皮肤不同层对脂溶性药物经皮渗透的影响

目的　评价皮肤角质层和真皮层对药物经皮渗透的影响。方法　选择 5 氟尿嘧啶 ,茶碱 ,氢醌 ,巴比妥 ,硝酸异山梨酯和酮基布洛芬共 6种具不同脂溶性的药物 ,以贴片为试验药剂 ,采用改进Franz扩散池法 ,考察药物经完整皮肤和剥离角质层皮肤的体外透皮能力。结果　药物的脂溶性LogPc和药物经完整或角质层剥离皮肤的透皮能力 (Kp ,cm·h-1)间均具有抛物线关系。然而 ,角质层剥离后 ,药物Kp增加率主要同药物在水中的溶解度有关。渗透促进剂肉豆蔻酸异丙酯 (IPM )加入到贴片中后 ,药物的脂溶性LogPc和其Kp间无抛物线关系。药物经完整皮肤渗透时 ,因加入IPM而引起的Kp增加率随药物LogPc的变小而增加。药物经角质层剥离皮肤渗透时 ,因加入IPM而引起的Kp增加率随药物在IPM中的溶解度增大而增加。结论　本实验为皮肤病态条件 ,如皮肤受伤或溃疡等时药物经皮渗透规律研究提供一种新的方法     

Mechanism for Species-Specific Induction of Leydig Cell Tumors in Rats by Lansoprazole

Lansoprazole is a substituted benzimidazole which inhibits gastricacid secretion by inhibiting the hydrogen-potassium ATPase (protonpump) in the parietal cell. The finding of Leydig cell hyperplasiaand Leydig cell tumors in 2-year oral studies in Sprague-Dawleyrats but not in CD-1 mice prompted investigative studies todetermine the mechanism for the Leydig cell changes. hCG challengestudies in Sprague-Dawley rats revealed decreased testosteroneresponsiveness in rats treated orally for 1 or 2 weeks withlansoprazole. After 4 weeks of daily oral treatment increasesin serum LH and decreases in serum testosterone were detectedwithin a few hours after dosing. In a study where 9-month-oldmale F344 rats were given testosterone supplementation via Silasticimplants and then treated with lansoprazole for 6 months, ahigh incidence of Leydig cell tumors was seen in lansoprazoletreated,unsupplemented rats, whereas no Leydig cell tumors were seenin testosterone supplemented rats. This implied that reductionof the normal feedback inhibition at the level of the hypothalaumsand/or pituitary due to reduced testosterone levels, thus givingrise to elevated levels of LH, was involved in the inductionof Leydig cell tumors by lansoprazole. In vitro studies withLeydig cells from rats using various stimulators and precursorsof testosterone biosynthesis demonstrated that the most sensitivesite for inhibition of testosterone synthesis by lansoprazoleis the transport of cholesterol to the cholesterol side chaincleavage enzyme. The IC50s for inhibition of LH or hCG-stimulatedtestosterone synthesis in Leydig cells from rats, mice, andmonkeys were 11–12, 8, and 27.4 µg/ml, respectively.In vitro studies with metabolites of lansoprazole revealed thatthree metabolites were more potent inhibitors of testosteronesynthesis than the parent drug, two of them being at least 10times more potent. These metabolites are present in rats atsubstantial levels but are undetectable in humans. The lackof induction of Leydig cell tumors in mice, lower sensitivityof primate Leydig cells, and the absence of testosterone synthesisinhibitingmetabolites in man suggest that Leydig cell tumors found inrats represent a species-specific sensitivity and does not implya risk for clinical use in man.     

Efficacy and safety of omalizumab in an Asian population with moderate-to-severe persistent asthma

Background and objective:   The efficacy and safety of the anti-IgE antibody, omalizumab, has been widely studied in patients with asthma. However to date, no large studies have been performed in Asian populations. The aim of this study was to compare the efficacy and safety of omalizumab with placebo, as add-on therapy in Asian patients with moderate-to-severe persistent asthma.
Methods:   Japanese patients (20–75 years of age) with uncontrolled asthma, despite receiving high-dose inhaled corticosteroids and other standard therapies, were randomized to receive add-on treatment with omalizumab or placebo in a 16-week, double-blind, parallel-group, multicentre study.
Results:   Altogether, 315 treated patients were included in the efficacy and safety analyses. The change from baseline in morning PEF was 15.45 L/min (least squares mean) with omalizumab versus 2.25 L/min with placebo, a statistically significant difference of 13.19 L/min ( P  = 0.0004). Clinically significant asthma exacerbations occurred in six patients (4.0%) treated with omalizumab and in 18 patients (11.0%) treated with placebo. The odds ratio for the risk of experiencing an asthma exacerbation was 0.32 in favour of omalizumab ( P  = 0.0192). Changes in asthma symptom scores, daily life activity scores, sleep scores and rescue medication use were in favour of omalizumab, but group differences did not reach statistical significance. Adverse event rates were similar between omalizumab and placebo, except for injection site reactions, which were more frequently observed in the omalizumab group.
Conclusions:   Add-on treatment with omalizumab improved asthma control without significant adverse events in Japanese patients with moderate-to-severe persistent asthma.     

Current Status and Future Objectives of Surgical Therapies for Epilepsy in Japan

This study investigated the number of epilepsy surgeries performed over time in Japan, and conducted a questionnaire survey of the Japan Neurosurgical Society (JNS) training program core hospitals to determine the current status and future objectives of surgical therapies and epilepsy training programs for physicians in Japan. This article presents part of a presentation delivered as a presidential address at the 44th Annual Meeting of the Epilepsy Surgery Society of Japan held in January 2021. The number of epilepsy surgeries performed per year has increased in Japan since 2011 to around 1,200 annually between 2015 and 2018. The questionnaire survey showed that 50% of the responding hospitals performed epilepsy surgery and 29% had an epilepsy center, and that these hospitals provided senior residents with education regarding epilepsy surgery. The presence of an epilepsy center in a hospital was positively correlated with the availability of long-term video electroencephalography monitoring beds as well as the number of epilepsy surgeries performed at the hospital. In regions with no medical facilities offering specialized surgical therapies for epilepsy, the JNS training program core hospitals may help improve epilepsy diagnosis and treatment. They may also increase the number of safe and effective surgeries by establishing epilepsy centers that can perform long-term video electroencephalography monitoring, providing junior neurosurgeons with training regarding epilepsy, and playing a core role in surgical therapies for epilepsy in tertiary medical areas in close cooperation with neighboring medical facilities.     

Chronic Phase Intracranial Hemorrhage Caused by Ruptured Pseudoaneurysm Induced by Carmustine Wafer Implantation for Insulo-opercular Anaplastic Astrocytoma: A Case Report

Carmustine wafers improve the survival of patients with high-grade gliomas, but several adverse events have been reported. A 42-year-old man with left insulo-opercular anaplastic astrocytoma developed a massive intra-cavital hematoma with subarachnoid hemorrhage caused by ruptured pseudoaneurysm of the left middle cerebral artery (MCA) adjacent to the site of carmustine wafers implanted 6 months previously. Intraoperative finding demonstrated a dissection of the insular portion of the MCA, and pathological examination identified the resected pseudoaneurysm. This case demonstrates that carmustine wafers can cause changes in local vessels. Therefore, implantation of carmustine wafers near to important vessels passing close to the resection cavity should be considered with great caution.