Guanfacine hydrochloride

Guanfacine, an anti-hypertensive agent, is a selective agonist of α2A-adrenoceptor (α2AR) with a Kd value of 31 nM, displaying 60-fold selectivity over α2B-adrenoceptors.
In 5-choice serial reaction-time task (5-CSRTT), guanfacine treated at a low dose has been shown to increase attention in NK1R knockout mice, but not in WT mice. Guanfacine treated at a high dose reduced impulsivity in both NK1R-/- and WT mice [1].
Guanfacine has been demonstrated to reduce alcohol intake in high alcohol-consuming rats. Guanfacine treatment has been revealed to decrease the alcohol deprivation effect (ADE) and reduce the alcohol seeking and cue/priming-mediated reinstatement of alcohol seeking in rats [2].
Guanfacine has shown to reduce C-fiber-evoked field potentials in a rat model induced by spinal nerve ligation, the effect of which was reduced by treatment of receptors of the delta (DOR) antagonist naltrindole, but not by treatment of receptors of the mu (MOR) antagonist CTOP. On the contrary, DOR agonist deltorphin II, but not MOR agonist DAMGO-mediated depression of C-fiber-evoked spinal field potentials was increased by guanfacine. Additionally, co-administration of guanfacine at a low dose with deltorphin II could enhance the effect of deltorphin II mediated production of stable thermal and mechanical antinociception in nerve-ligated rats [3].
References:
1.Pillidge K1, Porter AJ, Dudley JA, Tsai YC, Heal DJ, Stanford SC. The behavioural response of mice lacking NK₁ receptors to guanfacine resembles its clinical profile in treatment of ADHD. Br J Pharmacol. 2014 Oct;171(20):4785-96. doi: 10.1111/bph.12860.
2.Fredriksson I1, Jayaram-Lindström N1, Wirf M1, Nylander E1, Nyström E1, Jardemark K2, Steensland P1.Evaluation of Guanfacine as a Potential Medication for Alcohol Use Disorder in Long-Term Drinking Rats: Behavioral and Electrophysiological Findings. Neuropsychopharmacology. 2014 Oct 31. doi: 10.1038/npp.2014.294. [Epub ahead of print]
3.Aira Z1, Barrenetxea T1, Buesa I1, Azkue JJ2. Plasticity of α2-adrenergic spinal antinociception following nerve injury: Selective, bidirectional interaction with the delta opioid receptor. Brain Res. 2015 Jan 12;1594:190-203. doi: 10.1016/j.brainres.2014.11.009.

Extended-release guanfacine hydrochloride in 6-17-year olds with ADHD: a randomised-withdrawal maintenance of efficacy study.[Pubmed:26871297]

J Child Psychol Psychiatry. 2016 Jun;57(6):717-28.

BACKGROUND: Extended-release Guanfacine hydrochloride (GXR), a selective alpha2A-adrenergic agonist, is a nonstimulant medication for attention-deficit/hyperactivity disorder (ADHD). This phase 3, double-blind, placebo-controlled, randomised-withdrawal study evaluated the long-term maintenance of GXR efficacy in children/adolescents with ADHD. METHODS: Children/adolescents (6-17 years) with ADHD received open-label GXR (1-7 mg/day). After 13 weeks, responders were randomised to GXR or placebo in the 26-week, double-blind, randomised-withdrawal phase (RWP). The primary endpoint was the percentage of treatment failure (>/=50% increase in ADHD Rating Scale version IV total score and >/=2-point increase in Clinical Global Impression-Severity compared with RWP baseline, at two consecutive visits). The key secondary endpoint was time to treatment failure (TTF). TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01081145; EudraCT 2009-018161-12. RESULTS: A total of 528 participants enrolled; 316 (59.8%) entered the RWP. Treatment failure occurred in 49.3% of the GXR and 64.9% of the placebo group (p = 0.006). TTF was significantly longer in GXR versus placebo (p = 0.003). GXR was well tolerated. CONCLUSIONS: Guanfacine hydrochloride demonstrated long-term maintenance of efficacy compared with placebo in children/adolescents with ADHD. Implications of the placebo substitution design and findings with different ADHD medications are discussed.

Efficacy and safety of extended-release guanfacine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder: a randomized, controlled, phase III trial.[Pubmed:25453486]

Eur Neuropsychopharmacol. 2014 Dec;24(12):1861-72.

Guanfacine extended-release (GXR), a selective alpha2A-adrenergic agonist, is a non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD). This study assessed the efficacy (symptoms and function) and safety of dose-optimized GXR compared with placebo in children and adolescents with ADHD. An atomoxetine (ATX) arm was included to provide reference data against placebo. Patients (6-17 years) were randomized at baseline to dose-optimized GXR (0.05-0.12mg/kg/day - 6-12 years: 1-4mg/day; 13-17 years: 1-7mg/day), ATX (10-100mg/day) or placebo for 4 or 7 weeks. The primary efficacy measure was change from baseline in ADHD Rating Scale version IV (ADHD-RS-IV). Key secondary measures were Clinical Global Impression-Improvement (CGI-I) and the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P; learning and school, and family domains). Safety assessments included treatment-emergent adverse events (TEAEs), electrocardiograms and vital signs. A total of 272 (80.5%) patients from Europe, the USA and Canada completed the study. Significant differences were observed in least squares mean change from baseline in ADHD-RS-IV total score (placebo-adjusted differences) (GXR: [-8.9, p<0.001]; ATX: [-3.8, p<0.05]), the difference from placebo in the percentage of patients showing improvement (1 ['very much improved'] or 2 ['much improved']) for CGI-I (GXR: [23.7, p<0.001]; ATX: [12.1, p<0.05]), WFIRS-P learning and school domain (GXR: [-0.22, p<0.01]; ATX: [-0.16, p<0.05]) and WFIRS-P family domain (GXR: [-0.21, p<0.01]; ATX: [-0.09, p=0.242]). Most common TEAEs for GXR were somnolence, headache and fatigue; 70.1% of GXR subjects reported mild-to-moderate TEAEs. GXR was effective and well tolerated in children and adolescents with ADHD.

Supplementary guanfacine hydrochloride as a treatment of attention deficit hyperactivity disorder in adults: A double blind, placebo-controlled study.[Pubmed:26730446]

Psychiatry Res. 2016 Feb 28;236:136-141.

The purpose of this study was to examine the efficacy of an extended release Guanfacine hydrochloride supplement relative to a placebo supplement in adults (19-62) with ADHD and a sub-optimal response to a stimulant-only treatment program. The study's primary outcome measures were the Attention Deficit Hyperactivity Disorder Rating Scale and the Clinical Global Impression - Severity. Twenty-six adults who met criteria for attention deficit hyperactivity disorder and sub-optimal functioning were randomly assigned to supplement their existing psychostimulant treatment regimen with either a titrated dose (1-6mg) of extended release Guanfacine hydrochloride or a matching placebo for a 10-week trial. The data were analyzed with standard mixed model analysis of variance procedures, and participants in both the investigational agent group and the placebo group showed statistically significant improvement in their symptoms and functioning over the course of the trial. The treatments did not differ in terms of their efficacy, safety, or tolerability. Although these results do suggest that both treatments were associated with clinical improvement, the possible impacts of socially desirable responding and regression to the mean on these results are discussed.

Alpha-2a/d adrenoceptor subtype stimulation by guanfacine increases osmolar clearance.[Pubmed:9103479]

J Pharmacol Exp Ther. 1997 Apr;281(1):48-53.

We have previously demonstrated that the osmolar and free water responses to an intrarenal infusion of clonidine could be dissociated pharmacologically into naltrexone-sensitive and prazosin-sensitive responses, respectively. These results supported the notion that two distinct alpha-2 adrenoceptor sites were mediating the effects of clonidine. The ability of prazosin to selectively block the increase in free water clearance suggested the involvement of the alpha-2b subtype. Based on the identification by others of only the alpha-2a/d and alpha-2b subtypes in the rat kidney, the osmolar response was, by deduction only, speculated but not proven to involve the alpha-2a/d subtype. To provide evidence that the alpha-2a/d subtype mediated osmolar clearance, we investigated the effects of intrarenal infusion of the selective alpha-2a/d adrenoceptor agonist guanfacine. Studies were conducted in anesthetized Sprague-Dawley rats that were unilaterally nephrectomized 7 to 10 days before the experiment. The infusion of guanfacine (3.0 nmol/kg/min) into the remaining renal artery increased urine flow without altering blood pressure or creatinine clearance. The increase in urine flow was associated with an increase in osmolar clearance but no increase in free water clearance. The effects of the alpha-2a/d adrenoceptor selective antagonist, RX-821002, on the renal actions of guanfacine were determined. RX-821002 (3.0 mg/kg) attenuated the ability of guanfacine to increase urine flow rate and osmolar clearance. Similarly to the increase in osmolar clearance observed with clonidine, the guanfacine-induced increase in osmolar clearance was attenuated by naltrexone (3.0 mg/kg) and unaltered by prazosin (0.15 mg/kg) pretreatment (i.e., naltrexone-sensitive and prazosin-insensitive). These results were consistent with the alpha-2a/d adrenoceptor subtype in the rat kidney which mediated an increase in osmolar clearance. A physiological function of this alpha-2a/d adrenoceptor subtype may therefore involve regulation of solute/sodium excretion.

Delineation of rat kidney alpha 2A- and alpha 2B-adrenoceptors with [3H]RX821002 radioligand binding: computer modelling reveals that guanfacine is an alpha 2A-selective compound.[Pubmed:1666366]

Eur J Pharmacol. 1991 Sep 17;202(2):235-43.

We developed a method for the simultaneous determination of drug affinity constants for rat alpha 2A- and alpha 2B-adrenoceptor subtypes by using [3H]RX821002 radioligand binding in the kidney. Three competition curves were obtained for each drug: one for the test compound in the absence of ARC 239 (a drug found to have 108-fold higher affinity for alpha 2B- than for alpha 2A-adrenoceptors), one in the presence of ARC 239, and one for ARC 239. It is possible to determine the Kds of a tested drug for both alpha 2A- and alpha 2B-adrenoceptors by simultaneous computer modelling because of the increased constraint in the calculations given by the inclusion of ARC 239 into the assay. Using this approach, we found guanfacine and oxymetazoline to be highly alpha 2A-selective. The most alpha 2B-selective were ARC 239, prazosin and corynanthine. A number of other drugs, for example UK-14,304, rilmenidine and clonidine, were non-selective or showed minor selectivity for alpha 2A- or alpha 2B-adrenoceptors. Moreover, using Monte Carlo simulations, we showed that the three-curve method gives more accurate estimates of drug binding constants for assays when two receptor sites are present than methods analysing only one competition curve.

Guanfacine hydrochloride, an anti-hypertensive agent, is a selective α2A-adrenoceptor agonist with Kd of 31 nM and displays 60-fold selectivity over α2B-adrenoceptors.

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