Enhanced antitumour activity of doxorubicin and simvastatin combination loaded nanoemulsion treatment against a Swiss albino mouse model of Ehrlich ascites carcinoma

Doxorubicin (DOX) is the most commonly used anticancer drug; however, it has limited use because prolonged administration may result in severe cardiotoxicity. Simvastatin (SIM), generally prescribed for hypercholesterolaemia, has also shown salubrious results in the monotherapy or combinational drug therapy of different cancers in various models. Nanoparticle drug delivery systems are a novel way of improving therapeutics and also improving the absorption and specificity of drugs towards tumour cells. In this study, we exploited this technology to increase drug specificity and minimize imminent adverse effects. In this study, the antitumour activity of the combination formulas of DOX and SIM, either loaded in water (DOX‐SIM‐Solution) or nanoemulsions (NEs) (DOX‐SIM‐NE), was evaluated in a Swiss albino mouse model of Ehrlich ascites carcinoma. The anticancer effect was assessed by quantifying the change in body weight, mean survival time, and percent increase in lifespan (%ILS), determining haematological and serum biochemical parameters (liver function test, kidney function test and lipid profile parameters) as well as studying the histopathological alterations in liver tissues. We observed a clear increase in %ILS of the DOX‐SIM‐Solution group (265.30) that was double the %ILS of the DOX‐SIM‐NE group (134.70). However, DOX‐SIM‐NE had a non‐toxic effect on the haematological parameters, whereas DOX‐SIM‐Solution increased the levels of haemoglobin and lymphocytes. Furthermore, the encapsulation of SIM and DOX into NEs improved the levels of all serum biochemical parameters compared to the DOX‐SIM‐Solution. A reduction in the side effects of DOX‐SIM‐NE on the liver was also established using light microscopy, which revealed that the morphologies of the hepatocytes of the mice were less affected by administration of the DOX‐SIM‐NE treatment than with the DOX‐SIM‐Solution treatment. The study showed that incorporating SIM into the DOX‐loaded‐NE formulation remarkably improved its efficiency and simultaneously reduced its adverse effects.     

高脂血症患者细胞色素P450 3A4~* 18B基因多态性对辛伐他汀稳态血药浓度及其对降脂疗效的影响

目的分析高脂血症患者细胞色素P450 3A4~*18B(CYP3A4~*18B)基因多态性对辛伐他汀稳态血药浓度及其对降脂疗效的影响。方法 115名高脂血症患者均予以辛伐他汀每次20 mg,qd,口服,连续用药4周。在治疗前和治疗后,分别抽取空腹外周静脉血2 mL,用聚合酶链反应-限制性片段长度多态性分析法分析CYP3A4~*18B的等位基因,用全自动生化分析仪测定血总胆固醇、低密度脂蛋白胆固醇等。在最后一次服药前0.5 h内,抽取外周静脉血4 mL,用HPLC法测定血中辛伐他汀的稳态药物浓度。结果 115名高血脂症患者中,CYP3A4~*18B基因型分布符合Hardy-Weinberg遗传平衡(P>0.05),CYP3A4~*18B等位基因突变率为41.74%。CYP3A4~*1/~*1、CYP3A4~*1/~*18B和CYP3A4~*18B/~*18B的辛伐他汀稳态血药浓度分别为(4.88±0.44),(4.90±0.38)和(4.71±0.36)ng·mL^-1,总胆固醇分别为(5.78±0.47),(5.84±0.47)和(5.82±0.52)mmol·L^-1,低密度脂蛋白胆固醇分别为(2.63±0.04),(2.60±0.08)和(2.58±0.12)mmol·L^-1,差异均无统计学意义(均P>0.05)。结论 CYP3A4~*18B基因多态性对辛伐他汀稳态血药浓度及降脂疗效无明显影响。     

羟基红花黄色素A和三七总皂苷对高脂血症的影响与机制研究

目的: 研究比较羟基红花黄色素A(HSYA)和三七总皂苷(PNS)对高脂血症大鼠的血脂及动脉粥样硬化相关炎症因子的作用和机制。方法：以高脂血症大鼠为模型,辛伐他汀为阳性对照药品,分别给予实验组大鼠不同剂量的HSYA和PNS,给药期满后取血测定大鼠血脂及CRP、IL-10和IL-6。结果：HSYA高剂量组可显著降低TC、TG,升高HDL-C,但大鼠死亡率最高;低剂量组则可显著降低CRP、IL-6,升高IL-10;PNS高、中剂量组可显著降低TC、TG和LDL-C,各剂量组对IL-6、IL-10和CRP的作用不明显,大鼠死亡率低。结论：HSYA低剂量给药具有抗炎作用,同时安全性高,临床应用建议以低剂量抗炎作用为主。治疗剂量下PNS的降血脂与抗炎作用均不优于辛伐他汀和HSYA,可认为其用于动脉粥样硬化的作用位点与HSYA不同,在临床应用时也应当考虑其适应症区别。     

Topical administration of simvastatin recovers alveolar bone loss in rats

Background and Objective:  Simvastatin, a cholesterol-lowering drug, has been reported to show anabolic effects on bone metabolism. We examined the effects of simvastatin in vitro using cultured rat calvaria cells and in vivo using periodontitis-induced rats.
Material and Methods:  Alkaline phosphatase activity and bone nodule formation were measured in cultured rat calvaria cells. Nylon ligature was placed around the maxillary molars of Fischer male rats for 20 d to induce alveolar bone resorption. After ligature removal, simvastatin was topically injected into the buccal gingivae for 70 d and then microcomputed tomography and histological examinations were performed.
Results:  Simvastatin maintained high alkaline phosphatase activity and increased bone nodule formation in rat calvaria cells in a dose-dependent manner, showing that simvastatin increased and maintained a high level of osteoblastic function. Microcomputed tomography images revealed that treatment with simvastatin recovered the ligature-induced alveolar bone resorption, showing a 46% reversal of bone height. Histological examination clarified that low-mineralized alveolar bone was formed in simvastatin-treated rats.
Conclusion:  These findings demonstrate that simvastatin has the potential to stimulate osteoblastic function and that topical administration of simvastatin may be effective for the recovery of alveolar bone loss in rats.     

Subcutaneous administration of lactone form of simvastatin stimulates ectopic osteoinduction by rhBMP-2

OBJECTIVE: To evaluate the effects of various 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) on ectopic osteoinduction by recombinant human bone morphogenetic protein-2 (rhBMP-2) using different administration methods. MATERIALS AND METHODS: Disks containing 5 mug of rhBMP-2 and type I collagen were implanted into the calf muscles of 6-week-old male rats (n = 64). Either the lactone form of simvastatin (SV), open hydroxy-acid form of simvastatin (SVA), cerivastatin (CVA), or vehicle (control) was then administered per orally (PO group) or subcutaneously (SC group) for 20 days. The disks were removed on day 21 after implantation, and ectopic induced bone formation was evaluated by radiographic, histologic, and biochemical analysis. RESULTS: Both the projected and radiopaque area on X-ray film, and the calcium content of the SV group in the SC group (SV-SC group) were significantly greater than those in the other SC and PO groups. Alkaline phosphatase activity and tartrate-resistant acid phosphatase activity in the SV-SC group were significantly lower than those in the other SC and PO groups. Histologic examination revealed an increase of ectopic induced bone volume in the SV-SC group. CONCLUSION: Subcutaneous administration of SV stimulates ectopic osteoinduction by rhBMP-2 through reduction of bone turnover.     

清肝益肾祛风复方对自发性高血压大鼠血压及胸腺的干预作用研究

目的：观察越鞠保和丸联用辛伐他汀能否增强对动脉粥样硬化引起的心肌纤维化的逆转作用。方法：采用高脂饲料饲养ApoE-/-小鼠建立动脉粥样硬化斑块模型和心肌纤维化模型,越鞠保和丸和辛伐他汀联用和单用对ApoE-/-小鼠进行干预,同时设立高脂饲料饲养的模型对照组和普通饲料饲养的正常对照组,Elisa法检测小鼠血清血脂、血管紧张素Ⅱ（AngⅡ）、基质金属蛋白酶-1（MMP-1）含量,心肌组织masson染色定量分析胶原容积分数（CVF）,高通量转录组测序分析各组心肌组织差异表达基因。结果：越鞠保和丸和辛伐他汀联用相比单用能更有效的降低总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白（LDL-C）、AngⅡ和升高高密度脂蛋白（HDL-C）、MMP-1,并且masson染色CVF值也明显降低,从高通量转录组测序差异基因分析结果来看,越鞠保和丸联合辛伐他汀与正常对照组相比,差异基因表达主要集中在脂肪酸代谢、延长及降解等相关通路上,而与模型对照组相比,差异基因表达主要集中在原发性免疫缺陷和肠道免疫网络的IgA的产生等相关通路上。结论：越鞠保和丸联合辛伐他汀可以更有效的逆转动脉粥样硬化导致的心肌纤维化,其机制与调控免疫炎性反应有关。     

3种抗菌药物对辛伐他汀在人肝微粒体中代谢的影响

目的 体外研究人肝微粒体中罗红霉素、左氧氟沙星和氟康唑分别对辛伐他汀代谢的影响。方法 分别将罗红霉素、左氧氟沙星、氟康唑与辛伐他汀在人肝微粒体中共孵育,采用UPLC-MS/MS测定辛伐他汀的浓度。结果 罗红霉素和左氧氟沙星对辛伐他汀的代谢没有影响,氟康唑剂量依赖性抑制辛伐他汀的代谢,其IC₅₀值为36.6 μmol·L^-1。结论 氟康唑显著抑制辛伐他汀的代谢,罗红霉素与左氧氟沙星对辛伐他汀在人肝微粒体中代谢无明显药物相互作用。     

Behavior of Lp(a) and apoproteins (A1, B,C2, C3, E) during and after therapy with simvastatin

Summary The efficacy of simvastatin in reducing plasma cholesterol is well documented. Other molecules within the apo lipoprotein family, particularly lipoprotein (a) Lp(a), have recently been found to have a predictive and/or causative role in atherosclerosis. Based on these considerations, we studied 15 patients affected by primary hypercholesterolemia to evaluate the effect of simvastatin in Lp(a) and apoprotein plasma levels (A1, B, C2, C3, E), in addition to the classic lipid parameters. Clinical and laboratory parameters were evaluated before therapy, after 12 weeks of therapy, and after 5 weeks of drug withdrawal. Simvastatin therapy produced a significant reduction in total cholesterol (CH) and LDL-CH (p<0.0001), and a significant increase in HDL-CH (p<0.01); no variation was observed in triglyceride (TG) levels. Simvastatin therapy further showed a significant decrease in apoC2 (p<0.05), the apo C2/C3 ratio (p<0.01), and apoE (p<0.01), as well as a significant increase in Lp(a) plasma levels (p<0.05). All of the parameters studied returned to pretreatment values 5 weeks after drug withdrawal; only HDL-CH persisted above the values reached during therapy. Our data agree with those documenting the beneficial effect of simvastatin in greatly decreasing CH and LDL-CH, but point out the need for further studies on the long-term effect of simvastatin on apoprotein molecules, such as on Lp(a), in order to fully establish its role in the secondary prevention of atherosclerosis.     

Inhibition of autophagy potentiates pemetrexed and simvastatin-induced apoptotic cell death in malignant mesothelioma and non-small cell lung cancer cells

Pemetrexed, a multitarget antifolate used to treat malignant mesothelioma and non-small cell lung cancer (NSCLC), has been shown to stimulate autophagy. In this study, we determined whether autophagy could be induced by pemetrexed and simvastatin cotreatment in malignant mesothelioma and NSCLC cells. Furthermore, we determined whether inhibition of autophagy drives apoptosis in malignant mesothelioma and NSCLC cells. Malignant mesothelioma MSTO-211H and A549 NSCLC cells were treated with pemetrexed and simvastatin alone and in combination to evaluate their effect on autophagy and apoptosis. Cotreatment with pemetrexed and simvastatin induced greater caspase-dependent apoptosis and autophagy than either drug alone in malignant mesothelioma and NSCLC cells. 3-Methyladenine (3-MA), ATG5 siRNA, bafilomycin A, and E64D/pepstatin A enhanced the apoptotic potential of pemetrexed and simvastatin, whereas rapamycin and {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 attenuated their induction of caspase-dependent apoptosis. Our data indicate that pemetrexed and simvastatin cotreatment augmented apoptosis and autophagy in malignant mesothelioma and NSCLC cells. Inhibition of pemetrexed and simvastatin-induced autophagy was shown to enhance apoptosis, suggesting that this could be a novel therapeutic strategy against malignant mesothelioma and NSCLC.