请输入您要查询的百科知识：

　

词条 Besipirdine
释义

  1. History

  2. Mechanism of Action

  3. Medical Uses

      Alzheimer's Disease    Other  

  4. Pharmacology

  5. Pharmacokinetics

  6. Adverse Effects

      General    Cardiovascular    Gastrointestinal    Sleep    Psychological  

  7. See also

  8. References

{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 451560333
| IUPAC_name = N-propyl-N-(4-pyridinyl)-1H-indol-1-amine
| image = Besipirdine structure.png
| width = 220
| tradename =
| pregnancy_category =
| legal_status = Unscheduled
| routes_of_administration =
| bioavailability =
| metabolism =
| excretion =
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 119257-34-0
| ATC_prefix = none
| PubChem = 60691
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 95PY16J933
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 2106094
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 54696
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C16H17N3/c1-2-12-18(15-7-10-17-11-8-15)19-13-9-14-5-3-4-6-16(14)19/h3-11,13H,2,12H2,1H3
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = OTPPJICEBWOCKD-UHFFFAOYSA-N
| C=16 | H=17 | N=3
| molecular_weight = 251.326 g/mol
| smiles = CCCN(C1=CC=NC=C1)N2C=CC3=CC=CC=C32
}}Besipirdine (besipirdine hydrochloride, or HP749), an indole-substituted analog of 4-aminopyridine, is a nootropic drug developed for the treatment of Alzheimer's disease (AD).[1][2]

History

Besipirdine was first considered for the treatment of obsessive-compulsive disorder (OCD). Hoechst-Roussel Pharmaceuticals, Inc. (Hoecst AG) filed a patent in July 1993 protecting the use of N-(pyridinyl)-1H-indol-1-amines, including besipirdine, for the treatment of OCD, supported by preliminary data gathered from rat studies {{cite patent |country=US |number=5356910 A |status=patent}}. In 1995, Hoechst AG filed a patent protecting the production of besipirdine, this time describing its memory-enhancing, analgetic and antidepressant qualities {{cite patent |country=US |number=5459274 A|status=patent}} . With increasing research on besipirdine uncovering its effects on the cholinergic system, Hoechst AG filed a patent in the following year to protect substituted n-(pyrrol-1-yl)pyridinamines as anticonvulsant agents

{{cite patent
|country=WO
|number=1997004777 A1
|status= application
|title=Use off unsubstituted and substituted n-(pyrrol-1-yl)pyridinamines as anticonvulsant agents
|pubdate=1997-02-13
|fdate=1996-07-08
|pridate=1995-07-27
|invent1= Huger FP, Kongasamut S, Smith CP, Tang L
|assign1= Hoechst Marion Roussel Inc

}}. In the midst of Phase II clinical studies of besipirdine in Alzheimer's disease, Hoechst AG merged with Rhône-Poulenc S.A. to form Aventis Pharma Limited. Under the new company Aventis, besipirdine ultimately failed in Phase III clinical trials due to severe cardiovascular side effects observed in a few patients in separate studies.[3][4] In January 2004, UroGene acquired exclusive development and commercialization rights to besipirdine from Aventis in order to study its application in urology

{{cite patent
|country=WO
|number=2005035496 A1
|status= application
|title=Process for the preparation of n-amino substituted heterocyclic compounds
|pubdate=2005-04-21
|fdate=2004-10-01
|pridate=2003-10-03
|invent1= Dubberke S, Hanna RD, Lee GE, Mueller-Lehar J, Utz R, Weiberth F
|assign1= Aventis Pharma Inc

}}. In February 2007, UroGene filed its own patent protecting the crystal form of besipirdine chlorhydrate, its production process, and its applications in the pharmaceutical field. The drug is currently undergoing Phase III development for treatment of Lower Urinary Tract Dysfunctions

{{cite patent
|country=WO
|number=2007096777 A2
|status= application
|title=Crystal form of besipirdine chlorhydrate, process preparation and use thereof
|pubdate=2007-08-30
|fdate=2007-02-20
|pridate=2007-02-30
|invent1= Bienayme H, Ferte J
|assign1= Urogene

}}.

Mechanism of Action

As a member of the aminopyridine class, besipirdine enhances the release of acetylcholine by blocking M-channels, voltage-gated K+ channels, increasing neuronal excitation by depolarizing the cell.[5][4][6][7] Additionally, besipirdine antagonizes the noradrenergic α2 receptor, increasing electrically-stimulated and spontaneous [3H]norepinephrine release from cortical tissue slices, and inhibits norepinephrine uptake.[8][4][6][7][9][10] The exact pathway is not yet understood but it has been shown that besipirdine does not open sodium channels, so its consequential effect on norephinephrine release may be Ca2+-independent.[11] Further, [3H]norepinephrine release seems to be dependent on frequency and concentration of besipirdine in that higher frequency of stimulation causes a concentration-dependent inhibition of voltage-dependent K+ channels, which leads to inhibition of norepinephrine release.[9][9][12]

Medical Uses

Alzheimer's Disease

The most successful treatments for AD have been strategies targeting the cholinergic activity in the central nervous system, like acetylcholinesterase inhibitors.[13] Other treatments target the adrenergic system and have been shown to improve memory deficits associated with AD. It was hypothesized that simultaneous treatment for both cholinergic and adrenergic deficits would be more effective than treatment that targeted individual systems alone. Besipirdine was shown to target dysfunctional cholinergic and adrenergic systems in Alzheimer's disease.[14][4][6][7] It has been suggested as an anticonvulsant because of its adrenergic effects. Its effects on the cholinergic system may improve memory and cognitive deficits symptomatic of AD.[9][15]

Other

Besipirdine was originally suggested as a treatment for OCD due to its effects on the adrenergic and serotonergic systems.[16] "In vitro" studies of besipirdine indicated its potency in inhibiting serotonin reuptake in addition to norepinephrine reuptake.[12][16] "In vivo", besipirdine showed efficacy in reducing schedule-induced polydipsia (SIP) in rats.[17] The drug's anticonvulsant properties ultimately led Hoechst AG to pursue it as a treatment for Alzheimer's disease.

After its discontinuation in the mid-90's, besipirdine was re-evaluated as an oral treatment for Over Active Bladder (OAB) and is currently undergoing Phase III clinical trials, under UroGene.[18][19] Interest in besipirdine as a treatment for OAB was piqued by its known effects on the adrenergic system. In isolated studies, besipirdine showed greater potency than duloxetine on bladder capacity, micturition volume, intercontraction interval, and an increase in striated sphincter EMG activity.[18][20]

Pharmacology

Besipirdine primarily acts to enhance both cholinergic and adrenergic neurotransmission in the central nervous system. It is administered orally[2][4][6] at a maximum tolerated dose (MTD) of 50 mg BID.[21][2][4][22] In Phase II clinical trials, patients were administered 5 mg or 20 mg BID doses of besipirdine.[23][2][4] Its N-despropyl metabolite, P86-7480, exhibits transient vasoconstrictor effects, producing a pressor effect of 16 ± 4 mm Hg after intravenous administration of 0.1 mg/kg, in monkey, rat and dog models.[4][6][24]

Pharmacokinetics

The pharmacokinetics of besipirdine have been studied in conscious monkey. The calculated elimination half-life (t1/2) of besipirdine and P86-7480 after oral administration of 10, 20, and 40 mg/kg doses is 7.4 ± 2.1 hours. The t1/2 after intravenous administration of 10 mg/kg is 1.5 hours. Besipirdine is cleared through the kidneys at 0.13 ± 0.04 mL/min/kg; only 1% of the administered dose is excreted unused via the kidneys.[6] In humans, using doses up to 30 mg, the t1/2 of besipirdine and P86-7480 were calculated as 3 hours, and 5.5–7 hours, respectively. Peak plasma concentrations of besipirdine and P86-7480 were calculated as 1.5–2 hours, and 2–3 hours, respectively.[4]

Adverse Effects

Besipirdine is reported to be well-tolerated. More severe adverse effects, such as bradycardia and postural hypotension, may have been a result of a high ratio of adrenergic to cholinergic potency caused by the metabolite P86-7480, which has direct vasoconstrictor effects.[25][4] Some studies suggest that the effects of besipirdine on cognition are reversible after withdrawal from treatment, indicating that the efficacy of the drug is primarily symptomatic and not neuroprotective.[26]

General

{{Plainlist|
  • Nausea and vomiting[4]
  • Dry mouth[4]
  • Headache[4]
  • Rash[4]
  • Eye disorder[4]
  • Urinary frequency[4]
  • Mouth ulceration[4]
  • Loss of appetite[27]
  • Dizziness[28]
  • Paresthesia[4]
  • General pain[4]

Cardiovascular

  • Bradycardia[4]
  • Postural hypotension[4]
  • Premature ventricular contractions[4]
  • Angina[4]
  • Arrhythmia[4]

Gastrointestinal

  • Gastrointestinal disorder[4]
  • Flatulence[4]
  • Constipation[4]

Sleep

  • Insomnia[29]
  • Somnolence[4]

Psychological

  • Mood changes[30][4]
  • Agitation[31]
  • Nervousness[32]
  • Abnormal thinking[33]

}}

See also

  • Linopirdine
  • Sibopirdine

References

1. ^{{cite journal | pmid = 8727171| year = 1996| author1 = Huff| first1 = F. J.| title = A treatment and withdrawal trial of besipirdine in Alzheimer disease| journal = Alzheimer Disease and Associated Disorders| volume = 10| issue = 2| pages = 93–102| last2 = Antuono| first2 = P. G.| last3 = Delagandara| first3 = J. E.| last4 = McDonald| first4 = M. A.| last5 = Cutler| first5 = N. R.| last6 = Cohen| first6 = S. R.| last7 = Green| first7 = R. C.| last8 = Zemlan| first8 = F. P.| last9 = Crismon| first9 = M. L.| last10 = Alter| first10 = M| last11 = Shipley| first11 = J. E.| last12 = Reichman| first12 = W. E. | doi=10.1097/00002093-199601020-00007}}
2. ^1 2 3 {{cite journal | pmid = 1818073| year = 1991| author1 = Hsu| first1 = R. S.| title = Determination of HP 749, a potential therapeutic agent for Alzheimer's disease, in plasma by high-performance liquid chromatography| journal = Journal of Chromatography| volume = 572| issue = 1–2| pages = 352–9| last2 = Dileo| first2 = E. M.| last3 = Chesson| first3 = S. M.| last4 = Klein| first4 = J. T.| last5 = Effland| first5 = R. C. | doi=10.1016/0378-4347(91)80503-5}}
3. ^{{cite journal | pmid = 8727171| year = 1996| author1 = Huff| first1 = F. J.| title = A treatment and withdrawal trial of besipirdine in Alzheimer disease| journal = Alzheimer Disease and Associated Disorders| volume = 10| issue = 2| pages = 93–102| last2 = Antuono| first2 = P. G.| last3 = Delagandara| first3 = J. E.| last4 = McDonald| first4 = M. A.| last5 = Cutler| first5 = N. R.| last6 = Cohen| first6 = S. R.| last7 = Green| first7 = R. C.| last8 = Zemlan| first8 = F. P.| last9 = Crismon| first9 = M. L.| last10 = Alter| first10 = M| last11 = Shipley| first11 = J. E.| last12 = Reichman| first12 = W. E. | doi=10.1097/00002093-199601020-00007}}
4. ^1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 {{cite journal | doi = 10.1016/0024-3205(95)02068-T| pmid = 7674813| title = A "bridging" (safety/tolerance) study of Besipirdine Hydrochloride in patients with Alzheimer's disease| journal = Life Sciences| volume = 57| issue = 12| pages = 1241–8| year = 1995| last1 = Sramek | first1 = J. J. | last2 = Viereck | first2 = C. | last3 = Jacob Huff | first3 = F.| last4 = Wardle | first4 = T. | last5 = Hourani | first5 = J. | last6 = Stewart | first6 = J. A. | last7 = Cutler | first7 = N. R. }}
5. ^{{cite journal | pmid = 8727171| year = 1996| author1 = Huff| first1 = F. J.| title = A treatment and withdrawal trial of besipirdine in Alzheimer disease| journal = Alzheimer Disease and Associated Disorders| volume = 10| issue = 2| pages = 93–102| last2 = Antuono| first2 = P. G.| last3 = Delagandara| first3 = J. E.| last4 = McDonald| first4 = M. A.| last5 = Cutler| first5 = N. R.| last6 = Cohen| first6 = S. R.| last7 = Green| first7 = R. C.| last8 = Zemlan| first8 = F. P.| last9 = Crismon| first9 = M. L.| last10 = Alter| first10 = M| last11 = Shipley| first11 = J. E.| last12 = Reichman| first12 = W. E. | doi=10.1097/00002093-199601020-00007}}
6. ^1 2 3 4 5 {{cite journal | pmid = 7560249| year = 1995| author1 = Hubbard| first1 = J. W.| title = The pharmacokinetics and cardiovascular pharmacodynamics of HP 749 (besipirdine HCl) and metabolite P86-7480 in the conscious monkey| journal = Journal of Clinical Pharmacology| volume = 35| issue = 7| pages = 688–96| last2 = Hsu| first2 = R. S.| last3 = Griffiths| first3 = L| last4 = Natarajan| first4 = C| last5 = Dean| first5 = R| last6 = Dileo| first6 = E. M.| last7 = Hintze| first7 = T. H. | doi=10.1002/j.1552-4604.1995.tb04109.x}}
7. ^1 2 {{cite journal | pmid = 8558529| year = 1996| author1 = Klein| first1 = J. T.| title = Synthesis and structure-activity relationships of N-propyl-N-(4-pyridinyl)-1H-indol-1-amine (besipirdine) and related analogs as potential therapeutic agents for Alzheimer's disease| journal = Journal of Medicinal Chemistry| volume = 39| issue = 2| pages = 570–81| last2 = Davis| first2 = L| last3 = Olsen| first3 = G. E.| last4 = Wong| first4 = G. S.| last5 = Huger| first5 = F. P.| last6 = Smith| first6 = C. P.| last7 = Petko| first7 = W. W.| last8 = Cornfeldt| first8 = M| last9 = Wilker| first9 = J. C.| last10 = Blitzer| first10 = R. D.| last11 = Landau| first11 = E| last12 = Haroutunian| first12 = V| last13 = Martin| first13 = L. L.| last14 = Effland| first14 = R. C.| doi = 10.1021/jm9506433}}
8. ^{{cite journal | pmid = 8727171| year = 1996| author1 = Huff| first1 = F. J.| title = A treatment and withdrawal trial of besipirdine in Alzheimer disease| journal = Alzheimer Disease and Associated Disorders| volume = 10| issue = 2| pages = 93–102| last2 = Antuono| first2 = P. G.| last3 = Delagandara| first3 = J. E.| last4 = McDonald| first4 = M. A.| last5 = Cutler| first5 = N. R.| last6 = Cohen| first6 = S. R.| last7 = Green| first7 = R. C.| last8 = Zemlan| first8 = F. P.| last9 = Crismon| first9 = M. L.| last10 = Alter| first10 = M| last11 = Shipley| first11 = J. E.| last12 = Reichman| first12 = W. E. | doi=10.1097/00002093-199601020-00007}}
9. ^1 2 3 {{cite journal | doi = 10.1016/0014-2999(96)00002-7| pmid = 8741167| title = Frequency-dependent inhibition of neurotransmitter release by besipirdine and HP 184| journal = European Journal of Pharmacology| volume = 300| issue = 1–2| pages = 71–4| year = 1996| last1 = Tang | first1 = L. | last2 = Kongsamut | first2 = S. }}
10. ^{{cite journal | pmid = 10071091| year = 1999| author1 = Francis| first1 = P. T.| title = The cholinergic hypothesis of Alzheimer's disease: A review of progress| journal = Journal of Neurology, Neurosurgery, and Psychiatry| volume = 66| issue = 2| pages = 137–47| last2 = Palmer| first2 = A. M.| last3 = Snape| first3 = M| last4 = Wilcock| first4 = G. K.| pmc = 1736202 | doi=10.1136/jnnp.66.2.137}}
11. ^{{cite journal | pmid = 1909035| year = 1991| author1 = Wagner| first1 = K. D.| title = Lithium and hair loss in childhood| journal = Psychosomatics| volume = 32| issue = 3| pages = 355–6| last2 = Teicher| first2 = M. H.| doi = 10.1016/S0033-3182(91)72077-X}}
12. ^1 {{cite journal | doi = 10.1007/BF01006816| pmid = 7891842| title = HP 749 enhances calcium-independent release of [3H]norepinephrine from rat cortical slices and synaptosomes| journal = Neurochemical Research| volume = 19| issue = 10| pages = 1265–70| year = 1994| last1 = Smith | first1 = C. P. | last2 = Huger | first2 = F. P. | last3 = Petko | first3 = W. | last4 = Kongsamut | first4 = S. }}
13. ^{{cite journal | pmid = 8727171| year = 1996| author1 = Huff| first1 = F. J.| title = A treatment and withdrawal trial of besipirdine in Alzheimer disease| journal = Alzheimer Disease and Associated Disorders| volume = 10| issue = 2| pages = 93–102| last2 = Antuono| first2 = P. G.| last3 = Delagandara| first3 = J. E.| last4 = McDonald| first4 = M. A.| last5 = Cutler| first5 = N. R.| last6 = Cohen| first6 = S. R.| last7 = Green| first7 = R. C.| last8 = Zemlan| first8 = F. P.| last9 = Crismon| first9 = M. L.| last10 = Alter| first10 = M| last11 = Shipley| first11 = J. E.| last12 = Reichman| first12 = W. E. | doi=10.1097/00002093-199601020-00007}}
14. ^{{cite journal | pmid = 8727171| year = 1996| author1 = Huff| first1 = F. J.| title = A treatment and withdrawal trial of besipirdine in Alzheimer disease| journal = Alzheimer Disease and Associated Disorders| volume = 10| issue = 2| pages = 93–102| last2 = Antuono| first2 = P. G.| last3 = Delagandara| first3 = J. E.| last4 = McDonald| first4 = M. A.| last5 = Cutler| first5 = N. R.| last6 = Cohen| first6 = S. R.| last7 = Green| first7 = R. C.| last8 = Zemlan| first8 = F. P.| last9 = Crismon| first9 = M. L.| last10 = Alter| first10 = M| last11 = Shipley| first11 = J. E.| last12 = Reichman| first12 = W. E. | doi=10.1097/00002093-199601020-00007}}
15. ^{{cite journal | pmid = 8581286| year = 1995| author1 = Tang| first1 = L| title = Effects of besipirdine at the voltage-dependent sodium channel| journal = British Journal of Pharmacology| volume = 116| issue = 5| pages = 2468–72| last2 = Smith| first2 = C. P.| last3 = Huger| first3 = F. P.| last4 = Kongsamut| first4 = S| pmc = 1909035 | doi=10.1111/j.1476-5381.1995.tb15097.x}}
16. ^1 {{cite journal | pmid = 8879677| year = 1996| author1 = Woods-Kettelberger| first1 = A. T.| title = Besipirdine (HP 749) reduces schedule-induced polydipsia in rats| journal = Brain Research Bulletin| volume = 41| issue = 2| pages = 125–30| last2 = Smith| first2 = C. P.| last3 = Corbett| first3 = R| last4 = Szewczak| first4 = M. R.| last5 = Roehr| first5 = J. E.| last6 = Bores| first6 = G. M.| last7 = Klein| first7 = J. T.| last8 = Kongsamut| first8 = S | doi=10.1016/s0361-9230(96)00163-3}}
17. ^{{cite book | pmid = 18428677| year = 2008| author1 = Platt| first1 = B| title = Current Protocols in Neuroscience| editor=Jacqueline N. Crawley| volume = Chapter 9| pages = Unit 9.27| last2 = Beyer| first2 = C. E.| last3 = Schechter| first3 = L. E.| last4 = Rosenzweig-Lipson| first4 = S| doi = 10.1002/0471142301.ns0927s43| chapter = Schedule-Induced Polydipsia: A Rat Model of Obsessive-Compulsive Disorder| isbn = 0-471-14230-1}}
18. ^1 {{cite journal | pmid = 21071917| year = 2011| author1 = Pérez-Martínez| first1 = F. C.| title = Halothane-anesthetized rabbit: A new experimental model to test the effects of besipirdine and duloxetine on lower urinary tract function| journal = Urologia Internationalis| volume = 86| issue = 2| pages = 210–9| last2 = Vela-Navarrete| first2 = R| last3 = Virseda| first3 = J| last4 = Ocaña| first4 = A. V.| last5 = Lluel| first5 = P| last6 = Rekik| first6 = M| last7 = Bienaymé| first7 = H| last8 = Ferté| first8 = J| last9 = Attali| first9 = P| last10 = Palea| first10 = S| doi = 10.1159/000321226}}
19. ^{{cite journal |vauthors=Sacco E, Bientinesi R |title= Future Perspective in Pharmacological Treatment Options for Overactive Bladder Syndrome |journal= European Urological Review |volume=7 |issue= 2 |pages=120–6 |date=April 2012}}
20. ^{{cite journal |vauthors=Haab F, Vela-Navarrete R, Perez-Martinez F, Castilla-Reparaz C, Ferte J, Bienayme H, Attali P |title= Effects of besipirdine on acetic acid-induced bladder irritation in rabbits. Comparison with duloxetine |journal=ICS|url=http://www.ics.org/Abstracts/Publish/44/000064.pdf}}
21. ^{{cite journal | pmid = 8727171| year = 1996| author1 = Huff| first1 = F. J.| title = A treatment and withdrawal trial of besipirdine in Alzheimer disease| journal = Alzheimer Disease and Associated Disorders| volume = 10| issue = 2| pages = 93–102| last2 = Antuono| first2 = P. G.| last3 = Delagandara| first3 = J. E.| last4 = McDonald| first4 = M. A.| last5 = Cutler| first5 = N. R.| last6 = Cohen| first6 = S. R.| last7 = Green| first7 = R. C.| last8 = Zemlan| first8 = F. P.| last9 = Crismon| first9 = M. L.| last10 = Alter| first10 = M| last11 = Shipley| first11 = J. E.| last12 = Reichman| first12 = W. E. | doi=10.1097/00002093-199601020-00007}}
22. ^{{cite journal | doi = 10.1016/0006-3223(95)94593-L| title = Tolerability and pharmacodynamics of besipirdine in Alzheimer's disease| journal = Biological Psychiatry| volume = 37| issue = 9| pages = 643| year = 1995| last1 = Cutler | first1 = N. R. | last2 = Sramek | first2 = J. J. | last3 = Viereck | first3 = C.| last4 = Stewart | first4 = J.| last5 = Huff | first5 = F. J. }}
23. ^{{cite journal | pmid = 8727171| year = 1996| author1 = Huff| first1 = F. J.| title = A treatment and withdrawal trial of besipirdine in Alzheimer disease| journal = Alzheimer Disease and Associated Disorders| volume = 10| issue = 2| pages = 93–102| last2 = Antuono| first2 = P. G.| last3 = Delagandara| first3 = J. E.| last4 = McDonald| first4 = M. A.| last5 = Cutler| first5 = N. R.| last6 = Cohen| first6 = S. R.| last7 = Green| first7 = R. C.| last8 = Zemlan| first8 = F. P.| last9 = Crismon| first9 = M. L.| last10 = Alter| first10 = M| last11 = Shipley| first11 = J. E.| last12 = Reichman| first12 = W. E. | doi=10.1097/00002093-199601020-00007}}
24. ^{{cite journal | pmid = 9103515| year = 1997| author1 = Hubbard| first1 = J. W.| title = Alpha-Adrenergic activity and cardiovascular effects of besipirdine HCl (HP 749) and metabolite P7480 in vitro and in the conscious rat and dog| journal = The Journal of Pharmacology and Experimental Therapeutics| volume = 281| issue = 1| pages = 337–46| last2 = Nordstrom| first2 = S. T.| last3 = Smith| first3 = C. P.| last4 = Brooks| first4 = K. M.| last5 = Laws-Ricker| first5 = L| last6 = Zhou| first6 = L| last7 = Vargas| first7 = H. M.}}
25. ^{{cite journal | pmid = 8727171| year = 1996| author1 = Huff| first1 = F. J.| title = A treatment and withdrawal trial of besipirdine in Alzheimer disease| journal = Alzheimer Disease and Associated Disorders| volume = 10| issue = 2| pages = 93–102| last2 = Antuono| first2 = P. G.| last3 = Delagandara| first3 = J. E.| last4 = McDonald| first4 = M. A.| last5 = Cutler| first5 = N. R.| last6 = Cohen| first6 = S. R.| last7 = Green| first7 = R. C.| last8 = Zemlan| first8 = F. P.| last9 = Crismon| first9 = M. L.| last10 = Alter| first10 = M| last11 = Shipley| first11 = J. E.| last12 = Reichman| first12 = W. E. | doi=10.1097/00002093-199601020-00007}}
26. ^{{cite journal | pmid = 8727171| year = 1996| author1 = Huff| first1 = F. J.| title = A treatment and withdrawal trial of besipirdine in Alzheimer disease| journal = Alzheimer Disease and Associated Disorders| volume = 10| issue = 2| pages = 93–102| last2 = Antuono| first2 = P. G.| last3 = Delagandara| first3 = J. E.| last4 = McDonald| first4 = M. A.| last5 = Cutler| first5 = N. R.| last6 = Cohen| first6 = S. R.| last7 = Green| first7 = R. C.| last8 = Zemlan| first8 = F. P.| last9 = Crismon| first9 = M. L.| last10 = Alter| first10 = M| last11 = Shipley| first11 = J. E.| last12 = Reichman| first12 = W. E. | doi=10.1097/00002093-199601020-00007}}
27. ^{{cite journal | pmid = 8727171| year = 1996| author1 = Huff| first1 = F. J.| title = A treatment and withdrawal trial of besipirdine in Alzheimer disease| journal = Alzheimer Disease and Associated Disorders| volume = 10| issue = 2| pages = 93–102| last2 = Antuono| first2 = P. G.| last3 = Delagandara| first3 = J. E.| last4 = McDonald| first4 = M. A.| last5 = Cutler| first5 = N. R.| last6 = Cohen| first6 = S. R.| last7 = Green| first7 = R. C.| last8 = Zemlan| first8 = F. P.| last9 = Crismon| first9 = M. L.| last10 = Alter| first10 = M| last11 = Shipley| first11 = J. E.| last12 = Reichman| first12 = W. E. | doi=10.1097/00002093-199601020-00007}}
28. ^{{cite journal | pmid = 8727171| year = 1996| author1 = Huff| first1 = F. J.| title = A treatment and withdrawal trial of besipirdine in Alzheimer disease| journal = Alzheimer Disease and Associated Disorders| volume = 10| issue = 2| pages = 93–102| last2 = Antuono| first2 = P. G.| last3 = Delagandara| first3 = J. E.| last4 = McDonald| first4 = M. A.| last5 = Cutler| first5 = N. R.| last6 = Cohen| first6 = S. R.| last7 = Green| first7 = R. C.| last8 = Zemlan| first8 = F. P.| last9 = Crismon| first9 = M. L.| last10 = Alter| first10 = M| last11 = Shipley| first11 = J. E.| last12 = Reichman| first12 = W. E. | doi=10.1097/00002093-199601020-00007}}
29. ^{{cite journal | pmid = 8727171| year = 1996| author1 = Huff| first1 = F. J.| title = A treatment and withdrawal trial of besipirdine in Alzheimer disease| journal = Alzheimer Disease and Associated Disorders| volume = 10| issue = 2| pages = 93–102| last2 = Antuono| first2 = P. G.| last3 = Delagandara| first3 = J. E.| last4 = McDonald| first4 = M. A.| last5 = Cutler| first5 = N. R.| last6 = Cohen| first6 = S. R.| last7 = Green| first7 = R. C.| last8 = Zemlan| first8 = F. P.| last9 = Crismon| first9 = M. L.| last10 = Alter| first10 = M| last11 = Shipley| first11 = J. E.| last12 = Reichman| first12 = W. E. | doi=10.1097/00002093-199601020-00007}}
30. ^{{cite journal | pmid = 8727171| year = 1996| author1 = Huff| first1 = F. J.| title = A treatment and withdrawal trial of besipirdine in Alzheimer disease| journal = Alzheimer Disease and Associated Disorders| volume = 10| issue = 2| pages = 93–102| last2 = Antuono| first2 = P. G.| last3 = Delagandara| first3 = J. E.| last4 = McDonald| first4 = M. A.| last5 = Cutler| first5 = N. R.| last6 = Cohen| first6 = S. R.| last7 = Green| first7 = R. C.| last8 = Zemlan| first8 = F. P.| last9 = Crismon| first9 = M. L.| last10 = Alter| first10 = M| last11 = Shipley| first11 = J. E.| last12 = Reichman| first12 = W. E. | doi=10.1097/00002093-199601020-00007}}
31. ^{{cite journal | pmid = 8727171| year = 1996| author1 = Huff| first1 = F. J.| title = A treatment and withdrawal trial of besipirdine in Alzheimer disease| journal = Alzheimer Disease and Associated Disorders| volume = 10| issue = 2| pages = 93–102| last2 = Antuono| first2 = P. G.| last3 = Delagandara| first3 = J. E.| last4 = McDonald| first4 = M. A.| last5 = Cutler| first5 = N. R.| last6 = Cohen| first6 = S. R.| last7 = Green| first7 = R. C.| last8 = Zemlan| first8 = F. P.| last9 = Crismon| first9 = M. L.| last10 = Alter| first10 = M| last11 = Shipley| first11 = J. E.| last12 = Reichman| first12 = W. E. | doi=10.1097/00002093-199601020-00007}}
32. ^{{cite journal | pmid = 8727171| year = 1996| author1 = Huff| first1 = F. J.| title = A treatment and withdrawal trial of besipirdine in Alzheimer disease| journal = Alzheimer Disease and Associated Disorders| volume = 10| issue = 2| pages = 93–102| last2 = Antuono| first2 = P. G.| last3 = Delagandara| first3 = J. E.| last4 = McDonald| first4 = M. A.| last5 = Cutler| first5 = N. R.| last6 = Cohen| first6 = S. R.| last7 = Green| first7 = R. C.| last8 = Zemlan| first8 = F. P.| last9 = Crismon| first9 = M. L.| last10 = Alter| first10 = M| last11 = Shipley| first11 = J. E.| last12 = Reichman| first12 = W. E. | doi=10.1097/00002093-199601020-00007}}
33. ^{{cite journal | pmid = 8727171| year = 1996| author1 = Huff| first1 = F. J.| title = A treatment and withdrawal trial of besipirdine in Alzheimer disease| journal = Alzheimer Disease and Associated Disorders| volume = 10| issue = 2| pages = 93–102| last2 = Antuono| first2 = P. G.| last3 = Delagandara| first3 = J. E.| last4 = McDonald| first4 = M. A.| last5 = Cutler| first5 = N. R.| last6 = Cohen| first6 = S. R.| last7 = Green| first7 = R. C.| last8 = Zemlan| first8 = F. P.| last9 = Crismon| first9 = M. L.| last10 = Alter| first10 = M| last11 = Shipley| first11 = J. E.| last12 = Reichman| first12 = W. E. | doi=10.1097/00002093-199601020-00007}}

1 : Nootropics
随便看

　

开放百科全书收录14589846条英语、德语、日语等多语种百科知识，基本涵盖了大多数领域的百科知识，是一部内容自由、开放的电子版国际百科全书。

　

Copyright © 2023 OENC.NET All Rights Reserved
京ICP备2021023879号 更新时间：2024/11/12 20:15:22