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Functional organization of the central cough generation mechanism.

Recent studies evaluating the effects of pulmonary afferents, chemoreceptors, and antitussive drugs on the cough motor pattern indicate that this reflex is regulated in a different manner than breathing. Furthermore, regulatory differences exist between tracheobronchial and laryngeal cough. We propose a functional model of the brainstem elements participating in the production of cough that accounts for these regulatory differences. The model incorporates known brainstem interneuronal pathways as well as novel regulatory elements for tracheobronchial and laryngeal cough. Each of these novel regulatory elements controls the excitability of a common motor pattern generation network. Given that cough and breathing are associated with profoundly different spatiotemporal alterations in motor drive to respiratory motoneurons, brainstem elements common to the generation of both behaviours must be capable of a high degree of plasticity.

Antitussive Agents↗

The powerful placebo in cough studies?

Placebo treatment has been reported to improve subjective and objective measures of disease in up to 30-40% of patients with a wide range of clinical conditions. A review of 8 clinical trials on the effects of antitussive medicines on cough associated with acute upper respiratory tract infection shows that 85% of the reduction in cough is related to treatment with placebo, and only 15% attributable to the active ingredient Treatment with a cough medicine can be viewed as consisting of three components: pharmacological, physiological (demulcent) and placebo. The placebo effect is related to belief in the effectiveness of the treatment and this idea must in some way influence the central control of cough. Studies on the placebo effect of analgesics indicate that the placebo effect may be mediated by endogenous opioid neurotransmitters and this may explain the analgesic potency of opioid medicines such as morphine. In the present paper a model is proposed to explain the antitussive effects of placebo treatment on the basis of endogenous opioid neurotransmitters. With active pharmacological ingredients contributing only 15% to the effects of cough treatment it seems reasonable to conduct more research on the other components of treatment such as placebo.

Antitussive Agents↗

Mechanism of irritant-induced cough: studies with a kinin antagonist and a kallikrein inhibitor.

It has been suggested that bradykinin may play a role in stimulating cough in at least one pathological condition in humans. We have employed an animal model to investigate the possible role of this peptide in irritant-induced cough. The kinin antagonist Hoe 140 and codeine both produced dose-related inhibition of cough responses to inhalation of citric acid or bradykinin aerosols by conscious guinea pigs. The selective tissue kallikrein inhibitor CH694 inhibited cough caused by citric acid but not by bradykinin. Indomethacin pretreatment attenuated the responses to both stimuli as did phosphoramidon. It is concluded that cough produced by citric acid inhalation may be mediated, at least in part, by generation of kinins; secondary to this, a release of prostanoids also appears to participate in the response.

Administration, Inhalation↗

Effects of glycopyrrolate on capsaicin-induced cough in normal volunteers treated with captopril.

The effects of inhibition of angiotensin converting enzyme (ACE) and glycopyrrolate on cough caused by inhaled capsaicin were investigated in a double-blind, randomised cross-over study in twelve normal volunteers. The capsaicin challenge was performed before and 2 h after dosing with 75 mg captopril or matched placebo given orally, and 20, 40 and 60 min after giving 1 mg glycopyrrolate i.v. to each subject. Captopril and placebo did not alter the cough response when compared to baseline. Glycopyrrolate, however, caused a significant increase in the threshold sensitivity (D2) from baseline, and a significant decrease in the total cough response at 40 and 60 min both after captopril and placebo. The D2-baseline and D2-40 min after glycopyrrolate (mean SD), respectively, were 3.2 (1.0); 17.9 (4.2) after placebo and 2.5 (8.5); 23.6 (6.9) after captopril. Elimination of vagal influences implies attenuation of the effects of tachykinins but not those prostaglandins. We postulate that tachykinins, such as substance P, play a more important role than prostaglandins in capsaicin-induced cough. We conclude that the vagus is important in the capsaicin-induced cough reflex, but, as suppression of this reflex by glycopyrrolate was delayed, the relevant receptors are either poorly accessible peripheral receptors or they are located in the central nervous system.

Administration, Inhalation↗

ACE-inhibitor-induced cough, an adverse drug reaction unrecognised for several years: studies in prescription-event monitoring.

OBJECTIVE. This study examines cough recorded in Prescription-Event Monitoring (PEM) of four ACE-inhibitors. Particular attention was paid to the study of enalapril because the drug was monitored before the causal relationship between cough and ACE-inhibitors had been widely accepted. RESULTS. Several factors which had obscured the causal relationship in the individual cases were found to be also an obstacle in PEM. For example, cough was a common and non-serious event and was under-reported in the PEM study of enalapril and the rate was not strikingly different from that recorded for other drugs. Cough induced by ACE-inhibitors has several characteristics which reduce the chance of a recognisable "signal'. The original questionnaires returned from doctors in the PEM study of enalapril have been reexamined. The observation that the rate of cough diminished after enalapril had been stopped rather than increased after starting, provided the best evidence of causality, because this was not affected by many biases such as the publicity that had occurred prior to doctors participating in PEM completed later reports.

Adult↗

The effect of the neurokinin antagonist FK-224 on the cough response to inhaled capsaicin in a new model of guinea-pig eosinophilic bronchitis induced by intranasal polymyxin B.

Eosinophilic bronchitis without asthma can cause a persistent non-productive cough which is resistant to bronchodilator therapy. To understand the mechanism of the cough in this disorder, an animal model of eosinophilic bronchitis was developed. Guinea-pigs were treated with transnasal administration of polymyxin B or saline twice a week for 3 weeks. The number of eosinophils in bronchoalveolar lavage fluid increased in polymyxin B-treated animals when compared with those treated with saline. In addition, histological examination showed that the number of eosinophils infiltrated into the tracheal epithelium increased; injury to the tracheal epithelium was greater in polymyxin B-treated animals. The numbers of coughs induced by saline and each concentration of capsaicin (10(-18), 10(-16), 10(-14) M) were greater in the polymyxin B-treated animals. FK-224 (a neurokinin receptor antagonist) decreased the heightened cough reflex in this animal model of eosinophilic bronchitis. These findings suggest that neuropeptides, and particularly neurokinins, are involved in the heightened cough receptor sensitivity in eosinophilic bronchitis without asthma. This has implications for better understanding of this disorder and its treatment.

Administration, Inhalation↗

PaO2 increases with coughing in patients with chronic lung disease.

We considered if the cyanosis frequently observed during a cough attack in patients with chronic lung disease was due to worsening hypoxemia. To investigate the effects of cough on PaO2, we measured arterial blood gases before and after a voluntary coughing period of 45 sec, in 11 patients with Interstitial Lung Disease (ILD) and 14 patients with Chronic Obstructive Lung Disease (COPD). All patients significantly increased (p less than 0.05) their PaO2 (COPD: from 49 +/- 2 to 60 +/- 2 mmHg; ILD from 44 +/- 2 to 51 +/- 3 mmHg, mean +/- SD) and decreased their PaCO2. We conclude that stable patients with COPD and ILD increase their PaO2 with coughing most likely due to hyperventilation. The cyanosis observed could be due to peripheral circulatory effects of coughing.

Adult↗

Humidification reduces coughing and breath-holding during inhalation induction with isoflurane in children.

PURPOSE: Inhalation induction using isoflurane is associated with airway irritability, coughing, breath-holding and laryngospasm. These complications are more common in children. This study was designed to determine if humidification of isoflurane in oxygen/nitrous oxide would reduce respiratory complications and hypoxic episodes at induction. METHODS: Fifty-nine unpremedicated children, aged three months to 12 yr, were enrolled in the study and randomised to receive either humidified isoflurane (n = 27, Group A), or non-humidified isoflurane (n = 32, Group B). All inductions of anaesthesia were with isoflurane 4% in 50% oxygen/nitrous oxide. Subjects were observed for the occurrence of breath-holding, coughing, laryngospasm, bronchospasm, secretions, and hiccoughs. The severity of each complication was graded on a scale of 0-3. The need to administer 100% oxygen and/or succinylcholine was also identified. RESULTS: Coughing (33% vs 53%) was more frequent in Group B (P < 0.05). Coughing severity scores (13 vs 36) and breath-holding severity scores (8 vs 19) were also greater in Group B (P < 0.05). A change in FIO2 was required more frequently in Group B (4% vs 16%). Although there was a high incidence of laryngospasm in both groups (52% vs 59%), no other differences were identified, breath-holding (26% vs 31%), secretions (30% vs 31%), hiccough (11% vs 12.5%) (P > 0.05). CONCLUSION: Humidification of inspired isoflurane reduces the frequency and severity of coughing, the severity of breath-holding, and the need to increase supplemental inspired oxygen concentration, when isoflurane is used for inhalation induction of anaesthesia in children. Humidification has no effect, however, on the frequency and severity of laryngospasm, or on the frequency of occurrence of arterial oxygen desaturation.

Anesthetics, Inhalation↗

Identification of independent risk factors for fentanyl-induced cough.

PURPOSE: To determine how the probability of fentanyl-induced cough is affected by patient characteristics and/or anesthetic technique. METHODS: We analyzed data from a cohort of 1,311 adult patients undergoing elective surgery under general anesthesia, accompanied by i.v. fentanyl. The following data were collected: patient demographics, history of cigarette smoking, presence of bronchial asthma or chronic obstructive pulmonary disease, administration of angiotensin converting enzyme inhibitors; and anesthetic technique, including: preanesthetic anxiolytic medication, prior use of atropine, epidural lidocaine, a priming dose of vecuronium, and the dose of i.v. fentanyl. Associations between individual variables in the clinical evaluation model and the likelihood of fentanyl-induced cough were characterized by calculating odds ratios. Multiple logistic regression analysis was used to examine the independent contribution of each variable while controlling for all variables. RESULTS: Fentanyl-induced cough was independently associated with the following: aging, cigarette smoking, a prior epidural injection of lidocaine, and a priming dose of vecuronium. Fentanyl-induced cough was unaffected by gender, the presence of either bronchial asthma or chronic obstructive pulmonary disease, or prior use of atropine. CONCLUSIONS: Fentanyl-induced cough may be suppressed by aging, cigarette smoking, prior epidural injection of lidocaine, or a priming dose of vecuronium. These findings may allow insights into the mechanism of this phenomenon, thereby leading to its prevention.

Adult↗

Treatment of atopic cough caused by Basidiomycetes antigen with low-dose itraconazol.

We report two patients with atopic cough due to Basidiomycetes antigen. One patient was a 27 year-old woman and the other was a 17 year-old boy. Both patients visited our hospital because of severe nonproductive cough. They did not have bronchial hyperresponsiveness to methacholine or heightened bronchomotor tone. Bronchodilator therapy was not effective for their cough. Her symptoms worsened in her office and his in his house, suggesting existence of etiologic agent(s) in their environments. Basidiomycetes was isolated from the woman's office and from the boy's house, and the bronchoprovocation test with Basidiomycetes antigen was positive. Low dose itraconazol (50 or 100 mg/day) given for two weeks eliminated cough in both patients. This is the first report describing the effectiveness of low dose antifungal therapy for atopic cough caused by Basidiomycetes antigen.

Adolescent↗

Dopaminergic control of the cough reflex as demonstrated by the effects of apomorphine.

The effect of apomorphine on the cough reflex induced by electrical stimulation of the superior laryngeal nerve was studied in cats anesthetized with pentobarbital. Intravenous administration of apomorphine in doses which ranged from 0.1 to 1.0 mg/kg decreased the number of coughs in a dose-dependent manner. Haloperidol (0.3 mg/kg i.v.) did not significantly change the number of coughs. However, haloperidol administered 15 min prior to administration of apomorphine abolished the apomorphine-induced decrease in the number of coughs. These results suggest that dopaminergic mechanisms could have an important role in the regulation of the cough reflex.

Animals↗

Effects of N-methyl-D-aspartate antagonists on the cough reflex.

The effects of antagonists of N-methyl-D-aspartate (NMDA) on the capsaicin-induced cough reflex in rats were studied. Intracisternal (i. cist.) injection of MK-801, a non-competitive antagonist of NMDA, significantly decreased the number of coughs in a dose-dependent manner. The competitive antagonists of NMDA, 2-DL-amino-5-phosphonovalerate and 2-DL-amino-7-phosphonoheptanoate, also decreased the number of coughs after i. cist. injection. The antitussive potencies of both the competitive and non-competitive antagonists were similar to that of dextromethorphan. Intraperitoneal injection of MK-801 also decreased the number of coughs in a dose-dependent manner. These data suggest that excitatory amino acid neurotransmitters and NMDA receptors may be involved in the regulation of the cough reflex.

Animals↗

Effects of GABA antagonists on the pentobarbital-induced depression of respiration and cough in rats.

In order to determine the possible involvement of GABA-ergic mechanisms in the modulation of the cough reflex, the effects of GABA antagonists on the pentobarbital-induced depression of respiration and cough were examined in a comparative study in rats. The cough reflex was induced by application of electrical stimulation to the tracheal mucosa by the puncture electrode-induced cough method. The 50% antitussive dose (AtD50) of pentobarbital was calculated by the "up and down" method. Pentobarbital (10 mg/kg, IP) caused a reduction of tidal volume, which was counteracted by pretreatment with picrotoxin (3 mg/kg, IP) or bicuculline (3 mg/kg, IP). However, neither picrotoxin nor bicuculline were able to counteract the reduction in frequency of respiration. The AtD50 of pentobarbital was 1.95 mg/kg when administered IP. The AtD50 of pentobarbital was not altered after pretreatment of rats with picrotoxin (1.85 mg/kg, IP) or with bicuculline (1.55 mg/kg). These results suggest that GABA-ergic mechanisms may not be involved in the cough-depressant effect of pentobarbital.

Animals↗

Subsensitivity to the cough-depressant effects of opioid and nonopioid antitussives in morphine-dependent rats: relationship to central serotonin function.

The present study was designed to determine whether morphine-dependent rats have a decreased sensitivity to the cough-depressant effects of both opioid and nonopioid antitussives. Morphine dependence was induced by treatment with morphine-admixed food (0.5 mg/g of food) for 7 days. The cough reflex was induced by application of electrical stimulation to the tracheal mucosa by the puncture electrode-induced cough method. The cough-depressant effect was evaluated as the antitussive ED50 calculated by the method of Litchfield and Wilcoxon. The effects of both opioid (morphine and dihydrocodeine) and nonopioid (dextromethorphan and noscapine) antitussive drugs were diminished in morphine-dependent rats. The values of ED50 of these antitussive drugs in morphine-dependent rats were about 3-fold higher than those in control rats. A significantly lower number of serotonin receptors was found in the brainstem of morphine-dependent rats (Bmax: 2.88 +/- 0.32 pmoles/mg protein) than in controls (Bmax: 4.93 +/- 0.50 pmoles/mg protein). It is possible that the decreased sensitivity to both opioid and nonopioid antitussive drugs, in terms of the depression of the cough reflex, in morphine-dependent rats may be due to changes in the number of serotonin receptors.

Animals↗

The role of the methacholine challenge in children with chronic cough.

Thirty-nine male and 35 female subjects, aged 6 to 20 years, with chronic cough were studied with spirometry and standard methacholine (MCH) challenge. The duration of their cough before the MCH challenge ranged from 2 months to 13 years. Their FEV1 ranged 62% to 132% predicted. Thirty-six (49%) patients had a positive MCH challenge. The MCH concentration inhaled to decrease the FEV1 by 20% ranged from 0.55 to 25 mg/ml. Follow-up data (mean 14 months) were available on all 74 patients. Fifty-four patients received asthma medications, and 93% improved in mean 3.6 weeks. At the end of the follow-up, 22 (30%) were asymptomatic, 39 (53%) were improved, and 13 patients (17%) were symptomatic. We were unable to predict bronchial hyperreactivity in this population on the basis of duration of the cough, personal or family history of allergies, or baseline spirometry. Thus, MCH challenge is helpful in evaluating children with chronic cough and in guiding therapy. Follow-up of children with chronic cough is important. Eleven percent of this study population progressed to develop bronchial asthma. Forty percent of these patients, initially doing well, were asymptomatic at the end of the follow-up period.

Adolescent↗

The activities of lung stretch and irritant receptors during cough.

In unilaterally vagotomized rabbits, changes in single vagal nerve fibers from the lung stretch and irritant receptors were studied during the cough reflex following ammonia vapour administered into the lungs. The discharge rates of slowly adapting pulmonary stretch receptors (SARs) before the onset of cough and at the onset of cough did not change significantly. In contrast, the occurrence of cough after ammonia inhalation was usually preceded by vigorous stimulation of the rapidly adapting pulmonary stretch receptors (RARs). These results suggest that the genesis of cough provoked by ammonia is mainly mediated by afferent input from RARs.

Action Potentials↗

Cough induced activity of spirapril in rats.

1. We examined the effect of spirapril, a potent angiotensin converting enzyme (ACE) inhibitor, on the number of capsaicin-induced coughs in rats and compared with that of enalapril. 2. Chronic treatment with enalapril, at doses of 1 and 3 mg/kg, p.o., significantly and dose-dependently enhanced the number of capsaicin-induced coughs. 3. Chronic treatment with higher dose of spirapril (3 mg/kg, p.o.) also significantly enhanced the number of capsaicin-induced coughs. However, lower dose (1 mg/kg, p.o.) of spirapril had no significant effect on the number of capsaicin-induced coughs. 4. These results suggest that cough induced activity, one of the most serious side effects associated with chronic treatment with ACE inhibitors, of spirapril is relatively lower than that of enalapril.

Angiotensin-Converting Enzyme Inhibitors↗

The effect of oral terfenadine on the sensitivity of the cough reflex in normal volunteers.

Antihistamines have been reported to have antitussive actions in allergic rhinitis which may be due to an effect of the drug on the cough reflex. We have studied the effect on induced cough in normal volunteers. Ten volunteers inhaled capsaicin at concentrations between 0.78 and 200 microM, in increasing dose order, until they coughed more than five times. The challenge was performed three times before and three times each at 2 and 4 h after 120 mg terfenadine or matched placebo tablet in a double-blind, randomized, cross-over study. Neither affected the capsaicin cough challenge. Thus, any antitussive effect of terfenadine is more likely to be via an indirect mechanism such as inhibition of released histamine rather than on the cough reflex itself.

Administration, Oral↗