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Haruto Hayashi,1 Takehide Nogita,2,3 Hideki Maeda1,2 1Department of Regulatory Science, Faculty of Pharmacy, Meiji Pharmaceutical University, Tokyo, Japan; 2Department of Regulatory Science, Graduate School of Pharmaceutical Science, Meiji Pharmaceutical University, Tokyo, Japan; 3CMIC Co Ltd., Tokyo, JapanCorrespondence: Hideki Maeda, Department of Regulatory Science, Faculty of Pharmacy, Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose-city, Tokyo, 204-5255, Japan, Tel/Fax +81-42-495-8952, Email maeda@my-pharm.ac.jpPurpose: An expanded access clinical trials (EACTs) provides exceptional patient access to investigational new drugs for life-threatening diseases for which no effective treatment exists. Based on public information, we have studied EACTs since 2016, when the EACT system was launched in Japan. In this study, we investigated the reality of EACTs by interviewing pharmaceutical companies and clarifying how they view them.Patients and Methods: We conducted semi-structured interviews with 10 pharmaceutical companies developing new drugs. This study aims to clarify the status of EACTs, so we selected pharmaceutical companies that develop innovative drugs for which they may perform EACTs (however, experience in conducting EACTs was optional).Results: All those surveyed were aware of EACTs. Twelve access clinical trials were conducted, and the EACT implementation rate for pivotal clinical trials was 2.5%. The most common reason for implementing an EACT was “requests from physicians and medical institutions” (nine companies, 90.0%), and the most common reason for not implementing an EACT was “the applicability of the system” (five companies). Improvements to EACTs were identified by eight companies (80.0%); financial assistance by six companies (60.0%); reducing the scope of data to be collected and simplifying the procedure by six companies (60.0%). Seven companies (70.0%) responded that a Single Patient Investigational New Drug Application should be conducted, suggesting that the system should be revised.Conclusion: An interview survey of ten pharmaceutical companies developing new drugs in Japan regarding expanded access clinical trials indicated that there were issues with the system. Many wished to improve the system by establishing a single patient access system, supporting resources, and simplifying procedures. Based on our interviews with 10 Japanese pharmaceutical companies, it was found that the system needed to be improved by introducing a single patient access system, providing supporting resources, and simplifying procedures. In Japan, about eight years have passed since EACT was established, and it appears a revision of the EACT legislation is due.Keywords: clinical trials, investigational new drugs, patient access, semi-structured interview

Neural stem cells (NSCs) are progenitor cells which have the ability to self‑renewal and potential for differentiating into neurons, oligodendrocytes, and astrocytes. The in vitro isolation, culturing, identification, cryopreservation were investigated to produce neural stem cells in culture as successful sources for further studies before using it for clinical trials. In this study, mouse bone marrow was the source of neural stem cells. The results of morphological study and immunocytochemistry of isolated cells showed that NSCs can be produced successfully and maintaining their self‑renewal and successfully forming neurosphere for multiple passages. The spheres preserved their morphology in culture and cryopreserved to be a ready source for use in experiments as a model for neurological disorders.

Hiromichi Maeda,1,* Ken-ichi Okada,2,* Tsutomu Fujii,3 Mari S Oba,4 Manabu Kawai,2 Seiko Hirono,2 Yasuhiro Kodera,5 Masayuki Sho,6 Takahiro Akahori,6 Yasuhiro Shimizu,7 Yoshiyasu Ambo,8 Naru Kondo,9 Yoshiaki Murakami,9 Jiro Ohuchida,10 Hidetoshi Eguchi,11 Hiroaki Nagano,12 Junichi Sakamoto,13 Hiroki Yamaue2 1Department of Surgery, Kochi Medical School, Nankoku, Kochi 780-8505, Japan; 2Second Department of Surgery, Wakayama Medical University, Wakayama 641-8510, Japan; 3Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan; 4Department of Medical Statistics Faculty of Medicine, Toho University, Ota-ku, Tokyo 143-8540, Japan; 5Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8560, Japan; 6Department of Surgery, Nara Medical University, Kashihara, Nara 634-8521, Japan; 7Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan; 8Department of Surgery, Teine-Keijinkai Hospital, Sapporo, Hokkaido 006-8555, Japan; 9Department of Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; 10Department of Surgery, Miyazaki Prefectural Miyazaki Hospital, Miyazaki 889-1692, Japan; 11Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; 12Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan; 13Tokai Central Hospital, Kakamigahara, Gifu 504-8601, Japan*These authors contributed equally to this workCorrespondence: Hiroki YamaueSecond Department of Surgery, Wakayama Medical University, Kimiidera, Wakayama 641-8510, JapanTel +81-73-441-0613Email yamaue-h@wakayama-med.ac.jpAim and Background: TJ-100 is a traditional Japanese medicine that affects inflammation and gastrointestinal motility, and is used as a preventive and treatment for paralytic ileus. This study aims at determining the effect of TJ-100 on the peritoneal levels of IFN-γ/IL-9, cytokines related to ileus, after pancreaticoduodenectomy (PD) in a clinical setting.Methods: This was a subsidiary study of the clinical trial investigating the effect of TJ-100 on postoperative bowel function. Ascites was collected from 180 patients using an abdominal drainage tube on postoperative day 1 and 3 after PD (POD 1 or POD 3) and used to measure 27 cytokines. We performed univariate and multivariate analyses using several perioperative variables and administration of TJ-100/placebo to determine the effect of TJ-100 on the levels of IFN-γ and IL-9.Results: Peritoneal levels of IL-9 and IFN-γ decreased between POD 1 and 3 (Wilcoxon signed-rank test p< 0.001). Multivariate analysis was performed after univariate analysis to select the variables and patients with a body mass index of ≥ 22 kg/m2, older age, use of epidural anesthesia, and longer surgery correlated with the levels of IL-9 and IFN-γ. However, we could not detect a correlation between the use of TJ-100 and cytokine levels in ascites either on POD 1 or 3.Conclusion: TJ-100 did not affect peritoneal IL-9 and IFN-γ levels after PD. This was in accordance with published clinical findings showing no improvement in bowel function after PD and TJ-100 treatment.Keywords: TNF, Kampo, Daikenchuto, herbal medicine, pancreatic cancer

Abstract Background Plantago lanceolata L. is used in Iraqi folklore medicine to treat injuries, and its extract is prescribed by some herbalists for cancer patients. This research aimed to evaluate the effect of P. lanceolata leaf extract on breast cancer cell lines in vitro and to identify its active compounds. Crystal violet viability assay was used to determine the cytotoxicity of methanolic P. lanceolata leaf extract against various breast cancer cell lines. MCF7, AMJ13, MDAMB, and CAL51 human breast cancer cells were treated with different concentrations of the extract for 72 h. The morphology of the treated cells was examined under a phase-contrast inverted microscope. The clonogenic ability was assessed through a clonogenic assay. High-performance liquid chromatography (HPLC) analysis was performed to measure the concentrations of phenols and flavonoids in the extract. Results The methanolic P. lanceolata leaf extract significantly inhibited the proliferation of triple-negative CAL51 cells but showed minor effect on the other breast cancer cells. In addition, at high doses, it induced cytopathic morphological changes. The clonogenic assay showed low colony formation in the exposed cells, especially CAL51 cells. Furthermore, HPLC study revealed that the methanolic extract contained important flavonoid glycosides, especially rutin, myricetin quercetin, and kaempferol. Conclusions P. lanceolata leaf extract selectively inhibited the proliferation of CAL51 triple-negative breast cancer cells and showed minor effect on the other breast cancer cells types studied. Thus, this study showed P. lanceolata as a possible natural source of selective anti-triple-negative breast cancer drugs.

In this article, the density effect on superradiance is investigated through the field suppression of superradiance. It is shown that increasing density, which increases the number of atoms and leads to a greater macroscopic dipole, causes line broadening. In other words, it is harder to stop superradiance by an external electric field at higher density. The results reported here are essential to the superradiance detection and are critical steps towards creating and controlling ultracold plasma. Key words: superradiance, Rydberg atoms, cold gas, field suppression, laser. Nous etudions ici les effets de la densite sur la superradiance via la suppression de champ de superradiance. Nous montrons qu'une augmentation de la densite, qui augmente le nombre d'atomes et mene a un plus grand dipole macroscopique, cause un elargissement de raie. En d'autres termes, il est plus difficile d'arreter la supperradiance par un champ electrique externe a plus haute densite. Les resultats presentes ici sont essentiels dans la detection de superradiance et presentent des etapes critiques pour creer et controler des plasmas ultra-froids. [Traduit par la Redaction] Mots-cles: superradiance, atomes de Rydberg, gaz froid, suppression de champ, laser., 1. Introduction Superradiance, cooperative radiation, was proposed by Dicke in 1954 [1] and intensively studied in the 1970s [2, 3]. A comprehensive review of superradiance can be found in refs. [...]

We measured the cross section and the proton analyzing power Ay for p–3He elastic scattering at the angles θ = 26.9◦–170.1◦ in the center of mass system with a 65 MeV polarized proton beam. We compared the data with the rigorous numerical calculations based on the various nucleon–nucleon potentials. For the cross section, clear discrepancy is seen at the angles where the cross section takes minimum. For the proton analyzing power Ay, the calculations have moderate agreements to the data. In this proceedings, we show only the experimental results.

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Keiji Yoshikawa,1 Jun Kozaki,2 Hidetaka Maeda3 1Yoshikawa Eye Clinic, Tokyo, Japan; 2Kozaki Eye Clinic, Osaka, Japan; 3Maeda Eye Clinic, Osaka, Japan Purpose: To evaluate the efficacy and safety of brinzolamide 1%/timolol 0.5% fixed-combination (BRINZ/TIM-FC) therapy compared with timolol 0.5% (TIM) monotherapy in Japanese patients with open-angle glaucoma or ocular hypertension. Methods: This randomized, double-masked, multicenter study included Japanese patients aged ≥20 years. Patients were treated during a 4-week observation period with TIM monotherapy in advance of randomization to treatment with topical BRINZ/TIM-FC or TIM monotherapy twice daily for 8 weeks. The primary endpoint was mean reduction in intraocular pressure (IOP) from baseline to week 8 at 2 hours postinstillation. Adverse events (AEs) were recorded at each visit. Results: A total of 301 patients (BRINZ/TIM-FC, n=150; TIM, n=151; age [mean ± standard deviation], 61±13 years) were enrolled. Mean IOP reductions from baseline were greater with BRINZ/TIM-FC than with TIM at weeks 4 and 8 at 0 and 2 hours postinstillation (all P≤0.0001), with mean reductions of -3.2 mmHg with BRINZ/TIM-FC and -1.4 mmHg with TIM at week 8, 2 hours postinstillation. Although AEs were observed in 19% of all patients (BRINZ/TIM-FC, 20%; TIM, 19%), all AEs were mild or moderate. Conclusion: BRINZ/TIM-FC therapy was associated with significantly greater reductions in IOP compared with TIM, and it was well tolerated in Japanese patients with open-angle glaucoma or ocular hypertension. Keywords: Azarga, intraocular pressure, carbonic anhydrase inhibitor, beta blocker