RESUMEN
The rapid serial visual presentation (RSVP) task and continuous performance tasks (CPT) are used to assess attentional impairments in patients with psychiatric and neurological conditions. This study developed a novel touchscreen task for rats based on the structure of a human RSVP task and used pharmacological manipulations to investigate their effects on different performance measures. Normal animals were trained to respond to a target image and withhold responding to distractor images presented within a continuous sequence. In a second version of the task, a false-alarm image was included, so performance could be assessed relative to two types of nontarget distractors. The effects of acute administration of stimulant and nonstimulant treatments for ADHD (amphetamine and atomoxetine) were tested in both tasks. Methylphenidate, ketamine, and nicotine were tested in the first task only. Amphetamine made animals more impulsive and decreased overall accuracy but increased accuracy when the target was presented early in the image sequence. Atomoxetine improved accuracy overall with a specific reduction in false-alarm responses and a shift in the attentional curve reflecting improved accuracy for targets later in the image sequence. However, atomoxetine also slowed responding and increased omissions. Ketamine, nicotine, and methylphenidate had no specific effects at the doses tested. These results suggest that stimulant versus nonstimulant treatments have different effects on attention and impulsive behaviour in this rat version of an RSVP task. These results also suggest that RSVP-like tasks have the potential to be used to study attention in rodents.
Asunto(s)
Anfetamina , Clorhidrato de Atomoxetina , Atención , Estimulantes del Sistema Nervioso Central , Ketamina , Metilfenidato , Nicotina , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Estimulantes del Sistema Nervioso Central/administración & dosificación , Clorhidrato de Atomoxetina/farmacología , Clorhidrato de Atomoxetina/administración & dosificación , Atención/efectos de los fármacos , Atención/fisiología , Masculino , Ratas , Metilfenidato/farmacología , Metilfenidato/administración & dosificación , Nicotina/farmacología , Nicotina/administración & dosificación , Anfetamina/farmacología , Anfetamina/administración & dosificación , Ketamina/farmacología , Ketamina/administración & dosificación , Estimulación Luminosa/métodos , Inhibidores de Captación Adrenérgica/farmacología , Inhibidores de Captación Adrenérgica/administración & dosificación , Aprendizaje Seriado/efectos de los fármacos , Aprendizaje Seriado/fisiología , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Percepción Visual/efectos de los fármacos , Percepción Visual/fisiología , Ratas Sprague-DawleyRESUMEN
The current study aimed to evaluate the efficacy of orally administered rapid mini-tablets containing atomoxetine hydrochloride (ODMT) relative to the conventional capsule formulation of atomoxetine hydrochloride (ATO). To mask the bitter taste of ATO and render it more palatable for pediatric administration in individuals with Attention Deficit Hyperactivity Disorder (ADHD), an inclusion complex of ATO with ß-cyclodextrin (ß-CD) was synthesized. The ODMT and conventional capsule ATO formulations were administered orally to a cohort of ADHD rat pups born to nicotine-exposed dams, facilitating an in vivo efficacy assessment. Behavioral assays, including the open field test, novel object recognition test, and Barnes maze test, were conducted pre- and post-administration of the therapeutics. The outcomes suggested that the ODMT formulation, incorporating ATO-ß-CD inclusion complexes, shows promise as a viable alternative to the capsule form of ATO. Conclusively, the preparation of the ATO-ß-CD complexes and ODMTs leveraged a factorial experimental design, with the animal model being subjected to nicotine-induced hyperactivity to provide a unique evaluative framework for the ODMT formulation under development.
Asunto(s)
Clorhidrato de Atomoxetina , Trastorno por Déficit de Atención con Hiperactividad , Modelos Animales de Enfermedad , Nicotina , beta-Ciclodextrinas , Animales , Clorhidrato de Atomoxetina/farmacología , Clorhidrato de Atomoxetina/administración & dosificación , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Nicotina/administración & dosificación , Ratas , beta-Ciclodextrinas/farmacología , beta-Ciclodextrinas/administración & dosificación , Masculino , Administración Oral , Femenino , Conducta Animal/efectos de los fármacos , Ratas Sprague-Dawley , Inhibidores de Captación Adrenérgica/farmacología , Inhibidores de Captación Adrenérgica/administración & dosificaciónRESUMEN
A subset of rats that self-administer 3,4-methylenedioxypyrovalerone (MDPV) develop unusually high levels of drug taking. A history of responding maintained by cocaine, but not food, prevents the development of this high-responder phenotype; however, it is unclear how histories of noncontingent cocaine exposure or self-administering drugs from other pharmacological classes would affect its development. In the current studies, 5 groups of male Sprague-Dawley rats were used to determine whether histories of responding maintained by drugs from different pharmacological classes (e.g., MDPV, cocaine, fentanyl, nicotine, or ketamine) would differentially impact the development of the high-responder phenotype when MDPV was available for self-administration. Two additional groups were used to determine whether noncontingent exposure to cocaine would prevent the development of the high-responder phenotype when MDPV was available for self-administration, and whether noncontingent exposure to MDPV would facilitate the development of the high-responder phenotype when cocaine was available for self-administration. Consistent with previous reports, a history of response-contingent cocaine, and to a lesser extent noncontingent cocaine, prevented the MDPV high-responder phenotype; however, when responding was initially maintained by fentanyl, nicotine, or ketamine, the MDPV high-responder phenotype developed in â¼45% of rats. By manipulating behavioral and pharmacological histories prior to evaluating MDPV self-administration, the current studies provide additional evidence that a history of response-contingent (or noncontingent) cocaine can prevent the transition from well regulated to aberrant drug-taking when responding is maintained by MDPV. Although the mechanism(s) that underlies this novel high-responder phenotype are unknown, elucidation may provide insight into individual differences relating to substance use disorder. SIGNIFICANCE STATEMENT: A subset of outbred Sprague-Dawley rats self-administer high levels of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV). Understanding the behavioral and/or pharmacological factors that can prevent the development of dysregulated MDPV self-administration may provide insight into individual differences in vulnerability to develop a substance use disorder.
Asunto(s)
Conducta Adictiva/psicología , Benzodioxoles/administración & dosificación , Pirrolidinas/administración & dosificación , Esquema de Refuerzo , Inhibidores de Captación Adrenérgica/administración & dosificación , Animales , Conducta Adictiva/genética , Cocaína/administración & dosificación , Fentanilo/administración & dosificación , Ketamina/administración & dosificación , Masculino , Nicotina/administración & dosificación , Ratas , Ratas Sprague-Dawley , Autoadministración/psicología , Cathinona SintéticaRESUMEN
BACKGROUND: Noradrenaline has an important role as a neuromodulator of the central nervous system. Noradrenergic enhancement was recently shown to enhance glutamate-dependent cortical facilitation and long term potentiation-like plasticity. As cortical excitability and plasticity are closely linked to various cognitive processes, here we aimed to explore whether these alterations are associated with respective cognitive performance changes. Specifically, we assessed the impact of noradrenergic enhancement on motor learning (serial reaction time task), attentional processes (Stroop interference task), and working memory performance (n-back letter task). METHODS: The study was conducted in a cross-over design. Twenty-five healthy humans performed the respective cognitive tasks after a single dose of the noradrenaline reuptake inhibitor reboxetine or placebo administration. RESULTS: The results show that motor learning, attentional processes, and working memory performance in healthy participants were improved by reboxetine application compared with placebo. CONCLUSIONS: The results of the present study thus suggest that noradrenergic enhancement can improve memory formation and executive functions in healthy humans. The respective changes are in line with related effects of noradrenaline on cortical excitability and plasticity.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Atención/efectos de los fármacos , Aprendizaje/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Nootrópicos/farmacología , Norepinefrina , Reboxetina/farmacología , Inhibidores de Captación Adrenérgica/administración & dosificación , Adulto , Estudios Cruzados , Femenino , Humanos , Masculino , Nootrópicos/administración & dosificación , Reboxetina/administración & dosificación , Adulto JovenRESUMEN
BACKGROUND: Viloxazine extended-release is a novel nonstimulant under investigation as a potential treatment for attention-deficit/hyperactivity disorder (ADHD). Given the potential for viloxazine extended-release to be co-administered with stimulant ADHD pharmacotherapies, this trial investigated the pharmacokinetics and safety of combination viloxazine extended-release + lisdexamfetamine dimesylate (lisdexamfetamine) versus viloxazine extended-release and lisdexamfetamine alone. METHODS: In this single-center, cross-over, open-label trial, healthy, non-ADHD adults received single oral doses of 700 mg viloxazine extended-release alone, 50 mg lisdexamfetamine alone, and a combination of viloxazine extended-release (700 mg) + lisdexamfetamine (50 mg), with blood samples collected over 4 days postadministration. The active drug in viloxazine extended-release (viloxazine) and primary metabolite of lisdexamfetamine (d-amphetamine) were measured using chromatographic tandem mass spectrometry. Safety assessments included adverse events, vital signs, echocardiograms, and clinical laboratory evaluations. RESULTS: Thirty-six adults were enrolled, and 34 completed the trial. The least squares geometric mean ratios are reported as [combination / single drug (90% confidence intervals)]. Viloxazine extended-release: Cmax = 95.96% (91.33-100.82), area under the concentration-time curve from 0 to the last measurable time (AUC0-t) = 99.19% (96.53-101.91), and area under the concentration-time curve from 0 to infinity (AUCinf) = 99.23% (96.61-101.93). Lisdexamfetamine: Cmax = 112.78% (109.93-115.71), AUC0-t = 109.64% (105.25-114.22), and AUCinf = 109.52% (105.19-114.03). All reported adverse events, except 1 (moderate vomiting), were mild in severity. CONCLUSIONS: Co-administration of viloxazine extended-release and lisdexamfetamine did not impact the pharmacokinetics of viloxazine or d-amphetamine relative to administration of either drug alone. After single dose administration, the combination appeared to be safe and well tolerated.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacocinética , Estimulantes del Sistema Nervioso Central/farmacocinética , Dimesilato de Lisdexanfetamina/farmacocinética , Viloxazina/farmacocinética , Administración Oral , Inhibidores de Captación Adrenérgica/administración & dosificación , Inhibidores de Captación Adrenérgica/efectos adversos , Adulto , Área Bajo la Curva , Estimulantes del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/efectos adversos , Estudios Cruzados , Preparaciones de Acción Retardada , Interacciones Farmacológicas , Femenino , Humanos , Dimesilato de Lisdexanfetamina/administración & dosificación , Dimesilato de Lisdexanfetamina/efectos adversos , Masculino , Persona de Mediana Edad , Viloxazina/administración & dosificación , Viloxazina/efectos adversos , Adulto JovenRESUMEN
PURPOSE: This phase 3 clinical trial evaluated the efficacy and safety of viloxazine extended-release capsules (VLX-ER) as a monotherapy for attention-deficit/hyperactivity disorder (ADHD) in adolescents (12-17 years). METHODS: Eligible subjects (n = 310) were randomized to receive once-daily 200 and 400 mg VLX-ER, or placebo for 6 weeks. The primary efficacy end point was change from baseline (CFB) at the end of study (EOS) in ADHD Rating Scale-5 Total score. Key secondary end points were Clinical Global Impression-Improvement score at EOS, CFB at EOS in Conners 3-Parent Short Form Composite T-score, and CFB at EOS in Weiss Functional Impairment Rating Scale-Parent Total average score. RESULTS: In the 200-mg/d and 400-mg/d VLX-ER treatment groups, a significant improvement was found in the CFB at EOS in ADHD Rating Scale-5 Total (P = 0.0232, P = 0.0091) and Inattention (P = 0.0424, P = 0.0390) and Hyperactivity/Impulsivity (P = 0.0069, P = 0.0005) subscale scores versus placebo. The Clinical Global Impression-Improvement score was significantly improved at EOS in the 200-mg/d and 400-mg/d VLX-ER groups versus placebo (P = 0.0042, P = 0.0003). The Conners 3-Parent Short Form composite T-score and Weiss Functional Impairment Rating Scale-Parent Total average score exhibited improvement in both VLX-ER groups; however, the difference versus placebo was not statistically significant. The most common treatment-related adverse events were somnolence, headache, decreased appetite, nausea, and fatigue. The adverse event-related discontinuation rates were <5% in all groups. CONCLUSIONS: Viloxazine extended-release demonstrated statistically significant and clinically meaningful improvement in ADHD symptoms in adolescents and was generally well tolerated.
Asunto(s)
Conducta del Adolescente , Trastorno por Déficit de Atención con Hiperactividad , Viloxazina , Adolescente , Conducta del Adolescente/efectos de los fármacos , Conducta del Adolescente/psicología , Inhibidores de Captación Adrenérgica/administración & dosificación , Inhibidores de Captación Adrenérgica/efectos adversos , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/psicología , Síntomas Conductuales/diagnóstico , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Monitoreo de Drogas/métodos , Femenino , Humanos , Masculino , Escalas de Valoración Psiquiátrica , Evaluación de Síntomas/métodos , Resultado del Tratamiento , Viloxazina/administración & dosificación , Viloxazina/efectos adversosRESUMEN
Repeated exposure to drugs produces a plethora of persistent brain changes, some of which underlie the development of drug addiction. An important objective of addiction research is to identify the brain changes that might mediate the transition from drug use to drug misuse. The persistent accumulation of the transcription factor, ∆FosB, following repeated drug exposure provides a means of achieving this objective. Experiments were conducted on sexually mature male Sprague-Dawley rats. The effects of extensive 3,4-methylenedioxymethamphetamine (MDMA) self-administration on immunohistochemical measurements of ∆FosB accumulation in 12 brain regions was compared with a matched, drug-naive, control group. Other groups were pretreated with MDMA (0.0 or 10.0 mg/kg, ip, once daily for 5 days), and the locomotor-activating effect of MDMA (200 µg/side) microinjected bilaterally into brain regions selected on the basis of the ∆FosB results was subsequently determined. MDMA self-administration significantly increased ∆FosB expression in the nucleus accumbens core, ventromedial and dorsomedial caudate-putamen, anterior cingulate, prelimbic, infralimbic, and orbitofrontal cortex, and both the central and basolateral amygdala, but not in the ventrolateral or dorsolateral caudate-putamen. Increases in the nucleus accumbens shell were substantial but were not significant following statistical correction for multiple comparisons. MDMA pretreatment enhanced MDMA-produced hyperactivity only when administered into the nucleus accumbens or the medial, but not the lateral, caudate-putamen, mirroring the ∆FosB results. These data compare favorably to results following repeated exposure to other drugs of abuse and support the idea of common neuroplastic changes following repeated drug exposure.
Asunto(s)
Inhibidores de Captación Adrenérgica/administración & dosificación , Encéfalo/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/administración & dosificación , Proteínas Proto-Oncogénicas c-fos/genética , Trastornos Relacionados con Sustancias/fisiopatología , Inhibidores de Captación Adrenérgica/farmacología , Animales , Modelos Animales de Enfermedad , Masculino , N-Metil-3,4-metilenodioxianfetamina/farmacología , Ratas , Ratas Sprague-Dawley , AutoadministraciónRESUMEN
Various three-dimensional printing (3DP) technologies have been investigated so far in relation to their potential to produce customizable medicines and medical devices. The aim of this study was to examine the possibility of tailoring drug release rates from immediate to prolonged release by varying the tablet thickness and the drug loading, as well as to develop artificial neural network (ANN) predictive models for atomoxetine (ATH) release rate from DLP 3D-printed tablets. Photoreactive mixtures were comprised of poly(ethylene glycol) diacrylate (PEGDA) and poly(ethylene glycol) 400 in a constant ratio of 3:1, water, photoinitiator and ATH as a model drug whose content was varied from 5% to 20% (w/w). Designed 3D models of cylindrical shape tablets were of constant diameter, but different thickness. A series of tablets with doses ranging from 2.06 mg to 37.48 mg, exhibiting immediate- and modified-release profiles were successfully fabricated, confirming the potential of this technology in manufacturing dosage forms on demand, with the possibility to adjust the dose and release behavior by varying drug loading and dimensions of tablets. DSC (differential scanning calorimetry), XRPD (X-ray powder diffraction) and microscopic analysis showed that ATH remained in a crystalline form in tablets, while FTIR spectroscopy confirmed that no interactions occurred between ATH and polymers.
Asunto(s)
Inhibidores de Captación Adrenérgica/química , Clorhidrato de Atomoxetina/química , Inhibidores de Captación Adrenérgica/administración & dosificación , Clorhidrato de Atomoxetina/administración & dosificación , Liberación de Fármacos , Excipientes/química , Redes Neurales de la Computación , Polietilenglicoles/química , Impresión Tridimensional , ComprimidosRESUMEN
Recent behavioral modeling and pupillometry studies suggest that neuromodulatory arousal systems play a role in regulating decision formation but neurophysiological support for these observations is lacking. We employed a randomized, double-blinded, placebo-controlled, crossover design to probe the impact of pharmacological enhancement of catecholamine levels on perceptual decision-making. Catecholamine levels were manipulated using the clinically relevant drugs methylphenidate and atomoxetine, and their effects were compared with those of citalopram and placebo. Participants performed a classic EEG oddball paradigm that elicits the P3b, a centro-parietal potential that has been shown to trace evidence accumulation, under each of the four drug conditions. We found that methylphenidate and atomoxetine administration shortened RTs to the oddball targets. The neural basis of this behavioral effect was an earlier P3b peak latency, driven specifically by an increase in its buildup rate without any change in its time of onset or peak amplitude. This study provides neurophysiological evidence for the catecholaminergic enhancement of a discrete aspect of human decision-making, that is, evidence accumulation. Our results also support theoretical accounts suggesting that catecholamines may enhance cognition via increases in neural gain.
Asunto(s)
Encéfalo/fisiología , Catecolaminas/fisiología , Toma de Decisiones/fisiología , Percepción Visual/fisiología , Adolescente , Inhibidores de Captación Adrenérgica/administración & dosificación , Adulto , Clorhidrato de Atomoxetina/administración & dosificación , Encéfalo/efectos de los fármacos , Citalopram/administración & dosificación , Estudios Cruzados , Toma de Decisiones/efectos de los fármacos , Inhibidores de Captación de Dopamina/administración & dosificación , Método Doble Ciego , Electroencefalografía , Potenciales Evocados Visuales/efectos de los fármacos , Humanos , Masculino , Metilfenidato/administración & dosificación , Persona de Mediana Edad , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Percepción Visual/efectos de los fármacos , Adulto JovenRESUMEN
AIMS: There are few effective therapies for vasovagal syncope (VVS). Pharmacological norepinephrine transporter (NET) inhibition increases sympathetic tone and decreases tilt-induced syncope in healthy subjects. Atomoxetine is a potent and highly selective NET inhibitor. We tested the hypothesis that atomoxetine prevents tilt-induced syncope. METHODS AND RESULTS: Vasovagal syncope patients were given two doses of study drug [randomized to atomoxetine 40 mg (n = 27) or matched placebo (n = 29)] 12 h apart, followed by a 60-min drug-free head-up tilt table test. Beat-to-beat heart rate (HR), blood pressure (BP), and cardiac haemodynamics were recorded using non-invasive techniques and stroke volume modelling. Patients were 35 ± 14 years (73% female) with medians of 12 lifetime and 3 prior year faints. Fewer subjects fainted with atomoxetine than with placebo [10/29 vs. 19/27; P = 0.003; risk ratio 0.49 (confidence interval 0.28-0.86)], but equal numbers of patients developed presyncope or syncope (23/29 vs. 21/27). Of patients who developed only presyncope, 87% (13/15) had received atomoxetine. Patients with syncope had lower nadir mean arterial pressure than subjects with only presyncope (39 ± 18 vs. 69 ± 18 mmHg, P < 0.0001), and this was due to lower trough HRs in subjects with syncope (67 ± 30 vs. 103 ± 32 b.p.m., P = 0.006) and insignificantly lower cardiac index (2.20 ± 1.36 vs. 2.84 ± 1.05 L/min/m2, P = 0.075). There were no significant differences in stroke volume index (32 ± 6 vs. 35 ± 5 mL/m2, P = 0.29) or systemic vascular resistance index (2156 ± 602 vs. 1790 ± 793 dynes*s/cm5*m2, P = 0.72). CONCLUSION: Norepinephrine transporter inhibition significantly decreased the risk of tilt-induced syncope in VVS subjects, mainly by blunting reflex bradycardia, thereby preventing final falls in cardiac index and BP.
Asunto(s)
Clorhidrato de Atomoxetina/administración & dosificación , Presión Sanguínea/fisiología , Frecuencia Cardíaca/fisiología , Volumen Sistólico/fisiología , Síncope Vasovagal/prevención & control , Pruebas de Mesa Inclinada/métodos , Inhibidores de Captación Adrenérgica/administración & dosificación , Adulto , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Síncope Vasovagal/diagnóstico , Síncope Vasovagal/fisiopatología , Resultado del TratamientoRESUMEN
OBJECTIVE: Multicenter studies have shown that cardiovascular risks of ADHD medication are extremely low. However, QTc length has been shown to be increased in smaller samples of patients or case reports after stimulant and atomoxetine medication. Based on recent studies of genetic polymorphisms associated with drug-induced QTc prolongation and polymorphisms linkage to regional populations, we hypothesized that the drug-induced QTc prolongation could be a factor of particular polymorphisms linked to specific regional populations undistinguished in multicenter studies. METHODS: We included 69 patients from a region of central Slovakia, 36 patients were taking atomoxetine and 33 patients methylphenidate. QTc, heart rate, potassium levels and BMI were examined before and after 8 weeks of treatment. Therapeutic effect was measured by ADHD-RS-IV. RESULTS: We found QTc prolongation after 8 weeks of treatment both with atomoxetine and methylphenidate that was neither followed by the significant changes in BMI and potassium levels nor the significant increase of heart rate. CONCLUSION: This is the first study revealing QTc prolongation in the group of ADHD children from the same region after 8-week treatment with atomoxetine and methylphenidate, indicating the potential discrete abnormalities in cardiac functioning associated with polymorphisms in genes of dopaminergic and noradrenergic system.
Asunto(s)
Arritmias Cardíacas/inducido químicamente , Clorhidrato de Atomoxetina/efectos adversos , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Estimulantes del Sistema Nervioso Central/efectos adversos , Frecuencia Cardíaca/efectos de los fármacos , Metilfenidato/efectos adversos , Adolescente , Inhibidores de Captación Adrenérgica/administración & dosificación , Inhibidores de Captación Adrenérgica/efectos adversos , Clorhidrato de Atomoxetina/administración & dosificación , Clorhidrato de Atomoxetina/uso terapéutico , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Estimulantes del Sistema Nervioso Central/administración & dosificación , Niño , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Metilfenidato/administración & dosificación , EslovaquiaRESUMEN
Two thousand eight hundred ninety-four children and adolescents treated by 243 pediatricians were analyzed. Patients receiving attention deficit hyperactivity disorder (ADHD) medications were at a lower risk of fractures than patients without ADHD medications. The strongest impact was in the age group of 6-9 years. Finally, there was a significant association between therapy duration and fracture risk. INTRODUCTION: The aim of this study was to analyze the impact of ADHD therapy on fracture risk in children treated by German pediatricians. METHODS: Children and adolescents initially diagnosed with ADHD and fractures between 2010 and 2015 were identified by 243 pediatricians. In this nested case-control study, each ADHD case with a fracture was matched (1:1) to an ADHD control without a fracture for age, gender, index year, and physician. In total, 2894 individuals were available for analysis. The main outcome of the study was the risk of fracture as a function of ADHD therapy. Multivariate logistic regression models were created to determine the effect of ADHD therapy on the risk of fracture in the entire population and in three age-specific subgroups. RESULTS: Patients receiving ADHD medications were at a lower risk of fracture than patients without ADHD medications (OR = 0.61). The impact of ADHD therapy on the risk of fracture was stronger in the age group of 6-9 years (OR = 0.41) than in the age groups of 10-13 years (OR = 0.68) and 14-17 years (OR = 0.74). Finally, a significant correlation was found between therapy duration and fracture risk (OR = 0.71 per month). CONCLUSION: ADHD therapy was associated with a decrease in the risk of fracture in children and adolescents treated by German pediatricians.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Fracturas Óseas/etiología , Adolescente , Inhibidores de Captación Adrenérgica/administración & dosificación , Inhibidores de Captación Adrenérgica/uso terapéutico , Factores de Edad , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Estudios de Casos y Controles , Niño , Bases de Datos Factuales , Esquema de Medicación , Prescripciones de Medicamentos/estadística & datos numéricos , Femenino , Fracturas Óseas/epidemiología , Fracturas Óseas/prevención & control , Alemania/epidemiología , Humanos , Masculino , Medición de Riesgo/métodosRESUMEN
Background: Noradrenaline is a major neuromodulator in the central nervous system, and it is involved in the pathophysiology of diverse neuropsychiatric diseases. Previous transcranial magnetic stimulation studies suggested that acute application of selective noradrenaline reuptake inhibitors enhances cortical excitability in the human brain. However, other, such like clinical effects, usually require prolonged noradrenaline reuptake inhibitor treatment, which might go along with different physiological effects. Methods: The purpose of this study was to investigate the acute and chronic effects of the selective noradrenaline reuptake inhibitor reboxetine on cortical excitability in healthy humans in a double-blind, placebo-controlled, randomized crossover study. Sixteen subjects were assessed with different transcranial magnetic stimulation measurements: motor thresholds, input-output curve, short-latency intracortical inhibition and intracortical facilitation, I-wave facilitation, and short-interval afferent inhibition before and after placebo or reboxetine (8 mg) single-dose administration. Afterwards, the same subjects took reboxetine (8 mg/d) consecutively for 21 days. During this period (subjects underwent 2 experimental sessions with identical transcranial magnetic stimulation measures under placebo or reboxetine), transcranial magnetic stimulation measurements were assessed before and after drug intake. Results: Both single-dose and chronic administration of reboxetine increased cortical excitability; increased the slope of the input-output curve, intracortical facilitation, and I-wave facilitation; but decreased short-latency intracortical inhibition and short-interval afferent inhibition. Moreover, chronic reboxetine showed a larger enhancement of intracortical facilitation and I-wave facilitation compared with single-dose application. Conclusions: The results show physiological mechanisms of noradrenergic enhancement possibly underlying the functional effects of reboxetine regarding acute and chronic application.
Asunto(s)
Inhibidores de Captación Adrenérgica/administración & dosificación , Morfolinas/administración & dosificación , Corteza Motora/efectos de los fármacos , Adolescente , Adulto , Análisis de Varianza , Estudios Cruzados , Método Doble Ciego , Potenciales Evocados Motores/efectos de los fármacos , Femenino , Estudios de Seguimiento , Mano , Humanos , Masculino , Persona de Mediana Edad , Corteza Motora/fisiología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Reboxetina , Factores de Tiempo , Estimulación Magnética Transcraneal , Adulto JovenRESUMEN
BACKGROUND: The effects of atomoxetine on QT in adults remain unclear. In this study, we examined whether the use of atomoxetine to treat attention-deficit hyperactivity disorder in adults is associated with QT prolongation. METHODS: Forty-one subjects with attention-deficit hyperactivity disorder were enrolled in this study. Participants were administered 40, 80, or 120 mg atomoxetine daily and were maintained on their respective dose for at least 2 weeks. We conducted electrocardiographic measurements and blood tests, measuring plasma atomoxetine concentrations after treatment. Electrocardiograms of 24 of the patients were also obtained before atomoxetine treatment. The QT interval was corrected using Bazett (QTcB) and Fridericia (QTcF) correction formulas. RESULTS: In these 24 patients, only the female patients had prolonged QTcB (P = 0.039) after atomoxetine treatment. There was no correlation between plasma atomoxetine concentrations and the corrected QT interval (QTc), or between atomoxetine dosage and the QTc. However, in female patients, there was a significant positive correlation between atomoxetine dosage and the QTcB (r = 0.631, P = 0.012), and there was a marginally significant positive correlation between atomoxetine dosage and the QTcF (r = 0.504, P = 0.055). In male patients, there was no correlation between atomoxetine dosage and the QTcB or QTcF intervals. There was no correlation between plasma atomoxetine concentrations and the QTc in either female or male patients. IMPLICATIONS: Clinicians should exhibit caution when prescribing atomoxetine, particularly for female patients.
Asunto(s)
Inhibidores de Captación Adrenérgica , Clorhidrato de Atomoxetina , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Electrocardiografía/efectos de los fármacos , Inhibidores de Captación Adrenérgica/administración & dosificación , Inhibidores de Captación Adrenérgica/efectos adversos , Inhibidores de Captación Adrenérgica/sangre , Adulto , Clorhidrato de Atomoxetina/administración & dosificación , Clorhidrato de Atomoxetina/efectos adversos , Clorhidrato de Atomoxetina/sangre , Femenino , Humanos , Masculino , Factores Sexuales , Adulto JovenRESUMEN
Hematopoietic stem cell (HSC) release is positively regulated by the sympathetic nervous system through the ß3 adrenergic receptor. Preclinical studies have demonstrated that the combination of desipramine and G-CSF resulted in improved HSC mobilization. Here, we present the results of an open-label single-arm pilot study in patients with multiple myeloma undergoing autologous stem cell transplantation (ASCT) to assess the safety and efficacy of desipramine combined with G-SCF to induce HSC mobilization. The primary endpoint was safety of the combination including engraftment kinetics. The secondary endpoint was the proportion of patients who collected ≥5 × 106 CD34+ cells/kg. Outcomes were compared with historical matched controls during the same time period with multiple myeloma mobilized with G-CSF. All study patients received desipramine 100 mg daily for 7 days, starting 4 days prior to G-CSF administration (D-3) and continued taking it along with G-CSF for a total of 7 days. Six of ten patients enrolled completed the protocol with minimal side effects. All of them achieved the target collection of 5 × 106 CD34 cells/kg in a median of 1.5 apheresis session with two patients needing additional plerixafor (16%), while 11 out of 13 patients (85%) achieved the target of 5 × 106 CD34 cells/kg in the historical control group in a median of 2 apheresis procedures and seven patients needed plerixafor (54%). The combination of desipramine and G-CSF is safe and signals improved mobilization over G-CSF alone, providing a possible alternative means of mobilization that needs further investigation.
Asunto(s)
Inhibidores de Captación Adrenérgica/uso terapéutico , Antígenos CD34/inmunología , Desipramina/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple/terapia , Adolescente , Inhibidores de Captación Adrenérgica/administración & dosificación , Adulto , Anciano , Bencilaminas , Ciclamas , Desipramina/administración & dosificación , Quimioterapia Combinada , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/metabolismo , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/efectos adversos , Compuestos Heterocíclicos/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Proyectos Piloto , Receptores Adrenérgicos beta 3/metabolismo , Adulto JovenRESUMEN
Parkinson's disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect â¼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson's disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson's disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson's disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson's disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced stop-signal reaction time) following atomoxetine correlated with structural connectivity as measured by the fractional anisotropy in the white matter underlying the inferior frontal gyrus. Using multiple regression models, we examined the factors that influenced the individual differences in the response to atomoxetine: the reduction in stop-signal reaction time correlated with structural connectivity and baseline performance, while disease severity and drug plasma level predicted the change in fronto-striatal effective connectivity following atomoxetine. These results suggest that (i) atomoxetine increases sensitivity of the inferior frontal gyrus to afferent inputs from the pre-supplementary motor cortex; (ii) atomoxetine can enhance downstream modulation of frontal-subcortical connections for response inhibition; and (iii) the behavioural consequences of treatment are dependent on fronto-striatal structural connections. The individual differences in behavioural responses to atomoxetine highlight the need for patient stratification in future clinical trials of noradrenergic therapies for Parkinson's disease.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Clorhidrato de Atomoxetina/farmacología , Cuerpo Estriado , Dopaminérgicos/uso terapéutico , Función Ejecutiva/efectos de los fármacos , Inhibición Psicológica , Red Nerviosa , Evaluación de Resultado en la Atención de Salud , Enfermedad de Parkinson , Corteza Prefrontal , Índice de Severidad de la Enfermedad , Inhibidores de Captación Adrenérgica/administración & dosificación , Inhibidores de Captación Adrenérgica/sangre , Anciano , Clorhidrato de Atomoxetina/administración & dosificación , Clorhidrato de Atomoxetina/sangre , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/efectos de los fármacos , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/efectos de los fármacos , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/tratamiento farmacológico , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/efectos de los fármacosRESUMEN
RATIONALE: Obstructive sleep apnea is a state-dependent disease. One of the key factors that triggers upper airway collapse is decreased pharyngeal dilator muscle activity during sleep. To date, there have not been effective methods to reverse pharyngeal hypotonia pharmacologically in sleeping humans. OBJECTIVES: We tested the hypothesis that administration of desipramine 200 mg prevents the state-related reduction in genioglossus activity that occurs during sleep and thereby decreases pharyngeal collapsibility. METHODS: We conducted a placebo-controlled, double-blind, crossover trial with 10 healthy participants. Participants received active treatment or placebo in randomized order 2 hours before sleep in the physiology laboratory. MEASUREMENTS AND MAIN RESULTS: Genioglossus activity during wakefulness and sleep, genioglossus muscle responsiveness to negative epiglottic pressure, and upper airway collapsibility during passive and active conditions were compared between on- and off-drug states. Desipramine abolished the normal reduction of genioglossus activity from wakefulness to non-REM sleep that occurred on the placebo night. Specifically, tonic (median, 96% [86-120] vs. 75% [50-92] wakefulness; P = 0.01) but not phasic genioglossus activity was higher with desipramine compared with placebo. Upper airway collapsibility was also reduced with desipramine compared with placebo (-10.0 cm H2O [-15.2 to -5.8] vs. -8.1 cm H2O [-10.4 to -6.3]; P = 0.037). CONCLUSIONS: Desipramine reduces the state-related drop in tonic genioglossus muscle activity that occurs from wakefulness to non-REM sleep and reduces airway collapsibility. These data provide a rationale for a new pharmacologic therapy for obstructive sleep apnea. Clinical trial registered with www.clinicaltrials.gov (NCT02428478).
Asunto(s)
Desipramina/farmacología , Músculos Faríngeos/efectos de los fármacos , Apnea Obstructiva del Sueño/fisiopatología , Sueño/efectos de los fármacos , Inhibidores de Captación Adrenérgica/administración & dosificación , Inhibidores de Captación Adrenérgica/farmacología , Adulto , Presión de las Vías Aéreas Positiva Contínua/métodos , Estudios Cruzados , Desipramina/administración & dosificación , Electromiografía/efectos de los fármacos , Femenino , Voluntarios Sanos , Humanos , Masculino , Músculos Faríngeos/fisiología , Sueño/fisiología , Apnea Obstructiva del Sueño/tratamiento farmacológico , Adulto JovenRESUMEN
BACKGROUND/AIMS: Attention deficit hyperactivity disorder (ADHD) is frequently associated with other psychiatric pathologies. Therefore, the present study investigated a possible pharmacokinetic interaction between atomoxetine (ATX), a treatment option for ADHD, and an antidepressant, namely, fluvoxamine (FVX). METHODS: Designed as an open-label, non-randomized clinical trial, the study included 2 periods. In period 1 (reference), each subject received ATX 25 mg (single-dose), whereas in period 2 (test), all subjects were given a combination of ATX 25 mg + FVX 100 mg, following a 6-day pretreatment regimen with the enzymatic inhibitor. Non-compartmental methods were employed to determine the pharmacokinetic parameters of ATX and its main active metabolite (glucuronidated form), 4-hydroxyatomoxetine-O-glucuronide. RESULTS: The results revealed significant differences between the study periods for Cmax, AUC0-t and AUC0-∞ values corresponding to ATX and its metabolite. Small, but statistically significant increases in AUC values were reported for both parent drug (1,583.05 ± 1,040.29 vs. 2,111.55 ± 1,411.59 ng*h/ml) and 4-hydroxyatomoxetine-O-glucuronide (5,754.71 ± 1,235.5 vs. 6,293.17 ± 1,219.34 ng*h/ml) after combined treatment of ATX and the enzymatic inhibitor. CONCLUSION: FVX had a modest effect on the pharmacokinetics of ATX and 4-hydroxyatomoxetine-O-glucuronide. The presence or absence of any clinical consequences associated with this pharmacokinetic drug-drug interaction needs to be established in future studies.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacocinética , Antidepresivos/farmacocinética , Clorhidrato de Atomoxetina/farmacocinética , Fluvoxamina/farmacocinética , Adolescente , Inhibidores de Captación Adrenérgica/administración & dosificación , Adulto , Antidepresivos/administración & dosificación , Clorhidrato de Atomoxetina/administración & dosificación , Interacciones Farmacológicas/fisiología , Quimioterapia Combinada , Femenino , Fluvoxamina/administración & dosificación , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
We designed this experiment to evaluate the effects of nortriptyline on testicular injury after torsion/detorsion (T/D). Ninety-six adult Wistar rats were divided into six groups 16 each in control group (Group 1), sham operated (Group 2), T/D + saline (Group 3), and in groups 4-6; were administered 2, 10 and 20 mg kg-1 , i.p. of nortriptyline 30 and 90 min after torsion respectively. Testicular torsion was created by twisting the right testis 720° in clockwise direction for 1 h. In six rats of each group, tissue MDA level and caspase-3 activity increased and the activities of catalase, superoxide dismutase and glutathione peroxidase decreased in compared with control group 4 h after detorsion (P < 0.001). In six rats of each group 24 h after detorsion, histopathological changes and germ cell apoptosis were significantly deteriorated by measuring mean of seminiferous tubules diameters (MSTD) and TUNEL test. Moreover, 30 days after T/D, sperm concentration and motility were examined in rest of rats. Pre- and post-reperfusion nortriptyline could reduce MDA and caspase-3 levels and normalise antioxidant enzymes activities, dose dependently. Germ cell apoptosis was significantly decreased, and the MSTD, as well as sperm functions, were significantly improved. Inhibition of mitochondrial permeability transition pore is probably involved in protective effects of nortriptyline against testicular T/D cell damages.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Apoptosis/efectos de los fármacos , Citoprotección , Nortriptilina/farmacología , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión/prevención & control , Torsión del Cordón Espermático/complicaciones , Espermatozoides/efectos de los fármacos , Testículo/efectos de los fármacos , Inhibidores de Captación Adrenérgica/administración & dosificación , Animales , Caspasa 3/metabolismo , Catalasa/metabolismo , Modelos Animales de Enfermedad , Glutatión Peroxidasa/metabolismo , Humanos , Etiquetado Corte-Fin in Situ , Masculino , Malondialdehído/metabolismo , Nortriptilina/administración & dosificación , Ratas , Ratas Wistar , Daño por Reperfusión/etiología , Daño por Reperfusión/patología , Recuento de Espermatozoides , Torsión del Cordón Espermático/patología , Espermatozoides/patología , Superóxido Dismutasa/metabolismo , Testículo/irrigación sanguínea , Testículo/patologíaRESUMEN
Phasic norepinephrine (NE) release events are involved in arousal, novelty detection and in plasticity processes underlying learning and memory in mammalian systems. Although the effects of phasic NE release events on plasticity and memory are prevalently documented, it is less understood what effects chronic NE reuptake inhibition and sustained increases in noradrenergic tone, might have on plasticity and cognitive processes in rodent models of learning and memory. This study investigates the effects of chronic NE reuptake inhibition on hippocampal plasticity and memory in rats. Rats were administered NE reuptake inhibitors (NRIs) desipramine (DMI; 0, 3, or 7.5mg/kg/day) or nortriptyline (NTP; 0, 10 or 20mg/kg/day) in drinking water. Long-term potentiation (LTP; 200 Hz) of the perforant path-dentate gyrus evoked potential was examined in urethane anesthetized rats after 30-32 days of DMI treatment. Short- (4-h) and long-term (24-h) spatial memory was tested in separate rats administered 0 or 7.5mg/kg/day DMI (25-30 days) using a two-trial spatial memory test. Additionally, the effects of chronically administered DMI and NTP were tested in rats using a two-trial, Object Recognition Test (ORT) at 2- and 24-h after 45 and 60 days of drug administration. Rats administered 3 or 7.5mg/kg/day DMI had attenuated LTP of the EPSP slope but not the population spike at the perforant path-dentate gyrus synapse. Short- and long-term memory for objects is differentially disrupted in rats after prolonged administration of DMI and NTP. Rats that were administered 7.5mg/kg/day DMI showed decreased memory for a two-trial spatial task when tested at 4-h. In the novel ORT, rats receiving 0 or 7.5mg/kg/day DMI showed a preference for the arm containing a Novel object when tested at both 2- and 24-h demonstrating both short- and long-term memory retention of the Familiar object. Rats that received either dose of NTP or 3mg/kg/day DMI showed impaired memory at 2-h, however this impairment was largely reversed at 24-h. Animals in the high-dose NTP (20mg/kg/day) group were impaired at both short- and long-term intervals. Activity levels, used as an index of location memory during the ORT, demonstrated that rats receiving DMI were again impaired at retaining memory for location. DMI dose-dependently disrupts LTP in the dentate gyrus of anesthetized rats and also disrupts memory for tests of spatial memory when administered for long periods.