Removing barriers to accessing medical cannabis for paediatric patients.

Medical cannabis (MC) may offer therapeutic benefits for children with complex neurological conditions and chronic diseases. In Canada, parents, and caregivers frequently report encountering barriers when accessing MC for their children. These include negative preconceived notions about risks and benefits, challenges connecting with a knowledgeable healthcare provider (HCP), the high cost of MC products, and navigating MC product shortages. In this manuscript, we explore several of these barriers and provide recommendations to decision-makers to enable a family-centered and evidence-based approach to MC medicine and research for children.

Survival outcomes in endometrial cancer patients according to diabetes: a systematic review and meta-analysis.

BACKGROUND: Diabetes is an established risk factor for endometrial cancer development but its impact on prognosis is unclear and epidemiological studies to date have produced inconsistent results. We aimed to conduct the first systematic review and meta-analysis to compare survival outcomes in endometrial cancer patients with and without pre-existing diabetes. METHODS: We conducted a systematic search of MEDLINE, EMBASE and Web of Science databases up to February 2022 for observational studies that investigated the association between pre-existing diabetes and cancer-specific survival in endometrial cancer patients. Secondary outcomes included overall survival and progression or recurrence-free survival. Quality assessment of included studies was undertaken using the Newcastle-Ottawa Scale and a random-effects model was used to produce pooled hazard ratios (HRs) and 95% confidence intervals (CIs). (PROSPERO 2020 CRD42020196088). RESULTS: In total, 31 studies were identified comprising 55,475 endometrial cancer patients. Pooled results suggested a worse cancer-specific survival in patients with compared to patients without diabetes (n = 17 studies, HR 1.15, 95% CI 1.00-1.32, I2 = 62%). Similar results were observed for progression or recurrence-free survival (n = 6 studies, HR 1.23, 95% CI 1.02-1.47, I2 = 0%) and for overall survival (n = 24 studies, HR 1.42, 95% CI 1.31-1.54, I2 = 46%). CONCLUSION: In this systematic review and meta-analysis, we show that diabetes is associated with a worse cancer-specific and overall survival in endometrial cancer patients.

Factors associated with interobserver variation amongst pathologists in the diagnosis of endometrial hyperplasia: A systematic review.

OBJECTIVE: Reproducible diagnoses of endometrial hyperplasia (EH) remains challenging and has potential implications for patient management. This systematic review aimed to identify pathologist-specific factors associated with interobserver variation in the diagnosis and reporting of EH. METHODS: Three electronic databases, namely MEDLINE, Embase and Web of Science, were searched from 1st January 2000 to 25th March 2023, using relevant key words and subject headings. Eligible studies reported on pathologist-specific factors or working practices influencing interobserver variation in the diagnosis of EH, using either the World Health Organisation (WHO) 2014 or 2020 classification or the endometrioid intraepithelial neoplasia (EIN) classification system. Quality assessment was undertaken using the QUADAS-2 tool, and findings were narratively synthesised. RESULTS: Eight studies were identified. Interobserver variation was shown to be significant even amongst specialist gynaecological pathologists in most studies. Few studies investigated pathologist-specific characteristics, but pathologists were shown to have different diagnostic styles, with some more likely to under-diagnose and others likely to over-diagnose EH. Some novel working practices were identified, such as grading the "degree" of nuclear atypia and the incorporation of objective methods of diagnosis such as semi-automated quantitative image analysis/deep learning models. CONCLUSIONS: This review highlighted the impact of pathologist-specific factors and working practices in the accurate diagnosis of EH, although few studies have been conducted. Further research is warranted in the development of more objective criteria that could improve reproducibility in EH diagnostic reporting, as well as determining the applicability of novel methods such as grading the degree of nuclear atypia in clinical settings.

Cannabis for the Treatment of Attention Deficit Hyperactivity Disorder: A Report of 3 Cases.

Attention deficit hyperactivity disorder (ADHD) is a chronic neurobehavioral disorder that is highly prevalent in children and adults. An increasing number of patients with ADHD are self-medicating with cannabis, despite a lack of evidence on efficacy and safety. This case report describes 3 males (ages 18, 22, and 23) who have integrated cannabis into their treatment regimen with positive results. Semistructured interviews conducted with the patients describe subjective improvements in symptoms and on quality of life. Improvements on validated rating scales conducted post-cannabis initiation, compared to pre-cannabis initiation obtained from the medical chart, corroborated their personal accounts. Scores on the PHQ-9 (measuring depression) improved by 8-22 points (30-81%), and the SCARED (measuring anxiety) ranged from 0 to 27 points (up to 33%). Improvements on the CEER-9 scale (measuring regulation) ranged from 2 to 7 points (22-78%), and the 9-item SNAP scale (measuring inattention) showed improvements of 2-8 points (7-30%). Mild adverse events including short-term memory problems, dry mouth, and sleepiness were reported. Blood samples were also collected from the patients to determine the plasma concentrations of the cannabinoids and relevant metabolites before and after a cannabis administration. After cannabis use, the plasma levels for CBD and THC ranged from 0 to 15.29 ng/mL and 1.32 to 13.76 ng/mL, respectively. Cannabinoids, however, were not detected prior to dosing, suggesting that cannabis played a complimentary role in the therapeutic regimen of these 3 patients. Clinical trials are recommended to confirm the efficacy of cannabis in the treatment of ADHD.

Latent inhibition, aberrant salience, and schizotypy traits in cannabis users.

Aberrant salience processing may underlie the link between cannabis and psychosis, as posited in individuals with schizophrenia or high schizotypy. We investigated the relative effects of cannabis use, schizotypy status, and self-reported aberrant salience experiences on salience processing, measured using a latent inhibition (LI) task (Granger et al., 2016), in a non-clinical population. A university sample of 346 participants completed the Schizotypal Personality Questionnaire (SPQ), Aberrant Salience Inventory (ASI) the modified Cannabis Experience Questionnaire (CEQmv) and the LI task. Regression models and parallel (Bayesian and frequentist) t-tests or ANOVA (or non-parametric equivalents) examined differences in LI based on lifetime or current cannabis use (frequent use during previous year), as well as frequency of use. Mann-Whitney U tests assessed differences in SPQ and ASI scores based on current cannabis use. Neither lifetime nor current cannabis use was associated with significant change in LI scores. Current cannabis use was associated with both higher 'Disorganised' and 'Cognitive-perceptual' SPQ dimension scores and higher total and sub-scale ASI scores. No association was observed between LI score and SPQ total and dimension scores. Higher scores on 'Senses sharpening' and the 'Heightened cognition' ASI subscales predicted decreased LI scores. These data support previous findings of no association between cannabis use and abnormality in other associative learning tasks in young non-clinical populations, and elaborate the previously demonstrated association between self-reported cannabis use, schizotypy and aberrant salience. The association between dimensions of ASI and LI performance suggests this task may have potential as an experimental measure of aberrant salience.

Pharmacokinetics and Perceptions of Children and Young Adults Using Cannabis for Attention-Deficit/Hyperactivity Disorder and Oppositional Defiant Disorder: Protocol for a Mixed Methods Proof-of-Concept Study.

BACKGROUND: Despite the lack of evidence on the use of cannabis for the treatment of attention-deficit/hyperactivity disorder (ADHD), the growing perception that cannabis is safe has led more patients and caregivers to self-medicate. Some psychiatrists now authorize medicinal cannabis for patients with ADHD with features of oppositional defiant disorder (ODD) to curtail the unregulated (ie, self-medicated) use of recreational cannabis or to offer a therapeutic option to those who continue to experience symptoms after exhausting all other treatment options. OBJECTIVE: This protocol aims to explore the perceived effectiveness and pharmacokinetics of cannabis in youth and young adults, who are currently taking it as part of their treatment plan for ADHD with features of ODD, under the supervision of a psychiatrist. METHODS: Patients between the ages of 12 and 25 years with a diagnosis of ADHD and features of ODD, who are currently taking cannabis herbal extract (at a Δ9-tetrahydrocannabinol [THC]:cannabidiol [CBD] ratio of 1:20) as a treatment adjunct to stimulant pharmacotherapy will be recruited. A sample size of 10-20 individuals is estimated. The study interview will consist of (1) validated symptom rating scales (Swanson, Nolan, and Pelham-IV Questionnaire [SNAP-IV], 90-item; Patient Health Questionnaire, 9-item [PHQ-9]; and Screen for Child Anxiety Related Emotional Disorders [SCARED] tool to measure symptoms of ADHD and ODD, depression, and anxiety, respectively); (2) a semistructured interview to probe the experiences of using cannabis; and (3) a cannabis side effects survey. A cannabis product sample as well as 2 blood samples (a trough level and 2-hour postdose level) will be collected to measure plasma concentrations of cannabinoids and relevant metabolites (THC, CBD, 11-hydroxy-THC, 7-hydroxy-CBD, cannabichromene, and 11-nor-9-carboxy-THB) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Self-report rating scales (SNAP-IV, SCARED, and PHQ-9) will be scored in accordance with standard protocols and compared to retrospective scores obtained from the participant's chart. Demographic variables (age, weight, and race), symptom scores, and blood levels (peaks and troughs) of THC, CBD, cannabichromene (CBC), and metabolites will be summarized using descriptive statistics. Relationships between plasma concentrations and symptom scores will be determined using analysis of variance, and multiple regression analysis will be performed to determine associations between plasma concentrations and demographic variables (age, weight, and ethnicity). The qualitative data will be audio-recorded and transcribed and organized into themes. RESULTS: The protocol was approved by the Biomedical Research Ethics Board at the University of Saskatchewan (protocol #1726), and recruitment began in May 2021. CONCLUSIONS: This proof-of-concept study will explore the potential treatment effectiveness of medical cannabis in participants with ADHD and ODD through a mixed methods approach to inform future research in this area. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31281.

A Measure of Emotional Regulation and Irritability in Children and Adolescents: The Clinical Evaluation of Emotional Regulation-9.

Objective: To develop a scale for emotional regulation using item response theory. Method: Eighteen Swanson Nolan and Pelham (SNAP-IV) items that loaded on an emotional dysregulation factor were submitted to Rasch analysis. After eliminating the items that violated Rasch criteria, the remaining items were examined for reliability and validated against the Conners' emotional lability index. Results: A nine-item scale for emotional regulation was developed that satisfies the Rasch model and reliably distinguishes emotionally dysregulated/irritable children and adolescents. A score of 4 or higher in this scale has optimal accuracy for identifying children and adolescents with current significant dysfunction in emotional regulation. Among youth with ADHD inattentive, hyperactive-impulsive, and combined types, 42%, 56%, and 71% met the Clinical Evaluation of Emotional Regulation-9 (CEER-9) threshold for emotional lability, respectively. Conclusion: A nine-item scale whose sum total is a measure of emotional regulation is proposed as a tool for clinical and research purposes.

Concurrent and future risk of endometrial cancer in women with endometrial hyperplasia: A systematic review and meta-analysis.

BACKGROUND: To inform treatment decisions in women diagnosed with endometrial hyperplasia, quantification of the potential for concurrent endometrial cancer and the future risk of progression to cancer is required. METHODS: We identified studies up to September 2018 that reported on the prevalence of concurrent cancer (within three months of endometrial hyperplasia diagnosis), or the incidence of cancer, identified at least three months after hyperplasia diagnosis. Random-effects meta-analyses produced pooled estimates and 95% confidence intervals (CIs). RESULTS: A total of 36 articles were identified; 15 investigating concurrent and 21 progression to cancer. In pooled analysis of 11 studies of atypical hyperplasia, the pooled prevalence of concurrent endometrial cancer was 32.6% (95% CI: 24.1%, 42.4%) while no studies evaluated concurrent cancer in non-atypical hyperplasia. The risk of progression to cancer was high in atypical hyperplasia (n = 5 studies, annual incidence rate = 8.2%, 95% CI 3.9%, 17.3%) and only one study reported on non-atypical hyperplasia (annual incidence rate = 2.6%, 95% CI: 0.6%, 10.6%). CONCLUSIONS: Overall, a third of women with atypical hyperplasia had concurrent endometrial cancer, although the number of studies, especially population-based, is small. Progression to cancer in atypical hyperplasia was high, but few studies were identified. Population-based estimates are required, in both atypical and non-atypical hyperplasia patients to better inform treatment strategies.

Single-dose pharmacokinetics of multilayer-release methylphenidate and immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder.

The objective of this study was to compare the single-dose pharmacokinetics of multilayer-release and immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder. Patients 6- to 12-years-old with a DSM-IV diagnosis of attention-deficit/hyperactivity disorder were randomized to receive multilayer-release methylphenidate (qd) or immediate-release methylphenidate (bid) at equivalent doses, with a 14-day washout between treatments. Plasma samples were collected predosing and 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours postdose. Pharmacokinetic analysis was conducted on 14 patients (1 female, 13 male; mean age: 9.6 +/- 2.5 years [range, 6-12]). The mean dose of methylphenidate received by these patients in both phases of the study was 38.6 mg/d (range, 20-80 mg/d). The relative AUC(0-t) and C(max 0-4) ratios for multilayer-release compared with immediate-release methylphenidate were 100.8% and 78.8%, respectively. Multilayer-release methylphenidate produces a biphasic concentration-time profile, with a rapid initial increase in plasma concentration that is maintained throughout the school day.

Once-daily multilayer-release methylphenidate in a double-blind, crossover comparison to immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: The purpose of this study was to evaluate the comparative efficacy and safety of a novel long-duration multilayer-release (MLR) methylphenidate (MPH) formulation and immediate-release (IR) MPH in attention-deficit/hyperactivity disorder (ADHD) children. PATIENTS AND METHODS: This study was a randomized, double-blind, crossover comparison of once-daily MLR and twice-daily IR-MPH in home and school settings in children with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnosis of ADHD. Patients completed a 1-week baseline followed by two active medication titration phases. Each phase of treatment was 1-4 weeks of titration with an additional stable dose week. The final dose was based on efficacy and adverse events for each patient. Efficacy measures included Clinical Global Impressions (CGI) and Conners' Parent and Teacher Rating Scales (CPRS and CTRS). The Clinical Assessment of Side Effects (CASE) scale assessed frequency of adverse events. RESULTS: Of the 90 enrolled patients, aged 6.4-17.5 years, 79 (88%) completed the study. Stable daily doses were 32.0 and 32.5 mg for MLR and IR-MPH, respectively. All efficacy parameters were significantly improved from baseline. A total of 73.2% and 81.0% of patients on MLR and IR-MPH were rated as "much" or "very much improved" on the CGI. A total of 77.4% and 81.1% of patients were normalized on the CPRS-R and 78.9 and 90.4% of patients were normalized on the CTRS-R for MLR and IR-MPH, respectively. The mean CASE score was not different from baseline for either treatment.

Oppositional Defiant Disorder Is Better Conceptualized as a Disorder of Emotional Regulation.

OBJECTIVE: It has been reported that Oppositional Defiant Disorder (ODD) can be differentiated into distinct subtypes associated with different outcomes in adulthood. We examined whether ODD is conceptually independent and coherent, and whether ODD and Conduct Disorder (CD) are expressions of the same core deficit. METHOD: The data come from a sample of 4,380 children for whom SNAP rating scales were available. Parallel analysis was performed on the eight-item ODD diagnostic items and on the SNAP-90 scale. These were factor analyzed and the components were correlated. RESULTS: ODD has one underlying factor, whereas the parent-rated SNAP has nine underlying factors. ODD items grouped together with emotional lability and irritability items, which did not group with CD. Confirmatory factor analysis supported the separation of ODD and CD but not ODD and emotion dysregulation. CONCLUSION: The expanded ODD factor more likely captures a disorder of emotion regulation, rather than a disruptive behavior disorder.

Vaginal Hysterectomy using the ERBE BiClamp® Bipolar Vessel Sealing System: A Case Series.

The ERBE BiClamp® BVSS appears to be a safe and effective method of vaginal hysterectomy in this small single surgeon, single institution study; demonstrating efficient operative times, minimal blood loss and intraoperative morbidity with acceptable surgical outcomes. Its use contributes to the advancement of minimally invasive gynaecology and should be encouraged.

Remission versus response as the goal of therapy in ADHD: a new standard for the field?

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) has a substantial negative impact; however, within long-term follow-up studies, a proportion of patients do very well, both symptomatically and functionally, suggesting that the lower the symptom burden, the greater the functional improvements. Studies in major depressive disorder have identified a relationship between symptomatic remission and restoration of normal functioning. OBJECTIVE: The purpose of this article was to propose a definition of remission in ADHD, review remission rates in clinical trials for commonly used medications, and explore the relationship between symptomatic remission and optimal functioning. METHODS: Remission and response rates for medications were obtained through MEDLINE searches of English-language citations (1999-2005) and meeting abstracts (2003-2005) using the terms amphetamine, atomoxetine, methylphenidate, ADHD, efficacy, effectiveness, and controlled trial, as well as hand searches of efficacy studies. Evidence from randomized controlled trials, as well as effectiveness studies, where the proportions of patients achieving predefined cutoff points for remission or response are reported, was reviewed. Because higher remission rates were identified with the oral, osmotic, controlled-release system (OROS) of methylphenidate, a relationship between symptomatic response/remission and optimal functioning was explored further. RESULTS: Remission in ADHD should be defined as a loss of diagnostic status, minimal or no symptoms, and optimal functioning when individuals are being treated with or without medication. Symptomatic remission can be operationalized as a mean total score of S1 on most standardized questionnaires. For the medications examined (OROS methylphenidate, immediate-release methylphenidate, atomoxetine, and mixed amphetamine salts), response rates were comparable at approximately 70% to 75%; however, remission rates were higher with OROS methylphenidate compared with either immediate-release methylphenidate or atomoxetine (remission rates with amphetamines were not found). Benefits, including decreased illness burden as well as improved psychosocial and academic functioning, were associated with treatment versus no treatment and were greater with medication that offered higher remission rates. CONCLUSIONS: The literature provided evidence that greater symptom improvements are associated with greater functional improvements, emphasizing that remission of ADHD as defined should be the goal of therapy. Treatment ought to include the early use of strategies with the greatest chance of achieving remission. Future clinical research should use remission as the primary outcome.

The practice of conscious sedation by Senior Dental Surgeons in the Health Board Dental Service in the Republic of Ireland.

OBJECTIVE: To establish the nature and extent of the practice of conscious sedation by Senior Dental Surgeons in the Health Board Dental Service (HBDS) in the Republic of Ireland and to determine the barriers to the use of conscious sedation. DESIGN: Postal questionnaire survey. SETTING: The Health Board Dental Service in the Republic of Ireland in 2002. SUBJECTS AND MATERIALS: Questionnaires were sent to fifty-five Senior Dental Surgeons working in the HBDS. RESULTS: Fifty questionnaires (90.9%) were returned. Less than a quarter of Senior Dental Surgeons reported current sedation use in their area. Oral sedation was the most commonly used method with few using relative analgesia and less using intravenous sedation. Forty percent of Senior Dental Surgeons surveyed reported receiving training in conscious sedation as an undergraduate. Nearly 60% of those surveyed reported using conscious sedation in a previous employment. All respondents said the main barrier to the use of conscious sedation in the HBDS was the lack of training opportunities on the subject in Ireland. CONCLUSIONS: Conscious sedation techniques other than oral, are used to a very limited extent in the HBDS in Ireland. There is great interest amongst Senior Dental Surgeons in the increased use of conscious sedation techniques. A lack of training opportunities is the main barrier to the expansion of their use.

Canadian Rural/Remote Primary Care Physicians Perspectives on Child/Adolescent Mental Health Care Service Delivery.

INTRODUCTION: Primary Care Physicians (PCP) play a key role in the recognition and management of child/adolescent mental health struggles. In rural and under-serviced areas of Canada, there is a gap between child/adolescent mental health needs and service provision. METHODS: From a Canadian national needs assessment survey, PCPs' narrative comments were examined using quantitative and qualitative approaches. Using the phenomenological method, individual comments were drawn upon to illustrate the themes that emerged. These themes were further analyzed using chi-square to identify significant differences in the frequency in which they were reported. RESULTS: Out of 909 PCPs completing the survey, 39.38% (n = 358) wrote comments. Major themes that emerged were: 1) psychiatrist access, including issues such as long waiting lists, no child/adolescent psychiatrists available, no direct access to child/adolescent psychiatrists; 2) poor communication/continuity, need for more systemized/transparent referral processes, and need to rely on adult psychiatrists; and, 3) referral of patients to other mental health professionals such as paediatricians, psychologists, and social workers. CONCLUSIONS: Concerns that emerged across sites primarily revolved around lack of access to care and systems issues that interfere with effective service delivery. These concerns suggest potential opportunities for future improvement of service delivery. IMPLICATIONS: Although the survey only had one comment box located at the end, PCPs wrote their comments throughout the survey. Further research focusing on PCPs' expressed written concerns may give further insight into child/adolescent mental health care service delivery systems. A comparative study targeting urban versus rural regions in Canada may provide further valuable insights.

INTRODUCTION: Les médecins de soins de première ligne (MSPL) jouent un rôle essentiel dans la reconnaissance et la prise en charge des problèmes de santé mentale des enfants/adolescents. Dans les régions rurales et sous-desservies du Canada, il y a un écart entre les besoins de santé mentale des enfants/adolescents et la prestation de services. MÉTHODES: Tirés d'un sondage canadien national évaluant les besoins, les commentaires narratifs des MSPL ont été examinés à l'aide d'approches quantitatives et qualitatives. Au moyen de la méthode phénoménologique, les commentaires individuels ont servi à illustrer les thèmes dégagés. Ces thèmes ont ensuite été analysés avec le chi-carré afin d'identifier les différences significatives de la fréquence à laquelle ils étaient mentionnés. RÉSULTATS: Sur les 909 MSPL qui ont répondu au sondage, 39,38% (n = 358) ont écrit des commentaires. Les thèmes majeurs qui se sont dégagés étaient: 1) l'accès aux psychiatres, notamment des questions comme les longues listes d'attente, pas de pédopsychiatres disponibles, pas d'accès direct aux pédopsychiatres; 2) mauvaise communication/continuité, besoin de processus plus nombreux d'aiguillage systémique/transparent, et besoin de consulter des psychiatres pour adultes; 3) adresser les patients à d'autres professionnels de la santé comme les pédiatres, les psychologues et les travailleurs sociaux. CONCLUSIONS: Les préoccupations soulevées dans les divers centres s'articulaient autour de l'accès aux soins et des problèmes des systèmes qui empiètent sur la prestation efficace de services. Ces préoccupations suggèrent des possibilités pour l'amélioration future de la prestation de services. Implications: Bien que le sondage n'ait offert qu'un espace pour les commentaires à la fin, les MSPL ont écrit leurs commentaires sur tout le sondage. D'autres recherches portant sur les commentaires écrits des MSPL peuvent offrir d'autres idées sur les systèmes de prestation de services de santé mentale aux enfants/adolescents Une étude comparative ciblant les régions urbaines par rapport aux régions rurales du Canada peut fournir un apport valable.

Comparative pharmacodynamics and plasma concentrations of d-threo-methylphenidate hydrochloride after single doses of d-threo-methylphenidate hydrochloride and d,l-threo-methylphenidate hydrochloride in a double-blind, placebo-controlled, crossover laboratory school study in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: Methylphenidate has four optical isomers due to two asymmetries (erythro-threo and dextro-levo). The initial commercial formulation eliminated the erythro isomer, but the dextro-levo asymmetry was racemic, with equal amounts of d and l-threo isomers (d,l-MPH). Previous work has suggested that the d-threo isomer methylphenidate (d-MPH) rather than the l-threo isomer (l-MPH) is responsible for the clinical effects in children with attention-deficit/hyperactivity disorder (ADHD). This study compared the efficacy of acute equimolar doses of d-MPH and dl-MPH in reducing ADHD symptoms over an 8-hour period in a laboratory school setting and investigated the relationship of efficacy to plasma levels of MPH. METHOD: Thirty-two children with ADHD enrolled in this double-blind, placebo-controlled, crossover study, and 31 completed the study. On seven separate occasions separated by at least 6 days, the children received a single morning dose of d-MPH (2.5, 5, or 10 mg), d,l-MPH (5, 10, or 20 mg), or placebo and then were observed in a laboratory classroom setting for 8 hours. At specified intervals, blinded observers rated behavior, and the children performed a computerized math test. The plasma levels of MPH were related to the response to study medication. The safety profiles of the two formulations were compared. RESULTS: For both formulations, the responses to both MPH preparations were dose related, the plasma concentrations of l-MPH were negligible and of d-MPH were indistinguishable, and clinical efficacy was highly correlated with plasma concentrations of d-MPH. The efficacy of the d-isomer was equivalent to the racemic preparation in reducing ADHD symptoms and increasing academic productivity. CONCLUSIONS: The efficacy of MPH resides in the d-isomer. The elimination of the l-isomer does not diminish the efficacy of an acute dose of methylphenidate.

Efficacy and safety of Ritalin LA, a new, once daily, extended-release dosage form of methylphenidate, in children with attention deficit hyperactivity disorder.

OBJECTIVE: To evaluate the safety and efficacy of extended-release methylphenidate with a bimodal profile using SODAS technology (Ritalin LA ) compared with placebo in children aged 6-14 years with attention deficit hyperactivity disorder (ADHD). METHOD: This was a multicenter, double-blind, randomized, placebo-controlled, parallel-group study in children meeting Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for ADHD. Following titration and a 1-week placebo washout period, patients were randomized to 2 weeks of double-blind treatment with either Ritalin LA (10-40 mg/day) or placebo. The efficacy assessments used were the Conners' ADHD/DSM-IV Scales for teachers (CADS-T) and for parents (CADS-P), and the Clinical Global Impression-Improvement Scale (CGI-I) completed by the investigator. The primary efficacy variable was the change from baseline (end of placebo washout) to the final rating (end of 2-week double-blind treatment) in the CADS-T Total subscale score. RESULTS: One-hundred-and-sixty-one children were treated and 134 responders were included in the intent-to-treat analysis. Ritalin LA achieved a mean change from baseline (+/- SD) on the CADS-T Total subscale of -10.7 (+/-15.68) compared with 2.8 (+/-10.59) for placebo (p < 0.0001); the effect size on the CADS-T Total score with Ritalin LA was 0.90. Additionally, 69.8% of patients in the Ritalin LA group were rated as much or very much improved on the CGI-I at final assessment compared with 40% of patients in the placebo group (p = 0.0009). The adverse events reported were generally mild or moderate, and were similar in both groups. CONCLUSION: The results demonstrate that Ritalin LA administered once daily for up to 2 weeks achieved outcomes statistically superior to placebo in children with ADHD.

Does chirality matter? pharmacodynamics of enantiomers of methylphenidate in patients with attention-deficit/hyperactivity disorder.

Methylphenidate (MPH) is very effective in the treatment of attention-deficit/hyperactivity disorder (ADHD) in both children and adults. Blockade of the dopamine transporter is thought to produce the therapeutic effects of MPH by increasing concentrations of dopamine within the central nervous system. Although MPH is a racemic compound composed of a 50:50 mixture of dexmethylphenidate (d-MPH) and l-methylphenidate (l-MPH), animal and human studies have confirmed that the d-MPH isomer is responsible for the pharmacodynamic effect of MPH. Positron emission tomography scan images in rats and baboons treated with radiolabeled MPH have confirmed the specificity of the d-isomer and lack of specific binding of the l-isomer. Clinical studies evaluating d-MPH in both children and adults with ADHD have confirmed the efficacy and safety of the stereoselective isomer in the treatment of ADHD. The immediate-release formulation of d-MPH produces effects similar to d,l-MPH in children as measured by teacher-assessed Swanson, Nolan, and Pelham scores, Math test results, Conners Teacher and Parent Rating Scales, Attention Deficit Disorder Rating Scale, Global Assessment of Functioning scale, and Clinical Global Impression-Improvement scores. An extended-release formulation with a rapid onset of action and sustained benefit over 12 hours provides similar clinical benefit in children and adults with ADHD with excellent tolerability and the advantage of once-daily dosing.