Isoquinoline or Benzyl Isoquinoline Alkaloids

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Isoquinoline or Benzyl Isoquinoline Alkaloids
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• Isoquinoline Alkaloids??????????????,?????????????
  ??
• ??(Ipecac)-Emetine
• ????(Hydrastis)-Hydrastine?Berberine
• ??(Sanguinaria)-Sanguinarine
• ????(Curare)-Tubocurarine
• ??(Coptis)-Berberine
• ??(Opium) -Morphine?Codeine

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Fig. 9-7 Biosynthesis of Papaverine
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Biosynthesis of Morphine and Codeine
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• Papaver somniferum ?????????????????????????,?????
  ?P. bracteatum Lindley????????????????Thebaine
• Thebaine ? codeine, hydromorphone
• ?????????????????????
• ???????(Latex)???????????????,???????????????,????
  ????????????Morphine???

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Opium or Gum Opium

• ??-??
• ??-????????,??(Papaver somniferum Linné)????(P.
  somniferum Linné var. album DeCandolle)??????(Caps
  ules)????,??????,?????????Opium?????opion?????,?Pa
  paver???????,somniferum????????????

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?????

• ??-????????????????????????(???)??,??????????????
  ???????(Poppy straw),??????????????
• 1.?????(Turkish opium)??????????????(Druggists
  opium),???????????????(Soft opium),????1021
• 2. ????(Indian opium)?????????,???10 (????)
• 3. ????(Chinese opium)???411
• 4. ????(Persia opium)???412

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? ?

• ??30??????,??????Pantopon,????????????Noscapine
  (Narcotine),1806?Serturner???????????(Morphine)?
• Morphine421??-??????9.5???
• Codeine0.82.5
• Noscapine48
• Papaverine0.52.5
• Thebaine0.52.5
• othersnarceine, protopine, laudanine, codamine,
  cryptopine, lanthopine, meconidine

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Meconic acid 35

• ?????morphine, codeine?????????
• Meconic acid??????,???????????????????,???2????5ml
  ,?????,?????,??????,??FeCl3??,????,???????????

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????

• Paregoric tincture?Camphorated opium tincture
  (?????) ??????(antiperistaltic)
  ,????????????????,?????????????????????????????
• ?????0.05??????????????????????

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• Laudanum, Opium tincture, or Decolorized opium
  tincture
• ????????1?
• ???????????
• Poppy seed (Maw seed)P. somniferum var.
  nigrum???,????????
• ?50???,???????????????????

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Opium Alkaloids
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Morphine

• Morphinan isoquinoline alkaloid
• ????????????????????????????????????????
• ????????????(Prototype)??,?????????????????,??????
  ????

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• ???mu (m)?kappa (k)????????????(Agonist)
• ?supraspinal level???????,????????????????,????m??
  ?????
• k ??????spinal level?????????????????
• ???????????????,?????????,???????????????

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• ???????????????,???????
• ?????????(Quaternary carbon)
• ?????????(Isostere)????????
• ???????(?)??(Tertiary nitrogen)
• ?????????????2??
• ???????????????????????????,?????????C-13,????????
  ???????C1C4?C11C12,?????C15, C16????,?????

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Codeine

• ??-??????(0.20.7),??Morphine??????Thebaine??????
  ?????????
• Codeine (3-O-)methyl morphine
• Codeine????,??????????????,????????
• ???????????,?????,?????????,?????????????

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Diacetylmorphine or Heroin

• ?????,???morphine ??,?????,????????????,??????????
  ????

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Papaverine ???

• ??-??????1,??????????
• ?????(Papverine HCl) ,?????????????,??????
• Papverine???????,?????????????(Ischemia)???????,??
  ???????(arrhythmia) ?

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Hydromorphone HCl or Dihydromorphinone HCl

• ????6-OH??????D7??????,
• ?????????,????????????
• ????????,???????????????,????????????
• ???Dilaudid

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??Sanguinaria

• ??-Blood root?
• ??-????????,??(Sanguinaria canadensis
  Linné)??????????
• ??-???????

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• ??-???Benzophenanthridine?????(Sanguinarine)??????
  (Chelerythrine)?????(Protopine)?????(Allocryptopin
  e)?Sanguinarine????????????,?Chelerythrine????????
  
• ??-????????????????????????,??????????????

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Benzocphenanthridine
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???Chelidonium

• ??-????????????
• ??-????????,???(Chelidonium majus Linné)????
• ??-????????????????????????
• ??-????????Isoquinoline????
• 1. Benzophenanthridine??Chelidonine?Chelerythrine?
  Dihydrochelerythrine?Sanguinarine?Oxysanguinarine?
  ?
• 2. ????(Protoberberine)?????(Berberine)????(Coptis
  ine)??
• ??-???????????????????????

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????Hydrastis

• ??- Golden seal Root(???)?Yellow Root?
• ??-????????,????(Hydrastis canadensis
  Linne)?????????????????,?34???????
• ??-??????????????????????????
• ??-?????1.54??????(Hydrastine)?????(Berberine)
  2.5???????(Canadine)?
• ??-??????????????

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• ??-Labat's Test??Berberine HI?Methylene Dioxy
  Group
• Labat's Solution????(Gallic Acid) 1??20???????
• ?????????,?23?Labat's Solution,?????,???????,????
  ??

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??Coptis Rhizoma

• ??-????????,??(Coptis chinesis Franch)????(Coptis
  teeta Wallich????)???(Coptis japonica Makino)
  ??????(Coptis quinquefolia Miquel)???????
• ??-??????
• ??-????(Coptis teeta Wallich)?????,???(Berberine)?
  ???,????????????
• ????????????(Berberine),????Worenine,Coptisine,Pal
  matine?
• ??-?????

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Coptis chinensis
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Ipecac ??

• ??-Ipecacuanha
• ??-????????,??(Cephaelis ipecacuanha (Brotero) A.
  Richard)???????(C. acuminata Karsten)?????,??????,
  ??23??
• ??- C. ipecacuanha?????,????????(Rio
  Ipecac)?????(Brazilian Ipecac)? C.
  acuminata?????????????????,??????????(Cartagena
  Ipecac)???????(Nicaragua Ipecac)??????(Panama
  Ipecac) ?

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Cephaelis ipecacuanha
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C. acuminata
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• ??-Emetine?Cephaeline?Psychotrine?
• ??-?????????????????,????????????????,????????????
  ??
• ??-??????????????????????????????????????
• ??-????????????????15ml???,20????????????????????
  (Fluid extract)??????14?,??????
• Dovers powder-???????????,?????(Diaphoresis) ?

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• Emetine or Methylcephaeline-????????Cephaeline????
  ?
• Emetine HCl-???????,????????????,?????????,???????
  ?
• ?????????,??????????????????,???????????,?????????
  ??????,
• ???????????????,??????????????(Pyorrhea
  alveolaris)????????????????,??????????,??????????
  ??????????

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??Curare

• ??- South American arrow poison(????)?
• ??-???????????????????????
• Menispermaceae????(Chondodendron tomentosum Ruiz
  et Paivon),?Tube(bamboo) curare?
• Loganiaceae????(Strychnos castelnaei
  Weddel),?Calabash(gourd) curare ?
• ????(S. toxifera Bentham),?Pot(Clay pot) curare?
• curare??????woorari?urari??poison?
• ??-???

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S. Toxifera- Pot (Clay pot) curare
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• ??-
• d-Tubocurarine?????Bisbenzylisoquinoline???
• ?????- d-Tubocurarine??????????????,?????,?IV?IM??
  ,?????????????????Strynchnine??????(Tetanus)?????
  ???????????????????????????

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• ????-???head drop test?????

Chondodendron tomentosum -Tube(bamboo) curare
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Indole Alkaloids

• ??(Rauwolfia) -Reserpine
• ???(Vinca) - Vinblastine ? Vincristine
• ???(Physostigma) - Physostigmine
• ??(Ergot) -Ergotamine?Ergonovine????
• ???(Nux Vomica) -Strychnine)? Brucine?
• ??,Strychnine?Brucine??indole??,??Quinoline???

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Biosynthesis of Indole Alkaloids

• Indole????indole?????????????(Tryptophan),????????
  ??????(Monoterpenoid)?????????????Aspidosperma?Cor
  ynanthe?Iboga??,????????????????
• Aspidosperma??????????,????????????????C9???Secolo
  ganin???Terpene???,?Corynanthe-type ?????????????

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Nux Vomica???

• ??-????Strychni Semen?Dog button?Poison nut?
• ??-???????(Loganiaceae)??,???(Strychnos
  nux-vomica Linné)????????
• ??-Strychnos?"????"????,nux?"??"????,vomica?"??"??
  ,?nux-vomica?"?????"?
• ??-???????????????????????

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Preparation of strychnine and brucine Extracted
with diluted H2SO4 ? concentrated ? lime
precipitate ? separated by organic solvent ?
recrystallization
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• ??-?1.55???,??????(endosperm)?????????
• Strychnine???????????1/31/2?
• Brucine?Dimethoxystrychnine?????????????

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Strychnine

• Strychnine?????????(Phosphate)????(Sulfate) ,
• ??????????????????,????,???????(Central
  stimulant) ,????????,??????????????????????????(im
  pulse) ,????,??????????????????
• ?????6090mg
• Strychnine????(Vermin killer )?
• Brucine????,??????????

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• ???(Strychnos ignatii Bergius)????????????Strychni
  ne?Brucine???

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Physostigma ???

• ??-????Calabar bean?Ordeal bean,Physostigmatis
  Semen?
• ??-???????,???(Physostigma venenosum
  Balfour)????????
• ??-Physostigma ????,????????,venenosum????????
  ??Calabar???????eser,???????????
• ??-?????,??????????

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• ??-Physostigmine(Eserine)?Eseramine?Geneserine?Phy
  sovenine?????????????(Physostigmine),???0.04-0.3?
  
• ??-Physostigmine Salicylate ?Physostigmine
  Sulfate???????????(Inhibitor of Choline
  esterase),?????????,??????????anticholinergic
  agent??????Physostigmine??????????????????Eseroli
  ne,????????Rubreserine?
• Rubreserine????, Physostigmine ????????????,???1g?
  ??

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Rauwolfia ? ?

• ??-????????????Rauwolfia Serpentina?
• ??-?????????,(Rauvolfia serpentina (L.) Benthamex
  Kurz? R. vomitotria ???
• Dr. Leonhard Rauwolf, Germany botanist,
  physician, and explorer
• ??-????????????????????

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??-?????????????Alseroxylon fraction?

• ??????????????
• 1. ????Indole alkaloid
• ????Indole????(Reserpine)?Rescinnamine?Deserpidine
  (11-Desmethoxyreserpine),E??Carboxylic???
• ?????Indole?d-Yohimbine(?Ajmalicine)?Tetrahydrores
  erpine?Raubasine?Reserpinine,E??Heterocyclic???

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• Reserpine?Citric acid????,?????????,????Reserpic
  acid?3,4,5-Trimethoxybenzoic acid?Methanol?Rescinn
  amine?????Reserpic acid?Mathanol?3,4,5-Trimethoxyc
  innamic acid?

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1. ?????Indoline Alkaloid??Ajmaline?Isoajmaline?Rauw
   olfinine,????????
2. ????anhydronium alkaloid??Serpentine?Serpentinine
   ?Alstonine ?

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Action of Rauwolfia alkaloids

• ??????????catecholamine?serotonin???,???????????ca
  techolamine????(reuptake) ,?????????,?????????????
  ??????????

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Reserpine

• ??-???????????
• ????- Rauvolfia serpentina, R. micrantha Hooker
  filius, R. tetraphylla Linne, R. vomitoria
  Afzelius
• Isolation problems-
• R.Serpentina reserpine mixed with rescinnamine
• R. tetraphylla reserpine extracted with
  deserpidine
• R. vomitoria reserpine exist in resins

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Rauvolfia serpentina
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R. vomitoria
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R. tetraphylla
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Rescinnamine

• ???????????Reserpine
• ???????Methyl reserpate?3,4,5-trimethoxycinnamate
• ????????????(mild essential hypertension)

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Deserpidine (canescine, recanescine)

• ??R. canescens L. ?11-desmethoxyreserpine,???Rauwo
  lfia alkaloids?Reserpine??,?????????
• ?????????,Rauwolfia ?????,??????????????????????
• ??, Reserpine?Rauwolfia alkaloids????Thiazide?????
  ??????????????

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Yohimbe???

• ??-????????,???(Pausinystalia yohimba Pierre)????
• ??-???(Cameroon)?
• ??-6 mixed alkaloids???(Yohimbine)?
• ??-Yohimbine?????????????????????????(Impotance),?
  ?????????,???????????????????
• ??????????????,?????(aphrodisiac)????????

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• ????????????2004???-????(Yohimbe)???????Likely
  Hazardous ???
• ????????
• ????????
• ???????
• ????????
• ????????
• ???????

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Catharanthus ???

• ??-Vinca?????Madagascar periwinkle?
• ??-?????????,???(Catharanthus roseus G. Don
  Vinca rosea L.)??????
• ??-????????(Madagascar)?????????????,??????????,??
  ?????????????????????????

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? ?

• ??????????90??????,???Indole?Dihydroindole????,???
  ???????????????,??Ajmalicine?Tetrahydroalstonine?
  Serpentine?Lochnerine?
• ???????(Antineoplastic)?????????Bisindole???,?????
  ???Indole?? Dihydroindole?????,??Indole???Iboga
  type?,????Aspidospermane type?????????????

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? ? ? ?

• ??????????????????metaphase,???????(Colchicine)???
  ,Vinblastine?Vincristine??????(Tubulin)????,??????
  ? (microtubule)??,???????(Mitotic
  spindle)??????????????????????(Tubulin)???????(mic
  rotubule)?

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Vinblastine sulfate or Vincaleukoblastine sulfate
or VLB Velban ?????

• ??????,????Ampule??,?????????????
• ??-???????,?????(Hodgkin's disease)????????(Lympho
  cytic lymphoma)????(Histocytic lymphoma)?Mycosis
  fungoid??????(Advanced testicular
  carcinoma)???????(Kaposis sacoma)
  ?????(Choriocarcinoma)?????????????

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• Vinblastine?????????????,?????????????????,???????
  ??,??????,????????????????????????????

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Vincristine sulfate or Leurocristine sulfate or
VCR, or LCR Vincristine

• ????Vinblastine????,??????Dihydroindole??N(?)???,V
  incristine?formyl (CHO) ??,Vinblastine???? (CH3)
• ??-???????????(Lymphocytic leukemia)??????????????
  ??????(Lymphosacoma)???????(Reticulum cell
  sacoma)??????(Rhabdomyosacoma)???????(Neuroblastom
  a)?Wilms tumor?
• ??Vincristine sulfate????,????????Ampule??,???????
  
• 500??????1?? (Vincristine)?

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Vindesine

• Vinblastine ?Vindoline?C4???????????,???Vinblastin
  e ?????????Vincristine ???
• ????????????????????,??????,??,??Vinblastine?Vincr
  istine???????

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Vinorelbine tartrate

• Vinblastine ?Catharanthine?C4???,??,
  C4'????????C3' C4'??????????,???3'-Noranhydrovinbl
  astine
• ??????????cisplatin???????????(non-small cell
  lung cancer)

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Ergot ??

• ??-?????(Spurred Rye)?Rye Ergot?Secale Cornutum
• ??-?????????,???(Claviceps purpurea (Fries)
  Tulasne)????????,??(Secale cereale
  L.)?????????(Sclerotium)
• ??-Claviceps????????,purpurea???????,???????,?????
  ???????
• ??-??????????????

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Ecology of ergot

1. ????????(Sphacelial stage) ?????????????(Ovary)
   ,????????????????,??????????(Mycelium)??????,?????
   ??????(Conidiospore)????????????,?????????????????
   ????????

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• ??????Ascigerous stage?????????,????,?????,???????
  ,??????(Sclerotium)??????,?????????,??????(????Asc
  ospore),??????????????
• ????????????????????,?????,????????(Mycelium)?????
  ,??????????,?????????????????????????(Sclerotium)?
  ??,????????????????????????????

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???(Ergotism)

• ?????????,??????,?????????(Ergotism)
• ?????????????,????????????(Gangrene),?????????????
  ?????,????????????????????????,?????????
• ???????????????(St. Anthonys fire)??1582????????
  ??????

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• ??-
• ?????????????????????????
• ?????????(Claviceps purpurea(Fries)
  Tulasne)?????(Secale cereale L.)????????????Peptid
  e(????)?Nonpeptide(???)????
• ?????Claviceps paspali Stevens
  Hall???????????Nonpeptide???, Lysergic acid
  (???)???????????(Ergotamine)??????

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Biosynthesis of Lysergic acid
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Ergonovine maleate or Ergometrine maleate

• ??????????????,??????,???????????
• ??- Ergonovine (USA) ? Ergometrine (other
  country) ?ergobasine (Switzerland)
  ?1953??5??????????
• ?????ergonovine????,?????????????????????,?????,??
  ???5?????????,?????ergotoxine?ergotamine??????????
  ????????
• ????ergonovine?????,????????????????,????????????

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Methylergonovine maleate

• ??????????
• Methylergonovine maleate?Lysergic
  acid?2-Aminobutanol????,?????Ergonovine???????????
  

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Ergotamine tartrate

• ?????????????,????????
• ??????,???????,??????????????,??????(Migraine)
  ,????????,???????????????????????,????????????????
  ??(Norepinephrine)?Uptake,????serotonin????(Antago
  nist) ?
• Ergotamine??Caffeine????????????????????

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• Dihydroergotamine mesylate
• Ergotamine?D9??????,???????Ergotamine???,?????(Tol
  erated)?
• Ergotoxine
• ??Ergocristine?Ergokryptine?Ergocornine????????,??
  ??????(Ethyl sulfonate)?????,?????
• ?????????,?ergotoxine?D9??????, ???????ergoloid
  mesylate (Hydergine)
• ?????????????,???????,??????,????????????

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• Methylsergide maleate?Methylergonovine?1?N???????
  ?,?Serotonine????,??????????
• ???????,
• ???-??????????????????????????,??????

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Lysergic acid diethylamide or LSD

• ????????,LSD??????????????,?????Depression???,
• ?A. Hoffmann?1943???????(Analeptics)?????,????????
  ??30?50mg??,
• ??????????????????,???????,??????

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???Ololiugui

• ??-????????,???(Rivea corymbosa(L.) Hallier
  filius)????
• ??-?????(Ipomoea spp.)?Argyreia spp.???0.05????
• d-Lysergic acid amide (Ergine)????????????d-Isolys
  ergic acid (Erginine)?Ergonovine?()-Lysergic
  acid methylcarbinolamide???Clavine?
• ??-?????Aztec???????,???????????

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• ?????Claviceps??,????????Ergot???,???Clavine
• Aspergillus fumigatus Fres
• Penicillium chermesinum Biourge
• Penicillium roquefortii Thom.
• Rhizopus arrhizus Fischer
• Sphacelia typhina