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Plaque samples were collected and studied from orthodontic patients before and after placement of orthodontic bands and arch wires. The samples were assayed for changes in pH, carbohydrate content, and microbial populations of streptococci and lactobacilli. Statistically significant increases of plaque pH, carbohydrate content, and microbial populations were noted. [ABSTRACT FROM AUTHOR]

Zavegepant is a calcitonin gene-related peptide receptor antagonist for acute migraine treatment. This Phase I, open-label, fixed-sequence study evaluated the effects of itraconazole (a strong cytochrome P450 3A4 [CYP3A4] and P-glycoprotein [P-gp] inhibitor) on the pharmacokinetics of intranasal/oral zavegepant and the effects of rifampin (a strong inducer of CYP3A4 and P-gp; and an inhibitor of organic anion transporting polypeptide 1B3 [OATP1B3]) on oral zavegepant in healthy participants. In the intranasal/oral zavegepant-itraconazole cohort, participants received a single 10-mg dose of zavegepant nasal spray on Day 1, followed by oral zavegepant (50 mg) on Day 3. Itraconazole 200 mg once daily was administered from Days 4 to 12. On Day 7 zavegepant nasal spray and on Day 11 oral zavegepant were coadministered with itraconazole. In the oral zavegepant-rifampin cohort, participants received oral zavegepant (100 mg) on Day 1, rifampin 600 mg once daily on Days 2-10, and rifampin with zavegepant on Day 11. No significant change in zavegepant exposure was observed following coadministration of itraconazole with zavegepant nasal spray. For oral zavegepant coadministered with itraconazole, the area under the curve from 0 to infinity (AUC 0-inf ) and the maximum observed concentration (C max ) of oral zavegepant increased by 59% and 77%, respectively. For oral zavegepant coadministered with rifampin, the AUC 0-inf and C max of oral zavegepant increased by approximately 2.3- and 2.2-fold, respectively. These results suggest that OATP1B3 and intestinal P-gp are the more prominent pathways, as opposed to CYP3A4, for a zavegepant drug-drug interaction. Coadministration of OATP1B3 inhibitors with zavegepant nasal spray should be avoided., (© 2024 Pfizer Inc and The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: To compare the rate and extent of absorption of zavegepant 10 mg (therapeutic dose) or 20 mg (supratherapeutic dose) nasal spray during a migraine attack versus non-migraine period, assess safety, and explore efficacy and the relationship between zavegepant concentration and therapeutic response., Background: Physiologic changes occurring during a migraine attack could affect the pharmacokinetics of treatments for migraine., Methods: This was a Phase 1, multicenter, open-label, randomized, single-dose, two-period, fixed-sequence, comparative bioavailability study. Participants with a history of 2-8 migraine attacks per month of moderate or severe pain intensity were randomized to a single dose of zavegepant 10 or 20 mg, administered intranasally during a migraine attack (Period 1) and in a non-migraine period (Period 2). Blood samples were collected pre-dose and at pre-specified intervals up to 24 h post-dose for plasma zavegepant concentration measurement. Safety was monitored throughout, and efficacy (migraine pain intensity score, nausea, photophobia, phonophobia, aura, and functional disability) assessed during Period 1. Plasma zavegepant pharmacokinetic parameters were calculated by standard noncompartmental methods, including maximum plasma concentration (C max ), area under plasma concentration-time curve from time zero to infinity (AUC 0-inf ), and time of C max (T max )., Results: A total of 37 participants were evaluable for pharmacokinetics. Following administration of zavegepant 10 mg, geometric mean ratios for Period 1/Period 2 were 82.8% (90% confidence interval [CI] 60.5-113.2) for C max and 90.1% (90% CI 70.2-115.5) for AUC 0-inf . Following administration of zavegepant 20 mg, geometric mean ratios for Period 1/Period 2 were 72.5% (90% CI 57.9-90.8) for C max and 73.4% (90% CI 58.8-91.7) for AUC 0-inf . Averaging over the study period, geometric mean ratios for zavegepant 20 mg/10 mg were 142.5% (90% CI 118.6-171.4) for C max and 157.0% (90% CI 133.6-184.5) for AUC 0-inf . Median T max was 0.5 h for both doses regardless of Period. Zavegepant was well tolerated in both study periods and effective during Period 1 at both dose levels. There was no apparent correlation between concentration at 0.5 h or 2 h post-dose and efficacy outcomes., Conclusion: Zavegepant exposure was comparable during a migraine attack and a non-migraine period, particularly at the therapeutic dose of 10 mg. When averaging over migraine and non-migraine periods, there was a less-than-dose proportional increase in zavegepant exposure when the dose was doubled from 10 to 20 mg. The median T max was 0.5 h regardless of migraine attack or dose. Zavegepant 10 and 20 mg exhibited favorable safety profiles during migraine attacks and non-migraine periods, and were effective to relieve pain, associated symptoms, and functional disability during migraine attacks, with no apparent correlation between zavegepant concentration and efficacy outcomes., (© 2024 Pfizer Inc. and The Author(s). Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Objective: The potential for drug-drug interaction of multiple-dose intranasal zavegepant on the single-dose oral contraceptive ethinyl estradiol and levonorgestrel (EE-LNG) was evaluated., Background: Zavegepant (as a nasal spray) is a calcitonin gene-related peptide receptor antagonist approved in the United States for treatment of acute migraine in adults., Methods: This single-center, Phase 1, open-label, fixed-sequence study included healthy, nonsmoking females (18-45 years old). In treatment Period 1, a single oral dose of EE-LNG 0.02-0.10 mg was administered on Day 1. In treatment Period 2, intranasal zavegepant (20 mg daily; 10 mg per nostril separated by 1 h) was administered on Days 1-5; 1 oral dose of EE-LNG 0.02-0.10 mg was administered immediately after first 10 mg intranasal zavegepant dose on Day 2. Blood samples for EE-LNG concentrations were collected on Day 1, treatment Period 1, and Day 2, treatment Period 2, and zavegepant concentrations on Day 2, treatment Period 2. Noncompartmental pharmacokinetic parameters included maximum observed concentration (C max ), area under the concentration-time curve (AUC) from Time 0 to last non-zero concentration (AUC 0-t ), and AUC from Time 0 to infinity (AUC 0-inf ). The safety and pharmacokinetic sample sizes were 26 and 23, respectively., Results: Statistical comparisons of pharmacokinetic exposure parameters after co-administration of zavegepant and EE-LNG versus EE-LNG alone showed small, but statistically insignificant, changes in either EE or LNG exposure. EE comparison ratios (90% confidence intervals [CIs]) were 109.9% (105.3%, 114.8%) for AUC 0-inf and 110.2% (104.6%, 116.1%) for C max . LNG comparison ratios (90% CIs) were 107.0% (100.2%, 114.3%) for AUC 0-inf and 108.8% (99.9%, 118.4%) for C max . Frequently reported treatment-emergent adverse events included dysgeusia (n = 25, 96%), throat irritation (n = 11, 42%), headache (n = 10, 39%), nasal discomfort (n = 7, 27%), pharyngeal paresthesia (n = 5, 19%), and nausea (n = 4, 15%)., Conclusion: Co-administration of zavegepant nasal spray with a single dose of an oral contraceptive resulted in no clinically meaningful changes (<12% increase) in EE-LNG exposure., (© 2024 Pfizer Inc. and The Author(s). Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Objective: To evaluate the pharmacodynamic (PD) and pharmacokinetic (PK) interactions between zavegepant and sumatriptan in healthy adults., Background: Zavegepant is a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist administered as a nasal spray approved in the United States for the acute treatment of migraine. Triptans, including sumatriptan, are a different class of drugs for acute migraine treatment and are associated with a risk of increased blood pressure (BP). Hence, it is important to study the drug-drug interactions between zavegepant and sumatriptan due to potential coadministration in clinical settings., Methods: This was a Phase 1, single-center, partially blind, randomized, placebo-controlled, single-arm study. Eligible participants were males aged ≥ 18 and ≤ 40 years or females aged ≥ 18 and ≤ 50 years. On Day 1, participants received sumatriptan 2 × 6 mg subcutaneous injections (1 h apart) and were then randomized (6:1 ratio) to receive zavegepant 2 × 10 mg nasal spray (1 in each nostril) or placebo on Days 2 and 3. On Day 4, zavegepant or placebo was coadministered with sumatriptan after the second sumatriptan injection. BP, PK, and safety were evaluated at pre-specified time points., Results: Forty-two participants enrolled in the study received at least one dose of any treatment and were included in the safety analyses. Forty-one participants who completed the study were included in the BP and PK analyses. The mean (standard deviation) time-weighted average (TWA) of mean arterial pressure (MAP [sumatriptan + zavegepant 87.2 (6.8) vs. sumatriptan 86.9 (6.0)]), diastolic BP (DBP [sumatriptan + zavegepant 72.3 (6.8) vs. sumatriptan 72.1 (6.2)]), and systolic BP (SBP [sumatriptan + zavegepant 116.8 (10.2) vs. sumatriptan 116.2 (8.6)]) did not change following zavegepant and sumatriptan coadministration on Day 4 compared to sumatriptan alone on Day 1. Statistical comparisons of the TWA of MAP, DBP, and SBP between sumatriptan and zavegepant coadministration and sumatriptan alone were similar; the differences observed were 0.04 mmHg for MAP (90% confidence interval [CI]: -0.69, 0.77 mmHg), 0.00 mmHg for DBP (90% CI: -0.76, 0.76 mmHg), and 0.33 mmHg for SBP (90% CI: -0.97, 1.63 mmHg). Sumatriptan PK after sumatriptan and zavegepant coadministration versus sumatriptan alone was similar; the comparison ratios were 102.5% (90% CI: 100.7%, 104.2%) for AUC 0-inf and 104.1% (90% CI: 98.0%, 110.6%) for C max . A small difference in zavegepant PK exposure after sumatriptan and zavegepant coadministration versus zavegepant alone was not considered clinically relevant: the comparison ratios were 112.4% (90% CI: 103.4%, 122.3%) for AUC 0-24 and 96.7% (90% CI: 88.9%, 105.2%) for C max . Overall, 90% (38/42) of participants experienced ≥ 1 treatment-emergent adverse event that was mild or moderate in severity. All treatments were generally safe and well tolerated., Conclusion: Coadministration of zavegepant with sumatriptan was safe and without PD or PK interactions in healthy adults., (© 2024 Pfizer Inc and The Author(s). Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Zavegepant, a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist, is approved as a nasal spray for acute treatment of migraine in adults. This phase I, open-label, single-center, single-period, nonrandomized study in six healthy male subjects assessed mass balance recovery after a single 15-min intravenous (IV) infusion dose of carbon-14 ([ 14 C])-zavegepant. Blood, urine, and fecal samples were collected over 192 h for analysis of zavegepant in plasma and urine; total radioactivity (TR) in plasma, whole blood, urine, and feces; and zavegepant metabolite profiling and structural identification in plasma, urine, and feces. An average of 96.6% of radioactivity administered was recovered in excreta. Most TR (mean 84.9%) was recovered in the feces, indicating that biliary/fecal elimination was the main route. Volume of distribution of zavegepant based on the terminal phase (129 L) was higher than total body water (42 L), indicating substantial distribution into tissue. Total plasma clearance of zavegepant (220 mL/min) is identical to whole blood clearance given the blood/plasma partition ratio of 1, lower than typical hepatic blood flow (1450 mL/min). The observed plasma terminal half-life of zavegepant was 6.8 h. Exposure to zavegepant accounted for ~90% of circulating plasma TR, suggesting that very low levels of uncharacterized circulating metabolites were present. Metabolite profiling did not identify any metabolites representing ≥10% of radioactivity in plasma, urine, or feces. A single IV infusion of 5 mg [ 14 C]-zavegepant was well tolerated in healthy male subjects. Disposition findings of IV [ 14 C]-zavegepant are applicable to the disposition of the approved zavegepant nasal spray., (© 2024 Pfizer Inc and The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Zavegepant is the first small molecule calcitonin gene-related peptide receptor antagonist for intranasal administration for the acute treatment of migraine. The objective of this study was to evaluate the safety and tolerability of zavegepant in the acute treatment of migraine under repeated, as-needed dosing for up to one year., Methods: This phase 2/3, one-year open-label safety study of zavegepant 10 mg nasal spray for the acute treatment of migraine enrolled adults aged ≥18 years with a history of two to eight moderate to severe monthly migraine attacks. Participants used one dose of zavegepant as needed to self-treat migraine attacks of any severity, up to eight times per month, for 52 weeks., Results: Participants were enrolled between 29 June and 4 December 2020. Of the 608 participants entering long-term treatment, 603 were treated with study drug. Participants administered a mean (SD) of 3.1 (1.55) zavegepant doses per month. There were no deaths. Of the seven serious adverse events reported, none was considered related to treatment. Altogether, 6.8% (41/603) of treated participants had an adverse event leading to study drug discontinuation. The most frequent adverse event leading to discontinuation was dysgeusia (1.5% [9/603]). The most common treatment-emergent adverse events (≥5% of participants) were dysgeusia (39.1% [236/603]); nasal discomfort (10.3% [62/603]); COVID-19 (7.5% [45/603]); nausea (6.1% [37/603]); nasal congestion and throat irritation (5.5% [33/603] each); and back pain (5.3% [32/603]). Aminotransferases >3x the upper limit of normal occurred in 2.6% [16/603] of participants; none had concurrent elevations in bilirubin >2x upper limit of normal., Conclusions: One year of zavegepant 10 mg nasal spray up to eight times per month was safe and well tolerated. Trial registration: Clinicaltrials.gov: NCT04408794., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KM serves as a consultant, advisory board member, or has received honoraria from Amgen, Teva, Theranica, Vorso, Biohaven, electroCore, and Eli Lilly.RC was an employee of Biohaven Pharmaceuticals, owns stock in Biohaven Ltd, was an employee of Pfizer, has received research payments from Pfizer, and provides services to Collima LLC which has had consulting agreements with Pfizer, Actio Biosciences, Inc., Aptose Biosciences Inc., Manistee Therapeutics, and Vida Ventures Management Co., LLC.LM and TF are employed by Pfizer Inc. JM was employed by Biohaven Pharmaceuticals at the time the study was conducted. JM and LM own stock in Biohaven Pharmaceuticals. LM owns stock in Pfizer Inc.RBL serves on the editorial board of Neurology and as senior advisor to Headache but is not paid for his roles on these journals. He has received research support from the NIH. He also receives support from the National Headache Foundation. He receives research grants from Allergan/AbbVie, Amgen, Dr. Reddy's Laboratories, and Novartis. He has reviewed for the NIA and NINDS and serves as consultant, advisory board member, or has received honoraria from Allergan/AbbVie, Amgen, Biohaven, Dr. Reddy's Laboratories, electroCore, Eli Lilly, GlaxoSmithKline, Merck, Novartis, Teva, and Vedanta. He receives royalties from Wolff's Headache (8th Edition, Oxford University Press, 2009) and Informa. He holds stock options in Biohaven Pharmaceuticals and Manistee.

Zavegepant, a high-affinity, selective, small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is approved in the United States for acute treatment of migraine in adults. The effects of moderate hepatic impairment (8 participants with Child-Pugh score 7-9 points) on the pharmacokinetics of a single 10-mg intranasal dose of zavegepant versus eight matched participants with normal hepatic function were evaluated in a phase I study. Pharmacokinetic sampling determined total and unbound plasma zavegepant concentrations. Moderate hepatic impairment increased the exposure of total zavegepant (~2-fold increase in AUC 0-inf and 16% increase in C max ) versus normal hepatic function, which is not considered clinically meaningful. The geometric least squares mean ratios (moderate impairment/normal) of plasma zavegepant AUC 0-inf and C max were 193% (90% confidence interval [CI]: 112, 333; p = 0.051) and 116% (90% CI: 69, 195; p = 0.630), respectively. The geometric mean fraction unbound of zavegepant was similar for participants with moderate hepatic impairment (0.13; coefficient of variation [CV] 13.71%) versus those with normal hepatic function (0.11; CV 21.43%). Similar exposure findings were observed with unbound zavegepant versus normal hepatic function (~2.3-fold increase in AUC 0-inf and 39% increase in C max ). One treatment-emergent adverse event (mild, treatment-related headache) was reported in a participant with normal hepatic function. No dosage adjustment of intranasal zavegepant is required in adults with mild or moderate hepatic impairment., (© 2024 Pfizer Inc and The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in adults. The cardiovascular safety of zavegepant nasal spray was assessed in both single-ascending dose (SAD) and multiple-ascending dose (MAD) studies in healthy participants. The SAD study included 72 participants (54 active/18 placebo) who received 0.1-40 mg zavegepant or placebo. The MAD study included 72 participants (56 active/16 placebo) who received 5-40 mg zavegepant or placebo for 1-14 days. Plasma zavegepant pharmacokinetics and electrocardiographic (ECG) parameters (Fridericia-corrected QT interval [QTcF], heart rate, PR interval, ventricular depolarization [QRS], T-wave morphology, and U-wave presence) were analyzed pre- and post-zavegepant administration. Using pooled data from the SAD and MAD studies, the relationship between time-matched plasma zavegepant concentrations and QTc interval was assessed using a linear mixed-effects model to evaluate the potential for QTc interval prolongation. Results showed that single and multiple doses of zavegepant had no significant impact on ECG parameters versus placebo, and there was no concentration-dependent effect on QTcF interval. The estimated slope of the plasma zavegepant concentration-QTcF model was -0.053 ms per ng/mL with a 90% confidence interval of -0.0955 to -0.0110 (p = 0.0415), which is not considered clinically meaningful. At doses up to four times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent., (© 2024 Pfizer Inc and The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Intranasal formulations can provide treatment options for people with migraine in whom oral drugs are ineffective, slow-acting, or intolerable because of nausea and vomiting. Zavegepant, an intranasally administered small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, was previously assessed in a phase 2/3 trial. This phase 3 trial aimed to compare the efficacy, tolerability, safety, and timecourse of response for zavegepant nasal spray with placebo in the acute treatment of migraine., Methods: This double-blind, randomised, placebo-controlled, multicentre phase 3 trial, conducted at 90 academic medical centres, headache clinics, and independent research facilities in the USA, recruited adults (aged ≥18 years) with a history of two to eight moderate or severe migraine attacks per month. Participants were randomly assigned (1:1) to zavegepant 10 mg nasal spray or matching placebo and self-treated a single migraine attack of moderate or severe pain intensity. Randomisation was stratified by the use or non-use of preventive medication. Study centre personnel entered eligible participants into the study using an interactive web response system that was operated and managed by an independent contract research organisation. All participants, investigators, and the funder were masked to group assignment. The coprimary endpoints, freedom from pain and freedom from the most bothersome symptom at 2 h after the treatment dose, were assessed in all randomly assigned participants who took the study medication, had a migraine attack of moderate or severe pain intensity at baseline, and provided at least one evaluable post-baseline efficacy datapoint. Safety was analysed in all randomly assigned participants who received at least one dose. The study is registered with ClinicalTrials.gov, number NCT04571060, and is closed to accrual., Findings: Between Oct 27, 2020, and Aug 20, 2021, 1978 participants were recruited and assessed for eligibility. 1405 participants were eligible (703 were assigned to zavegepant and 702 to placebo), and 1269 were included in the efficacy analysis set (623 in the zavegepant group and 646 in the placebo group). 2 h after the treatment dose, more participants in the zavegepant group than in the placebo group had pain freedom (147 [24%] of 623 participants vs 96 [15%] of 646 participants, risk difference 8·8 percentage points, 95% CI 4·5-13·1; p<0·0001) and freedom from their most bothersome symptom (247 [40%] vs 201 [31%], risk difference 8·7 percentage points, 3·4-13·9; p=0·0012). The most common adverse events in either treatment group (≥2%) were dysgeusia (129 [21%] of 629 in the zavegepant group vs 31 [5%] of 653 in the placebo group), nasal discomfort (23 [4%] vs five [1%]), and nausea (20 [3%] vs seven [1%]). No signal of hepatotoxicity due to zavegepant was identified., Interpretation: Zavegepant 10 mg nasal spray was efficacious in the acute treatment of migraine, with favourable tolerability and safety profiles. Additional trials are needed to establish the long-term safety and consistency of effect across attacks., Funding: Biohaven Pharmaceuticals., Competing Interests: Declaration of interests RBL serves on the editorial board of Neurology and Cephalalgia and is a senior advisor to Headache but is not paid for his roles on these journals. He has received research support from the US National Institutes of Health, the US Food and Drug Administration, the National Headache Foundation, and the Marx Foundation. He receives research grants from Allergan/Abbvie, Amgen, and Novartis. He has reviewed for the National Institute on Aging and National Institute on Neurological Disorders and Stroke and serves as consultant, advisory board member, or has received honoraria from AEON, Allergan/Abbvie, Amgen, Biodelivery Sciences International, Biohaven, CoolTech, Dr Reddy's Laboratories, electroCore, Eli Lilly, GlaxoSmithKline, Impel Neuropharma, Lundbeck Manistee, Merck, Novartis, Satsuma, Teva, and Vedanta. He receives royalties from Wolff's Headache and Other Head Pain (8th edition, Oxford University Press, 2009) and Informa. He holds stock or options in Biohaven Pharmaceuticals and Manistee. RC, DAS, JM, MF, ML, LM, and VC are employed by and own stock or stock options in Biohaven Pharmaceuticals. PJG reports, over the past 36 months, grants and personal fees from Eli Lilly; a grant from Celgene; personal fees from Aeon Biopharma, Allergan/Abbvie, Amgen, Biodelivery Sciences International, Biohaven Pharmaceuticals, CoolTech, Dr Reddy's Laboratories, Epalex, Impel Neuropharma, Lundbeck, Novartis, Praxis, Sanofi, Satsuma, and Teva Pharmaceuticals; personal fees for advice through Gerson Lehrman Group, Guidepoint, SAI Med Partners, and Vector Metric; fees for educational materials from CME Outfitters, Omnia Education, and WebMD; publishing royalties or fees from Massachusetts Medical Society, Oxford University Press, UptoDate, and Wolters Kluwer, and for medicolegal advice in headache, and a patent magnetic stimulation for headache (number, WO2016090333 A1) assigned to eNeura without fee. RC, JM, and LM are employed by Pfizer., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy movement disorder that can be imaged by the 18 F-labeled tau PET tracer 2-(2-([ 18 F]fluoro)pyridin-4-yl)-9 H -pyrrolo[2,3- b :4,5- c ']dipyridine ( 18 F-PI-2620). The in vivo diagnosis is currently established on clinical grounds and supported by midbrain atrophy estimation in structural MRI. Here, we investigate whether 18 F-PI-2620 tau PET has the potential to improve the imaging diagnosis of PSP. Methods: In this multicenter observational study, dynamic (0-60 min after injection) 18 F-PI-2620 PET and structural MRI data for 36 patients with PSP, 22 with PSP-Richardson syndrome, and 14 with a clinical phenotype other than Richardson syndrome (i.e., variant PSP) were analyzed along with data for 10 age-matched healthy controls (HCs). The PET data underwent kinetic modeling, which resulted in distribution volume ratio (DVR) images. These and the MR images were visually assessed by 3 masked experts for typical PSP signs. Furthermore, established midbrain atrophy parameters were measured in structural MR images, and regional DVRs were measured in typical tau-in-PSP target regions in the PET data. Results: Visual assessments discriminated PSP patients and HCs with an accuracy of 63% for MRI and 80% for the combination of MRI and 18 F-PI-2620 PET. As compared with patients of the PSP-Richardson syndrome subgroup, those of the variant PSP subgroup profited more in terms of sensitivity from the addition of the visual 18 F-PI-2620 PET to the visual MRI information (35% vs. 22%). In quantitative image evaluation, midbrain-to-pons area ratio and globus pallidus DVRs discriminated best between the PSP patients and HCs, with sensitivities and specificities of 83% and 90%, respectively, for MRI and 94% and 100%, respectively, for the combination of MRI and 18 F-PI-2620 PET. The gain of sensitivity by adding 18 F-PI-2620 PET to MRI data was more marked in clinically less affected patients than in more affected patients (37% vs. 19% for visual, and 16% vs. 12% for quantitative image evaluation). Conclusion: These results provide evidence for an improved imaging-based PSP diagnosis by adding 18 F-PI-2620 tau PET to structural MRI. This approach seems to be particularly promising at earlier disease stages and could be of value both for improving early clinical PSP diagnosis and for enriching PSP cohorts for trials of disease-modifying drugs., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: Evaluate the efficacy, safety, and tolerability of zavegepant nasal spray in the acute treatment of migraine., Background: Calcitonin gene-related peptide-targeting agents are a novel class of therapeutics for migraine, but none are currently available as a nonoral option for acute treatment. Zavegepant, a high-affinity, selective, and structurally unique calcitonin gene-related peptide-receptor antagonist in late-stage development, is formulated as a nasal spray for the acute treatment of migraine., Methods: This randomized, dose-ranging, placebo-controlled, Phase 2/3 trial in adults aged ≥18 years with migraine (NCT03872453) was conducted at US study sites. Participants were randomized by an interactive web response system and treated a single attack of moderate to severe pain intensity with zavegepant nasal spray 5, 10, 20 mg, or placebo. Coprimary efficacy endpoints were pain freedom and freedom from the most bothersome symptom at 2 h postdose., Results: Of the 1673 participants aged 18 to 79 years who were randomized, 1588 were treated with study medication, and 1581 (mean age 40.8 years, 85.5% female) were analyzed for efficacy: zavegepant 5 mg (n = 387), 10 mg (n = 391), 20 mg (n = 402), and placebo (n = 401). Zavegepant 10 and 20 mg were more effective than placebo on the coprimary endpoints of pain freedom at 2 h postdose (placebo: 15.5% [98.3% confidence interval (CI), 11.1, 19.8]; 10 mg: 22.5% [98.3% CI, 17.5, 27.6; p = 0.0113]; 20 mg: 23.1% [98.3% CI, 18.1, 28.2; p = 0.0055]) and freedom from the most bothersome symptom at 2 h postdose (placebo: 33.7% [98.3% CI, 28.0, 39.3]; 10 mg: 41.9% [98.3% CI, 36.0, 47.9; p = 0.0155]; 20 mg: 42.5% [98.3% CI, 36.6, 48.4; p = 0.0094]). Findings for the 5 mg dose were not significant. The most common treatment-emergent adverse events with zavegepant 10 and 20 mg and placebo were dysgeusia (13.5% to 16.1% vs. 3.5%), nausea (2.7% to 4.1% vs. 0.5%), and nasal discomfort (1.3% to 5.2% vs. 0.2%). Most adverse events were mild or moderate and resolved without treatment. There was no signal of hepatotoxicity., Conclusion: Zavegepant nasal spray, in single doses of 10 or 20 mg, was effective for the acute treatment of migraine, with a favorable safety profile. Additional research is needed to confirm its potential as a nonoral medication for the acute treatment of migraine., (© 2022 Biohaven Pharmaceuticals, Inc. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Rimegepant (Nurtec ODT)-an orally administered, small-molecule calcitonin gene-related peptide receptor antagonist indicated for the acute and preventive treatment of migraine-is a substrate for both the P-glycoprotein and breast cancer resistance protein transporters in vitro. We evaluated the effects of concomitant administration of strong inhibitors of these transporters on the pharmacokinetics of rimegepant in healthy subjects. This single-center, open-label, randomized study was conducted in 2 parts, both of which were 2-period, 2-sequence, crossover studies. Part 1 (n = 15) evaluated the effect of a single oral dose of 200-mg cyclosporine, a strong inhibitor of the P-glycoprotein and breast cancer resistance protein transporters, on the pharmacokinetics of rimegepant 75 mg. Part 2 (n = 12) evaluated the effect of a single oral dose of 600-mg quinidine, a strong selective P-glycoprotein transporter, on the pharmacokinetics of rimegepant 75 mg. Coadministration with cyclosporine showed an increase in rimegepant area under the plasma concentration-time curve from time 0 to infinity and maximum observed concentration based on geometric mean ratios (90% confidence intervals [CIs]) of 1.6 (1.49-1.72) and 1.41 (1.27-1.57), respectively, versus rimegepant alone. Coadministration with quinidine showed an increase in rimegepant area under the plasma concentration-time curve from time 0 to infinity and maximum observed concentration geometric mean ratios (90% CIs) of 1.55 (1.40-1.72) and 1.67 (1.46-1.91), respectively, versus rimegepant alone. Strong P-glycoprotein inhibitors (cyclosporine, quinidine) increased rimegepant exposures (>50%, <2-fold). In parts 1 and 2, rimegepant coadministration was well tolerated and safe. The similar effect of cyclosporine and quinidine coadministration on rimegepant exposure suggests that inhibition of breast cancer resistance protein inhibition may have less influence on rimegepant exposure., (© 2022 Biohaven Pharmaceuticals. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Objective: Investigate whether rimegepant-an oral small molecule calcitonin gene-related peptide receptor antagonist for the treatment of migraine-is excreted in human milk after a single 75 mg dose and characterize its concentration-time profile in the plasma and milk of healthy lactating women to determine the relative infant dose (RID). Methods: This open-label, single-center study enrolled healthy lactating women aged 18-40 years with a gestation of 37-42 weeks and uncomplicated delivery of a single healthy child ≥2 weeks (14 days) and ≤6 months before study drug administration. Plasma samples were collected 0, 1, 2, 4, and 8 hours postdose; human milk samples were collected at 0, 1, 2, 4, 8, 12, 16, 24, 32, and 36 hours. The milk:plasma drug concentration ratio was estimated as the ratio of the human milk:plasma areas under the curve. The RID (%) was calculated as 100 times the quotient of the body weight-normalized infant and maternal doses. Results: Subjects ( N  = 12) were enrolled between 25 January and 15 September 2020. The mean (standard deviation [SD]) age was 29.8 (3.6) years; mean (SD) body mass index was 26.8 (4.9) kg/m 2 . The mean (SD) RID of rimegepant was 0.51% (0.14). The mean (SD) body-weight normalized infant dose was 0.005 (0.001) mg/kg/day, the mean (SD) body-weight normalized maternal dose was 1.04 (0.18) mg/kg/day, and mean (SD) maternal body weight was 74.0 (13.3) kg. Conclusion: On a weight-adjusted basis, the mean RID of rimegepant was <1% of the maternal dose.

The novel tau-PET tracer [ 18 F]PI-2620 detects the 3/4-repeat-(R)-tauopathy Alzheimer's disease (AD) and the 4R-tauopathies corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). We determined whether [ 18 F]PI-2620 binding characteristics deriving from non-invasive reference tissue modelling differentiate 3/4R- and 4R-tauopathies. Ten patients with a 3/4R tauopathy (AD continuum) and 29 patients with a 4R tauopathy (CBS, PSP) were evaluated. [ 18 F]PI-2620 PET scans were acquired 0-60 min p.i. and the distribution volume ratio (DVR) was calculated. [ 18 F]PI-2620-positive clusters (DVR ≥ 2.5 SD vs. 11 healthy controls) were evaluated by non-invasive kinetic modelling. R1 (delivery), k2 & k2a (efflux), DVR, 30-60 min standardized-uptake-value-ratios (SUVR 30-60 ) and the linear slope of post-perfusion phase SUVR (9-60 min p.i.) were compared between 3/4R- and 4R-tauopathies. Cortical clusters of 4R-tau cases indicated higher delivery (R1 SRTM : 0.92 ± 0.21 vs. 0.83 ± 0.10, p = 0.0007), higher efflux (k2 SRTM : 0.17/min ±0.21/min vs. 0.06/min ± 0.07/min, p < 0.0001), lower DVR (1.1 ± 0.1 vs. 1.4 ± 0.2, p < 0.0001), lower SUVR 30-60 (1.3 ± 0.2 vs. 1.8 ± 0.3, p < 0.0001) and flatter slopes of the post-perfusion phase (slope 9-60 : 0.006/min ± 0.007/min vs. 0.016/min ± 0.008/min, p < 0.0001) when compared to 3/4R-tau cases. [ 18 F]PI-2620 binding characteristics in cortical regions differentiate 3/4R- and 4R-tauopathies. Higher tracer clearance indicates less stable binding in 4R tauopathies when compared to 3/4R-tauopathies.

Purpose: The accumulation of misfolded tau is a common feature of several neurodegenerative disorders, with Alzheimer's disease (AD) being the most common. Earlier we identified JNJ-64326067, a novel isoquinoline derivative with high affinity and selectivity for tau aggregates from human AD brain. We report the dosimetry of [ 18 F] JNJ-64326067 and results of a proof-of-concept study comparing subjects with probable Alzheimer's disease to age-matched healthy controls., Methods: [ 18 F] JNJ-64326067 PET scans were acquired for 90 min and then from 120 to 180 min in 5 participants with [ 18 F]-florbetapir PET amyloid positive probable AD (73 ± 9 years) and 5 [ 18 F]-florbetapir PET amyloid negative healthy controls (71 ± 7 years). Whole-body [ 18 F] JNJ-64326067 PET CT scans were acquired in six healthy subjects for 5.5 h in 3 scanning sessions. Brain PET scans were visually reviewed. Regional quantification included kinetic analysis of distribution volume ration (DVR) estimated by Logan graphical analysis over the entire scan and static analysis of SUVr in late frames. Both methods used ventral cerebellar cortex as a reference region., Results: One of the healthy controls had focal areas of PET signal in occipital and parietal cortex underlying the site of a gunshot injury as an adolescent; the other four healthy subjects had no tau brain signal. Four of the 5 AD participants had visually apparent retention of [ 18 F] JNJ-64326067 in relevant cortical regions. One of the AD subjects was visually negative. Cortical signal in visually positive subjects approached steady state by 120 min. Temporal and frontal cortical SUVr/DVR values in visually positive AD subjects ranged from 1.21 to 3.09/1.2 to 2.18 and from 0.92 to 1.28/0.91 to 1.16 in healthy controls. Whole-body effective dose was estimated to be 0.0257 mSv/MBq for females and 0.0254 mSv/MBq for males., Conclusions: [ 18 F] JNJ-64326067 could be useful for detection and quantitation of tau aggregates.

Purpose: Second-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several β-amyloid and first-generation tau-PET radiotracers, it has been shown that early-phase images can be used as a surrogate of neuronal injury. Therefore, we investigated the performance of early acquisitions of the novel tau-PET radiotracer [ 18 F]PI-2620 as a potential substitute for [ 18 F]fluorodeoxyglucose ([ 18 F]FDG)., Methods: Twenty-six subjects were referred with suspected tauopathies or overlapping parkinsonian syndromes (Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, multi-system atrophy, Parkinson's disease, multi-system atrophy, Parkinson's disease, frontotemporal dementia) and received a dynamic [ 18 F]PI-2620 tau-PET (0-60 min p.i.) and static [ 18 F]FDG-PET (30-50 min p.i.). Regional standardized uptake value ratios of early-phase images (single frame SUVr) and the blood flow estimate (R 1 ) of [ 18 F]PI-2620-PET were correlated with corresponding quantification of [ 18 F]FDG-PET (global mean/cerebellar normalization). Reduced tracer uptake in cortical target regions was also interpreted visually using 3-dimensional stereotactic surface projections by three more and three less experienced readers. Spearman rank correlation coefficients were calculated between early-phase [ 18 F]PI-2620 tau-PET and [ 18 F]FDG-PET images for all cortical regions and frequencies of disagreement between images were compared for both more and less experienced readers., Results: Highest agreement with [ 18 F]FDG-PET quantification was reached for [ 18 F]PI-2620-PET acquisition from 0.5 to 2.5 min p.i. for global mean (lowest R = 0.69) and cerebellar scaling (lowest R = 0.63). Correlation coefficients (summed 0.5-2.5 min SUVr & R 1 ) displayed strong agreement in all cortical target regions for global mean (R SUVr 0.76, R R1  = 0.77) and cerebellar normalization (R SUVr 0.68, R R1  = 0.68). Visual interpretation revealed high regional correlations between early-phase tau-PET and [ 18 F]FDG-PET. There were no relevant differences between more and less experienced readers., Conclusion: Early-phase imaging of [ 18 F]PI-2620 can serve as a surrogate biomarker for neuronal injury. Dynamic imaging or a dual time-point protocol for tau-PET imaging could supersede additional [ 18 F]FDG-PET imaging by indexing both the distribution of tau and the extent of neuronal injury.

Importance: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis., Objective: To investigate the potential of the novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed PSP., Design, Setting, and Participants: In this cross-sectional study, participants underwent dynamic 18F-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019., Main Outcomes and Measures: Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, 18F-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex., Results: Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP-non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [50.0%] with Parkinson disease and multiple system atrophy, 7 were men; mean [SD] age, 61 [8] years; of 10 [50.0%] with Alzheimer disease, 5 were men; mean [SD] age, 69 [10] years). Postmortem autoradiography showed blockable 18F-PI-2620 binding in patients with PSP and no binding in healthy controls. The in vivo findings from the first large-scale observational study in PSP with 18F-PI-2620 indicated significant elevation of tracer binding in PSP target regions with strongest differences in PSP vs control groups in the globus pallidus internus (mean [SD] distribution volume ratios: PSP-RS, 1.21 [0.10]; PSP-non-RS, 1.12 [0.11]; healthy controls, 1.00 [0.08]; Parkinson disease/multiple system atrophy, 1.03 [0.05]; Alzheimer disease, 1.08 [0.06]). Sensitivity and specificity for detection of PSP-RS vs any control group were 85% and 77%, respectively, when using classification by at least 1 positive target region., Conclusions and Relevance: This multicenter evaluation indicates a value of 18F-PI-2620 to differentiate suspected patients with PSP, potentially facilitating more reliable diagnosis of PSP.

18 F-PI-2620 is a PET tracer with high binding affinity for aggregated tau, a key pathologic feature of Alzheimer disease (AD) and other neurodegenerative disorders. Preclinically, 18 F-PI-2620 binds to both 3-repeat and 4-repeat tau isoforms. The purpose of this first-in-humans study was to evaluate the ability of 18 F-PI-2620 to detect tau pathology in AD patients using PET imaging, as well as to assess the safety and tolerability of this new tau PET tracer. Methods: Participants with a clinical diagnosis of probable AD and healthy controls (HCs) underwent dynamic 18 F-PI-2620 PET imaging for 180 min. 18 F-PI-2620 binding was assessed visually and quantitatively using distribution volume ratios (DVR) estimated from noninvasive tracer kinetics and SUV ratio (SUVR) measured at different time points after injection, with the cerebellar cortex as the reference region. Time-activity curves and SUVR were assessed in AD and HC subjects, as well as DVR and SUVR correlations and effect size (Cohen's d) over time. Results: 18 F-PI-2620 showed peak brain uptake around 5 min after injection and fast washout from nontarget regions. In AD subjects, focal asymmetric uptake was evident in temporal and parietal lobes, precuneus, and posterior cingulate cortex. DVR and SUVR in these regions were significantly higher in AD subjects than in HCs. Very low background signal was observed in HCs. 18 F-PI-2620 administration was safe and well tolerated. SUVR time-activity curves in most regions and subjects achieved a secular equilibrium after 40 min after injection. A strong correlation ( R 2 > 0.93) was found between noninvasive DVR and SUVR for all imaging windows starting at more than 30 min after injection. Similar effect sizes between AD and HC groups were obtained across the different imaging windows. 18 F-PI-2620 uptake in neocortical regions significantly correlated with the degree of cognitive impairment. Conclusion: Initial clinical data obtained in AD and HC subjects demonstrated a high image quality and excellent signal-to-noise ratio of 18 F-PI-2620 PET for imaging tau deposition in AD subjects. Noninvasive quantification using DVR and SUVR for 30-min imaging windows between 30 and 90 min after injection-for example, 45-75 min-provides robust and significant discrimination between AD and HC subjects. 18 F-PI-2620 uptake in expected regions correlates strongly with neurocognitive performance., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

18 F-PI-2620 is a next-generation tau PET tracer that has demonstrated ability to image the spatial distribution of suspected tau pathology. The objective of this study was to assess the tracer biodistribution, dosimetry, and quantitative methods of 18 F-PI-2620 in the human brain. Full kinetic modeling to quantify tau load was investigated. Noninvasive kinetic modeling and semiquantitative methods were evaluated against the full tracer kinetics. Finally, the reproducibility of PET measurements from test and retest scans was assessed. Methods: Three healthy controls (HCs) and 4 Alzheimer disease (AD) subjects underwent 2 dynamic PET scans, including arterial sampling. Distribution volume ratio (DVR) was estimated using full tracer kinetics (reversible 2-tissue-compartment [2TC] model and Logan graphical analysis [LGA]) and noninvasive kinetic models (noninvasive LGA [NI-LGA] and the multilinear reference tissue model [MRTM2]). SUV ratio (SUVR) was determined at different imaging windows after injection. The correlation between DVR and SUVR, effect size (Cohen's d), and test-retest variability (TRV) were evaluated. Additionally, 6 HCs received 1 tracer administration and underwent whole-body PET for dosimetry calculation. Organ doses and the whole-body effective dose were calculated using OLINDA 2.0. Results: A strong correlation was found across different kinetic models ( R 2 > 0.97) and between DVR(2TC) and SUVR between 30 and 90 min, with an R 2 of more than 0.95. Secular equilibrium was reached at around 40 min after injection in most regions and subjects. TRV and effect size for SUVR across different regions were similar at 30-60 min (TRV, 3.8%; Cohen's d, 3.80), 45-75 min (TRV, 4.3%; Cohen's d, 3.77) and 60-90 min (TRV, 4.9%; Cohen's d, 3.73) and increased at later time points. Elimination was via the hepatobiliary and urinary systems. The whole-body effective dose was 33.3 ± 2.1 μSv/MBq for an adult female and 33.1 ± 1.4 μSv/MBq for an adult male, with a 1.5-h urinary bladder voiding interval. Conclusion: 18 F-PI-2620 exhibits fast kinetics, suitable dosimetry, and low TRV. DVR measured using the 2TC model with arterial sampling correlated strongly with DVR measured by NI-LGA, MRTM2, and SUVR. SUVR can be used for 18 F-PI-2620 PET quantification of tau deposits, avoiding arterial blood sampling. Static 18 F-PI-2620 PET scans between 45 and 75 min after injection provide excellent quantification accuracy, a large effect size, and low TRV., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

The effect of environment on temperature was examined by comparing tympanic, rectal, inguinal, and axillary temperatures for 63 term infants in three environments: incubator, bassinet, and radiant warmer. Tympanic temperatures were collected with a FirstTemp (Intelligent Medical Systems, Carlsbad, CA) infrared thermometer in the cal-tympanic mode. Rectal, inguinal, and axillary temperatures were collected with an IVAC digital thermometer (San Diego, CA) in the predictive mode. There were moderate correlations between the body site temperatures. The environment significantly influenced temperature readings at the different sites. Temperatures assessed in the superheated environments of the radiant warmer and the incubator were consistently higher than temperatures in the bassinet.

The effect of possible neutralizing agents on aqueous parachlorophenol were studied. Results indicated that saline, EDTAC, dentin, saliva, prolonged light exposure, and thermal extremes do not appreciably affect the antibacterial properties of aqueous parachlorophenol. The presence of blood and necrotic tissue demonstrated a marked inhibitory effect.

Coxsackie B-1 virus was injected into the ear vein of albino doe rabbits. Saliva and blood samples were taken before the injection of virus and at specific times thereafter. Virus was recovered in the whole saliva when the blood titer was approximately 10(4) TCID(50) per 0.1 ml or greater. The virus could be detected in the saliva as early as 2 min after the initiation of the viremia. The recovered virus was shown to be the same as the injected virus by serological identification of the recovered virus with neutralizing antibody for Coxsackie B-1 virus. These results suggest that virus may be transmitted to other animals in the saliva of animals who are in the viremic phase of infection without infection of the oropharyngeal tissues.

The ability of coxsackievirus B-1 to pass the barriers of the circulatory system into whole saliva has been shown previously. In this investigation, the major salivary glands and the oral mucosa were studied, and their role as participants in the excretion of coxsackievirus B-1 during viremia was evaluated. The effect of the salivary-gland stimulant pilocarpine nitrate on both the salivary flow rate and the recovery of virus during viremia was determined. A comparison was made between the amount of virus recovered from whole saliva during viremia in animals deficient in one or both of the major salivary-gland pairs and animals with a complete complement of salivary glands. The salivary glands in other animals were cannulated, and pure glandular secretions were collected during viremia and assayed for the presence of virus The amount of virus passing from the capillaries of the oral mucosa to the surface was also determined to evaluate this route as a possible site for the excretion of virus into saliva during viremia. The major salivary glands did not excrete appreciable quantities of virus during viremia. The submaxillary-gland secretions did not contain virus, and the parotid-gland secretions showed virus only at extremely high blood virus levels. Either removal of the major salivary glands or decreased salivary flow rates increased the concentration of virus in whole saliva. This observation suggested that the production of saliva by the major salivary glands tends to dilute the virus in the oral cavity. A 0.88-cm(2) sample of the oral mucosa excreted significantly large amounts of virus during viremia and suggested that the passage of virus through the oral mucosa was the major route for the excretion of virus into saliva during viremia.