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Masakazu Kotoda,1 Hirofumi Ino,1 Yasutomo Kumakura,1 Tetsuya Iijima,1 Tadahiko Ishiyama,2 Takashi Matsukawa11Department of Anesthesiology, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan; 2Surgical Center, University of Yamanashi Hospital, University of Yamanashi, Chuo, Yamanashi 409-3898, JapanPurpose: Although amiodarone is classified as a Vaughan-Williams class Ⅲ antiarrhythmic drug, it has inhibitory effects on voltage-gated sodium and calcium channels and on β-adrenergic receptors. Given these pharmacological profiles, amiodarone may have analgesic properties. Most patients who are prescribed amiodarone possess multiple cardiovascular risk factors. Despite the fact that pain plays a crucial role as a clinical indicator of cardiovascular events, the effects of amiodarone on pain have not been investigated. The aim of the current study was to investigate the analgesic effects of amiodarone by using mouse models of pain in an effort to elucidate underlying mechanisms.Methods: Adult male C57B6 mice received single bolus intraperitoneal injections of amiodarone at doses of 25, 50, 100, and 200 mg/kg, while the mice in the control group received only normal saline. The analgesic effects of amiodarone were evaluated using the acetic acid-induced writhing test, formalin test, and tail withdrawal test. In addition, the potassium channel opener NS1643, voltage-gated sodium channel opener veratrine, calcium channel opener BAYK8644, and selective β-adrenergic agonist isoproterenol were used to uncover the underlying mechanism.Results: During the acetic acid-induced writhing test, formalin test, and tail withdrawal test, amiodarone induced analgesic responses in a dose-dependent manner. The analgesic effects of amiodarone were abolished by veratrine but not by NS1643, BAYK8644, or isoproterenol.Conclusion: Amiodarone induced analgesic responses in a dose-dependent manner, likely by blocking voltage-gated sodium channels. These results indicate that clinical doses of amiodarone can affect nociception and may mask or attenuate pain induced by acute cardiovascular events.Keywords: amiodarone, antinociception, pain, sodium channels

Abstract: The main objective of this investigation was to test the hypothesis that brain serotonin (5-HT) synthesis, as measured by trapping of α-[11C]methyl-l-tryptophan (α-MTrp) using positron emission tomography (PET), can be modulated by changes in blood oxygen. The study involved six healthy participants (three male and three female), who breathed a 15% or 60% oxygen mixture starting 15 min before the injection of tracer and continuing during the entire acquisition period. Participants were injected with up to 12mCi of α-MTrp. Two sets of PET images were acquired while the participants were breathing each of the oxygen mixtures and, after reconstruction, all images were converted into brain functional images illustrating the brain trapping constant K * (μL/g/min). The K * values were obtained for 12 regions of interest outlined on the magnetic resonance images. The K * values obtained at high and low blood oxygen content were compared by paired statistics using Tukey''s post hoc correction. As there were no difference in plasma tryptophan concentrations, these K * values are directly related to regional 5-HT synthesis. The results showed highly significant increases (50% on average) in brain serotonin synthesis (K * values) at high (mean value of 223±41mmHg) relative to low (mean value 77.1±7.7mmHg) blood oxygen levels. This suggests that tryptophan hydroxylase is not saturated with oxygen in the living human brain and that increases in blood oxygen can elevate brain serotonin synthesis. [Copyright &y& Elsevier]

Serotonin (5-HT) plays an important role in the pathophysiology of irritable bowel syndrome (IBS). Usingα-[11C]methyl-l-tryptophan-positron emission tomography (PET), it was demonstrated that brain 5-HT synthesis is increased in patients with IBS, in a gender-specific manner. The aims of the study were to evaluate the effects of alosetron on brain 5-HT synthesis in patients with IBS. Six male and five female non-constipation-predominant IBS patients were enrolled. The subjects received alosetron or a placebo for 14 days, separated by a 2-week washout period. On day 14, rectal distensions commenced just prior to the PET scan (which was performed for 80 min), and continued for 20-min periods. The functional images were analysed with SPM99. Alosetronvsplacebo treatments, in a randomized, double-blinded, crossover manner, were studied. 5-HT synthesis was greater in several regions in the males than in the females during the alosetron treatment, whereas there was no region in which the females had greater synthesis. There were significant gender-treatment interactions of synthesis in the cingulate gyrus, caudate nucleus, globus pallidus, and cerebellum. The gender differences in the effect of alosetron on brain 5-HT synthesis may be related to the gender differences in the efficacy of alosetron. [ABSTRACT FROM AUTHOR]

Kumakura Y, Danielsen EH, Reilhac A, Gjedde A, Cumming P. Levodopa effect on [18F]fluorodopa influx to brain: normal volunteers and patients with Parkinson's disease. Acta Neurol Scand 2004 DOI: 10.1111/j.1600-0404.2004.00299.x © Blackwell Munksgaard 2004. Levodopa is the immediate precursor of dopamine and the substrate for DOPA decarboxylase, an enzyme subject to regulation in living brain. To test whether this regulation changes in disease, we used Positron Emission Tomography (PET) with parametric mapping to measure the effect of levodopa on the net clearance of [18F]fluorodopa to brain ( K, ml/g/min). Five patients with early Parkinson's disease with pause of medication for 3 days and six age-matched healthy volunteers were studied in a baseline condition and after levodopa challenge. Levodopa (200 mg as Sinemet) increased the magnitude of the net clearance K in the left and right putamen of the healthy volunteers by 11% relative to the baseline condition. In contrast, resumption of medication with levodopa did not significantly alter the magnitude of K in putamen of the Parkinson's disease patients. Compartmental analysis was used to probe the physiological basis of the activation of K: levodopa treatment increased by 15% the apparent distribution volume of [18F]fluorodopa in cerebellum ( , ml/g) of both patients and control subjects, without significantly altering the unidirectional blood–brain clearance ( , ml/g/min) or the relative activity of DOPA decarboxylase ( , min−1) in putamen. We conclude that levodopa treatment increases the distribution volume of [18F]fluorodopa in brain, increasing its availability for utilization in dopamine terminals. We speculate that levodopa act as a direct beta-adrenergic agonist at receptors regulating the permeability of the blood–brain barrier to levodopa. However, the PET analytical method was without sufficient power to detect the consequent increase in magnitude of K in brain of only five Parkinson's disease subjects. [ABSTRACT FROM AUTHOR]

Introduction: In this study, we aimed to identify biomarkers for predicting treatment outcomes and efficacy of chemotherapy plus nivolumab, as well as predict immune-related adverse events (irAEs) characteristics of immune checkpoint inhibitors., Methods: This multicenter study included 104 patients who received chemotherapy plus nivolumab as the primary treatment for unresectable advanced recurrent gastric cancer. Blood test results were collected before the start and after two courses of treatment. The neutrophil-lymphocyte ratio, prognostic nutritional index (PNI), and lactate dehydrogenase/albumin ratio (LAR) were examined after treatment in each case to determine changes compared to values before the start of treatment., Results: A total of 57 (54.8%) patients experienced a complete or partial response. The LAR of the stable disease (SD)/progressive disease (PD) group significantly increased (p=0.018). An examination of the presence of grade ≥3 irAEs and changes in related factors showed that the LAR of all patients increased., Conclusion: The LAR was correlated with the best therapeutic response; therefore, it may be a potential biomarker of treatment outcomes and efficacy., (S. Karger AG, Basel.)

Background: There are few reports on conversion surgery (CS) after chemotherapy plus nivolumab as a first-line treatment in patients with unresectable advanced or recurrent gastric cancer (GC). This multicenter study was conducted to analyze real-world data on CS after chemotherapy plus nivolumab as a first-line treatment and to identify predictive biomarkers., Methods: This multicenter study included 104 patients who received chemotherapy plus nivolumab as primary treatment for unresectable advanced recurrent GC from 12 institutes. We investigated and analyzed patient characteristics and blood test data in the presence or absence of CS, the relationship between the Gustave Roussy Immune Score (GRIm-s) and CS, and the characteristics of CS cases., Results: CS was performed in 12 patients (11.5%). Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was significantly better in patients who underwent CS (p < 0.0001). There were no CS cases with high-risk GRIm-s (0%), however there were 22 non-CS cases (23.9%). No high-risk GRIm-s cases were converted to CS. Minimally invasive surgery was performed in 50.0% of the cases, with R0 resection in all cases and only one case of urinary retention (Grade II) as a postoperative complication, indicating a good postoperative short-term outcome. There were two cases of postoperative recurrence (16.7%), both of which were grade 1b., Conclusions: The short-term postoperative results of CS after chemotherapy plus nivolumab as the first-line treatment for GC were acceptable in this study. There were no high-risk GRIm-s cases among those who underwent CS, suggesting that the GRIm-s may be a predictor of CS., (© 2024. Society of Surgical Oncology.)

There have been predictions that the use of the macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) in zirconium-89 ( 89 Zr) immuno-positron emission tomography ( 89 Zr-immunoPET) could enhance the in vivo stability of 89 Zr radioimmunoconjugates. However, conjugating [ 89 Zr]Zr-DOTA to a monoclonal antibody (mAb) remains a challenge as the heat treatment required for [ 89 Zr]Zr-DOTA chelation can lead to thermal denaturation of the mAb moieties. We developed a method for synthesizing [ 89 Zr]Zr-DOTA-mAb based on a tetrazine (Tz)-conjugated bifunctional DOTA derivative 2,2',2″-(10-(1-(4-(1,2,4,5-tetrazin-3-yl)phenyl)-3,21,26-trioxo-6,9,12,15,18-pentaoxa-29-carboxy-2,22,25-triazanonacosane-29-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTAGA-Tz) and the inverse electron-demand Diels-Alder (IEDDA) click chemistry reaction where trans -cyclooctene-modified mAbs are conjugated to [ 89 Zr]Zr-DOTAGA without being exposed to heat. The stability of IEDDA-derived [ 89 Zr]Zr-DOTAGA-trastuzumab was confirmed by in vitro, ex vivo, and in vivo testing and comparative analysis against the conventional deferoxamine (DFO) counterpart [ 89 Zr]Zr-DFO-trastuzumab. The in vivo immunoPET imaging using [ 89 Zr]Zr-DOTAGA-trastuzumab clearly visualized human epidermal growth factor receptor 2-positive malignancies in murine xenograft models. Greater tumor contrast was observed from [ 89 Zr]Zr-DOTAGA-trastuzumab at a 72-h delayed scan compared with [ 89 Zr]Zr-DFO-trastuzumab. These findings suggest that our IEDDA ligation approach can be an effective means of synthesizing [ 89 Zr]Zr-DOTA-mAb and can enhance the theranostic potential of 89 Zr-immunoPET in DOTA-mediated radioimmunotherapy.

Introduction: Individuals involved with the criminal justice system face challenges in receiving and maintaining substance use disorder (SUD) treatment and support. Although telephone monitoring (TM) could reduce these barriers, data on TM for community-dwelling individuals involved with the criminal justice system and research on individuals who drop out of TM are scarce. We examined the factors associated with dropping out early from the Voice Bridges Project, which provides TM for individuals on probation for drug-related convictions through community mental health centers in Japan., Methods: Participants (n = 546) were individuals aged ≥20 years with methamphetamine-related convictions who were on probation. Univariate analyses examine the associations between one-year follow-up status and baseline variables, and multivariate Cox proportional hazards regression analyses identify the risk and protective factors associated with dropping out. Stratified analyses report results based on sex and halfway-house residency., Results: The one-year dropout rate was 43.6 % (n = 238). Multivariate analysis identified two risk factors for dropping out-halfway-house residency and suicide attempts in the past year, and two protective factors-higher education and the current use of SUD services. Sex-stratified analyses showed that halfway-house residency was a risk factor for both men and women. Attempted suicide was a risk factor for women. Conversely, higher education and current use of SUD services were protective factors for men., Conclusions: Our results identify unique risk factors for women, such as a recent history of suicide attempts, and distinctive protective factors for men, including higher education and current use of SUD services, emphasizing the importance of sex-specific approaches. Furthermore, the study reveals that irrespective of sex, vulnerable individuals, such as halfway-house residents, are at a higher risk of dropping out from TM., Competing Interests: Declaration of competing interest Toshihiko Matsumoto received financial support for this research from the Ministry of Health, Labour and Welfare, Japan. Shiori Tsutsumi received financial support for this research from the Japan Science and Technology Agency and Keio University. The authors declare that although they received funding as mentioned above, this financial support did not influence the outcomes, interpretation, or presentation of the research findings. The research was conducted independently, and the views expressed in this paper are those of the authors and not necessarily those of the funding agencies., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The stereoselective 5- endo -trig oxygenative cyclization of α,β-unsaturated oximes was achieved using molecular oxygen (O 2 ) and a manganese catalyst. Several 4-hydroxy-4,5-dihydroisoxazoles were obtained in high yields by directly incorporating O 2 from the atmosphere (eliminating the necessity for a pure oxygen environment) and using an unprecedentedly low loading of Mn(acac) 3 (as little as 0.020 mol %) without additional additives. Because of its desirable features, such as operational simplicity, inexpensive catalyst, mild reaction conditions (open flask conditions at room temperature), and broad substrate compatibility, this novel reaction provides an attractive synthetic approach to producing 4-hydroxy-4,5-dihydroisoxazoles.

Radiotherapy combined with temozolomide (TMZ+RT) is the primary treatment for high-grade glioma. TMZ is classified as a moderate emetic risk agent and, thus, supportive care for nausea and vomiting is important. In Nagoya University Hospital, all patients are treated with a 5-hydroxy-tryptamine 3 receptor antagonist (5-HT 3 RA) for the first 3 days. The daily administration of 5-HT 3 RA is resumed after the 4th day based on the condition of patients during TMZ+RT. Therefore, the present study investigated risk factors for nausea and vomiting in patients requiring the daily administration of 5-HT 3 RA. Patients with high-grade glioma who received TMZ+RT between January 2014 and December 2019 at our hospital were included. Patients were divided into two groups: a control group (patients who did not resume 5-HT 3 RA) and resuming 5-HT 3 RA group (patients who resumed 5-HT 3 RA after the 4th day), and both groups were compared to identify risk factors for nausea and vomiting during TMZ+RT. There were 78 patients in the control group (68%) and 36 in the resuming 5-HT 3 RA group (32%). A multivariate analysis of patient backgrounds in the two groups identified age <18 years, PS 2 or more, and occipital lobe tumors as risk factors for nausea and vomiting. Nausea and vomiting were attenuated in 30 patients (83%) in the resuming 5-HT 3 RA group following the resumption of 5-HT 3 RA. The results obtained highlight the importance of extracting patients with these risk factors before the initiation of therapy and the early resumption or daily administration of 5-HT 3 RA according to the condition of each patient., Competing Interests: The authors declare no conflict of interest.

Background: Olaparib and niraparib (poly adenosine diphosphate [ADP]-ribose polymerase [PARP] inhibitors) have significant antitumor action in patients with ovarian cancer. However, the incidence of nausea and vomiting among patients on these drugs in clinical trials is rather high. There are no guidelines on antiemetic treatment for nausea caused by oral anticancer agents. This study aimed to investigate the incidence of nausea and vomiting caused by PARP inhibitors and the actual situation of antiemetic therapy in patients with gynecologic cancer. Methods: Patients with gynecologic cancer who were scheduled to receive PARP inhibitors were enrolled. Data on PARP inhibitor-induced nausea and vomiting were collected from patient diaries for 21 days. The primary endpoint was the incidence of vomiting during the 21 days after starting olaparib and niraparib. Results: Overall, between January 2020 and March 2023, 134 patients were enrolled. Of the 129 patients who were evaluated, 28 (21.7%) received prophylactic antiemetics for 21 days, and 101 (78.3%) did not. The overall incidence of PARP inhibitor-induced vomiting was 16.3%. The incidence of vomiting in the group that did not receive antiemetic prophylaxis was 13.9%. On dividing the group that did not receive antiemetic prophylaxis into the olaparib and niraparib subgroups, the incidence of vomiting was found to be 18.6% for the olaparib group and 10.3% for the niraparib group. Conclusion: The incidence of emesis without antiemetic prophylaxis among patients on olaparib and niraparib ranged from 10% to 30%. Therefore, olaparib and niraparib can be classified in the low emetogenic risk and prophylactic antiemetic therapy at the time of treatment initiation may be unnecessary., Competing Interests: Competing Interests: Ms. Yamamoto received personal fees from Chugai outside of the submitted work. Dr. Tsuchiya received personal fees from Chugai, Taiho, Ono, Sun Pharma, Kyowa-Kirin, Pfizer, Eizai, and Daiichi Sankyo outside the submitted work. Dr. Iihara received personal fees from Taiho, Chugai, Yakult, Astellas, Eli Lilly, Daiichi Sankyo, AstraZeneca, Nippon Kayaku, Ono, and Nippon Boehringer Ingelheim and consulting fees for their institution from Taiho and Eisai outside the submitted work. Dr. Suzuki received personal fees from Takeda and AstraZeneca outside of the submitted work. Mr. Watanabe received personal fees from Chugai outside of the submitted work. Dr. Suzuki A received personal fees from Toa Eiyo, Asahi Kasei, Daiichi Sankyo, Pfizer, Eisai, Nippon Shinyaku, Celltrion Healthcare Japan, Otsuka, Sandoz, Tsumura, Nipro, Taiho, Kyowa-Kirin, Nippon Chemiphar, Japan Blood Products Organization, Takeda, and Nippon Boehringer Ingelheim and grants for their institution from Nippon Kayaku, Asahi Kasei, Chugai, Taiho, Daiichi Sankyo, Japan Blood Products Organization, Mochida, and Sun Pharma outside the submitted work. Dr. Abe received personal fees from Taiho, Chugai, AstraZeneca, and Takeda outside the submitted work., (© The author(s).)

Purpose: We conducted muscle synergy and gait analyses in a monoplegic patient whose gait function improved through training, to explore the possibility of using these parameters as indicators of training., Case Presentation: A 49-year-old male had monoplegia of the right lower limb caused by infarction of the left paracentral lobule. After 2 months of training, he was able to walk and returned to work., Methods: Consecutive analyses were done after admission. Muscle synergy analysis: during walking, surface electromyograms of gluteus maximus, quadriceps femoris, adductor femoris, hamstrings, tibialis anterior, medial/lateral gastrocnemius, and soleus on both sides were recorded and processed for non-negative matrix factorization (NNMF) analysis. Gait analysis: markers were placed at foot, and walking movements were video recorded as changes in position of the markers., Results: Compared with three muscle synergies detected on the non-paretic side, two muscle synergies were extracted on the paretic side at admission, and the number increased to three and then four with progress in rehabilitation training. Changes in weighting and activity of the muscle synergies were greater on the non-paretic side than on the paretic side. With training, the knee joint flexor and the ankle dorsiflexor activities on the paretic side and the gluteus maximus activity on the non-paretic side increased during swing phase as shown by weight changes of muscle synergies, and gait analysis showed increased knee joint flexion and ankle joint dorsiflexion during swing phase in the paretic limb. On the non-paretic side, however, variability of muscle activity was observed, and three or four muscle synergies were extracted depending on the number of strides analyzed., Conclusion: The number of muscle synergies is considered to contribute to motor control. Rehabilitation training improves gait by increasing the number of muscle synergies on the paretic side and changing the weights of the muscles constituting the muscle synergies. From the changes on the non-paretic side, we propose the existence of compensatory mechanisms also on the non-paretic side. In muscle synergy analysis, in addition to the filters, the number of strides used in each analysis set has to be examined. This report highlights the issues of NNMF as analytical methods in gait training for stroke patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ebihara, Hirota, Kumakura and Nagaoka.)