Effect of norethisterone acetate on serum lipid and lipoprotein parameters as well as on blood coagulation in female monkeys (M. fascicularis)

The effects of daily oral administration of a high dose of 10 mg norethisterone acetate (NET-Ac.)/kg/day over 14 weeks on serum lipid and lipoprotein parameters as well as on blood coagulation were investigated in female monkeys (M. fascicularis). Measurements of lipids and lipoprotein cholesterol were performed in weeks —5 and — 1 before treatment and in weeks 4, 8 and 12 after treatment. In addition, various blood coagulation and fibrinolytic parameters were determined in weeks 11–14 after treatment with NET-Ac. Furthermore, the serum levels of norethisterone (NET) were determined in order to monitor the real systemic compound exposure and revealed that C_max and AUC (0–3 h) values reached for norethisterone in this experiment in monkeys were about 25 times higher than those obtained after an oral contraceptive dose of NET-Ac. in women.

The results of lipid and lipoprotein cholesterol determinations showed decreases in serum total lipids, phospholipids, triglycerides and total cholesterol associated with similar decreases in HDL-, LDL- and VLDL-cholesterol fractions after NET-Ac.-treatment in monkeys. These effects were observed from week 4 onwards and maintained their magnitude up to week 12 after treatment. Since both HDL- and LDL-cholesterol fractions decreased, the HDL/LDL-ratio remained almost unchanged. Thus, the results obtained in this study after high-dose treatment with NET-Ac. in monkeys did not indicate any changes of lipid and lipoprotein parameters which in humans are supposed to be associated with an increased risk of cardiovascular lesions, namely a decrease in HDL- and increase in LDL-cholesterol fractions.

The results of blood coagulation and fibrinolytic parameters showed increased antithrombin-III and plasminogen levels besides minor changes in other parameters, thus indicating that NET-Ac. -treatment does not contribute to an increased risk of cardiovascular thrombotic events in the cynomolgus monkey.     

Application of technetium-99m hexamethylpropylene amine oxime single-photon emission tomography to neurologic prognosis in patients undergoing urgent carotid surgery

In this study we aimed to work out a quantitative prognostic index for preoperative assessment of brain technetium-99m hexamethylpropylene amine oxime (HMPAO) single-photon emission tomography (SPET) in patients referred for urgent carotid endarterectomy due to acute obstructive disease of the internal carotid artery (ICA) and neurological deficit. To this end we compared data from preoperative SPET studies with the postinterventional changes in neurological status in 20 patients (17 males, three females; mean age 53 years, SD 4 years) with acute ischaemic cerebral disorders induced by obstruction of the ICA. Carotid obstruction was diagnosed by ultrasound B-mode study. All patients underwent urgent carotid endarterectomy from the ICA. Patients were divided into two groups in accordance with the results of postoperative follow-up: group A comprised patients with significant (more than 3 points) postoperative improvement in neurological condition as quantified by the Canadian Neurological Scale (11 patients); group B consisted of patients with minimal improvement or deterioration (nine, three of whom died). All patients were studied preoperatively by^99mTc-HMPAO SPET. The volume of nonperfused tissue (VS, cm³) was quantified using the Mountz technique. Hypoperfused volume (V _hypoperf, cm³) in the affected hemisphere was calculated as the total volume of voxels with^99mTc-HMPAO uptake <90% of the contralateral symmetric voxels. Discriminant prognostic function was calculated by discriminant analysis as:PF = 0.072×VS + 29.46×(VS/V _hypoperf). Patients with preoperativePF values <8.20 demonstrated postoperative improvement in neurological status, while the group withPF>8.90 comprised patients who demonstrated minimal improvement or deterioration. PF values in the range 8.20–8.90 carried an indefinite prognosis. We conclude that the preoperative^99mTc-HMPAO SPET can be used for the selection of patients in whom improvement in neurological status may be expected after urgent surgical correction of acute extracranial obstruction of the ICA.     

Assessment of changes in regional cerebral blood flow in patients with major depression using the 99mTc-HMPAO single photon emission tomography method

Regional cerebral blood flow was investigated in 14 patients with major depression diagnosed according to the DSM-III-R criteria (six patients with single and eight patients with recurrent episodes) and in ten healthy volunteers. The mean ages of the patients and the controls were 33.5 ± 2.7 and 31.6 ± 2.6 years, respectively. The severity of the depression was assessed using the 17-item Hamilton Depression Scale (mean: 23.2 ± 1.5). None of the patients was under medication. After administration of 500 MBq technetium-99m hexamethylpropylene amine oxime, a single photon emission tomography study was performed and then transaxial, sagittal and coronal slices were obtained. For the semiquantitative analysis of the data, the ratios of the mean counts/pixel to the whole slice were calculated for 24 regions on three consecutive transaxial slices in the orbitomeatal plane. Additionally, left/right and frontal/occipital ratios were calculated. Both sides of the temporal region had a significantly decreased cerebral blood flow (CBF) when compared to the controls. The left/right ratio of the prefrontal region was also significantly lower in the patients than in the controls. The Hamilton score had a negative correlation with blood flow in the anterofrontal and left prefrontal regions. According to our results, regional CBF seems to be decreased in the left prefrontal and in both temporal regions in major depression. The severity of depression is correlated with the reduction in CBF in the regions of the anterofrontal and left prefrontal cortex.     

The Influences of Mifepristone, Norethisterone and Tamoxifen on the Glycosph

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炔诺酮肟对大鼠抗着床抗早孕作用机理的形态学研究

大鼠从妊娠第一天开始每日灌服炔诺酮肟4mg/kg,共3天。结果能引起早孕大鼠黄体细胞滑面内质网减少;脂滴大量积贮;抑制卵巢3β-羟基甾体脱氢酶活性,从而使卵巢孕酮生物合成受阻。药物还能引起早孕大鼠子宫蜕膜的病理改变,蜕膜细胞出现变性,坏死,宫腔内大量出血,白细胞浸润,胚胎发育不良,蜕膜细胞内糖原及碱性磷酸酶含量均下降。本文还讨论了药物引起卵巢孕酮生物合成受阻与蜕膜变化的关系。     

Measurement of the secretion of technetium-99m hexamethylpropylene amine oxime into breast milk

There are no published data for the activity of technetium-99m hexamethylpropylene amine oxime (^99mTc-HMPAO) found 1in breast milk. The amount of radioactivity in breast milk following the administration of 500 MBq^99mTc-HMPAO for a brain perfusion study has been measured. The effective dose to the infant was calculated to be 0.26 mSv, so necessitating no interruption of breast feeding. Unbound^99mTc is readily secreted into breast milk and the effective dose will remain less than 1 mSv if the^99mTc-HMPAO labelling effici ency is 99% for the worse reported case, and could remain <1 mSv for the mean reported case for^99mTc-HMPAO labelling efficiencies down to 94%.     

红霉素A肟的新合成方法

目的 用一种全新的方法合成红霉素A肟(1)。方法 在酸碱缓冲溶液中由红霉素A(3)与盐酸羟胺缩合生成1。系统研究了反应体系的pH值、反应温度以及盐酸羟胺的加入量对反应结果的影响。同时对红霉素A肟化反应机理进行了推导。结果 红霉素A9—肟的收率达95％以上，产品纯度达92％。化合物1经红外、氢谱、碳谱、质谱鉴定，与文献报道相一致。结论 该方法有效地抑制了红霉素A的酸性分解，与文献方法相比，大幅度提高了反应的收率和产品的纯度。     

定坤丹联合炔诺酮治疗月经不调的临床研究

目的探讨定坤丹联合炔诺酮治疗月经不调的临床疗效。方法选取2017年3月—2019年3月在开封市人民医院治疗的月经不调患者92例,根据用药的差别分为对照组(46例)和治疗组(46例)。对照组口服炔诺酮片,2.5mg/次,4次/d;治疗组在对照组基础上口服定坤丹,7 g/次,2次/d。两组患者均经过3个月经周期治疗。观察两组患者临床疗效,同时比较治疗前后两组患者临床症候积分、性激素水平、月经失血图(PBAC)、中华生存质量量表(Ch QOL)、高温相评分(HPS)、匹茨堡睡眠质量指数量表(PSQI)评分以及血清细胞因子水平。结果治疗后,对照组临床有效率为82.61%,显著低于治疗组的97.83%,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者症候积分明显下降(P0.05),且治疗组临床症候积分明显低于对照组(P0.05)。治疗后,两组血清孕酮(P)、雌二醇(E2)水平显著升高(P0.05),黄体生成激素(LH)、促卵泡成熟激素(FSH)水平显著下降(P0.05),且治疗组E2、P、LH和FSH水平明显好于对照组(P0.05)。治疗后,两组PBAC和PSQI评分显著下降(P0.05),Ch QOL和HPS评分显著升高(P0.05),且治疗组PBAC、PSQI、Ch QOL和HPS评分明显好于对照组(P0.05)。治疗后,两组患者血清表皮生长因子(EGF)、血管内皮生长因子(VEGF)水平均明显升高(P0.05),且治疗组EGF和VEGF水平明显高于对照组(P0.05)。结论定坤丹联合炔诺酮片治疗月经不调可有效改善患者临床症状,改善机体性激素水平,提高患者睡眠和生活质量。     

A trivalent approach for determining in vitro toxicology: Examination of oxime K027

Unforeseen toxic effects contribute to compound attrition during preclinical evaluation and clinical trials. Consequently, there is a need to correlate in vitro toxicity to in vivo and clinical outcomes quickly and effectively. We propose an expedited evaluation of physiological parameters in vitro that will improve the ability to predict in vivo toxicity of potential therapeutics. By monitoring metabolism, mitochondrial physiology and cell viability, our approach provides insight to the extent of drug toxicity in vitro. To implement our approach, we used human hepatocellular carcinoma cells (HepG2) and neuroblastoma cells (SH‐SY5Y) to monitor hepato‐ and neurotoxicity of the experimental oxime K027. We utilized a trivalent approach to measure metabolism, mitochondrial stress and induction of apoptosis in 96‐well formats. Any change in these three areas may suggest drug‐induced toxicity in vivo. K027 and pralidoxime, an oxime currently in clinical use, had no effect on glycolysis or oxygen consumption in HepG2 and SH‐SY5Y cells. Similarly, these oximes did not induce oxidant generation nor alter mitochondrial membrane potential. Further, K027 and pralidoxime failed to activate effector caspases, and these oximes did not alter viability. The chemotherapeutic agent, docetaxel, negatively affected metabolism, mitochondrial physiology and viability. Our studies present a streamlined high‐throughput trivalent approach for predicting toxicity in vitro, and this approach reveals that K027 has no measurable hepatotoxicity or neurotoxicity in vitro, which correlates with their in vivo data. This approach could eliminate toxic drugs from consideration for in vivo preclinical evaluation faster than existing toxicity prediction panels and ultimately prevent unnecessary experimentation. Copyright © 2014 John Wiley & Sons, Ltd.