Chemistry:Guanfacine

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Guanfacine, sold under the brand name Tenex (immediate-release) and Intuniv (extended-release) among others, is an oral alpha-2a agonist medication used to treat attention deficit hyperactivity disorder (ADHD) and high blood pressure.[1][2]

Common side effects include sleepiness, constipation, and dry mouth.[2] Other side effects may include low blood pressure and urinary problems.[3] It appears to work by activating α2A-adrenergic receptors in the brain, thereby decreasing sympathetic nervous system activity.[2]

Guanfacine was first described in 1974[4] and was approved for medical use in the United States in 1986.[2] It is available as a generic medication.[2] In 2023, it was the 263rd most commonly prescribed medication in the United States, with more than 1 million prescriptions.[5][6] Guanfacine is approved in the US for monotherapy treatment of attention deficit hyperactivity disorder,[1] as well as being used for augmentation of stimulant medications.[1][2] Guanfacine is also used off-label to treat tic disorders, anxiety disorders, and post-traumatic stress disorder (PTSD).[7]

Medical uses

Red pills
1 mg guanfacine tablets.

Guanfacine IR (as brand name Tenex) is FDA approved for the management of hypertension.[8][9]

Guanfacine XR (as brand name Intuniv) is indicated for the treatment of attention deficit hyperactivity disorder (ADHD), primarily for hyperactive symptoms. It is used both as monotherapy and as adjunctive therapy to stimulant medications.[1][10] In some cases, it can also help control the side effect profile of stimulant medications.[2] Unlike stimulant medications, guanfacine is regarded as having no abuse potential.[11] However, stimulant medications still remain the first-line treatment for ADHD, and guanfacine is typically only prescribed by itself in patients who cannot take stimulant medications (due to mental or physical side effects).

For attention deficit hyperactivity disorder (ADHD), it is claimed that guanfacine helps individuals better control behavior, inhibit inappropriate distractions and impulses, and inhibit inappropriate aggressive impulses.[12] Systematic reviews and meta-analyses have found guanfacine to be effective in the treatment of ADHD in both children and adults, with a moderate effect size found in adults (Hedges' g = -0.66).[13][14][15] A systematic review and meta-analysis also found that guanfacine reduced oppositional behavior in children and adolescents with ADHD who also had or did not also have oppositional defiant disorder, with a small-to-moderate effect size.[16] In any case, guanfacine and other α2-adrenergic receptor agonists are considered to be less effective than stimulants in the treatment of ADHD, at least when compared on rating scales developed to assess stimulant efficacy.[16][17][15]

Guanfacine is also used off-label to treat tic disorders, anxiety disorders such as generalized anxiety disorder, and PTSD.[18][7] Guanfacine and other α2A-adrenergic receptor agonists have anxiolytic-like action,[19] thereby reducing the emotional responses of the amygdala, and strengthening prefrontal cortical regulation of emotion, action, and thought.[20] These actions arise from both inhibition of stress-induced catecholamine release, and from prominent, post-synaptic actions in the prefrontal cortex.[20] Due to its prolonged elimination half-life, it also has been seen to improve sleep interrupted by nightmares in PTSD patients.[21] All of these actions likely contribute to the relief of the hyperarousal, re-experiencing of memory, and impulsivity associated with PTSD.[22] Guanfacine appears to be especially helpful in treating children who have been traumatized or abused.[20]

Other indications for guanfacine are drug (opioid, nicotine, cocaine) withdrawals, migraine prophylaxis, and Fragile X Syndrome, among others.[11][23]

Adverse effects

Side effects of guanfacine are dose-dependent.[24]

Very common (>10% incidence) adverse effects include somnolence (drowsiness), fatigue, headache, and stomach ache.[25]

Common (1–10% incidence) adverse effects include decreased appetite, nausea, dry mouth, urinary incontinence, and rashes.[25]

Guanfacine has been reported to cause high rates of somnolence in children with attention deficit hyperactivity disorder, for instance 73% with guanfacine versus 6% with placebo in one trial.[26][27]

Guanfacine may worsen sleep in children with attention deficit hyperactivity disorder, including reduced total sleep time.[26][27]

A 2020 systematic review found side effects of guanfacine including abdominal pain, sedation, and QT prolongation.[28]

Interactions

Guanfacine availability is significantly affected by the CYP3A4 and CYP3A5 enzymes. Medications that inhibit or induce those enzymes change the amount of guanfacine in circulation and thus its efficacy and rate of adverse effects. Because of its impact on the heart, it should be used with caution with other cardioactive drugs. A similar concern is appropriate when it is used with sedating medications.[25]

Pharmacology

Pharmacodynamics

Guanfacine[29]
Site Ki (nM) Species Ref
α2A 50.3 – 93.3 Human [30][31]
α2B 1,020 – 1,380 Human [30][31]
α2C 1,120 – 3,890 Human [30][31]
The smaller the value, the more strongly the drug binds to the site.

Guanfacine is a highly selective agonist of the α2A-adrenergic receptor, with low affinity for other receptors.[29] However, it is also a serotonin 5-HT2B receptor agonist.[32][33][34][35]

Guanfacine works by activating α2A-adrenoceptors[36] within the central nervous system. This leads to reduced peripheral sympathetic outflow and thus a reduction in peripheral sympathetic tone, which lowers both systolic and diastolic blood pressure.[37]

In ADHD, guanfacine is thought to work by strengthening the regulation of attention and behavior by the prefrontal cortex.[38][12] These enhancing effects on prefrontal cortical functions are believed to be due to drug stimulation of post-synaptic α2A-adrenoceptors on dendritic spines, and are not dependent on activation of pre-synaptic α2A-adrenoceptors.[12] Cyclic adenosine monophosphate (cAMP)-mediated opening of HCN and KCNQ channels is inhibited, which enhances prefrontal cortical synaptic connectivity and neuronal firing.[38][39] In monkeys, guanfacine improves working memory, attention regulation, and behavioral inhibition, and these actions are independent of its sedative effects.[12] The use of guanfacine for treating prefrontal disorders was developed by the Arnsten Lab at Yale University.[38][12]

Guanfacine is much more selective for α2A-adrenergic receptors than clonidine, which binds to and activates not only the α2A-adrenergic receptor but also α2B- and α2C-adrenergic receptors and the imidazoline receptor.[12] It is weaker than clonidine in producing hypotension and sedation, has weaker pre-synaptic actions on the α2A-adrenergic receptor than clonidine (10-fold less effective in decreasing locus coeruleus activity and norepinephrine release), and may have greater efficacy in activating post-synaptic α2A-adrenergic receptors (as suggested by guanfacine being more potent than clonidine in enhancing prefrontal cortex-related working memory in aged monkeys).[12]

Activation of the 5-HT2B receptor is a well-known antitarget and is associated with cardiac valvulopathy.[32][33] However, not all 5-HT2B receptor agonists, for instance ropinirole, have this effect.[32][33] Guanfacine has not been associated with cardiac valvulopathy despite a long history of use, perhaps due to modest potency as a 5-HT2B receptor agonist.[35][40][41][42] In in vitro studies, guanfacine showed 100-fold lower affinity for the 5-HT2B receptor than for the α2A-adrenergic receptor, 30-fold lower affinity for the 5-HT2B receptor than serotonin, and 1,000-fold lower potency in activating the 5-HT2B receptor compared to serotonin.[40] It was concluded that at clinically relevant concentrations, guanfacine would not be expected to show significant binding to or activation of 5-HT2B receptors, and that it is unlikely that guanfacine is a cardiac valvulopathogen in humans.[40] In any case, different studies have reported different potencies of guanfacine as a 5-HT2B receptor agonist,[34][35][40][41] and as of 2018, no clinical data on the risk of cardiac valvulopathy with guanfacine were available.[43] As such, while the likelihood is thought to be low, guanfacine might still have a risk of cardiac valvulopathy.[40]

Guanfacine has been found to act as a full agonist of the trace amine-associated receptor 1 (TAAR1) with an EC50 and Emax of 20 nM and ≥85% respectively.[44][45]

Pharmacokinetics

Comparison of Intuniv 1mg QD and Tenex 1mg QD at steady-state.[46]

Guanfacine has an oral bioavailability of 80%. There is no clear evidence of any first-pass metabolism. Its elimination half-life is 17 hours with the major elimination route being renal. The principal metabolite is the 3-hydroxylated derivative, with evidence of moderate biotransformation, and the key intermediate is an epoxide.[47] Elimination is not impacted by impaired renal function. As such, metabolism by the liver is the assumption for those with impaired renal function, as supported by the increased frequency of known side effects of orthostatic hypotension and sedation.[48]

Pharmacokinetic Data[49][46]
Intuniv 1 mg QD Tenex 1 mg QD Unit
Cmax 1.0 ± 0.3 2.5 ± 0.6 ng/mL
AUC∞ 32 ± 9 56 ± 15 ng*h/mL
T1/2 18 ± 4 16 ± 3 h (hours)
Tmax 6.0 (4.0 - 8.0) 3.0 (1.5 - 4.0) h (hours)
Bioavailability 58% 80 - 100% unitless

Preparation

Guanfacine can be prepared from equal parts methyl 2,6-dichlorophenylacetate and guanidine:[50]

History

Guanfacine was first described in the literature by 1974.[4][51][52][53][54] In 1986, guanfacine was approved by the FDA for the treatment of hypertension under the brand name Tenex.[55] In 2010, guanfacine was approved by the FDA for the treatment of attention deficit hyperactivity disorder for people 6 to 17 years old.[10] It was approved for ADHD by the European Medicines Agency under the name Intuniv in 2015.[56] It was added to the Australian Pharmaceutical Benefits Scheme for the treatment of ADHD in 2018.[57] In February 2025, the first generic drug of guanfacine extended-release in China was approved for marketing, and the trade name is Le'erjing(乐儿静).[58][59]。

Society and culture

In December 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Paxneury, intended for the treatment of attention deficit hyperactivity disorder in children.[60] The applicant for this medicinal product is Neuraxpharm Pharmaceuticals S.L.[60] Paxneury is a generic of Intuniv, which has been authorized in the EU since September 2015.[60] It is also a hybrid medicine of Intuniv.[60] It contains the same active substance as Intuniv, but is available at higher strengths.[60] Paxneury was authorized for medical use in the European Union in February 2025.[60][61]

Brand names

Brand names for instant release formulations include Tenex, Afken, and Estulic; and Intuniv and Paxneury (as extended release formulations).[60]

Research

Guanfacine has been studied as a treatment for post-traumatic stress disorder (PTSD). Evidence of efficacy in adults is limited, but one study found positive results in children with comorbid ADHD.[62] It may be also useful in adult PTSD patients who do not respond to selective serotonin reuptake inhibitors (SSRIs).[63]

Results of studies using guanfacine to treat Tourette's syndrome have been mixed.[64]

Guanfacine does not appear to be effective for improving sleep in children with ADHD and behavioral insomnia.[26] Instead, guanfacine worsened certain sleep parameters, for instance total sleep time, in one clinical trial.[26][27]

Guanfacine has been investigated for treatment of withdrawal for opioids, ethanol, and nicotine.[65] Guanfacine has been shown to help reduce stress-induced craving of nicotine in smokers trying to quit, which may involve strengthening of prefrontal cortex-mediated self-control.[66]

Guanfacine has been researched for treatment of a variety of conditions impacting prefrontal cortex function, including cognitive and attentional problems in people with traumatic brain injury, stroke, schizophreniform disorders, and the elderly.[12][67]

Guanfacine is being studied for the possible treatment of long COVID.[68][69][70]

References

  1. ↑ 1.0 1.1 1.2 1.3 Cite error: Invalid <ref> tag; no text was provided for refs named Intuniv FDA label
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "Guanfacine Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/guanfacine.html. 
  3. ↑ British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 349–350. ISBN 978-0-85711-338-2. 
  4. ↑ 4.0 4.1 Turner, A. S. (1974). BS 100-141 in the treatment of arterial hypertension. Seventh World Congr. of Cardiol., Abstr, 336.
  5. ↑ "The Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  6. ↑ "Guanfacine Drug Usage Statistics, United States, 2014 - 2023". https://clincalc.com/DrugStats/Drugs/Guanfacine. 
  7. ↑ 7.0 7.1 Kaplan & Sadock's Concise Textbook of Clinical Psychiatry (5th ed.). Philadelphia: Wolters Kluwer. 2023. pp. 1811–1812. ISBN 978-1-9751-6748-6. OCLC 1264172789. 
  8. ↑ "Tenex- guanfacine hydrochloride tablet". 8 May 2013. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=886e050c-dd22-4f35-ac3b-243f091125c3. 
  9. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named MSR
  10. ↑ 10.0 10.1 "Effects of FDA advisories on the pharmacologic treatment of ADHD, 2004-2008". Psychiatric Services 64 (4): 339–346. April 2013. doi:10.1176/appi.ps.201200147. PMID 23318985. 
  11. ↑ 11.0 11.1 "The potential for misuse and abuse of medications in ADHD: a review". Postgraduate Medicine 126 (5): 64–81. September 2014. doi:10.3810/pgm.2014.09.2801. PMID 25295651. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 "Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale". The Yale Journal of Biology and Medicine 85 (1): 45–58. March 2012. PMID 22461743. 
  13. ↑ "Nonstimulant Medications for Attention-Deficit/Hyperactivity Disorder (ADHD) in Adults: Systematic Review and Meta-analysis". CNS Drugs 37 (5): 381–397. May 2023. doi:10.1007/s40263-023-01005-8. PMID 37166701. https://eprints.soton.ac.uk/477815/1/Manuscript_revision_02272023.docx. 
  14. ↑ "Guanfacine for the Treatment of Attention-Deficit Hyperactivity Disorder: An Updated Systematic Review and Meta-Analysis". J Child Adolesc Psychopharmacol 33 (2): 40–50. March 2023. doi:10.1089/cap.2022.0038. PMID 36944092. 
  15. ↑ 15.0 15.1 "The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: A systematic review with network meta-analyses of randomised trials". PLOS ONE 12 (7). 2017. doi:10.1371/journal.pone.0180355. PMID 28700715. Bibcode: 2017PLoSO..1280355C. 
  16. ↑ 16.0 16.1 "The pharmacological management of oppositional behaviour, conduct problems, and aggression in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder: a systematic review and meta-analysis. Part 1: psychostimulants, alpha-2 agonists, and atomoxetine". Can J Psychiatry 60 (2): 42–51. February 2015. doi:10.1177/070674371506000202. PMID 25886655. 
  17. ↑ "Efficacy and safety of drugs for attention deficit hyperactivity disorder in children and adolescents: a network meta-analysis". Eur Child Adolesc Psychiatry 27 (10): 1335–1345. October 2018. doi:10.1007/s00787-018-1125-0. PMID 29460165. 
  18. ↑ "Off-label psychopharmacologic prescribing for children: history supports close clinical monitoring". Child and Adolescent Psychiatry and Mental Health 2 (1). September 2008. doi:10.1186/1753-2000-2-24. PMID 18793403. 
  19. ↑ "Noradrenergic alpha-2 agonists have anxiolytic-like actions on stress-related behavior and mesoprefrontal dopamine biochemistry". Brain Research 1027 (1–2): 173–178. November 2004. doi:10.1016/j.brainres.2004.08.057. PMID 15494168. 
  20. ↑ 20.0 20.1 20.2 "The Effects of Stress Exposure on Prefrontal Cortex: Translating Basic Research into Successful Treatments for Post-Traumatic Stress Disorder". Neurobiology of Stress 1: 89–99. January 2015. doi:10.1016/j.ynstr.2014.10.002. PMID 25436222. 
  21. ↑ "Psychopharmacotherapy of posttraumatic stress disorder". Croatian Medical Journal 49 (4): 459–475. August 2008. doi:10.3325/cmj.2008.4.459. PMID 18716993. 
  22. ↑ "Post-traumatic stress disorder in children". World Psychiatry 4 (2): 121–125. June 2005. PMID 16633528. 
  23. ↑ "Intuniv(guanfacine) dosing, indications, interactions, adverse effects, and more". https://reference.medscape.com/drug/intuniv-guanfacine-342384. 
  24. ↑ "Clinical experience with guanfacine in long-term treatment of hypertension. Part II: adverse reactions to guanfacine". British Journal of Clinical Pharmacology 10 (Suppl 1): 157S–164S. 1980. doi:10.1111/j.1365-2125.1980.tb04924.x. PMID 6994770. 
  25. ↑ 25.0 25.1 25.2 "Intuniv 1 mg, 2 mg, 3 mg, 4 mg prolonged-release tablets - Summary of Product Characteristics". UK Electronic Medicines Compendium. June 2017. https://www.medicines.org.uk/emc/medicine/31294. 
  26. ↑ 26.0 26.1 26.2 26.3 "Safety, Tolerability and Efficacy of Drugs for Treating Behavioural Insomnia in Children with Attention-Deficit/Hyperactivity Disorder: A Systematic Review with Methodological Quality Assessment". Paediatr Drugs 19 (3): 235–250. June 2017. doi:10.1007/s40272-017-0224-6. PMID 28391425. https://eprints.soton.ac.uk/412343/1/Anand.docx. 
  27. ↑ 27.0 27.1 27.2 "Effect on Primary Sleep Disorders When Children With ADHD Are Administered Guanfacine Extended Release". J Atten Disord 22 (1): 14–24. January 2018. doi:10.1177/1087054714554932. PMID 25376194. 
  28. ↑ "Safety of 80 antidepressants, antipsychotics, anti-attention-deficit/hyperactivity medications and mood stabilizers in children and adolescents with psychiatric disorders: a large scale systematic meta-review of 78 adverse effects". World Psychiatry 19 (2): 214–232. June 2020. doi:10.1002/wps.20765. PMID 32394557. 
  29. ↑ 29.0 29.1 "PDSP Ki Database". University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. 12 January 2011. http://pdsp.med.unc.edu/pdsp.php. 
  30. ↑ 30.0 30.1 30.2 "Ligand efficacy and potency at recombinant alpha2 adrenergic receptors: agonist-mediated [35S]GTPgammaS binding". Biochemical Pharmacology 55 (7): 1035–1043. April 1998. doi:10.1016/s0006-2952(97)00631-x. PMID 9605427. 
  31. ↑ 31.0 31.1 31.2 "The novel alpha-2 adrenergic radioligand [3H]-MK912 is alpha-2C selective among human alpha-2A, alpha-2B and alpha-2C adrenoceptors". The Journal of Pharmacology and Experimental Therapeutics 271 (3): 1558–1565. December 1994. doi:10.1016/S0022-3565(25)24043-5. PMID 7996470. 
  32. ↑ 32.0 32.1 32.2 "2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery". J Med Chem 66 (16): 11027–11039. August 2023. doi:10.1021/acs.jmedchem.3c01178. PMID 37584406. "These results strongly indicate substantial risks for treatments involving 5-HT2B agonists, and it has been recommended that all serotonergic drugs be screened for this functional profile.43,59 [...] Additionally, there are cases of marketed drugs that were only later determined to have 5-HT2B activity. Of particular note is guanfacine, an FDA-approved medication for the treatment of attention deficit hyperactivity disorder (ADHD) that possesses potent 5-HT2B agonist activity in functional readouts to a similar degree as known valvulopathogens.66". 
  33. ↑ 33.0 33.1 33.2 "Serotonin receptors and heart valve disease--it was meant 2B". Pharmacol Ther 132 (2): 146–57. November 2011. doi:10.1016/j.pharmthera.2011.03.008. PMID 21440001. 
  34. ↑ 34.0 34.1 "Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine(2B) receptor agonists: implications for drug safety assessment". Molecular Pharmacology 76 (4): 710–722. October 2009. doi:10.1124/mol.109.058057. PMID 19570945. 
  35. ↑ 35.0 35.1 35.2 "Kinetics of 5-HT2B receptor signaling: profound agonist-dependent effects on signaling onset and duration". J Pharmacol Exp Ther 347 (3): 645–59. December 2013. doi:10.1124/jpet.113.207670. PMID 24049061. 
  36. ↑ "A Comprehensive Literature Review on Guanfacine as a Potential Treatment for Attention-Deficit/Hyperactivity Disorder (ADHD)". International Journal of Environmental Science and Technology. May 2023. https://www.ijest.org/guanfacine-adhd-tardner-2023/. 
  37. ↑ "Centrally mediated hypotensive activity of B-HT 933 upon infusion via the cat's vertebral artery". Pharmacology 21 (5): 327–332. 1983. doi:10.1111/j.1365-2125.1983.tb00311.x. PMID 7433512. 
  38. ↑ 38.0 38.1 38.2 "The use of α-2A adrenergic agonists for the treatment of attention-deficit/hyperactivity disorder". Expert Review of Neurotherapeutics 10 (10): 1595–1605. October 2010. doi:10.1586/ern.10.133. PMID 20925474. 
  39. ↑ "Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex". Cell 129 (2): 397–410. April 2007. doi:10.1016/j.cell.2007.03.015. PMID 17448997. 
  40. ↑ 40.0 40.1 40.2 40.3 40.4 Therapeutic Goods Administration (May 2018). "Australian Public Assessment Report for Guanfacine (as hydrochloride)". https://www.tga.gov.au/sites/default/files/auspar-guanfacine-180503.pdf. 
  41. ↑ 41.0 41.1 Roihuvuo, E. (2022). Classical psychedelics and NBOMes as serotonin 2B receptor agonists: Valvulopathogenic signaling pathways and cardiac safety concerns (Master's thesis, Itä-Suomen yliopisto). http://urn.fi/urn:nbn:fi:uef-20220118
  42. ↑ "Recommendation for complete response action for SPD503 (guanfacine) extended release tablets for the treatment of attention deficit hyperactivity disorder (ADHD)". 27 July 2009. https://www.fda.gov/files/drugs/published/22037-Guanfacine-DD-memo1-PREA.pdf. ""Guanfacine IR has been marketed since 1986 for the treatment of hypertension, and in more recent years has also been used off-label for the treatment of ADHD. We have conducted an AERS search and have not found a single report of valvulopathy for this drug. We have also conducted a literature search and have found no reports of valvulopathy for this drug. This is somewhat reassuring, since reports emerged fairly quickly for the drugs believed to be valvulopathogens."" 
  43. ↑ "Comprehensive review of cardiovascular toxicity of drugs and related agents". Med Res Rev 38 (4): 1332–1403. July 2018. doi:10.1002/med.21476. PMID 29315692. "The list of valvulopathic drugs is short and can be seen in Table 7. According to a recent analysis, other drugs, in particular guanfacine, might possess some risk, but clinical data are yet not available.368–370". 
  44. ↑ "Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Studies and Biological Assays". Pharmaceuticals 16 (11): 1632. 2023. doi:10.3390/ph16111632. PMID 38004497. 
  45. ↑ "Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Studies and Biological Assays". Pharmaceuticals 16 (11): 1632. November 2023. doi:10.3390/ph16111632. PMID 38004497. 
  46. ↑ 46.0 46.1 (PDF) INTUNIV® (guanfacine) - Prescribing Information (Report). Food and Drug Administration. April 2019. Reference ID: 4426258. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022037s018lbl.pdf. 
  47. ↑ "Pharmacokinetics and metabolism of guanfacine in man: a review". British Journal of Clinical Pharmacology 10 (Suppl 1): 25S–32S. 1980. doi:10.1111/j.1365-2125.1980.tb04901.x. PMID 6994775. 
  48. ↑ "Elimination of guanfacine in patients with normal and impaired renal function". British Journal of Clinical Pharmacology 10 (Suppl 1): 33S–35S. 1980. doi:10.1111/j.1365-2125.1980.tb04902.x. PMID 6994776. 
  49. ↑ (PDF) INTUNIV® (guanfacine) - Prescribing Information (Report). Food and Drug Administration. February 2013. Reference ID: 3361918. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022037s009lbl.pdf. 
  50. ↑ , John Bernard & Claude W. Picard"Substituted phenylacetyl derivatives of guanidine o-alkylisoureas s-alkylisothioureas and p-nitrobenzylisothiourea" patent US3632645A, issued 1972-01-04
  51. ↑ "Proceedings: Inhibition of effects of accelerator nerve stimulation in cats and rabbits by BS 100-141 and guanabenz". Naunyn-Schmiedeberg's Arch Pharmacol 282 (Suppl): suppl 282:R86. 1974. PMID 4276642. 
  52. ↑ "Substituted phenylacetylguanidines: a new class of antihypertensive agents". Arzneimittelforschung 25 (10): 1477–82. October 1975. PMID 1243024. 
  53. ↑ "Pharmacology of BS 100-141, a centrally acting antihypertensive drug". Clinical and Experimental Pharmacology & Physiology 1975 (Suppl 2): 207–212. 1975. PMID 241524. 
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  57. ↑ "New drugs listed on the PBS for rheumatoid arthritis, cystic fibrosis and ADHD". Newsgp (Royal Australian College of General Practitioners). https://www.racgp.org.au/newsGP/Clinical/New-drugs-listed-on-the-PBS-for-rheumatoid-arthrit. 
  58. ↑ "填补国内空白！"温江造"儿童注意缺陷多动障碍药品获批上市". 2 March 2025. https://www.wenjiang.gov.cn/wjzzw/c152764/2025-03/03/content_fdede6841de548cdba0c80f189787e48.shtml. 
  59. ↑ "儿童注意力缺陷多动症新药获批上市". 5 March 2025. http://www.rrrry.com/art_78496.htm. 
  60. ↑ 60.0 60.1 60.2 60.3 60.4 60.5 60.6 "Paxneury EPAR". 12 December 2024. https://www.ema.europa.eu/en/medicines/human/EPAR/paxneury.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  61. ↑ "Paxneury PI". 4 March 2025. https://ec.europa.eu/health/documents/community-register/html/h1908.htm. 
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  63. ↑ "Alpha-2 receptor agonists for the treatment of posttraumatic stress disorder". Drugs in Context 4. 2015. doi:10.7573/dic.212286. PMID 26322115. 
  64. ↑ "Psychopharmacology of tic disorders". Journal of the Canadian Academy of Child and Adolescent Psychiatry 17 (3): 150–159. August 2008. PMID 18769586. 
  65. ↑ "Norepinephrine and stimulant addiction". Addiction Biology 14 (2): 119–129. April 2009. doi:10.1111/j.1369-1600.2008.00138.x. PMID 18811678. 
  66. ↑ "A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation". Journal of Psychopharmacology 29 (3): 300–311. March 2015. doi:10.1177/0269881114562091. PMID 25516371. 
  67. ↑ "Guanfacine's mechanism of action in treating prefrontal cortical disorders: Successful translation across species". Neurobiol Learn Mem 176. December 2020. doi:10.1016/j.nlm.2020.107327. PMID 33075480. 
  68. ↑ "Scientific Rationale for the Treatment of Cognitive Deficits from Long COVID". Neurol Int 15 (2): 725–742. May 2023. doi:10.3390/neurolint15020045. PMID 37368329. 
  69. ↑ "Scientific rationale for the use of α2A-adrenoceptor agonists in treating neuroinflammatory cognitive disorders". Mol Psychiatry 28 (11): 4540–4552. April 2023. doi:10.1038/s41380-023-02057-4. PMID 37029295. 
  70. ↑ "Alzheimer's-like signaling in brains of COVID-19 patients". Alzheimer's & Dementia 18 (5): 955–965. May 2022. doi:10.1016/j.nerep.2022.100154. PMID 35112786. 



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