Effect of clonidine on induced cough and bronchoconstriction in guinea pigs and healthy humans

1994 ◽  
Vol 76 (3) ◽  
pp. 1082-1087 ◽  
Author(s):  
F. O′Connell ◽  
V. E. Thomas ◽  
R. W. Fuller ◽  
N. B. Pride ◽  
J. A. Karlsson
Keyword(s):  
Citric Acid ◽  
Guinea Pigs ◽  
Human Subjects ◽  
Inhibitory Effect ◽  
Healthy Human ◽  
Oral Clonidine ◽  
Healthy Humans ◽  
Human Volunteers ◽  
Dependent Inhibition ◽  
Time To Onset

We examined the effects of the alpha 2-receptor agonist clonidine, administered orally and by inhalation, on citric acid- and capsaicin-induced reflexes in guinea pigs and healthy human subjects. In groups (n = 8-10) of conscious guinea pigs, oral clonidine (10 and 100 micrograms/kg) was without effects, whereas inhaled clonidine (10–1,000 microM) caused a concentration-dependent inhibition of citric acid-induced cough (coughs during 3 min: control, 6.5 +/- 0.9; 1,000 microM clonidine, 1.7 +/- 1.0; P < 0.05) and reflex bronchoconstriction (time to onset of bronchoconstriction: control, 191 +/- 24 s; 1,000 microM clonidine, 317 +/- 33 s; P < 0.05). The inhibitory effect of inhaled clonidine on both reflexes was completely reversed by pretreatment with yohimbine but not with prazosin. In 12 healthy human volunteers, oral clonidine (150 mg) caused a significant fall in supine and erect systolic blood pressure and a significant increase in drowsiness as measured on a visual analogue scale 1 and 2 h after administration. Despite these effects, oral clonidine had no effect on capsaicin-induced cough or reflex bronchoconstriction in humans. In contrast to the effects in guinea pigs, inhaled clonidine (281 microM) had no effect on capsaicin-induced cough or reflex bronchoconstriction in humans. These data suggest that peripheral alpha 2-receptors exert an inhibitory effect on sensory neurotransmission in the guinea pig but not in the healthy human airway, indicating an important difference between the two species.

scholarly journals BIMG-13. A NOVEL RADIOPHARMACEUTICAL ([18F]DASA-23) TO MONITOR PYRUVATE KINASE M2 INDUCED GLYCOLYTIC REPROGRAMMING IN GLIOBLASTOMA

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i3-i4
Author(s):  
Corinne Beinat ◽  
Chirag Patel ◽  
Tom Haywood ◽  
Surya Murty ◽  
Lewis Naya ◽  
...  
Keyword(s):  
Cell Culture ◽  
Pyruvate Kinase ◽  
Cancer Metabolism ◽  
Human Subjects ◽  
Normal Brain ◽  
Healthy Human ◽  
Pyruvate Kinase M2 ◽  
Molar Activity ◽  
Pet Tracer ◽  
Human Volunteers

Abstract BACKGROUND Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain, making it an important biomarker of cancer glycolytic re-programming. We describe the bench-to-bedside development, validation, and translation of a novel positron emission tomography (PET) tracer to study PKM2 in GBM. Specifically, we evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and GBM patients. METHODS [18F]DASA-23 was synthesized with a molar activity of 100.47 ± 29.58 GBq/µmol and radiochemical purity &gt;95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next we produced [18F]DASA-23 under current Good Manufacturing Practices United States Food and Drug Administration (FDA) oversight, and evaluated it in healthy volunteers and a pilot cohort of patients with gliomas. RESULTS In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from the surrounding healthy brain tissue and had a tumor-to-brain ratio (TBR) of 3.6 ± 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood-brain barrier and was rapidly cleared. In GBM patients, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced magnetic resonance imaging (MRI). The uptake of [18F]DASA-23 was markedly elevated in GBMs compared to normal brain, and it was able to identify a metabolic non-responder within 1-week of treatment initiation. CONCLUSION We developed and translated [18F]DASA-23 as a promising new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These encouraging results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy-induced normalization of aberrant cancer metabolism.

Selective effects of serotonergic psychoactive agents on gastrointestinal functions in health

2003 ◽  
Vol 284 (1) ◽  
pp. G130-G137 ◽  
Author(s):  
Heather J. Chial ◽  
Michael Camilleri ◽  
Duane Burton ◽  
George Thomforde ◽  
Kevin W. Olden ◽  
...  
Keyword(s):  
Reuptake Inhibitor ◽  
Human Subjects ◽  
Functional Gastrointestinal Disorders ◽  
Gastric Volume ◽  
Colonic Transit ◽  
Selective Serotonin ◽  
Healthy Human ◽  
Double Blind ◽  
Solid Meal ◽  
Healthy Humans

This study evaluated the effects of serotonergic psychoactive agents on gastrointestinal functions in healthy human subjects. Participants received one of four regimens in a randomized, double-blind manner: buspirone, a 5-HT1Areceptor agonist (10 mg twice daily); paroxetine, a selective serotonin reuptake inhibitor (20 mg daily); venlafaxine-XR, a selective serotonin and norepinephrine reuptake inhibitor (75 mg daily); or placebo for 11 days. Physiological testing performed on days 8–11included scintigraphic assessment of gastrointestinal and colonic transit, the nutrient drink test, and assessment of the postprandial change in gastric volume. Fifty-one healthy adults (40 females, 11 males) participated in this study. No effects on gastric emptying or colonic transit were identified with any agent. Small bowel transit of a solid meal was accelerated by paroxetine. Buspirone decreased postprandial aggregate symptom and nausea scores. Venlafaxine-XR increased the postprandial change in gastric volume. Buspirone, paroxetine, and venlafaxine-XR affect upper gastrointestinal functions in healthy humans. These data support the need for clinical and physiological studies of these agents in functional gastrointestinal disorders.

Time course of ozone-induced changes in breathing pattern in healthy exercising humans

2007 ◽  
Vol 102 (2) ◽  
pp. 688-697 ◽  
Author(s):  
Edward S. Schelegle ◽  
William F. Walby ◽  
William C. Adams
Keyword(s):  
Time Course ◽  
Breathing Pattern ◽  
Human Subjects ◽  
Minute Ventilation ◽  
Cumulative Exposure ◽  
Healthy Human ◽  
Percent Change ◽  
Atropine Treatment ◽  
Induced Changes ◽  
Time To Onset

We examined the time course of O3-induced changes in breathing pattern in 97 healthy human subjects (70 men and 27 women). One- to five-minute averages of breathing frequency (fB) and minute ventilation (V̇e) were used to generate plots of cumulative breaths and cumulative exposure volume vs. time and cumulative exposure volume vs. cumulative breaths. Analysis revealed a three-phase response; delay, no response detected; onset, fB began to increase; response, fB stabilized. Regression analysis was used to identify four parameters: time to onset, number of breaths at onset, cumulative inhaled dose of ozone at onset of O3-induced tachypnea, and the percent change in fB. The effect of altering O3 concentration, V̇e, atropine treatment, and indomethacin treatment were examined. We found that the lower the O3 concentration, the greater the number of breaths at onset of tachypnea at a fixed ventilation, whereas number of breaths at onset of tachypnea remains unchanged when V̇e is altered and O3 concentration is fixed. The cumulative inhaled dose of O3 at onset of tachypnea remained constant and showed no relationship with the magnitude of percent change in fB. Atropine did not affect any of the derived parameters, whereas indomethacin did not affect time to onset, number of breaths at onset, or cumulative inhaled dose of O3 at onset of tachypnea but did attenuate percent change in fB. The results are discussed in the context of dose response and intrinsic mechanisms of action.

Capsazepine inhibits cough induced by capsaicin and citric acid but not by hypertonic saline in guinea pigs

1995 ◽  
Vol 79 (4) ◽  
pp. 1082-1087 ◽  
Author(s):  
U. G. Lalloo ◽  
A. J. Fox ◽  
M. G. Belvisi ◽  
K. F. Chung ◽  
P. J. Barnes
Keyword(s):  
Citric Acid ◽  
Hypertonic Saline ◽  
Guinea Pigs ◽  
Specific Inhibitor ◽  
Inhibitory Effect ◽  
Sensory Nerves ◽  
Cough Reflex ◽  
Acidic Solutions ◽  
Nasal Irritation ◽  
Cough Response

Acidic solutions mimick many of the effects of capsaicin (Cap), including pain, bronchoconstriction, cough, and sensory neuropeptide release. Evidence from the use of the Cap antagonist capsazepine suggests that in some cases protons act at the Cap receptor. In the present study, we have investigated whether cough evoked by Cap and citric acid (CA) is mediated specifically via the Cap receptor on airway sensory nerves. We have examined the effects of capsazepine on Cap-, CA-, and hypertonic saline-induced cough and also on CA-induced nasal irritation in awake guinea pigs. Capsazepine was nebulized for 5 min before cough challenges with Cap for 5 min and CA for 10 min. Control animals were pretreated with vehicle alone. Capsazepine (100 microM) inhibited the cough response to 30 microM Cap from 0.77 +/- 0.14 coughs/min in control animals to 0.23 +/- 0.08 coughs/min (P < 0.05) and to 80 microM Cap from 1.4 +/- 0.23 to 0.3 +/- 0.11 coughs/min (P < 0.01). There was no effect, however, of lower concentrations of capsazepine (5 and 10 microM) against Cap-evoked cough. At a concentration of 100 microM, capsazepine also inhibited the coughing induced by 0.25 M CA from 1.8 +/- 0.26 to 0.93 +/- 0.31 coughs/min (P < 0.05) but not that induced by 0.5 M CA. Nasal irritation induced by 0.25 M CA, but not by 0.5 M CA, was also inhibited by capsazepine from 2.47 +/- 0.37 to 0.75 +/- 0.31 nose wipes/min (P < 0.05). This inhibitory effect of capsazepine did not appear to reflect a nonspecific suppression of the cough reflex, since cough evoked by exposure to hypertonic (7%) saline for 10 min was unaffected by pretreatment with capsazepine (100 microM). These data show that capsazepine is a specific inhibitor of Cap- and CA-induced cough in guinea pigs. Moreover, they suggest that low pH stimuli evoke cough and nasal irritation by an action at the Cap receptor, either directly or through the release of an intermediate agent.

The inhibitory effect of GLP-1 on food intake is augmented by gastric distension in healthy human subjects

2000 ◽  
Vol 118 (4) ◽  
pp. A74-A75 ◽  
Author(s):  
Daniel Matzinger ◽  
Lukas Degen ◽  
Markus Knupp ◽  
Christoph Beglinger
Keyword(s):  
Food Intake ◽  
Human Subjects ◽  
Inhibitory Effect ◽  
Gastric Distension ◽  
Healthy Human ◽  
Healthy Human Subjects

Interactions Between Ethanol and Dietary Fat in Determining Human Platelet Function

1984 ◽  
Vol 51 (01) ◽  
pp. 050-053 ◽  
Author(s):  
Christopher G Fenn ◽  
John M Littleton
Keyword(s):  
Platelet Aggregation ◽  
Dietary Fat ◽  
Saturated Fat ◽  
Inhibitory Effect ◽  
White Wine ◽  
Healthy Human ◽  
Saturated Fats ◽  
Human Volunteers ◽  
Before And After

SummaryPlatelet aggregation to collagen and ADP in vitro was assessed in the plasma of healthy human volunteers both before and after drinking 700 ml of white wine. This had no effect on platelet aggregation when compared with samples from the same individuals taken on a separate occasion without alcohol consumption. However, when alcohol was taken with a meal high in saturated fat, a significant inhibitory effect on platelet aggregation was observed when compared to the effect of the meal alone. There was no such interaction when the meal associated with alcohol ingestion contained mainly unsaturated fats. The fatty acid composition of plasma and platelet membranes from these volunteers showed a significantly increased proportion of saturated fats after the saturated fat meal. The concomitant ingestion of ethanol did not prevent this change. The concentration of alcohol in plasma achieved (c. 25 mM) may directly inhibit platelet aggregation when the platelet membrane content of saturated fats is high.

scholarly journals Oxyphytosterols are present in plasma of healthy human subjects

2004 ◽  
Vol 91 (1) ◽  
pp. 101-106 ◽  
Author(s):  
André Grandgirard ◽  
Lucy Martine ◽  
Luc Demaison ◽  
Catherine Cordelet ◽  
Corinne Joffre ◽  
...  
Keyword(s):  
Human Subjects ◽  
Plasma Samples ◽  
Healthy Human ◽  
Human Samples ◽  
Human Volunteers ◽  
Healthy Human Subjects ◽  
Few Data ◽  
Derivatives Of

The oxidised derivatives of phytosterols (oxyphytosterols) were identified in plasma samples from thirteen healthy human volunteers, using MS. All the samples contained noticeable quantities of (24R)-5β,6β-epoxy-24-ethylcholestan-3β-ol (β-epoxysitostanol) and (24R)-ethylcholestan-3β,5α,6β-triol (sitostanetriol) and also trace levels of (24R)-5α,6α-epoxy-24-ethylcholestan-3β-ol (α-epoxysitostanol), (24R)-methylcholestan-3β,5α,6β-triol (campestanetriol) and (24R)-ethylch olest-5-en-3β-ol-7-one(7-ketositosterol). The amounts of these oxyphytosterols in plasma varied from 4·8 to 57·2 ng/ml. There are two possibilities concerning the origin of these compounds. First, they could come from the small amounts of oxyphytosterols in food. Second, they could originate from the in vivo oxidation of phytosterols in plasma. Very few data actually exist concerning these compounds. Their identification in human samples suggests that further research is necessary in this field.

Osmoregulation of thirst and vasopressin secretion in human subjects: effect of various solutes

1983 ◽  
Vol 244 (6) ◽  
pp. E607-E614 ◽  
Author(s):  
R. L. Zerbe ◽  
G. L. Robertson
Keyword(s):  
Hypertonic Saline ◽  
Human Subjects ◽  
Plasma Osmolality ◽  
Detectable Effect ◽  
Healthy Human ◽  
Hypertonic Glucose ◽  
Plasma Vasopressin ◽  
Human Volunteers ◽  
Vasopressin Secretion ◽  
High Degree

Various hypertonic solutions were infused in healthy human volunteers to determine their effect on thirst and vasopressin secretion. Hypertonic saline and mannitol produced prompt and parallel increases in plasma osmolality and vasopressin concentration. For both of these solutes, there was a high degree of correlation between these measurements. The slope describing this relationship varied considerably between individuals, but the same subjects showed similar slopes with either saline or mannitol. Both solutions stimulated thirst. Hypertonic urea infusions produced a comparable rise in osmolality but produced a smaller increase in plasma vasopressin and stimulated thirst in only one of the subjects. With urea, the correlation between plasma osmolality and vasopressin was significantly lower. Within individuals, the slope describing this relationship was significantly correlated with that seen during hypertonic saline. Hypertonic glucose significantly increased plasma osmolality but decreased plasma vasopressin and had no detectable effect on thirst. We conclude that osmoregulation of vasopressin in humans is mediated by a selective osmoreceptor that is located primarily outside of the blood-brain barrier and that individual differences in osmoregulatory sensitivity are not solute specific.

Species-Dependent Inhibition of Platelet Aggregation by Adenosine and Dipyridamole: Paradoxical Potentiation in the Rat

1970 ◽  
Vol 23 (01) ◽  
pp. 129-139 ◽  
Author(s):  
R. B Philp ◽  
B Bishop ◽  
Keyword(s):  
Platelet Aggregation ◽  
Guinea Pig ◽  
Adenosine Receptors ◽  
Guinea Pigs ◽  
Human Subjects ◽  
Adenosine Diphosphate ◽  
Inhibition Of Platelet Aggregation ◽  
Rabbit Platelets ◽  
Dependent Inhibition ◽  
Rat Platelets

SummaryPlatelets of cats, rabbits, guinea pigs, rats and human subjects were aggregated with adenosine diphosphate after having been in contact with adenosine or dipyridamole for 5 to 60 min. The species profiles of both agents were the same. Both inhibited aggregation of human and rabbit platelets and the degree of inhibition increased with the time of contact. Neither inhibited aggregation of cat or guinea-pig platelets and both potentiated the rate and extent of aggregation of rat platelets: the degree of potentiation increased with the time of contact. Some reports on the related effects of adenosine and dipyridamole are reviewed and it is suggested that the effects of dipyridamole might be due to an affinity for adenosine receptors.

scholarly journals Caffeine induces gastric acid secretion via bitter taste signaling in gastric parietal cells

2017 ◽  
Vol 114 (30) ◽  
pp. E6260-E6269 ◽  
Author(s):  
Kathrin Ingrid Liszt ◽  
Jakob Peter Ley ◽  
Barbara Lieder ◽  
Maik Behrens ◽  
Verena Stöger ◽  
...  
Keyword(s):  
Acid Secretion ◽  
Gastric Acid Secretion ◽  
Gastric Acid ◽  
Functional Role ◽  
Bitter Taste ◽  
Human Subjects ◽  
Inhibitory Effect ◽  
Healthy Human ◽  
Healthy Human Subjects ◽  
Gastric Parietal Cells

Caffeine, generally known as a stimulant of gastric acid secretion (GAS), is a bitter-tasting compound that activates several taste type 2 bitter receptors (TAS2Rs). TAS2Rs are expressed in the mouth and in several extraoral sites, e.g., in the gastrointestinal tract, in which their functional role still needs to be clarified. We hypothesized that caffeine evokes effects on GAS by activation of oral and gastric TAS2Rs and demonstrate that caffeine, when administered encapsulated, stimulates GAS, whereas oral administration of a caffeine solution delays GAS in healthy human subjects. Correlation analysis of data obtained from ingestion of the caffeine solution revealed an association between the magnitude of the GAS response and the perceived bitterness, suggesting a functional role of oral TAS2Rs in GAS. Expression of TAS2Rs, including cognate TAS2Rs for caffeine, was shown in human gastric epithelial cells of the corpus/fundus and in HGT-1 cells, a model for the study of GAS. In HGT-1 cells, various bitter compounds as well as caffeine stimulated proton secretion, whereby the caffeine-evoked effect was (i) shown to depend on one of its cognate receptor,TAS2R43,and adenylyl cyclase; and (ii) reduced by homoeriodictyol (HED), a known inhibitor of caffeine’s bitter taste. This inhibitory effect of HED on caffeine-induced GAS was verified in healthy human subjects. These findings (i) demonstrate that bitter taste receptors in the stomach and the oral cavity are involved in the regulation of GAS and (ii) suggest that bitter tastants and bitter-masking compounds could be potentially useful therapeutics to regulate gastric pH.

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