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.

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.

Electrocardiographic Markers of Appropriate Implantable Cardioverter-Defibrillator Therapy in Young People with Congenital Heart Diseases.

Implantable cardioverter-defibrillators (ICDs) are increasingly utilized in patients with congenital heart disease (CHD). Prediction of the occurrence of shocks is important if improved patient selection is desired. The electrocardiogram (ECG) has been the first-line tool predicting the risk of sudden death, but data in CHD patients are lacking. We aim to evaluate the predictive value of electrocardiographic markers of appropriate therapy of ICD in young people with CHD. We conducted a prospective, longitudinal study, in twenty-six CHD patients (mean age 24.7 ± 5.3 years) who underwent first ICD implantation. Forty-two age- and diagnosis-matched controls were recruited. Twelve-lead ECG and 24 h Holter analysis were performed during a mean follow-up of 38.9 months. Data included heart rate, heart rate variability, QRS duration (QRSd), QTc interval and its dispersion, Tpeak-Tend (Tp-Te) interval and its dispersion, presence of fragmented QRS (fQRS), T wave alternans, atrial arrhythmias, and non-sustained ventricular tachycardia. Implant indication was primary prevention in ten cases (38.5%) and secondary prevention in 16 (61.5%). Overall, 17 subjects (65.3%) received at least one appropriate and effective ICD discharge. fQRS was present in 64.7% of cases with ICD therapy compared with patients without events or controls (p < 0.0001). Tp-e and Tp-e dispersion were significantly prolonged in patients with recurrences (113.5 and 37.2 ms) versus patients without ICD discharge (89.6 and 24.1 ms) or controls (72.4 and 19.3 ms) (p < 0.0001 and p < 0.0001, respectively). On univariate Cox regression analysis QRSd (hazard ratio: 1.19 per ms, p = 0.003), QTc dispersion (hazard ratio: 1.57 per ms, p = 0.002), fQRS (hazard ratio: 3.58 p < 0.0001), Tp-e (hazard ratio: 2.27 per ms, p < 0.0001), and Tp-e dispersion (hazard ratio: 4.15 per ms, p < 0.0001), emerged as strong predictors of outcome. On multivariate Cox analysis fQRS, Tp-e and Tp-e dispersion remained in the model. The presence of fQRS, and both Tp-e and Tp-e dispersion are useful ECG tools in daily clinical practice to identify CHD patients at risk for appropriate ICD therapy.

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.

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.

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.

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.

Assessing effects of treatment with lisdexamfetamine dimesylate for pediatric ADHD using a parental survey.

INTRODUCTION: Lisdexamfetamine dimesylate (LDX) is a prodrug stimulant approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in adults and children 6-12 years of age. Parent surveys provide valuable information regarding the impact of ADHD treatments. METHODS: Parents of children with ADHD beginning treatment with LDX voluntarily completed surveys through an automated telephone system or the Internet before and 6 weeks after LDX treatment initiation. Prescribing physicians received individual reports of the responses for each survey completed by their patients' parents. All patients whose parents completed both baseline and 6 week surveys were included in the analyses. Subgroup analyses were conducted for those previously treated with medications to treat ADHD, including mixed amphetamine salts-extended release. RESULTS: LDX treatment was associated with a significant decrease in ADHD symptom interference with school activities, family interactions, homework, and social interactions (P<.01; N=11,576). Parents rated satisfaction with LDX as significantly higher than with their child's previous treatment (P<.01). On average, global improvement, tolerability, convenience, and satisfaction with LDX were all highly rated. CONCLUSION: Patients treated with LDX showed significant symptom improvement and parents reported significantly greater satisfaction than with prior treatment.

Effects of once-daily oral and transdermal methylphenidate on sleep behavior of children with ADHD.

OBJECTIVE: Methylphenidate is a leading first-line treatment for ADHD (AD/HD). This stimulant has long been suspected to adversely affect sleeping patterns of treated individuals, especially children. There are few studies on the effects of recently developed longer-acting methylphenidate treatments, such as once-daily oral or transdermal formulations, on sleep. METHOD: The authors examined eight indices of sleep behavior among children treated with either of these two methylphenidate preparations or placebo in a randomized, double-blind, multicenter, parallel-group study. RESULTS: The main predictor of sleep problems was baseline numbers or severity of preexisting sleep problems, whereas the different treatments and placebo varied little in their propensity to elicit such problems. There was no significant relationship between dosage and severity or frequency of sleep problems. CONCLUSION: The authors found little evidence that methylphenidate treatment (at least in sustained-release forms) was a significant cause of sleep problems in treated children who were carefully titrated to an optimal dose.

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.

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.

A randomized, double-blind, crossover study of once-daily dexmethylphenidate in children with attention-deficit hyperactivity disorder: rapid onset of effect.

BACKGROUND: Long-acting methylphenidate formulations provide control of attention-deficit hyperactivity disorder (ADHD) symptoms for up to 12 hours; however, not all formulations have rapid onset of therapeutic effect, which is essential for providing symptom control during morning hours. The primary objective of this randomized, double-blind, crossover study was to assess the efficacy of dexmethylphenidate extended release (ER) versus placebo by measuring the change from pre-dose to 0.5 hours post-dose on the Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) rating scale. METHODS: Eighty-six children (6-12 years) with ADHD diagnosed using the DSM-IV criteria were randomized to receive dexmethylphenidate ER 20 mg/day or placebo, sequentially, for 7 days, with the final dose administered in a laboratory classroom setting on day 7 of each treatment period. The primary efficacy comparison was change in the SKAMP-Combined score from pre-dose to 0.5 hours post-dose, with additional secondary assessments at 1, 2, 4, 6 and 8 hours post-dose. Secondary efficacy measures included change from pre-dose at all timepoints in the SKAMP-Attention and SKAMP-Deportment, Math Test-Attempted and Math Test-Correct scores, and change from baseline on the Conners' ADHD/DSM-IV Scale for Parents (CADS-P). In an exploratory analysis, a daily diary card was completed by parents on the children's in-home behaviour before school. Safety was assessed by occurrence of adverse events, monitoring of vital signs and interpretation of ECGs. RESULTS: Significant improvements were noted at 0.5 hours and at all timepoints post-dose throughout the 8-hour laboratory classroom day for dexmethylphenidate ER vs placebo in the primary outcome measure of the SKAMP-Combined scores (p < 0.001), as well as SKAMP-Attention, SKAMP-Deportment, Math Test-Attempted and Math Test-Correct scores (p < 0.05). The changes from baseline in CADS-P scores were significantly greater with dexmethylphenidate ER than placebo (-16.382 vs -4.622; p < 0.001). Responses to all diary questions indicated significant improvement with dexmethylphenidate ER treatment versus placebo (all p < 0.001). The most common adverse events were abdominal pain (dexmethylphenidate ER 3.5%; placebo 4.7%), headache (dexmethylphenidate ER 3.5%; placebo 2.3%) and increased appetite (dexmethylphenidate ER 0%; placebo 3.5%). CONCLUSION: Compared with placebo, once-daily dexmethylphenidate ER 20 mg provided rapid and significant improvement at 0.5 hours post-dose in attention, deportment and academic performance, which was sustained for 8 hours post-dose. Overall, once-daily dexmethylphenidate ER 20 mg was well tolerated. In an analysis of parental assessment of diary responses, children appeared more organized, and morning preparation for school was smoother and less frustrating with once-daily dexmethylphenidate ER compared with placebo.

Lisdexamfetamine dimesylate and mixed amphetamine salts extended-release in children with ADHD: a double-blind, placebo-controlled, crossover analog classroom study.

BACKGROUND: Lisdexamfetamine dimesylate is a therapeutically inactive prodrug in which d-amphetamine is covalently bound to l-lysine, a naturally occurring amino acid. Pharmacologically active d-amphetamine is released from lisdexamfetamine following oral ingestion. METHODS: This phase 2, randomized, double-blind, placebo- and active-controlled crossover study compared the efficacy and safety of lisdexamfetamine (LDX: 30, 50, or 70 mg) with placebo, with mixed amphetamine salts extended-release (MAS XR: 10, 20, or 30 mg) included as a reference arm of the study, in 52 children aged 6 to 12 years with attention-deficit/hyperactivity disorder (ADHD) in an analog classroom setting. The primary efficacy measure was the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale; secondary efficacy measures included the Permanent Product Measure of Performance (PERMP) Derived Measures, and the Clinical Global Impression (CGI) Scale. RESULTS: LDX treatment significantly improved scores on SKAMP-deportment, SKAMP-attention, PERMP-attempted, PERMP-correct, and CGI-improvement from baseline. Adverse events were similar for both active treatments. CONCLUSIONS: In a laboratory classroom environment, LDX significantly improved ADHD symptoms versus placebo in school-age children with ADHD.

Atomoxetine treatment for pediatric patients with attention-deficit/hyperactivity disorder with comorbid anxiety disorder.

OBJECTIVE: Research suggests 25% to 35% of children with attention-deficit/hyperactivity disorder (ADHD) have comorbid anxiety disorders. This double-blind study compared atomoxetine with placebo for treating pediatric ADHD with comorbid anxiety, as measured by the ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-PI) and the Pediatric Anxiety Rating Scale (PARS). METHOD: Patients (ages 8-17 years) meeting DSM-IV criteria for ADHD and generalized anxiety disorder, separation anxiety disorder, and/or social phobia were randomized to 12 weeks of atomoxetine (n = 87) or placebo (n = 89). ADHDRS-IV-PI and PARS total scores were analyzed using analysis of covariance last observation carried forward and repeated-measures analyses. RESULTS: Sixty-six patients in each group completed the study. Mean ADHDRS-IV-PI total score improved significantly for atomoxetine (n = 55; -10.5, SD 10.6) relative to placebo (n = 58; -1.4, SD 8.3; p < .001). Mean PARS total score also improved significantly for atomoxetine (n = 55; -5.5, SD 4.8) relative to placebo (n = 58; -3.2, SD 5.0; p = .011). CONCLUSIONS: Atomoxetine was efficacious in reducing ADHD symptoms in patients who have ADHD with comorbid anxiety and was well tolerated. There was also a significant reduction in independently assessed anxiety symptoms using both clinician-rated and self-rated measures, which merits further investigation. Results support consideration of atomoxetine for the treatment of ADHD in youths who have ADHD with comorbid anxiety disorder. CLINICAL TRIAL REGISTRATION INFORMATION: The LYBP study, on which this article is based, was not registered at clinicaltrials.gov because the last patient visit occurred before July 1, 2005. Results, however, are publicly posted at lillytrials.com and clinicalstudyresults.org. The unique study ID at both sites is 6477a.

ADHD Symptom Rebound and Emotional Lability With Lisdexamfetamine Dimesylate in Children Aged 6 to 12 Years.

OBJECTIVE: To describe symptom rebound in children with ADHD treated with lisdexamfetamine dimesylate (LDX) or placebo. METHOD: During a 4-week, randomized, double-blind, placebo-controlled trial of LDX, parents/caregivers completed the Conners' Parent Rating Scale-Revised: Short Form symptom rating scale throughout the day. Response, rebound, and emotional lability (EL) were assessed post hoc based on predefined criteria. RESULTS: Most participants given LDX ( n = 207) were responders throughout the day (50.7%-55.6%) versus placebo ( n = 72; 11.1%-22.2%). A total of seven (3.4%) LDX participants showed rebound in the afternoon and/or evening versus seven (9.7%) with placebo. In both groups, most incidences of rebound occurred in the evening. EL (mean) was higher in LDX rebounders and nonresponders (range = 4.2-9.0) versus LDX responders (range = 1.3-1.6) and versus placebo rebounders (range = 0.7-1.9). CONCLUSION: ADHD symptom rebound occurred in few participants (3.3%) given LDX (accompanied by clinically significant EL). Overall, more participants given LDX versus placebo responded throughout the day.

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.

A comparison of once-daily and divided doses of modafinil in children with attention-deficit/hyperactivity disorder: a randomized, double-blind, and placebo-controlled study.

OBJECTIVE: This randomized, double-blind, placebo-controlled study assessed the efficacy and tolerability of several modafinil dosing regimens in children with attention-deficit/hyperactivity disorder (ADHD) to determine whether modafinil can be given once daily in pediatric ADHD. METHOD: Children and adolescents (age range, 6-13 years) (N = 248) with DSM-IV-defined ADHD were enrolled in a 4-week, double-blind, placebo-controlled study, conducted February-May 2002. The group was assigned to receive oral (100-mg tablets) modafinil 300 mg once daily (300 mg in the morning followed by placebo at midday), modafinil 300 mg as a divided dose (100/200 mg or 200/100 mg), or matching placebo. In children weighing > or = 30 kg, a higher dose of 400 mg (200/200 mg) was evaluated. Efficacy measures included the teacher-rated School Version and clinician-rated Home Version of the ADHD Rating Scale-IV and the parent-completed Conners' ADHD/DSM-IV Scales. RESULTS: 223 children completed the study. Those who received modafinil 300 mg once daily showed a significantly greater improvement (change from baseline) than those who received placebo in symptoms of ADHD across all rating scales and subscales (all p < .05). Divided 300-mg doses of modafinil provided some significant but inconsistent improvements in ADHD symptoms. In children weighing > or = 30 kg, modafinil 400 mg (200/200 mg) was significantly superior to placebo on clinician- and parent-completed scales (all p < .05). Insomnia was the only adverse event to occur with significantly greater frequency in a modafinil group (200/100) than in the placebo group (14% vs. 2%) (p = .03). CONCLUSION: Modafinil significantly improved ADHD symptoms in children. Once-daily dosing (300 mg) provided the most consistent improvement in symptoms. All dosing regimens of modafinil were well tolerated.