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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.

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 ( C max ), extended time to C max ( T max ) 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.

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.

Background Ravulizumab, an anti‐complement C5 monoclonal antibody, was efficacious with acceptable safety in the randomized controlled period (RCP) and interim open‐label extension (OLE) periods of the CHAMPION MG phase 3 trial in adults with anti‐acetylcholine receptor antibody‐positive (AChR‐Ab+) generalized myasthenia gravis (gMG). Here, we report final results from the OLE. Methods Patients who completed the 26‐week RCP could enter the OLE and receive ravulizumab for up to 4 years. Efficacy and safety were assessed throughout the OLE. Results Among all ravulizumab‐treated patients (n = 169; median [range] ravulizumab treatment, 759.0 [14.0, 1265.0] days), 161 entered the OLE (ravulizumab‐ravulizumab: n = 78; placebo‐ravulizumab: n = 83). Sustained improvements were observed in Myasthenia Gravis Activities of Daily Living (MG‐ADL) total scores (ravulizumab‐ravulizumab, least squares mean [95% CI] change from RCP baseline at week 164: −4.0 [−5.3, −2.8]; p < 0.0001; placebo‐ravulizumab, change from OLE baseline after 138 weeks of treatment: −2.1 [−3.3, −0.9]; p = 0.0005). One hundred and forty‐one out of 160 (88.1%) patients achieved a ≥ 2‐point improvement in MG‐ADL total score, and 59/141 (41.8%) achieved a score of 0 or 1; once achieved, 32/59 (54.2%) sustained this status for > 50% of their remaining time in the study. Similar improvements were observed in Quantitative Myasthenia Gravis and Myasthenia Gravis Quality of Life‐15 revised scores, and Neurological Quality of Life Fatigue subscale scores. Clinical deterioration event rates were reduced in the OLE versus placebo in the RCP. Corticosteroid usage was reduced in the OLE. Ravulizumab was well tolerated; no meningococcal infections were reported. Conclusion Ravulizumab demonstrated clinically meaningful and durable efficacy and safety in adults with AChR‐Ab+ gMG. Ravulizumab demonstrated clinically meaningful and durable efficacy and safety in adults with anti‐acetylcholine receptor antibody‐positive generalized myasthenia gravis in the CHAMPION MG open‐label extension (OLE) study. Improvements from baseline in MG‐ADL, QMG, and MG‐QOL15r total scores, and the NeuroQOL Fatigue subscale scores achieved in patients who received ravulizumab during the randomized controlled period of CHAMPION were sustained throughout the OLE. Similar rapid improvements versus OLE baseline were achieved in patients who switched from placebo to ravulizumab at the start of the OLE.

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.

In the adult nervous system, neurotransmitters act as chemical signals between neurons by binding to ligand-gated and second-messenger-coupled receptors. This role appears to have evolved from a more primitive function in lower organisms where these same molecules often subserve roles other than intercellular communication. Dopamine (DA) is one of the neurotransmitters that has been shown to act as a growth-regulatory signal or morphogenic factor during prenatal development in the rat. Although DA is no longer believed to be acting as a morphogenic factor during postnatal development, this neurotransmitter has been shown to continue to play an important role guiding development during the postnatal period. Therefore, one can hypothesize that an alteration of the levels of synaptic DA during critical periods of development could potentially lead to changes in the normal functioning of the dopaminergic system which may persist into adulthood and thus be permanent in nature. The present study examined the short- and long-term effects on cerebral glucose utilization (GU) and DA D1 and D2 receptor binding of DA reuptake transporter blockade during the late postnatal period (postnatal days 11–21) of development in the rat. Blockade of the DA transporter elevates extracellular DA by preventing the normal removal of DA from the synapse following release from synaptic vesicles. DA D1 and D2 receptor binding was examined following chronic late postnatal blockade of the dopamine transporter at 21- and 60-days-of-age. At 21-days-of-age, chronic selective blockade by GBR12909 (GBR) (25mg/kg) and nonselective blockade by cocaine (25mg/kg) produced widespread increases in cerebral glucose utilization and marked decreases in Dopamine D1and D2 receptor binding. The majority of these changes occurred in female rats. The changes in D1 and D2 receptor binding appear to reflect a downregulation of these receptors in response to increased levels of synaptic DA which is suggested by the increases in cerebral GU rates, in many brain regions in these same animals. At 60-days-of-age, no significant changes in DA D1 or D 2 receptors by analysis of variance (ANOVA) were observed in any individual brain regions compared to control following late postnatal blockade of the DA transporter in female rats. On the other hand, significant changes in the patterns of receptor binding were seen (significant Chi-square result). Both low-dose GBR (25mg/kg) and cocaine (50mg/kg) produced a significant pattern of decreased D1 and increased D2 receptor binding while high-dose GBR (50mg/kg) produced a significant pattern of increased D 1 binding and had no effect on D2 binding. These patterns likely represent the effects of chronic late postnatal alteration of synaptic DA concentration. Furthermore, both cocaine and low-dose GBR produced changes in the patterns of DA D1/D2 receptor binding that were similar and likely the result of a common mechanism. However, the significant patterns of increased cerebral GU in the low-dose GBR group and decreased cerebral GU in the cocaine group suggest that additional mechanisms may also be responsible for the significant changes in the patterns of DA D1/D 2 receptor binding in each of the treatment groups. The results of this body of work suggest that blockade of the DA transporter is an important mechanism of cocaine's actions in the developing brain. These studies lend support to the hypothesis that DA continues to act as a development-regulating factor in the brain during the late postnatal period in the rat, and that alteration of the levels of this neurotransmitter during this critical period of development has both short- and long-term effects on brain development.