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Morphine sulfate is an effective antitussive in intractable chronic cough at the doses of 5 to 10 mg twice daily.

We conclude that dispositional optimism is associated with healthy ageing. The relationship between optimism and healthy ageing was only partly mediated by the health behaviours assessed in this sample.

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We postulate that most patients with chronic cough have a single discrete clinical entity: cough hypersensitivity syndrome. We constructed a questionnaire that elicits the major components of the syndrome. Here we describe the validation of this questionnaire. Following iterative development, the Hull Airway Reflux Questionnaire (HARQ) was administered to patients and normal volunteers. It is self-administered and comprises 14 items with a maximum score of 70. Unselected patients were recruited sequentially from the Hull Cough Clinic. Preclinic questionnaires were compared with those obtained at the clinic. Responsiveness was assessed 2 months after the clinic visit. One hundred eighty-five patients and 70 normal volunteers were included in this study. There was a marked difference in HARQ scores between patients with chronic cough and normal volunteers. The sensitivity (94%) and specificity (95%) of the HARQ was high, with an area under the ROC curve of 0.99. All items of the scale significantly correlated positively with others in the scale and with the total score. On repeatability testing using Cohen's kappa with quadratic weights, significant agreement was noted for all items. Good correlation was observed between the total scores (r = 0.78). The questionnaire was also responsive to treatment; the minimum clinically significant change was estimated to be 16 points. We have demonstrated the HARQ to have good construct and criterion validity. It is both reproducible and responsive to change. It can be used as a diagnostic instrument and demonstrates that chronic cough represents a single coherent entity: cough hypersensitivity syndrome.

We evaluated the effect of gefapixant on cough reflex sensitivity to evoked tussive challenge.In this phase 2, double-blind, two-period study, patients with chronic cough (CC) and healthy volunteers (HV) were randomised to single-dose gefapixant 100 mg or placebo in a crossover fashion. Sequential inhalational challenges with ATP, citric acid, capsaicin and distilled water were performed 1, 3 and 5 h after dosing. Mean concentrations evoking ≥2 coughs (C2) and ≥5 coughs (C5) post dose versus baseline were co-primary endpoints. Objective cough frequency (coughs·h−1) over 24 h and a cough severity visual analogue scale (VAS) were assessed in CC patients. Adverse events were monitored.24 CC patients and 12 HV were randomised (mean age 61 and 38 years, respectively). The cough challenge threshold increased for ATP by 4.7-fold (C2, p≤0.001) and 3.7-fold (C5, p=0.007) for gefapixant versus placebo in CC patients; in HV, C2 and C5 increased 2.4-fold (C2, p=0.113; C5, p=0.003). The distilled water C2 and C5 thresholds increased significantly (p<0.001) by a factor of 1.4 and 1.3, respectively, in CC patients. Gefapixant had no effect on capsaicin or citric acid challenge. Median cough frequency was reduced by 42% and the least squares mean cough severity VAS was 18.0 mm lower for gefapixant versus placebo in CC patients. Dysgeusia was the most frequent adverse event (75% of HV and 67% of CC patients).ATP-evoked cough was significantly inhibited by gefapixant 100 mg, demonstrating peripheral target engagement. Cough count and severity were reduced in CC patients. Distilled water may also evoke cough through a purinergic pathway.

Carotid body-mediated ventilatory increases in response to acute hypoxia are attenuated in animals reared in an hypoxic environment. Normally, 02-sensitive K+ channels in neurosecretory type I carotid body cells are intimately involved in excitation of the intact organ by hypoxia. We have therefore studied K+ channels and their sensitivity to acute hypoxia The ventilatory responses to acute hypoxia of animals and humans change dramatically from fetal to adult life: in fetal animals, exposure to hypoxia is inhibitory to breathing movements (1), whereas in the adult, hypoxia causes a sustained increase in ventilation (2). Neonatal animals produce an intermediate biphasic response, with ventilation increasing and then falling again during sustained hypoxia (3). This transient increase, along with the sustained increase seen in adults, is a result of stimulation of peripheral chemoreceptors, primarily the carotid body (4, 5). Ventilatory responses to acute hypoxia of neonatal animals born and raised in hypoxic environments are blunted or absent (6), and a similar lack of ventilatory response to hypoxia has also been noted in adult animals exposed to hypoxia chronically (7) and in high-altitude residents (8). It is conceivable that common mechanisms underlie the lack of ventilatory response to hypoxia of chronically hypoxic neonatal animals and high-altitude residents.The carotid bodies of chronically hypoxic animals or humans show dramatic morphological changes following prolonged hypoxia: most notably, type I carotid body cellsThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. undergo hyperplasia and hypertrophy (9, 10). Type I cells are widely accepted as the chemosensory element of the carotid body, and various stimuli including hypoxia stimulate Ca2+-dependent release of neurotransmitters from these cells in a manner that correlates with increased discharge of afferent chemosensory fibers (5, 11). In recent years, several groups have used patchclamp techniques to investigate ion channels in type I cells, and there are several reports describing 02-sensitive K+ channels in these cells (12)(13)(14)(15)(16). These findings have given rise to a proposed mechanism for hypoxic chemotransduction in which inhibition of K+ channels by hypoxia leads to depolarization and increased excitability of type I cells sufficient to activate voltage-gated Ca2+ channels. This leads to Ca2+ influx and triggering of neurosecretion, an essential step in the chemotransductive pathway (5). Here we have compared ionic channels and their modulation by acute hypoxia in type I cells isolated from neonatal rats born and raised in normoxia and hypoxia in order to investigate whether the lack of chemoreceptor-mediated increases in ventilation seen in animals reared under chronically hypoxic conditions can be attributed to altered electrophysiological properties of type I cells. ...

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