Cambrian origin but no early burst in functional disparity for Class Bivalvia.

Both the Cambrian explosion, more than half a billion years ago, and its Ordovician aftermath some 35 Myr later, are often framed as episodes of widespread ecological opportunity, but not all clades originating during this interval showed prolific rises in morphological or functional disparity. In a direct analysis of functional disparity, instead of the more commonly used proxy of morphological disparity, we find that ecological functions of Class Bivalvia arose concordantly with and even lagged behind taxonomic diversification, rather than the early-burst pattern expected for clades originating in supposedly open ecological landscapes. Unlike several other clades originating in the Cambrian explosion, the bivalves' belated acquisition of key anatomical novelties imposed a macroevolutionary lag, and even when those novelties evolved in the Early Ordovician, functional disparity never surpassed taxonomic diversity. Beyond this early period of animal evolution, the founding and subsequent diversification of new major clades and their functions might be expected to follow the pattern of the early bivalves-one where interactions between highly dynamic environmental and biotic landscapes and evolutionary contingencies need not promote prolific functional innovation.

Digest: Evolution of plasticity and its potential role in the decline of specialists.

How does plasticity evolve over relatively short timescales? Through a series of common garden and reciprocal transplant experiments, Walter et al. found distinct patterns of variation in the phenotype and gene expression for two closely related Sicilian daisy species of the genus Senecio across an elevational gradient. This suggests that adaptive divergence may produce interspecific differences in both the magnitude and direction of plasticity. The nonadaptive nature of the plasticity found in Senecio aethnensis has important implications for conservation efforts and evolutionary modeling.

Effect of Lorcaserin Alone and in Combination with Phentermine on Food Cravings After 12-Week Treatment: A Randomized Substudy.

OBJECTIVE: This study evaluated the effect of lorcaserin 10 mg twice daily (LOR BID), or with phentermine 15 mg once daily (LOR BID + PHEN QD) and 15 mg twice daily (LOR BID + PHEN BID), in conjunction with energy restriction on food cravings. METHODS: Two hundred and thirty-five patients without diabetes but with obesity or overweight and ≥ 1 comorbidity received LOR BID, LOR BID + PHEN QD, or LOR BID + PHEN BID for 12 weeks in a randomized double-blind study. The Food Craving Inventory (FCI) and the Control of Eating Questionnaire (COEQ) were administered over 12 weeks. RESULTS: The FCI total score and the subscale scores reduced from baseline in all groups. The least squares means (95% confidence intervals) for the total scores were -0.65 (-0.75 to -0.55), -0.75 (-0.84 to -0.65), and -0.84 (-0.95 to -0.74) in the LOR BID, LOR BID + PHEN QD, and LOR BID + PHEN BID groups, respectively. Cravings assessed by COEQ reduced from baseline in all groups. In general, the combination treatments were more effective than lorcaserin alone. At week 12, except for fruit juice and dairy products, general and specific cravings reduced in LOR BID + PHEN BID compared with LOR BID (P < 0.05). CONCLUSIONS: Lorcaserin in combination with phentermine improves control of food cravings during short-term energy restriction.

Coadministration of lorcaserin and phentermine for weight management: A 12-week, randomized, pilot safety study.

OBJECTIVE: To assess the short-term tolerability of lorcaserin alone or with two dose regimens of phentermine. METHODS: This was a 12-week, randomized, double-blind, pilot safety study of N = 238 nondiabetic patients with obesity or overweight with ≥1 comorbidity randomized to lorcaserin 10 mg twice daily (BID; LOR BID) alone or with phentermine 15 mg once daily (QD; LOR BID+PHEN QD) or 15 mg twice daily (LOR BID+PHEN BID). Patients reporting ≥ 1 of 9 potentially serotonergic adverse events (AEs), mean weight loss (WL), and ≥5% WL are reported. RESULTS: N = 238 were randomized, and N = 235 were treated. N = 94 reported potentially serotonergic AEs: 37.2% LOR BID, 42.3% LOR BID+PHEN QD, and 40.5% LOR BID+PHEN BID. AEs leading to discontinuation were reported approximately twice as often in the LOR BID+PHEN BID group versus the LOR BID group. Mean WL was 3.5 kg/3.3%, 7.0 kg/6.7%, and 7.6 kg/7.2% for LOR BID, LOR BID+PHEN QD, and LOR BID+PHEN BID, respectively. At least 5% WL was achieved by 28.2% LOR BID, 59.0% LOR BID+PHEN QD (P = 0.0002 vs. LOR BID), and 70.9% LOR BID+PHEN BID (P < 0.0001 vs. LOR BID) patients. CONCLUSIONS: Phentermine added to lorcaserin enhanced short-term weight loss but did not increase incidence of potentially serotonergic AEs; however, phentermine twice daily increased discontinuation compared to both lorcaserin alone and lorcaserin plus phentermine once daily.

Effect of lorcaserin on glycemic parameters in patients with type 2 diabetes mellitus.

OBJECTIVE: Lorcaserin, a 5-HT2C receptor agonist approved for chronic weight management, is also associated with improvements in glycemic parameters in patients with/without type 2 diabetes mellitus (T2DM), but the extent to which these effects are mediated by weight loss is unknown. This post hoc analysis further examines glycemic data from the Phase III BLOOM-DM study stratified by weight changes. METHODS: Patients with T2DM were randomized to lorcaserin 10 mg twice daily or placebo. Glycemic parameters were reported by Week (W) 12 weight loss status ≥5% (Group ≥5%) or <5% (Group <5%). Glycemic parameter changes were analyzed using ANCOVA; the relationship between glycemic parameter changes and percent weight loss was assessed by simple regression modeling. RESULTS: Group ≥5% receiving lorcaserin had greater improvements in fasting plasma glucose (FPG) at W2 (prior to significant weight loss) and greater improvements in glycated hemoglobin (HbA1c) at W12 versus placebo. These improvements were maintained through W52 (FPG, -29.3 mg/dL vs. -24.2 mg/dL; HbA1c, -1.2% vs. -1.1%). Group <5% treated with lorcaserin also had larger decreases in FPG (-28.3 mg/dL vs. -10.0 mg/dL) and HbA1c (-0.8% vs. -0.4%) at W52 versus placebo despite limited weight loss. CONCLUSIONS: Lorcaserin may have beneficial effects on glycemic control with or without weight loss.

Analysis of falls in patients with epilepsy enrolled in the perampanel phase III randomized double-blind studies.

OBJECTIVE: To analyze occurrence of falls among patients with partial seizures, with/without secondarily generalized seizures (SGS), and primary generalized tonic-clonic seizures (PGTCS) in the perampanel phase III clinical studies. METHODS: Studies 304, 305, and 306 randomized subjects (≥12 years) with drug-resistant partial seizures (with/without SGS) to perampanel 2, 4, 8, or 12 mg or placebo for double-blind treatment. The adverse event (AE) of falls was analyzed in the Safety Analysis Set (N = 1480). Study 332 randomized subjects aged ≥12 years with a diagnosis of PGTCS into perampanel 8 mg or placebo groups for double-blind treatment. In a systematic review of reported falls in the study 332 Safety Analysis Set (N = 163), falls were queried to establish whether each was seizure related; subjects with falls resulting from a seizure were not included in this analysis. RESULTS: For studies 304/305/306, treatment-emergent falls occurred in 5.1% perampanel-treated versus 3.4% placebo-treated subjects with partial seizures. Exposure-adjusted rate for falls (falls/subject-month of exposure) was greater for total perampanel than for placebo (0.0175 vs. 0.0093) and was dose related for those receiving perampanel. In subjects with SGS, incidence of treatment-emergent falls was 4.3% in perampanel and 4.0% in placebo groups. Exposure-adjusted rates were 0.0169 and 0.0097 falls per subject-month of exposure in perampanel and placebo, respectively. For study 332, 2.5% perampanel-treated and 1.2% placebo-treated subjects with PGTCS had treatment-emergent falls that were not part of a seizure. Exposure-adjusted rates were 0.0169 and 0.0032 falls per subject-month of exposure in perampanel and placebo, respectively. SIGNIFICANCE: Results of the perampanel studies suggest that patients with epilepsy should be monitored due to the common risk of falls.

Lorcaserin in Obese and Overweight Patients Taking Prohibited Serotonergic Agents: A Retrospective Analysis.

PURPOSE: Lorcaserin is a selective serotonin 2C receptor (5-HT2C) agonist approved in the United States for use in chronic weight management as an adjunct to a reduced-calorie diet and increased physical activity. Its pharmacologic activity is limited to 5-HT subtype 2 receptors. The potency of lorcaserin for the 5-HT2C receptor is 14-fold greater than its potency for the 5-HT2A receptor and 61-fold greater than its potency for the 5-HT2B receptor. Although 5-HT receptors have been implicated in serotonin syndrome, the precise pathogenesis is unknown. Given a theoretic risk for this syndrome in patients administered lorcaserin either alone or in combination with certain serotonergic agents (eg, selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]), patients taking prohibited serotonergic agents were excluded from the Phase III clinical trials. This retrospective analysis evaluated the tolerability of lorcaserin in patients who took protocol-allowed or proscribed serotonergic agents for varying durations of up to 1 year during the BLOOM, BLOSSOM, and BLOOM-DM studies. METHODS: Patients randomly assigned to receive either lorcaserin 10 mg QD, lorcaserin 10 mg BID, or placebo and who took a spectrum of serotonergic agents were evaluated at week 52 of treatment (814 and 624 patients receiving lorcaserin and placebo, respectively, were found to have taken allowed or prohibited serotonergic agents during these trials). After the use of a proscribed serotonergic agent was discovered, these patients were discontinued from the trial and followed. FINDINGS: None of the patients in the serotonergic agent subpopulation or in the overall safety population met the clinical criteria of serotonin syndrome. The proportions of patients experiencing any adverse event (AE) were balanced in the lorcaserin and placebo groups in the prohibited serotonergic agent subpopulation. The prevalences of the most common AEs were similar between the serotonergic agent subpopulation and the overall safety population. IMPLICATIONS: The concurrent use of lorcaserin and prohibited or allowed serotonergic agents did not appear to have increased the spectrum or intensity of AEs potentially associated with serotonin excess in this limited dataset. However, the sample population was too small to rule out an effect on a rare event such as serotonin syndrome. ClinicalTrials.gov identifiers: NCT00395135, NCT00603902, and NCT00603291.

Psychiatric and behavioral adverse events in randomized clinical studies of the noncompetitive AMPA receptor antagonist perampanel.

OBJECTIVE: Perampanel, a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist, is indicated for adjunctive treatment of partial seizures in patients ≥12 years based on three phase III clinical studies. The perampanel U.S. Prescribing Information includes a boxed warning for serious psychiatric and behavioral adverse reactions. To provide context for this warning, detail on psychiatric and behavioral safety data from perampanel clinical studies is presented. METHODS: An analysis of pooled safety data from three phase III studies in patients with partial seizures is presented. Data from phase I and phase II studies in patients with and without epilepsy were also analyzed. Psychiatric and behavioral treatment-emergent adverse events (TEAEs) were evaluated according to Medical Dictionary for Regulatory Activities (MedDRA) terms, using "narrow" and "narrow-and-broad" standardized MedDRA queries (SMQs) for TEAEs suggestive of hostility/aggression. RESULTS: From the three phase III partial-seizure studies, the overall rate of psychiatric TEAEs was higher in the 8 mg (17.2%) and 12 mg (22.4%) perampanel groups versus placebo (12.4%). In the "narrow" SMQ, hostility/aggression TEAEs were observed in 2.8% for 8 mg and 6.3% for 12 mg perampanel groups, versus 0.7% of placebo patients. "Narrow-and-broad" SMQs for hostility/aggression TEAE rates were 12.3% for 8 mg and 20.4% for 12 mg perampanel groups, versus 5.7% for placebo; rates for events resulting in discontinuation were perampanel = 1.6% versus placebo = 0.7%. For events reported as serious AEs (SAEs), rates were perampanel = 0.7% versus placebo = 0.2%. In nonepilepsy patients, psychiatric TEAEs were similar between patients receiving perampanel and placebo. In phase I subjects/volunteers, all psychiatric TEAEs were mild or moderate. These analyses suggest that psychiatric adverse effects are associated with use of perampanel. SIGNIFICANCE: Patients and caregivers should be counseled regarding the potential risk of psychiatric and behavioral events with perampanel in patients with partial seizures; patients should be monitored for these events during treatment, especially during titration and at higher doses.

Efficacy and safety of perampanel in patients with drug-resistant partial seizures after conversion from double-blind placebo to open-label perampanel.

OBJECTIVE: To evaluate the efficacy and safety of perampanel in patients with drug-resistant partial seizures after the conversion from double-blind placebo in three phase III studies to open-label perampanel, and to assess the impact of perampanel titration rates through a comparison of weekly vs biweekly dose increases. METHODS: Patients who completed the three multinational, double-blind, placebo-controlled, phase III core studies (studies 304, 305, or 306) were eligible to enroll in the extension study (study 307). Patients completing the double-blind treatment (6-week titration, 13-week maintenance) with placebo (DB-PBO) or perampanel (DB-PER) began the extension study with a 16-week blinded conversion period, during which DB-PBO patients were switched to perampanel. Doses were titrated in 2-mg increments (biweekly) to an individualized maximum tolerated dose of perampanel (up to 12 mg/day). Patients then entered a planned, open-label treatment period. RESULTS: Perampanel treatment during the extension study reduced total seizure frequency/28 days relative to the double-blind prerandomization baseline regardless of prior perampanel or placebo treatment in the core studies. In the DB-PBO patients, median percent reductions in seizure frequency at the end of the double-blind period, at the end of the conversion period, and at Weeks 40-52 in the open-label maintenance period were 18.6%, 44.3%, and 55.0%, respectively. Seizure control was also improved in the DB-PER patients during the extension period compared to the end of the double-blind period. Responder rates were similar between the 2 patient groups at the end of the conversion period. Perampanel was well tolerated, with the most common treatment-emergent adverse events being dizziness, somnolence, weight increase, irritability, fatigue, and headache. For those patients randomized to the 12 mg group (DB-PER 12 mg), 78.4% reached the daily dose of 10 or 12 mg by the end of the 6-week titration period of the double-blind phase. By the end of the 16-week conversion period of the extension study, 64.0% of DB-PBO patients reached the daily dose of 10 or 12 mg. Seizure frequency reduction was greater after the first 13-week maintenance period of the extension study in the DB-PBO group compared to patients assigned to DB-PER 12mg during the 13-week maintenance period of the double-blind study. CONCLUSION: Patients who received placebo in the phase III core DB studies and transitioned to perampanel in the open-label extension study (DB-PBO) achieved seizure control at the end of the conversion period similar to that of patients who had been previously exposed to perampanel (DB-PER) as well as comparable safety outcomes. Patients who received perampanel during the core studies and continued with treatment during the extension study (DB-PER) also showed sustained improvements in seizure control with long-term exposure to perampanel.

Perampanel efficacy and safety by gender: Subanalysis of phase III randomized clinical studies in subjects with partial seizures.

The antiepileptic drug (AED) perampanel is approved in ≥40 countries as adjunctive therapy for drug-resistant partial seizures in patients with epilepsy. This post hoc analysis of pooled data from three phase III, double-blind, randomized studies of perampanel examines between-gender differences in perampanel efficacy and safety. Of the 1,478 subjects in the pooled analysis (719 male, 759 female), 1,109 were included in the pharmacokinetic/pharmacodynamic analysis. Perampanel oral clearance was 17% lower in female than in male patients not receiving enzyme-inducing AEDs. Pooled efficacy analysis revealed that seizure frequency was reduced with perampanel treatment regardless of gender; a greater numerical reduction in seizure frequency and increased responder rates occurred in female participants at perampanel doses of 4, 8, and 12 mg. Tolerability was similar between groups, although common adverse events such as dizziness and headache occurred more frequently in female subjects. Modest elevations in perampanel exposure in female patients may result in meaningful between-gender differences in efficacy and safety; therefore, dosing should be individualized and clinical response monitored.

Absence of Liver Toxicity in Perampanel-Treated Subjects: Pooled results from partial seizure phase III perampanel clinical studies.

OBJECTIVE: The liver plays a major role in the metabolism and elimination of many antiepileptic drugs (AEDs), including perampanel. Some of the metabolites identified for perampanel are likely formed via reactive intermediates, which have the potential to covalently bind to protein and cause idiosyncratic toxicities, including hepatotoxicity. The approved AED perampanel is a selective, noncompetitive AMPA receptor antagonist. The safety and tolerability of perampanel have been well documented in 3 double-blind, randomized, placebo-controlled, phase III studies. Here we report the effects of perampanel on liver function in patients from the phase III studies to assess the potential for liver toxicity. METHODS: Following 6-week baseline, patients (≥12 years old) with drug-resistant partial seizures were randomized to once-daily double-blind treatment (6-week titration, 13-week maintenance) with 2, 4, 8, or 12mg perampanel (n=1038) or with placebo (n=442). Clinical laboratory tests for hepatobiliary laboratory parameters were evaluated at baseline and at end of treatment. These included alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and total bilirubin. Treatment-emergent markedly abnormal values (an increase in NCI-CTC grade relative to baseline and a grade ≥2) and treatment-emergent adverse events (TEAEs) related to hepatobiliary parameters were also recorded. RESULTS: Mean hepatobiliary values were within normal ranges at baseline and end of treatment for all perampanel groups and placebo. Mean changes from baseline to end of treatment were small. The incidence of markedly abnormal results was very low for perampanel and placebo. TEAEs related to hepatobiliary parameters occurred in 0.4% of perampanel patients and 0% of placebo patients. Hepatobiliary disorders included cholelithiasis (n=3 in perampanel) and abnormal hepatic function (n=1 in perampanel). None of the events were serious or led to perampanel discontinuation. No subject had values that met the criteria for Hy's Law. CONCLUSION: Hepatobiliary laboratory data and related TEAEs were not notably different between perampanel and placebo treatment groups, and no dose-related trends were observed. Based on the laboratory results from the 3 Phase III studies, perampanel (2, 4, 8, and 12mg) demonstrated no clinically important effects on liver function tests, indicating perampanel is an AED with a low potential for drug-induced liver toxicity.

Efficacy and safety of perampanel in the subgroup of elderly patients included in the phase III epilepsy clinical trials.

Clinical data regarding use of antiepileptic drugs in the elderly are generally scarce. Therefore, a subanalysis of subjects aged ≥ 65 years who participated in the 3 phase III perampanel studies was undertaken to determine efficacy and safety in these patients. Efficacy (change in seizure frequency/28 days and 50% responder rate) in the elderly subgroup was found to be consistent with the adult population. Adverse event rates were also largely similar, with some exceptions. Because risks of falls, dizziness, and fatigue were greater in the elderly, careful titration of perampanel in patients aged ≥ 65 years is suggested, especially at higher doses, where balancing tolerability and clinical response is necessary.

Endosomal/lysosomal processing of gangliosides affects neuronal cholesterol sequestration in Niemann-Pick disease type C.

Niemann-Pick disease type C (NPC) is a severe neurovisceral lysosomal storage disorder caused by defects in NPC1 or NPC2 proteins. Although numerous studies support the primacy of cholesterol storage, neurons of double-mutant mice lacking both NPC1 and an enzyme required for synthesis of all complex gangliosides (ß1,4GalNAc transferase) have been reported to exhibit dramatically reduced cholesterol sequestration. Here we show that NPC2-deficient mice lacking this enzyme also exhibit reduced cholesterol, but that genetically restricting synthesis to only a-series gangliosides fully restores neuronal cholesterol storage to typical disease levels. Examining the subcellular locations of sequestered compounds in neurons lacking NPC1 or NPC2 by confocal microscopy revealed that cholesterol and the two principal storage gangliosides (GM2 and GM3) were not consistently co-localized within the same intracellular vesicles. To determine whether the lack of GM2 and GM3 co-localization was due to differences in synthetic versus degradative pathway expression, we generated mice lacking both NPC1 and lysosomal ß-galactosidase, and therefore unable to generate GM2 and GM3 in lysosomes. Double mutants lacked both gangliosides, indicating that each is the product of endosomal/lysosomal processing. Unexpectedly, GM1 accumulation in double mutants increased compared to single mutants consistent with a direct role for NPC1 in ganglioside salvage. These studies provide further evidence that NPC1 and NPC2 proteins participate in endosomal/lysosomal processing of both sphingolipids and cholesterol.

Prevalence of risk factors, and not gender per se, determines short- and long-term survival after coronary artery bypass surgery.

OBJECTIVE: Much attention has been directed towards female gender as an independent risk factor for in-hospital mortality after coronary artery bypass grafting surgery; however, the effects of surgery are known to persist for 6 months or more. Studies that have compared postoperative survival in women and men beyond hospital discharge report disparate results with regard to the independent effect of gender per se on ultimate survival. DESIGN: This investigation was a prospective, observational study. SETTING: The study was a multicenter investigation involving 24 US medical centers. PARTICIPANTS: There were 2,048 patients undergoing isolated coronary artery bypass graft surgery enrolled between September 1991 and September 1993 and after discharge. INTERVENTIONS: There were no interventions with this prospective observational study. MEASUREMENTS AND MAIN RESULTS: Preoperative demographic variables, medical history, and angiographic data were collected for each patient at the time of enrollment. Patients' vital status through the National Death Index up to August 31, 1998, were added to assess postoperative long-term survival. For survivorship analysis, the Kaplan-Meier product-limit method was used with Cox regression model. Survivorship analyses were performed separately and in combination on mortality within 30 days and 6 months of coronary artery bypass graft surgery and during the entire postoperative follow-up period. Among women, preoperative disease status, as expected, was more severe than that in men. Women were older (p = 0.0001) and had more comorbidity, such as congestive heart failure (p = 0.0019), diabetes (p = 0.0001), anemia, and hypertension (p = 0.0001). After surgery, unadjusted survival of 6 months and 5 years in women was worse than that in men. However, there were no gender-related differences in short- or long-term survival after adjusting for covariates in the multivariate model. Preoperative conditions, such as congestive heart failure, anemia, diabetes, and advanced age, are indicative of greater risk in both women and men for lower survival after coronary artery bypass graft surgery. CONCLUSIONS: Disease prevalence in women, and not gender per se, affects mid- and long-term survival after cardiac surgery. Attention, therefore, should be focused on efforts to reduce or modify such disease prevalence earlier in women, which may in turn allow longer survival after surgical intervention. Differences in postoperative survival between women and men were related to the gender differences in the distribution of preoperative risk factors.