RESUMEN
BACKGROUND: This study examined the cutaneous analgesic effects of lidocaine co-injected with guanfacine and its comparison with dexmedetomidine. METHODS: Cutaneous analgesic effects are quantified through the blocking effects of the cutaneous trunci muscle reflex against skin pinpricks in rats. The dose-response curves of guanfacine, dexmedetomidine, and lidocaine were constructed and drug-drug interactions were analyzed by the ED50 isobologram. RESULTS: Subcutaneous injections of guanfacine, dexmedetomidine, and lidocaine produced dose-dependently nociceptive/sensory blockade. On the ED50 (50% effective dose) basis, the potency rankings of the drug are dexmedetomidine (0.09 [0.08-0.11] µmol/kg) > guanfacine (3.98 [2.96-5.34] µmol/kg) > lidocaine (25.40 [23.51-27.44] µmol/kg) (p < 0.01). On their equipotent doses (ED25, ED50, and ED75), the duration of sensory blockade induced by guanfacine or dexmedetomidine was longer than lidocaine's (p < 0.01). Both guanfacine and dexmedetomidine showed synergistic effects with lidocaine. CONCLUSIONS: We showed that guanfacine elicits dose-dependent cutaneous analgesia when administered subcutaneously. Lidocaine is less potent than guanfacine or dexmedetomidine. Both guanfacine and dexmedetomidine enhance the potency and duration of lidocaine. Better synergistic responses we are getting with guanfacine plus lidocaine.
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Anestésicos Locales , Dexmedetomidina , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Guanfacina , Lidocaína , Ratas Sprague-Dawley , Animales , Dexmedetomidina/farmacología , Dexmedetomidina/administración & dosificación , Lidocaína/farmacología , Lidocaína/administración & dosificación , Masculino , Guanfacina/farmacología , Guanfacina/administración & dosificación , Anestésicos Locales/farmacología , Anestésicos Locales/administración & dosificación , Ratas , Analgesia/métodos , Analgésicos no Narcóticos/farmacología , Analgésicos no Narcóticos/administración & dosificación , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Quimioterapia CombinadaAsunto(s)
Antipsicóticos , Bradicardia , Guanfacina , Humanos , Antipsicóticos/efectos adversos , Bradicardia/inducido químicamente , Guanfacina/efectos adversos , Guanfacina/administración & dosificación , Masculino , Agonistas de Receptores Adrenérgicos alfa 2/efectos adversos , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Interacciones Farmacológicas , Femenino , Persona de Mediana Edad , ElectrocardiografíaRESUMEN
Attention-deficit/hyperactivity disorder (ADHD) is characterized by age-inappropriate and impairing levels of inattention, hyperactivity, or impulsivity, or a combination of these characteristics. It is estimated to affect around 4% of adults worldwide. In the past few decades, prescriptions for ADHD drugs (psychostimulants and non-psychostimulants) have increased significantly. However, the efficacy and safety of adult ADHD medications remains controversial. Guanfacine extended-release (GXR) is a non-psychostimulant ADHD drug that is a selective α2A-adrenergic receptor agonist, first approved for treatment of adult ADHD in Japan in June 2019. Our aim was to provide an overview of GXR pharmacology and review the studies on efficacy and safety that have been conducted in adults with ADHD. The beneficial actions of guanfacine are thought to be attributed to the strengthening of prefrontal cortical network connections, which regulate attention, emotion, and behavior via the activity at post-synaptic α2A receptors. Current evidence of GXR efficacy and safety suggests that GXR is an effective monotherapy treatment option for adults with ADHD.
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Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Guanfacina/administración & dosificación , Agonistas de Receptores Adrenérgicos alfa 2/efectos adversos , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Adulto , Animales , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Preparaciones de Acción Retardada , Diseño de Fármacos , Desarrollo de Medicamentos , Guanfacina/efectos adversos , Guanfacina/farmacología , HumanosRESUMEN
It has been established that the selective α2A adrenoceptor agonist guanfacine reduces hyperactivity and improves cognitive impairment in patients with attention-deficit/hyperactivity disorder (ADHD). The major mechanisms of guanfacine are considered to involve the activation of the postsynaptic α2A adrenoceptor of glutamatergic pyramidal neurons in the frontal cortex, but the effects of chronic guanfacine administration on catecholaminergic and glutamatergic transmissions associated with the orbitofrontal cortex (OFC) are yet to be clarified. The actions of guanfacine on catecholaminergic transmission, the effects of acutely local and systemically chronic (for 7 days) administrations of guanfacine on catecholamine release in pathways from the locus coeruleus (LC) to OFC, the ventral tegmental area (VTA) and reticular thalamic-nucleus (RTN), from VTA to OFC, from RTN to the mediodorsal thalamic-nucleus (MDTN), and from MDTN to OFC were determined using multi-probe microdialysis with ultra-high performance liquid chromatography. Additionally, the effects of chronic guanfacine administration on the expression of the α2A adrenoceptor in the plasma membrane fraction of OFC, VTA and LC were examined using a capillary immunoblotting system. The acute local administration of therapeutically relevant concentrations of guanfacine into the LC decreased norepinephrine release in the OFC, VTA and RTN without affecting dopamine release in the OFC. Systemically, chronic administration of therapeutically relevant doses of guanfacine for 14 days increased the basal release of norepinephrine in the OFC, VTA, RTN, and dopamine release in the OFC via the downregulation of the α2A adrenoceptor in the LC, OFC and VTA. Furthermore, systemically, chronic guanfacine administration did not affect intrathalamic GABAergic transmission, but it phasically enhanced thalamocortical glutamatergic transmission. The present study demonstrated the dual actions of guanfacine on catecholaminergic transmission-acute attenuation of noradrenergic transmission and chronic enhancement of noradrenergic transmission and thalamocortical glutamatergic transmission. These dual actions of guanfacine probably contribute to the clinical effects of guanfacine against ADHD.
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Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Guanfacina/farmacología , Corteza Prefrontal/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Tálamo/efectos de los fármacos , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Animales , Dopamina/metabolismo , Ácido Glutámico/metabolismo , Guanfacina/administración & dosificación , Guanfacina/uso terapéutico , Masculino , Norepinefrina/metabolismo , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiopatología , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos alfa 2/metabolismo , Tálamo/metabolismo , Tálamo/fisiopatología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
AIM: To assess the empirical evidence for the treatment of attention deficit/hyperactivity disorder (ADHD) in populations with autism spectrum disorder (ASD). METHODS: A systemic PubMed, PsychINFO, Embase, and Medline database search of peer-reviewed literature was conducted. Included in the review were controlled trials published in English with sample sizes ⩾10 participants examining the safety and efficacy of anti-ADHD medication in ASD populations. Data was extracted on relevant variables of study design, demographics, associated psychopathology, medication dose, efficacy, and tolerability. RESULTS: Nine controlled trials met the inclusion and exclusion criteria: five with methylphenidate, three with atomoxetine, and one with guanfacine. Sample sizes ranged from 10 to 128 with 430 children participating across all the trials. In all the trials, treatment response was significantly superior to placebo. However, almost all trials assessed only hyperactivity, and most included only participants with intellectual disability with high levels of irritability. None of the trials distinguished agitation from hyperactivity. The response on hyperactivity for methylphenidate and atomoxetine was less than that observed in the neurotypical population; however, the response for guanfacine surpassed results observed in neurotypical populations. Treatment-emergent mood lability (i.e. mood dysregulation and mood-related adverse events) was frequently associated with methylphenidate and guanfacine treatments. Worse treatment outcomes were associated with individuals with lower intellectual capability compared with those with higher IQs. CONCLUSIONS: here is a scarcity of controlled trials examining ADHD treatments in ASD populations, particularly in intellectually capable individuals with ASD and in adults. Response to ADHD medications in ASD were adversely moderated by the presence of intellectual disability and mood lability.
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Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno del Espectro Autista/tratamiento farmacológico , Discapacidad Intelectual/complicaciones , Clorhidrato de Atomoxetina/administración & dosificación , Clorhidrato de Atomoxetina/efectos adversos , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Trastorno del Espectro Autista/fisiopatología , Niño , Guanfacina/administración & dosificación , Guanfacina/efectos adversos , Humanos , Metilfenidato/administración & dosificación , Metilfenidato/efectos adversos , Resultado del TratamientoRESUMEN
AIM: Previously, we reported on the efficacy and safety of guanfacine extended-release (GXR) in Japanese adults with attention-deficit/hyperactivity disorder (ADHD) from a phase 3, double-blind, placebo-controlled, randomized trial. In this exploratory post hoc analysis, we assessed the efficacy and/or safety of GXR in the following subgroups: ADHD-combined (ADHD-C) and ADHD-predominantly inattentive (ADHD-I) subtypes, age (≥31, <31 years), sex (male, female), and body weight (≥50, <50 kg). METHODS: The primary efficacy endpoint was change from baseline in the Japanese version of the investigator-rated ADHD-Rating Scale-IV (ADHD-RS-IV) with adult prompts (total scores) at week 10. RESULTS: The efficacy analysis population included 200 patients (GXR, 100; placebo, 100). ADHD-RS-IV total score effect sizes (GXR vs placebo) were similar across all subgroups (total population: 0.52, ADHD-C: 0.51, ADHD-I: 0.52, ≥31 years: 0.61, <31 years: 0.47, male: 0.50, female: 0.57). There were no major differences in the incidence/types of treatment-emergent adverse events (TEAEs) across the subgroups. The incidence of significant TEAEs (34.3%, 10.6%) and TEAEs leading to discontinuation (34.3%, 12.1%) were approximately three times higher in females than males, respectively. The incidence of TEAEs in patients weighing <50 kg and ≥50 kg was 100% and 73.6% during dose optimization and 40% and 24.4% during the maintenance period, respectively. CONCLUSION: Findings from this post hoc analysis in adults with ADHD support the efficacy and safety of GXR regardless of ADHD subtype, age, or sex and suggest that careful monitoring for TEAEs and GXR dose optimization is considered for all patients, as needed.
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Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Guanfacina/farmacología , Evaluación de Resultado en la Atención de Salud , Adolescente , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Agonistas de Receptores Adrenérgicos alfa 2/efectos adversos , Adulto , Trastorno por Déficit de Atención con Hiperactividad/clasificación , Interpretación Estadística de Datos , Preparaciones de Acción Retardada , Método Doble Ciego , Femenino , Guanfacina/administración & dosificación , Guanfacina/efectos adversos , Humanos , Japón , Masculino , Adulto JovenRESUMEN
Although norepinephrine (NE) does not appear to play a prominent role in mediating the abuse-related effects of cocaine, studies have indicated that NE α-2 receptor agonists can attenuate reinstatement of extinguished cocaine self-administration in rats and monkeys and can decrease cocaine craving in humans. In the present studies, we examined the effects of two α-2 receptor agonists, lofexidine and guanfacine, on choice between food and cocaine (0.0-0.1 mg/kg per injection) in cynomolgus monkeys. Male and female subjects were housed in stable same-sex social groups of four; social rank did not influence the effects of lofexidine and guanfacine. When administered acutely, lofexidine (0.03-3.0 mg/kg, i.v.) significantly decreased cocaine choice in females (n = 7) but not males (n = 8). However, in males, the same lofexidine doses produced dose-dependent decreases in core body temperature (n = 7), and acute guanfacine (0.003-1.0 mg/kg, i.v.) significantly decreased cocaine choice (n = 11). When lofexidine was administered for five consecutive days to a subset of the monkeys in whom lofexidine acutely decreased cocaine choice, tolerance to this effect developed to varying degrees of completeness in three of three males and two of four females. Taken together, these data suggest that α-2 receptor agonists can produce small decreases in the reinforcing strength of cocaine relative to food and that, even when efficacy is observed after acute administration, tolerance to the decreases in cocaine choice are apparent and more likely in males compared with females. SIGNIFICANCE STATEMENT: Cocaine use disorder remains a significant public health problem with no US Food and Drug Administration-approved treatments. Although cocaine elevates dopamine, serotonin, and norepinephrine (NE), the latter target has received less research. The present study noted modest effects of NE agonists on the relative reinforcing strength of cocaine with greater efficacy in female compared with male monkeys.
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Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Conducta de Elección/efectos de los fármacos , Clonidina/análogos & derivados , Cocaína/administración & dosificación , Conducta Alimentaria/efectos de los fármacos , Guanfacina/farmacología , Caracteres Sexuales , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Animales , Clonidina/administración & dosificación , Clonidina/farmacología , Femenino , Guanfacina/administración & dosificación , Macaca fascicularis , Masculino , Refuerzo en Psicología , AutoadministraciónRESUMEN
Noncompetitive N-methyl-D-aspartate/glutamate receptor (NMDAR) antagonists contribute to the pathophysiology of schizophrenia and mood disorders but improve monoaminergic antidepressant-resistant mood disorder and suicidal ideation. The mechanisms of the double-edged sword clinical action of NMDAR antagonists remained to be clarified. The present study determined the interaction between the NMDAR antagonist (MK801), α1 adrenoceptor antagonist (prazosin), and α2A adrenoceptor agonist (guanfacine) on mesocortical and mesothalamic catecholaminergic transmission, and thalamocortical glutamatergic transmission using multiprobe microdialysis. The inhibition of NMDAR in the locus coeruleus (LC) by local MK801 administration enhanced both the mesocortical noradrenergic and catecholaminergic coreleasing (norepinephrine and dopamine) transmissions. The mesothalamic noradrenergic transmission was also enhanced by local MK801 administration in the LC. These mesocortical and mesothalamic transmissions were activated by intra-LC disinhibition of transmission of γ-aminobutyric acid (GABA) via NMDAR inhibition. Contrastingly, activated mesothalamic noradrenergic transmission by MK801 enhanced intrathalamic GABAergic inhibition via the α1 adrenoceptor, resulting in the suppression of thalamocortical glutamatergic transmission. The thalamocortical glutamatergic terminal stimulated the presynaptically mesocortical catecholaminergic coreleasing terminal in the superficial cortical layers, but did not have contact with the mesocortical selective noradrenergic terminal (which projected terminals to deeper cortical layers). Furthermore, the α2A adrenoceptor suppressed the mesocortical and mesothalamic noradrenergic transmissions somatodendritically in the LC and presynaptically/somatodendritically in the reticular thalamic nucleus (RTN). These discrepancies between the noradrenergic and catecholaminergic transmissions in the mesocortical and mesothalamic pathways probably constitute the double-edged sword clinical action of noncompetitive NMDAR antagonists.
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Maleato de Dizocilpina/administración & dosificación , Guanfacina/administración & dosificación , Locus Coeruleus/metabolismo , Prazosina/administración & dosificación , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Corteza Cerebral/metabolismo , Maleato de Dizocilpina/farmacología , Dopamina/metabolismo , Guanfacina/farmacología , Hipotálamo/metabolismo , Locus Coeruleus/efectos de los fármacos , Masculino , Microdiálisis/instrumentación , Norepinefrina/metabolismo , Prazosina/farmacología , Ratas , Transmisión Sináptica/efectos de los fármacosRESUMEN
OBJECTIVE: To assess guanfacine extended-release (GXR) efficacy and safety in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: This phase 3, double-blind, placebo-controlled study (conducted between October 2016 and July 2017) included Japanese patients aged ≥ 18 years with ADHD (DSM-5). Patients received GXR (n = 101) or placebo (n = 100) titrated from 2 mg/d to 4-6 mg/d (dose-optimization; 5 weeks), followed by 4-6 mg/d (dose-maintenance; 5 weeks), then tapered doses to 2 mg/d (2 weeks). Primary endpoint was change from baseline in total score on the Japanese version of the ADHD-Rating Scale IV with adult prompts (ADHD-RS-IV) at week 10. Other measures were ADHD-RS-IV subscales, Clinical Global Impression-Improvement scale (CGI-I) and Patient Global Impression-Improvement scale (PGI-I) (percentage of patients very much improved/much improved), treatment-emergent adverse event (TEAE) incidences, and TEAEs leading to discontinuation. RESULTS: Compared with placebo, there was statistically significantly greater improvement in ADHD-RS-IV total score reduction with GXR (least squares mean ± SE: GXR vs placebo, -11.55 ± 1.10 vs -7.27 ± 1.07; P = .0005; effect size 0.52). There were significantly greater improvements in GXR for ADHD-RS-IV inattention (-7.39 ± 0.79 vs -4.89 ± 0.76; P = .0032) and hyperactivity-impulsivity (-3.84 ± 0.54 vs -2.10 ± 0.52; P = .0021) subscale scores, CGI-I scores (48.1% vs 22.6%; P = .0007), and PGI-I scores (25.3% vs 11.8%; P = .0283). More patients in the GXR versus the placebo group reported TEAEs (81.2% vs 62.0%) and discontinued due to TEAEs (19.8% vs 3.0%). The main TEAEs in the GXR group were somnolence, thirst, blood pressure decrease, nasopharyngitis, postural dizziness, and constipation; most TEAEs were mild to moderate in severity. CONCLUSIONS: In Japanese adults with ADHD, GXR improved ADHD symptoms without any major safety concerns. Trial Registration: Japan Primary Registries Network (https://rctportal.niph.go.jp/en): JapicCTI-163231
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Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Guanfacina/administración & dosificación , Administración Oral , Adolescente , Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Guanfacina/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Resultado del Tratamiento , Adulto JovenRESUMEN
Introduction: Attention-deficit/hyperactivity disorder (ADHD) commonly occurs in children, adolescents, and adults. Although symptoms of ADHD often respond robustly to treatment with stimulants (amphetamine or methylphenidate), not all patients are appropriate candidates for treatment with these drugs. Guanfacine extended-release (GXR) is a non-stimulant alternative drug approved for the treatment of ADHD in the United States (U.S.), Canada, and Europe.Areas covered: The chemistry, pharmacokinetics, mechanism of action and dosage of GXR are presented. Efficacy and safety data obtained in clinical trials with subjects aged 6-17 years for both GXR monotherapy and use in combination with stimulants are described. Meta-analyses comparing GXR to other drugs are presented. MedWatch surveillance data collected for GXR since approval in the U.S. are also discussed.Expert opinion: Although GXR is effective for the treatment of ADHD and has a different side effect profile than stimulants, it is not as impressive in reducing symptoms. Despite the availability of multiple pharmacological treatments for ADHD, there remains an unmet need for formulations as potent as stimulants but with fewer adverse effects. Several pharmacological agents for ADHD treatment are in development. It is not clear that any of these compounds will replace currently available formulations as first-line alternatives.
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Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Guanfacina/uso terapéutico , Adolescente , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Agonistas de Receptores Adrenérgicos alfa 2/efectos adversos , Estimulantes del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/efectos adversos , Niño , Preparaciones de Acción Retardada , Composición de Medicamentos , Quimioterapia Combinada , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Guanfacina/administración & dosificación , Guanfacina/efectos adversos , Humanos , Metilfenidato/uso terapéutico , Estados UnidosRESUMEN
Objective: To assess treatment patterns, health care resource utilization, and health care costs associated with use of atypical antipsychotics (AAPs) or the nonstimulant guanfacine extended release (GXR) after stimulant therapy for attention-deficit/hyperactivity disorder (ADHD). In Canada, GXR is approved as a monotherapy for children and adolescents with ADHD or as an adjunct to stimulants, and AAPs are commonly used off-label as an adjunct to stimulants. Methods: Health care claims data (January 1, 2007 to March 31, 2016) from Quebec's provincial health plan were assessed for individuals with ADHD, 6-17 years of age, who received ≥1 stimulant followed by a first AAP or GXR prescription (index medication), without a diagnosis for which AAPs are indicated. Results: Overall, 1327 individuals were included (AAPs, 1098; GXR, 229). Rates of discontinuation, augmentation, or switching of the index medication did not differ between AAPs and GXR during the first follow-up year. Discontinuation rates were significantly lower with GXR than with AAPs during the second year (22.0% vs. 35.9%; p = 0.03). GXR and AAPs resulted in similar increases in total health care cost. In GXR users, the increase in prescription drug cost after 6 months was higher than in AAP users, whereas the increase in overall medical cost was higher with AAPs than GXR, owing to more psychiatric department visits. Conclusions: In children and adolescents with ADHD who used AAPs or GXR after stimulants, secondary treatment changes were similar with both treatments after 1 year, but discontinuation rates were significantly lower with GXR than with AAPs in the second year. The greater increase in prescription cost with GXR was balanced by a greater increase in overall medical costs with AAPs, resulting in no overall difference in total health care cost between the two treatments.
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Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Antipsicóticos/administración & dosificación , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Guanfacina/administración & dosificación , Costos de la Atención en Salud , Uso Fuera de lo Indicado , Aceptación de la Atención de Salud/estadística & datos numéricos , Risperidona/administración & dosificación , Adolescente , Niño , Preparaciones de Acción Retardada/administración & dosificación , Costos de los Medicamentos , Femenino , Humanos , Masculino , Quebec , Estudios RetrospectivosRESUMEN
Guanfacine is used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), metabolite profiling of guanfacine was performed in plasma and urine collected from healthy Japanese adults following repeated oral administration of guanfacine extended-release formulation. Unchanged guanfacine was the most abundant component in both plasma and urine (from the MS signal intensity). In plasma, the M3 metabolite (a sulfate of hydroxy-guanfacine) was the prominent metabolite; the M2 metabolite (a glucuronide of a metabolite formed by monooxidation of guanfacine), 3-hydroxyguanfacine and several types of glucuronide at different positions on guanfacine were also detected. In urine, the M2 metabolite and 3-hydroxyguanfacine were the principal metabolites. From metabolite analysis, the proposed main metabolic pathway of guanfacine is monooxidation on the dichlorobenzyl moiety, followed by glucuronidation or sulfation. A minor pathway is glucuronidation at different positions on guanfacine. As the prominent metabolites in plasma were glucuronide and sulfate of hydroxyguanfacine, which have no associated toxicity concerns, further toxicity studies of the metabolites, for example in animals, were not deemed necessary.
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Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Glucurónidos/farmacocinética , Guanfacina/administración & dosificación , Sulfatos/farmacocinética , Administración Oral , Agonistas de Receptores Adrenérgicos alfa 2/farmacocinética , Adulto , Cromatografía Liquida , Preparaciones de Acción Retardada , Guanfacina/farmacocinética , Humanos , Japón , Masculino , Comprimidos , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
Objectives: To assess the impact of long-term pharmacotherapy with guanfacine immediate- or extended-release (GXR), administered alone or as an adjunctive to a stimulant, on weight and height in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Methods: Data were extracted from U.S. Department of Defense medical records for patients 4-17 years of age at index date (initiation of any study medication following a year without ADHD medications, or diagnosis if unmedicated) with weight/height measurements for the analysis period (January 2009-June 2013) and the previous year (baseline). Longitudinal weight and height z-scores were analyzed using multivariable regression in three cohorts: guanfacine (initial period of guanfacine exposure), first-line stimulant monotherapy (initial period of exposure), and unmedicated. Guanfacine cohort subgroups were based on previous/concurrent stimulant exposure. Results: The weight analyses included 47,910 patients (66.8% male) and the height analyses 41,248 (67.2% male). Mean initial exposure in the weight analyses was 237 days (standard deviation [SD] = 258, median = 142) for guanfacine and 257 days (SD = 284, median = 151) for first-line stimulant monotherapy, and was similar in the height analyses. Modeling indicated that guanfacine monotherapy was not associated with clinically meaningful deviations from normal z-score trajectories for weight (first-line, n = 943; nonfirst-line, n = 796) or height (first-line, n = 741; nonfirst-line, n = 644). In patients receiving guanfacine adjunctive to a stimulant, modeled weight (n = 1657) and height (n = 1343) z-scores followed declining trajectories. In this subgroup, mean standardized weight/height had decreased during previous stimulant monotherapy. For first-line stimulant monotherapy, modeled weight (n = 32,999) and height (n = 28,470) z-scores followed declining trajectories during year 1. In the unmedicated cohort, modeled weight (n = 11,515) and height (n = 10,050) z-scores were stable. Conclusions: Guanfacine monotherapy (first-line or nonfirst-line) was not associated with marked deviations from normal growth in this modeling study of children and adolescents with ADHD. In contrast, growth trajectories followed an initially declining course with stimulants, whether given alone or with adjunctive guanfacine.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Estimulantes del Sistema Nervioso Central/administración & dosificación , Guanfacina/administración & dosificación , Adolescente , Agonistas de Receptores Adrenérgicos alfa 2/efectos adversos , Estatura/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/efectos adversos , Niño , Preescolar , Estudios de Cohortes , Bases de Datos Factuales , Preparaciones de Acción Retardada , Quimioterapia Combinada , Femenino , Guanfacina/efectos adversos , Humanos , Estudios Longitudinales , Masculino , Estudios RetrospectivosRESUMEN
The selective α2A adrenoceptor agonist guanfacine reduces hyperactivity and improves cognitive impairment in patients with attention-deficit/hyperactivity disorder (ADHD). The major mechanisms of guanfacine have been considered to involve activation of postsynaptic α2A adrenoceptor in frontal pyramidal neurons. However, the effects of chronic guanfacine administration on catecholaminergic transmissions associated with the orbitofrontal cortex (OFC) remain unclear. To explore the mechanisms of action of guanfacine on catecholaminergic transmission, the effects of its acute local or sub-chronic systemic administration on catecholamine release within pathways from locus coeruleus (LC) to OFC and reticular thalamic nucleus (RTN), from RTN to mediodorsal thalamic nucleus (MDTN), and from MDTN to OFC were determined using multi-probe microdialysis with ultra-high performance liquid chromatography. Acute OFC local administration of guanfacine did not affect catecholamine release in OFC. Acute LC local and sub-chronic systemic administrations of guanfacine reduced norepinephrine release in LC, OFC and RTN, and also reduced GABA release in MDTN, whereas AMPA-induced (perfusion with AMPA into NDTN) releases of l-glutamate, norepinephrine and dopamine in OFC were enhanced by sub-chronic systemic guanfacine administration. This study identified that catecholaminergic transmission is composed of three pathways: direct noradrenergic and co-releasing catecholaminergic LC-OFC pathways and intermediate LC-OFC (LC-RTN-MDTN-OFC) pathway. We demonstrated the dual actions of guanfacine on catecholaminergic transmission: attenuation of direct noradrenergic LC-OFC transmission at the resting stage and enhancement of direct co-releasing catecholaminergic LC-OFC transmission via GABAergic disinhibition in the intermediate LC-OFC pathway. These dual actions of guanfacine probably contribute to clinical actions of guanfacine against ADHD and its comorbid symptoms. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Dopamina/metabolismo , Guanfacina/administración & dosificación , Norepinefrina/metabolismo , Corteza Prefrontal/metabolismo , Transmisión Sináptica , Animales , Núcleos Talámicos Intralaminares/efectos de los fármacos , Núcleos Talámicos Intralaminares/metabolismo , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/metabolismo , Masculino , Núcleo Talámico Mediodorsal/efectos de los fármacos , Núcleo Talámico Mediodorsal/metabolismo , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/metabolismo , Corteza Prefrontal/efectos de los fármacos , Ratas Sprague-Dawley , Transmisión Sináptica/efectos de los fármacosRESUMEN
BACKGROUND: Guanfacine is Food and Drug Administration approved for hypertension and attention-deficit hyperactivity disorder and has been used off-label for migraine prophylaxis, heroin withdrawal, and more recently smoking cessation. Previous studies have shown positive effects of 3 mg/d of immediate-release (IR) guanfacine on smoking outcomes, but the dose equivalency of the IR and extended-release (ER) formulations is unknown. PROCEDURES: A within-subject design was used to compare the pharmacokinetics and pharmacodynamics of 3 mg/d of IR, 4 mg/d of ER, and 6 mg/d of ER guanfacine in adult daily smokers (n = 5). Plasma medication levels, vital signs, cigarettes per day, tobacco craving, and adverse events were assessed. Medication was titrated to stable dosing after each laboratory day (3 mg/d IR, then 4 mg/d ER, then 6 mg/d ER). RESULTS: Plasma medication levels did not differ between the 3 mg/d of IR and 4 mg/d of ER doses after 24 hours from last dose and were highest at the 6 mg/d of ER dose (3 mg/d IR: M = 3.40 ng/mL, SE = 0.34 vs 4 mg/d ER: M = 3.46 ng/mL, SE = 0.67 vs 6 mg/d ER: M = 5.92 ng/mL, SE = 1.02). All doses of guanfacine decreased heart rate and blood pressure from baseline. Absolute values of cigarettes per day (6 mg/d ER) and tobacco craving (4 and 6 mg/d ER) were lowest with the ER formulations. Treatment-emergent adverse events were subject rated as minimal to mild, except dry mouth. CONCLUSIONS: We demonstrated similar pharmacokinetic profiles between 3 mg/d of IR guanfacine and 4 mg/d of ER guanfacine, as hypothesized. All doses of guanfacine were well tolerated.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Guanfacina/administración & dosificación , Cese del Hábito de Fumar/métodos , Agonistas de Receptores Adrenérgicos alfa 2/farmacocinética , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Adulto , Presión Sanguínea/efectos de los fármacos , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Liberación de Fármacos , Femenino , Guanfacina/farmacocinética , Guanfacina/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Objective: To examine the role of Guanfacine Extended Release (GXR) in the management of behavioral disturbances in patients with Prader-Willi Syndrome (PWS). Methods: Twenty from a total of 27 individuals with genetically confirmed PWS, 6-26 years of age, with the following symptoms were identified: significant aggression/agitation, skin picking, and/or symptoms of attention-deficit/hyperactivity disorder (ADHD). Response to GXR for the above noted symptoms was categorized as improved, worsened, or unchanged, while assessing for side effects and tolerability. Results: Eleven of the 20 individuals reported skin-picking, 17 reported aggression/agitation, and 16 reported symptoms of ADHD. Nine (81.8%), 14 (82.3%), and 15 (93.7%) individuals showed an improvement in skin-picking, aggression/agitation, and ADHD, respectively, while on GXR treatment. Two patients with prior complaints of psychotic symptoms did not respond to GXR. Of note, no abnormal weight gain or significant adverse reaction was observed in this group, while on GXR. Conclusions: In this study, GXR demonstrated improvement in symptoms of skin picking, aggression/agitation, and ADHD in patients with PWS. GXR was not effective in reducing psychosis or agitation related to psychotic symptoms. Future studies are warranted to further establish the utility of GXR in PWS patients.
Asunto(s)
Agresión/efectos de los fármacos , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Guanfacina/administración & dosificación , Síndrome de Prader-Willi/tratamiento farmacológico , Conducta Autodestructiva/tratamiento farmacológico , Adolescente , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Agonistas de Receptores Adrenérgicos alfa 2/efectos adversos , Adulto , Trastorno por Déficit de Atención con Hiperactividad/etiología , Niño , Estudios de Cohortes , Preparaciones de Acción Retardada , Femenino , Guanfacina/efectos adversos , Humanos , Masculino , Síndrome de Prader-Willi/fisiopatología , Estudios Retrospectivos , Conducta Autodestructiva/etiología , Adulto JovenRESUMEN
Stress is a precipitating agent in neuropsychiatric disease and initiates relapse to drug-seeking behavior in addicted patients. Targeting the stress system in protracted abstinence from drugs of abuse with anxiolytics may be an effective treatment modality for substance use disorders. α2A-adrenergic receptors (α2A-ARs) in extended amygdala structures play key roles in dampening stress responses. Contrary to early thinking, α2A-ARs are expressed at non-noradrenergic sites in the brain. These non-noradrenergic α2A-ARs play important roles in stress responses, but their cellular mechanisms of action are unclear. In humans, the α2A-AR agonist guanfacine reduces overall craving and uncouples craving from stress, yet minimally affects relapse, potentially due to competing actions in the brain. Here, we show that heteroceptor α2A-ARs postsynaptically enhance dorsal bed nucleus of the stria terminalis (dBNST) neuronal activity in mice of both sexes. This effect is mediated by hyperpolarization-activated cyclic nucleotide-gated cation channels because inhibition of these channels is necessary and sufficient for excitatory actions. Finally, this excitatory action is mimicked by clozapine-N-oxide activation of the Gi-coupled DREADD hM4Di in dBNST neurons and its activation elicits anxiety-like behavior in the elevated plus maze. Together, these data provide a framework for elucidating cell-specific actions of GPCR signaling and provide a potential mechanism whereby competing anxiogenic and anxiolytic actions of guanfacine may affect its clinical utility in the treatment of addiction.SIGNIFICANCE STATEMENT Stress affects the development of neuropsychiatric disorders including anxiety and addiction. Guanfacine is an α2A-adrenergic receptor (α2A-AR) agonist with actions in the bed nucleus of the stria terminalis (BNST) that produces antidepressant actions and uncouples stress from reward-related behaviors. Here, we show that guanfacine increases dorsal BNST neuronal activity through actions at postsynaptic α2A-ARs via a mechanism that involves hyperpolarization-activated cyclic nucleotide gated cation channels. This action is mimicked by activation of the designer receptor hM4Di expressed in the BNST, which also induces anxiety-like behaviors. Together, these data suggest that postsynaptic α2A-ARs in BNST have excitatory actions on BNST neurons and that these actions can be phenocopied by the so-called "inhibitory" DREADDs, suggesting that care must be taken regarding interpretation of data obtained with these tools.
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Ansiedad/fisiopatología , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/fisiología , Neuronas/fisiología , Receptores Adrenérgicos alfa 2/fisiología , Núcleos Septales/fisiología , Estrés Psicológico/fisiopatología , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Animales , Catecolaminas/metabolismo , Femenino , Guanfacina/administración & dosificación , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Núcleos Septales/diagnóstico por imagen , Núcleos Septales/metabolismoAsunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Guanfacina/administración & dosificación , Trastorno Obsesivo Compulsivo , Psicofarmacología , Furor/fisiología , Adolescente , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Femenino , Humanos , Masculino , Trastorno Obsesivo Compulsivo/psicología , Ideación SuicidaRESUMEN
This article is the first reported case describing the off-label use of enteral immediate-release guanfacine, a long-acting α-2 adrenergic agonist most commonly used in the treatment of attention-deficit hyperactivity disorder, for sedation in a patient with severe anxiety and agitation limiting mechanical ventilation weaning several days after cardiac surgery. In this case, after several days of unsuccessful attempts to control his agitation and anxiety with conventional therapies, guanfacine therapy was initiated, and the patient was rapidly weaned from all other sedatives and mechanical ventilation shortly thereafter. The patient was weaned from guanfacine therapy without evidence of bradycardia, hypotension, or rebound syndrome. Enteral guanfacine therapy should be further studied as a potentially useful and cost-effective sedative therapy for patients with severe anxiety and/or agitation in the intensive care unit following cardiac and thoracic surgical procedures.
Asunto(s)
Ansiedad/tratamiento farmacológico , Procedimientos Quirúrgicos Cardíacos/métodos , Guanfacina/administración & dosificación , Agitación Psicomotora/tratamiento farmacológico , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Adulto , Ansiedad/etiología , Cuidados Críticos/métodos , Guanfacina/farmacología , Humanos , Unidades de Cuidados Intensivos , Masculino , Agitación Psicomotora/etiología , Respiración Artificial/métodos , Índice de Severidad de la Enfermedad , Desconexión del Ventilador/métodosRESUMEN
In a prior report, we showed that extended-release guanfacine (GEXR) is safe and effective for children with autism spectrum disorder (ASD) accompanied by ADHD symptoms. Here, we examine the impact of GEXR on oppositional behavior, anxiety, repetitive behavior, and sleep disturbance. Sixty-two subjects with ASD (53 boys, 9 girls; ages 5-14 years) were randomly assigned to GEXR (n = 30) or placebo (n = 32) for 8 weeks. Outcomes include the Home Situation Questionnaire-Modified for ASD (HSQ-ASD), Anxiety scale of the Child and Adolescent Symptom Inventory (CASI), Children's Yale-Brown Obsessive-Compulsive Scale-Modified for ASD (CYBOCS-ASD), and Children's Sleep Habits Questionnaire (CSHQ). A repeated measures linear mixed model was used to determine the effects of treatment group and time on HSQ scores. For other measures, change from baseline was evaluated with Analysis of Covariance (ANCOVA).After 8 weeks of treatment, parent ratings of oppositional behavior on the HSQ declined by 44% (per item mean from 3.4 to 1.9) in the GEXR group compared to 12% (from 3.3 to 2.9) for placebo (p = 0.004). Repetitive behavior on the CYBOCS-ASD showed a significantly greater decline in GEXR-treated participants compared to placebo (24% vs. <1%, p = 0.01). No group differences were observed on CASI Anxiety or CSHQ (p = 0.64 and 0.75, respectively). GEXR was effective in reducing oppositional behavior and, more modestly, repetitive behavior. GEXR was not superior to placebo for anxiety, though baseline anxiety ratings were low. GEXR did not significantly improve sleep habits. Future studies could focus on repetitive behavior or anxiety, symptoms with limited treatment options.