Takenao Koseki

mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have played a key role in reducing morbidity and mortality from coronavirus disease 2019 (COVID-19). We conducted a double-blind, placebo-controlled phase I/II trial to evaluate the safety, tolerability, and immunogenicity of EXG-5003, a two-dose, controllable self-replicating RNA vaccine against SARS-CoV-2. EXG-5003 encodes the receptor binding domain (RBD) of SARS-CoV-2 and was administered intradermally without lipid nanoparticles (LNPs). The participants were followed for 12 months. Forty healthy participants were enrolled in Cohort 1 (5 µg per dose, n = 16; placebo, n = 4) and Cohort 2 (25 µg per dose, n = 16; placebo, n = 4). No safety concerns were observed with EXG-5003 administration. SARS-CoV-2 RBD antibody titers and neutralizing antibody titers were not elevated in either cohort. Elicitation of antigen-specific cellular immunity was observed in the EXG-5003 recipients in Cohort 2. At the 12-month follow-up, participants who had received an approved mRNA vaccine (BNT162b2 or mRNA-1273) >1 month after receiving the second dose of EXG-5003 showed higher cellular responses compared with equivalently vaccinated participants in the placebo group. The findings suggest a priming effect of EXG-5003 on the long-term cellular immunity of approved SARS-CoV-2 mRNA vaccines.

Naldemedine is structurally designed to prevent passage across the blood–brain barrier (BBB), resulting in the attenuation of opioid-induced constipation without interfering with the analgesic effects of opioids. However, the influence of brain metastasis (BM), as one indicator of BBB disruption, on the analgesic effects of opioids in patients treated with naldemedine remains unclear. To examine whether the analgesic effects of opioids following naldemedine treatment are lower in patients with BM than in those without BM, we surveyed inpatients with lung and breast cancers treated with naldemedine at Fujita Health University Hospital between April 2017 and March 2022. Changes in the numeric rating scale (NRS) scores, morphine milligram equivalents (MMEs), and the number of rescues were assessed as analgesia-related outcomes during the first 7 days of naldemedine treatment in patients with or without BM, matched by the propensity score. In total, 172 patients were enrolled. After propensity-score matching, 30 patients with BM and 60 patients without BM were included in the analysis. Changes in NRS scores, MMEs, and the number of rescues did not differ between patients with and without BM. In the linear mixed-effects model, the coefficient of interaction between patients with or without BM and the days for each outcome was not statistically significant. BM does not influence the analgesic effect of opioids in patients with lung and breast cancers treated with naldemedine. Naldemedine may be useful for treating BM.

Purpose: An intraocular hemorrhage is an adverse event that can lead to visual acuity impairment. Antithrombotic therapy with antiplatelet agents and anticoagulants may increase intraocular hemorrhage. However, since their frequency is low, studies on the risk of intraocular hemorrhage with these drugs, especially under combination therapy, are limited. This study aimed to investigate the occurrence of intraocular hemorrhages under monotherapy and combination therapy with antiplatelets and anticoagulants by analyzing a large pharmacovigilance database. Methods: Intraocular hemorrhage signals with oral antiplatelets and anticoagulants were evaluated by calculating reporting odds ratios and information components using the Japan Adverse Drug Reactions Report database from April 2004 to March 2022. In addition, differences in signals between younger and elderly patients, affecting factors, and time-to-onset from initial antiplatelet and anticoagulant treatments were analyzed. Results: Aspirin, clopidogrel, warfarin, apixaban, and rivaroxaban, but not ticagrelor, ticlopidine, prasugrel, dabigatran, and edoxaban showed intraocular hemorrhage signals under monotherapy. In combination therapy, dual therapy (aspirin + P2Y₁₂ inhibitors, warfarin, direct oral anticoagulants, and P2Y₁₂ inhibitors + warfarin) and triple therapy (aspirin + P2Y₁₂ inhibitors + warfarin) resulted in intraocular hemorrhage signals. Intraocular hemorrhage signals were observed in younger patients receiving monotherapy with aspirin and in elderly patients receiving monotherapy and combination therapy with warfarin. Affecting factors were diabetes mellitus in patients with prasugrel, use of medications for intravitreal injections, and posterior sub-Tenon injections with some antiplatelets and anticoagulants. The median period of intraocular hemorrhage occurrence after starting monotherapy with aspirin, clopidogrel, warfarin, or rivaroxaban was within 90 days. Conclusion: In addition to monotherapy with several antiplatelets and anticoagulants, combination therapy using aspirin, P2Y₁₂ inhibitors, and warfarin has the potential risk of intraocular hemorrhage. Particular attention should be paid to the occurrence of intraocular hemorrhages in younger patients taking aspirin, in elderly patients taking warfarin, and within the first 90 days of antiplatelet and anticoagulant use.

Increased suicidality after antiepileptic drug (AED) treatment remains controversial. This study aimed to investigate the occurrence of suicide-related events (SREs) in Japan. SREs signals with AEDs used orally were evaluated by calculating reporting odds ratios (RORs) and information components (ICs) using the Japanese Adverse Drug Event Report (JADER) database from April 2004 to December 2021. Additionally, factors affecting the occurrence of SREs and time-to-onset from the initial AED treatment were analyzed. Of 22 AEDs, 12 (perampanel hydrate, nitrazepam, levetiracetam, clonazepam, clobazam, sodium valproate, phenobarbital, lamotrigine, lacosamide, gabapentin, zonisamide, and carbamazepine) showed signals of SREs. Patients in their 20 and 30 s, female sex, and concomitant use of multiple AEDs affected the occurrence of SREs. In six AEDs, the median time-to-onset of SREs in patients taking all AEDs was <100 days. The pharmacovigilance approach revealed that several AEDs displayed suicidality signals. Female patients, those in their 20 and 30 s, undergoing combination therapy with ≥2 AEDs, and patients early (<100 days from the initial treatment) in the course of AED therapy should be cautioned about SREs.

Purpose: Coronavirus disease 2019 (COVID-19) mRNA vaccines are used worldwide to prevent severe symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. IgA nephropathy (IgAN) is the most common form of glomerular injury after COVID-19 vaccination; however, because of the low frequency of such events, only a few reports have been published. A large pharmacovigilance database of real-world spontaneous adverse event (AE) reports is essential for evaluating the drug-associated safety signals regarding rare AEs. Herein, we aimed to investigate the frequency of IgAN after the COVID-19 vaccination, using the Japanese Adverse Drug Event Report (JADER) database. Methods: Data on drug-associated AEs reported between April 2004 and May 2022 were obtained from the JADER database on the Pharmaceuticals and Medical Devices Agency website. To evaluate the safety signals for the targeted AEs, reporting odds ratios (RORs), information components (ICs), and their 95% confidence intervals (CIs) were calculated using two-by-two contingency tables. Results: A total of 697,885 cases were included in the analysis. Safety signals were detected for IgAN (ROR: 6.49, 95% CI: 4.38-9.61; IC: 2.27, 95% CI: 1.70-2.83). Of 30 cases for IgAN associated with COVID-19 mRNA vaccines, 16 had information available on time to onset. Of the 16 cases, 11 occurred ≤2 days after vaccination, and two occurred >28 days after vaccination. Conclusion: These results suggest that, compared with other drugs, COVID-19 vaccination is associated with a higher frequency of IgAN. Monitoring of gross hematuria following COVID-19 vaccination should be needed.