Acute effects of angiotensin II on fibrinolysis in healthy volunteers.

Recent studies have suggested that angiotensin II may inhibit fibrinolysis. In order to further test this hypothesis, we investigated the acute effects of angiotensin II (intravenous infusion of 10 ng/kg per min over 15-20 min) on fibrinolytic function in 18 healthy men. Time-controls (n=11) and control experiments with a placebo infusion (n = 13) were also performed. The activities of plasmin activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA), as well as t-PA antigen levels, were determined in plasma before, during and 60 min after the infusion of angiotensin II. Angiotensin II caused a clear-cut elevation in blood pressure; heart rate and plasma noradrenaline levels tended to decrease during the infusion but increased afterwards, indicating reflexogenic adjustments. Plasma t-PA activity and antigen levels increased by 81+/-11 and 14+/-3%, respectively, during angiotensin II infusion (both P < 0.001), whereas t-PA activity was unchanged and t-PA antigen decreased (P < 0.05) in placebo experiments. PAI-1 activity decreased similarly in time-controls and during angiotensin infusion (P < 0.001). Thus, short-term infusion of angiotensin II enhances fibrinolysis by elevating plasma t-PA. It is not clear whether this is a direct angiotensin-receptor-mediated effect or if it is related to the hemodynamic effects of the infusion.     

Antiinflammatory effects of salmeterol after inhalation of lipopolysaccharide by healthy volunteers

RATIONALE: Salmeterol is a beta2-adrenoreceptor agonist used in the treatment of obstructive pulmonary disease. Salmeterol inhibits inflammatory responses by neutrophils and mononuclear cells in vitro and in mouse models of lung inflammation in vivo. OBJECTIVE: To determine the effect of salmeterol on LPS-induced lung inflammation in humans.Methods: Thirty-two healthy subjects were enrolled in a single-blinded, placebo-controlled study. Subjects inhaled 100 microg salmeterol or placebo (t=-0.5 h) followed by 100 microg LPS or normal saline (t=0 h; n=8/group). Measurements were performed in bronchoalveolar lavage fluid and purified alveolar macrophages obtained 6 h post-challenge. MEASUREMENTS AND MAIN RESULTS: Inhalation of LPS was associated with neutrophil influx, neutrophil degranulation (myeloperoxidase, bactericidal/permeability-increasing protein and elastase), release of cytokines (tumor necrosis factor alpha and interleukin 6) and chemokines (interleukin 8, epithelial cell-derived neutrophil attractant 78, macrophage inflammatory proteins 1alpha and 1beta), activation of alveolar macrophages (upregulation of HLA-DR and CD71; enhanced expression of mRNAs for 13 different mediators of inflammation), and protein leakage (all p<0.05 vs. placebo/saline). Pretreatment with salmeterol inhibited LPS-induced neutrophil influx, neutrophil degranulation (myeloperoxidase), tumor necrosis factor alpha release, and HLA-DR expression (all p<0.05 vs. placebo/LPS), while not significantly influencing other responses. CONCLUSION: Salmeterol exerts antiinflammatory effects in the pulmonary compartment of humans exposed to LPS.     

支气管扩张剂雾化吸入在支气管镜检查患者肺功能保护中的临床应用

目的探索操作前应用短效支气管扩张剂雾化吸入对接受支气管镜检查的患者肺功能的保护作用。 方法分析我院2019年2月至2019年4月收治的拟行气管镜检查的患者36例,随机分为对照组和观察组：对照组患者接受操作前常规的丁卡因压缩空气雾化机雾化吸入,观察组患者接受操作前丁卡因联合短效支气管扩张剂压缩空气雾化机雾化吸入;比较两组患者支气管镜检查前、后生命征、氧饱和度、肺功能指标变化。 结果操作前两组患者生命征、氧饱和度、通气功能指标等均无统计学差异,支气管镜检查后患者的收缩压、氧饱和度、通气功能指标等较操作前明显变化,而接受操作前短效支气管扩张剂雾化吸入的患者通气功能、氧饱和度等指标明显优于对照组患者,而且心率更加稳定。 结论支气管镜操作可导致操作后患者通气功能指标下降,支气管镜操作前应用短效支气管扩张剂雾化吸入治疗可有效保护患者肺功能,提高了围操作期的安全性。     

The effects of salbutamol aerosol on lung function in patients with pulmonary emphysema

The effects of inhaling 400 μg of salbutamol were compared with identical placebo inhaler in a double blind cross-over study of 20 patients with radiological evidence of pulmonary emphysema. There was a small but significant rise in the forced expiratory volume in one second (FEV₁), but there was a much greater increase in vital capacity (VC), which was accompanied by a reduction in residual volume. Symptomatic improvement after salbutamol was reported by 14 of the patients and VC increased significantly in this group; there was no significant increase in VC in patients who did not prefer the active inhaler. There was no consistent change in the FEV₁/VC ratio after salbutamol administration and this ratio is misleading as an indicator of bronchodilator responsiveness in patients with emphysema. Salbutamol is thus a valuable addition to treatment in patients with pulmonary emphysema and the response to treatment is best judged by measuring the improvement in VC.     

Effects of nabumetone on platelet function in healthy volunteers

Non-steroidal anti-inflammatory drugs (NSAID) are frequently prescribed but gastrointestinal haemorrhages and inhibition of platelet function are two side effects that limit their use. Nabumetone belongs to a new prostaglandin-sparing class of NSAID with a low potential for causing gastrointestinal mucosal irritancy and inhibition of platelet function. We have used flow cytometry and in vitro bleeding time (IVBT) to measure the effects of nabumetone on platelet function in healthy volunteers. Nabumetone was found to cause a significant decrease in platelet-bound fibrinogen after adenosine diphosphate (ADP) activation using flow cytometry and a significant increase in IVBT when using CaCl(2) as activating substance. The platelet inhibitory effect was less pronounced than the changes seen with low dose aspirin. Flow cytometry and IVBT are two sensitive methods well suited for clinical use and could both be used to monitor drug-induced inhibition of platelet function.     

Pramiracetam effects on scopolamine-induced amnesia in healthy volunteers

Pramiracetam has been evaluated for its potential antiamnesic properties in scopolamine-induced amnesia in healthy volunteers. Two groups of twelve males, 18-42 and 55-65 years old, respectively, were randomly assigned to oral treatment with pramiracetam (600 mg twice a day) or with placebo for 10 consecutive days. On day 11 each subject was injected intramuscularly with scopolamine hydrobromide (0.5 mg). Before scopolamine injection and then 1, 3 and 6 h after it, subjects were administered the following psychometric tests: simple and choice visual reaction times, digit symbol substitution test, Rey's 15 words test for short and long term verbal memory. Scopolamine significantly impaired episodic memory and selective attention tests in both scopolamine and placebo groups. Instead visuo-motor and incidental learning measures were unaffected. Pramiracetam, when compared to placebo, was able to partially reduce the amnesic effects induced by scopolamine both in young and old subjects.     

Lack of effects of moderate-high altitude upon lung function in healthy middle-aged volunteers

This study investigates the effects of moderate-high altitude on lung function and exercise performance in 46 volunteers (19 females, 27 males), with a mean age of 42.4 +/- 1.4 years (+/- SEM) and varying smoking and exercise habits, who were not previously acclimatized. Measures obtained in the base camp (1140 m) and at altitude (2630 m), in random order, included forced spirometry, maximal voluntary ventilation, maximal inspiratory and expiratory pressures, arterial oxygen saturation and capillary lactate concentration after a standardized exercise test. The smoking history, Fagerstr?m test and degree of habitual physical activity were also recorded for each participant. The percentage of smokers was similar in males (19%) and females (21%) (P = n.s.). Mean habitual physical activity index was 8.2 +/- 0.2 (range, 5.88-11.63). At the base camp, all lung function variables were within the normal range. Lactate concentration after exercise averaged 3.7 +/- 0.3 mm l-1. No significant change was observed at altitude, except for a higher heart rate and a lower arterial oxygen saturation (SaO2) (both at rest and after inspiratory manoeuvres). The smoking history and the degree of physical activity did not influence lung function or exercise performance at altitude. The results of this study show that in middle-aged, healthy, not particularly well-trained individuals, lung function is not significantly altered by moderate-high altitude, despite the absence of any acclimatization period and independent of their smoking history and previous exercise habits.     

Acute effects of 0.12 ppm ozone or 0.12 ppm nitrogen dioxide on pulmonary function in healthy and asthmatic adolescents

Adolescent asthmatic subjects have been shown to be much more sensitive than healthy adolescents to the inhaled effects of sulfur dioxide. To test whether similar adolescent asthmatics are more sensitive to other common ambient air pollutants, 10 healthy and 10 asthmatic adolescent subjects were exposed for 60 min to filtered air, 0.12 ppm ozone (O3), and 0.12 ppm nitrogen dioxide (NO2) on separate days at rest. The following pulmonary functional values were measured before, at 30 min, and after 60 min of exposure: peak flow, total pulmonary resistance (RT), thoracic gas volume at functional residual capacity (FRC), maximal flow at 50 and 75% of expired vital capacity (Vmax50 and Vmax75), and forced expiratory volume in one second (FEV1). Following 60 min of exposure at rest to low concentrations of O3 or NO2, there were no consistent significant functional changes in either healthy or asthmatic adolescent subjects. There also were no measurable differences between the 2 groups.     

Recombinant human serum amyloid P in healthy volunteers and patients with pulmonary fibrosis

PRM-151, recombinant human Pentraxin-2 (PTX-2) also referred to as serum amyloid P (SAP), is under development for treatment of fibrosis. A First-in-Human (FIH) trial was performed to assess the safety, tolerability, and pharmacokinetics of single ascending intravenous doses of PRM-151 administered to healthy subjects, using a randomized, blinded, placebo controlled study design. Each cohort included three healthy subjects (PRM-151:placebo; 2:1). SAP levels were assessed using a validated ELISA method, non-discriminating between endogenous and exogenous SAP. At a dose level of 10 mg/kg, at which a physiologic plasma level of SAP was reached, two additional healthy volunteers and three pulmonary fibrosis (PF) patients were enrolled enabling comparison of the pharmacokinetic SAP profile between healthy volunteers and PF patients. In addition, the percentage of fibrocytes (CD45+/Procollagen-1+ cells) in whole blood samples was assessed to demonstrate biological activity of PRM-151 in the target population.PRM-151 administration was generally well tolerated. In two pulmonary fibrosis patients non-specific, transient skin reactions (urticaria and erythema) were observed. PRM-151 administration resulted in a 6-to 13-fold increase in mean baseline plasma SAP levels at dose levels of 5, 10, and 20 mg/kg. The estimated t_1/2 of PRM-151 in healthy volunteers was 30 h. Pharmacokinetic profiles were comparable between healthy volunteers and PF patients. PRM-151 administration resulted in a 30–50% decrease in fibrocyte numbers 24 h post-dose. This suggests that administration of PRM-151 may be associated with a reduction of fibrocytes in PF patients, a population for which current pharmacotherapeutic options are limited. The pharmacological action of PRM-151 should be confirmed in future research.     

Effects of carbamazepine on pituitary-adrenal function in healthy volunteers.

Carbamazepine (CBZ) is a widely used therapeutic agent in seizure, pain, and mood disorders. Although CBZ has been shown to inhibit hypothalamic CRH secretion in vitro, limited data suggest that systemic CBZ induces pituitary-adrenal activation. Few data are available to reconcile these effects or clarify their mechanism(s), particularly in healthy human subjects. We report here a study of basal ACTH and cortisol secretion and their responses to ovine CRH administration in nine healthy volunteers, studied both during repeated (2-3 weeks) administration of CBZ and while medication free. CBZ significantly increased mean 24-h urinary free cortisol (mean +/- SE, 197 +/- 17 vs. 137 +/- 24 nmol/day; P less than 0.02) and evening basal total plasma cortisol (113 +/- 17 vs. 83 +/- 14 nmol/L; P less than 0.05) as well as cortisol-binding globulin-binding capacity (497 +/- 36 vs. 433 +/- 28 nmol/L; P less than 0.01). Despite the CBZ-induced hypercortisolism, plasma ACTH responses to CRH during CBZ treatment remained robust, rather than being suppressed by basal hypercortisolism. In fact, during CBZ treatment, we noted a positive correlation between the increase in basal plasma cortisol and the increase in the plasma ACTH response to CRH (r = 0.65; P less than 0.05). We also observed a reduction in cortisol-binding globulin-binding capacity after CRH administration (315 +/- 25 vs. 433 +/- 28 nmol/L; P less than 0.001), which was accentuated by CBZ treatment (342 +/- 19 vs. 497 +/- 36 nmol/L; P less than 0.001; magnitude of fall, -155 +/- 22 nmol/L on CBZ vs. -118 +/- 11 nmol/L off CBZ; P less than 0.05). We conclude that CBZ increases plasma cortisol secretion in healthy volunteers independent of its effect on plasma cortisol-binding capacity. This pituitary-adrenal activation seems to reflect a pituitary, rather than a hypothalamic, effect of CBZ. Hence, despite CBZ-induced hypercortisolism, the ACTH response to CRH remained robust in direct proportion to the CBZ-induced rise in basal plasma cortisol. Thus, we propose that the increased cortisol secretion observed during CBZ treatment reflects a relative inefficacy of glucocorticoid negative feedback at the pituitary. This pituitary-driven increase in cortisol secretion combined with the expected reduction in centrally directed CRH secretion could contribute to the anticonvulsant properties of CBZ.     

Acute effects of triiodothyronine on endothelial function in human subjects

CONTEXT: Thyroid hormone regulates several cardiovascular functions, and low T(3) levels are frequently associated with cardiovascular diseases. Whether T(3) exerts any acute and direct effect on endothelial function in humans is unknown. OBJECTIVE: Our objective was to clarify whether acute changes in serum T3 concentration affect endothelial function. DESIGN, SETTING, AND SUBJECTS: Ten healthy subjects (age, 24 +/- 1 yr) participated in a double-blind, placebo-controlled trial at a university hospital. INTERVENTIONS: T3 (or placebo) was infused for 7 h into the brachial artery to raise local T3 to levels observed in moderate hyperthyroidism. Vascular reactivity was tested by intraarterial infusion of vasoactive agents. MAIN OUTCOME MEASURES: We assessed changes in forearm blood flow (FBF) measured by plethysmography. RESULTS: FBF response to the endothelium-dependent vasodilator acetylcholine was enhanced by T3 (P = 0.002 for the interaction between T3 and acetylcholine). The slopes of the dose-response curves were 0.41 +/- 0.06 and 0.23 +/- 0.04 ml/dl x min/microg in the T3 and placebo study, respectively (P = 0.03). T3 infusion had no effect on the FBF response to sodium nitroprusside. T3 potentiated the vasoconstrictor response to norepinephrine (P = 0.006 for the interaction). Also, the slopes of the dose-response curves were affected by T3 (1.95 +/- 0.77 and 3.83 +/- 0.35 ml/dl x min/mg in the placebo and T3 study, respectively; P < 0.05). The increase in basal FBF induced by T3 was inhibited by NG-monomethyl-L-arginine. CONCLUSIONS: T3 exerts direct and acute effects on the resistance vessels by enhancing endothelial function and norepinephrine-induced vasoconstriction. The data may help clarify the vascular impact of the low T3 syndrome and point to potential therapeutic strategies.     

Acute effects of intravenously administered ethanol on retinal vessel diameters and flicker induced vasodilatation in healthy volunteers

There is evidence from several vascular beds that acute alcohol consumption causes ocular hypotension and peripheral vasodilatation. The current study investigated the effects of intravenously administered ethanol on retinal vessel diameters and on flicker induced retinal vasodilatation. For this purpose, ethanol (0.35 g/kg) or placebo (physiologic saline solution) was administered intravenously for 40 min in a randomized, double masked, two way cross-over design to 12 healthy male volunteers. Retinal vessel diameters and flicker induced vasodilatation were measured before administration of ethanol as well as 30, 50, 90 and 130 min after the start of infusion with a retinal vessel analyzer. Intraocular pressure, systemic blood pressure and blood ethanol concentration were determined at the same time points. Intravenous administration of ethanol increased blood ethanol concentration from 0.0 g/l to 0.56 ± 0.10 g/l. Ethanol reduced IOP, but did not change ocular perfusion pressure. After cessation of the infusion blood ethanol concentration started to drop reaching a blood ethanol concentration of 0.22 ± 0.06 g/l 130 min after the start of infusion. Retinal arterial diameters increased significantly after administration of ethanol by a maximum of + 4.2 ± 4.0%, whereas no change was observed in retinal veins. Neither arterial nor venous diameters were influenced by administration of placebo. Flicker stimulation induced a significant dilatation in both arterial and venous diameters. Ethanol did not change flicker responses in arteries or in retinal veins. In conclusion, intravenous administration of ethanol increases retinal arterial diameters, whereas venous diameters remained unchanged. Whether this is related to a direct vasodilator effect or to a hitherto unidentified mechanism remains to be clarified.     

Somatostatin effect on rectal muscle in human healthy volunteers

The effect of somatostatin on the rectal muscle has been studied in 15 healthy volunteers who received on 2 separate days and in a random order a continuous 1-hour infusion somatostatin (250 micrograms initially as an intravenous bolus and then 250 micrograms/h via infusion) or placebo (saline 0.15 M). Our results show that somatostatin significantly reduces the rectal basal tone after 30 and 50 min of infusion without modifying the rectal distensibility. Although they were obtained through a pharmacological increase of plasma somatostatin levels, these data suggest that somatostatin could play a part in the reservoir function of the rectum.     

Acute effects of growth hormone on vascular function in human subjects

GH is involved in the long-term regulation of peripheral vascular resistance and vascular reactivity. We determined whether GH plays a role in the acute regulation of vascular function in humans. The acute vascular effects of GH were studied in eight healthy subjects according to a double-blind, placebo-controlled design. Forearm blood flow (FBF), vascular resistance, and nitric oxide (NO) production were monitored during a 4-h infusion of GH into the brachial artery at a rate chosen to raise local GH to stress levels (approximately 40 ng/ml). During GH infusion, FBF rose 75% (P < 0.05), whereas forearm vascular resistance decreased comparably (P < 0.05). These changes were paralleled by augmented forearm release of NO (P < 0.02). GH heightened the response of FBF to the endothelium-dependent vasodilator acetylcholine (Ach; P < 0.02). With the highest Ach dose, FBF reached 30.4 +/- 4.2 and 16.9 +/- 3.1 ml/dl x min in the GH and placebo studies, respectively (P < 0.005). The slopes of the dose-response curves also differed markedly (0.45 +/- 0.07 and 0.25 +/- 0.05 ml/dl x min/ microg in the GH and placebo studies, respectively; P < 0.01). GH caused an upward shift of the FBF response to the endothelium-independent vasodilator sodium nitroprusside (P < 0.01), but did not affect the slope of the dose-response curve. GH infusion did not cause any appreciable increment in the venous IGF-I concentration in the test arm. In conclusion, GH acutely lowers peripheral vascular resistance and stimulates endothelial function. These effects are mediated by activation of the NO pathway and appear to be independent of IGF-I.     

Acute effects of positive end-expiratory pressure on left ventricle diastolic function in healthy subjects

We evaluated the acute effect of the application of positive end-expiratory pressure (PEEP) on LV diastolic function in 10 healthy subjects. We assessed load dependent diastolic function by Doppler examination of transmitral flow and load independent diastolic function by color M-mode propagation velocity of early flow into the LV cavity (Vp). During the application of PEEP in comparison to the baseline, we found a significant reduction of the E wave peak velocity [79 (64–83) vs. 65 (57–72) cm/s; p = 0.028] and a significant reduction in Vp [84 (73–97) vs. 53 (48–66); p = 0.012]. Moreover, we found a significant reduction in left atrial area [15 (13–18) vs. 12 (10–14) cm²; p = 0.018] and right atrial area [12 (11–15) vs. 11 (9–12) cm²; p = 0.015]. No difference was found in global LV systolic function. The application of PEEP acutely modifies the diastolic flow pattern across the mitral valve, and reduces atrial dimensions. The work was presented in part as an oral communication at the 2004 SMART.     

雾化吸入布地奈德治疗AECOP D合并2型糖尿病患者疗效及对肺通气功能和糖代谢的影响

目的 分析雾化吸入布地奈德治疗慢性阻塞性肺疾病急性加重(AECOPD)合并2型糖尿病(T2DM)患者疗效及对肺通气功能和糖代谢指标的影响.方法 选择四川大学华西医院2019年1月至2020年5月诊治的120例AECOPD合并T2DM患者作为对象,根据非随机临床同期对照研究及患者自愿原则分为对照组58例和观察组62例,其...