Pulmonary hypertension (PH) is common in COPD and may predict mortality in this disorder. We have compared the pulmonary vasodilator effects, dose-response characteristics, and tolerability of two ...calcium channel blockers, amlodipine and extendedrelease (ER) felodipine, in 10 patients (seven men, age 68±4.8 SD years) with clinically stable COPD and PH.
Drugs were given in equal single daily oral doses (2.5, 5, and 10 mg), increasing weekly for 3 weeks, in a randomized investigator-blinded crossover manner with a 1-week wash-out period between the two treatments.
Doppler measurements of pulmonary hemodynamics were made on the seventh day of treatment at each drug dose. Lung function, arterial blood gases, and adverse events were also monitored weekly.
A dose-dependent decline of pulmonary artery pressure (PAP) was observed with each drug. A dose of 2.5 mg produced a significant decrease in PAP compared with baseline (20% amlodipine, 17% felodipine ER). Additional decreases in PAP were observed at 5 mg and 10 mg that were similar for both drugs, but did not reach statistical significance compared with 2.5 mg. There was a dose-related decrease in pulmonary vascular resistance and increase in oxygen delivery with amlodipine and felodipine ER. Lung function and blood gas values were stable throughout. Side effects (headache and ankle edema) were less frequent during amlodipine treatment (p<0.05).
Both amlodipine and felodipine ER, given as a single daily oral dose of ≥2.5 mg, are effective pulmonary vasodilators in COPD patients with PH. Their dose-response characteristics are similar, but amlodipine treatment was associated with fewer side effects.
There is a major need for new adjuvants to improve the efficacy of seasonal and pandemic influenza vaccines. Advax is a novel polysaccharide adjuvant based on delta inulin that has been shown to ...enhance the immunogenicity of influenza vaccine in animal models and human clinical trials. To better understand the mechanism for this enhancement, we sought to assess its effect on the plasmablast response in human subjects. This pilot study utilised cryopreserved 7 day post-vaccination (7dpv) peripheral blood mononuclear cell samples obtained from a subset of 25 adult subjects from the FLU006-12 trial who had been immunized intramuscularly with a standard dose of 2012 trivalent inactivated influenza vaccine (TIV) alone (n=9 subjects) or combined with 5mg (n=8) or 10mg (n=8) of Advax adjuvant. Subjects receiving Advax adjuvant had increased 7dpv plasmablasts, which in turn exhibited a 2-3 fold higher rate of non-silent mutations in the B-cell receptor CDR3 region associated with higher expression of activation-induced cytidine deaminase (AID), the major enzyme controlling BCR affinity maturation. Together, these data suggest that Advax adjuvant enhances influenza immunity in immunized subjects via multiple mechanisms including increased plasmablast generation, AID expression and CDR3 mutagenesis resulting in enhanced BCR affinity maturation and increased production of high avidity antibody. How Advax adjuvant achieves these beneficial effects on plasmablasts remains the subject of ongoing investigation. Trial Registration Australia New Zealand Clinical Trials Register ACTRN12612000709842 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=3 6 2709
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•First report of clinical use of Stratis jet injector device for vaccine administration.•Addresses new FDA guidance mandating clinical validation of new vaccine administration devices.•Influenza ...vaccine immunogenicity maintained when delivered via Stratis device.•Stratis device associated with reduced systemic adverse reactions.•Stratis device caused increased local adverse reactions but only in mild category.
The Stratis® disposable syringe jet injection (DSJI) system (PharmaJet Inc., Denver, USA) delivers vaccine utilizing a spring powered energy source to create a fine high-velocity jet of liquid that directly penetrates the skin without using a needle. We performed a study to collect data on the effect of the Stratis DSJI device on influenza immunization in 46 predominantly elderly subjects (28M, 18F; mean age 61 years) who were randomized 1:1 to receive Fluvax 2012 trivalent inactivated influenza vaccine via prefilled N–S or Stratis DSJI. H1N1 seroprotection was not significantly different for vaccine delivered by DSJI (86.4%, 95% CI 72.1–100) or N–S (79.2%, 95% CI 63.0–95.4), and likewise for H3N2 and B strains. The DSJI had a ∼2-fold higher mean injection pain score (DSJI: 3.0 versus N–S 1.58, p = 0.045) plus increased rates of swelling and tenderness but this was offset by a lower rate of elicited systemic reactions, particularly the frequency of post-immunization headaches (DSJI: 9% vs N–S: 33.3%). This study suggests that subject to confirmation of non-inferiority in an appropriately powered study, the Stratis DSJI is a viable alternative strategy for the administration of seasonal influenza vaccines with particular appeal for individuals with needle phobia. Australia New Zealand Clinical Trials Register: ACTRN12612000709842.
It is controversial whether obstructive sleep apnea (OSA) causes pulmonary hypertension (PH) in the absence of hypoxemic lung disease. To investigate this further we measured awake pulmonary ...hemodynamics, pulmonary gas exchange, and small airways function in 32 patients with OSA (apnea- hypopnea index, mean +/- SE, 46.2 +/- 3. 9/h) who had normal screening lung function. Pulmonary artery pressure (Ppa) and cardiac output were measured by Doppler echocardiography at three levels of inspired oxygen (FIO2 0.50, 0.21, and 0.11) and during incremental increases in pulmonary blood flow (10, 20, and 30 microgram/kg/min dobutamine infusions) while breathing 50% oxygen. Eleven patients had PH (mean Ppa >/= 20 mm Hg, Group I). They did not differ from patients without PH (Group II) in lung function, severity of sleep-disordered breathing, age, or body mass. Compared with Group II, Group I patients had increased small airways closure during tidal breathing (FRC-closing capacity: Group I, -0.16 +/- 0.11; Group II, 0.27 +/- 0.09 L; p < 0.05), more ventilation-perfusion inequality (AaPO2: 23.8 +/- 2.8; 19.8 +/- 1.4 mm Hg; p = 0.08), a greater pulmonary artery pressor response to hypoxia (DeltaPpa FIO2, 0.50 to 0.11: 16.4 +/- 1.93; 6.4 +/- 0.77 mm Hg; p < 0.05) and a marked rise in Ppa during increased pulmonary blood flow. We conclude that PH may develop in some patients with OSA without lung disease and that it is associated with small airways closure during tidal breathing and heightened pulmonary pressor responses to hypoxia and during increased pulmonary blood flow. Such changes are consistent with remodeling of the pulmonary vascular bed in affected patients with OSA, seemingly unrelated to severity of sleep-disordered breathing.
In preparation for a vasodilator study on chronic obstructive pulmonary disease (COPD), we investigated the reliability of recently described pulsed Doppler techniques for estimating pulmonary artery ...pressure (PAP) and cardiac output (CO). Our aims were to determine the following: (1) the imaging success rate for pulsed Doppler measurements; (2) the repeatability of the measurements, and interobserver and intraobserver variability; and (3) the accuracy of Doppler compared with catheter measurements. Doppler studies were attempted in 81 patients (cardiac diseases 23, COPD 22, sleep apnea 32, and normal subjects 4). Suitable images were obtained in 68 subjects (84 percent) and in 76 subjects (94 percent) for PAP and CO estimations, respectively. The lowest imaging success rates were in COPD patients (68 percent for PAP and 86 percent for CO estimation). Repeatability of the techniques was assessed in four cardiac patients and three healthy volunteers by performing four replicate studies in each subject over 1 h. Intrasubject coefficient of variation was <10 percent for PAP and <5 percent for CO. The intraobserver variability for Doppler estimation of systolic and mean PAP was 5.5 percent and 5.8 percent, respectively. The corresponding values for interobserver variability were 6.7 percent and 6.2 percent. Intraobserver and interobserver variability for “nongeometric” method of estimating CO was 5.1 percent and 5.9 percent, respectively. Agreement was good between catheter-measured and Doppler-estimated PAP in the 27 patients tested (cardiac 19 and COPD 8) for both mean and systolic pressures (r=0.96 and r=0.97, respectively). The correlations between thermodilution and Doppler estimations of CO in eight COPD patients were 0.77 (“geometric” technique) and 0.97 (“nongeometric” technique). We conclude that pulsed Doppler techniques can be used to obtain accurate and reproducible quantitative information on pulmonary hemodynamics in a wide range of patients. Suitable Doppler images can be obtained in more than two thirds of COPD patients.
Pulmonary hypertension in chronic obstructive pulmonary disease (COPD) is associated with a poor prognosis. Reduction of pulmonary artery pressure in COPD by prolonged oxygen treatment has been shown ...to be associated with increased survival. In an attempt to find a suitable pharmacologic method of reducing pulmonary artery pressure and pulmonary vascular resistance in COPD, we enrolled 13 stable pulmonary-hypertensive, hypoxemic COPD patients in a study to test the effects of felodipine, a relatively new, vascular-selective calcium antagonist. Doppler echocardiography was used to estimate pulmonary artery pressure and cardiac output before treatment, 2, 7, and 12 weeks during felodipine treatment (10 to 20 mg/d), and after a 1-week placebo washout period. Measurements of lung function, arterial blood gases, and exercise capacity during an incremental bicycle ergometer test were also performed at intervals during the study period. Three patients withdrew from the study and of the remaining 10, 8 had some side effects of medication (peripheral edema or headache) that improved either spontaneously or following a reduction in drug dose. In the 10 patients who completed the study (8 male; mean age, 67 years), felodipine resulted in significant reductions in mean pulmonary artery pressure (22 percent) and total pulmonary (vascular) resistance (30 percent) and increases in cardiac output (15 percent) and stroke volume (13 percent) compared with baseline measurements and those taken after placebo washout. These effects were sustained over the 12 weeks of felodipine treatment. There was no adverse effect of felodipine treatment on pulmonary gas exchange at rest or during exercise and no change in lung function or exercise capacity. We conclude that in pulmonary hypertensive, hypoxemic COPD patients, felodipine substantially improves pulmonary hemodynamics.
To determine whether pulmonary hypertension (PH) can occur in obstructive sleep apnea syndrome (OSAS) in the absence of lung or primary cardiac disease, we studied 27 patients (26 males, mean age 49 ...+/- 10 yr) with OSAS (respiratory disturbance index RDI > 10 events/h) in whom clinically significant lung or cardiac diseases were excluded. Pulsed Doppler measurements of pulmonary hemodynamics, pulmonary function tests, arterial blood gas analysis, and polysomnography were performed. A total of 11 OSAS patients (41%) were found to have pulmonary hypertension. The levels of PH were relatively mild (Ppa < or = 26 mm Hg). There were no differences between PH and non-PH patients in body mass index (BMI), smoking history, or lung function. PH patients were more hypoxemic when awake than non-PH patients (PaO2 = 72.2 +/- 7.6 versus 77.6 +/- 7.3 mm Hg, respectively; p < 0.05) but did not differ in severity of sleep apnea (RDI = 51.9 +/- 25.1 versus 56.8 +/- 26.2 events/h, respectively; p = NS) or indices of sleep desaturation. The hypoxemia in PH patients could not be explained by impairment of lung function, greater body mass, or a higher prevalence of smoking, and PaO2 in the study population was significantly correlated with Ppa (r = -0.46, p < 0.02) but not with FEV1 or BMI. We conclude that lung disease is not a prerequisite for PH in OSAS.
Changes in sleep posture have been shown to improve obstructive sleep apnea (OSA). To investigate the mechanisms by which this occurs we assessed upper airway stability in eight patients with severe ...OSA in three postures (supine, elevated to 30 degrees, and lateral). We used a specially adapted nasal continuous positive airway pressure (nCPAP) mask to measure upper airway closing pressure (UACP) and upper airway opening pressure (UAOP) during non-REM sleep. Statistical comparisons were made between postures using ANOVA for repeated measures. Elevation resulted in a less collapsible airway compared with both the supine and lateral positions (mean UACP: 30 degrees elevation -4.0 +/- 3.2 compared with supine 0.3 +/- 2.4 cm H2O, p < 0.05 and; lateral -1.1 +/- 2.2 cm H2O, p < 0.05). Supine UACP and lateral UACP were not significantly different. Elevation or lateral positioning produced a 50% reduction in mean UAOP (supine 10.4 +/- 3.5 cm H2O compared with 30 degrees elevation 5.3 +/- 2.1, p < 0.05; and lateral 5.5 +/- 2.1 cm H2O, p < 0.05). We conclude that in severely affected OSA patients upper body elevation, and to a lesser extent lateral positioning, significantly improve upper airway stability during sleep, and may allow therapeutic levels of nCPAP to be substantially reduced.
PDF
