Buspirone

Buspirone, sold under the brand name Buspar among others, is a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder.[9][10] Benefits support its short term use.[11] It is not useful for psychosis.[9] It is taken by mouth, and it may take up to four weeks for an effect.[9][10]

Buspirone
Clinical data
Pronunciation/ˈbjuːspɪroʊn/ (BEW-spi-rohn)
Trade namesBuspar
Other namesMJ 9022-1[1]
AHFS/Drugs.comMonograph
MedlinePlusa688005
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
    Routes of
    administration    		By mouth
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability3.9%[2]
    Protein binding86–95%[3]
    MetabolismLiver (via CYP3A4)[4][5]
    Metabolites5-OH-Buspirone; 6-OH-Buspirone; 8-OH-Buspirone; 1-PP[6][7][8]
    Elimination half-life2.5 hours[4]
    ExcretionUrine: 29–63%[3]
    Feces: 18–38%[3]
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.048.232
    Chemical and physical data
    FormulaC21H31N5O2
    Molar mass385.50314 g/mol g·mol−1
    3D model (JSmol)
      (verify)

    Common side effects include nausea, headaches, dizziness, and trouble concentrating.[9][11] Serious side effects may include hallucinations, serotonin syndrome, and seizures.[11] Use in pregnancy appears to be safe but has not been well studied, while use during breastfeeding is not recommended.[11][12] How it works is not clear but it is unrelated to benzodiazepines.[9]

    Buspirone was first made in 1968 and approved for medical use in the United States in 1986.[9][10] It is available as a generic medication.[11] A month supply in the United Kingdom costs the NHS about 10 GBP as of 2019.[11] In the United States the wholesale cost of this amount is about 2.65 USD.[13] In 2016 it was the 90th most prescribed medication in the United States with more than 8 million prescriptions.[14]

    Medical uses

    Anxiety

    Buspirone is used for the short-term treatment of anxiety disorders or symptoms of anxiety.[15][16][17][18][19] It is generally less preferred than selective serotonin reuptake inhibitors (SSRIs).[10]

    Buspirone has no immediate anxiolytic effects, and hence has a delayed onset of action; its full clinical effectiveness may require 2 to 4 weeks to manifest.[20] The drug has been shown to be similarly effective in the treatment of GAD to benzodiazepines including diazepam, alprazolam, lorazepam, and clorazepate.[2] Buspirone is not known to be effective in the treatment of other anxiety disorders besides GAD,[21] although there is some limited evidence that it may be useful in the treatment of social phobia as an adjunct to selective serotonin reuptake inhibitors (SSRIs).[2][22]

    Other uses

    Sexual dysfunction

    There is some evidence that buspirone on its own may be useful in the treatment of hypoactive sexual desire disorder (HSDD) in women.[23]

    Miscellaneous

    Buspirone is not effective as a treatment for benzodiazepine withdrawal, barbiturate withdrawal, or alcohol withdrawal/delirium tremens.[24]

    SSRI and SNRI antidepressants may cause jaw pain/jaw spasm reversible syndrome (although it is not common). Buspirone appears to be successful in treating bruxism on SSRI/SNRI induced jaw clenching.[25][26]

    Contraindications

    Buspirone has these contraindications:[27][28]

    Side effects
    Main article: List of side effects of buspirone

    Known side effects associated with buspirone include dizziness, headaches, nausea, nervousness, and paresthesia.[2] Buspirone is relatively well-tolerated, and is not associated with sedation, cognitive and psychomotor impairment, muscle relaxation, physical dependence, or anticonvulsant effects.[2] In addition, buspirone does not produce euphoria,[20] and is not a drug of abuse.[16]

    Overdose

    Buspirone appears to be relatively benign in cases of single-drug overdose, although no definitive data on this subject appear to be available.[29] In one clinical trial, buspirone was administered to healthy male volunteers at a dosage of 375 mg/day, and produced side effects including nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress.[15][16][18] In early clinical trials, buspirone was given at dosages even as high as 2,400 mg/day, with akathisia, tremor, and muscle rigidity observed.[30] Deliberate overdoses with 250 mg and up to 300 mg buspirone have resulted in drowsiness in about 50% of individuals.[30] One death has been reported in association with 450 mg buspirone together with alprazolam, diltiazem, alcohol, cocaine.[30]

    Interactions

    Buspirone has been shown in vitro to be metabolized by the enzyme CYP3A4.[5] This finding is consistent with the in vivo interactions observed between buspirone and these inhibitors or inducers of cytochrome P450 3A4 (CYP3A4), among others:[27]

    Elevated blood pressure has been reported when buspirone has been administered to patients taking monoamine oxidase inhibitors (MAOIs).[27]

    Pharmacology

    Pharmacodynamics
    Buspirone[33]
    SiteKi (nM)SpeciesRef
    5-HT1A3.98–214
    21 (median)    		Human[34]
    [33]
    5-HT1B>100,000Rat[35]
    5-HT1D22,000–42,700Human[36][37]
    5-HT2A138
    759–1,300    		Human
    Rat    		[38]
    [38][35]
    5-HT2B214Human[38]
    5-HT2C490
    1,100–6,026    		Human
    Rat/pig    		[38]
    [38][35]
    5-HT3>10,000Rat[39][40]
    5-HT4>10,000Rat[40]
    5-HT6398Mouse[41]
    5-HT7375–381Rat[42][43]
    α11,000Rat[35]
    α26,000Rat[44]
      α2A7.3 (1-PP)Human[35]
    β8,800Rat[35]
    D133,000Rat[35]
    D2484
    240    		Human
    Rat    		[45]
    [35]
    D398Human[45]
    D429Human[45]
    mACh38,000Rat[35]
    GABAA
    (BDZ)    		>100,000Rat[35]
    Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

    Buspirone acts as an agonist of the serotonin 5-HT1A receptor with high affinity.[2][35] It is a preferential full agonist of presynaptic 5-HT1A receptors, which are inhibitory autoreceptors, and a partial agonist of postsynaptic 5-HT1A receptors.[2] In accordance, an animal study found that buspirone dose-dependently decreases serotonin levels in specific brain areas while increasing dopamine and norepinephrine levels.[2] It is thought that the main effects of buspirone are mediated via its interaction with the 5-HT1A receptor.[2] Some of its effects may be mediated via oxytocin release secondary to 5-HT1A receptor agonism.[46][47] Buspirone also has lower affinity for the serotonin 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7 receptors.[33]

    In addition to binding to serotonin receptors, buspirone is an antagonist of the dopamine D2 receptor with weak affinity.[2][35] It preferentially blocks inhibitory presynaptic D2 autoreceptors, and antagonizes postsynaptic D2 receptors only at higher doses.[2] In accordance, buspirone has been found to increase dopaminergic neurotransmission in the nigrostriatal pathway at low doses, whereas at higher doses, postsynaptic D2 receptors are blocked and antidopaminergic effects such as hypoactivity and reduced stereotypy, though notably not catalepsy, are observed in animals.[2] Buspirone has also been found to bind with much higher affinity to the dopamine D3 and D4 receptors, where it is similarly an antagonist.[45]

    A major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP), occurs at higher circulating levels than buspirone itself, and is known to act as a potent α2-adrenergic receptor antagonist.[44][48][49] It may be responsible for the increased noradrenergic and dopaminergic activity observed with buspirone in animals.[48][50] In addition, 1-PP may play an important role in the antidepressant effects of buspirone.[50] Buspirone also has very weak and probably clinically unimportant affinity for the α1-adrenergic receptor.[35][51] However, buspirone has been reported to have shown "significant and selective intrinsic efficacy" at the α1-adrenergic receptor expressed in a "tissue- and species-dependent manner".[51]

    Unlike benzodiazepines, buspirone does not interact with the GABAA receptor complex.[2][52]

    Pharmacokinetics

    Buspirone has a low oral bioavailability of 3.9% relative to intravenous injection due to extensive first-pass metabolism.[2] The time to peak plasma levels following ingestion is 0.9 to 1.5 hours.[2] It is reported to have an elimination half-life of 2.8 hours,[2] although a review of 14 studies found that the mean terminal half-life ranged between 2 and 11 hours, and one study even reported a terminal half-life of 33 hours.[6] Buspirone is metabolized primarily by CYP3A4, and prominent drug interactions with inhibitors and inducers of this enzyme have been observed.[4][5] Major metabolites of buspirone include 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-PP.[6][7][8] 6-Hydroxybuspirone has been identified as the predominant hepatic metabolite of buspirone, with plasma levels that are 40-fold greater than those of buspirone after oral administration of buspirone to humans.[7] The metabolite is a high-affinity partial agonist of the 5-HT1A receptor (Ki = 25 nM) similarly to buspirone, and has demonstrated occupancy of the 5-HT1A receptor in vivo.[7] As such, it is likely to play an important role in the therapeutic effects of buspirone.[7] 1-PP has also been found to circulate at higher levels than those of buspirone itself and may similarly play a significant role in the clinical effects of buspirone.[48][50]

    Phase I Metabolism of buspirone in humans.[53][54][55]

    Chemistry

    Buspirone is a member of the azapirone chemical class, and consists of azaspirodecanedione and pyrimidinylpiperazine components linked together by a butyl chain.

    Analogues

    Structural analogues of buspirone include other azapirones like gepirone, ipsapirone, perospirone, and tandospirone.[56]

    Synthesis
    Buspirone synthesis:[57] DE 2057845 U.S. Patent 3,717,634 U.S. Patent 3,907,801 U.S. Patent 3,976,776

    Alkylation of 1-(2-pyrimidyl)piperazine (1) with 3-chloro-1-cyanopropane (2, 4-chlorobutyronitrile) gives 3, which is reduced either by hydrogenation over Raney nickel catalyst, or with LAH. The resulting 1° amine (4) from the previous step is then reacted with 3,3-tetramethyleneglutaric anhydride (5, 8-Oxaspiro[4.5]decane-7,9-dione) in order to yield buspirone (6).

    History

    Buspirone was first synthesized, by a team at Mead Johnson, in 1968,[21] but was not patented until 1975.[58][59] It was initially developed as an antipsychotic drug acting on the D2 receptor, but was found to be ineffective in the treatment of psychosis and was repurposed as an anxiolytic.[2] In 1986, Bristol-Myers Squibb gained FDA approval for buspirone in the treatment of GAD.[21][60] The patent placed on buspirone expired in 2001 and it is now available as a generic drug.

    Society and culture
    Buspar (buspirone) 10-mg tablets.

    Generic names

    Buspirone is the INN, BAN, DCF, and DCIT of buspirone, while buspirone hydrochloride is its USAN, BANM, and JAN.[1][61][62][63]

    Brand name

    Buspirone was primarily sold under the brand name Buspar.[61][63] Buspar is currently listed as discontinued by the US Federal Drug Administration.[64] In 2010, in response to a citizen petition, the US FDA determined that Buspar was not withdrawn for sale because of reasons of safety or effectiveness.[65]

    2019 Shortage

    Due to interrupted production at a Mylan Pharmaceuticals plant in Morgantown West Virginia, the United States experienced a shortage of buspirone in 2019.[66]

    Research

    Some tentative research supports other uses such as depression and behavioral problems following brain damage.[67]

    References
    1. J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 192–. ISBN 978-1-4757-2085-3.
    2. Loane C, Politis M (2012). "Buspirone: what is it all about?". Brain Research. 1461: 111–8. doi:10.1016/j.brainres.2012.04.032. PMID 22608068.
    3. "buspirone (Rx) - BuSpar, Buspirex, more." Medscape Reference. WebMD. Retrieved 14 November 2013.
    4. Mahmood I, Sahajwalla C (1999). "Clinical pharmacokinetics and pharmacodynamics of buspirone, an anxiolytic drug". Clin Pharmacokinet. 36 (4): 277–87. doi:10.2165/00003088-199936040-00003. PMID 10320950.
    5. Zhu M, Zhao W, Jimenez H, Zhang D, Yeola S, Dai R, Vachharajani N, Mitroka J (2005). "Cytochrome P450 3A-mediated metabolism of buspirone in human liver microsomes". Drug Metab. Dispos. 33 (4): 500–7. doi:10.1124/dmd.104.000836. PMID 15640381.
    6. Gammans RE, Mayol RF, LaBudde JA (1986). "Metabolism and disposition of buspirone". Am. J. Med. 80 (3B): 41–51. doi:10.1016/0002-9343(86)90331-1. PMID 3515929.
    7. Alan F. Schatzberg; Charles B. Nemeroff (2009). The American Psychiatric Publishing Textbook of Psychopharmacology. American Psychiatric Pub. pp. 490–. ISBN 978-1-58562-309-9.
    8. Wong H, Dockens RC, Pajor L, Yeola S, Grace JE, Stark AD, Taub RA, Yocca FD, Zaczek RC, Li YW (2007). "6-Hydroxybuspirone is a major active metabolite of buspirone: assessment of pharmacokinetics and 5-hydroxytryptamine1A receptor occupancy in rats". Drug Metab. Dispos. 35 (8): 1387–92. doi:10.1124/dmd.107.015768. PMID 17494642.
    9. "Buspirone Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 3 March 2019.
    10. Wilson, TK; Tripp, J (January 2018). "Buspirone". StatPearls. PMID 30285372.
    11. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 338. ISBN 9780857113382.
    12. "Buspirone Pregnancy and Breastfeeding Warnings". Drugs.com. Retrieved 3 March 2019.
    13. "NADAC as of 2019-02-27". Centers for Medicare and Medicaid Services. Retrieved 3 March 2019.
    14. "The Top 300 of 2019". clincalc.com. Retrieved 22 December 2018.
    15. "BUSPIRONE HCL (buspirone hydrochloride) tablet [Watson Laboratories, Inc.]". DailyMed. Watson Laboratories, Inc. July 2013. Retrieved 14 November 2013.
    16. "BUSPAR® (buspirone hydrochloride) Tablets 5 mg & 10 mg PRODUCT INFORMATION" (PDF). TGA eBusiness Services. Aspen Pharma Pty Ltd. January 2010. Retrieved 14 November 2013.
    17. Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
    18. "Buspirone 10mg Tablets". electronic Medicines Compendium. Actavis UK Ltd. 10 September 2012. Retrieved 14 November 2013.
    19. Joint Formulary Committee. British National Formulary (BNF). Pharmaceutical Press. p. 224.
    20. Benjamin J. Sadock; Virginia A. Sadock; Pedro Ruiz (22 September 2014). Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry. Wolters Kluwer Health. pp. 3211–. ISBN 978-1-4698-8375-5.
    21. Howland RH (2015). "Buspirone: Back to the Future". J Psychosoc Nurs Ment Health Serv. 53 (11): 21–4. doi:10.3928/02793695-20151022-01. PMID 26535760.
    22. Masdrakis VG, Turic D, Baldwin DS (2013). "Pharmacological treatment of social anxiety disorder". Anxiety Disorders. Modern Trends in Pharmacopsychiatry. 29. pp. 144–53. doi:10.1159/000351960. ISBN 978-3-318-02463-0. PMID 25225024.
    23. Goldstein I, Kim NN, Clayton AH, DeRogatis LR, Giraldi A, Parish SJ, Pfaus J, Simon JA, Kingsberg SA, Meston C, Stahl SM, Wallen K, Worsley R (2017). "Hypoactive Sexual Desire Disorder: International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel Review". Mayo Clin. Proc. 92 (1): 114–128. doi:10.1016/j.mayocp.2016.09.018. PMID 27916394.
    24. Sontheimer DL, Ables AZ (March 2001). "Is imipramine or buspirone treatment effective in patients wishing to discontinue long-term benzodiazepine use?". The Journal of Family Practice. 50 (3): 203. PMID 11252203.
    25. Garrett, A. R.; Hawley, J. S. (2018). "SSRI-associated bruxism: A systematic review of published case reports". Neurology. Clinical Practice. 8 (2): 135–141. doi:10.1212/CPJ.0000000000000433. ISSN 2163-0402. PMC 5914744. PMID 29708207.
    26. Prisco, V.; Iannaccone, T.; Di Grezia, G. (2017-04-01). "Use of buspirone in selective serotonin reuptake inhibitor-induced sleep bruxism". European Psychiatry. Abstract of the 25th European Congress of Psychiatry. 41: S855. doi:10.1016/j.eurpsy.2017.01.1701. ISSN 0924-9338.
    27. "Buspirone monograph". Drugs.com. Retrieved 2011-08-27.
    28. Geddes, John; Gelder, Michael G.; Mayou, Richard (2005). Psychiatry. Oxford [Oxfordshire]: Oxford University Press. p. 237. ISBN 978-0-19-852863-0.
    29. Fulton, Bret; Brogden, Rex N. (1997). "Buspirone". CNS Drugs. 7 (1): 68–88. doi:10.2165/00023210-199707010-00007. ISSN 1172-7047.
    30. Richard C. Dart (2004). Medical Toxicology. Lippincott Williams & Wilkins. pp. 886–. ISBN 978-0-7817-2845-4.
    31. Lilja JJ, Kivistö KT, Backman JT, Lamberg TS, Neuvonen PJ (December 1998). "Grapefruit juice substantially increases plasma concentrations of buspirone". Clinical Pharmacology and Therapeutics. 64 (6): 655–60. doi:10.1016/S0009-9236(98)90056-X. PMID 9871430.
    32. Lamberg, T. S; Kivistö, K. T; Laitila, J; Mårtensson, K; Neuvonen, P. J (1998). "The effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of buspirone". European Journal of Clinical Pharmacology. 54 (9–10): 761–766. doi:10.1007/s002280050548. ISSN 0031-6970. PMID 9923581.
    33. Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
    34. Boess FG, Martin IL (1994). "Molecular biology of 5-HT receptors". Neuropharmacology. 33 (3–4): 275–317. doi:10.1016/0028-3908(94)90059-0. PMID 7984267.
    35. Hamik A, Oksenberg D, Fischette C, Peroutka SJ (1990). "Analysis of tandospirone (SM-3997) interactions with neurotransmitter receptor binding sites". Biol. Psychiatry. 28 (2): 99–109. doi:10.1016/0006-3223(90)90627-e. PMID 1974152.
    36. Peroutka SJ, Switzer JA, Hamik A (1989). "Identification of 5-hydroxytryptamine1D binding sites in human brain membranes". Synapse. 3 (1): 61–6. doi:10.1002/syn.890030109. PMID 2521959.
    37. Waeber C, Schoeffter P, Palacios JM, Hoyer D (1988). "Molecular pharmacology of 5-HT1D recognition sites: radioligand binding studies in human, pig and calf brain membranes". Naunyn Schmiedebergs Arch. Pharmacol. 337 (6): 595–601. doi:10.1007/bf00175783. PMID 2975354.
    38. Bonhaus DW, Weinhardt KK, Taylor M, DeSouza A, McNeeley PM, Szczepanski K, Fontana DJ, Trinh J, Rocha CL, Dawson MW, Flippin LA, Eglen RM (1997). "RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist". Neuropharmacology. 36 (4–5): 621–9. doi:10.1016/s0028-3908(97)00049-x. PMID 9225287.
    39. Nelson DR, Thomas DR (1989). "[3H]-BRL 43694 (Granisetron), a specific ligand for 5-HT3 binding sites in rat brain cortical membranes". Biochem. Pharmacol. 38 (10): 1693–5. doi:10.1016/0006-2952(89)90319-5. PMID 2543418.
    40. Borsini F, Giraldo E, Monferini E, Antonini G, Parenti M, Bietti G, Donetti A (1995). "BIMT 17, a 5-HT2A receptor antagonist and 5-HT1A receptor full agonist in rat cerebral cortex". Naunyn Schmiedebergs Arch. Pharmacol. 352 (3): 276–82. doi:10.1007/bf00168557. PMID 8584042.
    41. Plassat JL, Amlaiky N, Hen R (1993). "Molecular cloning of a mammalian serotonin receptor that activates adenylate cyclase". Mol. Pharmacol. 44 (2): 229–36. PMID 8394987.
    42. Lovenberg TW, Baron BM, de Lecea L, Miller JD, Prosser RA, Rea MA, Foye PE, Racke M, Slone AL, Siegel BW (1993). "A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms". Neuron. 11 (3): 449–58. doi:10.1016/0896-6273(93)90149-l. PMID 8398139.
    43. Ruat M, Traiffort E, Leurs R, Tardivel-Lacombe J, Diaz J, Arrang JM, Schwartz JC (1993). "Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation". Proc. Natl. Acad. Sci. U.S.A. 90 (18): 8547–51. Bibcode:1993PNAS...90.8547R. doi:10.1073/pnas.90.18.8547. PMC 47394. PMID 8397408.
    44. Blier P, Curet O, Chaput Y, de Montigny C (1991). "Tandospirone and its metabolite, 1-(2-pyrimidinyl)-piperazine--II. Effects of acute administration of 1-PP and long-term administration of tandospirone on noradrenergic neurotransmission". Neuropharmacology. 30 (7): 691–701. doi:10.1016/0028-3908(91)90176-c. PMID 1681447.
    45. Bergman J, Roof RA, Furman CA, Conroy JL, Mello NK, Sibley DR, Skolnick P (2013). "Modification of cocaine self-administration by buspirone (buspar®): potential involvement of D3 and D4 dopamine receptors". Int. J. Neuropsychopharmacol. 16 (2): 445–58. doi:10.1017/S1461145712000661. PMC 5100812. PMID 22827916.
    46. Uvnäs-Moberg K, Hillegaart V, Alster P, Ahlenius S (1996). "Effects of 5-HT agonists, selective for different receptor subtypes, on oxytocin, CCK, gastrin and somatostatin plasma levels in the rat". Neuropharmacology. 35 (11): 1635–40. doi:10.1016/S0028-3908(96)00078-0. PMID 9025112.
    47. Chiodera P, Volpi R, Capretti L, Caffarri G, Magotti MG, Coiro V (April 1996). "Different effects of the serotonergic agonists buspirone and sumatriptan on the posterior pituitary hormonal responses to hypoglycemia in humans". Neuropeptides. 30 (2): 187–92. doi:10.1016/S0143-4179(96)90086-4. PMID 8771561.
    48. Tunnicliff G (1991). "Molecular basis of buspirone's anxiolytic action". Pharmacol. Toxicol. 69 (3): 149–56. doi:10.1111/j.1600-0773.1991.tb01289.x. PMID 1796057.
    49. Zuideveld KP, Rusiç-Pavletiç J, Maas HJ, Peletier LA, Van der Graaf PH, Danhof M (2002). "Pharmacokinetic-pharmacodynamic modeling of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in rats". J. Pharmacol. Exp. Ther. 303 (3): 1130–7. doi:10.1124/jpet.102.036798. PMID 12438536.
    50. Fava M (2007). "The combination of buspirone and bupropion in the treatment of depression". Psychother Psychosom. 76 (5): 311–2. doi:10.1159/000104708. PMID 17700052.
    51. Theodore A. Stern; Maurizio Fava; Timothy E. Wilens; Jerrold F. Rosenbaum (27 April 2015). Massachusetts General Hospital Psychopharmacology and Neurotherapeutics E-Book. Elsevier Health Sciences. pp. 29–. ISBN 978-0-323-41323-7.
    52. David J. Nutt; James C. Ballenger (15 April 2008). Anxiety Disorders. John Wiley & Sons. pp. 395–. ISBN 978-0-470-98683-7.
    53. Dockens, RC; Salazar, DE; Fulmor, IE; Wehling, M; Arnold, ME; Croop, R (November 2006). "Pharmacokinetics of a newly identified active metabolite of buspirone after administration of buspirone over its therapeutic dose range". Journal of Clinical Pharmacology. 46 (11): 1308–12. doi:10.1177/0091270006292250. PMID 17050795.
    54. Jajoo, HK; Mayol, RF; LaBudde, JA; Blair, IA (1989). "Metabolism of the antianxiety drug buspirone in human subjects". Drug Metabolism and Disposition. 17 (6): 634–40. PMID 2575499.
    55. Zhu, M; Zhao, W; Jimenez, H; Zhang, D; Yeola, S; Dai, R; Vachharajani, N; Mitroka, J (April 2005). "Cytochrome P450 3A-mediated metabolism of buspirone in human liver microsomes". Drug Metabolism and Disposition. 33 (4): 500–7. doi:10.1124/dmd.104.000836. PMID 15640381.
    56. Taylor DP, Moon SL (1991). "Buspirone and related compounds as alternative anxiolytics". Neuropeptides. 19 Suppl: 15–9. doi:10.1016/0143-4179(91)90078-w. PMID 1679210.
    57. Allen LE, Ferguson HC, Kissel JW (May 1972). "Psychosedative agents. 2. 8-(4-Substituted 1-piperazinylalkyl)-8-azaspiro(4.5)decane-7,9-diones". Journal of Medicinal Chemistry. 15 (5): 477–9. doi:10.1021/jm00275a009. PMID 5035267.
    58. Wu Y-H, Rayburn LE, Ferguson JW (1972). "Psychosedative agents. 2. 8-(4-Substituted 1-piperazinylalkyl)-8-azaspiro[4.5]decane-7,9-diones". J. Med. Chem. 15 (5): 477–479. doi:10.1021/jm00275a009. PMID 5035267.
    59. US Patent 3907801 N-(8 (4-pyridyl-piperazino)-alkyl(9 -azaspiroalkanediones
    60. United States Federal Drug Administration (September 9, 1986). Approval Type-1 New Molecular Entry. https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/018731Orig1s000rev.pdf
    61. Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 149–. ISBN 978-3-88763-075-1.
    62. I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 57–. ISBN 978-94-011-4439-1.
    63. "Buspirone".
    64. "Drugs@FDA: FDA Approved Drug Products". www.accessdata.fda.gov. Retrieved 2019-09-20.
    65. "Determination That BUSPAR (Buspirone Hydrochloride) Tablets, 10 Milligrams, 15 Milligrams, and 30 Milligrams, Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness". Federal Register. 2010-10-19. Retrieved 2019-09-20.
    66. Rabin, Roni Caryn (2019-02-01). "Shortage of Anxiety Drug Leaves Patients Scrambling". The New York Times. ISSN 0362-4331. Retrieved 2019-09-20.
    67. Loane, C; Politis, M (21 June 2012). "Buspirone: what is it all about?". Brain Research. 1461: 111–8. doi:10.1016/j.brainres.2012.04.032. PMID 22608068.
    This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.