Objectives This study sought to evaluate thoracoscopic stand-alone left atrial appendectomy for thromboembolism prevention in nonvalvular atrial fibrillation (AF). Background Closing the left atrial ...appendage (LAA) is an efficacious alternative to oral anticoagulation as prevention against AF-induced thromboembolism, provided that the procedure is safe and complete. Methods Thirty patients (mean age, 74 ± 5.0 years) who had had thromboembolisms were selected. A subgroup of 21 patients (mean age, 75 years; mean CHA2 DS2 VASc score, 4.5) urgently needed an alternative treatment to anticoagulation: warfarin was contraindicated due to hemorrhagic side effects in 13, the international normalized ratio was uncontrollable in 7, and transient ischemic attacks had developed immediately after the warfarin dose was reduced for oncological treatment in 1. The LAA was thoracoscopically excised with an endoscopic cutter. Results Thoracoscopic appendectomy (mean operating time, 32 min, switched to mini-thoracotomy in 2 cases) led to no mortality and no major complications. Three-month post-operative 3-dimensional enhanced computed tomography, performed with patients' consent, confirmed the completeness of the appendectomy. Patients have been followed for 1 to 38 months (mean, 16 ± 9.7 months 18 ± 9.4 months for the subgroup). One patient died of breast cancer 28 months after surgery. Despite discontinued anticoagulation, no patients have experienced recurrence of thromboembolism. Conclusions Thoracoscopic stand-alone appendectomy is potentially safe and may allow surgeons to achieve relatively simple, complete LAA closure. Further experience may demonstrate this technique to be a viable option for thromboembolism prevention in nonvalvular AF.
Mirogabalin is a novel α2δ ligand approved in Japan for the treatment of peripheral neuropathic pain. However, the sites of action of α2δ ligands to produce analgesic effects on inflammatory pain ...remain unclear. In this study, we investigated the analgesic effect and site of action of mirogabalin using the rat formalin test, an acute inflammatory pain model. Mirogabalin was administered orally, intrathecally, and intracerebroventricularly. Open field tests were performed to evaluate the effect of oral-, intrathecally, and intracerebroventricularly administered mirogabalin on locomotor activity and orientation ability. Oral mirogabalin produced an analgesic effect when the formalin test was performed 4 h, but not 1 or 2 h, after oral administration. Intrathecal, but not intracerebroventricular, administration of mirogabalin produced analgesic effects when mirogabalin was administered 10 min before formalin injection. These analgesic effects were not antagonized by idazoxan, an α2 adrenergic antagonist; WAY100135, a 5-HT1A antagonist; or naloxone, an opioid receptor antagonist. Mirogabalin attenuated moving distances 1 and 2 h after oral administration and 10 min after intracerebroventricular administration, but not 10 min after intrathecal administration. In the oral administration group, the time course of the analgesic effect was different from that of moving distance. In the intracerebroventricular group, mirogabalin attenuated moving distances but did not produce an analgesic effect. In the intrathecal group, mirogabalin produced an analgesic effect but did not affect moving distances. These findings suggest that the analgesic effect of mirogabalin on the rat formalin test is mediated by spinal action and not by the activation of α2, 5-HT1A, or opioid receptors, and that the inhibitory effect of mirogabalin on moving distances is mediated by the supraspinal brain.
Abstract
Background
Risk management in the post-marketing phase is crucial to minimize health problems caused by drugs. Because ethnic factors may affect drug safety, the objective of this study was ...to explore concrete approaches to reflecting ethnic factors in risk management under multi-regional drug development.
Methods
We assessed Pharmaceuticals and Medical Devices Agency (PMDA) review reports on antineoplastic drugs approved as new molecular entities in the last 10 years to identify any differences in the incidence of adverse drug reactions (ADRs) related to myelosuppression, hepatic impairment, renal impairment, and interstitial lung disease between Japanese and non-Japanese populations. In addition, we investigated how those ADRs were handled in the labeling of each drug.
Results
In total, 44 drugs were available for comparing the incidence of ADRs between Japanese and non-Japanese populations. Of these, 32 drugs had a higher incidence of ADRs in the Japanese population. However, the incidence of ADRs in the Japanese population was described in the labeling for 7 drugs, and only the incidence in the overall population in multi-regional phase III trials was described in the labeling for the remaining 25 drugs. Of these 25 drugs, two drugs were immediately placed under emergency safety control measures after approval because of the high incidence of ADRs in Japanese patients.
Conclusions
For drugs that might cause serious ADRs and with a higher incidence in the Japanese population, information should be provided on the incidence in the Japanese population as well as in the overall population.
Neuropeptide W (NPW) messenger ribonucleic acid (mRNA) and NPBW1 and/or NPBW2 mRNA are expressed in the descending pain inhibitory system. In the present study, we examined whether NPW microinjected ...into the descending pain inhibitory system, such as the periaqueductal gray (PAG), locus coeruleus (LC), and rostral ventromedial medulla (RVM), produces an analgesic effect using a rat formalin test. Microinjections of NPW into the PAG ipsilateral and contralateral to the formalin-injected side, LC ipsilateral and contralateral to the formalin-injected side, and RVM produced an analgesic effect. In the RVM study, the analgesic effect was antagonized by WAY100135, a 5-HT1A antagonist, and enhanced by prazosin, an α1 antagonist, and SB269970, a 5-HT7 antagonist. Naloxone, an opioid antagonist, also antagonized the effect of NPW in the RVM study. In the ipsilateral LC study, the analgesic effect was antagonized by WAY100135, idazoxan, an α2 antagonist, and naloxone and was enhanced by prazosin and SB269970. In the contralateral LC study, the analgesic effect was antagonized by prazosin, idazoxan, SB269970, and naloxone. The analgesic effect was antagonized by WAY100135, SB269970, idazoxan, and naloxone in the ipsilateral and contralateral PAG studies. These findings strongly suggest that NPBW1/W2 activation by NPW microinjection into the RVM, LC, and PAG affect the descending pain modulatory system and produce anti-nociceptive and pro-nociceptive effects in the rat formalin test.
The Japanese Ministry of Health, Labour and Welfare approved a drug called borofalan (10B), a treatment system, and a dose calculation program for boron neutron capture therapy (BNCT) in March 2020. ...The application pertaining to the products submitted to the Pharmaceuticals and Medical Devices Agency was supported by a Japanese, open‐label, uncontrolled trial (Study 002) in patients with unresectable, locally recurrent head and neck squamous cell carcinoma after chemoradiotherapy or radiotherapy, or in those with unresectable locally advanced or locally recurrent (LA/LR) head and neck nonsquamous cell carcinoma. The drug was administered as a single intravenous dose using infusion rates of 200 mg/kg per hour for the first 2 hours after the start of administration and 100 mg/kg per hour during irradiation. Neutron irradiation was performed using the devices at a single dose of 12 Gy‐equivalent for oral, pharyngeal, or laryngeal mucosa for up to 60 minutes from 2 hours after the start of drug administration. The primary endpoint was the overall response rate (ORR). The results of Study 002 showed that the ORR based on an assessment of the Independent Central Review Committee per RECIST version 1.1 was 71.4% (90% confidence interval CI, 51.3%–86.8%). The lower limit of the 90% CI exceeded the prespecified threshold for ORR. When BNCT is applied to patients with unresectable LA/LR head and neck cancer, precautions should be taken, and patients should be monitored for possible onset of dysphagia, brain abscess, skin disorder, crystal urine, cataract, and/or carotid hemorrhage.
Implications for Practice
Borofalan (10B), a treatment system and a dose calculation program for boron neutron capture therapy (BNCT), demonstrated significant efficacy in an open‐label, uncontrolled trial in which overall response rate was the primary endpoint for patients with unresectable locally advanced or locally recurrent head and neck cancer. Although no information about survival benefits was obtained, BNCT will become an effective treatment option that is expected to manage local lesions that are intractable with any standard therapy. In addition, BNCT is expected to maintain quality of life of the intended patient population, on account of its high tumor selectivity and low invasiveness.
This article summarizes the regulatory review of data leading to the approval of borofalan in Japan.
The mechanism by which acetaminophen produces its analgesic effects is not fully understood. One possible mechanism is the activation of the spinal 5-hydroxytryptamine (5-HT) receptor, although ...direct evidence of spinal 5-HT release has not yet been reported. N-arachidonoylphenolamine (AM404), a metabolite of acetaminophen, is believed to be the key substance that contributes to the analgesic effects of acetaminophen. In this study, we examined whether acetaminophen and AM404 induce spinal 5-HT release and the mechanism through which spinal 5-HT receptor activation exerts analgesic effects in a rat formalin test in an inflammatory pain model. Spinal 5-HT release was examined by intrathecal microdialysis in conscious and freely moving rats. Acetaminophen was administered orally, and AM404 was administered intracerebroventricularly. In rat formalin tests, oral acetaminophen and intracerebroventricular AM404 induced significant spinal 5-HT release and produced analgesic effects. The analgesic effect of oral acetaminophen was partially antagonized by intrathecal administration of WAY100135 (a 5-HT1A receptor antagonist) and SB269970 (a 5-HT7 receptor antagonist). In contrast, the analgesic effect of intracerebroventricular AM404 was completely antagonized by WAY100135, while SB269970 had no effect. Our data suggest that while oral acetaminophen and intracerebroventricular AM404 activate the spinal 5-HT system, the role of the spinal 5-HT system activated by oral acetaminophen differs from that activated by intracerebroventricular AM404.
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•Mechanisms underlying acetaminophen-induced analgesia are not fully understood.•Oral acetaminophen administration induced spinal 5-HT release.•ICV AM404, a metabolite of acetaminophen, induced spinal 5-HT release.•Spinal 5-HT release induced by oral acetaminophen and ICV AM404 produced analgesic effects.•The role of spinal 5-HT-induced release of oral acetaminophen differs from that of ICV AM404.
Left atrial appendage (LAA) closure can be an alternative to oral anticoagulation to prevent cardiogenic thromboembolisms in patients with nonvalvular atrial fibrillation.
The purpose of this study ...was to retrospectively evaluate the safety, completeness, and mid-term prevention of our thoracoscopic stapler-and-loop technique for LAA closure.
Patients operated on between October 2008 and February 2017 were reviewed. Endoscopic stapler and ligation loops were used. Patients received 1 month of anticoagulation before discontinuation. Hospital death and procedure-related major complications (thromboembolism, hemorrhagic events, phrenic palsy) were the primary composite endpoint for safety, and cardiogenic thromboembolisms were the endpoint for prevention. Brain magnetic resonance imaging investigated new thromboembolic spots 1 year after surgery.
There were 201 patients (118 men, 83 women) with a mean age of 74 years (range 68-94) years, mean CHA
DS
-VASc score (± SD) 4.1 ±1.4, and mean HAS-BLED score 2.9 ± 1.0. Mean operation time was 28 minutes. All LAAs were removed, and intraoperative transesophageal echocardiography confirmed completeness of the closure in each patient. No hospital deaths or major procedure-related complications occurred. Follow-up results for 198 patients (98%) over a mean period of 48 months (range 12-110) revealed that 2 patients developed cardiogenic thromboembolisms (0.25 event per 100 patient-years). Magnetic resonance imaging of 51 patients with a mean CHA
DS
-VASc score of 4.7 ± 1.6 revealed 1 new small spot in each of 2 patients (3.9%; 3.9 spots per 100 patient-years).
Our thoracoscopic stapler-and-loop technique swiftly, safely, and completely closed LAAs in patients with nonvalvular atrial fibrillation and provided acceptable mid-term prevention without anticoagulation.
Mycoplasma mobile is a fish pathogen that glides on solid surfaces by means of its own gliding machinery composed of internal and surface structures. In the present study, we focused on the function ...and structure of Gli123, a surface protein that is essential for the localization of other surface proteins. The amino acid sequence of Gli123, which is 1,128 amino acids long, contains lipoprotein-specific repeats. We isolated the native Gli123 protein from M. mobile cells and a recombinant protein, rGli123, from Escherichia coli. The isolated rGli123 complemented a nonbinding and nongliding mutant of
that lacked Gli123. Circular dichroism and rotary-shadowing electron microscopy (EM) showed that rGli123 has a structure that is not significantly different from that of the native protein. Rotary-shadowing EM suggested that Gli123 adopts two distinct globular and rod-like structures, depending on the ionic strength of the solution. Negative-staining EM coupled with single-particle analysis revealed that Gli123 forms a globular structure featuring a small protrusion with dimensions of approximately 15.7, 14.7, and 14.1 nm for the "height," major axis and minor axis, respectively. Small-angle X-ray scattering analyses indicated a rod-like structure composed of several tandem globular domains with total dimensions of approximately 34 nm in length and 6 nm in width. Both molecular structures were suggested to be dimers, based on the predicted molecular size and structure. Gli123 may have evolved by multiplication of repeating lipoprotein units and acquired a role for Gli521 and Gli349 assembly.
Mycoplasmas are pathogenic bacteria that are widespread in animals. They are characterized by small cell and genome sizes but are equipped with unique abilities for infection, such as surface variation and gliding. Here, we focused on a surface-localizing protein named Gli123 that is essential for Mycoplasma mobile gliding. This study suggested that Gli123 undergoes drastic conformational changes between its rod-like and globular structures. These changes may be caused by a repetitive structure common in the surface proteins that is responsible for the modulation of the cell surface structure and related to the assembly process for the surface gliding machinery. An evolutionary process for surface proteins essential for this mycoplasma gliding was also suggested in the present study.
To evaluate the risk of neutropenia during treatment with anti-IL-23 antibodies in patients with psoriasis.BACKGROUNDTo evaluate the risk of neutropenia during treatment with anti-IL-23 antibodies in ...patients with psoriasis.We conducted an observational study with cohort design using MID-NET® in Japan. We identified patients with psoriasis who were newly prescribed anti-IL-23 antibodies, anti-IL-17-antibodies, adalimumab, or apremilast between January 1, 2009, and March 31, 2021. We estimated the adjusted hazard ratio (aHR) of anti-IL-23 antibodies compared to that of anti-IL-17 antibodies, adalimumab, or apremilast, for the risk of grade 2 (neutrophil count < 1,500/μL) or grade 3 (neutrophil count < 1,000/μL) neutropenia.METHODWe conducted an observational study with cohort design using MID-NET® in Japan. We identified patients with psoriasis who were newly prescribed anti-IL-23 antibodies, anti-IL-17-antibodies, adalimumab, or apremilast between January 1, 2009, and March 31, 2021. We estimated the adjusted hazard ratio (aHR) of anti-IL-23 antibodies compared to that of anti-IL-17 antibodies, adalimumab, or apremilast, for the risk of grade 2 (neutrophil count < 1,500/μL) or grade 3 (neutrophil count < 1,000/μL) neutropenia.Overall, 287 patients on anti-IL-23 antibodies, 189 patients on anti-IL-17 antibodies, 293 patients on adalimumab, and 540 patients on apremilast were included. Compared with anti-IL-17 antibodies, the aHR (95% confidence interval (CI)) of anti-IL-23 antibodies was 0.83 (0.27-2.51) for grade 2 and 0.40 (0.02-7.60) for grade 3 neutropenia; that when compared with adalimumab was 0.76 (0.28-2.06) for grade 2 but was not calculated for grade 3 as no cases were found; and that compared with apremilast was 3.88 (0.62-24.48) for grade 2 and 0.43 (0.02-11.63) for grade 3 neutropenia.RESULTSOverall, 287 patients on anti-IL-23 antibodies, 189 patients on anti-IL-17 antibodies, 293 patients on adalimumab, and 540 patients on apremilast were included. Compared with anti-IL-17 antibodies, the aHR (95% confidence interval (CI)) of anti-IL-23 antibodies was 0.83 (0.27-2.51) for grade 2 and 0.40 (0.02-7.60) for grade 3 neutropenia; that when compared with adalimumab was 0.76 (0.28-2.06) for grade 2 but was not calculated for grade 3 as no cases were found; and that compared with apremilast was 3.88 (0.62-24.48) for grade 2 and 0.43 (0.02-11.63) for grade 3 neutropenia.No clear increase in the risk of neutropenia with anti-IL-23 antibodies was observed.CONCLUSIONNo clear increase in the risk of neutropenia with anti-IL-23 antibodies was observed.
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