New aspects of the Slug Mucosal Irritation assay: predicting nasal stinging, itching and burning sensations

Stinging, itching and/or burning (SIB) sensations cannot be detected by animal tests or in vitro models. In the past, the Slug Mucosal Irritation (SMI) assay demonstrated a relation between an increased mucus production in slugs and an elevated incidence of SIB sensations in humans. A new 1-day SMI test procedure was developed focusing on the prediction of these short-term sensations. The objective of this study was to verify whether this new procedure is capable predicting mucosal tolerance of several marketed nasal formulations using the slug Arion lusitanicus. Irritation and tissue damage were quantified with a 5-day repeated exposure study by means of the mucus produced and proteins and enzymes released. The new protocol predicted SIB sensations by means of mucus production. The effects of six liquid nasal formulations were tested with both protocols, while five physiologic saline solutions were only tested with the new protocol to optimize it. None of the tested liquid nasal formulations resulted in tissue damage; however, exposure to the different formulations had a clear effect on the mucus production of the slugs and moderate discomfort was observed in some cases. These effects were due to the active ingredient, the presence of benzalkonium chloride as a preservative or the hyperosmolality of the formulation. For the most part results agreed with clinical data found in literature. It was concluded that the SMI assay, and the new 1-day protocol in particular, is a good tool to predict nasal clinical discomfort.     

厄贝沙坦和依那普利对原发性高血压患者肾功能的影响

目的探讨血管紧张素Ⅱ受体拮抗剂(ARB)和血管紧张素转换酶抑制剂(ACEI)对原发性高血压(EH)患者肾功能的影响。方法采用随机、单盲和平行对照方法,经2周冲洗期后,60例EH患者随机分为2组进行16周治疗,每日1次口服厄贝沙坦150 mg(n=30)或依那普利5 mg(n=30),4周后如舒张压(DBP)≥90 mm Hg则剂量加倍。治疗后测量血压、心率(HR)并记录症状、体征。治疗前后分别测定血清肌酐(Cr)、尿素氮(BUN)、内生肌酐清除率(Ccr)和24 h尿蛋白(UTP)、尿白蛋白(Alb),血、尿α_1及β_2微球蛋白(α_1-MG和β_2-MG)的排泄率。20例健康体检者作为健康对照组。结果(1)2组血压均明显降低(P<0.05)。(2)治疗前EH组患者Ccr显著低于健康对照组(P<0.01),血、尿α_1-MG和β_2-MG及UTP、Alb显著高于健康对照组(P<0.05或P<0.01)。(3)治疗16周后,2组UTP、Alb,血、尿α_1-MG和β_2-MG均显著下降(P<0.05或P<0.01),其中病程≥10年者较病程<10年者下降幅度较大(P<0.05)。(4)咳嗽发生率厄贝沙坦组(6.7%)明显低于依那普利组(26.7%)(P<0.01)。结论(1)EH患者早期即有肾功能损害。(2)厄贝沙坦可减轻和延缓高血压引起的肾功能损害,且病程较长者获益较大,其效果可能与依那普利相似。     

依那普利与缬沙坦对慢性心力衰竭患者基质金属蛋白酶-9及左室重构的影响

目的 探讨慢性心力衰竭(CHF)应用依那普利和(或)缬沙坦对调节细胞外基质降解和改善心室重构的作用.方法 将90例CHF患者随机分为3组,每组30例.A组:依那普利10 mg/d,B组:缬沙坦80 mg/d,C组:依那普利10 mg/d+缬沙坦80 mg/d,均服药8周.治疗前后分别测定血清基质金属蛋白酶-9(MMP-9)及超声心动图指标[左室收缩末期容积(LVESV)、左室舒张末期容积(LVEDV)和左室射血分数(LVEF)].结果 (1)3组CHF患者治疗后MMP-9及超声心动图指标比较,差别均有统计学意义(P＜0.01);CHF患者MMP-9与LVEF呈负相关(r=-0.355,P=0.001),与LVEDV呈正相关(r=0.346,P=0.001).(2)3组患者治疗后血清MMP-9、LVESV、LVEDV均较治疗前减少,LVEF较治疗前均升高,差异有统计学意义(P＜0.05).(3)C组患者治疗后MMP-9、LVESV、LVEDV低于A、B组,LVEF高于A、B组,差异均有统计学意义(P＜0.05);A、B两组MMP-9及超声心动图指标比较,差异均无统计学意义(P＞0.05).结论 依那普利联合缬沙坦治疗CHF效果明显优于单用依那普利或缬沙坦治疗,能更有效地降低MMP-9质量浓度,调节基质金属蛋白酶,改善心室重构.     

渴络欣联合依那普利治疗糖尿病肾病的临床研究

目的:观察渴络欣联合依那普利治疗糖尿病肾病(DN)的临床疗效。方法:早期糖尿病肾病(DNⅢ期)患者43例和临床糖尿病肾病(DNⅣ期)37例分别随机分为依那普利对照组和渴络欣联合依那普利治疗组,疗程均为2个月。结果:与治疗前比较,治疗组治疗后血清总胆固醇(TC)、血清甘油三酯(TG)、血清低密度脂蛋白胆固醇(LDL-C)明显下降(P<0.05,P<0.01),血清高密度脂蛋白胆固醇(HDL-C)明显上升(P<0.05),对照组上述指标变化无统计学意义(P>0.05)。治疗后治疗组和对照组早期DN患者尿白蛋白排泄率(UAER)、尿α1微球蛋白(α1-MG)、尿β2微球蛋白(β2-MG)均明显减少(P<0.05,P<0.01),而治疗组较对照组疗效更为显著(P<0.05)。对临床DN患者的尿蛋白定量、尿α1-MG、尿β2-MG、血白蛋白(ALB),治疗组和对照组均改善显著(P<0.05,P<0.01),但治疗组优于对照组(P<0.05);对临床DN患者的血肌酐(Cr),对照组无明显改善(P>0.05),但治疗组却改善显著(P<0.05)。结论:渴络欣联合依那普利治疗DN疗效肯定,在减少尿蛋白、改善肾功能方面明显优干单用依那普利,提示两药合用在延缓DN进展方面能够发挥各自的优势,起到协同作用。     

硝苯地平与依那普利联用治疗原发性高血压的临床效果

目的 通过临床观察,评价硝苯地平与依那普利联合用药对原发性高血压的临床效果.方法 将研究对象在分层的前提下再随机分为3组,其中2组为对照组,患者分别单独口服硝苯地平(圣通平)缓释片和依那普利,研究组则同时服用上述2种药物,对比单独用药与联合用药的临床效果.结果 单独口服硝苯地平(圣通平)缓释片和依那普利的临床有效率分别为77.17%,74.24%,其效果不如联合用药的95.08%,经统计学处理,两者差异有统计学意义.结论 原发性高血压的治疗,联合应用硝苯利平与依那普利的疗效比单独分别用药效果更好,且临床副作用更少.     

灯盏生脉胶囊联合依那普利治疗2型糖尿病早期肾病的临床研究

目的探讨灯盏生脉治疗2型糖尿病早期肾病的临床疗效。方法将90例2型糖尿病早期肾病患者随机分为2组,每组45例。A组为治疗组,采用灯盏生脉+依那普利治疗,B组为对照组,单用依那普利治疗。观察尿微量清蛋白排泄率(UALB)、血糖、血脂,比较2组患者的疗效。结果 2组患者治疗后UALB较治疗前均降低,差异均有统计学意义(P<0.01)。2组患者治疗后疗效比较,差异有统计学意义(P<0.05),A组优于B组。2组治疗前血清总胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、差异均无统计学意义(P>0.05);但2组治疗后上述指标比较,差异有统计学意义(P<0.05),其中A优于B组。结论灯盏生脉与依那普利均能降低2型糖尿病早期肾病患者的UALB,但灯盏生脉联合依那普治疗效果优于单用依那普利,且灯盏生脉有改善血脂的作用。     

依那普利联合卡维地洛治疗老年慢性心力衰竭临床分析

目的观察并探讨依那普利联合卡维地洛治疗老年慢性心力衰竭的临床效果及安全性。方法选取本院2009年1月～2011年5月收治老年慢性心力衰竭患者85例,随机分为两组,其中对照组43例,在综合抗心力衰竭治疗基础上,采用依那普利口服治疗;实验组42例,在对照组治疗基础上,加用卡维地洛口服治疗;比较两组患者临床治疗总有效率,治疗前后心功能分级、心率及超声心动图指标等。结果实验组患者临床治疗总有效率明显高于对照组,组间比较差异有统计学意义（P〈0.05）;治疗后实验组患者心功能分级及心率改善程度均明显优于对照组,组间比较差异有统计学意义（P〈0.05）;治疗后实验组患者左室射血分数（LVEF）、左室舒张末期内径（LVD）、左室收缩末期内径（LVS）及心输出量（CO）等超声心动图指标改善程度均明显优于对照组,组间比较差异有统计学意义（P〈0.05）;同时两组患者不良反应发生率组间比较差异无统计学意义（P〉0.05）。结论依那普利联合卡维地洛治疗老年慢性心力衰竭能够显著改善患者心功能,缓解临床症状,且不良反应少。     

拉西地平与依那普利治疗老年高血压疗效对比

目的对比拉西地平、依那普利治疗老年高血压的临床疗效。方法回顾性分析2009年8月～2012年4月笔者所在医院治疗的160例老年高血压患者的临床记录资料。随机将其分成拉西地平治疗组和依那普利治疗组,每组各80例,对比分析两组患者的临床疗效。结果经过治疗,拉西地平治疗组和依那普利治疗组的总有效率分别为83.75%、85.00%,差异无统计学意义(x2=0.0474,P>0.05);另外,两组患者的并发症均较少。结论拉西地平和依那普利对老年高血压均有较好的治疗效果,且均无明显的不良反应,两种药物疗效相当。     

MTHFR和MTR的基因多态性对马来酸依那普利叶酸片药动学影响的研究

目的:考察亚甲基四氢叶酸还原酶(MTHFR)和蛋氨酸合成酶(MTR)的基因多态性对中国健康成年人口服马来酸依那普利叶酸片后依那普利药动学的影响。方法:36名健康志愿者单剂量口服10mg/0.8mg马来酸依那普利叶酸片后,于不同时间点取血,采用液-质联用法测定血药浓度,并进行血样基因型分析及同型半胱氨酸水平测定。结果:MTHFR存在CC、CT和TT3种基因型,其多态性对依那普利的主要药动学参数未见显著影响;而MTR存在AA、AG2种类型,与AA型相比,AG型对依那普利吸收很好,但排泄较慢。结论:MTHFR基因多态性不影响所研究人群的依那普利药动学,而MTR的AA和AG基因型引起依那普利药动学的差异。     

Design and evaluation of oral bioadhesive controlled release formulations of miglitol, intended for prolonged inhibition of intestinal α-glucosidases and enhancement of plasma glucagon like peptide-1 levels

α-Glucosidase enzyme is present ubiquitously throughout the lumen of the small intestine. It is responsible for the breakdown of complex into simple carbohydrates. α-Glucosidase inhibitors such as miglitol, are drugs that have greater affinity towards this enzyme in comparison to carbohydrates. Miglitol regulates the postprandial glucose levels directly by inhibiting the enzyme reversibly and also indirectly by including the secretion of glucagon like peptide-1 (GLP-1). The aims of this study were (i) to design a controlled release (CR) mucoadhesive (in the intestine) formulation of miglitol which would inhibit the α-glucosidase enzyme for a longer duration of time (in comparison to the non-controlled release (IR) formulation) thus reducing the dosing frequency, and also controlling the postprandial glucose levels more effectively over a longer period of time; (ii) to assess the effect of different formulation parameters on the release of miglitol in vitro from the CR pellets; (iii) to evaluate the mucoadhesion of pellets in the intestine ex vivo; (iv) to study the effect of formulation parameters on plasma GLP-1 levels; and (v) to find out the effect of formulations on postprandial glucose levels. The data obtained was analysed to find out whether there was a correlation between these different parameters. Four controlled release formulations (CR1, CR2, CR3 and CR4) of miglitol comprising of multilayered pellets were designed successfully. The CR4 formulation containing 30% of 20 cps of ethyl cellulose (the retarding layer of the formulation) displayed slowest release of miglitol in vitro in comparison to other formulations. We designed an ex vivo experimental setup for studying the mucoadhesion of the pellets in the lumen of the intestine. Results indicated that amongst all of the adherent pellets, 5% were found to be adhering in the duodenal region, 61% in the jejunum, 32% in the ileum and 2% in the colon. Two of the controlled release formulations CR1 and CR4 were evaluated in vivo in dogs. Both the formulations displayed significantly higher and more prolonged (greater AUC) levels of GLP-1 in comparison to either the placebo or the immediate release (IR) formulations. They even displayed a significantly better control of postprandial glucose in comparison to either placebo or IR formulations. However, a comparison between the two controlled release formulations (CR1 and CR4) revealed that the plasma GLP-1 (AUC by CR1 = 63.1 ± 1.32 and CR4 = 66.2 ± 0.82) and postprandial glucose values due to both the formulations were rather similar despite their differences in in vitro release as well as pharmacokinetic profiles (plasma miglitol AUC of CR1 = 16.17 ± 4.11 and CR4 = 27.17 ± 4.33).