Effects of experimental potassium depletion on renal function and urinary prostanoid excretion in normal women during moderate anti-diuresis

Summary. The hypothesis that potassium depletion (KD) might play a role in stimulating the renal synthesis of prostanoids, and that these materials can contribute to hypokalaemic renal dysfunction, has been tested. Healthy women were studied either in normal potassium balance (N, n= 14), or in experimental KD. KD was induced by low dietary potassium intake (10 mmol day^-1) and natriuretic treatment, associated with replacement of net NaCl and water loss. By using different depletive patterns, two groups with estimated cumulative potassium deficits of 160 ± 43 mmol (KD1, n= 8) and 198±22 mmol (KD2, n= 6), respectively, were obtained. Renal function by the clearance (cl.) method and urinary PGE₂, 6-keto-PGF_lä, TxB₂ concentrations by the RIA method were measured during hypotonic polyuria (oral water load) and subsequent moderate antidiuresis induced by the infusion of low-dose lysine-8-vasopressin (LVP). Compared to the N group, only in the KD2 group do glomerular and tubular dysfunctions typical of hypokalaemia and reduced prostanoid excretions (significant for 6-keto-PGF_lä and TxB₂ but not for PGE₂) appear during polyuria besides the significant reductions of plasma potassium concentration, urinary potassium excretion and the significant increase in plasma renin activity. During LVP infusion the urinary prostanoid excretions were all significantly lower in absence of significant differences in urinary flow rate. Concerning its renal effects, LVP lost its ability to reduce the creatinine cl., while expressing a trend towards reduction in fractional chloride excretion. Indomethacin pretreatment restored the LVP effect on creatinine cl. and increased the antichloruretic LVP effect (although not significantly). To the extent that urinary prostanoid excretions reflect their intrarenal synthesis, our data demonstrate that KD inhibits this biosynthesis. A depressed production of prostanoids endowed with vasodilating and chloruretic activity probably played a role in attenuating the renal vascular hyporeactivity and the urinary chloride dispersion induced by KD.     

不同NSAIDs肠病模型中肠黏膜通透性的比较研究

目的探讨不同NSAIDs肠病模型中肠黏膜通透性改变的研究。方法选用不同NSAIDs(阿司匹林、吲哚美辛、双氯芬酸钠)制备小鼠NSAIDs肠病模型。其中阿司匹林组(500 mg.kg-1)、吲哚美辛组(5 mg.kg-1)、双氯芬酸钠(10 mg.kg-1)灌胃给药3 d。在此基础上,进行不同剂量双氯芬酸钠不同时间灌胃给药。实验结束后取小鼠小肠进行Evans-blue通透性检测,并计算小肠溃疡数目。结果在不同NSAIDs肠病模型中,阿司匹林组小鼠小肠黏膜未见明显溃疡,小肠黏膜通透性轻度升高(621.1±114.2 vs 460.6±89.7μg.g-1),吲哚美辛组小鼠小肠黏膜损害明显,小肠溃疡明显增多(8.2±1.9 vs 0),小肠通透性显著升高(2132.0±315.7 vs 460.6±89.7μg.g-1),双氯芬酸钠组小肠黏膜损伤和小肠黏膜通透性升高均较吲哚美辛组减轻。随着双氯芬酸钠给药剂量增加和给药时间延长,小鼠小肠黏膜损害和肠黏膜通透性增高越明显。结论在不同NSAIDs肠病模型中,阿司匹林组小鼠小肠损害轻,吲哚美辛组小肠损伤严重,双氯芬酸钠2.5 mg.kg-1灌胃3 d可引起小肠黏膜通透性和肠黏膜损害,适用于NSAIDs肠病模型的研究。     

HPLC法测定盐酸吲哚美辛2-[2-(6-甲氧基-2-萘基)吗啉基]乙酯的平衡溶解度和脂水分配系数

目的:测定盐酸吲哚美辛2-[2-(6-甲氧基-2-萘基)吗啉基]乙酯在乙醇、乙腈、丙酮、乙酸乙酯等溶剂中的平衡溶解度以及在正辛醇-水和正辛醇-缓冲液体系中的表观油水分配系数。方法:采用HPLC法测定盐酸吲哚美辛2-[2-(6-甲氧基-2-萘基)吗啉基]乙酯的浓度,采用摇瓶法测定其表观油水分配系数。结果:25℃时盐酸吲哚美辛2-[2-(6-甲氧基-2-萘基)吗啉基]乙酯在乙醇、乙腈、丙酮、乙酸乙酯中的平衡溶解度分别为31.36,141.50,575.77,598.68 g.L-1。pH=4时此目的化合物的平衡溶解度最小,而表观油水分配系数最大。结论:盐酸吲哚美辛2-[2-(6-甲氧基-2-萘基)吗啉基]乙酯的平衡溶解度及油水分配系数与介质的pH有关。其水溶性较差,脂溶性好。     

微粉硅胶对固体自微乳化给药系统小肠吸收的影响

固体载体对固体自微乳化给药系统(solid self-microemulsifying drug delivery systems,S-SMEDDS)的体内外性质有重要影响。本文探讨微粉硅胶对S-SMEDDS药物吸收的影响,为选择适宜固体载体提供依据。通过研究微粉硅胶对小肠脂解和S-SMEDDS体外释放的影响,并采用新型体外脂解-吸收模型研究微粉硅胶对S-SMEDDS离体小肠吸收的影响。结果发现微粉硅胶既能提高脂解速率,增加脂解后水性分散相中药物分配,促进药物吸收;又会延缓S-SMEDDS体外释药,影响药物的吸收速度;最终导致对S-SMEDDS的离体小肠吸收没有显著性影响。而且微粉硅胶对脂解和释药的影响都与其用量有关,这提示微粉硅胶适合作为S-SMEDDS的固体载体,其用量需要进一步筛选优化。     

吲哚美辛微观结晶机制及纳米包衣的影响

药物的无定形状态比晶态具有更大的溶解度,可以促进吸收,提高口服生物利用度,但是稳定性差,易转变为晶体状态。本文采用偏光显微镜、扫描电子显微镜、差示扫描量热法、X-射线衍射法和拉曼光谱法等研究无定形吲哚美辛的微观结晶机制,并对药物表面进行喷金包衣,厚度为10 nm,研究结晶行为变化。结果发现,无定形吲哚美辛自由表面的结晶速率远大于其内部,金包衣可显著抑制自由表面的结晶。这提示,自由表面的结晶是影响无定形药物稳定性的关键因素,纳米包衣可用于增强无定形药物的稳定性。     

吲哚美辛对大鼠胃功能的影响及作用机制研究

目的 研究吲哚美辛对大鼠胃酸分泌及胃蛋白酶活力的影响及其作用机制。方法 大鼠分为对照组和吲哚美辛低、中、高剂量组。测定各组大鼠胃酸分泌量及胃蛋白酶活力,测定血清胃泌素含量。结果 吲哚美辛可显著增加胃酸分泌量、增加胃酸分泌速度及增加胃蛋白酶活力,促进胃泌素分泌。结论 吲哚美辛可显著促进胃酸分泌,增加胃蛋白酶活力,这与其促进胃秘素分泌有关。     

Upregulation of intrinsic apoptotic pathway in NSAIDs mediated chemoprevention of experimental lung carcinogenesis

BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) act by inhibition of cyclooxygenase-2 (COX-2), which is overexpressed in cancer. The role of COX-2 and apoptosis were evaluated in 9,10-dimethylbenz(a)anthracene (DMBA)-induced lung cancer in rat and chemoprevention with indomethacin, a traditional NSAID and etoricoxib, a selective COX-2 inhibitor.MethodsThe animals were divided into Control, DMBA, DMBA + indomethacin and DMBA + etoricoxib groups. They received a single intratracheal instillation of DMBA while NSAIDs were given orally daily for 32 weeks. Besides morphology and histology of lungs, RT-PCR, western blots and immunohistochemistry were performed for the expression of apoptotic proteins and COX enzymes. Apoptosis was studied by DNA fragmentation and fluorescent staining.ResultsThe occurrence of tumors and lesions was noted in the DMBA animals, besides constricted alveolar spaces and hyperplasia. COX-1 was found to be uniformly expressed while COX-2 level was raised significantly in DMBA group. The apoptotic proteins, apaf-1, caspase-9 and caspase-3 were highly diminished in DMBA group but restored to normal level in NSAIDs groups. Also, apoptosis was suppressed in carcinogen group by DNA fragmentation analysis and fluorescent staining of the lung cells while coadministration of NSAIDs along with DMBA led to the restoration of apoptosis.ConclusionDMBA administration to the rats led to tumorigenesis in the lungs, had no effects on COX-1 expression, while elevating the COX-2 levels and suppressing apoptosis. The treatment with NSAIDs led to the amelioration of these effects. However, etoricoxib which is a COX-2 specific inhibitor, was found to be more effective than the traditional NSAID, indomethacin.     

反相高效液相色谱法测定吲哚美辛微乳中吲哚美辛的含量

目的 建立吲哚美辛微乳中吲哚美辛的含量测定方法.方法 采用反相高效液相色谱法,以甲醇-水-冰醋酸=73∶27:0.05为流动相,检测波长254nm,流速1.0mL·min-1.结果 吲哚美辛在3.349-33.49 μg·mL-1与峰面积线性关系良好,r=0.9999.平均回收率为95.4％,RSD为2.2％.结论 该法简便、快速、重复性好,可用于吲哚美辛微乳中吲哚美辛的含量测定.     

Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats

Adolescent brain development seems to be important for the maturation of brain structures and behaviour. Intermittent binge ethanol drinking is common among adolescents, and this type of drinking can induce brain damage. Because we have demonstrated that chronic ethanol treatment induces inflammatory processes in the brain, we investigate whether intermittent ethanol intoxication enhances cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in adolescent rats, and whether these mediators induce brain damage and cause permanent cognitive dysfunctions. Adolescent rats were exposed to ethanol (3.0 g/kg) for two consecutive days at 48-h intervals over 14 days. Levels of COX-2, iNOS and cell death were assessed in the neocortex, hippocampus and cerebellum 24 h after the final ethanol administration. The following day or 20 days after the final injection (adult stage), animals were tested for different behavioural tests (conditional discrimination learning, rotarod, object recognition, beam-walking performance) to assess cognitive and motor functions. Our results show that intermittent ethanol intoxication upregulates COX-2 and iNOS levels, and increases cell death in the neocortex, hippocampus and cerebellum. Furthermore, animals treated with ethanol during adolescence exhibited behavioural deficits that were evident at the end of ethanol treatments and at the adult stage. Administration of indomethacin, a COX-2 inhibitor, abolishes the induction of COX-2 and iNOS expression and cell death, preventing ethanol-induced behavioural deficits. These findings indicate that binge pattern exposure to ethanol during adolescence induces brain damage by inflammatory processes and causes long-lasting neurobehavioural consequences. Accordingly, administering indomethacin protects against ethanol-induced brain damage and prevents detrimental ethanol effects on cognitive and motor processes.     

The effects of desensitization of capsaicin-sensitive afferent neurons on the microcirculation in the stomach in rats depend on the blood glucocorticoid hormone level

The effects of densensitization of capsaicin-sensitive afferent neurons on the microcirculation in the stomach were studied before and after administration of indomethacin at an ulcerogenic dose in adrenalectomized rats receiving and not receiving replacement therapy with corticosterone and in sham-operated animals. Measures of the microcirculation consisted of blood flow rates in microvessels in the submucous layer of the stomach and the diameter and permeability of microvessels in the mucosa. Desensitization of capsaicin-sensitive afferent neurons was performed by administration of capsaicin at a dose of 100 mg/kg for two weeks and adrenalectomy one week before the experiment. Blood flow rates in microvessels and microvessel diameters were assessed in non-anesthetized rats by direct video recording methods using a special optical system with a contact dark-field epiobjective. Administration of indomethacin at an ulcerogenic dose led to decreases in blood flow rate in microvessels in the submucous layer, dilation of superficial microvessels in the mucosa of the stomach, and an increase in their permeability. Desensitization of capsaicin-sensitive neurons potentiated indomethacin-induced impairments to the microcirculation in the submucous layer and the mucosa of the stomach. These effects of densensitization were significantly enhanced in conditions of glucocorticoid hormone deficiency. Thus, glucocorticoid hormones have favorable effects on the gastric microcirculation in rats with desensitization of capsaicin-sensitive afferent neurons. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 94, No. 6, pp. 700–709, June, 2008.