A multicenter, open-label long-term safety study of rimegepant for the acute treatment of migraine.

BACKGROUND: The present study evaluated the long-term safety and tolerability of rimegepant, an orally administered small molecule calcitonin gene-related peptide receptor antagonist, in people with migraine. METHODS: This multicenter, long-term, open-label safety study included adults (≥18 years) with ≥1 year history of migraine who were sequentially enrolled into three groups: participants in the first two groups had either 2-8 or 9-14 moderate to severe migraine attacks per month by history and treated as needed (pro re nata [PRN]) with one rimegepant 75 mg oral tablet up to once per calendar day for 52 weeks (PRN 2-8 and PRN 9-14); a third group, included to collect safety data during higher-frequency dosing, had 4-14 moderate to severe migraine attacks per month by history and who took one rimegepant tablet every other day as scheduled dosing plus PRN dosing of one rimegepant tablet for migraine attacks of any severity on nonscheduled dosing days for 12 weeks (every other day (EOD) + PRN). RESULTS: Overall, 1800 participants self-administered rimegepant (PRN 2-8: n = 1033; PRN 9-14: n = 481; EOD + PRN: n = 286). The most common on-treatment adverse events (AEs) were upper respiratory tract infection (8.8%), nasopharyngitis (6.8%) and sinusitis (5.1%). Most AEs were mild or moderate and considered unrelated to rimegepant. Serious AEs considered possibly (n = 1) or unlikely (n = 9) related to rimegepant were reported in ten (0.6%) participants. No signal of drug-induced liver injury because of rimegepant was identified. CONCLUSIONS: Rimegepant 75 mg up to once per day as EOD + PRN for 12 weeks or PRN for up to 52 weeks was safe and well tolerated. No signal of hepatotoxicity, potential drug abuse, or medication-overuse headache was identified.Trial registration: Clinicaltrials.gov: NCT03266588.

Chemical control of spin-lattice relaxation to discover a room temperature molecular qubit.

The second quantum revolution harnesses exquisite quantum control for a slate of diverse applications including sensing, communication, and computation. Of the many candidates for building quantum systems, molecules offer both tunability and specificity, but the principles to enable high temperature operation are not well established. Spin-lattice relaxation, represented by the time constant T 1, is the primary factor dictating the high temperature performance of quantum bits (qubits), and serves as the upper limit on qubit coherence times (T 2). For molecular qubits at elevated temperatures (>100 K), molecular vibrations facilitate rapid spin-lattice relaxation which limits T 2 to well below operational minimums for certain quantum technologies. Here we identify the effects of controlling orbital angular momentum through metal coordination geometry and ligand rigidity via π-conjugation on T 1 relaxation in three four-coordinate Cu2+ S = ½ qubit candidates: bis(N,N'-dimethyl-4-amino-3-penten-2-imine) copper(ii) (Me2Nac)2 (1), bis(acetylacetone)ethylenediamine copper(ii) Cu(acacen) (2), and tetramethyltetraazaannulene copper(ii) Cu(tmtaa) (3). We obtain significant T 1 improvement upon changing from tetrahedral to square planar geometries through changes in orbital angular momentum. T 1 is further improved with greater π-conjugation in the ligand framework. Our electronic structure calculations reveal that the reduced motion of low energy vibrations in the primary coordination sphere slows relaxation and increases T 1. These principles enable us to report a new molecular qubit candidate with room temperature T 2 = 0.43 µs, and establishes guidelines for designing novel qubit candidates operating above 100 K.

Patient-Reported Outcomes from a 1-Year, Real-World, Head-to-Head Comparison of OnabotulinumtoxinA and Topiramate for Headache Prevention in Adults With Chronic Migraine.

INTRODUCTION/OBJECTIVE: Chronic migraine (CM) is associated with impaired health-related quality of life and substantial socioeconomic burden, but many people with CM are underdiagnosed and do not receive appropriate preventive treatment. OnabotulinumtoxinA and topiramate have demonstrated efficacy (treatment benefit under ideal conditions) for the prevention of headaches in people with CM in clinical trials, but real-world studies suggest markedly different clinical effectiveness (treatment benefit based on a blend of efficacy and tolerability). This study sought to evaluate patient-reported outcomes (PROs) of onabotulinumtoxinA versus topiramate immediate release for people with CM. METHODS: FORWARD was a prospective, multicenter, randomized, parallel-group, open-label, phase 4 study comparing onabotulinumtoxinA 155 U every 12 weeks with topiramate 50 to 100 mg/day for ≤36 weeks in people with CM. PROs measured included the Headache Impact Test (HIT-6), 9-item Patient Health Questionnaire Quick Depression Assessment (PHQ-9), Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP), and Functional Impact of Migraine Questionnaire (FIMQ). RESULTS: A total of 282 patients were randomized and treated with onabotulinumtoxinA (n = 140) or topiramate (n = 142). From baseline to week 30, mean HIT-6 test scores improved significantly in patients taking onabotulinumtoxinA compared with topiramate (P < .001). Improvements in depression over time were observed via larger changes in PHQ-9 scores with onabotulinumtoxinA than topiramate (P < .001). Work productivity assessed via WPAI:SHP scores revealed significant improvements with onabotulinumtoxinA versus topiramate in Work Productivity Loss (P = .024) and Activity Impairment (P < .001) domains. Results from the FIMQ also revealed a larger reduction from baseline with onabotulinumtoxinA vs topiramate (P < .0001). CONCLUSION: OnabotulinumtoxinA treatment had more favorable real-world effectiveness than topiramate on depression, headache impact, functioning and daily living, activity, and work productivity. The overall study results suggest that the beneficial effects on a range of PROs are the result of improved effectiveness when onabotulinumtoxinA is used as preventive treatment for CM. TRIAL REGISTRATION: CLINICALTRIALS.GOV: NCT02191579; https://clinicaltrials.gov/ct2/show/NCT02191579.

Room Decontamination Using Ionized Hydrogen Peroxide Fog and Mist Reduces Hatching Rates of Syphacia obvelata Ova.

This study evaluated the efficacy of ionized hydrogen peroxide (iHP) fog and mist for environmental and surface decontaminationof Syphacia obvelata ova in rodent rooms. Ova were collected by perianal tape impression from S. obvelata infectedmice. In experiment 1, ova were exposed to iHP using a whole-room fogging decontamination system with a 15 min initialfog application cycle in unoccupied rodent rooms. Ova were removed from the fogged environment after a 15 min, 30 min, 90min, or 240 min iHP exposure time. In experiment 2, a second cohort of ova were exposed to iHP using the whole-room foggingdecontamination system. Ova were removed after 3, 4 or 6 continuous fog application cycles with 45 min dwelling timebetween each cycle and 15 h dwelling time for the last time point. In experiment 3, a third set of ova was exposed to an iHPsurface misting unit with 1, 2, or 3 iHP mist applications. A 7 min contact time followed each application. After exposure, ovawere incubated in a hatching medium for 6 h. Control ova were maintained at room temperature without iHP exposure beforeincubation in the hatching medium. After incubation, the number of ova hatched was assessed by microscopic examination.For experiment 1, results ranged from 46% to 57% of exposed ova hatched. For experiment 2, results ranged from 43% to 49%of ova hatched. For experiment 3, 37% to 46% of exposed ova hatched. Conversely, for the control groups above 80% of ovahatched for all 3 experiments. These data suggest that exposure to iHP fog and mist has variable effectiveness in reducingviability of S. obvelata ova at the time points tracked. Further studies are needed to identify iHP exposures that will furtherreduce or eliminate the hatching of rodent pinworm ova.

Potential for treatment benefit of small molecule CGRP receptor antagonist plus monoclonal antibody in migraine therapy.

OBJECTIVE: To provide the first clinical report that 2 calcitonin gene-related peptide (CGRP) therapies, a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody, can be used concomitantly to treat refractory migraine. METHODS: Case reports are presented of 2 patients participating in a long-term safety study of rimegepant 75 mg oral tablets for acute treatment (NCT03266588). After Food and Drug Administration approval of erenumab, both patients started subcutaneous erenumab monthly as allowed per protocol. RESULTS: Patients were women 44 and 36 years of age with ≥2 decades of self-reported suboptimal response to multiple migraine medications. Patient 1 used rimegepant for 6 months and then started erenumab 70 mg subcutaneous monthly. Despite a response to preventive treatment with erenumab, she experienced substantial relief treating 7 of 7 acute attacks with rimegepant and eliminated regular, frequent use of ibuprofen and a caffeinated analgesic. Patient 2 used rimegepant for 60 days before starting erenumab 140 mg subcutaneously monthly. While on erenumab, 9 of 9 attacks treated with rimegepant responded. She stopped near-daily use of injectable ketorolac and diphenhydramine. While using rimegepant alone or together with erenumab, patients reported no related adverse events. CONCLUSIONS: Rimegepant 75 mg may be effective for acute treatment during concomitant erenumab preventive administration. The mechanism underlying the benefits of concomitant use of a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody is unknown and requires further study. CLINICALTRIALSGOV IDENTIFIER: NCT03266588. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with migraine using erenumab, rimegepant is effective for acute treatment.

Correlation of Hemorrhage Near Developing Opossum Skull With Pulsed Ultrasound Exposure Parameters.

OBJECTIVES: High-intensity focused ultrasound (HIFU) has been used noninvasively for therapeutic applications. Before HIFU can be used therapeutically on a human fetus, the bioeffects related to HIFU must be studied, and the mechanism causing the bioeffects should be understood. Previous studies have shown that HIFU, when targeted on fetal rat and mice bones. resulted in hemorrhage. However, the mechanism responsible has not been identified. In this study, we looked at ultrasound parameters related to hemorrhage in an effort to better understand the mechanism. METHODS: Brazilian opossum pups (7-8 postnatal days) were exposed to a 1.1-MHz f/1 spherically focused transducer (6.3 cm focal length). Four treatment groups of n = 14 and a control group of n = 14 were exposed to rarefactional pressures of 3.6 to 6 MPa with spatial-peak temporal average intensity values of 5.4 to 10.8 W/cm(2). The pulse repetition frequency was varied from 500 to 1000 Hz with exposure durations of 1 to 4 minutes. RESULTS: Four groups with sample sizes of 14 had hemorrhage percentages of 43%, 36%, 29%, and 36%, respectively. Hemorrhage occurrence and size were found to correlate strongly with the nonlinear product of energy density and number of pulses, with correlation values of 0.92 and 0.97, respectively. CONCLUSIONS: The dependence of hemorrhage on energy density and the number of pulses suggests that the hemorrhage may be due to high-stress, low-cycle mechanical fatigue damage. Hence, for therapeutic applications, the product of energy density and number of pulses should not exceed a certain predetermined limit.

Education and decision making at the time of triptan prescribing: patient expectations vs actual practice.

BACKGROUND: Optimizing patient satisfaction with their medical care and maximizing patient adherence with treatment plans requires an understanding of patient preferences regarding education and their role in decision making when treatments are prescribed. OBJECTIVE: To assess the congruence between patient expectations and actual practice regarding education and decision making at the time a triptan is prescribed. METHODS: This multicenter cross-sectional survey was performed by headache fellow members of the American Headache Society Headache Fellows Research Consortium at their respective tertiary care headache clinics. Migraine patients who were new patients to the headache clinic and who were current triptan users (use within prior 3 months and for ≥1 year) or past triptan users (no use within 6 months; prior use within 2 years) completed questionnaires that assessed the education they received and their role in decision making at the time a triptan was first prescribed as well as their desire for education and participation in decision making when a triptan is prescribed. RESULTS: Consistent with patient preference, most participants received the majority of their education about the triptan from the prescriber's office (70.2%). In descending rank order, participants most desired to be informed about how to decide if a triptan should be taken, when during the course of migraine a triptan should be taken, possible side effects, cost, and how to obtain refills. Regarding side effects, most participants preferred to receive education about the most common side effects of a triptan rather than addressing all possible side effects. Regarding triptan dosing, participants desired to be informed in descending order of importance about taking other medications with triptans, how many doses can be taken for each migraine, how many doses can be taken each week/month, what to do if the triptan does not work, and the triptan mechanism of action. The vast majority of participants (92%) preferred that the decision to prescribe a triptan be a joint decision between the patient and the provider. In actual practice, participants were not as involved in decision making as they would like to be, with patients reporting that the prescriber was the sole decision maker 55.1% of the time. Participants had confidence in their providers (87.7%) and generally felt they did a good job educating them about the triptan (71.1%). CONCLUSIONS: Based on this study, it is clear that patients prefer the shared model approach to medical decision making in regards to the prescription of triptans. The majority of patients received education that was generally consistent with their desires. Patients preferred that the prescribing provider be the primary source of information. The most desired educational topics included when/if a triptan should be taken, the number of times a triptan can be taken for a single migraine, co-administration with other acute medications, and the most common side effects. Focusing on these topics should enhance patient satisfaction and may improve compliance.

Transplacental transmission of Leishmania infantum as a means for continued disease incidence in North America.

BACKGROUND: Dogs are the predominant domestic reservoir for human L. infantum infection. Zoonotic visceral leishmaniasis (ZVL) is an emerging problem in some U.S. dog breeds, with an annual quantitative PCR prevalence of greater than 20% within an at-risk Foxhound population. Although classically Leishmania is transmitted by infected sand flies and phlebotomine sand flies exist in the United States, means of ongoing L. infantum transmission in U.S. dogs is currently unknown. Possibilities include vertical (transplacental/transmammary) and horizontal/venereal transmission. Several reports have indicated that endemic ZVL may be transmitted vertically. AIMS: Our aims for this present study were to establish whether vertical/transplacental transmission was occurring in this population of Leishmania-infected US dogs and determine the effect that this means of transmission has on immune recognition of Leishmania. METHODOLOGY: A pregnant L. infantum-infected dam donated to Iowa State University gave birth in-house to 12 pups. Eight pups humanely euthanized at the time of birth and four pups and the dam humanely euthanized three months post-partum were studied via L. infantum-kinetoplast specific quantitative PCR (kqPCR), gross and histopathological assessment and CD4+ T cell proliferation assay. KEY RESULTS: This novel report describes disseminated L. infantum parasites as identified by kqPCR in 8 day old pups born to a naturally-infected, seropositive U.S. dog with no travel history. This is the first report of vertical transmission of L. infantum in naturally-infected dogs in North America, emphasizing that this novel means of transmission could possibly sustain infection within populations. MAJOR CONCLUSIONS: Evidence that vertical transmission of ZVL may be a driving force for ongoing disease in an otherwise non-endemic region has significant implications on current control strategies for ZVL, as at present parasite elimination efforts in endemic areas are largely focused on vector-borne transmission between canines and people. Determining frequency of vertical transmission and incorporating canine sterilization with vector control may have a more significant impact on ZVL transmission to people in endemic areas than current control efforts.

Reduced hamster usage and stress in propagating Leishmania chagasi promastigotes using cryopreservation and saphenous vein inoculation.

Leishmania chagasi, a causal agent of visceral leishmaniasis, requires passage through lab animals such as hamsters to maintain its virulence. Hamster infection is typically accomplished via cardiac puncture or intraperitoneal injection, procedures accompanied by risks of increased animal stress and death. The use of the hamster model also necessitates a regular supply of infected animals, because L. chagasi parasites newly isolated from an infected hamster can be grown in culture for only several weeks before loss of function/phenotype occurs. In an effort to decrease animal usage and animal stress, experiments were performed to assess a more gentle inoculation procedure (saphenous vein inoculation) and the use of cryopreserved parasite cells for research experiments. Of 81 hamsters inoculated by the saphenous vein, 80 became infected as determined ante mortem, by display of clinical symptoms of leishmaniasis (onset of symptoms at 105 +/- 22 days post-inoculation), and postmortem by the presence of parasites within the spleen. Splenic parasite load calculated for a subset (n = 34) of infected hamsters was 124 to 26,177 Leishmania donovani infection units. Cryopreserved, and never-stored, cells were equivalent in all properties evaluated, including developmental changes in morphology during culture, culture growth rates, parasite resistance to serum-mediated lysis, and expression of developmentally regulated surface proteins major surface protease and promastigote surface antigen.

Immunologic indicators of clinical progression during canine Leishmania infantum infection.

In both dogs and humans Leishmania infantum infection is more prevalent than disease, as infection often does not equate with clinical disease. Previous studies additively indicate that advanced clinical visceral leishmaniasis is characterized by increased production of anti-Leishmania antibodies, Leishmania-specific lymphoproliferative unresponsiveness, and decreased production of gamma interferon (IFN-gamma) with a concomitant increase of interleukin-10 (IL-10). In order to differentiate infection versus progressive disease for better disease prognostication, we temporally evaluated humoral and cellular immunologic parameters of naturally infected dogs. The work presented here describes for the first time the temporal immune response to natural autochthonous L. infantum infection in foxhounds within the United States. Several key changes in immunological parameters should be considered when differentiating infection versus clinical disease, including a dramatic rise in IgG production, progressive increases in antigen-specific peripheral blood mononuclear cell proliferation, and IFN-gamma production. Polysymptomatic disease is precluded by increased IL-10 production and consistent detection of parasite kinetoplast DNA in whole blood. This clinical presentation and the immuno-dysregulation mirror those observed in human patients, indicating that this animal model will be very useful for testing immunomodulatory anti-IL-10 and other therapies.

Fox squirrels (Sciurus niger) develop West Nile virus viremias sufficient for infecting select mosquito species.

The West Nile virus (WNV) viremia and shedding profiles of 11 adult fox squirrels (Sciurus niger) infected by needle inoculation or mosquito bite were characterized. Daily mean titers (95% confidence intervals) for all squirrels on days 1 through 6 postexposure (p.e.) were: 10(1.7 (1.32.1)), 10(4.4 (4.04.8)), 10(5.3 (5.05.6)), 10(4.4 (3.94.9)), 10(2.7 (2.03.4)), and 10(1.1 (0.52.1)) plaque-forming units (PFU)/mL. The highest WNV serum titers of individual squirrels infected by needle inoculation or mosquito bite ranged from 10(4.5) to 10(6.1) and from 10(5.1) to 10(5.3) PFU/mL, respectively. Nine (82%) squirrels, including all 4 squirrels infected by mosquito bite, had WNV serum titers > or =10(5.1) PFU/mL that persisted on average for 1.6 +/- 0.3 days. Infection and dissemination rates of Culex pipiens (L.) that fed on squirrels with serum titers of 10(4.4 +/- 0.1) PFU/mL were 56% and 13%, respectively. Both of these rates increased to over 80% when fed on squirrels with a mean WNV titer of 10(5.5 +/- 0.1) PFU/mL. Infection and dissemination also occurred in Aedes triseriatus (Say) but at a much lower rate. WNV was isolated from the oral and rectal cavities of all squirrels and from urine that was opportunistically collected from 5 squirrels. The largest quantity of WNV recovered from swabs of the oral cavity and urine was 10(3.1) PFU. The longest periods after exposure that WNV was isolated from the oral cavity and urine from a squirrel were 22 and 17 days p.e., respectively. WNV RNA was also detected in kidney tissue in 1 squirrel 29 days p.e., suggesting that fox squirrels can be persistently infected. Collectively these observations provide further evidence that squirrels can contribute to the natural history and epidemiology of WNV, especially in peridomestic environments.

Disseminated Leishmania infantum infection in two sibling foxhounds due to possible vertical transmission.

Two sibling foxhounds born to a Leishmania seropositive bitch were presented after testing seropositive for Leishmania. Leishmania infantum infection was detected via histopathology, culture, and quantitative polymerase chain reaction (q-PCR). This is the first report of natural infection with Leishmania infantum with the possibility for vertical transmission in North America.