Are all ADHD medications created equal? Exploring the differences that enable evening dosing.

With more than 30 available stimulant medications, choosing among therapeutic options for attention-deficit/hyperactivity disorder (ADHD) has become increasingly complex and patient specific. All ADHD stimulants owe their action to variants of either amphetamine or methylphenidate, yet formulation and delivery system differences create unique pharmacokinetic and clinical profiles for each medication. A benefit of the diversity within ADHD pharmacotherapy is that it facilitates tailoring treatment to meet patient needs. Historically, there has been a constant among long-acting stimulant options, regardless of formulation, which was morning dosing. The introduction of delayed-release and extended-release methylphenidate (DR/ER-MPH) is the first long-acting stimulant that patients take in the evening, with the clinical effect delayed until awakening in the morning. This paradigm shift has generated questions among clinicians and continued interest in real-world experience and data. This review used available clinical data, real-world evidence, emerging analyses, and clinical experience to evaluate the characteristics of DR/ER-MPH and its clinical utility within the greater context of ADHD medications and to provide clinicians with practical guidance on the use of DR/ER-MPH in children, adolescents, and adults with ADHD.

Expert consensus statement for telepsychiatry and attention-deficit hyperactivity disorder.

Changing practice patterns caused by the pandemic have created an urgent need for guidance in prescribing stimulants using telepsychiatry for attention-deficit hyperactivity disorder (ADHD). A notable spike in the prescribing of stimulants accompanied the suspension of the Ryan Haight Act, allowing the prescribing of stimulants without a face-to-face meeting. Competing forces both for and against prescribing ADHD stimulants by telepsychiatry have emerged, requiring guidelines to balance these factors. On the one hand, factors weighing in favor of increasing the availability of treatment for ADHD via telepsychiatry include enhanced access to care, reduction in the large number of untreated cases, and prevention of the known adverse outcomes of untreated ADHD. On the other hand, factors in favor of limiting telepsychiatry for ADHD include mitigating the possibility of exploiting telepsychiatry for profit or for misuse, abuse, and diversion of stimulants. This Expert Consensus Group has developed numerous specific guidelines and advocates for some flexibility in allowing telepsychiatry evaluations and treatment without an in-person evaluation to continue. These guidelines also recognize the need to give greater scrutiny to certain subpopulations, such as young adults without a prior diagnosis or treatment of ADHD who request immediate-release stimulants, which should increase the suspicion of possible medication diversion, misuse, or abuse. In such cases, nonstimulants, controlled-release stimulants, or psychosocial interventions should be prioritized. We encourage the use of outside informants to support the history, the use of rating scales, and having access to a hybrid model of both in-person and remote treatment.

A Post-Hoc Analysis of Emotional Lability With Delayed-Release/Extended-Release Methylphenidate in Children Aged 6 to 12 Years of Age Participating in Two Phase 3 Clinical Trials.

OBJECTIVE: DR/ER-MPH (formerly HLD200) is an evening-dosed delayed-release and extended-release methylphenidate approved for the treatment of ADHD in patients ≥6 years. Post hoc analyses of two pivotal Phase 3 trials: HLD200-107 (NCT02493777) and HLD200-108 (NCT02520388) evaluated emotional lability (EL) with DR/ER-MPH treatment. METHODS: Differences in Conners Global Index-Parent (CGI-P) EL subscale scores and age- and gender-adjusted T-scores over an open-label titration phase (HLD200-107) and between treatment and placebo groups at endpoint (HLD200-108) were evaluated. RESULTS: In HLD200-107 (N = 117) mean CGI-P EL subscale scores improved from 5.3 to 1.3 (p < .0001) after 6 weeks; in HLD200-108 significant improvements were observed in the treatment group (n = 81) versus placebo (n = 80; 3.11 vs. 4.08; p = .0053). T-scores showed an improvement with DR/ER-MPH treatment in both trials. Few emotional adverse events (AEs) were reported. CONCLUSION: DR/ER-MPH treatment resulted in statistically significant improvements in EL to the level of non-ADHD peers as contextualized by T-scores.

BEHIND THE PROTON PUMP INHIBITOR PRESCRIPTION: AN INTERNATIONAL SURVEY ON PHYSICIAN PRACTICES AND KNOWLEDGE.

BACKGROUND: Proton pump inhibitors (PPIs) are widely prescribed worldwide, often resulting in their overuse. Consequently, it is essential to identify the likely causes of this overuse to facilitate their appropriate prescription. OBJECTIVE: This study aims to assess physician prescribing patterns, their knowledge of PPIs, and factors affecting their knowledge. METHODS: An online survey was conducted among Latin American and Spanish physicians, collecting the following data: professional information, patterns of PPI usage, familiarity with published evidence, and the management approach in three hypothetical case-scenarios. Participant knowledge was categorized as sufficient or insufficient based on the results of the case scenarios. Subsequently, subgroup analysis was performed based on physician training level, years in practice, specialty, and time since the last PPI literature review. RESULTS: A total of 371 physicians participated in the survey. Thirty-eight percent frequently prescribe PPIs, primarily for prophylactic purposes (57.9%). Eighty percent were unfamiliar with PPI deprescribing strategies, and 54.4% rarely reviewed the ongoing indication of patients taking a PPI. Sixty-four percent demonstrated sufficient knowledge in the case-scenarios. A significant association was observed between specialty type (medical vs surgical: 69.4% vs 46.8%, P<0.001), the timing of the PPI indication literature review (<5 years vs >5 years: 71.4% vs 58.7%, P=0.010), and sufficient knowledge. CONCLUSION: While most participants prescribed PPIs regularly and for prophylaxis purposes, the majority were unfamiliar with deprescribing strategies and rarely reviewed ongoing indications. Sufficient knowledge is correlated with recent literature reviews and medical specialty affiliation. BACKGROUND: • The study aims to evaluate physician prescribing patterns, assess their knowledge of proton pump inhibitors, and identify factors influencing their knowledge. BACKGROUND: • An online survey of Latin American and Spanish physicians assessed proton pump inhibitor usage patterns and case-scenario responses, categorizing knowledge, and conducting subgroup analysis based on training, experience, specialty, and literature review timing. BACKGROUND: • Thirty-eight percent of surveyed physicians commonly prescribed proton pump inhibitors, and among them, 80% were unfamiliar with deprescribing strategies, with 54.4% rarely reviewing ongoing indications. BACKGROUND: • Sufficient knowledge was correlated with recent literature reviews and medical specialty affiliations.

Bastidores da prescrição de inibidores de bomba de prótons: uma pesquisa internacional sobre práticas e conhecimentos médicos / Behind the proton pump inhibitor prescription: an international survey on physician practices and knowledge

ABSTRACT Background: Proton pump inhibitors (PPIs) are widely prescribed worldwide, often resulting in their overuse. Consequently, it is essential to identify the likely causes of this overuse to facilitate their appropriate prescription. Objective: This study aims to assess physician prescribing patterns, their knowledge of PPIs, and factors affecting their knowledge. Methods: An online survey was conducted among Latin American and Spanish physicians, collecting the following data: professional information, patterns of PPI usage, familiarity with published evidence, and the management approach in three hypothetical case-scenarios. Participant knowledge was categorized as sufficient or insufficient based on the results of the case scenarios. Subsequently, subgroup analysis was performed based on physician training level, years in practice, specialty, and time since the last PPI literature review. Results: A total of 371 physicians participated in the survey. Thirty-eight percent frequently prescribe PPIs, primarily for prophylactic purposes (57.9%). Eighty percent were unfamiliar with PPI deprescribing strategies, and 54.4% rarely reviewed the ongoing indication of patients taking a PPI. Sixty-four percent demonstrated sufficient knowledge in the case-scenarios. A significant association was observed between specialty type (medical vs surgical: 69.4% vs 46.8%, P<0.001), the timing of the PPI indication literature review (<5 years vs >5 years: 71.4% vs 58.7%, P=0.010), and sufficient knowledge. Conclusion: While most participants prescribed PPIs regularly and for prophylaxis purposes, the majority were unfamiliar with deprescribing strategies and rarely reviewed ongoing indications. Sufficient knowledge is correlated with recent literature reviews and medical specialty affiliation.

RESUMO Contexto: Os inibidores da bomba de prótons (IBPs) são amplamente prescritos em todo o mundo, muitas vezes resultando em seu uso excessivo. Consequentemente, é essencial identificar as prováveis causas desse uso excessivo para facilitar sua prescrição adequada. Objetivo: Este estudo tem como objetivo avaliar o padrão de prescrição dos médicos, seu conhecimento sobre IBPs e fatores que afetam seu conhecimento. Métodos: Uma pesquisa on-line foi conduzida entre médicos latino-americanos e espanhóis, coletando os seguintes dados: informações profissionais, padrões de uso de IBP, familiaridade com evidências publicadas e abordagem de manejo em três casos-cenários hipotéticos. O conhecimento dos participantes foi categorizado em suficiente ou insuficiente com base nos resultados dos cenários de caso. Posteriormente, a análise de subgrupos foi realizada com base no nível de formação do médico, anos de prática, especialidade e tempo desde a última revisão da literatura dos IBPs. Resultados: Um total de 371 médicos participaram da pesquisa. Trinta e oito por cento prescrevem frequentemente IBP, principalmente para fins profiláticos (57,9%). Oitenta por cento não estavam familiarizados com as estratégias de prescrição de IBP, e 54,4% raramente revisaram a indicação contínua de pacientes em uso de IBP. Sessenta e quatro por cento demonstraram conhecimento suficiente nos cenários-caso. Observou-se associação significativa entre o tipo de especialidade (médica vs cirúrgica: 69,4% vs 46,8%, P<0,001), o momento da revisão da literatura de indicação do IBP (<5 anos vs >5 anos: 71,4% vs 58,7%, P=0,010) e conhecimento suficiente. Conclusão: Embora a maioria dos participantes prescrevesse IBPs regularmente e para fins de profilaxia, no entanto, não estava familiarizada com estratégias de prescrição e raramente revisava as indicações em andamento. O conhecimento suficiente está correlacionado com revisões recentes da literatura e afiliação à especialidade médica.

Acute hepatitis secondary to febuxostat.

Febuxostat is a drug from the group of xanthine dehydrogenase inhibitors and is used in the treatment of hyperuricemia and gouty arthritis. However, it is not free of adverse effects, including alteration of liver profile tests. This is why we must pay attention to this type of adverse events in case it is necessary to suspend treatment. We present a clinical case of acute hepatitis secondary to Febuxostat.

The Effect of Viloxazine Extended-Release Capsules on Functional Impairments Associated with Attention-Deficit/Hyperactivity Disorder (ADHD) in Children and Adolescents in Four Phase 3 Placebo-Controlled Trials.

PURPOSE: The ADHD Rating Scale (ADHD-RS) assesses 18 symptoms of inattention and hyperactivity/impulsivity and has been used in many clinical trials to evaluate the treatment effect of drugs on ADHD. The fifth edition of this scale (ADHD-RS-5) also assesses the impact of inattention and hyperactivity/impulsivity symptoms on six domains of functional impairment (FI): family relationships, peer relationships, completing/returning homework, academic performance at school, controlling behavior at school, and self-esteem. Here, we report the effect of viloxazine extended-release capsules (viloxazine ER), a novel nonstimulant treatment for ADHD in children and adolescents (ages 6-17 years), on FI from a post hoc analysis of four randomized, double-blind, placebo-controlled Phase 3 clinical trials (N=1354). PATIENTS AND METHODS: ADHD-RS-5 investigator ratings of ADHD symptoms and FIs were conducted at baseline and weekly post-baseline for 6-8 weeks in the four trials. Change from baseline (CFB) in ADHD-RS-5 FI scores (Total score [sum of 12 FI items] and Inattention and Hyperactivity/Impulsivity subscale scores [sum of 6 corresponding FI items]) and the 30% and 50% Responder Rates (ADHD-RS-5 FI Total score) were compared between viloxazine ER and placebo. RESULTS: The reduction (improvement) in ADHD-RS-5 FI scores (Total and subscale scores) and the percentage of responders (30% and 50%) at Week 6 were significantly greater in each viloxazine ER dose group vs placebo. In the 100-400 mg/day viloxazine ER groups, improvements were found as early as Week 1 (100-mg/day) or Week 2 (200-, 400-mg/day) of treatment. Analysis of individual items of ADHD-related FIs demonstrated that the effect of viloxazine ER was observed across all domains of impairment. CONCLUSION: Significant improvements observed in ADHD-related FIs are consistent with the reduction in inattention and hyperactivity/impulsivity symptoms demonstrated in the viloxazine ER Phase 3 pediatric trials. Therefore, viloxazine ER provides clinically meaningful improvement of ADHD symptoms and functioning in children and adolescents with ADHD, starting as early as Week 1-2 of treatment.

El fenómeno de la memoria eléctrica como simulador de isquemia miocárdica

RESUMEN Los trastornos de la repolarización ventricular son manifestaciones comunes de una amplia variedad de situaciones, entre las que se incluye la memoria cardíaca; un fenómeno no reconocido frecuentemente en la práctica diaria. La gravedad de cada una de estas causas es muy variable; sin embargo, el diagnóstico definitivo de cada una de ellas no siempre es evidente. Se presenta el caso de un paciente que acude al servicio de urgencias con dolor torácico y ondas T negativas profundas en el electrocardiograma, que simulan una isquemia miocárdica grave, y que fue definido como memoria eléctrica cardíaca.

ABSTRACT The abnormalities in ventricular repolarization are common manifestations of several conditions, among these, we can include cardiac memory, a frequently unrecognized phenomenon in medical practice. The severity of each of these causes is variable; nonetheless, a definitive diagnosis of each of them is not always evident. We present the case of a patient admitted at the emergency room with chest pain and deeply inverted T waves in the electrocardiogram, mimicking a severe myocardial ischemia, which was defined as cardiac electrical memory.

Evaluating the likelihood to be helped or harmed after treatment with viloxazine extended-release in children and adolescents with attention-deficit/hyperactivity disorder.

AIMS: When clinicians evaluate potential medications for their patients, they must weigh the probability of a treatment's benefits against the possible risks. To this end, the present analyses evaluate the novel nonstimulant viloxazine extended-release (viloxazine ER) using measures of effect size to describe the potential benefits of its treatment in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) as well as the risk of discontinuation because of intolerable adverse events. METHODS: These post hoc analyses use pooled data from four pivotal Phase 3 trials in paediatric patients treated with viloxazine ER. The Likelihood to be Helped or Harmed (LHH) effect size measure was calculated to describe the probability of patients benefiting from treatment vs discontinuing. The Number Needed to Treat (NNT) was calculated from frequently used thresholds of response. The Number Needed to Harm (NNH) was calculated using discontinuations because of adverse events. RESULTS: LHH values for viloxazine ER ranged from 5 to 13, suggesting that subjects were 5-13 times more likely to benefit from, rather than discontinue, viloxazine ER treatment. Specifically, NNT values for viloxazine ER treatment ranged from 6 to 7. NNH values for viloxazine ER treatment ranged from 31 to 74. By convention, single-digit NNTs (<10) suggest the intervention is potentially useful, while NNH values ≥10 for adverse events suggest it is potentially safe or tolerable. CONCLUSIONS: These results indicate that patients with ADHD are likely to benefit from treatment with viloxazine ER, and are unlikely to discontinue, as viloxazine ER treatment was associated with favourable LHH, NNT, and NNH values. Clinicaltrials.gov: NCT03247530, NCT03247543, NCT03247517, NCT03247556.

Effect of Delayed-Release and Extended-Release Methylphenidate on Caregiver Strain and Validation of Psychometric Properties of the Caregiver Strain Questionnaire: Results from a Phase 3 Trial in Children with Attention-Deficit/Hyperactivity Disorder.

Objectives: Inadequately controlled symptoms and associated impaired functioning have a significant negative impact on caregivers of children with attention-deficit/hyperactivity disorder (ADHD). This study aimed to assess the impact of evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH) treatment on caregiver strain, measured by the Caregiver Strain Questionnaire (CGSQ), and present post hoc psychometric analyses assessing the reliability and validity of the CGSQ, its ability to detect change (responsiveness), and to derive responder definitions. Methods: The CGSQ was an exploratory efficacy endpoint in a phase 3, 3-week, randomized, double-blind, multicenter, placebo-controlled, forced-dose titration trial of DR/ER-MPH in children aged 6-12 years with ADHD (NCT02520388). Psychometric properties of the CGSQ evaluated post hoc included internal consistency using Cronbach's alpha; test/retest reliability using intraclass correlation coefficients (ICCs); construct validity (known groups and convergent/divergent validity); responsiveness to changes in assessments of ADHD severity (ADHD Rating Scale-IV [ADHD-RS-IV], Conners' Global Index-Parent [CGI-P], and Clinical Global Impression-Severity [CGI-S]/CGI-Improvement [CGI-I]); and meaningful change threshold (MCT) using receiver operating characteristic curves, which were used to compare response between DR/ER-MPH and placebo groups. Results: Randomized DR/ER-MPH (54.5) and placebo (54.9) groups had similar mean CGSQ scores at screening. Caregivers of children on DR/ER-MPH reported significant reductions in CGSQ scores after 3 weeks of DR/ER-MPH treatment versus placebo (least-squares mean: 41.2 vs. 49.1; p < 0.001). The CGSQ demonstrated strong internal consistency (Cronbach's alpha = 0.93) and good test/retest reliability (ICC = 0.72). Known groups, convergent/divergent validity, and responsiveness were demonstrated from relationships between the CGSQ and the CGI-S, ADHD-RS-IV, and CGI-P. The mean anchor-based MCT for CGSQ total score was estimated as -9.0 (DR/ER-MPH vs. placebo: 53.2% vs. 29.9% p = 0.003). Conclusions: CGSQ scores significantly decreased after 3 weeks of DR/ER-MPH treatment versus placebo, and the CGSQ was found to be a valid and reliable measure of strain in caregivers of children with ADHD. Clinical trial registration identification number: NCT02520388.

Taquicardia incesante del tracto de salida del ventrículo derecho - ¿Taquimiocardiopatía?: El enigma / Incessant right ventricular outflow tract tachycardia - Tachycardiomyopathy? The enigma

RESUMEN Las taquicardias ventriculares de larga duración o incesantes pueden causar insuficiencia cardíaca, disfunción del ventrículo izquierdo y cardiomiopatía, cuadros que revierten una vez resueltas las arritmias. Se trata de un diagnóstico de exclusión: puede existir una cardiopatía de base que empeora con la taquicardia y debe precisarse si la arritmia lleva a la cardiomiopatía (puede existir un subregistro) o viceversa. Se presenta un paciente con taquicardia incesante del tracto de salida del ventrículo derecho, de larga evolución, con repercusión hemodinámica, cardiomiopatía dilatada y disfunción grave del ventrículo izquierdo, rebelde a fármacos antiarrítmicos y con dos ablaciones fallidas, pendiente de biopsia endomiocárdica y nueva ablación de su taquicardia. Se discuten algunas pistas para diferenciar las arritmias del tracto de salida del ventrículo derecho, en sus variantes benignas (las más frecuentes) y malignas. Algunas pistas para diferenciarlas son: la duración del complejo QRS, el intervalo de acoplamiento de la extrasístole y la frecuencia de la taquicardia.

ABSTRACT Long-lasting or incessant ventricular tachycardias may cause heart failure, left ventricular dysfunction, and cardiomyopathy; conditions that reverse once the arrhythmias have been solved. This is a diagnosis of exclusion: there may be a basic heart disease that worsens with the tachycardia and it must be clarified whether the arrhythmia leads to cardiomyopathy (there may be an underregistration) or vice versa. A patient with incessant right ventricular outflow tract tachycardia, with long evolution, hemodynamic repercussion, dilated cardiomyopathy and severe dysfunction of the left ventricle, refractory to antiarrhythmic drugs and with two failed ablations, pending endomyocardial biopsy and new ablation of his tachycardia is presented. Some clues to differentiate right ventricular outflow tract arrhythmias, in their benign (most frequent) and malignant variants, are discussed. Some clues to differentiate them are: the duration of the QRS complex, the coupling interval of premature contractions and the heart rate of the tachycardia.

Terapia de resincronización cardíaca: Índice del QRS como predictor de respuesta / Cardiac resynchronization therapy: QRS index as a response predictor

RESUMEN Introducción: La terapia de resincronización cardíaca (TRC) es indicación en la insuficiencia cardíaca con QRS ancho y disminución grave de la fracción de eyección del ventrículo izquierdo. Objetivos: Definir los predictores de respuesta favorable a la TRC. Método: Se realizó un estudio observacional, descriptivo, retrospectivo, para evaluar el índice del QRS (diferencia entre anchura del QRS antes y después del implante, dividido entre su valor antes del implante, multiplicado por 100) como predictor de respuesta favorable a la TRC. Se realizaron electrocardiogramas antes del procedimiento, a los 6 y a los 12 meses del implante. Las mediciones se hicieron por dos observadores independientes, la primera digital en el monitor del salón de operaciones y el resto manual. Resultados: Se incluyeron 91 pacientes (edad media 61,2 años, 76% hombres), QRS mayor de 120 ms y fracción de eyección menor de 35%. Se obtuvo respuesta favorable en un 59%. No hubo diferencias significativas pre-implante en la duración del QRS entre respondedores y no respondedores (151,3 ms vs 151,34 ms, p=0,98), pero sí post-implante (100 vs 115 ms, p<0,0001), así como en el porcentaje de disminución del QRS (33,2% vs 24,3%, p<0,0001). La curva ROC mostró que un valor de corte del índice de QRS del 30% fue sensible (62%) y específico (75%), para predecir respuesta favorable. Conclusiones: La disminución de la anchura del QRS luego del implante de la TRC se relaciona con una respuesta favorable a la misma.

ABSTRACT Introduction: Cardiac resynchronization therapy (CRT) is an indication in heart failure with wide QRS and severely reduced left ventricular ejection fraction. Objectives: To define the response predictors favorable to CRT. Method: An observational, descriptive, retrospective study was conducted to evaluate the QRS index (difference between the QRS width before and after implantation, divided by its value before implantation, multiplied by 100) as a predictor of favorable response to CRT. Electrocardiograms were performed before the procedure, at 6 and 12 months after implantation. The measurements were made by two independent observers, the first digital on the operating room monitor and the rest manual. Results: A total of 91 patients (mean age 61.2 years, 76% men) were included, with QRS wider than 120 ms and ejection fraction less than 35%. A favorable response was obtained in 59%. There were no significant pre-implant differences in the QRS duration between responders and non-responders (151.3 ms vs. 151.34 ms, p=0.98), but there were differences post-implant (100 vs. 115 ms, p<0.0001), as well as in the QRS percentage of decrease (33.2% vs. 24.3%, p<0.0001). The ROC curve showed that a cut-off value of the QRS index of 30% was sensitive (62%) and specific (75%) in order to predict a favorable response. Conclusions: The decrease in the QRS width after the CRT implant is related to a favorable response to it.

Endocarditis por Pseudomonas spp: Descripción de un caso poco frecuente / Endocarditis caused by Pseudomonas spp: description of a rare case

RESUMEN Las infecciones por los dispositivos cardiovasculares son cada vez más frecuentes. Se presenta el caso de un hombre de 62 años edad con fiebre y toma del estado general, que había sido intervenido hacía siete años para la implantación de un marcapasos. En los complementarios se observaron leucocitosis y hemoglobina por debajo de 10 g/L; y en el ecocardiograma, un electrodo de marcapaso en cavidades derechas con múltiples masas ecodensas que indicaban endocarditis infecciosa. Se realizó extracción quirúrgica del dispositivo y cultivo de muestras de las vegetaciones, con aislamiento de Pseudomonas spp. Se administró terapia antimicrobiana sobre la base del antibiograma y el paciente evolucionó satisfactoriamente. Se debe pensar en esta enfermedad ante todo paciente con marcapasos que presente fiebre y sintomatología general, una vez que se han descartado otros posibles focos de infección; además, se debe actuar rápido para lograr un tratamiento adecuado.

ABSTRACT Infections due to cardiovascular devices are becoming more frequent. Here is presented the case of a 62-year-old male patient with fever and poor general condition, who had been intervened seven years ago for the implantation of a pacemaker. In the blood tests, leukocytosis and hemoglobin below 10 g/L were observed. The echocardiogram showed a pacemaker electrode in the right cavities with multiple echo-dense masses indicating infectious endocarditis. A surgical extraction of the device was performed as well as culture of vegetation samples with the isolation of Pseudomonas spp. An antimicrobial therapy was provided on the basis of the antibiogram, and the patient progressed satisfactorily. This clinical entity should be considered in any patient with a pacemaker who presents fever and general symptoms, once other possible sources of infection are ruled out; in addition to acting quickly in order to achieve an adequate treatment.

A randomized, double-blind, 3-way crossover, analog classroom study of SHP465 mixed amphetamine salts extended-release in adolescents with ADHD.

OBJECTIVES: To evaluate the duration of efficacy, safety, and tolerability of SHP465 mixed amphetamine salts (MAS) extended-release versus placebo and immediate-release MAS (MAS IR) in adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS: This phase 2, randomized, 3-period, 3-treatment crossover study compared SHP465 MAS (25/50 mg) with placebo and MAS IR (12.5 mg) in 13-17-year-old adolescents with ADHD having ADHD Rating Scale, Version IV (ADHD-RS-IV) total scores ≥24. A laboratory classroom served as a controlled environment during 16-hour observations, with efficacy assessed on the last day of each 7-day treatment period. The primary efficacy analysis compared SHP465 MAS with placebo on Permanent Product Measure of Performance (PERMP) total score averaged over the 16-hour postdose period using a mixed linear model. Comparisons were also conducted between MAS IR and placebo (for assay sensitivity) and between SHP465 MAS and MAS IR. PERMP problems attempted and answered correctly and ADHD symptoms based on ADHD-RS-IV; participant self-report; Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale; and Revised Conner's Parent Rating Scale scores were also evaluated. Safety and tolerability assessments included treatment-emergent adverse events and vital signs. RESULTS: The intent-to-treat population included 84 participants. Least squares mean (95% CI) PERMP total score treatment differences significantly favored SHP465 MAS (combined 25/50 mg) over placebo for the average of all postdose assessment time points (41.26 [32.24, 50.29]; P < 0.0001) and each postdose assessment time point (all P < 0.0001). Similar results were observed for MAS IR versus placebo (all postdose assessment time points averaged: nominal P < 0.0001; each postdose assessment time point: all nominal P < 0.004). The safety and tolerability of SHP465 MAS were consistent with previous reports. CONCLUSIONS: SHP465 MAS significantly improved PERMP total scores versus placebo from 2 to 16 hours postdose in adolescents with ADHD. The safety and tolerability profile of SHP465 MAS was consistent with previous reports of SHP465 MAS in individuals with ADHD.

Multiple serial ECGs aid with the diagnosis and prognosis of Brugada syndrome.

BACKGROUND: A spontaneous coved-type ST segment elevation in the electrocardiogram (ECG) has long been recognized as a risk stratification tool in patients with Brugada syndrome (BrS). This Type-I ST segment elevation is known to exhibit high dynamicity, fluctuating between coved-type and non-coved ST segment elevation. Our objectives in this study were to: 1) Compare ECG parameters in patients with spontaneous coved-type (Type-I) vs. non-coved-type ST segment ECGs; 2) Determine the variability of these ECG parameters with repeated measurements; and 3) Assess the predictive value of ECG parameters in these two groups during follow-up. METHODS: Forty-two consecutive patients with BrS and implanted ICD were studied between 2000 and 2017. Serial ECGs and clinical characteristics were obtained over a period of 199 months. RESULTS: QT-interval, QTc-interval, QRS duration, Tp-e interval and Tp-e dispersion were all significantly longer in spontaneous Type I vs. non-Type 1 ECGs and all ECG parameters displayed significant variability during serial recording obtained throughout the follow-up period. Patients with a spontaneous Type I ECG during the 114 ±â€¯56 months follow-up period were at a much higher risk for VT/VF than those without a Type I ECG (p = 0.016). Moreover, the risk for development of life-threatening ventricular arrhythmias was directly related to the fraction of ECGs displaying a spontaneous Type I pattern during follow-up. CONCLUSION: Our study illustrates the need for multiple ECGs to aid with both the diagnosis and prognosis of BrS. Serial ECGs can assist with risk stratification based on the fraction of ECGs that display a spontaneous Type-I BrS ECG.

Efficacy and Safety of HLD200, Delayed-Release and Extended-Release Methylphenidate, in Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Evening-dosed HLD200 is a delayed-release and extended-release methylphenidate (DR/ER-MPH) formulation consisting of uniform, dual-layered microbeads with an inner drug-loaded core. DR/ER-MPH is designed to delay the initial release of drug by 8-10 hours, and thereafter, provide a controlled, extended drug release to target onset of effect upon awakening that lasts into the evening. This phase 3 study evaluated the safety and efficacy of DR/ER-MPH on symptoms and temporal at-home functional impairment in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: This 3-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group, forced-dose titration trial evaluated DR/ER-MPH (40-80 mg/day) in children aged 6-12 years with ADHD. Primary efficacy endpoint was the ADHD rating scale-IV (ADHD-RS-IV), and the key secondary endpoints were the Before-School Functioning Questionnaire (BSFQ), and Parent Rating of Evening and Morning Behavior-Revised, morning (PREMB-R AM) and evening (PREMB-R PM). Safety measures included spontaneously reported treatment-emergent adverse events (TEAEs) and two TEAEs of special interest, appetite suppression and insomnia (with direct questioning on sleep disturbance). RESULTS: One hundred sixty-one participants were included in the intent-to-treat population (DR/ER-MPH, n = 81; placebo, n = 80). After 3 weeks, DR/ER-MPH achieved significant improvements versus placebo in ADHD symptoms (least-squares [LS] mean ADHD-RS-IV: 24.1 vs. 31.2; p = 0.002), and at-home early morning (LS mean BSFQ: 18.7 vs. 28.4; p < 0.001; LS mean PREMB-R AM: 2.1 vs. 3.6; p < 0.001) and late afternoon/evening (LS mean PREMB-R PM: 9.4 vs. 12.2; p = 0.002) functional impairment. Commonly reported TEAEs (≥10%) were insomnia and decreased appetite. CONCLUSIONS: DR/ER-MPH was generally well tolerated and demonstrated significant improvements versus placebo in ADHD symptoms and at-home functional impairments in the early morning, late afternoon, and evening in children with ADHD.