A multicenter, open-label, long-term safety and tolerability study of DFN-02, an intranasal spray of sumatriptan 10 mg plus permeation enhancer DDM, for the acute treatment of episodic migraine.

BackgroundDFN-02 is a novel intranasal spray formulation composed of sumatriptan 10 mg and a permeation-enhancing excipient comprised of 0.2% 1-O-n-Dodecyl-β-D-Maltopyranoside (DDM). This composition of DFN-02 allows sumatriptan to be rapidly absorbed into the systemic circulation and exhibit pharmacokinetics comparable to subcutaneously administered sumatriptan. Rapid rate of absorption is suggested to be important for optimal efficacy. The objective of this study was to evaluate the safety and tolerability of DFN-02 (10 mg) in the acute treatment of episodic migraine with and without aura over a 6-month period based on the incidence of treatment-emergent adverse events and the evaluation of results of clinical laboratory tests, vital signs, physical examination, and electrocardiograms.MethodsThis was a multi-center, open-label, repeat-dose safety study in adults with episodic migraine with and without aura. Subjects diagnosed with migraine with or without aura according to the criteria set forth in the International Classification of Headache Disorders, 2nd edition, who experienced 2 to 6 attacks per month with fewer than 15 headache days per month and at least 48 headache-free hours between attacks, used DFN-02 to treat their migraine attacks acutely over the course of 6 months.ResultsA total of 173 subjects was enrolled, 167 (96.5%) subjects used at least 1 dose of study medication and were evaluable for safety, and 134 (77.5%) subjects completed the 6-month study. A total of 2211 migraine attacks was reported, and 3292 doses of DFN-02 were administered; mean per subject monthly use of DFN-02 was 3.6 doses. Adverse events were those expected for triptans, as well as for nasally administered compounds. No new safety signals emerged. Dysgeusia and application site pain were the most commonly reported treatment-emergent adverse events over 6 months (21% and 30.5%, respectively). Most of the treatment-emergent adverse events were mild. There were 5 serious adverse events, all considered unrelated to the study medication; the early discontinuation rate was 22.5% over the 6-month treatment period.ConclusionDFN-02 was shown to be well tolerated when used over 6 months to treat episodic migraine acutely

NON-PHARMACEUTICAL TREATMENT OF DEPRESSION USING A MULTIMODAL APPROACH

One hundred forty-one individuals suffering from chronic depression, unresponsive to previous drug therapy, were treated with a 44-hour program of education, Cranial Electrical Stimulation (CES), Brain Wave Synchronization (BWS), musical conditioning, and a mentally programmed quartz or glass "crystal" randomly assigned with therapists and patients blinded to the crystal's composition. Eighty· four percent of the depressed patients were improved at the end of two weeks of therapy, apparently as a result of the multimodal therapy and group interaction. The results at three months follow-up suggest a positive subtle energy effect of quartz: 70% of the depressed patients who received quartz remained improved, while only 31.5% of the depressed patients receiving glass remained improved. These differences are highly statistically significant. It appears that mentally "programmed" quartz may offer a significant reinforcement to allow patients better long-term recovery than would occur with placebo (glass). The cost effectiveness of such a therapeutic approach is significant. Other therapists are encouraged to replicate these studies

Shift in diagnostic classification of migraine after initiation of preventive treatment with eptinezumab: post hoc analysis of the PROMISE studies

Efficacy; Eptinezumab; PreventionEficacia; Eptinezumab; PrevenciónEficàcia; Eptinezumab; PrevencióBackground Monthly headache frequency directly correlates with personal/societal burden and impacts severity and preventive treatment decisions. This post hoc analysis identified shifts from higher to lower frequency headache categories over 6 months in patients with migraine participating in the PROMISE clinical trials receiving two eptinezumab doses. Methods Headache frequency at baseline and over study months 1–6 was categorized into 4 groups: chronic migraine (CM; ≥ 15 monthly headache days [MHDs]), high-frequency episodic migraine (HFEM; 10–14 MHDs), low-frequency episodic migraine (LFEM; 4–9 MHDs), and ≤ 3 MHDs. Outcomes included the percentage of patients within each MHD category, the percentage of patients improving by ≥ 1 MHD category, and the number of months with reduction of ≥ 1 MHD category. Data from patients who received approved eptinezumab doses (100 mg or 300 mg) or placebo were included. Results Mean headache frequency at baseline in PROMISE-1 was 10 MHDs; most patients were classified as having HFEM (48.6%) or LFEM (43.9%). At Month 1, 62/221 (28.1%), 75/222 (33.8%), and 45/222 (20.3%) patients who received eptinezumab 100 mg, 300 mg, and placebo had ≤ 3 MHDs, with 97/221 (43.9%), 108/222 (48.6%), and 84/222 (37.8%), respectively, falling below the diagnostic EM threshold at Month 6. More than one-third (79/221 [35.7%], 83/222 [37.4%], and 68/222 [30.6%] of patients in the eptinezumab 100 mg, 300 mg, and placebo groups, respectively), had 6 months of reduction of ≥ 1 frequency category. At baseline in PROMISE-2, mean headache frequency was 20.5 MHDs. All patients (100%) in the eptinezumab 100 mg and placebo groups had CM, as did 99.4% of patients receiving eptinezumab 300 mg. At Month 1, 209/356 (58.7%), 216/350 (61.7%), and 167/366 (45.6%) patients treated with eptinezumab 100 mg, 300 mg, and placebo had ≤ 14 MHDs, with 240/356 (67.4%), 249/350 (71.1%), and 221/366 (60.4%), respectively, falling below CM threshold at Month 6. Additionally, 153/356 (43.0%), 169/350 (48.3%), and 116/366 (31.7%) patients in the eptinezumab 100 mg, 300 mg, and placebo groups, respectively, had 6 months of reduction of ≥ 1 frequency category. Conclusion In the PROMISE studies, episodic and chronic migraine patients treated with eptinezumab were more likely to reduce their headache frequency versus placebo, which directly and in a sustained way improved their diagnostic category classification.The PROMISE trials were funded by Lundbeck Seattle BioPharmaceuticals, Inc., Bothell, WA, USA. The sponsor participated in the design and conduct of the study; data collection, management, analysis, and interpretation; and preparation, review, and approval of the manuscript. All statistical analyses were performed by a contracted research organization and were directed or designed by Pacific Northwest Statistical Consulting under contractual agreement with Lundbeck Seattle BioPharmaceuticals, Inc. All authors and H. Lundbeck A/S and Lundbeck Seattle BioPharmaceuticals, Inc. prepared, reviewed, and approved the manuscript and made the decision to submit the manuscript for publication. Editorial support for the development of this manuscript was funded by H. Lundbeck A/S

Signature Lipids and Stable Carbon Isotope Analyses of Octopus Spring Hyperthermophilic Communities Compared with those of Aquificales Representatives

The molecular and isotopic compositions of lipid biomarkers of cultured Aquificales genera have been used to study the community and trophic structure of the hyperthermophilic pink streamers and vent biofilm from Octopus Spring. Thermocrinis ruber, Thermocrinis sp. strain HI 11/12, Hydrogenobacter thermophilus TK-6, Aquifex pyrophilus, and Aquifex aeolicus all contained glycerol-ether phospholipids as well as acyl glycerides. The n-C20:1 and cy-C21 fatty acids dominated all of the Aquificales, while the alkyl glycerol ethers were mainly C18:0. These Aquificales biomarkers were major constituents of the lipid extracts of two Octopus Spring samples, a biofilm associated with the siliceous vent walls, and the well-known pink streamer community (PSC). Both the biofilm and the PSC contained mono- and dialkyl glycerol ethers in which C18 and C20 alkyl groups were prevalent. Phospholipid fatty acids included both the Aquificales n-C20:1 and cy-C21, plus a series of isobranched fatty acids (i-C15:0 to i-C21:0), indicating an additional bacterial component. Biomass and lipids from the PSC were depleted in 13C relative to source water CO2 by 10.9 and 17.2%, respectively. The C20?21 fatty acids of the PSC were less depleted than the iso-branched fatty acids, 18.4 and 22.6%, respectively. The biomass of T. ruber grown on CO2 was depleted in 13C by only 3.3% relative to C source. In contrast, biomass was depleted by 19.7% when formate was the C source. Independent of carbon source, T. ruber lipids were heavier than biomass (1.3%). The depletion in the C20?21 fatty acids from the PSC indicates that Thermocrinis biomass must be similarly depleted and too light to be explained by growth on CO2. Accordingly, Thermocrinis in the PSC is likely to have utilized formate, presumably generated in the spring source region

Rapid Responders to Frovatriptan in Acute Migraine Treatment: Results from a Long-Term, Open-Label Study

Background. the Chronic Nature of Migraine and the Reliance on Acute Treatment Constitute the Basis of the Present Long-Term, Open-Label Study. Objectives. First, Assessment of the Tolerability and Safety of Frovatriptan, 2.5-7.5 Mg Taken Orally over 24 Hours, for the Acute Treatment of Migraine, Repeatedly over a 12-Month Period. Second, Assessment of the Efficacy and Tolerability of a Second, Double-Blind Dose of 2.5-Mg Frovatriptan, Compared with Placebo, for Nonresponse at 2 Hours after Treatment of Moderate or Severe Headache with 2.5-Mg Frovatriptan. Results. with Regard to the First Attack Treated, 173 (36%) of the 486 Subjects in the Study Did Not Take a Second Dose at 2 Hours for Nonresponse. at 2 Hours and 4 Hours, These Rapid Responders Experienced a Decrease in Headache Intensity from Moderate or Severe to Mild or No Pain in 84% and 98%, Respectively ( Headache Response ). Six Percent of Them Experienced Recurrence of Moderate or Severe Headache within 24 Hours Following a Response at 4 Hours and 12% Took Rescue Medication. the Response, Measured in Terms of Median Time to Complete Migraine Relief, Was Maintained over 30 Subsequent Migraine Attacks, Treated from Attack 2 Onwards over the Course of 12 Months. Conclusion. Frovatriptan Provides a Remarkably Fast and High Headache Response in a Subgroup of More Than One-Third of Migraineurs, with a Very Low 24-Hour Headache Recurrence and Low Rescue Medication Intake. © 2009 American Academy of Pain Medicine

Eptinezumab for the prevention of chronic migraine: efficacy and safety through 24 weeks of treatment in the phase 3 PROMISE-2 (Prevention of migraine via intravenous ALD403 safety and efficacy-2) study.

BACKGROUND: PROMISE-2 was a phase 3, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of repeat intravenous (IV) doses of the calcitonin gene-related peptide-targeted monoclonal antibody eptinezumab (ALD403) for migraine prevention in adults with chronic migraine. This report describes the results of PROMISE-2 through 24 weeks of treatment. METHODS: Patients received up to two 30-min IV administrations of eptinezumab 100 mg, 300 mg, or placebo separated by 12 weeks. Patients recorded migraine and headache endpoints in a daily eDiary. Additional assessments, including patient-reported outcomes, were performed at regularly scheduled clinic visits throughout the 32-week study period (screening, day 0, and weeks 2, 4, 8, 12, 16, 20, 24, and 32). RESULTS: A total of 1072 adults received treatment: eptinezumab 100 mg, n = 356; eptinezumab 300 mg, n = 350; placebo, n = 366. The reduction in mean monthly migraine days observed during the first dosing interval (100 mg, - 7.7 days; 300 mg, - 8.2 days; placebo, - 5.6 days) was further decreased after an additional dose (100 mg, - 8.2 days; 300 mg, - 8.8 days; placebo, - 6.2 days), with both doses of eptinezumab demonstrating consistently greater reductions from baseline compared to placebo. The ≥50% and ≥ 75% migraine responder rates (MRRs) increased after a second dose, with more eptinezumab-treated patients experiencing migraine response than placebo patients (≥50% MRRs weeks 13-24: 100 mg, 61.0%; 300 mg, 64.0%; placebo, 44.0%; and ≥ 75% MRRs weeks 13-24: 100 mg, 39.3%; 300 mg, 43.1%; placebo, 23.8%). The percentages of patients who improved on patient-reported outcomes, including the Headache Impact Test and Patient Global Impression of Change, increased following the second dose administration at week 12, and were greater with eptinezumab than with placebo at all time points. No new safety concerns were identified with the second dose regarding the incidence, nature, and severity of treatment-emergent adverse events. CONCLUSION: Eptinezumab 100 mg or 300 mg administered IV at day 0 and repeated at week 12 provided sustained migraine preventive benefit over a full 24 weeks and demonstrated an acceptable safety profile in patients with chronic migraine. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT02974153 ). Registered November 23, 2016