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Frontiers in Psychiatry 2023Sleep-related problems are common in children with attention-deficit/hyperactivity disorder (ADHD). Sleep disorders are also side effects of all stimulant ADHD...
INTRODUCTION
Sleep-related problems are common in children with attention-deficit/hyperactivity disorder (ADHD). Sleep disorders are also side effects of all stimulant ADHD medications. Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) is a once-daily treatment approved for patients age 6 years and older with ADHD. In this analysis, sleep behavior was assessed during SDX/d-MPH treatment in children with ADHD.
METHODS
In a 12-month, dose-optimized, open-label safety study in 6- to 12-year-old participants (NCT03460652), a secondary endpoint was assessment of sleep behavior based on the Children's Sleep Habits Questionnaire (CSHQ) consisting of 8 sleep domains (bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night wakings, parasomnias, sleep-disordered breathing, and daytime sleepiness). This analysis examined the individual sleep domains in the 12-month safety study.
RESULTS
Of 282 participants enrolled, 238 were included in the sleep analysis. At baseline, mean (SD) CSHQ total sleep disturbance score was 53.4 (5.9). After 1 month of treatment, the mean (SD) CSHQ total score significantly decreased to 50.5 (5.4); least-squares mean change from baseline was -2.9 (95% CI: -3.5 to -2.4; < 0.0001) and remained decreased up to 12 months. Mean sleep-score improvements from baseline to 12 months were statistically significant ( < 0.0001) for 5 of 8 sleep domains, including bedtime resistance, sleep anxiety, night wakings, parasomnias, and daytime sleepiness. Parasomnias and daytime sleepiness sleep domains showed the greatest mean improvement from baseline to 12 months. Sleep onset delay and sleep duration scores increased from baseline to 12 months. No statistically significant worsening occurred from baseline in sleep duration and sleep-disordered breathing domains; however, worsening of sleep onset delay was statistically significant.
CONCLUSION
In this analysis of children taking SDX/d-MPH for ADHD, sleep problems did not worsen based on the mean CSHQ total sleep disturbance score. Statistically significant improvements in most CSHQ sleep domains were observed after 1 month and lasted for up to 12 months of treatment.
PubMed: 37426086
DOI: 10.3389/fpsyt.2023.1193455 -
BMC Chemistry Jul 2023Two Chromatographic methods have been established and optimized for simultaneous determination of serdexmethylphenidate (SER.DMP) and dexmethylphenidate (DMP) in the...
Chromatographic reversed HPLC and TLC-densitometry methods for simultaneous determination of serdexmethylphenidate and dexmethylphenidate in presence of their degradation products-with computational assessment.
Two Chromatographic methods have been established and optimized for simultaneous determination of serdexmethylphenidate (SER.DMP) and dexmethylphenidate (DMP) in the presence of their degradation products. The first method is a reversed phase high performance liquid chromatography with diode array detection (HPLC-DAD). Isocratic separation was carried out on Waters X-bridge Shield RP column (150×3.9×5 μm particle size) using a mixture of 5 mM phosphate buffer (pH 5.5): acetonitrile (40:60, v/v) as a mobile phase, flow rate 1 mL/min and detection at 220 nm. The second method is a thin-layer chromatography (TLC)-densitometry method using methanol: chloroform (70:30, v/v) as a mobile phase and UV scanning at 220 nm. In HPLC method, the linearity range of SER.DMP was (2.5-25 μg/mL); with LOD (0.051 μg/mL) and LOQ (0.165 μg/mL) while for DMP was (2.5-25 μg/mL); with LOD and LOQ of (0.098 μg/mL) and (0.186 μg/mL), respectively. For TLC method the sensitivity range of SER.DMP was (5-25 μg/mL), LOD was (0.184 μg/spot), while LOQ was (0.202 μg/ spot) whereas for DMP the sensitivity range was (5-25 μg/mL) with LOD of (0.115 μg/ spot) and LOQ of (0.237 μg/ spot), respectively. SER.DMP was found to be equally labile to acidic and alkaline hydrolysis, whereas DMP was sensitive to acidic hydrolysis only. Both drugs were successfully determined in presence of acidic and basic degradants by the two developed methods (stability indicating assay method). Chromatographic separation of the degradation products was carried out on TLC aluminum silica plates 60 F254, as a stationary phase, using methanol: dichloroethane: acetonitrile (60:20:20 v/v), as a mobile phase. The degradation pathway was confirmed using TLC, IR, H-NMR and mass spectroscopy; moreover, the separation power was correlated to the computational results by applying molecular dynamic simulation. The developed methods were validated according to the International Conference on Harmonization (ICH) guidelines demonstrating good accuracy and precision. They were successfully applied for quantitation of SER.DMP and DMP in pure and capsule forms. The results were statistically compared with those obtained by the reported method in terms of accuracy, precision and robustness, and no significant difference was found.
PubMed: 37454105
DOI: 10.1186/s13065-023-00986-3 -
Frontiers in Pharmacology 2023Methylphenidate, atomoxetine, and Amphetamine are the three most commonly used medications approved by the United States Food and Drug Administration (FDA) for the...
Safety profiles of methylphenidate, amphetamine, and atomoxetine: analysis of spontaneous reports submitted to the food and drug administration adverse event reporting system.
Methylphenidate, atomoxetine, and Amphetamine are the three most commonly used medications approved by the United States Food and Drug Administration (FDA) for the treatment of attention deficit/hyperactivity disorder (ADHD). However, a comprehensive analysis of their safety profiles across various age groups and genders in real-world contexts has yet to be conducted. In this study, a pharmacovigilance analysis was performed using the FDA Adverse Event Reporting System (FAERS) database to examine differences in adverse events between methylphenidate, atomoxetine, and Amphetamine. From January 2014 to September 2022, FAERS reports listing "Methylphenidate," "Dexmethylphenidate," "Atomoxetine," "Amphetamine," "Lisdexamfetamine," "Dextroamphetamine," and "Methamphetamine" as primary suspects were analyzed after removing duplicate reports. We used the standardized Medical Dictionary for Regulatory Activities (MedDRA) query generalized search for adverse events at the preferred term level based on case reports. After filtering duplicate reports, disproportionality analysis was used to detect safety signals according to the proportional reporting ratio (PRR). In order to delve into potential safety concerns, we undertook a two-step analysis of the data. Initially, the data was segmented based on age cohorts: 0-5 years, 6-12 years, 13-18 years, and individuals aged ≥19 years. Following this, after partitioning the data into males and females within the 0-18 years age group, and similarly for those aged ≥19 years, further analysis was conducted. The pharmacovigilance analysis uncovered substantial safety signals in the standardized MedDRA queries. Methylphenidate was associated with dyskinesia (PRR = 21.15), myocardial infarction (PRR = 12.32), and hypertension (PRR = 8.95) in children aged 0-5, 6-12, and 13-18 years, respectively, as well as neonatal exposures via breast milk (PRR = 14.10) in adults aged ≥19 years. Atomoxetine was linked to hostility/aggression (PRR = 15.77), taste and smell disorders (PRR = 6.75), and hostility/aggression (PRR = 6.74) in children aged 0-5, 6-12, and 13-18 years, respectively, as well as hostility/aggression (PRR = 14.00) in adults aged ≥19 years. Amphetamine was associated with psychosis and psychotic disorders (PRR = 16.78), hostility/aggression (PRR = 4.39), and Other ischaemic heart disease (PRR = 10.77) in children aged 0-5 years, 6-12 years, and 13-18 years, respectively, and hostility/aggression in adults aged ≥19 years (PRR = 9.16). Significant and noteworthy adverse event signals were also identified at the preferred term level. Specifically, methylphenidate was associated with myocardial infarction, acute myocardial infarction, coronary artery dissection, electrocardiogram QT prolonged, growth retardation, self-destructive behavior, suicidal ideation, and completed suicide. Atomoxetine was linked to electrocardiogram QT prolonged, growth retardation, and tic. Amphetamine was recorded for coronary artery dissection, suicidal ideation, and completed suicide. It was observed that male patients, including both children and adults, showed a more significant and frequent occurrence of adverse events compared to females, particularly in terms of cardiac disorders. The intensity and quantity of adverse event signals were distinctly different between the two genders, with males having a higher number of signals. All detected safety signals were confirmed using signals obtained from the disproportionality analysis. This pharmacovigilance analysis demonstrated significant variations in the safety profiles of methylphenidate, atomoxetine, and Amphetamine across different age groups and between different genders. Following an in-depth analysis of the FAERS database, we discerned prominent safety signals. Notably, the strength of the signals associated with coronary artery dissection induced by methylphenidate and amphetamine, as well as those related to suicide, demand particular attention. Consequently, it remains imperative to persist in monitoring these medications, assessing the associated risks, and carrying out comparative studies particularly geared towards ADHD drugs.
PubMed: 37645441
DOI: 10.3389/fphar.2023.1208456 -
Frontiers in Psychiatry 2024To evaluate treatment responder rate using the Attention-Deficit/Hyperactivity Disorder Rating Scale-5 (ADHD-RS-5) score based on optimized dose level of...
OBJECTIVE
To evaluate treatment responder rate using the Attention-Deficit/Hyperactivity Disorder Rating Scale-5 (ADHD-RS-5) score based on optimized dose level of serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) and changes in ADHD severity in children (aged 6-12 years) with ADHD.
METHODS
During a 21-day dose-optimization phase, 155 patients initiated treatment with 39.2/7.8 mg SDX/d-MPH in the first week and then were titrated to an optimum dose; 5 patients were downtitrated to 26.1/5.2 mg, 76 were uptitrated to 52.3/10.4 mg, and 69 remained at 39.2/7.8 mg during the following 2 weeks. Responder threshold values were 30% and 50% based on the percent change from baseline (day 0) to days 7, 14, and 21 in the ADHD-RS-5 score. The Conners 3rd Edition-Parent score was used to assess weekly changes in ADHD severity during the dose-optimization and treatment phases.
RESULTS
Of the 5 subjects whose dose was optimized at 26.1/5.2 mg, ≥80% across all days had ≥50% responder rate. Of the 69 subjects whose dose was optimized at 39.2/7.8 mg, 81.2% had ≥50% responder rate by day 21. Of the 76 subjects whose dose was optimized to 52.3/10.4 mg, 72.4% had ≥50% responder rate by day 21. Changes in ADHD severity, based on mean Conners 3rd Edition-Parent scores, improved from baseline at each visit during dose optimization for each subscale. At the dose-optimization phase, Conners 3rd Edition-Parent scores improved from baseline for SDX/d-MPH in all subscales.
CONCLUSION
A high percentage of subjects were responders upon reaching their final optimized dose. SDX/d-MPH demonstrated significant reductions in ADHD severity in children based on the Conners 3rd Edition-Parent scores. Determining the optimal dosage of SDX/d-MPH and its effect on ADHD severity could enable the development of a more clinically relevant treatment regimen in children with ADHD.
PubMed: 38566957
DOI: 10.3389/fpsyt.2024.1310483