Biological effects of aspirin and clopidogrel in a randomized cross-over study in 96 healthy volunteers

BACKGROUND: Some data suggest that biological 'resistance' to aspirin or clopidogrel may influence clinical outcome. OBJECTIVE: The aim of this study was to evaluate the relationship between aspirin and clopidogrel responsiveness in healthy subjects. METHODS: Ninety-six healthy subjects were randomly assigned to receive a 1-week course of aspirin 100 mg day(-1) followed by a 1-week course of clopidogrel (300 mg on day 1, then 75 mg day(-1)), or the reverse sequence, separated by a 2-week wash-out period. The drug effects were assessed by means of serum TxB2 assay, platelet aggregation tests, and the PFA -100 and Ultegra RPFA -Verify Now methods. RESULTS: Only one subject had true aspirin resistance, defined as a serum TxB2 level > 80 pg microL(-1) at the end of aspirin administration and confirmed by platelet incubation with aspirin. PFA-100 values were normal in 29% of the subjects after aspirin intake, despite a drastic reduction in TxB2 production; these subjects were considered to have aspirin pseudo-resistance. Clopidogrel responsiveness was not related to aspirin pseudo-resistance. Selected polymorphisms of platelet receptor genes were not associated with either aspirin or clopidogrel responsiveness. CONCLUSIONS: In healthy subjects, true aspirin resistance is rare and aspirin pseudo-resistance is not related to clopidogrel responsiveness.     

Effects of non-invasive ventilation on middle ear function in healthy volunteers

OBJECTIVES: To evaluate the effects of non-invasive ventilation (NIV) with facial mask or helmet on middle ear (ME). DESIGN. Prospective, randomised study. SETTING: University hospital. PARTICIPANTS: Ten healthy subjects randomly allocated in two groups of five subjects each. INTERVENTIONS: NIV for 1 h, with helmet (group H) or facial mask (group M). Flow-triggered pressure support was 10 cmH(2)O, PEEP 5 cmH(2)O, FiO(2) 0.21. MEASUREMENTS AND RESULTS: Impedenzometry was performed before NIV and 5 min after NIV ended; it was repeated 60 min later. In group H the acoustic compliance increased after NIV from 2.0+/-.6 ml to 2.3+/-.6 ml ( P<.01), suggesting that the tympanic membrane became less stiff; 1 h later the compliance returned to basal values (2.0+/-.7 ml); in group M the compliance was unaffected (from 2.0+/-.5 ml to 2.0+/-.4 ml; 1.9+/-.4 ml 1 h later). The acoustic reflex, i.e., the contraction of the stapedial muscle in response to an auditory stimulus, involving the acoustic and facial nerves, was also evaluated during impedenzometry at 250 Hz, 500 Hz, 1,000 Hz, and 4,000 Hz; no significant change of the threshold was observed. CONCLUSIONS: The tympanic membrane is tighten by the tensor tympani and a reversible loosening suggests muscle fatigue in response to the application of intermittent positive pressure applied to the external ear during NIV with helmet. The loss of tensor tympani protective action could theoretically predispose the middle and inner ear to mechanical damage during NIV with helmet, suggesting the use of protective devices (ear plugs) in selective cases requiring long-term, high-pressure treatment.     

Relative bioavailability of three newly developed albendazole formulations: a randomized crossover study with healthy volunteers

This study of healthy volunteers shows that the relative bioavailability of albendazole formulations that use arachis oil-polysorbate 80 or hydroxypropyl-beta-cyclodextrin as an excipient was enhanced 4.3- and 9.7-fold compared to the results seen with commercial tablets. Administration of macrogol suppositories did not result in measurable plasma concentrations of albendazole sulfoxide.     

Esophageal balloon calibration during Sigh: A physiologic,randomized, cross-over study

PurposeOptimal esophageal balloon filling volume (V_best) depends on the intrathoracic pressure. During Sigh breath delivered by the ventilator machine, esophageal balloon is surrounded by elevated intrathoracic pressure that might require higher filling volume for accurate measure of tidal changes in esophageal pressure (Pes). The primary aim of our investigation was to evaluate and compare V_best during volume controlled and pressure support breaths vs. Sigh breath.Materials and methodsTwenty adult patients requiring invasive volume-controlled ventilation (VCV) for hypoxemic acute respiratory failure were enrolled. After the insertion of a naso-gastric catheter equipped with 10 ml esophageal balloon, each patient underwent three 30-min trials as follows: VCV, pressure support ventilation (PSV), and PSV + Sigh. Sigh was added to PSV as 35 cmH₂O pressure-controlled breath over 4 s, once per minute. PSV and PSV + Sigh were randomly applied and, at the end of each step, esophageal balloon calibration was performed.ResultsV_best was higher for Sigh breath (4.5 [3.0–6.8] ml) compared to VCV (1.5 [1.0–2.9] ml, P = 0.0004) and PSV tidal breath (1.0 [0.5–2.4] ml, P < 0.0001).ConclusionsDuring Sigh breath, applying a calibrated approach for Pes assessment, a higher V_best was required compared to VCV and PSV tidal breath.     

Passive continuous positive airway pressure ventilation during cardiopulmonary resuscitation: a randomized cross-over manikin simulation study

While controlled ventilation is most frequently used during cardiopulmonary resuscitation (CPR), the application of continuous positive airway pressure (CPAP) and passive ventilation of the lung synchronously with chest compressions and decompressions might represent a promising alternative approach. One benefit of CPAP during CPR is the reduction of peak airway pressures and therefore a potential enhancement in haemodynamics. We therefore evaluated the tidal volumes and airway pressures achieved during CPAP–CPR. During CPR with the LUCAS? 2 compression device, a manikin model was passively ventilated at CPAP levels of 5, 10, 20 and 30 hPa with the Boussignac tracheal tube and the ventilators Evita^® V500, Medumat^® Transport, Oxylator^® EMX, Oxylog^® 2000, Oxylog^® 3000, Primus^® and Servo^®-i as well as the Wenoll^® diver rescue system. Tidal volumes and airway pressures during CPAP–CPR were recorded and analyzed. Tidal volumes during CPAP–CPR were higher than during compression-only CPR without positive airway pressure. The passively generated tidal volumes increased with increasing CPAP levels and were significantly influenced by the ventilators used. During ventilation at 20 hPa CPAP via a tracheal tube, the mean tidal volumes ranged from 125 ml (Medumat^®) to 309 ml (Wenoll^®) and the peak airway pressures from 23 hPa (Primus^®) to 49 hPa (Oxylog^® 3000). Transport ventilators generated lower tidal volumes than intensive care ventilators or closed-circuit systems. Peak airway pressures during CPAP–CPR were lower than those during controlled ventilation CPR reported in literature. High peak airway pressures are known to limit the applicability of ventilation via facemask or via supraglottic airway devices and may adversely affect haemodynamics. Hence, the application of ventilators generating high tidal volumes with low peak airway pressures appears desirable during CPAP–CPR. The limited CPAP–CPR capabilities of transport ventilators in our study might be prerequisite for future developments of transport ventilators.     

An evaluation of a supratherapeutic dose of inclisiran on cardiac repolarization in healthy volunteers: A phase I,randomized study

Inclisiran is a small interfering RNA molecule that has been shown to provide an effective and sustained reduction in low‐density lipoprotein cholesterol levels. This study aimed to determine whether a supratherapeutic dose of inclisiran affects cardiac repolarization and conduction in healthy volunteers. A phase I, randomized, double‐blind, double‐dummy, placebo‐ and positive‐controlled, three‐way crossover study was performed in 48 healthy volunteers. Volunteers were assigned to three treatments in a randomized sequence: a supratherapeutic dose of inclisiran sodium (900 mg), placebo, or moxifloxacin 400 mg as a positive control, with a minimum 7‐day washout period between treatments. Continuous electrocardiogram monitoring was performed from >60 min before dosing until 48 h after dosing. Pharmacokinetics, pharmacodynamics, and safety were also assessed. Inclisiran, at a supratherapeutic dose, did not show a clinically significant effect on the QT interval (Fridericia correction formula [QTcF]; maximal placebo‐ and baseline‐corrected change: 2.5 ms [90% confidence interval: 0.6, 4.5]) near the maximal plasma concentrations at 4 h. In addition, inclisiran did not show any effects on other electrocardiogram intervals or ST‐ and T‐wave morphology. The positive control, moxifloxacin, demonstrated the expected changes in QTcF interval, validating the adequate sensitivity of the study. A supratherapeutic dose of inclisiran sodium (900 mg) had no effect on the QTcF interval or other electrocardiogram parameters, providing additional insight and reassurance regarding the safety profile of inclisiran.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Inclisiran is a novel siRNA therapeutic agent that specifically targets the liver and has been shown to effectively, sustainably, and safely lower low‐density lipoprotein cholesterol levels, a proven risk factor for atherosclerotic cardiovascular disease. Prolongation of cardiac repolarization can result in life‐threatening arrhythmias; therefore, a thorough characterization of the effects of inclisiran on the QT/corrected QT interval is a premarketing requirement for this therapeutic agent. This is the first clinical study investigating the potential effects of an siRNA therapy on QT intervals to our best knowledge.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addressed whether or not a supratherapeutic dose of inclisiran had any effects on cardiac repolarization based on the corrected QT interval or other electrocardiogram parameters in healthy participants.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

A supratherapeutic dose of inclisiran sodium (900 mg) was generally safe and well‐tolerated and did not show a clinically relevant effect on the QT interval. Other electrocardiogram intervals and ST‐ and T‐wave morphology were also unaltered by a supratherapeutic dose of inclisiran.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study demonstrated that a supratherapeutic dose of inclisiran sodium (900 mg), a novel siRNA therapeutic agent, does not affect cardiac repolarization, providing additional reassurance regarding the safety profile of inclisiran. This is the first QT clinical study investigating the effects of a novel siRNA therapeutic agent.     

Validation of indirect calorimetry for measurement of energy expenditure in healthy volunteers undergoing pressure controlled non-invasive ventilation support

The aim of this validation study was to assess the reliability of gas exchange measurement with indirect calorimetry among subjects who undergo non-invasive ventilation (NIV). Oxygen consumption (VO₂) and carbon dioxide production (VCO₂) were measured in twelve healthy volunteers. Respiratory quotient (RQ) and resting energy expenditure (REE) were then calculated from the measured VO₂ and VCO₂ values. During the measurement period the subjects were breathing spontaneously and ventilated using NIV. Two different sampling air flow values 40 and 80 l/min were used. The gas leakage from the measurement setup was assessed with a separate capnograph. The mean weight of the subjects was 93 kg. Their mean body mass index was 29 (range 22–40) kg/m². There was no statistically significant difference in the measured values for VO₂, VCO₂, RQ and REE during NIV-supported breathing and spontaneous breathing. The change of sampling air flow had no statistically significant effect on any of the above parameters. We found that REE can be accurately measured with an indirect calorimeter also during NIV-supported breathing and the change of sampling air flow does not distort the gas exchange measurement. A higher sampling air flow in indirect calorimetry decreases the possibility for air leakages in the measurement system and increases the reliability of REE measurement.     

Effect of folic acid and betaine supplementation on flow-mediated dilation: a randomized, controlled study in healthy volunteers

Objectives:     

Alterations in coagulation and fibrinolysis after levothyroxine exposure in healthy volunteers: a controlled randomized crossover study

Summary. Background: Several hemostatic abnormalities have been reported in hyperthyroidism, but the overall effect of thyroid hormone excess on coagulation and fibrinolysis is unclear. Objective: Our aim was to assess whether the use of supraphysiological doses of levothyroxine leads to coagulation activation and inhibition of fibrinolysis. Patients and methods: Healthy volunteers were randomized to receive levothyroxine or no medication for 14 days with a washout period of at least 28 days in a crossover design. To study the effects of different degrees of thyroid hormone excess, 16 participants received levothyroxine in a dose of 0.3 mg per day, and 12 received levothyroxine 0.45 or 0.6 mg per day depending on body weight. Several variables of coagulation and fibrinolysis were measured. Results: Levels of von Willebrand factor activity (VWF:RiCo) and antigen (VWF:Ag), factor (F) VIII, plasminogen activator inhibitor‐1 (PAI‐1) and clot‐lysis time were slightly higher after levothyroxine 0.3 mg per day than after the control situation, but only levels of VWF showed a significant increase from baseline. After levothyroxine 0.45 or 0.6 mg per day, levels of fibrinogen increased by 17%, VWF activity by 24%, VWF antigen by 26%, FVIII by 19%, FIX by 14%, FX by 7%, PAI‐1 by 116% and clot‐lysis time by 14%, and activated partial thromboplastin time decreased by 3%; all were significant changes compared with the control situation. We did not observe clear evidence of coagulation activation. Conclusions: Our data suggest that thyroid hormone excess increases coagulation factor levels and inhibits fibrinolysis in a dose‐dependent fashion. This implies an increased risk of venous thrombosis during hyperthyroidism.     

Salbutamol delivery during non-invasive mechanical ventilation in patients with chronic obstructive pulmonary disease: a randomized, controlled study

OBJECTIVE: We investigated the clinical response to equivalent doses of salbutamol delivered, via metered dose inhaler (MDI) during non-invasive mechanical ventilation (NIMV-MDI), during spontaneous breathing using a spacer (MDI-Spacer), and also during intermittent positive pressure breathing (IPPB). SETTING: A respiratory intensive care unit. DESIGN: Prospective, randomized, and placebo-controlled study. PATIENTS: Eighteen stable patients with chronic obstructive pulmonary disease (mean FEV1=38.5+/-8.8% predicted). RESULTS: Overall salbutamol administration induced, compared to placebo, a significant improvement in FEV1, irrespective of the mode of administration (+7.9+/-7.1% or +108+/-91 ml for IPPB, +9.6+/-8.8% or 112+/-67 ml for MDI-NIMV (inspiratory pressure=14.3+/-1.8 cmH2O; expiratory pressure=none), and +10.8+/-11.4% or 119+/-114 ml for MDI-Spacer, respectively). DeltaFVC significantly increased from placebo only in MDI-NIMV (+214+/-182 ml P=0.02). A second set of experiments performed in eight patients to ascertain the possible effect of NIMV on pulmonary function tests, showed a significant improvement from baseline values in FVC both after the delivering of placebo or salbutamol via NIMV-MDI (+206+/-147 ml and 208+/-145, respectively). FEV1 significantly increased only after salbutamol. No changes in gas exchange were observed after bronchodilator delivery. CONCLUSIONS: We show that delivery of bronchodilators via MDI with a spacer chamber during NIMV is feasible and induces a significant bronchodilator effect compared to placebo, even though it may be slightly less effective than the classical delivery system (MDI-Spacer).     

Rewarming of healthy volunteers after induced mild hypothermia: a healthy volunteer study

Objectives: The study compares the efficacy of two active and one passive warming interventions in healthy volunteers with induced mild hypothermia.

Methods: Eight volunteers were studied in a random order crossover design. Each volunteer was studied during re-warming from a core temperature of 35°C with each of: a radiant warmer (Fisher & Paykel); a forced air warmer (Augustine Medical), and a polyester filled blanket, to re-warm.

Results: No significant differences in re-warming rates were observed between the three warming devices. It was found that the subject's endogenous heat production was the major contributor to the re-warming of these volunteers. Metabolic rates of over 350 W were seen during the study.

Conclusions: For patients with mild hypothermia and in whom shivering is not contraindicated our data would indicate that the rate of re-warming would be little different whether a blanket or one of the two active devices were used. In the field, this may provide the caregiver a useful choice.

     

The effects of heparins on the liver: application of mechanistic serum biomarkers in a randomized study in healthy volunteers

Heparins have been reported to cause elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) but have not been associated with clinically significant liver injury. The mechanisms underlying these benign laboratory abnormalities are unknown. Forty-eight healthy men were randomized to receive subcutaneous injections of unfractionated heparin (UFH; 150 U/kg), enoxaparin sodium (1 mg/kg), dalteparin sodium (120 IU/kg), or adomiparin sodium (125 IU/kg; a novel heparin) every 12 h for 4.5 days. Asymptomatic elevations in serum ALT or AST were observed in >90% of the subjects. Elevations were also observed in the levels of serum sorbitol dehydrogenase (SDH), glutamate dehydrogenase (GLDH), miR-122, high-mobility group box-1 protein (including the acetylated form), full-length keratin 18, and DNA. Keratin 18 fragments, which are apoptosis biomarkers, were not detected. Biomarker profiles did not differ significantly across heparin treatments. We conclude that heparins as a class cause self-limited and mild hepatocyte necrosis with secondary activation of an innate immune response.     

基于健康人急性骨筋膜室综合征模型的超声监测价值研究

目的:探讨超声在急性骨筋膜室综合征模型早期无创监测中的应用价值,为进一步的临床应用提供参考。方法:为前瞻性自身对照研究。通过袖带加压法建立小腿急性骨筋膜室综合征的健康志愿者模型,随机数字法确定一侧小腿为实验组,袖带依次给予0、20、30、40、50、60、70、80 mmHg (1 mmHg=0.133 kPa)压力,对照组的小腿袖带不加压。实验组每个压力水平持续5 min,期间应用超声测量双侧腘动脉、腘静脉及足背动脉的血流频谱及血管结构指标。采用重复测量方差分析和多变量方差分析进行统计分析。结果:研究共纳入25名健康志愿者,双侧小腿围和胫前筋膜室厚度的差异无统计学意义（ P=0.314、0.678）,小腿袖带加压期间心率及血压稳定（ P=0.235、0.358）。实验组腘动脉收缩期最大血流速、最小血流速均随袖带压力的增大而增加,从加压30 mmHg起实验组腘动脉最大血流速明显高于对照组[(73±19) cm/s vs (59±14) cm/s, P=0.023)],从加压20 mmHg起实验组腘动脉最小血流速显著高于对照组[(-28±8) cm/s vs (-22±6) cm/s, P=0.012)]。随着压力的增加,实验组腘动脉舒张期反向血流比增加（ P<0.001）,加压20 mmHg时即显著大于对照组[(0.42±0.14）cm/s vs (0.30±0.12) cm/s, P=0.009)]。实验组足背动脉正向血流比随压力增加而减小（ P=0.024）。 结论:在健康人急性骨筋膜室综合征模型中,随着筋膜室压力的增加,近端动脉的收缩期最大血流速、舒张期反向血流比例明显增加,远端动脉的收缩期正向血流比例明显减少,提示超声可用于急性骨筋膜室综合征的早期监测,值得进一步的临床研究。     

Bench comparative evaluation of a new generation and standard helmet for delivering non-invasive ventilation

Objective

To evaluate the performance of a new helmet (NH) recently introduced into clinical use relative to that of the standard helmet (SH) in terms of delivering non-invasive continuous positive airway pressure (nCPAP) and pressure support ventilation (nPSV).

Design

This was a bench study using a mannequin connected to an active lung simulator. The SH was fastened to the mannequin by armpit braces, which are not needed to secure the NH.

Measurements

The inspiratory and expiratory variations in nCPAP delivered with two different simulated efforts (Pmus), were determined relative to the preset CPAP level. nPSV was applied at two simulated respiratory rates (RR) and two cycling-off flow thresholds. We measured inspiratory trigger delay (Delay_trinsp), expiratory trigger delay (Delay_trexp), time of synchrony (Time_sync), trigger pressure drop (ΔP _trigger), airway pressure–time product during the triggering phase (PTPt), the initial 200 ms from the onset of the ventilator pressurization (PTP₂₀₀), and the initial 300 and 500 ms from the onset of the simulated effort; this two latter parameters were expressed as the percentage of the area of ideal pressurization (PTP_300-index and PTP_500-index, respectively).

Results

In nCPAP, at both Pmus, the differences between the two interfaces at both Pmus were small and clinically irrelevant. In nPSV, regardless of the setting, NH resulted in significantly smaller trigger delays, ΔP _trigger, and PTPt. Time_sync, PTP₂₀₀, PTP_300-index, and PTP_500-index were also significantly higher with the NH compared to the SH, irrespective of the setting.

Conclusions

Compared to the SH, the NH is equally effective in delivering nCPAP and more effective in delivering nPSV, and it is used to avoid the need for armpit braces.     

人工虫草提取物Cs-4改善人体心肺功能及增强耐力的临床研究

目的:探究人工虫草提取物Cs-4对健康老年志愿者有氧能力的影响。方法:采用随机双旨安慰剂对照研究方法,30例健康老年志愿者被随机分配到Cs-4组(n=16)或者安慰剂组(n=14),服用Cs-4(3g／d)或安慰剂共6周。实验前后,在第0周和第6周,通过测定症状限制性的增量功率运动试验期间的最大氧摄取(VO2max)、最大通气率(VEmax)、代谢当量(METs)和气体交换无氧阈值(VO2θ),以及试验前及试验终止后:3min,从手臂静脉取静脉血测定血乳酸浓度,来评估有氧能力、运动能力以及体能。结果:6周治疗后,安慰剂组的各项指标无明显变化;Cs-4组的VO2max较服药前的基线水平平均提高了7.0％±3.5％(P=0.05),最大METs明显提高了8.29％±3.33％(P<0.05),VEmax明显提高了10.4％±4.5％(P<0.05),无氧阈(VO2θ)较6周前明显提高了12.6％±4.3％(P<0.05);血清乳酸水平无明显变化。结论:人工虫草提取物Cs-4能够增强老年健康人的有氧能力、运动能力和肺通气容量,从而有力地支持了中医关于冬虫夏草具有提高运动能力和抗疲劳作用的理论。