非洛地平-美托洛尔复方透皮贴剂的研制及其药效实验研究

目的 制备非洛地平-美托洛尔复方透皮贴剂,研究其在自发性高血压大鼠(spontaneously hypertensive rats,SHR)上的降压作用特征.方法 50只3月龄SHR随机分为5组:空白对照组、非洛地平-美托洛尔剂量分别为1mg-10mg·kg-1口服混悬液治疗组及1mg-10mg·kg-1、3mg-30mg·kg-1、9mg-90mg·kg-1的透皮贴剂治疗组.另设同月龄正常血压Wistar大鼠为正常对照组.以无创性尾套法测定单次给药后大鼠血压和心率,初步评价贴剂的降压作用.结果 贴剂应用后2h起效,降压强度在18～24h达峰效应,作用可持续36～72h;对收缩压、舒张压和心率均有显著降低作用(P＜0.05);降压强度和持效时间具有剂量依赖性,效果显著优于两药口服联用(P＜0.05).结论 该贴剂使用方便,降压效果确切,作用平稳,持效时间长,可提高治疗安全性和患者依从性,适用于高血压的长期药物治疗.     

社区高血压患者应用可乐定透皮贴剂的降压疗效分析

[目的] 评价可乐定透度贴剂(C-TTS)的降压疗效. [方法] 在社区中选取1 320例1、2级原发性高血压患者,给C-TTS 1贴,贴于左胸上部,每7 d更换1次.在治疗期间,954例使用1贴,132例加用至2贴,共观察坐位血压3个月. [结果] 954例患者仅用l贴C-TTS血压就降至目标血压,132例患者使用2贴血压得到有效控制,总有效率为82.3%.治疗后平均血压明显降低(P<0.05),患者使用C-TTS方便性的满意度和对治疗的依从性为94.1%. [结论] C-TTS能持续有效降低24 h血压,治疗依从性好,副作用少.     

芬太尼透皮贴剂治疗中重度癌痛的疗效观察及安全评估

目的观察芬太尼透皮贴剂治疗中重度癌痛的近期疗效和不良反应。方法内脏痛、骨转移痛、侵犯和压迫神经痛、皮肤黏膜痛等慢性癌性疼痛42例,应用芬太尼透皮贴剂治疗,记录疗效及治疗期间便秘、恶心呕吐、嗜睡、头晕、呼吸抑制等不良反应出现的情况。结果总有效率为90．4％（38／42）,不良反应有便秘4例（9．5％）,恶心呕吐4例（9．5％）,其他有嗜睡、头晕、胃部不适、呼吸抑制,但发生率均〈5％。结论使用芬太尼透皮贴剂治疗中重度癌痛安全有效,可作为癌痛治疗的首选药物可作为癌痛治疗的首选药物。     

芬太尼透皮贴剂合用中枢抑制性镇痛剂不良反应4例

芬太尼透皮贴剂(多瑞吉)作为晚期癌症患者第三阶梯止痛药,具有给药方便、安全、无创伤、准确控制药物72h释放、疗效可靠的优点,目前临床应用广泛。但也观察到值得注意的药物不良反应,如呼吸力降低、呼吸抑制、便秘,恶心、呕吐等。     

芬太尼透皮贴剂合用中枢抑制性镇痛剂不良反应4例

芬太尼透皮贴剂（多瑞吉）作为晚期癌症患者第三阶梯止痛药．具有给药方便、安全、无创伤、准确控制药物72h释放、疗效可靠的优点,目前临床应用广泛。但也观察到值得注意的药物不良反应,如呼吸力降低、呼吸抑制、便秘,恶心、呕吐等。     

芬太尼缓释透皮贴剂治疗晚期癌症疼痛的临床观察

目的　观察芬太尼缓释透皮贴剂 (多瑞吉 )治疗晚期癌症中、重度癌痛的疗效和毒副反应。方法　对 6 3例晚期癌痛患者使用多瑞吉治疗 ,初始剂量从 2 5 μg h始 ,每 3天更换 1次 ,根据疼痛情况进行剂量调整 ,直到无痛或基本无痛。结果　疼痛缓解率达 96 .82 %。其中完全缓解34.92 % ,明显缓解 6 1.90 % ;生活质量评分提高。不良反应有头晕、恶心、呕吐、嗜睡、便秘、皮肤瘙痒等。结论　多瑞吉治疗晚期癌症疼痛疗效确切 ,病人耐受性好 ,明显改善生活质量。     

芬太尼透皮贴剂控制癌性疼痛的临床疗效观察

目的探讨芬太尼透皮贴剂控制癌性疼痛的临床疗效和安全性。方法 296例癌性疼痛患者随机分为观察组(148例)和对照组(148例),对照组给予注射盐酸哌替啶治疗,观察组采用芬太尼缓释透皮贴剂进行镇痛治疗。结果观察组治疗总有效率87.84%,对照组总有效率为48.65%,观察组的NRS评分差值大于对照组,P<0.05,差异具有显著性;两组患者均无严重的不良反应发生。结论芬太尼透皮贴剂控制癌性疼痛,疗效确切,副作用少,使用安全,值得推广使用。     

护理干预对芬太尼透皮贴剂治疗肿瘤疼痛的影响

目的探讨护理干预对芬太尼透皮贴剂治疗肿瘤疼痛的影响。方法将40例癌痛患者随机分为两组,每组20例,对照组单纯用芬太尼透皮贴剂止痛治疗,干预组在此基础上行护理干预。采用视觉模拟评分法（VAS）进行治疗前后疼痛程度的评估,同时比较两组治疗前后生活质量差异。结果与对照组相比,护理干预组VAS评分明显降低,差异有统计学意义（P〈0．05）;且能显著改善癌性疼痛患者生活质量的评分（P〈0．05）。结论通过护理干预,可降低芬太尼透皮贴剂治疗癌性疼痛患者VAS的评分,提高生活质量。     

美国药典与中国药典透皮贴剂释放度桨碟法测定装置的比较

[目的]对美国药典与中国药典透皮贴剂释放度桨碟法测定装置进行比较。[方法]分别使用美国药典与中国药典桨碟法装置对芬太尼透皮贴剂的释放曲线进行测定,释放介质为2.5mmol·L-1的磷酸和2.5mmol·L-1磷酸二氢钾等体积混合溶液900ml;以TC-C18为固定相的Agilent色谱柱(250mm×4.6mm×5μm),含0.2%三乙胺和0.2%磷酸的5mmol·L-1辛烷基磺酸钠溶液与乙腈的混合溶液(1.3︰1)为流动相,流速为1.0ml·min-1,柱温为25℃,检测波长为210nm。[结果]对于2.1mg规格的透皮贴剂采用不同方法所得的释放曲线存在差异。[结论]中国药典桨碟法装置在测量透皮贴剂释放度时不能完全替代美国药典桨碟法装置。     

芹菜素对自发性高血压大鼠的降压作用及对肾脏血管紧张素转化酶2表达的影响

目的探讨自发性高血压大鼠(SHR)肾脏血管紧张素转换酶2(ACE2)的表达,了解芹菜素对大鼠肾脏ACE2mRNA表达的影响,观察芹菜素的降压效果。方法 60只雄性SHR大鼠随机分为6组,每组10只:正常对照组、卡托普利阳性对照组以及0.007、0.026、0.104和0.417g/kg芹菜素剂量组。4周后,用荧光实时定量PCR法检测肾脏ACE2mRNA表达,免疫组化法检测肾脏ACE2表达。结果自灌胃第3周开始,卡托普利阳性对照组、0.026、0.104、0.417g/kg芹菜素剂量组的血压均显著低于对照组(P<0.05)。各剂量组大鼠心率、体重与对照组比较差异均无显著性(P>0.05)。给予芹菜素4周后,阳性对照和芹菜素高剂量组ACE2mRNA表达量明显升高(P<0.05)。免疫组化所见ACE2表达情况与mRNA表达水平基本类似。结论芹菜素降低SHR大鼠血压与增强ACE2表达有关。     

Fish protein improves blood pressure but alters HDL2 and HDL3 composition and tissue lipoprotein lipase activities in spontaneously hypertensive rats

Summary The two-month effects of dietary fish protein and casein on VLDL, HDL₂ and HDL₃ compositions and hepatic lipase (HTGL) and tissue lipoprotein lipase (LPL) activities were examined in spontaneously hypertensive rats (SHR) at 4 wk of age. After 2 mo of experiment, the fish protein diet induced lower blood pressure (–14 %) as compared to casein. Liver triacylglycerol and total cholesterol concentrations were 1.37- and 1.71-fold lower in the fish protein group than in the casein group, respectively. Total cholesterol concentration in plasma was also diminished by fish protein (–21 %) and was reflected in HDL₂ fraction (–44 %). SHR fed the fish protein diet as compared with those fed casein, showed a significantly low HDL₃ particle number, as measured by diminished HDL₃ mass and apo A-I. The consumption of fish protein did not affect VLDL particle number, but significantly decreased VLDL-triacylglycerol (–32 %) and adipose tissue total lipid concentrations as compared to casein. This was accompanied by diminished HTGL and adipose tissue LPL activities (–10%, –91%, respectively). These data demonstrate that fish protein plays an antihypertensive role and reduces plasma and tissue lipid concentrations. Thus, a fish protein intake might be beneficial for patients with hypertension.     

The potential of cod hydrolyzate to inhibit blood pressure in spontaneously hypertensive rats

Hypertension is an independent yet controllable risk factor for cardiovascular diseases. Synthetic angiotensin-converting enzyme (ACE) inhibitors used to treat hypertension are often associated with adverse effects, and the interest in diet-related inhibitors is increasing. We hypothesized that North Atlantic fish hydrolysate might inhibit ACE, thus preventing hypertension. We assessed the ACE inhibitory potential of various North Atlantic fish species and evaluated the effect of dietary supplementation of fish hydrolysates on the blood pressure of spontaneously hypertensive rats. Fish samples were hydrolyzed using simulated gastrointestinal digestion, and ACE inhibitory activity was evaluated using an ACE inhibitory activity assay. In vivo anti-hypertensive effects were evaluated by administering hydrolysates of wild Atlantic cod (Gadus morhua L.), haddock (Melanogrammus aeglefinus L.), or farmed Atlantic salmon (Salmo salar L.) to 10-week-old male, spontaneously hypertensive rats for 4 weeks. The dosing was 200 mg/kg body weight for 21 days, followed by 500 mg/kg body weight for 7 days. Water and Captopril (20 mg/kg body weight) were administered as the negative and positive controls, respectively. The analyzed fish hydrolysates exhibited a 50 % ACE inhibition coefficient (IC₅₀) of 1 to 2.7 μg/mU ACE. Fish hydrolysate supplements did not significantly inhibit the increase in blood pressure during the experimental period. The group receiving cod supplement had a lower (not significant) increase in blood pressure compared to the other groups. Although further studies are necessary to verify the antihypertensive effect of cod, the results obtained in this study indicate the potential that cod hydrolysate may have in inhibiting hypertension.     

Comparative effects of plant oils on the cerebral hemorrhage in stroke-prone spontaneously hypertensive rats

Objectives: Since oils and fats can induce metabolic syndrome, leading to cardiovascular and cerebrovascular diseases, the present study was performed to find out whether the plant oils affect the cerebral hemorrhage in stroke-prone spontaneously hypertensive (SHR-SP) rats.

Methods: From 47 days of age, male SHR-SP rats were given drinking water containing 1% NaCl to induce hypertension, and simultaneously fed semi-purified diets containing 10% perilla oil, canola oil, or shortening. The onset time of convulsion following cerebral hemorrhage was recorded, and the areas of hemorrhage and infarction were analyzed in the stroke brains.

Results: In comparison with 58-day survival of SHR-SP rats during feeding NaCl alone, perilla oil extended the survival time to 68.5 days, whereas canola oil shortened it to 45.7 days. Feeding perilla oil greatly reduced the total volume of cerebral hemorrhage from 17.27% in the control group to 4.53%, while shortening increased the lesions to 21.23%. In a microscopic analysis, perilla oil also markedly decreased the hemorrhagic and infarction lesions to 1/10 of those in control rats, in contrast to an exacerbating effect of shortening. In blood analyses, perilla oil reduced blood total cholesterol and low-density lipoproteins which were increased in SHR-SP, but canola oil further increased them and markedly lowered platelet counts.

Discussion: Perilla oil delayed and attenuated cerebral hemorrhage by improving hyperlipidemia in hypertensive stroke animals, in contrast to the aggravating potential of canola oil and shortening. It is suggested that perilla oil should be the first choice oil for improving metabolic syndrome in hypertensive persons at risk of hemorrhagic stroke.     

适量白酒对自发性高血压大鼠血压及血管内皮功能影响的研究

目的 研究适量白酒对自发性高血压大鼠的血压及血管内皮功能的影响。方法 48只自发性高血压大鼠(SHR)随机分为4组(12只/组):空白对照组、剂量①组[0.9ml/(kg·d)]、剂量②组[1.1ml/(kg·d)]、剂量③组[2.2ml/(kg·d)]。空白对照组给予2.2ml/(kg·d)纯水灌胃,各剂量组给予48°浓香型白酒灌胃。用无创套尾法测量大鼠血压,连续灌胃8周后采用酶联免疫吸附法测定SHR血清中内皮素(ET)、血管紧张素Ⅱ(Ang-Ⅱ)、一氧化氮(NO)、诱导型一氧化氮合酶(iNOS)、内皮型一氧化氮合酶(eNOS)及超敏C反应蛋白(hs-CRP)含量。结果 连续灌胃8周后与空白对照组比较,各剂量组大鼠血压无统计学差异(P>0.05);剂量②、③组ET、hs-CRP含量降低(P<0.05),剂量②组iNOS水平降低(P<0.05),各组Ang-Ⅱ、NO、eNOS水平无明显差异(P>0.05)。结论 适量白酒对SHR血压无直接的显著影响,但可降低其ET、hs-CRP和iNOS含量。     

Plant sterols and casein-derived tripeptides attenuate blood pressure increase in spontaneously hypertensive rats

In this study, we investigated the synergistic effects of plant sterols (PS) and casein-derived tripeptides on arterial tone and blood pressure in experimental hypertension. We hypothesized that PS and tripeptides could have positive, synergistic effects on the development of hypertension and endothelial dysfunction in young spontaneously hypertensive rats (SHR). Six-week-old male SHR were divided into 3 groups to receive milk products containing PS, or PS with tripeptides, or a control containing no active components for 8 weeks. Systolic blood pressure (SBP) was measured weekly, and vascular reactivity measurements with isolated mesenteric arteries were performed at the end of the study. Biochemical measurements for several parameters were performed by enzyme-linked immunosorbent assay using plasma samples. Levels of angiotensin-converting enzyme 1, cyclooxygenase-2, endothelial nitric oxide synthase, and P-selectin messenger RNA expressions were determined from aortic tissue by real-time polymerase chain reaction. The study showed that long-term treatment with PS + tripeptides attenuated the development of hypertension in SHR (SBP, 187 ± 5 mm Hg vs 169 ± 4 mm Hg in control group; P < .01). Plant sterols alone did not affect SBP significantly. Endothelial dysfunction was observed in all SHR; however, treatment with PS resulted in poorer endothelium-dependent and nitric oxide–mediated relaxation compared with other groups. Aortic cyclooxygenase-2 and P-selectin were significantly down-regulated in PS and PS + tripeptides groups when compared with the control group. The expression of endothelial nitric oxide synthase was significantly lower in PS than in PS + tripeptides group. In conclusion, long-term treatment with PS has a slight but not significant antihypertensive effect. Plant sterols do not provide any beneficial effects on endothelial function in hypertensive rats; however, treatment with both PS and tripeptides showed mild anti-inflammatory effects.     

In vitro intestinal transport and antihypertensive activity of ACE inhibitory pea and whey digests

Angiotensin I converting enzyme (ACE) inhibitory peptides cause an antihypertensive effect if they reach the systemic circulation. This was investigated for the high ACE inhibitory activity present in peas and whey in vitro gastrointestinal digests. The samples retained high ACE inhibitory activity when incubated in Caco-2 homogenates or rat intestinal acetone powder, both sources of small intestine peptidases. Only little ACE inhibitory activity was transported through Caco-2 cell monolayers in 1?h. As the Caco-2 model is tighter than intestinal mammalian tissue, sufficient absorption of these peptides might occur in vivo. After intravenous administration of 50?mg protein?kg^?1 BW in spontaneously hypertensive rats (SHR), pea digest exerted a transient, but strong antihypertensive effect of 44.4?mmHg. Whey digest exerted no effect at this dose. These results suggest that pea digest could be a promising source of ACE inhibitory peptides for use in the prevention and treatment of hypertension.     

The antihypertensive effect of ethyl acetate extract of radish leaves in spontaneously hypertensive rats

Radish (Raphanus sativus L.) is a cruciferous vegetable, and its leaves have antioxidant and anticancer properties. This study was conducted to evaluate the effects of ethyl acetate extracts from radish leaves on hypertension in 11-week-old spontaneously hypertensive rats (SHRs). The SHRs were randomly divided into 3 groups of 6 rats each on the basis of initial systolic blood pressure (SBP) and were treated with oral administration of radish leaf extract (0, 30, or 90 mg/kg body weight [bw], respectively) for 5 weeks. Six Wistar rats were used as normotensive controls. The amount of the radish leaf extract had no effect on body weight. The SBP of the SHRs showed a decreasing trend with the consumption of the radish leaf extract. In the third week, the SBP of the group fed 90 mg extract/kg bw reduced from 214 mmHg to 166 mmHg and was significantly lower than that of the normotensive and hypertensive controls. The extract did not show a significant effect on the angiotensin-converting enzyme (ACE) activity in the serum, kidney, and lung. The extract increased the concentration of NO in serum and the activities of antioxidant enzymes such as glutathione peroxidase and catalase in red blood cells (RBCs). The serum concentrations of Na⁺ and K⁺ were not significantly different between all groups. However, the fecal concentrations of Na⁺ and K⁺ increased; the fecal concentrations of Na⁺ and K⁺ for the normotensive and hypertensive controls were not different. Urinary excretion of Na⁺ was higher in the normotensive Wistar rats than in the SHRs, while that of K⁺ was not significantly different. These findings indicate that consumption of radish leaves might have had antihypertensive effects in SHRs by increasing the serum concentration of NO and fecal concentration of Na⁺ and enhancing antioxidant activities.     

Attenuation of alpha-adrenergic-induced vasoconstriction by dietary wild blueberries (Vaccinium angustifolium) is mediated by the NO-cGMP pathway in spontaneously hypertensive rats (SHRs)

Abstract

The role of wild blueberries (WB) on key signaling steps of nitric oxide (NO) and cyclooxygenase (COX) pathways was examined in spontaneously hypertensive rats (SHRs) after eight weeks on a control (C) or an 8% w/w WB diet. Aortic rings from SHRs were stimulated with phenylephrine (Phe) in the absence or presence of inhibitors of: soluble guanylyl cyclase (sGC), phosphodiesterase-5 (PDE₅), prostaglandin I₂ (PGI₂) synthase and thromboxane A₂ (TXA₂) synthase. Additionally, enzymatic activities in these pathways were determined by the concentration of NO, cyclic guanosine monophosphate (cGMP), PGI₂ and TXA₂. In the WB-fed SHR, attenuation of Phe-induced vasoconstriction was mediated by an increased synthesis or preservation of cGMP. Despite an increased release of PGI₂ in the WB group, neither inhibition of PGI₂ or TXA₂ synthase resulted in a different response to Phe between the control and the WB rings. Hence, in the SHR, WB decrease Phe-mediated vasoconstriction under basal conditions by enhancing NO-cGMP signaling without a significant involvement of the COX pathway.