verywelltoleratedinhumans.Forthelastfewyearsasmallquantityofdrugs, especially ivermectin, albendazole, piperazine, emodepsidehas addressed the need whereas ivermectin has been hugelysuccessfulbothinveterinaryandtropicalmedicine.
REFERENCES
1. Kokate CK, Purohit AK, Gokhale SB. History, definition andscopeofPharmacognosy.Pharmacognosy2005.p114.
2. Parekh J, Darshana J, Sumitra C. Efficacy of Aqueous andEthanol Extracts of some Medicinal Plants for PotentialAntibacterialActivity.TurkJBiol2005;29:203210.
3. BararFSK.EssentialofPharmacotherapeutics.2000.p.347453.4. Mohammed MS, Mohammed M, Yusuf OA, Joseph OA.
AnthelminticactivityofthecrudemethanolextractsofXylopiaaethiopica against Nippostrongylus brasiliensis in rats.VeterinarskiArhiv2005;75:487495.
5. BararFSK,EssentialofPharmacotherapeutics.2000.p.347453.6. IbrahimMA,NwudeN,OgunsusiRA,AlluYO.Apaperpresented
at the 5th International Symposium on Medicinal plants,Universityoflfe,llelfe,Nigeria;1983.p.1315.
7. BasuandSharma.TropicalgardeningplantinIndia.2005.p.1718
8. Ananthnarayan V, Thomson C. Structure function studies onHsp47: pH dependent inhibition of collagen. J Biochem2000;349:87783.
9. Mohammed MS, Mohammed M, Yusuf OA, Joseph OA.AnthelminticactivitiesofthecrudemethanolextractofXylopiaaethiopica against Nippostrongylus brasiliensis in rats.VeterinarskiArhiv2005;75:487495.
10. Anisuzzaman M, Rahman AHMM, HarunorRashid M,NaderuzzamanATM, IslamAKMR anEthnobotanical Study ofMdahupur,Tangail.JAppSciResearch2007;3:519530.
11. Vijayan A, Liju VB, Reena John JV, Parthipan B, Renekac.Traditional remedies of kani tribes of kotor reserve forest,Agasthyavanam,Thiruvanathapuramkerala. Ind. J TradKnow2007;6:589594.
12. GearyTG.Ivermectin20yearsonmaturationofawonderdrug.TrendsParasitol2005;21:530532.
13. Geary TG, Sangster, NC, Thompson, DP. Frontiers inanthelminticpharmacology.VetParasitol1999;84:275295.
14. GreenbergRM.Ca2+signaling,voltagegatedCa2+channelsandpraziquantel in flatworm neuromusculature. Parasitol 2005;131:S97S108.
15. BorgersM,DeNollinS.UltrastructuralchangesinAscarissuumintestineaftermebendazoletreatmentinvivo.JParasitol1975;61:110122.
16. DriscollM,Dean,E,ReillyE,Bergholz,E,ChalfieM.Geneticandmolecular analysis of a Caenorhabditis elegans betatubulinthat conveys benzimidazole sensitivity. J Cell Biol 1989; 109:29933003.
17. KwaM.S,Veenstra, JG,RoosMH.Benzimidazole resistance inHaemonchuscontortusiscorrelatedwithaconservedmutationat amino acid 200 in betatubulin isotype. Mol. BiochemParasitol1994;63:299303.
18. KwaMS,Veenstra JG,VanDM.,Roos,M.H.Betatubulingenesfrom the parasitic nematodeHaemonchus contortusmodulatedrug resistance in Caenorhabditis elegans. J. Mol Biol 1995;246:500510.
19. Aceves J, ErlijD,MartinezMaranon,R. Themechanismof theparalyzingactionoftetramisoleonAscarissomaticmuscle.BrJPharmacol1970;38:602607.
20. Martin,R.J,VermaS,LevandoskiM,ClarkCL,QianH,StewartM., Robertson A P. Drug resistance and neurotransmitterreceptorsofnematodes:recentstudiesonthemodeofactionoflevamisole.Parasitol2005;131:S71S84.
21. QianH,MartinRJ,RobertsonAP.PharmacologyofN,L,andBsubtypes of nematode nAChR resolved at the singlechannellevelinAscarissuum.FASEBJ2006;20:26062608.
22. CulettoE,BaylisHA,RichmondJE,JonesAK,FlemingJT,SquireMD, Lewis JA, Sattelle, DB. The Caenorhabditis elegans geneencodesalevamisolesensitivenicotinicacetylcholinereceptoralphasubunit. JBiolChem.2004;279:4247642483.Rand JB.Acetylcholine. Worm Book ed 2007 .The C. elegans ResearchCommunity,WormBook,doi/10.1895/wormbook.
23. Zinser EW, Wolfe ML, Alexander BSJ, Thomas EM, Davis JP,Groppi VE, Lee BH,et al. Anthelmintic paraherquamides arecholinergic antagonists in gastrointestinal nematodes andmammals.JVetPharmacolTherapy2002;25:241250.
24. Lee BH, Clothier MF, Dutton FE, Nelson SJ, Johnson SS,ThompsonDP,etal.MarcfortineandParaherquamideclassofanthelmintics: Discovery of PNU141962. Curr. Top. Med.Chem.2002;2:779793.
25. SchaefferJM,BlizzardTA,OndeykaJ,GoegelmanR,SinclairPJ,Mrozik H. [3H]Paraherquamide binding to Caenorhabditiselegans. Studiesonapotentnewanthelminticagent.BiochemPharmacol1992;43:679684.
26. Robertson AP, Clark C.L, Burns TA, Thompson DP, Geary TG,Trailovic SM, Martin RJ. Paraherquamide and 2deoxyparaherquamide distinguish cholinergic receptor subtypes inAscarismuscle.JPharmacolExpTher2002;302;853860.
27. Zinser EW, Wolfe ML, Alexander B SJ, Thomas EM, Davis JP,GroppiVE,etal.Anthelminticparaherquamidesarecholinergicantagonists ingastrointestinalnematodesandmammals. JVetPharmacolTherap2002;25:241250.
28. Haber CL, Heckaman C L, Li GP, Thompson DP, Whaley HA,WileyVH.Developmentofamechanismofactionbasedscreenfor anthelmintic microbial metabolites with avermectinlikeactivity and isolation of milbemycinproducing Streptomycesstrains.AntimicrobAgents.Chemother1991;35:18111817.
29. Brownlee DJ, HoldenD L, Walker RJ. (1997). Action of theanthelmintic ivermectin on the pharyngeal muscle of theparasiticnematode,Ascarissuum.Parasitology.1997;115;553561. Pemberton DJ, Franks CJ, Walker RJ, Holden DL.Characterization of glutamategated chloride channels in thepharynx of wildtype and mutant Caenorhabditis elegansdelineatestheroleof thesubunitGluClalpha2inthe functionofthenativereceptor.MolPharmacol2001;59:10371043.
30. Krause RM, Buisson B, Bertrand S, Corringer PJ, Galzi JL,ChangeuxJP,etal.Ivermectin:apositiveallostericeffectorofthe alpha7 neuronal nicotinic acetylcholine receptor. MolPharmacol1998;53:283294.
31. BokischAJ,WalkerRJ.TheactionofAvermectin(MK936)onidentifiedcentralneuronesfromHelixanditsinteractionwithacetylcholine and gammaaminobutyric acid (GABA)responses. Comp. Biochem. Physiol C Comp Pharmacol 1986;84:119125. HoldenDL, Walker RJ. Avermectin andavermectin derivatives are antagonists at the 4aminobutyric
Yadavetal.IntJPharmPharmSci,Vol3,Issue3,2011,1721
21
acid(GABA)receptoronthesomaticmusclecellsofAscaris;isthesiteofanthelminticaction.Parasitol1990;101:265271.
32. Zheng Y, Hirschberg B, Yuan J,Wang AP, Hunt DC, LudmererSW, et al. Identificationof twonovelDrosophilamelanogasterhistaminegated chloride channel subunits expressed in theeye.JBiolChem2002;277:20002005.
33. Shan,Q,Haddrill JL, Lynch JW. Ivermectin, anunconventionalagonist of the glycine receptor chloride channel. J Biol Chem2001;276:1255612564.
34. Cully DF, Vassilatis DK, Liu KK, Paress PS, Van der Ploeg LH,Schaeffer JM, et al. Cloning of an avermectinsensitiveglutamategatedchloridechannelfromCaenorhabditiselegans.Nature1994;371:707711.
35. Yates DM, Portillo V, Wolstenholme AJ. The avermectinreceptorsofHaemonchuscontortusandCaenorhabditiselegans.IntJParasitol2003;33:11831193.
36. Dent JA, Davis MW, Avery L. Encodes a chloride channelsubunit that mediates inhibitory glutamatergicneurotransmissionandivermectinsensitivityinCaenorhabditiselegans.EMBOJ1997;16:58675879.
37. HoldenDL,WalkerRJ.Actionsofglutamateandivermectinonthepharyngealmuscle ofAscaridiagalli: a comparative studywithCaenorhabditiselegans.IntJParasitol2006;36:395402.
38. Portillo V, Jagannathan S, Wolstenholme AJ. Distribution ofglutamategated chloride channel subunits in the parasiticnematode Haemonchus contortus. J Comp Neurol 2003; 462:213222.
39. Brockie PJ, Maricq, AV. Ionotropic glutamate receptors:genetics,behaviorandelectrophysiology,WormBooked.TheC. elegans Research Community, 2006; WormBook,doi/10.1895/wormbook.
40. Dent JA, Smith MM, Vassilatis DK, Avery L. The genetics ofivermectinresistanceinCaenorhabditiselegans.ProcNatAcadSciU.S.A2000;97:26742679.
41. Wolstenholme A J, Fairweather I, Prichard R, Himmelstjerna,VSG, Sangster NC. (2004). Drug resistance in veterinaryhelminths.TrendsParasitol2004;20:469476.
42. HarderA,HimmelstjernaVSG.Cyclooctadepsipeptidesanewclassofanthelminticallyactivecompounds.ParasitolRes2002;88:481488.
43. Willson J, Amliwala K, Harder A, Holden D L,Walker RJ. Theeffect of the anthelmintic emodepside at the neuromuscularjunction of the parasitic nematode Ascaris suum. Parasitol2003;126:7986.
44. SaegerB,SchmittWredeHP,DehnhardtM,BentenWP,KruckenJ,Harder A, et al. Latrophilinlike receptor from the parasiticnematode Haemonchus contortus as target for the anthelminticdepsipeptidePF1022A.FASEBJ2001;15:13321334.
45. Willson, J, Amliwala, K, Davis A, Cook A, Cuttle MF, Kriek N,Hopper NA, O'Connor V, Harder A, Walker RJ, Holden D L.Latrotoxin receptor signaling engages the UNC13dependentvesiclepriming pathway in C. elegans. Curr Biol 2004; 14:13741379.
46. GuestM,BullK,WalkerRJ,AmliwalaK,O'ConnorV,HarderA,etal.Thecalciumactivatedpotassiumchannel is required forthe action of the novel cyclooctadepsipeptide anthelmintic,emodepside,inCaenorhabditiselegans.IntJParasitol2007;37:15771588.
47. GuestM,BullK,WalkerRJ,AmliwalaK,O'ConnorV,HarderA,etal.Thecalciumactivatedpotassiumchannel is required forthe action of the novel cyclooctadepsipeptide anthelmintic,emodepside in Caenorhabditis elegans. Int J Parasitol 2007;37:15771588.
48. GillesHM,HoffmanPS.Treatmentofintestinalparasiticinfections:areviewofnitazoxanide.TrendsParasitol2002;18:9597.
49. Greenwood K, Williams T, Geary T. (2005). Nematodeneuropeptidereceptorsandtheirdevelopmentasanthelminticscreens.Parasitology2005;131:S169S177.