Efficacy and safety of eculizumab in Guillain-Barré syndrome: A phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial.

BACKGROUND AND AIMS: Guillain-Barré syndrome (GBS) is an acute, self-limited, immune-mediated peripheral neuropathy. Current treatments for GBS include intravenous immunoglobulin (IVIg) and plasma exchange, which may not sufficiently benefit severely affected patients. This study evaluated the efficacy and safety of eculizumab add-on therapy to IVIg (standard-of-care treatment) in patients with severe GBS. METHODS: This phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial (NCT04752566), enrolled Japanese adults (age ≥ 18 years) with severe GBS (Hughes functional grade [FG] score FG3 or FG4/FG5 within 2 weeks of onset of GBS). Participants were randomized 2:1 to receive intravenous infusion of eculizumab or placebo (once weekly for 4 weeks) with IVIg treatment with 20 weeks of follow-up. Primary efficacy endpoint was the time to first reach FG score ≤1 (able to run). Key secondary endpoints were proportion of participants achieving FG ≤1 at weeks 8 and 24 and FG improvement ≥3 at week 24. Pharmacodynamic analysis of serum free C5 concentration over time was performed. Safety was evaluated. RESULTS: The analysis included 57 participants (eculizumab, n = 37; placebo, n = 20). Primary endpoint was not achieved (hazard ratio, 0.9; 95% CI, 0.45-1.97; p = .89). Key secondary endpoints did not reach statistical significance. Serum C5 concentration was reduced by 99.99% at 1 h postdose and sustained to week 5 but returned to baseline at the end of follow-up period. No new safety signals for eculizumab were identified. INTERPRETATION: Although well tolerated, eculizumab treatment did not show significant effects on motor function recovery compared to placebo in patients with GBS.

Eculizumab in Adolescent Patients With Refractory Generalized Myasthenia Gravis: A Phase 3, Open-Label, Multicenter Study.

BACKGROUND: This study evaluated the efficacy and safety of eculizumab, a terminal complement C5 inhibitor, in juvenile generalized myasthenia gravis (gMG). METHODS: Adolescents aged 12 to 17 years with refractory anti-acetylcholine receptor (AChR) antibody-positive gMG received eculizumab (weekly induction [one to two doses of 600 mg or four doses of 900 mg] followed by maintenance doses [300 to 1200 mg] every two weeks for up to 26 weeks) in a phase 3, open-label multicenter study (NCT03759366). Change from baseline to week 26 in Quantitative Myasthenia Gravis (QMG) total score (primary end point) and secondary end points including Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score, Myasthenia Gravis Composite score, Myasthenia Gravis Foundation of America postintervention status, EuroQol 5-Dimensions (Youth) and Neurological Quality-of-Life Pediatric Fatigue questionnaire scores, as well as pharmacokinetics, pharmacodynamics, and safety, were recorded. RESULTS: Eleven adolescents (mean ± S.D. age 14.8 ± 1.8 years) were enrolled; 10 completed the primary evaluation period. Least-squares mean changes from baseline at week 26 were -5.8 (standard error [SE] 1.2; P = 0.0004) for QMG total score and -2.3 (SE 0.6; P = 0.0017) for MG-ADL total score. Overall, the primary and all secondary efficacy end point analyses met statistical significance from the first assessment and were sustained throughout. Complete terminal complement inhibition was sustained through 26 weeks in all patients. Treatment-emergent adverse events were all mild/moderate and predominantly unrelated to eculizumab. CONCLUSIONS: Eculizumab was effective in reducing disease burden and was well tolerated in adolescents with refractory AChR antibody-positive gMG.

Efficacy and Safety of Ravulizumab, a Complement C5 Inhibitor, in Adults With Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

Importance: Additional therapies for amyotrophic lateral sclerosis (ALS) are urgently needed. Immune-mediated complement activation may be involved in ALS pathogenesis as evidenced by the upregulation of terminal components; thus, complement inhibition could potentially slow progression. Objective: To evaluate the safety and efficacy of the terminal complement C5 inhibitor ravulizumab in adults with ALS. Design, Setting, and Participants: This double-blind, placebo-controlled, parallel-group, multinational, randomized, phase 3 clinical trial was conducted from March 30, 2020, to October 17, 2021, in 81 ALS specialty centers across 17 countries. A preplanned, unmasked, nonbinding interim futility analysis was conducted when 33% of participants had completed week 26, wherein a conditional power of less than 10% would halt the trial. A total of 478 individuals were screened, and 96 were excluded. Inclusion criteria were weight of 40 kg or more, fulfillment of the El Escorial diagnostic criteria, and a minimal prestudy Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) progression score of -0.3 points per month. Interventions: Study treatment consisted of placebo or a weight-based dose of intravenous ravulizumab every 8 weeks until week 42. Participants could continue standard-of-care treatment. Main Outcomes and Measures: The primary end point was change from baseline in ALSFRS-R score at week 50 based on the Combined Assessment of Function and Survival (CAFS). Results: A total of 382 participants were randomly assigned 2:1 to receive ravulizumab (n = 255; mean [SD] age, 58.6 [10.6] years; 94 female [36.9%] and 161 male [63.1%]) or placebo (n = 127; mean [SD] age, 58.0 [11.0] years; 58 female [45.7%] and 69 male [54.3%]). The interim analysis showed that the observed mean change from baseline in ALSFRS-R at week 50 was -14.67 points (SE, 0.89 points; 95% CI, -16.42 to -12.91 points) for ravulizumab and -13.33 points (SE, 1.22 points; 95% CI, -15.72 to -10.93 points) for placebo, with no significant difference between the groups (mean [SE] difference, -1.34 [1.46] points; 95% CI, -4.21 to 1.53 points). Based on these data, the trial was terminated for futility. The primary analysis at week 50 showed no significant difference in CAFS between groups (mean [SE], 5.5 [10.8] points; 95% CI, -15.7 to 26.6 points; P = .61). Overall incidence rates for treatment-emergent adverse events were similar for ravulizumab (204 participants [80.0%]) and placebo (108 participants [85.0%]). Conclusions and Relevance: This trial rapidly showed that terminal complement C5 inhibition with ravulizumab did not slow functional decline in participants with ALS and that the safety profiles of ravulizumab and placebo were similar. Highly effective, novel treatments are critically needed to slow functional decline and extend survival in patients with ALS. Trial Registration: ClinicalTrials.gov Identifier: NCT04248465.

Long-term efficacy and safety of ravulizumab in adults with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis: results from the phase 3 CHAMPION MG open-label extension.

INTRODUCTION: Ravulizumab demonstrated efficacy and an acceptable safety profile versus placebo in the randomized controlled period (RCP) of the phase 3 CHAMPION MG trial in patients with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis. We report an interim analysis of the ongoing open-label extension (OLE) designed to evaluate long-term treatment effects. METHODS: Following completion of the 26-week RCP, patients could enter the OLE; patients who received ravulizumab in the RCP continued the drug; patients who previously received placebo switched to ravulizumab. Patients receive body-weight-based maintenance dosing of ravulizumab every 8 weeks. Efficacy endpoints up to 60 weeks included Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores, with least-squares (LS) mean change and 95% confidence intervals (95% CI) reported. RESULTS: Long-term efficacy and safety in the OLE were analyzed in 161 and 169 patients, respectively. Improvements in all scores were maintained through 60 weeks in patients who received ravulizumab during the RCP; LS mean change from RCP baseline in MG-ADL score was - 4.0 (95% CI: - 4.8, - 3.1; p < 0.0001). Rapid (within 2 weeks) and sustained improvements occurred in patients previously receiving placebo; LS mean change in MG-ADL score from OLE baseline to Week 60 was - 1.7 (95% CI: - 2.7, - 0.8; p = 0.0007). Similar trends were seen in QMG scores. Ravulizumab treatment was associated with a decreased rate of clinical deterioration events compared with placebo. Ravulizumab was well tolerated; no meningococcal infections were reported. CONCLUSION: Findings support the sustained efficacy and long-term safety of ravulizumab, administered every 8 weeks, in adults with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis. CLINICALTRIALS: gov identifier: NCT03920293; EudraCT: 2018-003243-39.

A Long-Term, Open-Label, Safety Study of Triple-Bead Mixed Amphetamine Salts (SHP465) in Adults With ADHD.

Objective: The aim of this study was to evaluate the long-term safety of triple-bead mixed amphetamine salts (MAS) in adults with ADHD. Method: Adults meeting Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) ADHD criteria and satisfying study criteria from one of two antecedent studies were enrolled in this 52-week (dose titration, 4 weeks; dose maintenance, 11 months) open-label extension. The protocol included 12.5- to 75-mg triple-bead MAS but was amended to a maximum of 50-mg triple-bead MAS. Safety evaluations included treatment-emergent adverse events (TEAEs) and vital signs. Clinical outcome measures included ADHD Rating Scale-IV (ADHD-RS-IV) total score changes. Results: Of 505 enrolled participants, 266 completed the study; the M ± SD daily dose during the study was 48.0 ± 15.96 mg. The most frequent TEAEs were insomnia (initial insomnia, insomnia, early morning awakening, middle insomnia; 38.2%), headache (25.7%), and dry mouth (20.2%). Study discontinuations were more frequent with higher doses of triple-bead MAS (37.5-75 mg) than with lower doses (12.5 and 25 mg). Blood pressure and pulse increases were observed at end-of-study. Mean ADHD-RS-IV total score decreases from antecedent study and open-label baselines at end-of-study were -23.3 ± 11.44 and -7.9 ± 13.19, respectively. Conclusion: Triple-bead MAS exhibited a long-term safety profile comparable with previous reports and demonstrated evidence of continued symptom control for up to 12 months.

Triple-Bead Mixed Amphetamine Salts (SHP465) in Adults With ADHD: Results of a Phase 3, Double-Blind, Randomized, Forced-Dose Trial.

Objective: Evaluate the efficacy and tolerability of triple-bead mixed amphetamine salts (MAS) in ADHD. Method: Adults with ADHD Rating Scale IV (ADHD-RS-IV) total scores ≥32 were randomized to 6 weeks of triple-bead MAS (25, 50, or 75 mg) or placebo. The primary endpoint was ADHD-RS-IV total score change from baseline at end of study (EOS). Results: Least squares mean (95% confidence interval [CI]) treatment differences for ADHD-RS-IV total score changes from baseline to EOS significantly favored triple-bead MAS (all doses combined: -10.6 [-13.2, -8.0]; p < .0001); there were no significant differences between triple-bead MAS dosages. The most frequently reported TEAEs with triple-bead MAS (all doses combined) included insomnia, decreased appetite, and dry mouth. Mean ± SD pulse and systolic blood pressure increases at EOS were 3.5 ± 10.33 bpm and 0.3 ± 10.48 mmHg with triple-bead MAS (all doses combined). Conclusion: Triple-bead MAS significantly reduced adult ADHD symptoms; the safety profile was consistent with previous triple-bead MAS studies.

Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease.

The presenilin containing gamma-secretase complex is responsible for the regulated intramembraneous proteolysis of the amyloid precursor protein (APP), the Notch receptor, and a multitude of other substrates. gamma-Secretase catalyzes the final step in the generation of Abeta(40) and Abeta(42) peptides from APP. Amyloid beta-peptides (Abeta peptides) aggregate to form neurotoxic oligomers, senile plaques, and congophilic angiopathy, some of the cardinal pathologies associated with Alzheimer's disease. Although inhibition of this protease acting on APP may result in potentially therapeutic reductions of neurotoxic Abeta peptides, nonselective inhibition of the enzyme may cause severe adverse events as a result of impaired Notch receptor processing. Here, we report the preclinical pharmacological profile of GSI-953 (begacestat), a novel thiophene sulfonamide gamma-secretase inhibitor (GSI) that selectively inhibits cleavage of APP over Notch. This GSI inhibits Abeta production with low nanomolar potency in cellular and cell-free assays of gamma-secretase function, and displaces a tritiated analog of GSI-953 from enriched gamma-secretase enzyme complexes with similar potency. Cellular assays of Notch cleavage reveal that this compound is approximately 16-fold selective for the inhibition of APP cleavage. In the human APP-overexpressing Tg2576 transgenic mouse, treatment with this orally active compound results in a robust reduction in brain, plasma, and cerebral spinal fluid Abeta levels, and a reversal of contextual fear-conditioning deficits that are correlated with Abeta load. In healthy human volunteers, oral administration of a single dose of GSI-953 produces dose-dependent changes in plasma Abeta levels, confirming pharmacodynamic activity of GSI-953 in humans.

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.

Effects of SHP465 mixed amphetamine salts in adults with ADHD in a simulated adult workplace environment.

OBJECTIVES: Evaluate the efficacy, duration of effect, and safety of 25 mg SHP465 mixed amphetamine salts (MAS) extended-release versus placebo in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: Adults (18-55 years) with ADHD and with ADHD Rating Scale-IV (ADHD-RS-IV) scores ≥24 were randomized to treatment in a double-blind, 2-period, 2-treatment crossover study utilizing the Adult Workplace Environment (AWE), as described by Wigal and Wigal (J Atten Disord 2006;10:92-111). On day 7 of each 7-day treatment period, efficacy was assessed during a 16.5-hour postdose period. The primary endpoint, Permanent Product Measure of Performance (PERMP) total score, was analyzed in the intent-to-treat population using a mixed linear model of analysis of variance. Secondary endpoints, for which the study was not powered, included PERMP problems attempted and answered correctly, ADHD clinician ratings based on counselor observations and inputs during the Time Segment Rating System (Co-ADHD-RS TSRS), and the ADHD self-rating scale (ADHD-SRS). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and vital signs. RESULTS: The least squares mean (95% CI) treatment difference (SHP465 MAS-placebo) for PERMP total score significantly favored SHP465 MAS over placebo when averaged across all postdose assessments (19.29 [10.95, 27.63]; P < 0.0001), with significant treatment differences favoring SHP465 MAS over placebo observed at 4-16 hours postdose (all P < 0.01). TEAEs observed with SHP465 MAS (≥5% of participants) included insomnia, decreased appetite, dry mouth, headache, and anorexia. Mean pulse and blood pressure increases with SHP465 MAS exceeded those of placebo. CONCLUSIONS: SHP465 MAS (25 mg) was superior to placebo on PERMP total score, with treatment differences observed from 4 to 16 hours postdose; nominal treatment differences on the ADHD-SRS, but not the Co-ADHD-RS TSRS, were also observed. The safety and tolerability profile of SHP465 MAS was similar to previous reports for SHP465 MAS and other long-acting stimulants. Clinical trials registry: clinicaltrials.gov (NCT00202605; https://clinicaltrials.gov/ct2/show/NCT00202605 ).

A randomized, double-blind study of SHP465 mixed amphetamine salts extended-release in adults with ADHD using a simulated adult workplace design.

OBJECTIVES: The objective of this paper was to evaluate the efficacy, duration of effect, and tolerability of SHP465 mixed amphetamine salts (MAS) extended-release versus placebo and immediate-release MAS (MAS IR) in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: Adults with ADHD Rating Scale, Version IV (ADHD-RS-IV) scores ≥24 were randomized to SHP465 MAS (50 or 75 mg), placebo, or 25 mg MAS IR in a double-blind, three-period, crossover study using a simulated adult workplace environment. On the final day of each 7-day treatment period, efficacy was assessed for 16 h postdose. Primary efficacy analyses for Permanent Product Measure of Performance (PERMP) total score averaged across all postdose assessments and each postdose time point were conducted in the intent-to-treat population using a mixed linear model. Secondary end-points included PERMP problems attempted and answered correctly and ADHD-RS-IV scores based on clinician ratings of counselor observations using the Time Segment Rating System and participant self-report. Tolerability assessments included treatment-emergent adverse events (TEAEs) and vital signs. RESULTS: Least squares mean (95% CI) treatment differences (combined 50/75 mg SHP465 MAS-placebo) significantly favored SHP465 MAS over placebo for PERMP total score averaged across all postdose assessments (18.38 [11.28, 25.47]; P < .0001) and at each postdose assessment (all P < .02). Nominal superiority of MAS IR over placebo for PERMP total score averaged across all postdose assessments was observed (nominal P = .0001); treatment differences between SHP465 MAS and MAS IR were not significant (nominal P = .2443). The two most frequently reported TEAEs associated with SHP465 MAS were insomnia (36.5%) and anorexia (21.2%). Mean increases in pulse and blood pressure with SHP465 MAS exceeded those of placebo. CONCLUSIONS: SHP465 MAS (combined 50/75 mg) significantly improved PERMP total score versus placebo, with superiority observed from 2 to 16 h postdose. The tolerability profile of SHP465 MAS was similar to previous reports of SHP465 MAS in adults with ADHD. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00928148 identifier is NCT00928148.

Effect of aprepitant on the pharmacokinetics of intravenous midazolam.

Oral aprepitant 125 mg, an antiemetic and a moderate inhibitor of the metabolism of oral midazolam, was assessed for interaction with intravenous midazolam in 12 subjects randomized to intravenous midazolam 2 mg +/- oral aprepitant 125 mg. The hypothesis was that midazolam AUC would not change by more than 2-fold (consistent with no more than weak inhibition) when midazolam + aprepitant was compared with midazolam alone. An AUC geometric mean ratio (midazolam + aprepitant/midazolam) with 90% confidence interval upper bound < or =2.0 (an increase in midazolam felt to be of modest clinical significance in the highly monitored perioperative period) was prespecified. Aprepitant increased intravenous midazolam AUC(0-infinity) 1.47-fold (90% confidence interval, 1.36-1.59), which fell within the prespecified criterion.

Randomized, Double-Blind, Placebo-Controlled Acute Comparator Trials of Lisdexamfetamine and Extended-Release Methylphenidate in Adolescents With Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Psychostimulants are considered first-line pharmacotherapy for youth with attention-deficit/hyperactivity disorder (ADHD), but questions remain regarding the comparative efficacy of amphetamine- and methylphenidate-based agents. OBJECTIVE: Our objective was to describe two acute randomized, double-blind, placebo-controlled, head-to-head studies of lisdexamfetamine dimesylate (LDX) and osmotic-release oral system methylphenidate (OROS-MPH) in adolescents with ADHD. METHODS: Adolescents (13-17 years) diagnosed with ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria were enrolled in an 8-week flexible-dose study [LDX 30-70 mg/day (n = 186 randomized); OROS-MPH 18-72 mg/day (n = 185 randomized); placebo (n = 93 randomized)] or a 6-week forced-dose study [LDX 70 mg/day (n = 219 randomized); OROS-MPH 72 mg/day (n = 220 randomized); placebo (n = 110 randomized)]. Attention-Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) total score changes from baseline (primary endpoint) at week 8 (flexible-dose study) or week 6 (forced-dose study) were assessed with mixed-effects models for repeated measures. Secondary endpoints included improvement on the dichotomized Clinical Global Impressions-Improvement scale (CGI-I; key secondary endpoint) and changes from baseline on the ADHD-RS-IV subscales. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs. RESULTS: Least squares (LS) mean ± standard error of the mean (SEM) ADHD-RS-IV total score changes from baseline to end of treatment were -17.0 ± 1.03 with placebo, -25.4 ± 0.74 with LDX, and -22.1 ± 0.73 with OROS-MPH in the forced-dose study and -13.4 ± 1.19 with placebo, -25.6 ± 0.82 with LDX, and -23.5 ± 0.80 with OROS-MPH in the flexible-dose study. LS mean ± SEM treatment difference for the change from baseline significantly favored LDX over OROS-MPH in the forced-dose [-3.4 ± 1.04, p = 0.0013, effect size (ES) -0.33] but not the flexible-dose (-2.1 ± 1.15, p = 0.0717, ES -0.20) study. The percentage of improved participants on the dichotomized CGI-I at end of treatment was significantly greater with LDX than with OROS-MPH in the forced-dose study (81.4 vs. 71.3%, p = 0.0188) but not the flexible-dose study (LDX 83.1%, OROS-MPH 81.0%, p = 0.6165). The LS mean ± SEM treatment differences for change from baseline on the ADHD-RS-IV hyperactivity/impulsivity and inattentiveness subscales nominally favored LDX in the forced-dose study (hyperactivity/impulsivity subscale -1.3 ± 0.49, nominal p = 0.0081, ES -0.27; inattentiveness subscale -2.0 ± 0.63, nominal p = 0.0013, ES -0.33), but there were no significant differences between active treatments in the flexible-dose study. In both studies, LDX and OROS-MPH were superior to placebo for all efficacy-related endpoints (all nominal p < 0.0001; ES range -0.43 to -1.16). The overall frequency of TEAEs for LDX and OROS-MPH, respectively, were 66.5 and 58.9% in the forced-dose study and 83.2 and 82.1% in the flexible-dose study. TEAEs occurring in ≥ 5% of participants that were also reported at two or more times the rate of placebo were decreased appetite, decreased weight, insomnia, initial insomnia, dry mouth, and nasopharyngitis (LDX and OROS-MPH), irritability and dizziness (LDX only), and increased heart rate (OROS-MPH only) in the forced-dose study and decreased appetite, decreased weight, insomnia, and dizziness (LDX and OROS-MPH) and dry mouth and upper abdominal pain (LDX only) in the flexible-dose study. Mean ± standard deviation (SD) increases from baseline in vital signs (systolic and diastolic blood pressure, pulse) were observed in the forced-dose study [LDX 1.6 ± 9.65 and 3.3 ± 8.11 mmHg, 6.7 ± 12.78 beats per minute (bpm); OROS-MPH 2.6 ± 10.15 and 3.3 ± 9.13 mmHg, 7.6 ± 12.47 bpm] and the flexible-dose study (LDX 2.4 ± 9.46 and 2.8 ± 8.41 mmHg, 4.7 ± 11.82 bpm; OROS-MPH 0.4 ± 9.90 and 2.2 ± 8.64 mmHg, 6.0 ± 10.52 bpm) at the last on-treatment assessment. CONCLUSIONS: LDX was superior to OROS-MPH in adolescents with ADHD in the forced-dose but not the flexible-dose study. Safety and tolerability for both medications was consistent with previous studies. These findings underscore the robust acute efficacy of both psychostimulant classes in treating adolescents with ADHD. CLINICALTRIALS. GOV REGISTRY NUMBERS: NCT01552915 and NCT01552902.

Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine Exposure and Duration of Efficacy.

Lisdexamfetamine dimesylate (LDX) is a long-acting d-amphetamine prodrug used to treat attention-deficit/hyperactivity disorder (ADHD) in children, adolescents and adults. LDX is hydrolysed in the blood to yield d-amphetamine, and the pharmacokinetic profile of d-amphetamine following oral administration of LDX has a lower maximum plasma concentration (Cmax), extended time to Cmax (Tmax) and lower inter- and intra-individual variability in exposure compared with the pharmacokinetic profile of an equivalent dose of immediate-release (IR) d-amphetamine. The therapeutic action of LDX extends to at least 13 h post-dose in children and 14 h post-dose in adults, longer than that reported for any other long-acting formulation. Drug-liking scores for LDX are lower than for an equivalent dose of IR d-amphetamine, which may result from the reduced euphorigenic potential associated with its pharmacokinetic profile. These pharmacokinetic and pharmacodynamic characteristics of LDX may be beneficial in the management of symptoms in children, adolescents and adults with ADHD.

Effects of desvenlafaxine on the pharmacokinetics of desipramine in healthy adults.

The results of two single-center, two-period, open-label trials that evaluated the effects of multiple doses of desvenlafaxine on the pharmacokinetics of desipramine, a cytochrome P450 (CYP) 2D6 enzyme substrate, are presented. Healthy individuals aged 18-45 years were administered a single oral dose of 50 mg desipramine with and without 100 mg daily (n=34) or 400 mg daily (n=23) desvenlafaxine for 5 days. After coadministration of 100 mg desvenlafaxine, desipramine exposure, measured by peak plasma concentration (C(max)) and total area under the plasma concentration-versus-time curve (AUC), showed minimal increases of 25 and 17%, respectively; coadministration of 400 mg desvenlafaxine resulted in a 52% increase in desipramine C(max) and a 90% increase in AUC. For the 100 mg dose, the geometric least squares mean ratios and 90% confidence intervals (CIs) for desipramine AUC (117%; 90% CI 110-125%), 2-hydroxydesipramine AUC (114%; 90% CI 110-119%), and C(max) (110%; 90% CI 104-116%) were all within the 80-125% interval, showing the bioequivalence for AUC between desipramine administered alone and in combination with 100 mg desvenlafaxine. These results indicate that desvenlafaxine is a relatively weak inhibitor of CYP2D6 and that desvenlafaxine 100 mg, twice the recommended therapeutic dose of 50 mg, is unlikely to cause drug-drug interactions with CYP2D6 substrates.

Guanylyl cyclase C: a molecular marker for staging and postoperative surveillance of patients with colorectal cancer.

Staging patients with colorectal cancer defines their prognosis and therapeutic management. Unfortunately, histopathology, the current standard for staging, is relatively insensitive for detecting occult micrometastases and a significant fraction of patients are understaged and, consequently, undertreated. Similarly, current approaches to postoperative surveillance of patients with colorectal cancer detect disease recurrence at a point when interventions have little impact on survival. The detection of rare cells in tissue, for accurately staging patients, and in blood, for detecting disease recurrence, could be facilitated by employing sensitive and specific markers of disease. Guanylyl cyclase C (GCC), the receptor for the diarrheagenic bacterial heat-stable enterotoxin, is expressed selectively by cells derived from intestinal mucosa, including normal intestinal cells and colorectal tumor cells, but not by extragastrointestinal tissues and tumors. The nearly uniform expression of relatively high levels by metastatic colorectal tumors suggests that GCC may be a sensitive and specific molecular marker for metastatic colorectal cancer cells. Employing GCC reverse transcriptase PCR, occult colorectal cancer micrometastases were detected in lymph nodes that escaped detection by histopathology. Moreover, marker expression correlated with the risk of disease recurrence. Similarly, GCC reverse transcriptase PCR revealed the presence of tumor cells in blood of all patients examined with metastatic colorectal cancer and, in some studies, was associated with an increased risk of disease recurrence and mortality. These observations suggest that GCC reverse transcriptase PCR is a sensitive and specific technique for identifying tumor cells in extraintestinal sites and may be useful for staging and postoperative surveillance of patients with colorectal cancer.

Proliferative signaling by store-operated calcium channels opposes colon cancer cell cytostasis induced by bacterial enterotoxins.

Guanylyl cyclase C and accumulation of cGMP induced by bacterial heat-stable enterotoxins (STs) promote colon cancer cell cytostasis, serving as a tumor suppressor in intestine. Conversely, capacitative calcium entry through store-operated calcium channels (SOCs) is a key signaling mechanism that promotes colon cancer cell proliferation. The present study revealed that proliferative signaling by capacitative calcium entry through SOCs opposes and is reciprocally coupled to cytostasis mediated by guanylyl cyclase C in T84 human colon carcinoma cells. Elimination of capacitative calcium entry employing 2-aminoethoxydiphenylborate (2-APB), a selective inhibitor of SOCs, potentiated cytostasis induced by ST. Opposition of ST-induced cytostasis by capacitative calcium entry reflects reciprocal inhibition of guanylyl cyclase C signaling. Calcium entry through SOCs induced by the calcium-ATPase inhibitor thapsigargin or the receptor agonists UTP or carbachol inhibited guanylyl cyclase C-dependent cGMP accumulation. This effect was mimicked by the calcium ionophore ionomycin and blocked by 2-APB and intracellular 1,2-bis(o-amino-5,5'-dibromophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM), a chelator of calcium. Moreover, regulation by capacitative calcium entry reflected ligand-dependent sensitization of guanylyl cyclase C to inhibition by that cation. Although basal catalytic activity was refractory, ST-stimulated guanylyl cyclase C was inhibited by calcium, which antagonized binding of magnesium to allosteric sites required for receptor-effector coupling. These observations demonstrate that reciprocal regulation of guanylyl cyclase C signaling by capacitative calcium entry through SOCs represents one limb of a coordinated mechanism balancing colon cancer cell proliferation and cytostasis. They suggest that combining guanylyl cyclase C agonists and SOC inhibitors offers a novel paradigm for cGMP-directed therapy and prevention for colorectal tumors.