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1.
Pulmonary hypertension is a devastating disorder, characterized by vascular proliferation, intimal hypertrophy and vasoconstriction. In this disorder, alterations in the nitric oxide pathway have borne out to be important in not only vascular proliferation, but also in the maintenance of vascular tone. After synthesis by soluble guanylate cyclase, cGMP effects vasodilation via protein kinase G and other mediators, and is hydrolyzed by phosphodiesterases (PDEs). PDE5 is abundantly expressed in the mammalian lung and its inhibition by sildenafil has been demonstrated to improve pulmonary vascular physiology in vitro and in vivo animal models of pulmonary hypertension. Recent human data has confirmed the efficacy of sildenafil in therapy for humans with pulmonary arterial hypertension. The following review will discuss the underlying basic science supporting the use of sildenafil, as well as human evidence supporting the critical role of this drug in therapy of patients with pulmonary hypertension.  相似文献   

2.
ObjectiveTo investigate the therapeutic effect of implanting a three-piece inflatable penile prosthesis (IPP) combined with the phosphodiesterase-5 inhibitor sildenafil in severe erectile dysfunction (ED) patients.MethodsThis randomized controlled study included 123 ED patients. Sixty-two patients received the IPP implantation and 61 patients received the IPP implantation and the phosphodiesterase-5 inhibitor sildenafil. Erectile function and sexual life quality were evaluated using the five-item International Index of Erectile Function (IIEF) and modified Sexual Life Quality Questionnaire–Quality of Life domain (mSLQQ-QoL), respectively. Serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, vascular cell adhesion molecule (VCAM)-1, and intercellular adhesion molecule (ICAM)-1 levels were assessed. Kaplan–Meier curves were used to assess the overall IPP survival.ResultsImplantation of the three-piece IPP with sildenafil improved erectile function and sexual life quality, alleviated the inflammatory response, reduced the complication rate, and improved overall IPP survival.ConclusionImplantation of the three-piece IPP combined with a phosphodiesterase-5 inhibitor significantly improved clinical outcomes and the prognosis in ED patients.  相似文献   

3.

Background

Sepsis remains a difficult problem for clinicians, with its systemic effects and high morbidity and mortality rates. The roles of oxidative stress, endothelial dysfunction, and lipid peroxidation in sepsis-induced organ damage are being investigated.

Objective

The aim of this study was to investigate the effects of selective cyclooxygenase (COX)-2 inhibition on tissue lipid peroxidation, endothelial dysfunction, and hepatic cell morphology in a rat model of sepsis.

Methods

Thirty rats with sepsis induced by cecal ligation and puncture were divided equally into 3 groups: treatment group (rofecoxib 1 mg/kg PO), control group (saline 1 mL PO), and sham group (sham surgery only). All the rats were sacrificed 1 day after sepsis induction. The livers were removed using a median laparotomy for histopathologic and biochemical analysis.

Results

Histomorphologic hepatic damage and lipid peroxidation were significantly reduced in the rofecoxib treatment group compared with the control group (P < 0.05 and P = 0.001, respectively). Endothelial nitric oxide synthase and inducible nitric oxide synthase staining of liver samples was statistically significantly reduced in the treatment group compared with the control group (both, P < 0.001). The hepatic nitric oxide level and malonyldialdehyde activity decreased significantly (P < 0.001 and P = 0.001, respectively) in the rofecoxib group compared with the control group. Hepatic myeloperoxidase activity was similar between the treatment and control groups.

Conclusion

Further investigation of selective COX-2 inhibition as an alternate therapeutic choice for sepsis-induced hepatic damage should be considered.  相似文献   

4.
BACKGROUND: Recent evidence indicates that hyperhomocysteinaemia is an independent risk factor for atherosclerosis, thrombosis and other cardiovascular diseases. This may be secondary to impaired fibrinolysis or increased platelet reactivity. Nitric oxide (NO), a product from l-arginine by NOS and potent antiaggregating agent, plays an important role in the regulation of platelet function. DESIGN: The present study aimed to define the effect of homocysteine on the l-arginine/NO pathway in human platelets. l-Arginine uptake, NO formation and Ca2+ levels were measured. Moreover the homocysteine effect on platelet activation induced by thrombin was tested. RESULTS: Homocysteine causes a concentration-dependent inhibition of l-arginine transport. Results show that homocysteine does not modify the Km parameter, but it significantly decreases the Vmax value. The nitrite and nitrate formation, strictly correlated with the l-arginine transport, also significantly decreased. In contrast, cNOS activity remained unchanged upon homocysteine treatment. In addition homocysteine in a dose dependent manner increased the intracellular Ca2+ concentration and platelet response to thrombin. CONCLUSIONS: Results indicate that the l-arginine/NO pathway is one of the various targets of homocysteine in human platelets. The increased Ca2+ levels associated with reduced NO formation may generate hyperactivation and may contribute to the thrombogenic processes.  相似文献   

5.
目的 探讨卡介菌多糖核酸(BCG-PSN)对哮喘患者外周血辅助性T细胞亚群及气道炎症的影响.方法 26例慢性持续期中度哮喘患者,分为单药组(氟替卡松和沙美特罗)13例、联合组(氟替卡松和沙美特罗+BCG-PSN)13例.观察治疗前、用药1.5个月和3个月后外周血辅助性T细胞亚群(Th1、Th2、Th3)及其血清细胞因子、IgE含量、诱导痰炎症细胞和临床疗效的变化.结果 (1)哮喘患者治疗1.5个月时2组比较:联合组与单药组Th1/Th2[(1.20±0.57)与(0.79±0.39),t=2.129,P<0.05]、哮喘控制测试(ACT)[(18.31±1.75)与(15.54±2.40),t=3.359,P<0.01]比较差异有统计学意义.治疗3个月时2组比较:联合组较单药组Th1/Th2[(1.73±0.74)与(1.16±0.48),t=2.327,P<0.05]、ACT[(22.46±1.13)分与(20.23±2.59)分,t=2.851,P<0.01]明显升高;呼气峰流速(PEF)日内变异率3个月时联合组较单药组明显降低[(9.88±2.18)%与(12.05±2.74)%,t=2.235,P<0.05],差异亦有统计学意义.(2)外周血辅助性T细胞亚群及其血清细胞因子、IgE含量、诱导痰炎症细胞,2组间差异均无统计学意义(P均>0.05);2组Th3细胞与IgE水平之间均无明显相关性.结论 BCG-PSN联合氟替卡松和沙美特罗能进一步纠正Th1/Th2失衡,减轻哮喘临床症状和气道高反应性,随治疗时间延长,疗效进一步提高,对哮喘患者外周血Th3细胞无显著影响.
Abstract:
Objective To explore the effect of BCG-polysaccharide nucleic acid(BCG-PSN) on the numbers of Th3,Th2 and Th1 cells in peripheral blood mononuclear cell(PBMC) and airway inflammation status in patients with asthma.Methods Twenty-six patients with moderate persistent asthma were enrolled into the study and randomly divided into simple medication group(n=13,accepted Fluticasone/salmeterol alone) and combined medication group(n=13,accepted Fluticasone/salmeterol+BCG-PSN together).The numbers of Th3,Th1 and Th2 cells in PBMC, the serum levels of TGF-β,IFN-γ,IL-4 and IgE and the clinical effect and airway inflammation status were observed at three time points: before,1.5 months after and 3 months after treatment. Results (1)At 1.5 months after treatment,the Th1/Th2 number was significantly higher in the combined medication group than the simple medication group(1.20±0.57 vs 0.79±0.39,t= 2.129,P<0.05),and the asthma control test scale(ACT) showed similar difference(18.31±1.75 vs.15.54±2.40,t=3.359,P<0.01) between the two groups.(2)At 3 months after treatment,the Th1/Th2 number was significantly higher in the combined medication group than the simple medication group(1.73±0.74 vs1.16±0.48,t=2.327,P<0.05),and the ACT also showed the same kind of difference(22.46±1.13 vs.20.23±2.59,t=2.851,P<0.01) between the two groups.In addition,at this time point the PEF variability was significant lower in the combined medication group than the simple medication group([9.88±2.18]% vs.[12.05±2.74]%,t=2.235,P<0.05).(3)We found no significant differences in the comparisons of the numbers of T helper cell subsets in PBMC ,the serum levels of cytokines and IgE,the numbers of inflammatory cells in induced sputum between the two groups(Ps>0.05).(4)No correlation were found between Th3 cell numbers in PBMC and the serum levels of IgE in the two groups.Conclusion The combined use of Fluticasone/salmeterol and BCG-PSN can further correct the imbalance of Th1/Th2 cells,alleviate clinical symptom of asthma and airway hyper-responsiveness.The therapeutic efficacy improves along with the therapy period,better in the combined medication group than the simple medication group.BCG-PSN has no significant effects on the numbers of Th3 in PBMC in patients with asthma.  相似文献   

6.
目的:观察FasL基因和屋尘螨过敏原Derp2基因共表达质粒的DNA疫苗(DNA-FasL-Derp2)对屋尘螨致敏/激发小鼠气道炎症的作用。方法:DNA-FasL-Derp2肌注接种屋尘螨致敏/激发C57BL/6小鼠,再次激发后处死小鼠。观察肺组织病理变化,检测支气管肺泡灌洗液(BALF)细胞总数和分类计数,以及IL-5、IFN-γ水平。并与仅编码Derp2基因的DNA疫苗(DNA-Derp2)比较。结果:接种DNA-FasL-Derp2和DNA-Derp2均能显著减轻屋尘螨致敏/激发小鼠气道炎症,减少BALF中细胞总数和嗜酸粒细胞比例,降低BALF中IL-5水平,以DNA-FasL-Derp2更显著。结论:DNA-FasL-Derp2可有效抑制屋尘螨致敏/激发小鼠气道炎症,而且比DNA-Derp2更有效。  相似文献   

7.
目的 研究T细胞免疫球蛋白-黏蛋白-1(TIM-1)对卵蛋白(OVA)致敏小鼠气道MUC5AC及Th1/Th2细胞因子表达的影响,探讨气道黏液高分泌的机制.方法 OVA腹腔注射致敏小鼠,随机分组为:正常对照组(A组)、哮喘组(B组)和哮喘+ TIM-1抗体处理组(C组),每组8只,酶联免疫吸附试验(ELISA)检测小鼠肺泡灌洗液(BALD中IL-4、IFN-γ的水平变化,实时RT-PCR检测外周血单个核细胞(PBMCs) TIM-1 mRNA及气道MUC5AC mRNA表达.结果 (1)与A组小鼠外周血PBMCs表达TIM-1 mRNA(0.618±0.043)相比,B组(1.129±1.101)及C组(0.898±0.071)TIM-1 mRNA表达明显增多(P<0.01),且C组明显低于B组(P<0.01);(2)B组和C组小鼠BALF中IL-4表达分别为(67.123±3.341) ng/L和(44.217±2.201)ng/L,较A组[(23.211±2.142) ng/L]明显增多(P<0.01),且C组明显低于B组(P<0.01);B组及C组小鼠BALF表达IFN1分别为(53.475±4.776) ng/L和(87.116±5.611)ng/L,均低于A组[(124.624±9.292) ng/L] (P <0.01),而C组与B组相比,有所增加(P<0.01);(3)B组(1.004±0.081)及C组(0.673±0.029)小鼠气道MUC5A mRNA表达与A组(0.314±0.027)相比,明显增加(P<0.01),且C组低于B组(P<0.01);(4)小鼠外周血PBMCs TIM-1 mRNA表达与IL-4、MUC5AC表达呈正相关,而与IFN-γ表达呈负相关.结论 抑制TIM-1表达可减少IL-4和MUC5AC的分泌,提高IFN-γ表达,提示在调节黏液高分泌及哮喘治疗中具有意义.  相似文献   

8.
Nitric oxide (NO) plays an important role in hippocampal long‐term potentiation (LTP), which is involved in memory processes. This led to the hypothesis that nitric oxide synthase (NOS) inhibitors will have disturbing effects on learning and memory. The aim of our study was to investigate the effects of the new selective neuronal and inducible NOS inhibitor 1‐ (2‐trifluoromethylphenyl) imidazole (TRIM) (10–50 mg/kg) on learning and memory and compare it to the nonselective NOS inhibitor 7‐NI (15–45 mg/kg) using different behavioral tests in Swiss mice, thus clarifying the role of neuronal NOS (nNOS) and endothelial NOS (eNOS) in cognitive processes. TRIM had no specific effect on either learning or memory parameters, while 7‐NI (30 mg/kg) disturbed spatial memory in the probe trial of the Morris water maze test, which was performed on the last day of the test. No differences between TRIM and the control groups were observed, while 7‐NI (30 and 45 mg/kg) significantly disturbed memory in the novel object recognition test. In the social transmission of food preference test, both TRIM (50 mg/kg) and 7‐NI (45 mg/kg) impaired hippocampal olfactory memory, but the total food consumption was also significantly decreased at these doses. In the passive avoidance test, TRIM did not disturb the performance, while memory impairment was observed, even with lower doses of 7‐NI. All of these results suggest that TRIM has no clear effect on cognitive impairment compared to 7‐NI and that inhibition of both nNOS and eNOS are necessary for the deterioration of memory processes.  相似文献   

9.
目的 分析不同气道炎症表型的支气管哮喘患者的循环血辅助性T细胞1/2(Th1/Th2)和IgE水平与临床特征的关系。方法 选择2017年6月至2018年12月于该院诊断为支气管哮喘患者共180例,根据诱导痰液中性粒细胞(Neu)和嗜酸粒细胞(Eos)百分比分为Neu组、Eos组、混合组和寡细胞组,检测循环血Th1/Th2和IgE水平,Th1细胞分泌细胞因子血清干扰素-γ(IFN-)γ和Th2细胞分泌白细胞介素-4(IL-4),比较各组患者的临床特征。结果 Eos组和混合组的Th1/Th2(0.56±0.12、0.59±0.15)明显低于Neu组(0.77±0.23)和寡细胞组(0.72±0.19),但IgE水平[(12.3±4.5)、(11.9±4.3)mg/L],比Neu组和寡细胞组[(7.6±3.2)、(7.2±3.1)mg/L]增加,IFN-γ[(32.6±9.5)、(30.5±8.6)mg/L比(21.2±6.8)、(20.9±5.7)mg/L]和IL-4[(25.7±6.8)、(23.3±6.5)mg/L比(12.4±4.3)、(11.5±4.2)mg/L]水平升高,差异有统计学意义(P<0.05)。Neu组和混合组患者哮喘病程和严重程度明显大于其他两组,吸烟和气道感染率增加;Eos组和混合组患者过敏性鼻炎和皮肤点刺试验阳性率高于其他两组,差异有统计学意义(P<0.05)。4种炎症表型组患者的肺功能包括第1秒用力呼气容积(FEV1)及与用力肺活量的比值(FEV1/FVC)、用力呼气中段流量(MMEF%)、50%用力呼气流量(FEF 50%)和75%用力呼气流量(FEF 75%)比较差异无统计学意义(P>0.05)。结论 支气管哮喘患者具有不同的炎症细胞表型,与循环血Th1/Th2和IgE水平以及临床特征有密切联系。  相似文献   

10.
目的:观察运动对自发性高血压大鼠(SHR)主动脉一氧化氮合酶(NOS)、一氧化氮(NO)、胱硫醚-γ-裂解酶(CSE)和硫化氢(H2S)的影响,探讨运动干预后SHR大鼠内源性NO的变化对主动脉CSE/H2S体系的调节作用.方法:选用雄性SHR大鼠16只,随机分为高血压对照组(SC组)和高血压运动组(ST组),每组8只.同时选用雄性Wistar大鼠8只,为正常对照组(WC组).ST组大鼠进行8周、每周6次、每次90min中等强度的无负重游泳运动.结果:8周90min游泳运动后,SC组大鼠血压较实验前显著升高(P<0.01),ST组大鼠血压较SC组大鼠血压显著下降(P<0.01),且与实验前相比无显著性差异(P>0.05);ST组大鼠较SC组大鼠主动脉NOS、NO、CSE和H2S水平显著升高(P<0.05).结论:运动可抑制SHR的血压上升,增加SHR主动脉NOS和NO的含量,内源性NO对SHR主动脉CSE/H2S体系在运动缓解血压上升中呈促进作用,这一过程参与了运动降压的调控机制.  相似文献   

11.
目的研究血必净注射液对卵蛋白(OVA)致敏小鼠气道MUC5AC及Th1/Th2细胞因子表达的影响,探讨干预气道黏液高分泌的机制。方法卵蛋白腹腔注射致敏小鼠,32只小鼠随机分组为:对照组、哮喘组、地塞米松治疗组和血必净治疗组,每组8只,酶联免疫吸附试验(ELISA)检测小鼠肺泡灌洗液(BALF)中IL-4、IFN-γ的水平变化,实时RT-PCR检测小鼠肺组织MUC5AC mRNA表达变化。结果 (1)与对照组小鼠气道MUC5A mRNA表达(0.377±0.021)相比,哮喘组(1.103±0.087)明显增多(P〈0.01);地塞米松治疗组(0.403±0.038)及血必净治疗组(0.437±0.031)小鼠气道MUC5A mRNA表达较哮喘组明显降低(P〈0.01);(2)与对照组小鼠BALF表达IL-4[(22.812±1.978)ng/L]及IFN-γ[(101.232±9.664)ng/L]比较,哮喘组BALF表达IL-4[(87.234±6.901)ng/L]水平升高(P〈0.01),而IFN-γ表达[(47.231±3.887)ng/L]明显降低(P〈0.01);与哮喘组比较,地塞米松治疗组([36.289±3.012)ng/L]及血必净治疗组IL-4水平[(38.112±2.761)ng/L]均显著降低(P〈0.01);结论血必净注射液降低IL-4和MUC5AC的表达,提示在抑制气道黏液高分泌及控制哮喘方面具有意义。  相似文献   

12.
13.
本研究探讨外源性一氧化氮 (NO)供体硝普钠 (SNP)对HL 6 0细胞诱导凋亡的可能机制。将HL 6 0细胞与SNP在体外培养 ,用DNA片段原位末端标记法 (TUNEL)测定原位细胞凋亡率 ;用流式细胞仪测定细胞DNA倍体和周期分析及Bcl 2、Bax、线粒体膜蛋白表达率的变化。结果表明 :SNP可诱导HL 6 0细胞凋亡 ,两者之间有明显的量效和时效关系。 1.0mmol/LSNP作用 4 8小时后 ,HL 6 0细胞的凋亡率分别为亚二倍体峰 (4 2 .2± 3.5 ) % ,TUNEL测定凋亡细胞率为 (5 2 .5± 7.6 ) % ,显著高于空白对照组和同浓度的高铁氰化钾 (PFC)组 ;Bax基因蛋白和线粒体膜蛋白 (APO2 .7)表达增加 ,bcl 2基因蛋白表达降低。Bax、Bcl 2和APO2 .7的表达率与SNP两者之间也有明显的量效和时效关系。结论 :外源性一氧化氮供体诱导HL 6 0细胞凋亡过程中 ,线粒体膜蛋白表达显著上调并伴随Bax和Bcl 2蛋白的表达改变。  相似文献   

14.
目的观察甲基化酶抑制剂5-Aza-2’-CdR作用后K562细胞中miR-146a及miR-29b的表达水平变化及DNMT1、DNMT3a、DNMT3b三种甲基化酶水平的改变。方法 MTT法检测5-Aza-2’-CdR作用于K562细胞时的IC50浓度。通过茎环引物法及荧光定量PCR的方法检测miRNAs以及甲基化酶的水平。结果 5-Aza-2’-CdR作用于K562细胞时的IC50浓度随药物作用的时间不同而异。药物作用后72h进行检测,凋亡细胞比例上升,miR-146a、miR-29b的水平较对照组升高,而DNMT1、DNMT3a、DNMT3b的水平与对照组相比呈降低的趋势,DNMT3a在11μM 5-Aza-2’-CdR处理72h后虽表现出了升高的趋势,但差异无统计学意义。结论 5-Aza-2’-CdR能促进K562细胞的凋亡,5-Aza-2’-CdR作用后miR-146a、miR-29b表现出了上升的趋势而三种甲基化酶表达水平有所降低。  相似文献   

15.

Background

Many patients with type 2 diabetes mellitus (T2DM) also have hypertension, which is commonly treated with thiazide diuretics, including hydrochlorothiazide (HCTZ). Canagliflozin, a sodium glucose cotransporter 2 inhibitor developed for the treatment of T2DM, lowers plasma glucose by inhibiting renal glucose reabsorption, thereby increasing urinary glucose excretion and mild osmotic diuresis. Because patients with T2DM are likely to receive concurrent canagliflozin and HCTZ, potential interactions were evaluated.

Objective

This study evaluated the effects of HCTZ on the pharmacokinetic and pharmacodynamic properties and tolerability of canagliflozin in healthy participants.

Methods

This Phase I, single-center, open-label, fixed-sequence, 2-period study was conducted in healthy participants. During period 1, participants received canagliflozin 300 mg once daily for 7 days, followed by a 14-day washout period. During period 2, participants received HCTZ 25 mg once daily for 28 days, followed by canagliflozin 300 mg + HCTZ 25 mg once daily for 7 days. Blood samples were taken before and several times after administration on day 7 of period 1 and on days 28 and 35 of period 2 for canagliflozin and HCTZ pharmacokinetic analyses using LC-MS/MS. Blood and urine samples were collected for up to 24 hours after canagliflozin administration on day 1 of period 1 and day 35 of period 2 for pharmacodynamic glucose assessment. Tolerability was also evaluated.

Results

Thirty participants were enrolled (16 men, 14 women; all white; mean age, 43.7 years). Canagliflozin AUC during a dosing interval (T) at steady state (AUCτ,ss) and Cmax at steady state (Cmax,ss) were increased when canagliflozin was coadministered with HCTZ, with geometric mean ratios (90% CI) of 1.12 (1.08–1.17) and 1.15 (1.06–1.25), respectively. AUCτ,ss and Cmax,ss for HCTZ were similar with and without canagliflozin coadministration. The 24-hour mean renal threshold for glucose and mean plasma glucose were comparable for canagliflozin alone and coadministered with HCTZ. The change in 24-hour urine volume from baseline was −0.1 L with canagliflozin alone and 0.4 L with HCTZ alone and with canagliflozin + HCTZ. The overall incidence of adverse events (AEs) was higher with canagliflozin + HCTZ (69%) than with canagliflozin (47%) or HCTZ (50%) alone; most AEs were of mild severity. Overall, minimal changes in serum electrolytes (eg, sodium, potassium) were observed after coadministration of canagliflozin + HCTZ compared with individual treatments.

Conclusions

Adding canagliflozin treatment to healthy participants on HCTZ treatment had no notable pharmacokinetic or pharmacodynamic effects; canagliflozin coadministered with HCTZ was generally well tolerated, with no unexpected tolerability concerns. ClinicalTrials.gov identifier: NCT01294631.  相似文献   

16.
目的 探讨关节镜下半月板成形术(AMP)对膝关节半月板损伤患者血清疼痛因子、一氧化氮(NO)、透明质酸(HA)及关节活动度的影响.方法 选取2019年5月—2020年12月收治的90例膝关节半月板损伤为研究对象,根据治疗方法不同分为对照组和治疗组,每组45例.对照组接受保守治疗,治疗组行AMP治疗.比较两组的临床疗效,...  相似文献   

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目的 探讨糖类抗原125(CA125)、人附睾分泌蛋白4(HE4)联合血浆D-二聚体水平检测在卵巢癌早期诊断中的应用价值。方法 选取2014年1月至2016年6月该院妇科收治的确诊卵巢癌患者56例及50例良性卵巢肿瘤患者,同期选取该院健康体检女性50例,采用化学发光的方法测定血清CA125、HE4水平,采用免疫比浊法测定血浆D-二聚体水平。对比分析三者对卵巢癌的早期诊断价值。结果 癌症组CA125、HE4、血浆D-二聚体水平明显高于对照组,差异有统计学意义(P0.05),且HE4检测卵巢癌具有较高的灵敏度(89.28%)和特异度(88.00%),三者联合检测的灵敏度和特异度都得到了大幅度的提高。结论CA125、HE4、血浆D-二聚体联合检测可以提高卵巢癌早期诊断的准确度。  相似文献   

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