Modification of bronchial reactivity by physiological concentrations of plasma epinephrine

1992 ◽  
Vol 73 (3) ◽  
pp. 1004-1007 ◽  
Author(s):  
A. J. Knox ◽  
H. Campos-Gongora ◽  
A. Wisniewski ◽  
I. A. MacDonald ◽  
A. E. Tattersfield
Keyword(s):  
Geometric Mean ◽  
Plasma Concentrations ◽  
Challenge Test ◽  
Forced Expiratory Volume ◽  
Bronchial Reactivity ◽  
Plasma Epinephrine ◽  
Double Blind ◽  
Bronchial Responsiveness ◽  
Mean Values ◽  
Epinephrine Concentration

Circulating epinephrine concentrations are altered in certain pathophysiological states, but whether such changes in epinephrine concentrations can alter bronchial responsiveness in subjects with asthma has not been studied. We studied 10 subjects with asthma in a double-blind crossover study on 4 nonconsecutive days. After measurement of baseline forced expiratory volume in 1 s (FEV1) and plasma epinephrine concentration, subjects were given placebo or 4, 16, or 64 ng.kg-1.min-1 epinephrine by intravenous infusion for 45 min. Blood was taken for plasma epinephrine concentration before the infusion and at 30 min, when a histamine challenge test was performed. Mean plasma epinephrine concentrations ranged from 0.37 nmol/l on placebo to 3.76 nmol/l with the 64-ng/kg infusion. FEV1 increased progressively with increasing concentrations of infused epinephrine, the mean change ranging from -0.051 on placebo to 0.331 after the highest concentration of epinephrine. The provocative dose of histamine causing a 20% fall in FEV1 increased progressively with increasing concentrations of infused epinephrine, geometric mean values ranging from 0.61 mumol with placebo to 1.7 mumol after the highest dose of epinephrine. Thus epinephrine, at physiological plasma concentrations, can modify bronchial reactivity.

Effect of thromboxane A2-receptor antagonist on bradykinin-induced bronchoconstriction in asthma

1996 ◽  
Vol 80 (6) ◽  
pp. 1973-1977 ◽  
Author(s):  
K. Rajakulasingam ◽  
S. L. Johnston ◽  
J. Ducey ◽  
W. Ritter ◽  
P. H. Howarth ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Geometric Mean ◽  
Thromboxane A2 ◽  
Forced Expiratory Volume ◽  
Significant Inhibition ◽  
Prostaglandin D2 ◽  
Double Blind ◽  
Bronchial Responsiveness ◽  
Significant Difference ◽  
Txa2 Receptor

The role of the thromboxane A2 (TxA2) receptor in bradykinin-induced bronchial responses was investigated in this study by using a selective and potent TxA2-receptor antagonist BAY u 3405. Eleven asthmatic subjects were randomized to receive 50 mg of BAY u 3405 or matched placebo in a crossover and double-blind fashion. Ninety minutes after dosing, serum was taken for drug assay, and subjects underwent provocation with bradykinin or prostaglandin D2 (PGD2) to determine bronchial responsiveness [provocative concentration of agonist required to produce a 20% fall in forced expiratory volume in 1 s from the postdiluent baseline (PC20)]. Pretreatment with BAY u 3405 caused a twofold doubling-dilution reduction in bronchial reactivity to PGD2; the geometric mean PC20 values were 0.132 (0.015-0.871) and 0.034 (0.008-0.095) mg/ml, respectively, for active and placebo days (P = 0.001). There was, however, no significant difference in PC20 values for bradykinin between active and placebo treatment days. We have demonstrated that BAY u 3405 caused a significant inhibition of bronchconstriction induced by inhaled PGD2 but had no influence on bronchial responsiveness to inhaled bradykinin. This study suggests therefore that TxA2 receptors do not play a role in bradykinin-induced bronchoconstriction in asthma.

Effect of Vasopressin on Bronchial Reactivity to Histamine

1989 ◽  
Vol 77 (5) ◽  
pp. 467-471
Author(s):  
Alan J. Knox ◽  
John R. Britton ◽  
Anne E. Tattersfield
Keyword(s):  
Salt Intake ◽  
Plasma Concentrations ◽  
Normal Subjects ◽  
Underlying Mechanism ◽  
Forced Expiratory Volume ◽  
Bronchial Reactivity ◽  
Dietary Salt ◽  
Double Blind ◽  
Dietary Salt Intake ◽  
Significant Difference

1. Recent evidence suggests that a high salt diet increases bronchial reactivity, but the underlying mechanism is unclear. 2. To determine whether alterations in circulating vasopressin might be responsible, we have studied the effect of an infusion of vasopressin on the airways of six normal and eight asthmatic subjects measuring the response as expiratory flow at 30% of vital capacity (V̇30P) in the normal subjects and as forced expiratory volume in 1s (FEV1) in the asthmatic subjects, in a double-blind, placebo-controlled, cross-over study. 3. Vasopressin, given as an infusion at a rate of 2 i.u./h for 1 h, followed by 4 i.u./h for a further hour, produced plasma concentrations of 12.8 and 17 ng/l, respectively, compared with 2.0 and 2.0 ng/l on placebo. 4. Airway reactivity to histamine was measured after 1 and 2 h as the provocative doses of histamine causing a 40% reduction in V̇30P (PD40V̇30P) in the normal subjects and a 20% reduction in FEV1 (PD20FEV1) in the asthmatic subjects. 5. There was a small increase in PD40V̇30P after both vasopressin and placebo in normal subjects (refractoriness) but no change in PD20FEV1 in the asthmatic subjects. 6. There was no significant difference between vasopressin and placebo in V̇30P or PD40 V̇30P over the 2 h after the drug in the normal subjects or in FEV1 or PD20FEV1 over the 2 h after the drug in the asthmatic subjects. 7. We conclude that alterations in circulating vasopressin are unlikely to be responsible for the increase in bronchial reactivity when dietary salt intake is increased.

Dose-response relationship between plasma epinephrine concentration and alveolar liquid clearance in dogs

1998 ◽  
Vol 85 (5) ◽  
pp. 1702-1707 ◽  
Author(s):  
Michael B. Maron
Keyword(s):  
Dose Response ◽  
Respir Crit ◽  
Plasma Concentrations ◽  
Neurogenic Pulmonary Edema ◽  
Response Relationship ◽  
Plasma Epinephrine ◽  
Dose Response Relationship ◽  
Alveolar Liquid Clearance ◽  
Epinephrine Concentration ◽  
Alveolar Liquid

Previously, alveolar liquid clearance (ALC) was observed to increase in a canine model of neurogenic pulmonary edema (NPE) by adrenal epinephrine (S. M. Lane, K. C. Maender, N. E. Awender, and M. B. Maron. Am. J. Respir. Crit. Care Med. 158: 760–768, 1998). In this study the dose-response relationship between plasma epinephrine concentration and ALC was determined in anesthetized dogs by infusing epinephrine to produce plasma concentrations of 256 ± 37, 1,387 ± 51, 15,737 ± 2,161, and 363,997 ± 66,984 (SE) pg/ml ( n = 6 for each concentration) for 4 h and measuring the resultant ALC. The latter was determined by mass balance after instillation of autologous plasma into a lower lung lobe. These plasma concentrations produced ALCs of 14.3 ± 1.2, 20.5 ± 1.9, 30.1 ± 1.5, and 37.9 ± 2.7% of the instilled volume, respectively. ALC after the lowest infusion rate was not different from that previously observed under baseline conditions (14.1 ± 2.1%), whereas in a previous study of NPE, plasma epinephrine concentration increased to 7,683 ± 687 pg/ml and ALC was 30.4 ± 1.6%. These data indicate that, during recovery from canine NPE, ALC is not maximally stimulated and suggest that it might be possible to pharmacologically produce further increases in the rate of resolution of this form of edema.

Effect of Sodium-Transport Inhibitors on Bronchial Reactivity in Vivo

1990 ◽  
Vol 79 (4) ◽  
pp. 325-330 ◽  
Author(s):  
Alan J. Knox ◽  
John R. Britton ◽  
Anne E. Tattersfield
Keyword(s):  
Confidence Intervals ◽  
Sodium Transport ◽  
Geometric Mean ◽  
Normal Subjects ◽  
Bronchial Reactivity ◽  
Mean Values ◽  
Doubling Dose ◽  
The Difference

1. We have recently shown that ouabain, an inhibitor of Na+/K+-adenosine triphosphatase, causes contraction of bovine and human airways in vitro, and that amiloride causes relaxation and inhibits receptor-operated contraction in bovine trachealis. 2. To determine whether such drugs alter bronchial reactivity in vivo, we have studied the effect of oral digoxin (an inhibitor of Na+/K+-adenosine triphosphatase) and oral and inhaled amiloride on bronchial reactivity to histamine in three double-blind, placebo-controlled studies. 3. Histamine reactivity was measured as the provocative dose causing a 20% reduction in the forced expiratory volume in 1 s (PD20FEV1) or, when normal subjects were included, the provocative dose causing a 35% reduction in the specific airways conductance (PD35sGaw); the results are given as geometric mean values. 4. In study 1, 13 atopic asthmatic subjects were given 20 mg of oral amiloride or placebo on separate days. Two hours after the drug, the geometric mean PD20FEV1 for histamine was 0.43 μmol after amiloride and 0.54 μmol after placebo (95% confidence intervals for the difference: 0.9 to −0.2 doubling doses of histamine; P = 0.2). 5. In study 2, six normal and 24 atopic asthmatic men inhaled 10 ml of 10−2 mol/l amiloride or diluent control in a crossover study. The mean values of PD35sGaw for histamine immediately after inhalation of amiloride and placebo were 3.0 μmol and 4.3 μmol, respectively, in the normal subjects (95% confidence intervals for the difference: −0.53 to 1.52 doubling doses, P = 0.2), and 0.33 μmol and 0.29 μmol in the asthmatic subjects (95% confidence intervals for the difference: −0.95 to 0.57 doubling doses; P = 0.6). 6. In study 3, 24 atopic asthmatic men were treated for 7 days with placebo or oral digoxin (1.5 mg loading dose plus 0.25 mg twice daily for 6 days). The PD20FEV1 for histamine was measured before, 12 h after the loading dose and on day 7 of treatment. The change in PD20FEV1 did not differ significantly after digoxin and placebo, after either 1 day's treatment [mean (95% confidence intervals) difference: 0.56 doubling dose (−0.37 to 1.5 doubling dose)] or 7 day's treatment [mean (95% confidence intervals) difference: 0.3 doubling dose (−1.23 to 1.8 doubling doses)]. 7. Although our work in vitro has suggested that membrane sodium transport may play an important role in determining airway smooth muscle contractility, we have been unable to demonstrate any effect of the sodium-transport inhibitors amiloride and digoxin on histamine reactivity in these studies.

Does baseline airway caliber affect measurements of airway responsiveness to histamine

1993 ◽  
Vol 74 (6) ◽  
pp. 3034-3039 ◽  
Author(s):  
O. P. Twentyman ◽  
S. V. Hood ◽  
S. T. Holgate
Keyword(s):  
Time Course ◽  
Geometric Mean ◽  
Forced Expiratory Volume ◽  
Airway Responsiveness ◽  
Bronchial Responsiveness ◽  
Subsequent Response ◽  
Airway Caliber ◽  
Before And After ◽  
Airway Response ◽  
Considerable Controversy

Considerable controversy exists over the influence of baseline airway caliber on indexes of bronchial responsiveness in asthma. To directly investigate this, we used inhaled methacholine to alter baseline airway caliber to determine whether this altered the airway response to subsequent bronchoprovocation with inhaled histamine. Seventeen stable asthmatic subjects were studied; their median age was 22 yr, baseline forced expiratory volume in 1 s (FEV1) was 101.5 +/- 3.7% (SE) predicted, and geometric mean provocative concentration of inhaled methacholine causing a 20% fall in FEV1 (PC20) was 0.87 mg/ml. Initially the time course of bronchoconstriction to inhaled methacholine was determined. Subsequently the airway response to inhaled histamine administered as a single concentration was determined, both before and after reductions in baseline FEV1 by saline or methacholine of 0, 15, 25, and 35%, on 4 separate days. Altering baseline airway caliber had no effect on the subsequent response of the airways to inhaled histamine when calculated as percent fall from the new baseline. The power of the study to detect an effect of altering baseline FEV1 on the measured PC20 histamine of 0.5 doubling dilutions was > 55%, and the power to detect an effect of 1.0 doubling dilutions was > 98%.

scholarly journals First Assessment in Humans of the Safety, Tolerability, Pharmacokinetics, and Ex Vivo Pharmacodynamic Antimalarial Activity of the New Artemisinin Derivative Artemisone

2008 ◽  
Vol 52 (9) ◽  
pp. 3085-3091 ◽  
Author(s):  
Johannes Nagelschmitz ◽  
Barbara Voith ◽  
Georg Wensing ◽  
Axel Roemer ◽  
Burkhard Fugmann ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Ex Vivo ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Artemisinin Derivative ◽  
Active Metabolites ◽  
Multiple Dosing ◽  
Serious Adverse Events ◽  
Double Blind

ABSTRACT In preclinical studies, artemisone (BAY 44-9585), a new artemisinin derivative, was shown to possess enhanced efficacy over artesunate, and it does not possess the neurotoxicity characteristic of the current artemisinins. In a phase I program with double-blind, randomized, placebo-controlled, single and multiple ascending oral-dose studies, we evaluated the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of artemisone. Single doses (10, 20, 30, 40, and 80 mg) and multiple doses (40 and 80 mg daily for 3 days) of artemisone were administered orally to healthy subjects. Plasma concentrations of artemisone and its metabolites were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS). Artemisone was well tolerated, with no serious adverse events and no clinically relevant changes in laboratory and vital parameters. The pharmacokinetics of artemisone over the 10- to 80-mg range demonstrated dose linearity. After the single 80-mg dose, artemisone had a geometric mean maximum concentration of 140.2 ng/ml (range, 86.6 to 391.0), a short elimination half-life (t 1/2) of 2.79 h (range, 1.56 to 4.88), a high oral clearance of 284.1 liters/h (range, 106.7 to 546.7), and a large volume of distribution of 14.50 liters/kg (range, 3.21 to 51.58). Due to artemisone's short t 1/2, its pharmacokinetics were comparable after single and multiple dosing. Plasma samples taken after multiple dosing showed marked ex vivo pharmacodynamic antimalarial activities against two multidrug-resistant Plasmodium falciparum lines. Artemisone equivalent concentrations measured by bioassay revealed higher activity than artemisone measured by LC/MS-MS, confirming the presence of active metabolites. Comparable to those of other artemisinin's, artemisone's t 1/2 is well suited for artemisinin-based combination therapy for the treatment of P. falciparum malaria.

scholarly journals Randomised, double-blind, placebo-controlled pilot trial of omeprazole in idiopathic pulmonary fibrosis

Thorax ◽  
2019 ◽  
Vol 74 (4) ◽  
pp. 346-353 ◽  
Author(s):  
Prosenjit Dutta ◽  
Wendy Funston ◽  
Helen Mossop ◽  
Vicky Ryan ◽  
Rhys Jones ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Controlled Trial ◽  
Geometric Mean ◽  
Pilot Trial ◽  
Acid Reflux ◽  
Forced Expiratory Volume ◽  
Double Blind ◽  
Cough Frequency ◽  
Randomised Controlled

BackgroundCough is a common, disabling symptom of idiopathic pulmonary fibrosis (IPF), which may be exacerbated by acid reflux. Inhibiting gastric acid secretion could potentially reduce cough. This study aimed to determine the feasibility of a larger, multicentre trial of omeprazole for cough in IPF, to assess safety and to quantify cough.MethodsSingle-centre, double-blind, randomised, placebo-controlled pilot trial of the proton pump inhibitor (PPI) omeprazole (20 mg twice daily for 3 months) in patients with IPF. Primary objectives were to assess feasibility and acceptability of trial procedures. The primary clinical outcome was cough frequency.ResultsForty-five participants were randomised (23 to omeprazole, 22 to placebo), with 40 (20 in each group) having cough monitoring before and after treatment. 280 patients were screened to yield these numbers, with barriers to discontinuing antacids the single biggest reason for non-recruitment. Recruitment averaged 1.5 participants per month. Geometric mean cough frequency at the end of treatment, adjusted for baseline, was 39.1% lower (95% CI 66.0% lower to 9.3% higher) in the omeprazole group compared with placebo. Omeprazole was well tolerated and adverse event profiles were similar in both groups, although there was a small excess of lower respiratory tract infection and a small fall in forced expiratory volume and forced vital capacity associated with omeprazole.ConclusionsA large randomised controlled trial of PPIs for cough in IPF appears feasible and justified but should address barriers to randomisation and incorporate safety assessments in relation to respiratory infection and changes in lung function.

Safety, Tolerability, and Pharmacokinetics of Telacebec (Q203), a New Antituberculosis Agent, in Healthy Subjects

2021 ◽  
Author(s):  
Jeongjun Kim ◽  
Jinho Choi ◽  
Hwankyu Kang ◽  
Jiye Ahn ◽  
Jane Hutchings ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Drug Candidate ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Time Curve ◽  
Exponential Decline ◽  
Potent Drug

Telacebec (Q203) is a potent drug candidate under clinical development for the treatment of drug-naïve and drug-resistant tuberculosis. The first-in-human randomized, placebo-controlled, double-blind, dose-escalation Phase 1A trial (Q203-TB-PI-US001) was conducted to evaluate the safety, tolerability, and pharmacokinetics of telacebec. A total of 56 normal, healthy, male and female subjects (42 active and 14 placebo) were enrolled in the study. The doses of telacebec were 10 mg (Cohort 1), 30 mg (Cohort 2), 50 mg (Cohort 3), 100 mg (Cohort 4), 200 mg (Cohort 5), 400 mg (Cohort 6), and 800 mg (Cohort 7) in a fasted state. Subjects participating in Cohort 4 were also enrolled in Cohort 8 to investigate the food effect on the pharmacokinetics of telacebec after a high-fat meal. In all subjects dosed with telacebec (10 – 800 mg), telacebec was well tolerated and did not lead to any significant or serious adverse events. Following a single oral administration of telacebec (10 – 800 mg), telacebec plasma concentration reached the maximal plasma concentration (C max ) in average 2.0 – 3.5 h and showed multi-exponential decline thereafter. The area under the plasma concentration vs. time curve (AUC) was approximately dose-proportional. A significant increase in plasma concentrations was observed in the fed condition compared with the fasted condition with the geometric mean ratio of 3.93 for C max . Moderate delay in T max (4.5 h) was also observed in the fed condition. These results, combined with the demonstrated activity against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis , support further investigation of telacebec for the treatment of tuberculosis.

Effect of infusing epinephrine on liver and muscle glycogenolysis during exercise in rats

1986 ◽  
Vol 250 (6) ◽  
pp. E641-E649 ◽  
Author(s):  
D. A. Arnall ◽  
J. C. Marker ◽  
R. K. Conlee ◽  
W. W. Winder
Keyword(s):  
Muscle Glycogen ◽  
Vastus Lateralis ◽  
Plasma Concentrations ◽  
Physiological Saline ◽  
Threshold Concentration ◽  
Plasma Epinephrine ◽  
Glycogen Depletion ◽  
Epinephrine Infusion ◽  
Liver Glycogenolysis ◽  
Epinephrine Concentration

To determine the possibility of a threshold concentration of plasma epinephrine that stimulates liver glycogenolysis during exercise, adrenodemedullated (ADM) and sham-operated (SHAM) rats were infused with saline or epinephrine at rates that produced plasma concentrations ranging between 0.01 ng/ml (0.06 nM) and 4.3 ng/ml (23.7 nM). During the infusion rats were run on a rodent treadmill for 0, 30, or 60 min at 21 m/min up a 15% grade. Liver glycogen decreased at similar rates in all exercising rats regardless of plasma epinephrine concentration. Epinephrine infusion stimulated significant muscle glycogen depletion in the soleus and red and white vastus lateralis muscles. ADM saline-infused animals exhibited the least muscle glycogen depletion. Blood glucose and lactate in exercising ADM rats increased as the epinephrine infusion concentration increased. During exercise, there was no epinephrine concentration that stimulated liver glycogenolysis more effectively than physiological saline.

Combined Intravenous Lidocaine and Inhaled Salbutamol Protect against Bronchial Hyperreactivity More Effectively than Lidocaine or Salbutamol Alone 

1998 ◽  
Vol 89 (4) ◽  
pp. 862-868 ◽  
Author(s):  
Harald Groeben ◽  
Marie-Theres Silvanus ◽  
Mechthild Beste ◽  
Jurgen Peters
Keyword(s):  
Randomized Study ◽  
Combined Treatment ◽  
Plasma Concentrations ◽  
Animal Experiments ◽  
Forced Expiratory Volume ◽  
Bronchial Hyperreactivity ◽  
Placebo Control ◽  
Intravenous Lidocaine ◽  
Double Blind ◽  
Airway Irritation

Background Airway instrumentation in persons with asthma is linked to the risk of life-threatening bronchospasm. To attenuate the response to airway irritation, intravenous lidocaine is recommended (based on animal experiments) and mitigates the response to histamine inhalation in asthmatic volunteers. However, the effects of lidocaine have not been compared with standard prophylaxis with beta-sympathomimetic aerosols. Therefore, the effect of lidocaine, salbutamol, combined treatment, and placebo control were tested in awake volunteers with bronchial hyperreactivity. Methods After approval from the local ethics committee, 15 persons, who were selected because they showed a decrease in forced expiratory volume in 1 s (FEV1) more than 20% of baseline in response to inhaled histamine in a concentration less than 18 mg/ml (PC20), were enrolled in a placebo-controlled, double-blind, and randomized study. The challenge was repeated on four different days and the volunteers were pretreated with either intravenous lidocaine, inhalation of salbutamol, inhalation of salbutamol plus intravenous lidocaine, or placebo. Lidocaine plasma concentrations were also measured. Statistical analyses included the Friedman test and Wilcoxon's rank sum. Results The baseline PC20 was 6.4 +/- 4.3 mg/ml. Intravenous lidocaine and salbutamol aerosol both significantly increased the histamine threshold to 14.2 +/- 9.5 mg/ml and 16.8 +/- 10.9 mg/ml, respectively (mean +/- SD). However, the combination of lidocaine and salbutamol significantly increased the PC20 even further to 30.7 +/- 15.7 mg/ml than did salbutamol or lidocaine alone. Conclusions In volunteers with bronchial hyperreactivity, both lidocaine and salbutamol attenuate the response to an inhalational histamine challenge, and their combined administration has much greater effects than does either drug alone. Accordingly, pretreatment of patients with bronchial hyperreactivity with both beta-mimetic aerosol and intravenous lidocaine is recommended before airway irritation.

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