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BACKGROUNDBaicalein is the main active flavonoid in Scutellariae Radix and is included in shosaikoto, a Kampo formula used for treating hepatitis and jaundice. However, little is known about its hepatoprotective effects against hepatic ischemia-reperfusion injury (HIRI), a severe clinical condition directly caused by interventional procedures. We aimed to investigate the hepatoprotective effects of baicalein against HIRI and partial hepatectomy (HIRI + PH) and its potential underlying mechanisms.METHODS AND RESULTSMale Sprague-Dawley rats received either baicalein (5 mg/kg) or saline intraperitoneally and underwent a 70% hepatectomy 15 min after hepatic ischemia. After reperfusion, liver and blood samples were collected. Survival was monitored 30 min after hepatic ischemia and hepatectomy. In interleukin 1β (IL-1β)-treated primary cultured rat hepatocytes, the influence of baicalein on inflammatory mediator production and the associated signaling pathway was analyzed. Baicalein suppressed apoptosis and neutrophil infiltration, which are the features of HIRI + PH treatment-induced histological injury. Baicalein also reduced the mRNA expression of the proinflammatory cytokine tumor necrosis factor-α (TNF-α). In addition, HIRI + PH treatment induced liver enzyme deviations in the serum and hypertrophy of the remnant liver, which were suppressed by baicalein. In the lethal HIRI + PH treatment group, baicalein significantly reduced mortality. In IL-1β-treated rat hepatocytes, baicalein suppressed TNF-α and chemokine mRNA expression as well as the activation of nuclear factor-kappa B (NF-κB) and Akt.CONCLUSIONSBaicalein treatment attenuates HIRI + PH-induced liver injury and may promote survival. This potential hepatoprotection may be partly related to suppressing inflammatory gene induction through the inhibition of NF-κB activity and Akt signaling in hepatocytes.

01 Aug 2024·Life Sciences

Intracerebroventricular 2-hydroxypropyl-γ-cyclodextrin alleviates hepatic manifestations without distributing to the liver in a murine model of Niemann–Pick disease type C

Article

Author: Motoyama, Keiichi ; Matsuo, Muneaki ; Kondo, Yuki ; Higaki, Katsumi ; Shirakawa, Aina ; Yamada, Yusei ; Nakagata, Naomi ; Ikeda, Ryuji ; Era, Takumi ; Tanaka, Mayuko ; Seki, Takahiro ; Higashi, Taishi ; Ishitsuka, Yoichi ; Irie, Tetsumi ; Takeo, Toru ; Fukaura-Nishizawa, Madoka ; Kurauchi, Yuki ; Ishii, Akira ; Sakai, Taichi ; Arima, Hidetoshi ; Kawata, Tatsuya ; Katsuki, Hiroshi

Niemann-Pick disease type C (NPC) is a lysosomal lipid storage disorder characterized by progressive neurodegeneration and hepatic dysfunction. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is currently under clinical investigation for NPC, but its adverse events remain problematic. We previously identified that a cyclic octasaccharide, 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), also ameliorated NPC manifestations with higher biocompatibility than HP-β-CD. However, preclinical studies describing the associations between the biodistribution and pharmacodynamics of these compounds, which are essential for clinical application, are still lacking. Here, we investigated these properties of HP-γ-CD by measuring its organ biodistribution and therapeutic effect after systemic and central administration. The effect of HP-γ-CD on disturbed cholesterol homeostasis appeared within several hours after exposure and persisted for several days in NPC model cells and mice. Tissue distribution indicated that only a small fraction of subcutaneously administered HP-γ-CD rapidly distributed to peripheral organs and contributed to disease amelioration. We found that a subcutaneous dose of HP-γ-CD negligibly ameliorated neurological characteristics because it has limited penetration of the blood-brain barrier; however, an intracerebroventricular microdose unexpectedly attenuated hepatic dysfunction without the detection of HP-γ-CD in the liver. These results demonstrate that central administration of HP-γ-CD can indirectly attenuate peripheral manifestations of NPC.

01 Jul 2024·International Journal of Hygiene and Environmental Health

Cyclophosphamide exposure factors in family caregivers for pediatric cancer patients

Article

Author: Noda, Yuko ; Yamamura, Kenichiro ; Hamada, Yuko ; Koga, Yuhki ; Miyata, Junko ; Ohga, Shouichi

The exposure of family caregivers to anticancer drugs for pediatric patients with malignancy is a potential health risk that needs to be minimized. We monitored the amount of cyclophosphamide (CPM) that had adhered to the undershirts of patients and the personal protective equipment (PPE) of family caregivers as well as the caregivers' urine levels of CPM within the first three days after the first and second courses of high-dose CPM therapy. Liquid chromatography/mass spectrometry (LC/MS/MS) detected >0.03 ng/ml of CPM in 26% (23/88) of urine samples from 8 of 11 (72.7%) patients' family caregivers, with a peak of 0.7 ng/ml from 24 to 48 h after administration. Since urine CPM concentrations in family caregivers varied after the first and second courses, the exposure risk factors were analyzed by scoring the PPE-wearing time index (caring minutes × PPE points from wearing masks, gloves, and/or gowns) and CPM adhesion of PPE items with the caring patterns of diaper change, washing body care, oral care, eating assistance, emotional support, and co-sleeping. The closest association was observed for CPM adhesion between oral care gloves and undershirts (correlation coefficient 0.67, p = 0.001). The mixed-effect model analysis indicated only a significant correlation between the PPE-wearing time index and emotional care (playing, cuddling, and physical contact) (p = 0.016). These results suggest that prolonged emotional support results in poor PPE protection, which increases the risk of exposure in family caregivers. Strict PPE care within 48 h after high-dose CPM controls the exposure to high-risk anticancer drugs in caregivers of pediatric patients.

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Pipeline Snapshot as of 25 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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