加味痛泻要方对家兔体外结肠平滑肌的作用

[目的]观察加味痛泻要方对家兔体外结肠平滑肌的作用。[方法]用生理记录仪记录正常及药物致痉孪肠管蠕动曲线,分别加入加味痛泻要方40、80、160 mg/ml,记录用药后兔结肠的蠕动曲线。分别计算给药前、后的抑制率和拮抗率。[结果]加味痛泻要方不仅对正常家兔结肠蠕动呈明显抑制作用,而且对平滑肌兴奋药,包括乙酰胆碱及氯化钡引起的平滑肌痉挛均有明显的对抗作用,具有剂量依赖性。[结论]加味痛泻要方可以很好地改善肠痉挛,对家兔体外结肠平滑肌的非规律性收缩有明显的缓解作用,推测该方可能是通过拮抗乙酰胆碱M受体起作用。     

Dodecafluoropentane Emulsion in Acute Ischemic Stroke: A Phase Ib/II Randomized and Controlled Dose-Escalation Trial

PurposeThis randomized, placebo-controlled, double-blind, dose-escalation acute ischemic stroke trial was designed to demonstrate maximum tolerated dose, characterize adverse events (AEs), and explore clinical outcomes when intravenous dodecafluoropentane emulsion (DDFPe) was used as neuroprotection.MethodsAcute ischemic stroke patients (n = 24) with National Institutes of Health Stroke Scale (NIHSS) score of 2–20 were randomized to either 3 doses of intravenous DDFPe or placebo, 1 every 90 minutes, starting within 12 hours of symptom onset. Doses were given without affecting standard stroke care. Each of the 3 dose cohorts included 8 patients, with 2 receiving placebo and 6 receiving DDFPe. Primary outcomes were serious adverse events (SAEs), AEs, NIHSS score, and modified Rankin Score (mRS).ResultsNo dose-limiting toxicities were encountered, and no maximum tolerated dose was defined. One unrelated delayed death occurred in a DDFPe patient, and another occurred in the placebo group. Group SAEs and AEs were similar in incidence and severity. Early initiation of DDFPe treatment resulted in better NIHSS score response than late initiation (P = .03). Thirty- and 90-day mRS after high-dose therapy suggested clinical improvement (P = .01 and P = .03, respectively). However, the significance of differences in clinical outcomes was limited by small patient numbers and differences in stroke severity between cohorts.ConclusionsIntravenous DDFPe appears to be safe at all doses tested. Clinical improvements in NIHSS score and mRS were significant but compromised by small sample size.     

Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer

While PI3K/AKT/mTOR pathway is altered in a variety of cancers including non small cell lung cancer, abnormalities in this pathway are more common in squamous cell lung carcinoma than in adenocarcinoma of the lung. Moreover, aberrant activation of PI3K/AKT/mTOR pathway is one of the mechanisms of acquired resistance to EGFR-TK inhibitors in patients with adenocarcinoma carrying EGFR activating mutations.     

A learning method for the class imbalance problem with medical data sets

In medical data sets, data are predominately composed of “normal” samples with only a small percentage of “abnormal” ones, leading to the so-called class imbalance problems. In class imbalance problems, inputting all the data into the classifier to build up the learning model will usually lead a learning bias to the majority class. To deal with this, this paper uses a strategy which over-samples the minority class and under-samples the majority one to balance the data sets. For the majority class, this paper builds up the Gaussian type fuzzy membership function and α-cut to reduce the data size; for the minority class, we use the mega-trend diffusion membership function to generate virtual samples for the class.Furthermore, after balancing the data size of classes, this paper extends the data attribute dimension into a higher dimension space using classification related information to enhance the classification accuracy. Two medical data sets, Pima Indians’ diabetes and the BUPA liver disorders, are employed to illustrate the approach presented in this paper. The results indicate that the proposed method has better classification performance than SVM, C4.5 decision tree and two other studies.     

半夏泻心胶囊的制备工艺及药理作用

目的:研究半夏泻心汤由传统汤剂改制成胶囊剂的制备工艺条件及急性毒理试验.方法:①制备工艺:采用正交试验法.②急性毒理试验:设5个给药剂量组,组间距为0.75,给药剂量为成人日常常用药量的20倍.一次给药后,观察14 d.结果:进行最大耐受量测定.对小鼠的最大耐受量(MTD)为32 g/kg,小鼠的最大耐受量倍数为133.33.结论:动物急性试验初步表明:半夏泻心胶囊毒性甚小,临床应用安全可靠.     

A methylester of the glucuronide prodrug DOX-GA3 for improvement of tumor-selective chemotherapy

The glucuronide prodrug of doxorubicin, DOX-GA3, can be selectively activated in tumors by extracellular human beta-glucuronidase, resulting in a better therapeutic index than doxorubicin. DOX-GA3, however, is rapidly excreted by the kidney. We hypothesized that slow release of DOX-GA3 from its methylester, DOX-mGA3, by esterase activity in blood would result in improved circulation half-life (t(1/2)) of DOX-GA3. DOX-mGA3 was synthesized more efficiently with an overall yield of 60% as compared to 37% in the case of DOX-GA3. We showed that DOX-mGA3 was enzymatically converted to DOX-GA3 with a t(1/2) of approximately 0.5 min in mouse plasma to 2.5 h in human plasma, which was in agreement with differences in esterase activity between species. DOX-mGA3, similar to DOX-GA3, was at least 37-fold less potent than the parent drug doxorubicin in growth inhibition of four different human malignant cell lines in vitro. Incubation of OVCAR-3 cells with DOX-mGA3 in combination with an excess of human beta-glucuronidase (0.05 U mL(-1)) resulted in a similar growth inhibition to that of doxorubicin. Intravenous administration of DOX-mGA3 in FMa-bearing mice resulted in an area under the concentration versus time curve (AUC) of DOX-GA3 in tumor and most normal tissues that was 2.5- to 3-fold higher than after the same dose of DOX-GA3 itself. In tumor tissue, this was accompanied by a 2.7-fold increase in the AUC of doxorubicin from DOX-mGA3 than from DOX-GA3. In conclusion, an advantage of DOX-mGA3 over DOX-GA3 is that this prodrug can be produced with a higher yield. Another important advantage is the improved pharmacokinetics of the lipophilic DOX-mGA3 as compared to that of the hydrophilic DOX-GA3. This effect may even be more pronounced in man, because of the lower plasma esterase activity than measured in mice.     

卡培他滨应用于鼻咽癌同期放化疗的I期临床试验

背景与目的:卡培他滨(capecitabine)是一种口服的氟尿嘧啶类药物。在肿瘤组织中,由特异高表达的胸腺嘧啶磷酸化酶(thymidinephosphorylase,TP酶)转变为5-氟尿嘧啶(5-fluorouracil,5-FU),因此在肿瘤细胞内5-FU浓度较高。本试验探讨卡培他滨在鼻咽癌同期放化疗的最大耐受剂量(maximumtolerateddose,MTD)。方法:对36例病理诊断为鼻咽癌的放疗患者同时给予不同剂量单药卡培他滨化疗,观察不良反应并随访治疗效果。卡培他滨采用间断服用方法,放疗后开始口服,每天2次,服药14天,然后休息7天,再开始第二疗程化疗,一共2疗程。中位剂量为1600mg·(m2·d)-1,剂量为700～2500mg·(m2·d)-1。放疗剂量66～74Gy(6～7.4周)。结果:2例Ⅲ级剂量限制性毒性(dose-limitingtoxicity,DLT)发生在2300mg·(m2·d)-1剂量组,1例为Ⅲ级腹泻,1例为Ⅲ级手足综合症(hand-footsyndrome,HFS)。结论:鼻咽癌患者对卡培他滨单药化疗联合同期放疗耐受良好,最大耐受剂量为2300mg·(m2·d)-1。我们推荐卡培他滨Ⅱ期临床试验的剂量为1700mg·(m2·d)-1(间断服用方法)。     

Safety assessment of a novel ingredient for removable chewing gum

Rev7™ is an indigestible gum polymer used for the manufacturing of chewing gum. It allows for the formulation of chewing gum with low adhesion; thus can be readily removed from surfaces such as sidewalks, clothing, carpets and furniture. In a toxicological safety assessment, Rev7™ was found to be non-mutagenic in the AMES assay. The highest concentration tested in a mouse lymphoma thymidine kinase locus gene mutation assay induced a slight but biologically relevant increase in mutations under non-metabolic activation conditions after 24 h. Because of this finding, a mouse micronucleus assay was performed, and the test article was found to be negative for inducing chromosomal damage. A 28-day repeated oral toxicity study resulted in a NOAEL of 80,000 ppm; the highest concentration tested. Rev7™ was found to be free from contaminants such as heavy metals, monomers, and solvents. Lastly, Rev7™ did not demonstrate skin-sensitizing properties in the murine local lymph node assay.     

因宁片的急性和慢性毒性实验研究

目的:研究因宁片的急性和慢性毒性作用,评价其安全性。方法:40只昆明种小鼠随机分为空白对照(等容生理盐水)和因宁片(32g.kg-1)组。因宁片组24h内连续2次(间隔6h)灌胃给药后观察小鼠的一般状况、死亡情况、记录体重和摄食量,14d后处死并作大体解剖,肉眼观察各脏器变化,计算最大耐受量(MTD)。48只SD大鼠随机分为空白对照(等容生理盐水)与因宁片高、中、低剂量(6.0、3.0、0.6g.kg-1)组。灌胃给药,每天1次,连续30d,末次给药24h后处死大鼠,腹主动脉取血测定各项血液学指标和血液生化指标,记录各脏器重量、体重、摄食量,计算脏器系数,并作病理切片,观察组织形态学的变化。结果:急性毒性实验中因宁片组各项指标正常,MTD为32g.kg-1;慢性毒性实验中因宁片高、中、低剂量组大鼠一般状况正常,各组中未见多指标同时明显异常,组织结构未见明显异常。结论:因宁片毒性低,可为临床安全用药提供理论依据。