16171药学英语讲义Word文件下载.docx
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16171药学英语讲义Word文件下载.docx
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Therangeofnovelchemicalentitiesdevelopedhasoccasionallyledtounexpectedtoxicity.Asaconsequence,mostgovernmentshaveestablishedbodiestoregulatedrugmarketing,e.g.thecommitteeonSafetyofMedicinesinBritain,andtheFoodandDrugAdministrationintheUSA.Theseagenciessuperviseclinicalresearchonnewdrugsandlicensenewproducts.Althoughtheyservetoprotectthepublicandareseentodoso,thestatutoryproceduresthatmustbefollowedinapplyingforalicenseforanewdrugaddgreatlytothecostsandtimeofdevelopment1.
Thereissomeevidencethattherateofintroductionofentirelynovelagentsisslowingdown.Whetherthisreflectseconomicpressuresordiminishednovelsyntheticcapacityorabilityisnotclear.
2Drugdevelopmentstrategies
Severalstrategieshavebeenusedinthedevelopmentofnewdrugs.Overtheyearsallhavehadsuccessbutnosingleapproachhasbeenconsistentlysuccessful.
Serendipity,luckandintuition.
Thisapproachhasbeenappliedlessfrequentlyinrecentyears.ThediscoveryofpenicillinbyFlemingwasinthiscategory.
Molecularroulette.
Randomchemicalsynthesisofnewstructuresandpharmacologicalscreening.Thisapproachiswastefulanddependsontheavailabilityofsensitiveanimalorin-vitromodelsofhumandisease,whichoftendonotexist.
Minorstructuralchangesinexistingagents.
Occasionallythisleadstocompoundsofgreaterefficacyandrarelytodrugswithnovelactionsdetectedinpharmacologicalscreeningorclinicalpractice.Programmedbasicresearchwithsynthesisofspecificchemical.
Intellectuallythisapproachisthemostsatisfying.Therehavebeenspectacularresults,e.g.levodopaanddopamineagonistsinthetreatmentofParkinsonism;
beta-receptorblockersforangina;
histamine(H2)antagonistsinpepticulcerdisease;
convertingenzymeinhibitorsinhypertension.However,thisapproachisexpensiveandthereisnoguaranteeofsuccess.
Clinicalobservationofdrugactioninpractice.
Thisisthetraditionalmeansofdrugassessment.Newapplicationsarisefrommeasurementofdrugactioninmanindiseasestates.Theantihypertensiveeffectsofthiazidediureticsandbeta-blockerswerenotpredictedfromanimalscreeningtests.Theywereonlyidentifiedafterthedrugswereavailableandwerebeingusedinpractice.
3Experimentalpharmacology
Thesestudiesdeterminewhetherthedrughasthedesiredprofileofactioninmodelsystems.Themodelsareselectedtoprovideasreliableanindexofefficacyinmanaspossible.
Severalmodelsareusuallyemployed.Themodelsmaybesimpleorcomplexandinclude:
(1)Cellculturesorbacteria;
(2)Partiallypurifiedenzymesorsubcellularparticles;
(3)Isolatedtissues;
(4)Perfusedorgans;
(5)Intactanimalsfrommicetoprimates.
Theobjectistoidentifytherapeuticallyusefulpharmacologicalactivityandtocharacterizetheseactionsusingestablishedmodelsanddrugsofknownaction.
Whendrugswithspecificactionsonenzymesorreceptorsarebeingstudied,relativelysimplecellfreesystemsorisolatedtissuepreparationscanbeused3.Whenpoorlycharacterizedsubjectiveactionsaresought,particularlyinvolvingbehaviouraleffects,itmaybenecessarytoperformtestsinconsciousintactanimals.
4Toxicologicalassessment
Inparallelwithpharmacologicalexperimentsonefficacy,thetoxiceffectsofacuteandchronicdosingaredetermined.AcutetoxicityislessimportantaslongasLD50(thedosethatkills50%ofanimals)isnotclosetotheED50(thedosecausing50%ofmaximumpharmacologicalresponse).
Chronictoxicitytestingismorerelevanttoclinicalapplicationsandshouldtakeplacealongthefollowinglines4:
(1)Therouteofadministration,doserange,dosefrequencyandplasmalevelsshouldbeappropriatetolikelyclinicalindications.Ifpossible,methodsshouldbeavailabletomeasureplasmaconcentrationsandtodeterminepatternsofmetabolism.
(2)Atleasttwospeciesshouldbestudied,usuallydogandratormouse.Ifpossibleaspeciesshouldbeselectedwithasimilarprofileofmetabolismtoman.
(3)Thedurationoftreatmentshouldbeconsistentwiththelikelydurationofuseinmanandtherelativelifeexpectancyoftheanimalspecies.Usuallytoxicitystudiesareundertakenoveraperiodof4weekstoatleast1year.
(4)Haematologicalandbiochemicalmeasurementsshouldbemadeserially.Alltissuesshouldbeexaminedhistologicallyatdeathoronsacrificeoftheexperimentalgroup.Anuntreatedcontrolgroupoflittermatesshouldbemaintainedforcomparison.
Dependingontheproposedpatientgroupanddiseaseindication,attentionmustbepaidto:
(a)Effectsonfertilityinbothmalesandfemales.
(b)Teratogeniceffectsondevelopmentoftheembryo.Thevulnerableperiodisveryearlyindevelopment,duringorganogenesis.
(c)Mutagenicityoranincreasedrateofmutationingermcelllinesornonreproductivecells,e.g.bonemarrow.
(d)Carcinogenicityortheinductionorpromotionofmalignanttumours.
Thereisdisagreementovertherelevanceofsomeanimalcarcinogenicitystudiestoman5.
Extensiveformaltoxicologicaltestsarenowrequiredinmostcountriesbeforedrugscanbeusedonpatients.Thereisconsiderablecontroversyastothevalueofroutinetoxicologytesting,asmanydifferencesbetweenspecies,especiallybetweenmanandrat,mouse,anddog,havebeenreported6.
Paradoxically,thalidomide,whichwasthecauseofthetragedythatledtostricterdrugregulationandtoxicologytests,isnotteratogenicinmiceorratsbuthasateratogeniceffectinhumans,causinggrosslimbdeformities.
NEWWORDSANDEXPRESSIONS
acute[]adj.急性的
agonist[]n.激动剂
angina[]n.心绞痛
antagonist[]n.拮抗药;
对手
antibody[]n.抗体
antihypertensive[]adj.抗高血压的
beta-receptor[]n.β-肾上腺素受体
carcinogenicity[]n.致癌力
controversy[]n.&
vt.争论;
辩论;
~withsb.oversth.就某事与某人争论
deformity[]n.畸型;
残废
diuretics[]n.利尿剂
dopamine[]n.多巴胺
efficacy[]n.功效;
效验adverse[]adj.不利的;
有害的;
逆的;
相反的
embryo[]n.胚胎
empirical[]adj.根据经验的;
经验主义的
entity[]n.存在物;
药物;
实体;
统一体
enzyme[]n.酶
evolution[]n.发展;
演变/化/进;
进化
expectancy[]n.期待;
盼望
fertility[]n.生育力
genetic[]adj.遗传学的;
起源的;
普通的
gross[]adj.整个的;
全部的;
总的
haematological[]adj.血液学的
histamine[]n.组胺(旧时称作histamin)
hypertension[]n.高血压
inhibitor[]n.抑制剂,阻化剂;
抑制因素,阻止物
intact[]adj.完整的;
未经触动的
in-vitro[]adj.在试管内;
在活体外
levodopa[]n.左旋多巴;
左旋二羟基丙氨酸
littermate[]n.同窝仔畜,同胎仔畜
marrow[]n.髓;
脊髓;
精华
monoclonal[]adj.单克隆的;
单细胞的
mutagenicity[]n.诱变
nonreproductive[]adj.无生殖力的
novel[]adj.新(颖,奇)的;
n.小说
organogenesis[]n.器官形成
paradoxically[]adv.矛盾地;
似是而非地
parallel[]n.比较,平行
Parkinsonism[]n.帕金森氏神经机能障碍
peptic[]adj.助消化的;
消化性的
perfuse[]vt.灌注
pharmacological[]adj.药理学的;
药物学的
primate[]n.灵长目动物
profile[]n.轮廓;
侧面像
relevance[]n.相关联(性)
roulette[]n.轮盘赌
serendipity[]n.意外发现;
侥幸;
运气
serial[]adj.连续的,排成系列的,顺序排列的
specificity[]n.特性/征;
专一性
statutory[]adj.法定的
subcellular[]adj.亚细胞间的
supervise[]vt.监督;
管理
synthesize[]vt.合成
teratogenic[]adj.畸形发生的
thalidomide[]n.萨利多胺;
酞胺呱
thiazide[]n.噻嗪化物
toxicity[]n.毒性;
毒力
toxicological[]adj.毒理学的
ulcer[]n.溃疡
vulnerable[]adj.易受伤的;
敏感的;
脆弱的
TEXTB
DevelopmentofNewDrugs
(2)
5Clinicalevaluation
Onlyafteranimalstudieshaveprovedefficacy,andtoxicologicalstudieshaveprovidedameasureofthepossiblerisk,cannewdrugsbegiventohumans.Atthisstageafurtherrequirementisanalyticalevidenceofchemicalpurityandpharmaceuticalstability.
Evaluationinmancanbeconsideredinfourphases.Therelevanceandextentofstudiesatthesestagesdependsonthedruganditsindications.Drugsforuseinrarediseases,orinlife-threateningandasyetuntreatablestates,maybeevaluatedinpatientgroupsatanearlierstagethanthosewithreadilymeasurableeffectsoncommondiseases1.
Phase1involvessmallscalestudiesinnormalvolun
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