Objective: To review the primary and secondary findings from the Multimodal Treatment study of ADHD (MTA) published over the past decade as three sets of articles. Method: In a two-part article—Part ...I: Executive Summary (without distracting details) and Part II: Supporting Details (with additional background and detail required by the complexity of the MTA)—we address confusion and controversy about the findings. Results: We discuss the basic features of the gold standard used to produce scientific evidence, the randomized clinical trial, for which was used to contrast four treatment conditions: medication management alone (MedMgt), behavior therapy alone (Beh), the combination of these two (Comb), and a community comparison of treatment “as usual” (CC). For each of the three assessment points we review three areas that we believe are important for appreciation of the findings: definition of evidence from the MTA, interpretation of the serial presentations of findings at each assessment point with a different definition of long-term, and qualification of the interim conclusions about long-term effects of treatments for ADHD. Conclusion: We discuss the possible clinical relevance of the MTA and present some practical suggestions based on current knowledge and uncertainties facing families, clinicians, and investigators regarding the long-term use of stimulant medication and behavioral therapy in the treatment of children with ADHD. (J. of Att. Dis. 2008; 12(1) 4-14)
Objective: To review and provide details about the primary and secondary findings from the Multimodal Treatment study of ADHD (MTA) published during the past decade as three sets of articles. Method: ...In the second of a two part article, we provide additional background and detail required by the complexity of the MTA to address confusion and controversy about the findings outlined in part I (the Executive Summary). Results: We present details about the gold standard used to produce scientific evidence, the randomized clinical trial (RCT), which we applied to evaluate the long-term effects of two well-established unimodal treatments, Medication Management (MedMGT) and behavior therapy (Beh), the multimodal combination (Comb), and treatment “as usual” in the community (CC). For each of the first three assessment points defined by RCT methods and included in intent-to-treat analyses, we discuss our definition of evidence from the MTA, interpretation of the serial presentations of findings at each assessment point with a different definition of long-term varying from weeks to years, and qualification of the interim conclusions about long-term effects of treatments for ADHD based on many exploratory analyses described in additional published articles. Conclusions: Using a question and answer format, we discuss the possible clinical relevance of the MTA and present some practical suggestions based on current knowledge and uncertainties facing families, clinicians, and investigators regarding the long-term use of stimulant medication and behavioral therapy in the treatment of children with ADHD. (J. of Att. Dis. 2008; 12(1) 15-43)
To determine the pharmacokinetic and pharmacodynamic properties of once-daily versus twice-daily doses of Adderall.
Following a 1-week wash-out, 12 subjects with attention-deficit/hyperactivity ...disorder (ADHD) entered a double-blind crossover study comparing two conditions: QD (10 mg of Adderall at 7:30 a.m. and placebo at noon) or BID (10 mg of Adderall at 7:30 a.m. and at noon). At two sites, cohorts of six subjects each were assessed on two different days by a 12-hour laboratory school protocol. Plasma concentrations of d- and l-amphetamine, vital signs, teacher ratings of classroom behavior on the SKAMP, and 10-minute Math Test performance were measured repeatedly over 12 hours. An analysis of variance used center, subject-within-center, condition, and time-after-second-dose as independent variables.
The pharmacokinetic profiles revealed similar morning concentrations of d- and l-amphetamine. However, concentrations were twice as high in the afternoon for BID as QD. The two conditions showed similar pharmacodynamic profiles in the morning, although improvement in math performance and behavior was maintained into the afternoon only in the BID condition (p <.05).
This study suggests that twice-daily dosing of Adderall may be an effective strategy for afternoon control of attention and deportment for children with ADHD.
Recently, new long-acting formulations of racemic methylphenidate (MPH: Ritalin® LA, Metadate® CD and Concerta®) and amphetamine (AMP: Adderall XR®) were developed and are now approved by the Food ...and Drug Administration (FDA). In addition, dexmethylphenidate (Focalin ™), the pharmacologically active d-threo enantiomer of MPH, also was approved by the FDA. In the initial phases of development, prototypes of these five new formulations were evaluated using the University of California, Irvine (UCI) Laboratory School Protocol (LSP), in which surrogate measures of efficacy are collected in highly controlled settings rather than clinical measures of effectiveness in the less-controlled, natural environments of home or school. The LSP studies were followed by large effectiveness and safety studies required for gaining FDA approval. These initial efficacy and side effect studies in the LSP provided missing information about the basic pharmacokinetic (PK) and pharmacodynamic (PD) properties of MPH and AMP and produced some new discoveries (i.e., acute tolerance) that were used to help design the final products.
The final once-a-day formulations used different drug delivery systems to achieve long-acting efficacy (Ritalin® LA, Metadate® CD, Concerta®, Adderall XR®). All four drug delivery systems were based on two processes: first, a bolus delivery (BD) process to achieve rapid onset of efficacy (mg), and second, a controlled delivery (CD) process to achieve rates of delivery (mg/hr) or a delayed bolus (mg) to maintain efficacy. A theoretical approach was used to compare and contrast the new once-a day formulations of MPH by selecting total daily doses (mg/d) that would equate drug delivery by the first process (mg of the Initial bolus) and the second process (mg/hr over specified time period). In addition to efficacy, applications of the LSP to measure common side effects related to eating and sleeping were described and discussed.
The inflammatory response of immune cells to target cells and cell-matrix molecules is regulated by several receptor-ligand molecules. As fibrosis develops in ongoing chronic rejection after liver ...transplantation, it is of interest to analyze patterns of integrin receptors and cell-matrix molecules in order to study the relation between immune cells and the stromal and parenchymal cells. In the present study, we demonstrated the expression of these molecules in chronic rejected human liver grafts using immunohistochemical techniques. The results showed a differential expression and induction of integrin receptors and cell-matrix molecules on resident liver cells, especially on sinusoids, reflecting a state of chronic inflammation and a specific interaction between integrin receptors and cell-matrix molecules. The patterns of induced integrin receptors on graft-infiltrating cells was closely related to the local production of cell-matrix molecules and reflected the final sequence of a stepwise progress of the inflammatory reaction.
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