Development of New Drugs.docx

Development of New Drugs.docx

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DevelopmentofNewDrugs

DevelopmentofNewDrugs

Aim

Drugdevelopmentaimstoproduceanoveltherapeuticagentwhichissuperiorinefficacytoexistingremediesandwhichcauseslessfrequentorlesssevereadverseeffects.

1.Evolutionofanewdrug

Thedevelopmentofanewtherapeuticagentinvolvesamultidisciplinarygroupinmanyyearsofwork.Formerly,drugswereextractedfromnaturalplantandanimalsources.Therapeuticusewasempiricalandbasedontraditionalexperience.Overthelast80yearsanimpressivenumberofdrugshavebeensynthesizedchemically.Withthedevelopmentofgeneticengineeringandtheproductionofmonoclonalantibodiesitislikelythatevenmoreagentswillbeproducedartificially.

Synthetictechniqueshaveproducedpuresubstances.Thishasledtoincreasedspecificityofactionand,insomecases,greaterefficacyandreducedtoxicity.Unfortunatelynewdrugdevelopmentisexpensive,andonlyafewsubstances（lessthan1%）ofthosedevelopedareactuallymarketedandusedinpractice.

Therangeofnovelchemicalentitiesdevelopedhasoccasionallyledtounexpectedtoxicity.Asaconsequence,mostgovernmentshaveestablishedbodiestoregulatedrugmarketing,e.g.thecommitteeonSafetyofMedicinesinBritain,andtheFoodandDrugAdministrationintheUSA.Theseagenciessuperviseclinicalresearchonnewdrugsandlicensenewproducts.Althoughtheyservetoprotectthepublicandareseentodoso,thestatutoryproceduresthatmustbefollowedinapplyingforalicenseforanewdrugaddgreatlytothecostsandtimeofdevelopment.

Thereissomeevidencethattherateofintroductionofentirelynovelagentsisslowingdown.Whetherthisreflectseconomicpressuresordiminishednovelsyntheticcapacityorabilityisnotclear.

2Drugdevelopmentstrategies

Severalstrategieshavebeenusedinthedevelopmentofnewdrugs.Overtheyearsallhavehadsuccessbutnosingleapproachhasbeenconsistentlysuccessful.

Serendipity,luckanintuition

Thisapproachhasbeenappliedlessfrequentlyinrecentyears.ThediscoveryofpenicillinbyFlemingwasinthiscategory.

Molecularroulette

Randomchemicalsynthesisofnewstructuresandpharmacologicalscreening,thisapproachiswastefulanddependsontheavailabilityofsensitiveanimalorin-vitromodelsofhumandisease,whichoftendonotexist.

Minorstructuralchangesinexistingagents

Occasionallythisleadstocompoundsofgreaterefficacyandrarelytodrugswithnovelactionsdetectedinpharmacologicalscreeningorclinicalpractice.

Programmedbasicresearchwithsynthesisofspecificchemical

Intellectuallythisapproachisthemostsatisfying.Therehavebeenspectacularresults,e.g.levodopaanddopamineagonistsinthetreatmentofParkinsonism;beta-receptorblockersforangina;histamine（H2）antagonistsinpepticulcerdisease;convertingenzymeinhibitorsinhypertension.However,thisapproachisexpensiveandthisisnoguaranteeofsuccess.

Clinicalobservationofdrugactioninpractice

Thisisthetraditionalmeansofdrugassessment.Newapplicationsarisefrommeasurementofdrugactioninmanindiseasestates.Theantihypertensiveeffectsofthiazidediureticsandbeta-blockerswerenotpredictedfromanimalscreeningtests.Theywereonlyidentifiedafterthedrugswereavailableandwerebeingusedinpractice.

3.Experimentalpharmacology

Thesestudiesdeterminewhetherthedrughasthedesiredprofileofactioninmodelsystems.Themodelsareselectedtoprovideasreliableanindexofefficacyinmanaspossible.

Severalmodelsareusuallyemployed.Themodelsmaybesimpleorcomplexandinclude:

1）cellculturesorbacteria

2）partiallypurifiedenzymesorsub-cellularparticles

3）isolatedtissues

4）perfusedorgans

5）intactanimalsfrommicetoprimates

4.Toxicologicalassessment

Inparallelwithpharmacologicalexperimentsonefficacy,thetoxiceffectsofacuteandchronicdosingaredetermined.AcutetoxicityislessimportantaslongasLD50（thedosethatkills50%ofanimals）isnotclosetotheED50（thedosecausing50%ofmaximalpharmacologicalresponse）.

Chronictoxicitytestingismorerelevanttoclinicalapplicationsandshouldtakeplacealongthefollowinglines:

1）therouteofadministration,doserange,dosefrequencyandplasmalevelsshouldbeappropriatetolikelyclinicalindications.Ifpossible,methodsshouldbeavailabletomeasureplasmaconcentrationsandtodeterminepatternsofmetabolism.

2）Atleasttwospeciesshouldbestudied,usuallydogandratormouse.Ifpossible,aspeciesshouldbeselectedwithasimilarprofileofmetabolismtoman.

3）Thedurationoftreatmentshouldbeconsistentwiththelikelydurationofuseinmanandtherelativelifeexpectancyoftheanimalspecies.Usuallytoxicitystudiesareundertakenoveraperiodof4weekstoatleast1year.

4）Haematologicalandbio