dinoprost and Cough

Twenty-four Quarter Horse and Quarter Horse-cross yearlings were experimentally infected with influenza A virus (Influenza A/equine/Saskatoon/90 [H3N8]) by nebulisation. In a double blind controlled trial the horses were randomly assigned to 3 groups of 8 animals. Group 1 received a placebo, (carrier syrup), Group 2 the labelled dose and Group 3 twice the labelled dose of clenbuterol hydrochloride. All treatments were given per os b.i.d. for 10 days and started on the day of infection. The horses were monitored for clinical signs of influenza infection for 14 days. Bronchoalveolar lavages were performed 4 days prior to, and 5 and 13 days after infection. Cell counts and concentrations of prostaglandin E2 and prostaglandin F2alpha in the lavage fluid were determined. Blood samples for haematology and serology were taken 4 days before, on the day of infection, 5, 9 and 13 days after infection. All horses experienced a typical influenza infection with fever, coughing and secondary bacterial infections with mainly Actinobacillus spp. and Streptococcus spp. There was no statistically or clinically significant effect of treatment with clenbuterol hydrochloride on measured clinical or laboratory parameters within 14 days of infection.

Topics: Adrenergic beta-Agonists; Animals; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Clenbuterol; Cough; Dinoprost; Dinoprostone; Double-Blind Method; Female; Fever; Horse Diseases; Horses; Influenza A virus; Leukocyte Count; Male; Orthomyxoviridae Infections

Prostaglandins have been shown to influence the sensitivity of the cough reflex. To investigate putative mechanisms of this, we examined the effects of inhaled prostaglandins E2 (PGE2) and F2 alpha (PGF2 alpha) on human cough responses elicited by two challenges, low chloride solution and capsaicin, which may activate different neural pathways. Baseline cough challenges were followed after 2 h by five breaths of PGE2, PGF2 alpha, or citric acid as a control. Cough challenges were repeated after 1 min. Potentiation of capsaicin responses occurred after PGE2 (median increase 2 coughs/min, range 0-7, P less than 0.01) and PGF2 alpha (median increase 8 coughs/min, range -3 to 27, P less than 0.01) compared with control. The effect of PGF2 alpha was greater (P less than 0.05) than that of PGE2. Potentiation of low chloride responses also occurred after PGF2 alpha (median increase 7 coughs/2 min, range -1 to 19, P less than 0.01), but effects of PGE2 were insignificant against this challenge (median change -1 coughs/2 min, range -4 to 13). These data suggest that PGE2 and PGF2 alpha have different effects on the sensitivity of the human cough reflex, which may be relevant during airway disease.

Topics: Adolescent; Adult; Capsaicin; Chlorides; Citrates; Citric Acid; Cough; Dinoprost; Dinoprostone; Double-Blind Method; Female; Humans; Male; Nerve Fibers; Reflex

We examined whether inhaled frusemide could reduce the potentiation of capsaicin-induced cough by prostaglandin (PG) F2 alpha. Eight non-smoking normal subjects, after a baseline capsaicin challenge were given inhaled frusemide or saline followed by capsaicin challenge, then PGF2 alpha and finally capsaicin challenge again. PGF2 alpha-induced coughs were reduced after frusemide to 3.6 +/- 1.0 compared with 5.7 +/- 1.2 after saline (P less than 0.05). PGF2 alpha increased capsaicin-induced coughs by 11.1 +/- 3.7 and 7.9 +/- 3.4 after placebo and frusemide, respectively (P less than 0.05). Frusemide had no effect on capsaicin-induced cough alone. Changes in local ionic concentrations by frusemide, particularly chloride ions within the vicinity of epithelial cough receptors, may determine the cough response to low chloride solutions and to PGF2 alpha, but not to capsaicin which acts directly on the cough receptors, and alter the sensitivity of the receptors to capsaicin.

Topics: Administration, Inhalation; Capsaicin; Cough; Dinoprost; Drug Synergism; Furosemide; Humans

The effect of inhaled prostaglandin (PG) F2 alpha on the response to the inhaled tussive agent capsaicin was investigated in normal subjects. Seven subjects inhaled three breaths of four doses of capsaicin (0.3, 0.6, 1.2, and 2.4 nmol) before and immediately after inhaling PGF2 alpha (0.1 mumol) or placebo (0.15M NaCl) on separate days. The numbers of capsaicin induced coughs were greater after PGF2 alpha (mean 42.3 coughs) than after 0.15M sodium chloride (30.1). Visual analogue scores (0-10 on a 10 cm continuous scale) showed that capsaicin was more irritant after PGF2 alpha than after saline. Total respiratory resistance (Rrs), measured by the forced oscillation technique, was unaltered throughout the study. A double blind, placebo controlled study of the effects of inhaled salbutamol (200 micrograms, 0.6 mumol) and ipratropium bromide (40 micrograms, 0.1 mumol) on cough induced by capsaicin (2.4 nmol) and by PGF2 alpha (0.1 mumol) and on PGF2 alpha augmented, capsaicin induced coughing was performed in seven subjects. Neither drug had any effect on capsaicin induced coughing. Salbutamol reduced coughing due to PGF2 alpha (mean 7.7 coughs after salbutamol, 9.3 after placebo) but ipratropium bromide did not (mean 6.9 coughs after ipratropium bromide, 6.6 after placebo). Salbutamol also inhibited the augmentation of the capsaicin induced cough that followed inhalation of PGF2 alpha (mean augmentation 1.9 coughs after salbutamol, 4.1 after placebo), whereas ipratropium bromide did not (augmentation 1.7 coughs after ipratropium bromide, 2.7 after placebo). No changes in Rrs were seen after PGF2 alpha or either drug. Thus salbutamol reduces PGF2 alpha induced cough and the augmentation of capsaicin induced cough that follows PGF2 alpha.

Topics: Administration, Inhalation; Adult; Albuterol; Capsaicin; Cough; Dinoprost; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Ipratropium; Male

Inhaled PGF2 alpha and PGE2 were evaluated for relative tussive activity to non-prostanoid tussive agents. In addition a comparison was sought between the present observations and those in the cat, the only laboratory animal which consistently coughs to prostanoids. Five healthy volunteers were repeatedly challenged at 90 min intervals with aerosols of PGE2 (100-500 micrograms ml-1) and tussive activity was monitored. In a second separate study again monitoring tussive activity 10 healthy volunteers inhaled aerosols of either PGF2 alpha (0.1-100 micrograms ml-1), PGE2 (0.1-100 micrograms ml-1), acetylcholine (0.1-50 mg ml-1) or citric acid (5-20% w/v) in a randomised procedure. Objective measurement of tussive activity was achieved using a throat microphone linked via a discriminator to a pen recorder. All four compounds produced two distinct phases of tussive activity, an early phase during challenge and a late phase 1-15 min post-challenge. Repeated challenges with PGE2, produced significant (P less than 0.01) tachyphylaxis to the late phase responses only. Both PGF2 alpha and PGE2 were approximately 1000 and 10,000 times more potent than acetylcholine and citric acid respectively for both phases of tussive activity. Tussive activity was accompanied with retrosternal soreness and tightness of the chest for PGE2, increased sputum for PGF2 alpha, and sore throats with citric acid. Although a correlation exists for man and cat with regards to the tussive potency and the early and late phases of PGF2 alpha activity no such correlation seems to exist for PGE2. The high tussive potency of the prostaglandins in man suggest that their local release in various respiratory pathophysiological conditions may be responsible for the accompanying coughs/irritancy.

Topics: Acetylcholine; Aerosols; Citrates; Citric Acid; Cough; Dinoprost; Dinoprostone; Humans; Prostaglandins; Prostaglandins E; Prostaglandins F; Tachyphylaxis

The mechanisms of cough in asthma are unclear. Asthma is associated with an oxidative stress. Many reactive oxygen species sensitize or activate sensory C-fibers which are capable to induce cough. It was hypothesized that oxidative stress in the airways might contribute to the cough severity in asthma. Exhaled breath condensate samples were collected in ten healthy and 26 asthmatic subjects. The concentration of 8-isoprostane was measured. In addition, the subjects filled in Leicester Cough Questionnaire and underwent cough provocation tests with dry air hyperpnoea and hypertonic saline, among other measurements. Among the asthmatic subjects, high 8-isoprostane was associated with severe cough response to hyperpnoea (p=0.001), low Leicester Cough Questionnaire values (indicating severe subjective cough, p=0.02), and usage of combination asthma drugs (p=0.03-0.04). However, the 8-isoprostane concentrations did not differ significantly between the healthy and the asthmatic subjects. Airway oxidative stress may be associated with experienced cough severity and measured cough sensitivity in asthma.

Topics: Adult; Asthma; Breath Tests; Bronchial Provocation Tests; Case-Control Studies; Chronic Disease; Cohort Studies; Cough; Dinoprost; Exhalation; Female; Humans; Hyperventilation; Male; Middle Aged; Oxidative Stress; Reference Values; Severity of Illness Index; Spirometry; Statistics, Nonparametric

Severe asthma is characterized by persistent airway inflammation and increased formation of reactive oxygen species.. Glutathione (GSH) is an important antioxidant in the epithelial lining fluid (ELF). We hypothesized that airway GSH homeostasis was altered in children with severe asthma and was characterized by decreased GSH and increased glutathione disulfide (GSSG) concentrations.. Bronchoalveolar lavage was obtained from 65 children with severe asthma, including 35 children with baseline airway obstruction evidenced by FEV(1) <80%. Control data were obtained from 6 children with psychogenic (habit) cough or vocal cord dysfunction undergoing diagnostic bronchoscopy and 35 healthy adult controls. GSH, GSSG, and other determinants of airway oxidative stress including glutathione S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx), malondialdehyde, 8-isoprostane, and H(2)O(2) were measured in the ELF. The ELF redox potential was calculated from GSH and GSSG by using the Nernst equation.. Compared with controls, subjects with severe asthma had lower airway GSH with increased GSSG despite no differences in GST, GR, and GPx activities between groups. This was accompanied by increased malondialdehyde, 8-isoprostane, and H(2)O(2) concentrations in the ELF. GSH oxidation was most apparent in subjects with severe asthma with airway obstruction and was supported by an upward shift in the ELF GSH redox potential.. Children with severe asthma have increased biomarkers of oxidant stress in the ELF that are associated with increased formation of GSSG and a shift in the GSH redox potential toward the more oxidized state.

Topics: Adolescent; Adult; Antioxidants; Asthma; Biomarkers; Bronchoalveolar Lavage Fluid; Child; Child, Preschool; Cough; Dinoprost; Female; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; Homeostasis; Humans; Hydrogen Peroxide; Lung; Male; Malondialdehyde; Oxidation-Reduction; Oxidative Stress; Voice Disorders

1. There is considerable interest in novel therapies for cough, since currently used agents such as codeine have limited beneficial value due to the associated side effects. Sensory nerves in the airways mediate the cough reflex via activation of C-fibres and RARs. Evidence suggests that cannabinoids may inhibit sensory nerve-mediated responses. 2. We have investigated the inhibitory actions of cannabinoids on sensory nerve depolarisation mediated by capsaicin, hypertonic saline and PGE2 on isolated guinea-pig and human vagus nerve preparations, and the cough reflex in conscious guinea-pigs. 3. The non-selective cannabinoid (CB) receptor agonist, CP 55940, and the selective CB2 agonist, JWH 133 inhibited sensory nerve depolarisations of the guinea-pig vagus nerve induced by hypertonic saline, capsaicin and PGE2. These responses were abolished by the CB2 receptor antagonist SR144528, and unaffected by the CB1 antagonist SR141716A. Similarly, JWH 133 inhibited capsaicin-evoked nerve depolarisations in the human vagus nerve, and was prevented by SR144528. 4. Using a guinea-pig in vivo model of cough, JWH 133 (10 mg kg-1, i.p., 20 min) significantly reduced citric acid-induced cough in conscious guinea pigs compared to those treated with the vehicle control. 5. These data show that activation of the CB2 receptor subtype inhibits sensory nerve activation of guinea-pig and human vagus nerve, and the cough reflex in guinea-pigs, suggesting that the development of CB2 agonists, devoid of CB1-mediated central effects, will provide a new and safe antitussive treatment for chronic cough.

Topics: Animals; Camphanes; Cannabinoids; Capsaicin; Consciousness; Cough; Cyclohexanols; Dinoprost; Dose-Response Relationship, Drug; Guinea Pigs; Humans; Hypertonic Solutions; In Vitro Techniques; Male; Middle Aged; Neurons, Afferent; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Reflex; Rimonabant; Vagus Nerve

Prostaglandin D2 (PGD2) and some naturally occurring and synthetic prostaglandin (PG) analogues were evaluated for irritant/ tussive activity in cats. PGD2, PGF2 alpha and ICI81008 were potent tussive agents when inhaled, producing both an early and late phase of coughing. In addition all three prostaglandins decreased respiratory rate. In contrast PGE2, PGE1 and PGA1 were 100-1000 times less potent than PGF2 alpha as irritants and weakly stimulated respiratory rate. The PGE class of compounds only produced an early phase of coughing. The rank order of early phase tussive activity was ICI81008 greater than PGF2 alpha greater than PGF2 beta much greater than PGE1 = PGE2 = PGA1. This rank order is similar to that characterising the prostanoid 'X' contractant or class II receptor(s).

Topics: Aerosols; Animals; Cats; Cough; Dinoprost; Prostaglandin D2; Prostaglandins D; Prostaglandins F; Prostaglandins F, Synthetic; Receptors, Cell Surface; Receptors, Prostaglandin; Respiration