In-situ monitoring of in vitro drug release processes in tablets using optical coherence tomography.

Film-coated modified-release tablets are an important dosage form amenable to targeted, controlled, or delayed drug release in the specific region of the gastrointestinal (GI) tract. Depending on the film composition and interaction with the GI fluid, such coated products can modulate the local bioavailability, systemic absorption, protection as an enteric barrier, etc. Although the interaction of a dosage form with the surrounding dissolution medium is vital for the resulting release behavior, the underlying physicochemical phenomena at the film and core levels occurring during the drug release process have not yet been well described. In this work, we attempted to tackle this limitation by introducing a novel in vitro test based on optical coherence tomography (OCT) that allows an in-situ investigation of the sub-surface processes occurring during the drug release. Using a commercially available tablet based on osmotic-controlled release oral delivery systems (OROS), we demonstrated the performance of the presented prototype in terms of monitoring the membrane thickness and thickness variability, the surface roughness, the core swelling behavior, and the porosity of the core matrix throughout the in vitro drug release process from OROS. The superior spatial (micron scale) and temporal (less than 10 ms between the subsequent tomograms) resolution achieved in the proposed setup provides an improved understanding of the dynamics inside the microstructure at any given time during the dissolution procedure with the previously unattainable resolution, offering new opportunities for the design and testing of patient-centric dosage forms.

Dose titration of osmotic release oral system methylphenidate in children and adolescents with attention-deficit hyperactivity disorder: a retrospective cohort study.

BACKGROUND: Osmotic release oral system methylphenidate (OROS-MPH) is one of the most commonly used medication for attention-deficit hyperactivity disorder (ADHD), however, real-world knowledge on OROS-MPH dose titration has been limited. This study aims to summarize and visualise the OROS-MPH titration patterns in children and adolescents with ADHD in the United States (US) and Japan. METHODS: This retrospective cohort study used the US IBM® MarketScan® Commercial Claims and Encounters database from 2000 to 2019 and the Japan Medical Data Centre database from 2008 to 2019. New OROS-MPH users with ADHD were identified and split into child (6 to < 13 years) and adolescent (13 to < 18 years) groups according to age at OROS-MPH initiation/reinitiation. Patient characteristics and OROS-MPH treatment patterns were described. OROS-MPH dose titration pathways were visualised by Sankey diagrams. RESULTS: We included 98,973 children and 62,002 adolescents in the US cohort, and 4595 children and 1508 adolescents in the Japanese cohort. In Japanese cohort, 91.9% of children and 77.9% of adolescents initiated OROS-MPH at the lowest dose (18 mg/day), whereas US patients had a broader distribution of initial doses (e.g., 18-54 mg/day). The US patients had higher daily dose of OROS-MPH than Japanese patients. Overall, a minority (< 40%) of the OROS-MPH users underwent dose titration, and different titration patterns were observed between the US and Japanese patients. CONCLUSIONS: Different treatment and titration patterns of OROS-MPH were observed in the two countries. Additional real-world studies about clinical reasoning underlying dose selection are needed to support clinical decision-making.

Comparison between Atomoxetine and OROS Methylphenidate as an Adjunctive to SSRIs in Attention-deficit/Hyperactivity Disorder Adults with Comorbid Partially Responsive Major Depressive Disorder: A Head-to-head, 12-week, Randomized, Rater-blinded Clinical Trial.

OBJECTIVE: This study aimed to compare the efficacy and safety of atomoxetine (ATX) and OROS methylphenidate (MPH) as adjunctive to selective serotonin reuptake inhibitors (SSRIs) in adults with attention-deficit hyperactivity disorder (ADHD) with comorbid partially responsive major depressive disorder (MDD). METHODS: Sixty Korean adults with ADHD and comorbid partially responsive MDD were recruited in a 12-week, randomized, rater-blinded, active-controlled trial and were evenly randomized to ATX or OROS MPH treatment. RESULTS: Depressive symptoms measured using the Hamilton Depression Rating Scale and Clinically Useful Depression Outcome Scale, and ADHD symptoms measured using the Adult ADHD Self-Report Scale, as well as the Clinical Global Impression-Severity, Clinical Global Impression-Improvement, and the Sheehan Disability Scale scores were significantly improved in both groups during the 12 weeks of treatment. The changes in all outcome measures during the 12-week treatment were not significantly different between the two groups (all p > 0.05). No serious adverse events were reported and there were no significant differences in systolic and diastolic blood pressure, pulse rate, weight, or body mass index between the ATX and MPH groups. CONCLUSION: Our findings suggest that ATX and MPH can be used as adjunctive treatments in adults with ADHD and comorbid partially responsive MDD. The efficacy and tolerability of ATX and MPH in adults with ADHD did not differ significantly. Further studies should be conducted to draw a definitive conclusion.

Reversible Alopecia Secondary to OROS Methylphenidate. / Alopecia reversible secundaria a metilfenidato OROS.

INTRODUCTION: Attention deficit hyperactivity disorder has a prevalence of 1-4% of the Spanish school population. Its treatment consists of giving amphetamine derivatives and, recently, non-stimulant drugs, without finding any differences in efficacy in the studies performed. CLINICAL CASE: A 7-year-old girl was referred from neurology due to learning delay and behaviour disorders. Diagnosed as likely ADHD, treatment was started with immediate release methylphenidate, and later with an osmotic release oral system (OROS) methylphenidate. When alopecia areata appeared, this treatment was withdrawn. After the re-introduction of modified release methylphenidate 30:70, symptom control was achieved without the appearance of alopecia. DISCUSSION: There is a published history of two cases of alopecia areata with OROS methylphenidate that resolved after increasing the dose of the drug without clearly knowing the reason for this event. There is no consensus on the priority use of the immediate release formula or the OROS methylphenidate.

Alopecia reversible secundaria a metilfenidato OROS / Reversible Alopecia Secondary to OROS Methylphenidate

RESUMEN Introducción: El TDAH tiene una prevalencia del 1-4% de la población escolar española. Su tratamiento se realiza con derivados anfetamínicos y, recientemente, con fármacos no esti mulantes; los estudios realizados no han encontrado diferencias de eficacia. Caso clínico: Niña de 7 arios llegó derivada desde neurología por retraso en el aprendizaje y trastornos de conducta. Orientada como TDAH, se inició tratamiento con metilfenidato de liberación inmediata y posteriormente con la fórmula OROS; apareció alopecia areata y se retiró el tratamiento. Tras la reintroducción de metilfenidato de liberación modificada 30:70, se consiguió controlar los síntomas sin que apareciera alopecia. Discusión: Hay antecedentes publicados de 2 casos de alopecia areata con metilfenidato OROS, que se resolvieron tras el aumento de dosis del fármaco, aunque no se conoce clara mente el motivo de este suceso. No hay consenso sobre el uso prioritario de la fórmula de liberación inmediata o la fórmula OROS del metilfenidato.

ABSTRACT Introduction: Attention deficit hyperactivity disorder has a prevalence of 1-4% of the Spanish school population. Its treatment consists of giving amphetamine derivatives and, recently, non-stimulant drugs, without finding any differences in efficacy in the studies performed. Clinical case: A 7-year-old girl was referred from neurology due to learning delay and behaviour disorders. Diagnosed as likely ADHD, treatment was started with immediate release methylphenidate, and later with an osmotic release oral system (OROS) methylphenidate. When alopecia areata appeared, this treatment was withdrawn. After the re-introduction of modified release methylphenidate 30:70, symptom control was achieved without the appearance of alopecia. Discussion: There is a published history of two cases of alopecia areata with OROS methylp henidate that resolved after increasing the dose of the drug without clearly knowing the reason for this event. There is no consensus on the priority use of the immediate release formula or the OROS methylphenidate.

Randomised controlled trial of the short-term effects of OROS-methylphenidate on ADHD symptoms and behavioural outcomes in young male prisoners with attention-deficit/hyperactivity disorder (CIAO-II).

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.

Genetic imaging study with [Tc-99m] TRODAT-1 SPECT in adolescents with ADHD using OROS-methylphenidate.

AIM: To examine theeffects on the brain of 2-month treatment withamethylphenidate extended-release formulation (OROS-MPH) using [Tc-99m] TRODAT-1SPECT in a sample of treatment-naïve adolescents with Attention Deficit/Hyperactivity Disorder (ADHD). In addition, to assess whether risk alleles (homozygosity for 10-repeat allele at the DAT1 gene were associated with alterations in striatal DAT availability. METHODS: Twenty adolescents with ADHD underwent brain single-photon emission computed tomography (SPECT) scans with [Tc-99m] TRODAT-1 at baseline and two months after starting OROS-MPH treatment with dosages up to 1 mg/kg/day. Severity of illness was estimated using the Clinical Global Impression Scale (CGI-S) and DuPaul ADHD Rating Scale-Clinician version (ARS) before treatment,1 month and 2 months after initiating OROS-MPH treatment. RESULTS: Decreased DAT availability was found in both the right caudate (pretreatment DAT binding: 224.76 ±â€¯33.77, post-treatment DAT binding: 208.86 ±â€¯28.75, p = 0.02) and right putamen (pre-treatment DAT binding: 314.41 ±â€¯55.24, post-treatment DAT binding: 285.66 ±â€¯39.20, p = 0.05) in adolescents with ADHD receiving OROS-MPH treatment. Adolescents with ADHD who showed a robust response to OROS-MPH (n = 7) had significantly greater reduction of DAT density in the right putamen than adolescents who showed less robust response to OROS-MPH (n = 13) (p = 0.02). However, between-group differences by treatment responses were not related with DAT density in the right caudate. Risk alleles (homozygosity for the 10-repeat allele of DAT1 gene) in the DAT1 gene were not associated with alterations in striatal DAT availability. CONCLUSION: Two months of OROS-MPH treatment decreased DAT availability in both the right caudate and putamen. Adolescents with ADHD who showed a robust response to OROS-MPH had greater reduction of DAT density in the right putamen. However,our findings did not support an association between homozygosity for a 10-repeat allele in the DAT1 gene and DAT density, assessedusing[Tc-99m] TRODAT-1SPECT.

Effects of maternal symptom ratings and other clinical features on short-term treatment response to OROS methylphenidate in children and adolescents with ADHD in a naturalistic clinical setting.

OBJECTIVE: To investigate the effect of Attention Deficit Hyperactivity Disorder (ADHD), antisocial behavior and anxiety/depression ratings of mothers, and child and adolescents' age, gender, ADHD subtype, and comorbidity on one-month drug treatment response to OROS methylphenidate in ADHD in a naturalistic setting. METHODS: The analyses included 223 subjects (191 boys, 32 girls; age 6-15 years, mean: 9.4) treated with OROS methylphenidate (18-72 mg/day, mean: 31 mg/d; 0.4-1.4 mg/kg/d) for one-month. Treatment response was defined as larger than 25% or more decrease in pre-treatment the Conners Parent Rating Scale (CPRS) or the Conners Teacher Rating Scale (CTRS) total scores and the Clinical Global Impression improvement with drug treatment 3 (minimally improved) or higher. Maternal ADHD, antisocial behavior and anxiety/depression ratings were obtained by the Adult Self Rating (ASR). Logistic regression analyses were computed in order to calculate the effects of gender; age; ADHD subtype; comorbid anxiety disorder, learning disorder, oppositional defiant/conduct disorder; maternal ASR Anxiety/Depression, ADHD and Antisocial scores. RESULTS: 35.2% of subjects had statistically significant 25% or more decrease in pretreatment CPRS total scores and 38.6% of subjects had statistically significant 25% or more decrease in pretreatment CTRS total scores. The subjects with comorbid anxiety disorder had the poorest drug response. Maternal self-reported antisocial and anxiety/depressive symptomatology were statistically significantly associated with worse response to treatment in terms of CPRS (respectively, OR=0.83, 95% CI: 0.75-0.92, p<0.01; OR=0.95, 95% CI: 0.9-0.99, p<0.05) and CTRS total scores (OR=0.9, 95% CI: 0.82-0.99, OR=0.95, 95% CI: 0.91-1, p<0.05). Baseline rating scores were also important predictors of drug treatment response. Effects of age, gender and maternal ADHD were not statistically significant. CONCLUSION: ADHD children and adolescents with comorbid anxiety disorders and those whose mothers have more self-reports of antisocial and depressive symptoms showed less favorable short-term response to OROS-MPH. These subjects may require further attention and additional interventions to augment treatment with OROS methylphenidate.

Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin.

A new minimal Segmented Transit and Absorption model (mSAT) model has been recently proposed and combined with intrinsic intestinal effective permeability (P eff,int ) to predict the regional gastrointestinal (GI) absorption (f abs ) of several drugs. Herein, this model was extended and applied for the prediction of oral bioavailability and pharmacokinetics of oxybutynin and its enantiomers to provide a mechanistic explanation of the higher relative bioavailability observed for oxybutynin's modified-release OROS® formulation compared to its immediate-release (IR) counterpart. The expansion of the model involved the incorporation of mechanistic equations for the prediction of release, transit, dissolution, permeation and first-pass metabolism. The predicted pharmacokinetics of oxybutynin enantiomers after oral administration for both the IR and OROS® formulations were in close agreement with the observed data. The predicted absolute bioavailability for the IR formulation was within 5% of the observed value, and the model adequately predicted the higher relative bioavailability observed for the OROS® formulation vs. the IR counterpart. From the model predictions, it can be noticed that the higher bioavailability observed for the OROS® formulation was mainly attributable to differences in the intestinal availability (F G ) rather than due to a higher colonic f abs , thus confirming previous hypotheses. The predicted f abs was almost 70% lower for the OROS® formulation compared to the IR formulation, whereas the F G was almost eightfold higher than in the IR formulation. These results provide further support to the hypothesis of an increased F G as the main factor responsible for the higher bioavailability of oxybutynin's OROS® formulation vs. the IR.

Not All Generic Concerta Is Created Equal: Comparison of OROS Versus Non-OROS for the Treatment of ADHD.

Treatment effectiveness between equivalent doses of non-OROS (osmotic controlled release oral delivery system) methylphenidate ER and OROS methylphenidate ER (brand name Concerta) was examined in a clinical case series of children and adolescents followed for treatment of attention-deficit/hyperactivity disorder (ADHD). The Conners-Third Edition: Parent Rating Scale was used to compare ADHD symptoms when patients were taking non-OROS versus OROS at follow-up visits. A repeated-measures mixed-model approach was used to compare treatment effectiveness. The entire sample (N = 14) demonstrated a reduction in the mean score on the Inattention Scale from clinically significant (T-score > 65) to not clinically significant (T-score < 65) when patients were changed from non-OROS to OROS at the same dosage (mean T-score reduction = 23, p < .0001). The reduction in mean T-score after changing from non-OROS to OROS at the same dosage is indicative of improvement in symptoms of ADHD. Results provide empirical support for US Food and Drug Administration concerns regarding the therapeutic equivalence of non-OROS versus OROS for the treatment of ADHD.

Relationship between soluble intercellular adhesion molecules and attention-deficit/hyperactivity disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-oneset psychiatric disease, characterized by excessive overactivity, inattention, and impulsiveness. In recent studies, it is emphasized that inflammation may have a role in ADHD. In this study, we aimed to investigate whether there are associations between ADHD and serum levels of soluble intercellular adhesion molecules (s-ICAMs) which have important role in inflammatory diseases. We also measured the levels of these molecules after treatment with oros-methylphenidate. METHODS: Twenty-five patients diagnosed with ADHD according to Diagnostic and Statistical Manual of Mental Disorders-IV-TR criteria and 18 healthy volunteer controls were included in this study. The levels of sICAMs were measured in the serum of the patients and healthy volunteers by ELISA kit as described. RESULTS: The levels of sICAM-1 and sICAM-2 were significantly higher in patients compared with controls. The level of sICAM-2 was decreased significantly in group treated with oros-methylphenidate. CONCLUSIONS: This is the first study pointing out the relationship between sICAMs and ADHD. The changes in sICAM-2 level may have a role in the effect mechanism of oros-methylphenidate, used for the treatment of ADHD.

The clinical profile of children with ADHD that require OROS-methylphenidate combined with shorter-acting formulations.

Long-acting methylphenidate (MPH) formulations, including OROS-MPH, were found to be effective in alleviating ADHD symptoms throughout the day. However, sustained stimulant activity may lead to prolonged suppression of appetite and insomnia. In this study, we characterized the clinical profile of children and adolescents for whom a once-daily lower dose of OROS-MPH combined with a shorter-acting agent was more tolerable than single higher OROS-MPH dose. In our cohort of 128 children treated with OROS-MPH, 47 (36.7 %) better tolerated a lower dose of OROS-MPH combined with short-acting MPH formulations (Group I). Nevertheless, for the majority (81 patients-63.3 %), a standard single moderate dose of OROS-MPH was sufficient (Group II). The mean daily doses of MPH were: 0.83 ± 0.21 mg/kg for Group I and 1.06 ± 0.29 mg/kg for Group II. There were no significant differences in the prevalence of learning disorders, tic disorders, epilepsy and conduct disorders between these two groups. However, anxiety and marginally depression were more prevalent in Group I (46.8 and 9.7 %) than in Group II (27.2 and 1.2 %). Patients in Group I were also more tending to receive psychotherapy than patients in Group II.

Clinical Usefulness of Hydromorphone-OROS in Improving Sleep Disturbances in Korean Cancer Patients: A Multicenter, Prospective, Open-Label Study.

PURPOSE: To evaluate the efficacy of hydromorphone-OROS (HM-OROS) in reducing sleep disturbance and relieving cancer pain. MATERIALS AND METHODS: One hundred twenty cancer patients with pain (numeric rating scale [NRS] ≥ 4) and sleep disturbance (NRS ≥ 4) were evaluated. The initial HM-OROS dosing was based on previous opioid dose (HM-OROS:oral morphine=1:5). Dose adjustment of the study drug was permitted at the investigator's discretion. Pain intensity, number of breakthrough pain episodes, and quality of sleep were evaluated. RESULTS: A total of 120 patients received at least one dose of HM-OROS; 74 of them completed the final assessment. Compared to the previous opioids, HM-OROS reduced the average pain NRS from 5.3 to 4.1 (p < 0.01), worst pain NRS from 6.7 to 5.4 (p < 0.01), sleep disturbance NRS from 5.9 to 4.1 (p < 0.01), incidence of breakthrough pain at night from 2.63 to 1.53 times (p < 0.001), and immediate-release opioids use for the management of breakthrough pain from 0.83 to 0.39 times per night (p = 0.001). Of the 74 patients who completed the treatment, 83.7% indicated that they preferred HM-OROS to the previous medication. The adverse events (AEs) were somnolence, asthenia, constipation, dizziness, and nausea. CONCLUSION: HM-OROS was efficacious in reducing cancer pain and associated sleep disturbances. The AEs were manageable.

Evaluation of critical process parameters for inter-tablet coating uniformity of active-coated GITS using Terahertz Pulsed Imaging.

The aim of this study was the evaluation of critical process parameters (CPP) for inter-tablet coating uniformity in an active pan coating process using nondestructive Terahertz Pulsed Imaging (TPI). Coating uniformity was assessed by calculating the coefficient of variation (CV) of coating thickness measured by TPI, and the CV of API content measured by high performance liquid chromatography (HPLC). A design of experiments (DoE) was performed at pilot scale with drum load, drum speed, spray rate, run duration and spray pressure as factors. Good agreement in the CV of both analytical techniques was shown. The DoE models both revealed the same CPP: a low drum load, high drum speed, low spray rate and high run duration were beneficial for coating uniformity. The spray pressure was only significant in one of the DoE models. It was further shown that the negative impact of a high drum load on the CV cannot only be compensated by high drum speed, but also be compensated by a low spray rate and long run duration. It was demonstrated that TPI is a feasible tool for the measurement of inter-tablet coating uniformity and for the evaluation of CPP in an active pan coating process.

The effect of UGT2B7*2 polymorphism on the pharmacokinetics of OROS® hydromorphone in Taiwanese subjects.

This open-label, single-center, phase I study (NCT1487564) investigated the effect of uridine diphosphate-glucuronosyltransferase2B7 (UGT2B7*2) genetic polymorphism (H268Y) on the pharmacokinetics (PK) and safety of a single, oral, 16-mg dose of OROS® hydromorphone and its metabolite in healthy Taiwanese subjects. Plasma concentrations of hydromorphone and hydromorphone-3-glucuronide were determined in 28 subjects. PK parameters calculated included maximum plasma concentration (Cmax); time to reach maximum plasma concentration (tmax); area under plasma concentration-time curve from 0-48 hours (AUC0-48 h) and 0-infinite time (AUC∞); and hydromorphone-3-glucuronide:hydromorphone metabolic ratio (RM). Mean plasma concentrations of hydromorphone and hydromorphone-3-glucuronide reached a maximum between 12-18 hours and 18-21 hours, respectively. No clear trend in PK parameters and no clinically significant differences in the incidence of treatment-emergent adverse events (TEAEs) were observed among different UGT2B7 genotypes. Our study found UGT2B7 polymorphism had no apparent effect on PK of OROS® hydromorphone; hydromorphone was well tolerated in pain-free volunteers when coadministered with naltrexone.

OROS-methylphenidate efficacy on specific executive functioning deficits in adults with ADHD: a randomized, placebo-controlled cross-over study.

Attention-deficit/hyperactivity disorder (ADHD) is linked to impaired executive functioning (EF). This is the first study to objectively investigate the effects of a long-acting methylphenidate on neurocognitive test performance of adults with ADHD. Twenty-two adults with ADHD participated in a 6-weeks study examining the effect of osmotic-release oral system methylphenidate (OROS-mph) on continuous performance tests (CPTs; objective measures), and on the self-reported ADHD rating scale (subjective measure) using a randomized, double-blind, placebo-controlled cross-over design. OROS-mph significantly improved reaction time variability (RTV), commission errors (CE) and d-prime (DP) as compared to baseline (Cohen's d>.50), but did not affect hit reaction time (HRT) or omission errors (OE). Compared to placebo, OROS-mph only significantly influenced RTV on one of two CPTs (p<.050). Linear regression analyses showed predictive ability of more beneficial OROS-mph effects in ADHD patients with higher EF severity (RTV: ß=.670, t=2.097, p=.042; omission errors (OE): ß=-.098, t=-4.759, p<.001), and with more severe ADHD symptoms (RTV: F=6.363, p=.019; HRT: F=3.914, p=.061). Side effects rates were substantially but non-significantly greater for OROS-mph compared to placebo (77% vs. 46%, p=.063). OROS-mph effects indicated RTV as the most sensitive parameter for measuring both neuropsychological and behavioral deficits in adults with ADHD. These findings suggest RTV as an endophenotypic parameter for ADHD symptomatology, and propose CPTs as an objective method for monitoring methylphenidate titration.

Methylphenidate in children with ADHD with or without learning disability.

OBJECTIVE: To explore treatment response to Osmotic Release Oral System(®) (OROS) methylphenidate in children with ADHD with and without comorbid learning disability (LD). METHOD: Data were analyzed from two 6-week, double-blind, randomized, placebo-controlled, crossover studies evaluating individually determined doses of OROS methylphenidate versus placebo in 135 children (ages 9 to 12 years) with ADHD with or without an LD in reading, math, or both. The sample was demographically diverse, with 31% females and more than 40% minority, predominantly African American and Hispanic. On two laboratory school days, participants received either OROS methylphenidate or placebo and were given a battery of cognitive and behavioral tests. RESULTS: Treatment with OROS methylphenidate led to improvement in ADHD Rating Scale scores for participants with or without comorbid LD. Both groups performed better during treatment with OROS methylphenidate than placebo on measures of cognitive skills (i.e., Test of Variables of Attention, Finger Windows Backwards), academically related tasks (i.e., Dynamic Indicators of Basic Early Literacy Skills, Test of Handwriting Skills-Revised, Permanent Product Math Test), and observed classroom behavior (i.e., Swanson, Kotkin, Alger, M-Flynn, and Pelham Scale). CONCLUSION: In children with ADHD with or without comorbid LD, behavior and performance improved during treatment with OROS methylphenidate.

Treatment Adherence of Osmotic-Controlled Release Oral Delivery System Methylphenidate in Korean Children and Adolescents with Attention-Deficit Hyperactivity Disorder

OBJECTIVES: The objective of this study was to evaluate the treatment duration and adherence of osmotic-controlled release oral delivery system (OROS) methylphenidate for treatment of attention-deficit hyperactivity disorder (ADHD). METHODS: A total of 843 children with ADHD were recruited : 213 children (25.3%) who had previously taken medications for ADHD and 630 drug-naive children (74.7%) were recruited. The dosage was adjusted according to the clinician's judgment. The primary efficacy endpoint of this study was treatment retention rate, which was estimated at Week 12 and Week 20 using the Kaplan-Meier curve. The Swanson, Nolan and Pelham-IV (SNAP-IV), Clinical Global Impression-Severity (CGI-S), Clinical Global Impression-Improvement, and the side effect rating scale were measured at every visit. Remission rates were presented based on SNAP-IV and CGI-S, respectively. RESULTS: The treatment retention rate at 12 weeks and at 20 weeks was 76.2% and 66.8%, respectively. Divided according to 6-8, 9-11, 12-14 and 15-18 years of age, younger children tended to show a statistically higher treatment retention rate (p=.02). Based on SNAP-IV and CGI scores, children with better response to medication showed tendencies of statistically higher treatment retention rate. The most common adverse events included loss of appetite (7.1%) and insomnia (3.3%). There was no serious adverse event related to the treatment, such as death. CONCLUSION: The use of OROS methylphenidate for treatment of ADHD was safe and tolerable for children. In this study, lower age and better treatment response showed a statistically significant relationship with higher treatment adherence. Boys showed a trend of high treatment adherence. The treatment adherence at 20 weeks was satisfactory, however, the treatment adherence after 20 weeks showed a sharp decrease. Therefore, treatment persistence for six months after the beginning of ADHD treatment is important. In addition, the positive role of psycho-education for children and parents is necessary for increasing treatment adherence.

Clinical Usefulness of Hydromorphone-OROS in Improving Sleep Disturbances in Korean Cancer Patients: A Multicenter, Prospective, Open-Label Study / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: To evaluate the efficacy of hydromorphone-OROS (HM-OROS) in reducing sleep disturbance and relieving cancer pain. MATERIALS AND METHODS: One hundred twenty cancer patients with pain (numeric rating scale [NRS] > or = 4) and sleep disturbance (NRS > or = 4) were evaluated. The initial HM-OROS dosing was based on previous opioid dose (HM-OROS:oral morphine=1:5). Dose adjustment of the study drug was permitted at the investigator\'s discretion. Pain intensity, number of breakthrough pain episodes, and quality of sleep were evaluated. RESULTS: A total of 120 patients received at least one dose of HM-OROS; 74 of them completed the final assessment. Compared to the previous opioids, HM-OROS reduced the average pain NRS from 5.3 to 4.1 (p < 0.01), worst pain NRS from 6.7 to 5.4 (p < 0.01), sleep disturbance NRS from 5.9 to 4.1 (p < 0.01), incidence of breakthrough pain at night from 2.63 to 1.53 times (p < 0.001), and immediate-release opioids use for the management of breakthrough pain from 0.83 to 0.39 times per night (p = 0.001). Of the 74 patients who completed the treatment, 83.7% indicated that they preferred HM-OROS to the previous medication. The adverse events (AEs) were somnolence, asthenia, constipation, dizziness, and nausea. CONCLUSION: HM-OROS was efficacious in reducing cancer pain and associated sleep disturbances. The AEs were manageable.

Association of Norepinephrine Transporter Gene and Side Effects of Osmotic-Release Oral System Methylphenidate in Attention-Deficit Hyperactivity Disorder

OBJECTIVES: The aim of our study was to investigate association of norepinephrine transporter gene (SLC6A2) polymorphism and side effects of osmotic-release oral system methylphenidate (OROS MPH) in children with attention-deficit hyperactivity disorder (ADHD). METHODS: We recruited drug naive children with ADHD (N=97). We administered OROS MPH by tolerable dosage. At week 8 of treatment, parents completed the Barkley's side effect rating scale. We analyzed two SLC6A2 single nucleotide polymorphisms (SNPs), rs192303 and rs3785143, with blood of subjects. We compared the frequency and severity of each side effect among SLC6A2 genotypes of 2 SNPs. RESULTS: In the analysis of frequency of each side effect, irritability differed according to rs192303 and rs3785143 genotype. In comparisons of severity, talking less and disinterest differed according to rs192303 genotype. In the case of rs3785143, severities of disinterest and irritability were involved with genotype. CONCLUSION: Side effects of OROS MPH showed an association with SLC6A2 genotype.