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1.
Cochrane Database Syst Rev ; 1: CD013011, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33460048

RESUMO

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention or impulsivity or both, and hyperactivity, which affect children, adolescents, and adults. In some countries, methylphenidate is the first option to treat adults with moderate or severe ADHD. However, evidence on the efficacy and adverse events of immediate-release (IR) methylphenidate in the treatment of ADHD in adults is limited and controversial. OBJECTIVES: To evaluate the efficacy and harms (adverse events) of IR methylphenidate for treating ADHD in adults. SEARCH METHODS: In January 2020, we searched CENTRAL, MEDLINE, Embase, eight additional databases and three trial registers. We also searched internal reports on the European Medicines Agency and the US Food and Drug Administration websites. We checked citations of included trials to identify additional trials not captured by the electronic searches. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing IR methylphenidate, at any dose, with placebo or other pharmacological interventions (including extended-release formulations of methylphenidate) for ADHD in adults. Primary outcomes comprised changes in the symptoms of ADHD (efficacy) and harms. Secondary outcomes included changes in the clinical impression of severity and improvement, level of functioning, depression, anxiety and quality of life. Outcomes could have been rated by investigators or participants. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently on the characteristics of the trials, participants, interventions; outcomes and financial conflict of interests. We resolved disagreements by discussion or consulting a third review author. We obtained additional, unpublished information from the authors of one included trial that had reported efficacy data in a graph. We calculated mean differences (MDs) or standardized MDs (SMDs) with 95% confidence intervals (CIs) for continuous data reported on the same or different scales, respectively. We summarized dichotomous variables as risk ratios (RRs) with 95% CI. MAIN RESULTS: We included 10 trials published between 2001 and 2016 involving 497 adults with ADHD. Three trials were conducted in Europe and one in Argentina; the remaining trials did not report their location. The RCTs compared IR methylphenidate with placebo, an osmotic-release oral system (OROS) of methylphenidate (an extended-release formulation), an extended-release formulation of bupropion, lithium, and Pycnogenol® (maritime pine bark extract). Participants comprised outpatients, inpatients in addiction treatment, and adults willing to attend an intensive outpatient program for cocaine dependence. The duration of the follow-up ranged from 6 to 18 weeks. IR methylphenidate versus placebo We found very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce symptoms of ADHD when measured with investigator-rated scales (MD -20.70, 95% CI -23.97 to -17.43; 1 trial, 146 participants; end scores; Adult ADHD Investigator Symptom Report Scale (AISRS), scored from 0 to 54), but the evidence is uncertain. The effect of IR methylphenidate on ADHD symptoms when measured with participant-rated scales was moderate, but the certainty of the evidence is very low (SMD -0.59, 95% CI -1.25 to 0.06; I2 = 69%; 2 trials, 138 participants; end scores). There is very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce the clinical impression of the severity of ADHD symptoms (MD -0.57, 95% CI -0.85 to -0.28; 2 trials, 139 participants; I2 = 0%; change and end scores; Clinical Global Impression (CGI)-Severity scale (scored from 1 (very much improved) to 7 (very much worse))). There is low-certainty evidence that, compared with placebo, IR methylphenidate may slightly impact the clinical impression of an improvement in symptoms of ADHD (MD -0.94, 95% CI -1.37 to -0.51; 1 trial, 49 participants; end scores; CGI-Improvement scale (scored from 1 (very much improved) to 7 (very much worse))). There is no clear evidence of an effect on anxiety (MD -0.20, 95% CI -4.84 to 4.44; 1 trial, 19 participants; change scores; Hamilton Anxiety Scale (HAM-A; scored from 0 to 56); very low-certainty evidence) or depression (MD 2.80, 95% CI -0.09 to 5.69; 1 trial, 19 participants; change scores; Hamilton Depression Scale (HAM-D; scored from 0 to 52); very low-certainty evidence) in analyses comparing IR methylphenidate with placebo. IR methylphenidate versus lithium Compared with lithium, it is uncertain whether IR methylphenidate increases or decreases symptoms of ADHD (MD 0.60, 95% CI -3.11 to 4.31; 1 trial, 46 participants; end scores; Conners' Adult ADHD Rating Scale (scored from 0 to 198); very low-certainty evidence); anxiety (MD -0.80, 95% CI -4.49 to 2.89; 1 trial, 46 participants; end scores; HAM-A; very low-certainty evidence); or depression (MD -1.20, 95% CI -3.81 to 1.41, 1 trial, 46 participants; end scores; HAM-D scale; very low-certainty evidence). None of the included trials assessed participant-rated changes in symptoms of ADHD, or clinical impression of severity or improvement in participants treated with IR methylphenidate compared with lithium. Adverse events were poorly assessed and reported. We rated all trials at high risk of bias due to selective outcome reporting of harms and masking of outcome assessors (failure to blind outcome assessor to measure adverse events). Overall, four trials with 203 participants who received IR methylphenidate and 141 participants who received placebo described the occurrence of harms. The use of IR methylphenidate in these trials increased the risk of gastrointestinal complications (RR 1.96, 95% CI 1.13 to 2.95) and loss of appetite (RR 1.77, 95% CI 1.06 to 2.96). Cardiovascular adverse events were reported inconsistently, preventing a comprehensive analysis. One trial comparing IR methylphenidate to lithium reported five and nine adverse events, respectively. We considered four trials to have notable concerns of vested interests influencing the evidence, and authors from two trials omitted information related to the sources of funding and conflicts of interest. AUTHORS' CONCLUSIONS: We found no certain evidence that IR methylphenidate compared with placebo or lithium can reduce symptoms of ADHD in adults (low- and very low-certainty evidence). Adults treated with IR methylphenidate are at increased risk of gastrointestinal and metabolic-related harms compared with placebo. Clinicians should consider whether it is appropriate to prescribe IR methylphenidate, given its limited efficacy and increased risk of harms. Future RCTs should explore the long-term efficacy and risks of IR methylphenidate, and the influence of conflicts of interest on reported effects.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/administração & dosagem , Metilfenidato/administração & dosagem , Adulto , Antidepressivos de Segunda Geração/administração & dosagem , Ansiedade/tratamento farmacológico , Viés , Bupropiona/administração & dosagem , Estimulantes do Sistema Nervoso Central/efeitos adversos , Depressão/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Feminino , Flavonoides/administração & dosagem , Humanos , Compostos de Lítio/administração & dosagem , Masculino , Metilfenidato/efeitos adversos , Pessoa de Meia-Idade , Placebos/administração & dosagem , Extratos Vegetais/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Adulto Jovem
2.
Clin Drug Investig ; 41(2): 149-159, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33368026

RESUMO

BACKGROUND AND OBJECTIVES: Viloxazine extended-release (viloxazine ER, SPN-812) is a novel non-stimulant with activity at serotonin receptors and the norepinephrine transporter, which is under investigation as a potential treatment for attention-deficit/hyperactivity disorder. Given the potential for viloxazine ER to be coadministered with other pharmacotherapies, this trial investigated the pharmacokinetics and safety of combination viloxazine ER + methylphenidate versus viloxazine ER or methylphenidate alone. METHODS: In this single-center, crossover, open-label trial, healthy adult participants received oral administration of 700 mg viloxazine ER alone, 36 mg methylphenidate alone, and combination viloxazine ER (700 mg) + methylphenidate (36 mg), with blood samples collected over 4 days post-administration. The active drug in viloxazine ER (viloxazine) and methylphenidate was measured using chromatographic tandem mass spectrometry. Safety assessments included adverse events (AEs), vital signs, echocardiograms, and clinical laboratory evaluations. RESULTS: Of 36 healthy adults who were enrolled, 34 completed the trial. The geometric least squares mean ratios are reported as [combination/single drug (90% confidence intervals)]. For viloxazine ER, maximum measured plasma concentration (Cmax) = 100.98% (96.21-105.99), area under the concentration-time curve from time zero to the last measurable time (AUCt) = 98.62% (96.21-101.08), and area under the concentration-time curve from time zero to infinity (AUC∞) = 98.96% (96.55-101.44). For methylphenidate, Cmax = 103.55% (97.42-110.07), AUCt = 106.67% (101.01-112.64), and AUC∞ = 106.61% (100.99-112.54). All reported AEs were mild in severity. CONCLUSIONS: Coadministration of viloxazine ER and methylphenidate did not impact the pharmacokinetics of viloxazine or methylphenidate relative to administration of either drug alone. The combination appeared to be safe and well tolerated.


Assuntos
Estimulantes do Sistema Nervoso Central/administração & dosagem , Metilfenidato/administração & dosagem , Viloxazina/administração & dosagem , Administração Oral , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estudos Cross-Over , Preparações de Ação Retardada , Feminino , Humanos , Masculino , Metilfenidato/farmacocinética , Pessoa de Meia-Idade , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Viloxazina/farmacocinética , Adulto Jovem
3.
Rev. neurol. (Ed. impr.) ; 71(2): 69-73, 16 jul., 2020. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-195448

RESUMO

INTRODUCCIÓN: La discinesia de la mutación ADCY5 es un raro trastorno del movimiento de inicio en la infancia. Se caracteriza por movimientos coreicos aislados o asociados a mioclonías y distonías que afectan a las extremidades, el cuello y la cara. El escaso número de pacientes y familias no permite aún una adecuada relación genotipo-fenotipo. OBJETIVOS: Presentar el caso de un niño con trastornos del movimiento de inicio precoz en el seno de una familia con tres generaciones de afectados, y realizar una revisión actualizada de la casuística y el tratamiento de esta rara enfermedad. CASO CLÍNICO: Varón de 6 años, remitido por retraso del lenguaje e hiperactividad. Tras seis meses de seguimiento, comenzó a presentar movimientos coreicos de predominio facial y de la raíz de los miembros, especialmente al despertar. Al año de seguimiento, se evidenció corea generalizado en reposo con afectación orofacial y torpeza en la marcha. Como antecedentes familiares destacaban su madre, abuelo, tío y prima maternos, que fueron diagnosticados de síndrome de Meige (distonía oromandibular y músculos periorbitarios) con trastornos del movimiento de tipo coreiforme sin filiar desde la infancia. El estudio cerebral por resonancia magnética no presentó alteraciones. Se realizó un exoma clínico dirigido a trastornos del movimiento que descubrió la mutación patógena en el gen ADCY5 causante de la discinesia familiar autosómica. CONCLUSIÓN: La mutación c.1126G > A p.A376T muestra una historia natural con un fenotipo clínico no progresivo en tres generaciones de afectados, con inicio en la infancia y respuesta al tratamiento con guanfacina


INTRODUCTION. Dyskinesia of the ADCY5 mutation is a rare movement-onset disorder in childhood. It is characterized by isolated chorea movements or associated with myoclonus and dystonia affecting the limbs, neck and face. The low number of patients and families still does not allow an adequate genotype-phenotype relationship. AIMS. The case of a child with movement disorders of early onset is presented in a family with three generations of affected members. An updated review of the casuistry and management of this rare disease is made. CASE REPORT: A 6-year-old boy referred for language delay and hyperactivity. After six months of follow-up he begins to show chorea movements of predominantly facial and limb roots, especially when waking up. At one year of follow-up, generalized chorea at rest with orofacial involvement and awkward gait begins to show. His family history includes his mother, grandfather, maternal uncle and cousin, who were diagnosed with Meige's syndrome (oromandibular dystonia and periorbital muscles) with choreiform-like movement disorders without affiliation since childhood. The brain study by MRI showed no alterations. A clinical exome targeting movement disorders was performed that discovered the pathogenic mutation in the ADCY5 gene causing autosomal familial dyskinesia. CONCLUSION: The c.1126G>A p.A376T mutation shows a natural history with a non-progressive clinical phenotype in three generations of affected members, with childhood debut and response to guanfacine treatment


Assuntos
Humanos , Masculino , Criança , Discinesias/genética , Transtornos dos Movimentos/complicações , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Levetiracetam/administração & dosagem , Metilfenidato/administração & dosagem , Guanfacina/administração & dosagem , Transtornos dos Movimentos/etiologia , Mioclonia/complicações , Discinesia Tardia/complicações , Transtornos do Desenvolvimento da Linguagem/complicações , Síndrome de Meige/diagnóstico , Fenótipo , Genótipo
4.
Compr Psychiatry ; 100: 152178, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32386957

RESUMO

BACKGROUND: Emotional dysregulation (ED) and callous unemotional (CU) traits can be associated with ADHD in youth, influencing its natural history and outcome, but their effect on medication efficacy is unexplored. We examined whether two measures of baseline ED and CU traits, the Child Behavior Checklist-Dysregulation Profile (CBCL-DP) and the Antisocial Process Screening Device (APSD), respectively, were predictors of change of ADHD-Rating Scale (ADHD-RS) after a 4-week methylphenidate (MPH) monotherapy. METHODS: 43 patients (37 males, 8-16 years, mean 9.9 ± 2.7 years) were included. Hierarchical linear regression models were used to explore whether CBCL-DP and APSD might predict ADHD-RS score, controlling for baseline severity. RESULTS: Baseline CBCL-DP predicted higher post-treatment ADHD-RS scores in total and hyperactivity-impulsivity, but not in inattention subscale. Baseline APSD was not significantly related to ADHD-RS scores at the follow-up. LIMITATIONS: Small sample size, lack of gender diversity, non-blind design and short period of observation. CONCLUSION: ED, assessed with that CBCL-DP, might be a negative predictor of change of hyperactive-impulsive symptoms after MPH treatment and should be systematically assessed at baseline.


Assuntos
Transtorno da Personalidade Antissocial/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/efeitos adversos , Emoções/efeitos dos fármacos , Metilfenidato/efeitos adversos , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/uso terapêutico , Criança , Cognição , Feminino , Humanos , Comportamento Impulsivo , Masculino , Metilfenidato/administração & dosagem , Metilfenidato/uso terapêutico , Índice de Gravidade de Doença , Resultado do Tratamento
5.
Psychopharmacology (Berl) ; 237(6): 1873-1883, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32307560

RESUMO

BACKGROUND: The thalamus is a major target of dopaminergic projections and is densely connected with the prefrontal cortex. A better understanding of how dopamine changes thalamo-cortical communication may shed light on how dopamine supports cognitive function. Methylphenidate has been shown to facilitate cognitive processing and reduce connectivity between the thalamus and lateral prefrontal cortex. AIMS: The thalamus is a heterogeneous structure, and the present study sought to clarify how the intrinsic connections of thalamic sub-regions are differentially impacted by acute dopamine transporter blockade. METHODS: Sixty healthy volunteers were orally administered either 20 mg of methylphenidate (N = 29) or placebo (N = 31) in a double-blind, randomized, between-subject design. Multi-echo fMRI was used to assess intrinsic functional connectivity of sub-regions of the thalamus during a resting state scan. An N-back working-memory paradigm provided a measure of cognitive performance. RESULTS: Acute methylphenidate significantly reduced connectivity of the lateral prefrontal cortex with the motor and somatosensory sub-regions of the thalamus and reduced connectivity with the parietal and visual sub-regions at a trend level. Connectivity with the premotor, prefrontal, and temporal sub-regions was not impacted. The intrinsic connectivity between the thalamus and the lateral prefrontal cortex was not associated with working-memory performance. CONCLUSIONS: Methylphenidate decreases functional connections between the lateral prefrontal cortex and thalamus broadly, while sparing intrinsic connectivity with thalamic sub-regions involved with working-memory and language related processes. Collectively, our results suggest that the dopamine transporter regulates functional connections between the prefrontal cortex and non-cognitive areas of the thalamus.


Assuntos
Imagem por Ressonância Magnética/métodos , Memória de Curto Prazo/efeitos dos fármacos , Metilfenidato/administração & dosagem , Rede Nervosa/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Adulto , Inibidores da Captação de Dopamina/administração & dosagem , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Memória de Curto Prazo/fisiologia , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiologia , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiologia , Tálamo/diagnóstico por imagem , Tálamo/fisiologia , Adulto Jovem
6.
Sci Rep ; 10(1): 716, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959838

RESUMO

Methylphenidate (MPH) is a dopamine transporter (DAT) inhibitor used to treat attention-deficit/hyperactivity-disorder (ADHD). ADHD patients make impulsive choices in delay discounting tasks (DDT) and MPH reduces such impulsivity, but its therapeutic site of action remains unknown. Based on the high density of DAT in the striatum, we hypothesized that the striatum, especially the ventral striatum (VS) and caudate nucleus which both encode temporal discounting, can be preferential MPH action sites. To determine whether one of these striatal territories is predominantly involved in the effect of MPH, we trained monkeys to make choices during DDT. First, consistent with clinical observations, we found an overall reduction of impulsive choices with a low dose of MPH administered via intramuscular injections, whereas we reported sedative-like effects with a higher dose. Then, using PET-imaging, we found that the therapeutic reduction of impulsive choices was associated with selective DAT occupancy of MPH in the VS. Finally, we confirmed the selective involvement of the VS in the effect of MPH by testing the animals' impulsivity with microinjections of the drug in distinct striatal territories. Together, these results show that the therapeutic effect of MPH on impulsive decisions is mainly restricted to its action in the VS.


Assuntos
Desvalorização pelo Atraso/efeitos dos fármacos , Desvalorização pelo Atraso/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Comportamento Impulsivo/efeitos dos fármacos , Metilfenidato/administração & dosagem , Metilfenidato/farmacologia , Estriado Ventral/metabolismo , Animais , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Relação Dose-Resposta a Droga , Feminino , Injeções Intramusculares , Macaca fascicularis , Macaca mulatta , Masculino , Microinjeções
9.
Eur J Clin Pharmacol ; 76(2): 229-237, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31786618

RESUMO

PURPOSE: The primary aim of this study was to explore the potential of alternative sampling matrices for methylphenidate by assessing the correlations between dl-threo-methylphenidate and dl-threo-ritalinic acid concentrations in exhaled breath and oral fluid with those in plasma, in repeated samples collected after a single oral dose of methylphenidate. The secondary aim was to study the enantioselective pharmacokinetics of methylphenidate in plasma, with a focus on interindividual variability in the metabolism of methylphenidate to ritalinic acid. METHODS: Twelve healthy volunteers received a single oral dose of dl-threo-methylphenidate (Ritalin® capsules, 20 mg). Venous blood samples were collected for 24 h, and plasma analyzed for threo-enantiomers of methylphenidate and ritalinic acid with LC-MS/MS. Repeated sampling of exhaled breath, using a particle filter device, and of non-stimulated oral fluid, using a felt pad device, was also performed. Exhaled breath and oral fluid were analyzed with a non-enantioselective LC-MS/MS method for dl-threo-methylphenidate and dl-threo-ritalinic acid. RESULTS: In all subjects, d-threo-methylphenidate was detectable in plasma for at least 15 h after the dose with a biphasic profile. l-threo-Methylphenidate was measurable in only five subjects and in most cases in low concentrations. However, one female subject displayed a biphasic concentration-time profile for l-threo-methylphenidate. This subject also had the highest d-threo-methylphenidate AUC (191 ng*h/mL versus 32-119 ng*h/mL in the other subjects). d-threo-Ritalinic acid concentrations were on average 25-fold higher (range 6-126) than the corresponding d-threo-methylphenidate concentrations. Single-time point plasma concentration ratios between d-threo-ritalinic acid and d-threo-methylphenidate 1.5-12 h after dose correlated highly (r = 0.88-0.98) with the d-threo-ritalinic acid AUC/d-threo-methylphenidate AUC ratio. In eleven subjects, dl-threo-methylphenidate in oral fluid mirrored the biphasic profile of methylphenidate (sum of d- and l-threo-enantiomers) in plasma, but the concentrations in oral fluid were on average 1.8 times higher than in plasma. dl-threo-Methylphenidate was detected in exhaled breath in all subjects, but there was no consistent concentration-time pattern. CONCLUSIONS: In some subjects, the pharmacologically less active l-threo-enantiomer may contribute to the total plasma methylphenidate concentrations. Monitoring methylphenidate concentrations without enantiomeric determination carries the risk of missing such subjects, which might affect how the plasma concentrations of methylphenidate are interpreted and used for clinical decision making. The use of exhaled breath and oral fluid to assess medication adherence to MPH in patients with ADHD warrants further studies.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacocinética , Metilfenidato/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Testes Respiratórios/métodos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Cromatografia Líquida , Feminino , Humanos , Masculino , Adesão à Medicação , Metilfenidato/administração & dosagem , Metilfenidato/análogos & derivados , Estereoisomerismo , Espectrometria de Massas em Tandem , Adulto Jovem
10.
Anesth Analg ; 130(2): 518-524, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31206430

RESUMO

BACKGROUND: The incremental dose of opioids used in chronic pain management often leads to a reduced opioid analgesic effect, opioid misuse, and addiction. Central dopamine (DA) dysfunction contributes to the chronicity of pain and a decreased opioid analgesic effect. Methylphenidate (MPH/Ritalin) enhances central DA function by inhibiting DA reuptake. In this study, we used a rat model of chronic pain to examine whether combination of MPH with morphine (MOR) would improve the MOR analgesic effect under a chronic pain condition. METHODS: Tibiotarsal joint Complete Freund's Adjuvant (CFA) injection in rats was utilized to induce chronic nociception. The analgesic effect of low-dose MPH (0.25 mg/kg), low-dose MOR (2.5 mg/kg), and their combination was examined in CFA rats. Nociceptive behavior was assessed by von Frey test. Conditioned place preference (CPP) and open field tests (OFTs) were used to examine the rewarding behavior and locomotor activity in rats, respectively. RESULTS: Our findings are as follows: (1) in CFA rats with chronic pain, 2.5 mg/kg of MOR had less analgesic effect than 10 mg/kg of MOR at 28 days after injury (95% confidence intervals [CIs] for difference of means of von Frey threshold in gram: -11.9 [-6.5 to -17.3]); (2) in the 1-hour time window of 30-90 minutes after injection, the combination of MPH (0.25 mg/kg) with MOR (2.5 mg/kg) increased synergistically and prolonged the analgesic effect in CFA rats as compared with MPH or MOR alone (P = .01 for MPH by MOR interaction, and 95% CIs for difference of means of von Frey threshold in gram: 3.3 [1.37-6.12] for the combination versus MPH and 3.2 [1.35-5.74] for the combination versus MOR); (3) at the low dose (0.25 mg/kg), MPH did not increase locomotor activity (MOR + MPH versus MOR, P = .13) nor significantly enhanced MOR reward behavior (MOR + MPH versus MOR, P = .63) in CFA rats. CONCLUSIONS: Our data suggest that a combination therapy using low-dose MPH and MOR may produce a MOR-sparing effect in chronic pain management.


Assuntos
Analgésicos Opioides/administração & dosagem , Dor Crônica/tratamento farmacológico , Modelos Animais de Doenças , Inibidores da Captação de Dopamina/administração & dosagem , Metilfenidato/administração & dosagem , Morfina/administração & dosagem , Animais , Dor Crônica/induzido quimicamente , Dor Crônica/patologia , Quimioterapia Combinada , Adjuvante de Freund/toxicidade , Masculino , Ratos , Ratos Sprague-Dawley
11.
Dev Psychobiol ; 62(2): 170-180, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31456229

RESUMO

Methylphenidate (MP) is a commonly prescribed psychostimulant to individuals with Attention Deficit Hyperactivity Disorder, and is often used illicitly among healthy individuals with intermittent breaks to coincide with breaks from school. This study examined how intermittent abstinence periods impact the physiological and behavioral effects of chronic oral MP self-administration in rats, and whether these effects persist following prolonged abstinence from the drug. Rats were treated orally with water, low-dose (LD), or high-dose (HD) MP, beginning at PND 28. This daily access continued for three consecutive weeks followed by a 1-week abstinence; after three repeats of this cycle, there was a 5-week abstinence period. Throughout the study, we examined body weight, food intake, locomotor activity, and anxiety- and depressive-like behaviors. During the treatment phase, HD MP decreased body weight, food intake, and depressive- and anxiety-like behaviors, while it increased locomotor activity. During intermittent abstinence, the effects of MP on locomotor activity were eliminated. During prolonged abstinence, most of the effects of HD MP were ameliorated to control levels, with the exception of weight loss and anxiolytic effects. These findings suggest that intermittent exposure to chronic MP causes physiological and behavioral effects that are mostly reversible following prolonged abstinence.


Assuntos
Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Metilfenidato/farmacologia , Animais , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/administração & dosagem , Modelos Animais de Doenças , Masculino , Metilfenidato/administração & dosagem , Ratos , Ratos Sprague-Dawley
12.
Elife ; 82019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31850844

RESUMO

The remarkable expedience of human learning is thought to be underpinned by meta-learning, whereby slow accumulative learning processes are rapidly adjusted to the current learning environment. To date, the neurobiological implementation of meta-learning remains unclear. A burgeoning literature argues for an important role for the catecholamines dopamine and noradrenaline in meta-learning. Here, we tested the hypothesis that enhancing catecholamine function modulates the ability to optimise a meta-learning parameter (learning rate) as a function of environmental volatility. 102 participants completed a task which required learning in stable phases, where the probability of reinforcement was constant, and volatile phases, where probabilities changed every 10-30 trials. The catecholamine transporter blocker methylphenidate enhanced participants' ability to adapt learning rate: Under methylphenidate, compared with placebo, participants exhibited higher learning rates in volatile relative to stable phases. Furthermore, this effect was significant only with respect to direct learning based on the participants' own experience, there was no significant effect on inferred-value learning where stimulus values had to be inferred. These data demonstrate a causal link between catecholaminergic modulation and the adjustment of the meta-learning parameter learning rate.


Assuntos
Dopamina/metabolismo , Aprendizagem/efeitos dos fármacos , Norepinefrina/metabolismo , Adolescente , Adulto , Inibidores da Captação de Dopamina/administração & dosagem , Feminino , Humanos , Masculino , Metilfenidato/administração & dosagem , Placebos/administração & dosagem , Adulto Jovem
13.
Trials ; 20(1): 663, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791384

RESUMO

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent disorder, seen in 20-30% of young adult prisoners. Pharmacoepidemiological studies, a small randomised controlled trial and open trial data of methylphenidate suggest clinically significant reductions in ADHD symptoms, emotional dysregulation, disruptive behaviour and increased engagement with educational activities. Yet, routine treatment of ADHD in offenders is not yet established clinical practice. There is continued uncertainty about the clinical response to methylphenidate (MPH), a first-line treatment for ADHD, in offenders, who often present with an array of complex mental health problems that may be better explained by states of inattentive, overactive, restless and impulsive behaviours. To address this problem, we will conduct an efficacy trial to establish the short-term effects of osmotic-controlled release oral delivery system (OROS)-methylphenidate (Concerta XL), an extended release formulation of MPH, on ADHD symptoms, emotional dysregulation and behaviour. METHODS: This study is a parallel-arm, randomised, placebo-controlled trial of OROS-MPH on ADHD symptoms, behaviour and functional outcomes in young male prisoners aged 16-25, meeting Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria for ADHD. Participants are randomised to 8 weeks of treatment with OROS-MPH or placebo, titrated over 5 weeks to balance ADHD symptom improvement against side effects. Two hundred participants will be recruited with a 1:1 ratio of drug to placebo. The primary outcome is change in level of ADHD symptoms after 8 weeks of trial medication. DISCUSSION: Potential benefits include improvement in ADHD symptoms, emotional dysregulation, attitudes towards violence and critical incidents and increased engagement with educational and rehabilitation programmes. Demonstrating the efficacy and safety of MPH on ADHD symptoms and associated impairments may provide the data needed to develop effective healthcare pathways for a significant group of young offenders. Establishing efficacy of MPH in this population will provide the foundation needed to establish long-term effectiveness studies with the potential for demonstrating significant reductions in criminal behaviour and improved health-economic outcomes. TRIAL REGISTRATION: ISRCTN registry, ISRCTN16827947, 31st May 2016; EudraCT number, 2015-004271-78, 31st May 2016. Last particpant last visit 6 June 2019. Data lock 27 August 2019.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Metilfenidato/administração & dosagem , Prisioneiros/psicologia , Administração Oral , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Preparações de Ação Retardada , Humanos , Masculino , Metilfenidato/efeitos adversos , Avaliação de Resultados em Cuidados de Saúde , Seleção de Pacientes , Adulto Jovem
14.
Pharmacotherapy ; 39(12): 1167-1178, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31674031

RESUMO

OBJECTIVE: To examine whether concomitant use of quinolones and stimulants increases the risk of cardiac events in adults. STUDY DESIGN: A retrospective cohort study of privately insured adults using MarketScan® claims data from 2008 to 2015. PATIENTS: Stimulant (methylphenidate or mixed amphetamine salts) users (18-65 yrs old) with continuous health plan enrollment for the 6 months (baseline) prior to the first dispensation (index date) of oral quinolones or comparators (amoxicillin ± clavulanate or azithromycin). OUTCOMES DEFINITION: (1) Cardiac symptoms (palpitation, tachycardia, or syncope); (2) cardiac arrhythmias (ventricular arrhythmias, paroxysmal ventricular tachycardia, or cardiac arrest). ANALYSIS: Baseline covariates adjustment was through inverse probability of treatment weighting. Adults were followed until the antimicrobial therapy ended. The hazard of cardiac events in stimulant-quinolones-exposed adults was compared to those who were treated with stimulant-comparator antibiotics using a weighted Cox regression model. Several sensitivity analyses were performed to challenge the results robustness. RESULTS: The study cohorts comprised 390,490 stimulants users who initiated either quinolone or amoxicillin, and 387,574 patients receiving stimulants who initiated quinolone or azithromycin. The unadjusted incidence rate for cardiac symptoms in stimulant-quinolones users was 471 cases/10,000 patient-years, and it was 244 cases/10,000 patient-years in patients exposed to stimulant-amoxicillin; whereas the unadjusted incidence rate for cardiac symptoms was 728 and 358 per 10,000 patient-years for stimulant-quinolones and stimulant-azithromycin cohorts, respectively. Compared to stimulant-amoxicillin use, the adjusted hazard ratio (HR) for cardiac symptoms with stimulant-quinolones use was 1.61 (95% confidence interval [CI], 1.30-1.98). The HR for cardiac symptoms for patient exposed to stimulant-quinolones was 1.69 (95% CI, 1.32-2.13) when compared to stimulant-azithromycin. The sensitivity analysis findings were consistent with the primary analysis. A few patients across the study comparison groups developed cardiac arrhythmias. CONCLUSION: Concomitant use of stimulants and quinolone was associated with an increased hazard of cardiac symptoms in comparison to concomitant use of stimulants and amoxicillin or azithromycin, but there was no apparent difference in cardiac arrhythmias.


Assuntos
Antibacterianos/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Estimulantes do Sistema Nervoso Central/efeitos adversos , Quinolonas/efeitos adversos , Adolescente , Adulto , Idoso , Anfetaminas/administração & dosagem , Anfetaminas/efeitos adversos , Antibacterianos/administração & dosagem , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estudos de Coortes , Interações Medicamentosas , Feminino , Humanos , Masculino , Metilfenidato/administração & dosagem , Metilfenidato/efeitos adversos , Pessoa de Meia-Idade , Quinolonas/administração & dosagem , Estudos Retrospectivos , Adulto Jovem
15.
Einstein (Sao Paulo) ; 18: eAO4745, 2019.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31664322

RESUMO

OBJECTIVE: To estimate the prevalence of and factors associated with the use of methylphenidate for cognitive enhancement among undergraduate students. METHODS: Simple random sample of students of the Universidade Federal de Minas Gerais (n=438), invited to answer an online questionnaire about the use of methylphenidate. Data collection occurred from September 2014 to January 2015. The sample was described by means of proportions, means and standard deviations. A multivariate analysis was performed using the Classification and Regression Tree algorithm to classify the cases of use of methylphenidate for cognitive enhancement in groups, based on the exposure variables. RESULTS: Out of 378 students included, 5.8% (n=22) reported using methylphenidate for cognitive enhancement; in that, 41% (9/22) in the 4 weeks prior to the survey. The housing situation was the variable most often associated with the use of methylphenidate for cognitive enhancement. Eleven students reported using methylphenidate for cognitive enhancement and other purposes 4 weeks prior to the survey, 27% of whom had no medical prescription to purchase it. CONCLUSION: The use of methylphenidate for cognitive enhancement is frequent among Brazilian undergraduate students and should be considered a serious public health problem, especially due to risks of harm and adverse effects associated with its use.


Assuntos
Estimulantes do Sistema Nervoso Central/administração & dosagem , Nootrópicos/administração & dosagem , Nootrópicos/uso terapêutico , Estudantes/estatística & dados numéricos , Universidades/estatística & dados numéricos , Adulto , Brasil/epidemiologia , Estudos Transversais , Árvores de Decisões , Exercício Físico/psicologia , Feminino , Humanos , Masculino , Metilfenidato/administração & dosagem , Uso Off-Label/estatística & dados numéricos , Prevalência , Características de Residência/estatística & dados numéricos , Fatores de Risco , Fatores Socioeconômicos , Estudantes/psicologia , Inquéritos e Questionários , Adulto Jovem
16.
Expert Opin Drug Metab Toxicol ; 15(11): 937-974, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31581854

RESUMO

Introduction: Long-acting stimulant formulations are recommended as first-line pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD). Over the past 20 years, extended-release (ER) methylphenidate (MPH) and amphetamine (AMP) formulations have evolved to include varying drug delivery technologies, enantiomers/salts, and dosage forms. All formulations are characterized by a unique pharmacokinetic profile that is closely mirrored by pharmacodynamic response allowing clinicians to individualize therapy based on their patient's clinical needs and dosing preferences.Areas covered: This review provides an update on the pharmacokinetic properties of approved and investigational ER MPH and AMP formulations and highlights pharmacokinetic features that clinicians should consider when selecting a long-acting stimulant.Expert opinion: Since there are no reliable biomarkers that can predict individualized response to long-acting stimulants, clinicians need to consider their distinctive pharmacokinetic properties, including the pharmacokinetic profile, rate and extent of absorption, variability, dose proportionality, bioequivalence, and potential for accumulation. Clinicians also need to understand that certain factors can contribute to increased variability in pharmacokinetics and potentially affect outcomes. Less invasive, high-throughput techniques and novel time-based scales are being developed to advance research on the pharmacokinetic-pharmacodynamic relationships of stimulants. Model-based pharmacokinetic-pharmacodynamic approaches can be applied to aid the development of novel formulations and individualize therapy with existing drugs.


Assuntos
Anfetamina/administração & dosagem , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Metilfenidato/administração & dosagem , Anfetamina/farmacocinética , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/farmacocinética , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos , Desenvolvimento de Medicamentos , Humanos , Metilfenidato/farmacocinética , Modelos Biológicos , Medicina de Precisão
17.
P R Health Sci J ; 38(3): 185-188, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31536633

RESUMO

OBJECTIVE: The purpose of this study was to determine the prevalence of medical and nonmedical use of prescription attention deficit hyperactive disorder (ADHD) stimulant medication among medical students. MATERIALS AND METHODS: An IRB approved 19-question web survey was sent out to all students from a Puerto Rico (PR) medical school to assess use of ADHD medication. Out of the 250 stu-dents consulted there was a response of 152 surveys. Data was cross-referenced and compared with data from other studies. RESULTS/DISCUSSION: From the results gathered, the study's sample had a higher prevalence of use than the 15% reported in previous studies, reaching 47.4%. Among students who had used these drugs, 89.4% indicated using it without a prescription. 86.8% of all respondents used some form of stimulant or substance in order to cope with the academic workload of medical school, includ-ing coffee, energy drinks, cigarettes, and alcohol. The majority of students (60.5%) considered study techniques workshops and exercise programs to succeed academically. CONCLUSION: This study suggests a higher prevalence of ADHD medication use amongst the PR medical student sample compared to findings reported of US medical students, as well as a high prevalence related to nonmedical use as a means for medical students to cope with their training. The nonmedical use of stimulants in the medical school setting remains of utmost public health and clinical concern. The results of this study could help develop proper workshops and non-pharmacological techniques to help medical students cope with their workload.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/epidemiologia , Dextroanfetamina/administração & dosagem , Metilfenidato/administração & dosagem , Estudantes de Medicina/estatística & dados numéricos , Adaptação Psicológica , Adulto , Estimulantes do Sistema Nervoso Central/administração & dosagem , Feminino , Humanos , Masculino , Prevalência , Porto Rico , Estudantes de Medicina/psicologia , Inquéritos e Questionários , Adulto Jovem
19.
Expert Rev Pharmacoecon Outcomes Res ; 19(6): 677-684, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31456453

RESUMO

Introduction: The prevalence of Attention-Deficit/Hyperactivity Disorder (ADHD) has risen over the last two decades, with a corresponding increase in the cost of its medication. Drug utilization studies in South Africa focusing on ADHD are limited.Areas covered: The primary aim was to determine the cost of methylphenidate and atomoxetine (used for ADHD). The Intercontinental Marketing Service (IMS) database which contains data of the private healthcare sector was interrogated from 2013 to 2016 (48-month period) focussing on methylphenidate and atomoxetine. Drug consumption was expressed in number of DDDs, DDDs/1000 inhabitants/day and cost in Rands.Expert opinion: Methylphenidate-containing products constituted a considerably higher percentage of the market share when compared to atomoxetine (90.30% versus 9.70%). The DDD/1000 inhabitants/day for methylphenidate was 6.010 with an annual cost for R266 691 778 in 2013, which increased to 7.827 DDDs/1000 inhabitants/day with an annual cost of R436 041 506 in 2016. Consumption of both methylphenidate and atomoxetine increased from 2013 to 2016. There was a preference for long-acting extended-release methylphenidate tablets even though the unit costs were higher when compared to the short-acting formulations. Despite increases in unit costs, the spend in South Africa showed an upward trend for methylphenidate and atomoxetine.


Assuntos
Cloridrato de Atomoxetina/administração & dosagem , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Metilfenidato/administração & dosagem , Inibidores da Captação Adrenérgica/administração & dosagem , Inibidores da Captação Adrenérgica/economia , Cloridrato de Atomoxetina/economia , Transtorno do Deficit de Atenção com Hiperatividade/economia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/economia , Humanos , Metilfenidato/economia , Setor Privado/economia , África do Sul
20.
Complement Ther Clin Pract ; 37: 39-46, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31445366

RESUMO

BACKGROUND AND PURPOSE: There is growing interest in how mindful parenting interventions (MPI) may support families of children with attention deficit hyperactivity disorder (ADHD). The aim of this study was to explore the potential barriers and enablers to parents' participation in a MPI from the perspectives of parents of children with ADHD and healthcare providers. MATERIALS AND METHODS: Thirteen parents of children with ADHD attended focus groups, and seven healthcare providers participated in semi-structured phone interviews. Transcripts of the focus groups and interviews were analysed using inductive thematic analysis. RESULTS: Three overarching themes related to potential barriers and enablers were identified: parent motivation and capacity to engage in a MPI, the need for multimodal and personalised delivery, and considerations for real-world program implementation. CONCLUSION: Parents of children with ADHD appear to require flexible, multimodal MPIs that consider parents' emotional experiences, priorities, and personal struggles.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Atenção Plena , Poder Familiar , Pais/psicologia , Adulto , Criança , Feminino , Grupos Focais , Humanos , Amor , Masculino , Metilfenidato/administração & dosagem , Pessoa de Meia-Idade
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