[A Case of Stage â £ Gastric Cancer with Multiple Liver Metastases, Resected Primary Tumor after Chemotherapy, and Alive for 3.5 Years without Recurrence].

A 67-year-old man visited our hospital for epigastric pain. Esophagogastroduodenoscopy(EGD)revealed type 2 gastric cancer from the cardia to the gastric angle, and histopathological examination revealed papillary adenocarcinoma(pap), HER2-positive. Contrast-enhanced CT showed wall thickening mainly in the posterior wall of the gastric body, enlarged lymph nodes that were lumped together with the main lesion, and 8 low-absorption areas with ring shaped contrast effects in both lobes of the liver. The patient was diagnosed as gastric cancer cT4aN(+)M1[HEP], clinical Stage ⅣB. Six courses of capecitabine plus cisplatin plus trastuzumab(XP plus Tmab)therapy and 17 courses of capecitabine plus trastuzumab(X plus Tmab)therapy were performed. After chemotherapy, liver and lymph node metastases disappeared on CT and MRI. EGD showed residual gastric cancer, and the policy was to resect the primary tumor. Laparoscopic total gastrectomy with D2 lymph node dissection was performed. Pathological results showed T1b(SM)depth, no lymph node metastasis, and histologic response was Grade 2a. Six courses of X plus Tmab were administered as postoperative adjuvant chemotherapy, but were discontinued at the patient's request. Currently, 5 years have passed since the first chemotherapy and 3.5 years have passed since the surgery, and the patient is alive without recurrence, suggesting that the conversion surgery may have contributed to the prolonged survival.

Pharmacokinetic control of orally dosed cyclosporine A with mucosal drug delivery system.

This study aimed to control the oral absorption of cyclosporine A (CsA) with the use of a mucosal drug delivery system (mDDS). Mucopenetrating nanocarriers (MP/NCs) and mucoadhesive nanocarriers (MA/NCs) were prepared by flash nanoprecipitation employing polystyrene-block-poly(ethylene glycol) and polystyrene-block-poly(N,N-dimethyl aminoethyl methacrylate), respectively. Their particle distribution in the rat gastrointestinal tract were visualized by fluorescent imaging. Plasma concentrations were monitored after oral administration of CsA-loaded MP/NCs (MP/CsA) and MA/NCs (MA/CsA) to rats. MP/NCs and MA/NCs had a particle size below 200 nm and ζ-potentials of 4 and 40 mV, respectively. The results from in vitro experiments demonstrated mucopenetration of MP/NCs and mucoadhesion of MA/NCs. Confocal laser scanning microscopic images showed diffusion of MP/NCs in the gastrointestinal mucus towards epithelial cells and localization of MA/NCs on the surface of the gastrointestinal mucus layer. In a pH 6.8 solution, rapid and sustained release of CsA were observed for MP/CsA and MA/CsA, respectively. After oral dosing (10 mg-CsA/kg) to rats, amorphous CsA powder exhibited a time to maximum plasma concentration (Tmax) of 3.4 h, maximum plasma concentration (Cmax) of 0.12 µg/mL, and bioavailability of 0.7%. Compared with amorphous CsA powder, MP/CsA shortened Tmax by 1.1 to 2.3 h and increased the bioavailability by 43-fold to 30.1%, while MA/CsA prolonged Tmax by 3.4 to 6.8 h with Cmax and bioavailability of 0.65 µg/mL and 11.7%, respectively. These pharmacokinetic behaviors would be explained by their diffusion and release properties modulated by polymeric surface modification. The mDDS approach is a promising strategy for the pharmacokinetic control of orally administered CsA.

Evaluation of the physiological changes in prehospital health-care providers influenced by environmental factors in the summer of 2020 during the COVID-19 pandemic.

AIM: Wearing personal protective equipment (PPE) is essential to prevent infection transmission, but the risk of heatstroke increases with wearing PPE in a humid and hot environment. Therefore, we aimed to examine how environmental parameters change the body physiology in a hot environment during the coronavirus disease (COVID-19) pandemic. METHODS: This was a retrospective cohort study extracted from the MEDIC Japan heatstroke prevention database, which was recorded between 1 August and 7 September, 2020. Its database is a registry collection from seven healthy health-care providers. Subjects recorded their own vital signs (forehead and tympanic temperature, blood pressure, pulse rate, and oxygen saturation) and environmental factors (type of weather, wet-bulb globe temperature [WBGT], air temperature, humidity, and location) every hour during their working shift. RESULTS: From 323 records, a weak positive but statistically significant correlation was observed between WBGT and pulse rate (correlation coefficient [95% confidence interval], r = 0.34 [0.23, 0.45]) and between WBGT and core body temperature. Forehead temperature had a stronger correlation than tympanic temperature (forehead, r = 0.33 [0.21, 0.43]; tympanic, r = 0.17 [0.05, 0.28]), which also showed a larger effect (forehead, η2 = 0.08; tympanic, η2 = 0.05). The effect size of oxygen saturation measured outdoors was large (η2 = 0.30). Forehead temperature increased abruptly at 28°C WBGT and at 33°C air temperature. CONCLUSION: A hot environment significantly affected forehead temperature, and the daytime imposed a high risk of heatstroke. To avoid heatstroke, environmental parameters are important to note as outdoor environments had a large effect on vital sign changes depending on the time of day.

Novel approach for attenuation of pirfenidone-induced digestive symptoms: a respirable powder formulation of pirfenidone.

Aim: Orally taken pirfenidone (PFD) often causes digestive symptoms. A respirable powder formulation of PFD (PFD-RP) was previously developed, and this study aimed to verify the risk of digestive symptoms after insufflation of PFD-RP. Materials & methods: Intestinal motility and gastrointestinal exposure levels was evaluated in PFD-RP (0.3-mg PFD/rat: a pharmacologically effective dose) and orally taken PFD (10-100 mg/kg) groups. Results & conclusion: Orally taken PFD at doses above 30 mg/kg significantly inhibited intestinal motility. In contrast, insufflated PFD-RP led to comparable intestinal motility in control group, and gastrointestinal exposure levels in PFD-RP group were markedly lower than those in orally taken PFD groups. Inhalation therapy using PFD-RP may be efficacious to reduce the risk of digestive symptoms frequently induced by orally taken PFD.

Polymeric Nanocarriers With Mucus-Diffusive and Mucus-Adhesive Properties to Control Pharmacokinetic Behavior of Orally Dosed Cyclosporine A.

The present study develops cyclosporine A (CsA)-loaded polymeric nanocarriers with mucus-diffusive and mucus-adhesive potential to control pharmacokinetic behavior after oral administration for the treatment of inflammatory bowel diseases (IBD). CsA-loaded nanocarriers consisting of polystyrene-block-polyethylene glycol (PEG-CsA) and polystyrene-block-polyacrylic acid (PAA-CsA) were prepared by a flash nanoprecipitation. Both nanocarriers showed redispersibility from lyophilized powder back to uniform nanocarrier with a mean diameter of approximately 150 nm. The nanocarriers exhibited significantly improved release behavior of CsA under pH 6.8 condition compared. A test of mucodiffusion, using artificial mucus, demonstrated the mucus-diffusive and mucus-adhesive potential of PEG-CsA and PAA-CsA, respectively, dependent on the lack of electrostatic interactions between the surface-coated polymer and mucin. Oral administrations of PEG-CsA and PAA-CsA (10 mg-CsA/kg) in rats resulted in significant improvements of absorption, as evidenced by 50- and 25-fold higher bioavailability than crude CsA, respectively. PAA-CsA exhibited more sustained and slower absorption process of CsA than PEG-CsA because of the different diffusion behavior within the mucus layer. In the rat model of IBD, significant suppression of inflammatory symptoms could be achieved by oral treatment with both CsA nanoparticles. These polymeric nanocarriers are promising dosage options to control pharmacokinetic behavior of orally dosed CsA, contributing to the development of safe and effective treatment for IBD.

Enhanced biopharmaceutical effects of tranilast on experimental colitis model with use of self-micellizing solid dispersion technology.

The present study aimed to clarify the applicability of a self-micellizing solid dispersion of tranilast (SMSD/TL) to the treatment of inflammatory bowel diseases (IBD) using an experimental colitis model. SMSD/TL with several loading amounts ranging from 10 to 50% was prepared using a wet-milling system. The physicochemical properties of SMSD/TL were evaluated in terms of the dissolution behavior, morphology, and particle size distribution. Animal studies were conducted to evaluate oral bioavailability in rats and anti-inflammatory effects in a rat model of chemically induced colitis. SMSD/TL with drug loading of 15% (SMSD/TL15) showed enhanced dissolution behavior at pH 1.2, compared with other tested other formulations. After the dispersion of SMSD/TL15 in deionized water, fine micelles formed with an average diameter of 137 nm. SMSD/TL15 (10 mg-TL/kg) exhibited about 147- and 34-fold greater value for Cmax and the area under the curve of plasma concentration vs. time than crystalline TL, respectively. Although the anti-inflammatory effect on the colitis model was very limited in the crystalline TL (2 mg/kg) group, inflammatory events, such as myeloperoxidase activity and thickening of the submucosa in colon tissues, were significantly suppressed in the SMSD/TL15 (2 mg-TL/kg) group. Based on these findings, SMSD/TL might be a more efficacious dosage option for improved IBD treatment.

Protective effects of tranilast on experimental colitis in rats.

The present study aimed to verify the efficacy of tranilast (TL) for treating inflammatory bowel disease (IBD) with the use of an experimental colitis model. The experimental colitis model was prepared by intrarectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS; 40mg/kg) dissolved in water containing 25% ethanol. The pharmacological effects of TL after repeated oral administration were evaluated by biomarker and histological analyses, and the pharmacokinetic behavior of TL was also examined after single oral administration. The intrarectal instillation of TNBS solution caused colitis, as evidenced by ca. 2.2-, 5-, and 3-fold increases in myeloperoxidase (MPO) activity, infiltrated cell numbers, and the thickness of the submucosa in the colon, respectively. However, orally-taken TL (10mg/kg, twice a day for 9days) led to a 92% reduction in the increase of the MPO level by TNBS enema, and cellular infiltration and thickened submucosa in the experimental colitis model tended to also be suppressed by repeated oral administration of TL. The oral bioavailability of TL in TNBS-treated rats was calculated to be as low as ca. 6.5%, and the poor oral absorption of TL may be a limitation of the treatment for IBD. TL could attenuate TNBS-induced colitis on the basis of the obtained results, and the anti-inflammatory effects would have clinical relevance to the therapeutic outcomes of TL in IBD patients. Although further improvement in the oral bioavailability of TL might be required for better pharmacological outcomes, TL would be an efficacious agent for treating IBD.