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Objective To investigate the relationship of A1298C (rs1801131) polymorphism in the MTHFR gene encoding methylenetetrahydrofolate reductase with the cerebrospinal fluid β-amyloid 1-42 subtype (Aβ1-42) level, cognitive level, and brain structure changes in patients with Alzheimer’s disease (AD). Methods A total of 1 271 subjects who met the inclusion criteria in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were selected. A multivariable linear regression model was used to analyze the relationship of MTHFR gene A1298C (rs1801131) polymorphism with cerebrospinal fluid Aβ1-42 level, cognitive level, and brain structure changes in AD patients. A mediation model was used to analyze the role of cerebrospinal fluid Aβ1-42 level in mediating the relationship between MTHFR gene A1298C (rs1801131) polymorphism and cognitive level. Results Multivariable linear regression model analysis showed that A1298C-C allele was negatively correlated with the level of Aβ1-42 in cerebrospinal fluid, hippocampal volume, and cognitive level (β=-0.121--0.084,t=-3.308--1.953,P

Background: Fremanezumab, a fully humanized monoclonal antibody targeting calcitonin gene-related peptide, has demonstrated efficacy for the preventive treatment of migraine in adults. Objective: To evaluate the effect of fremanezumab treatment on acute headache medication use and migraine-associated symptoms in patients with episodic migraine. Methods: In the Phase 3 HALO trial, patients with episodic migraine were randomized to receive subcutaneous fremanezumab monthly (225 mg at baseline, weeks 4 and 8), fremanezumab quarterly (675 mg at baseline, placebo at weeks 4 and 8), or placebo over a 12-week period. The secondary endpoint was change from baseline in the monthly number of days with use of any acute headache mediation or migraine-specific acute headache medication; exploratory endpoints were change from baseline in the monthly number of days with nausea or vomiting, photophobia, or phonophobia. Results: Of 875 patients randomized, 865 were included in the analysis (monthly, n = 287; quarterly, n = 288; placebo, n = 290). Baseline mean ± standard deviation days with: Any acute headache medication use (monthly: 7.7 ± 3.4; quarterly: 7.8 ± 3.7; placebo: 7.7 ± 3.6), migraine-specific acute headache medication use (6.1 ± 3.1; 6.6 ± 3.1; 7.1 ± 3.0), nausea or vomiting (4.5 ± 3.6; 4.9 ± 3.7; 4.5 ± 3.3) and photophobia and phonophobia (5.5 ± 4.1; 6.3 ± 4.1; 6.0 ± 3.9) were similar among treatment arms. Fremanezumab reduced the number of days of acute headache medication use ([least-squares mean change vs. placebo] monthly: −1.4 [95% confidence interval: −1.84, −0.89], p < 0.001; quarterly: −1.3 [−1.76, −0.82], p < 0.001) and migraine-specific acute headache medication use (monthly: −2.2 [−2.80, −1.56], p < 0.001; quarterly: −2.2 [−2.81, −1.58], p < 0.001) compared with placebo. Fremanezumab also reduced nausea or vomiting, photophobia, and phonophobia compared with placebo. Conclusions: Fremanezumab reduced the need for acute headache medications, including migraine-specific medications, while treating migraine-associated symptoms in patients with episodic migraine. Trial registration: Clinicaltrials.gov NCT02629861 [ABSTRACT FROM AUTHOR]

Objective: To assess the intranasal abuse potential of hydrocodone extended-release (ER) tablets developed with CIMA Abuse-Deterrence Technology compared with hydrocodone powder and hydrocodone bitartrate ER capsules (Zohydro ER, original formulation [HYD-OF])., Design: Single-dose, randomized, double-blind, quadruple-dummy, active- and placebo-controlled, crossover study., Setting: One US site., Subjects: Healthy, adult, nondependent, recreational opioid users., Methods: Subjects able to tolerate intranasal hydrocodone and discriminate hydrocodone from placebo were eligible for study enrollment. Eligible participants randomly received intranasal hydrocodone ER, intranasal hydrocodone powder, intranasal HYD-OF, intact oral hydrocodone ER, and placebo. Coprimary pharmacodynamic end points were a maximum effect on "at the moment" Drug Liking visual analog scale and Overall Drug Liking visual analog scale. Pharmacokinetics and safety were assessed., Results: Mean maximum effect for "at the moment" Drug Liking was significantly (P < 0.01) lower for intranasal hydrocodone ER (72.8) compared with hydrocodone powder (80.2) and HYD-OF (83.2). Similar results were observed for Overall Drug Liking maximum effect (68.5 vs 77.1 and 79.8, respectively; P < 0.01). Secondary end points, including balance of effects and positive, sedative, and other effects, were consistent with these results. Intranasal treatments showed significantly greater effects vs placebo, while intact oral hydrocodone ER was similar to placebo. For each treatment, plasma concentration-time profiles paralleled "at the moment" Drug Liking over time. Incidences of adverse events for intranasal treatments were 52% for hydrocodone ER, 53% for hydrocodone powder, and 61% for HYD-OF., Conclusions: The statistically significant differences between hydrocodone ER vs hydrocodone powder and HYD-OF for the primary drug liking end points indicate a lower intranasal abuse potential with hydrocodone ER in healthy, nondependent, recreational opioid users.

Objective: To evaluate long-term safety, maintenance of analgesia, and aberrant drug-related behaviors of hydrocodone extended release (ER) formulated with CIMA® Abuse-Deterrence Technology., Design: Phase 3, multicenter, open-label extension., Setting: Fifty-six US centers., Patients: Adults with chronic low back pain completing a 12-week placebocontrolled study of abuse-deterrent hydrocodone ER were eligible. One hundred eighty-two patients enrolled and received ≥1 dose of study drug, 170 entered openlabel treatment, and 136 completed the study., Interventions: Patients receiving hydrocodone ER in the 12-week, placebo-controlled study continued their previous dose unless adjustment was needed; those previously receiving placebo (n=78) underwent dose titration/adjustment to an analgesic dose (15-90 mg every 12 hours). Patients received 22 weeks of open-label treatment., Safety: adverse events (AEs). Maintenance of analgesia: worst pain intensity (WPI) and average pain intensity (API) at each study visit. Aberrant drug behavior: study drug loss and diversion., Results: AEs were reported for 65/182 (36 percent) patients during dose titration/ adjustment and 88/170 (52 percent) during open-label treatment. No treatmentrelated serious AEs were reported. There were no clinically meaningful trends in other safety assessments, including physical examinations and pure tone audiometry. One patient receiving hydrocodone ER 30 mg twice daily experienced a severe AE of neurosensory deafness that was considered treatment related. Mean WPI and API remained steady throughout open-label treatment. Six (3 percent) patients reported medication loss, and 5 (3 percent) reported diversion., Conclusions: Abuse-deterrent hydrocodone ER was generally well tolerated in patients with chronic low back pain, maintained efficacy, and was associated with low rates of loss and diversion.

Objective: To evaluate long-term safety of hydrocodone extended-release (ER) formulated with CIMA(®) Abuse-Deterrence Technology platform., Design: Phase 3, open-label study., Setting: Sixty-one US study centers., Patients: Patients with chronic pain newly enrolled or rolled over from a 12-week, placebo-controlled hydrocodone ER study; 330 patients enrolled, 329 patients received study drug, and 189 completed the study., Intervention: After titrating to an analgesic dose (15-90 mg every 12 hours), patients received ≤ 52 weeks of open-label treatment., Safety: adverse events (AEs), vital signs, laboratory values, electrocardiograms, and audiometry. Abuse potential: drug loss and diversion, Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R), Addiction Behaviors Checklist (ABC), Current Opioid Misuse Measure (COMM) questionnaires, and Patient Global Assessment (PGA) of pain control., Results: Of 329 patients who received ≥ 1 hydrocodone ER dose, 284 (86 percent) reported ≥ 1 AE and 27 (8 percent) experienced ≥ 1 serious AE. Sixty-two (19 percent) patients withdrew because of AEs, and two AEs leading to death were reported. No serious AEs or AEs leading to death were considered treatment related by the investigator. There were no clinically meaningful trends in other safety assessments. SOAPP-R, ABC, and COMM scores demonstrated low risk of aberrant drug-related behavior. Good/excellent PGA responses were reported by 20 percent of patients at baseline and 75 percent at endpoint. The incidence of drug loss (11 percent) and diversion (2 percent) was low., Conclusions: Hydrocodone ER demonstrated acceptable safety when administered for ≤ 12 months in patients with chronic pain. Low occurrence of aberrant drugrelated behavior may support the abuse-deterrence properties of hydrocodone ER.