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Theobromine inhibits sensory nerve activation and cough

  • Pfizer Rome Italy

Abstract and Figures

Cough is a common and protective reflex, but persistent coughing is debilitating and impairs quality of life. Antitussive treatment using opioids is limited by unacceptable side effects, and there is a great need for more effective remedies. The present study demonstrates that theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid-induced cough in guinea-pigs in vivo. Furthermore, in a randomized, double-blind, placebo-controlled study in man, theobromine suppresses capsaicin-induced cough with no adverse effects. We also demonstrate that theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve suggestive of an inhibitory effect on afferent nerve activation. These data indicate the actions of theobromine appear to be peripherally mediated. We conclude theobromine is a novel and promising treatment, which may form the basis for a new class of antitussive drugs.
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©2004 FASEB
The FASEB Journal express article 10.1096/fj.04-1990fje. Published online November 17, 2004.
Theobromine inhibits sensory nerve activation and cough
Omar S. Usmani,* Maria G. Belvisi,
Hema J. Patel,
Natascia Crispino,
Mark A. Birrell,
Márta Korbonits,
Dezső Korbonits,
and Peter J. Barnes*
Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College London,
London, United Kingdom;
Respiratory Pharmacology Group, National Heart and Lung Institute,
Imperial College London, London, United Kingdom;
Department of Endocrinology, St.
Bartholomew’s Hospital, London, United Kingdom;
Chinoin Co. Ltd., Budapest, Hungary
Corresponding author: Professor Maria G. Belvisi, Respiratory Pharmacology Group,
Department of Airway Diseases, National Heart and Lung Institute, Dovehouse Street, London
SW3 6LY. E-mail:
Cough is a common and protective reflex, but persistent coughing is debilitating and impairs
quality of life. Antitussive treatment using opioids is limited by unacceptable side effects, and
there is a great need for more effective remedies. The present study demonstrates that
theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid-
induced cough in guinea-pigs in vivo. Furthermore, in a randomized, double-blind, placebo-
controlled study in man, theobromine suppresses capsaicin-induced cough with no adverse
effects. We also demonstrate that theobromine directly inhibits capsaicin-induced sensory nerve
depolarization of guinea-pig and human vagus nerve suggestive of an inhibitory effect on
afferent nerve activation. These data indicate the actions of theobromine appear to be
peripherally mediated. We conclude theobromine is a novel and promising treatment, which may
form the basis for a new class of antitussive drugs.
Key words: vagus • methylxanthines
ough is a protective, primitive reflex, in healthy individuals (1). However, when cough
serves no useful role, it is the most common respiratory complaint for which medical
attention is sought (2). Persistent cough can be debilitating, socially distressing, and
adversely impairs quality of life (3). Cough leads patients to use over-the-counter remedies as
first-line treatments; in the United States alone, sales for these over-the-counter remedies exceed
$2 billion dollars (4). A recent meta-analysis, however, established that evidence regarding the
effectiveness of such remedies was inconclusive (5).
Narcotic agents with a morphine skeleton, such as the opioids codeine and dextromethorphan,
are the most widely used antitussives in cough remedies, but they have unpredictable efficacy
and undesirable central nervous and peripheral side effects that often lead to their discontinuation
(6, 7). The 2nd International Cough Symposium concluded that there is a great need for effective
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new cough treatments, as well as a better understanding of the complex genesis and
pathophysiology of cough to guide the development of pharmacological approaches (8).
The cough reflex is initiated by stimulation of two different classes of sensory afferent fiber,
namely the myelinated rapidly adapting receptors (RAR) and nonmyelinated C-fibers with
bronchial or pulmonary endings (9, 10). Inappropriate activation of these nerves can occur in
allergic diseases (e.g., asthma) and chronic obstructive pulmonary disease (COPD) and lead to
many of the symptoms such as coughing. However, the mechanisms involved in the abnormal
functioning of airway nerves have not yet been described. They are thought to involve the release
of inflammatory mediators which sensitize the nerve fibers leading to increased electrical activity
of these fibers and an increase in the release of various neurotransmitters from the nerve endings
We hypothesize that agents that inhibit sensory nerve activity, that is nerve depolarization, will
also inhibit the cough reflex. Although many compounds demonstrate promising characteristic
antitussive effects in animal models, few have shown any clinical benefit (11). In this paper, we
describe theobromine, a methylxanthine alkaloid derivative predominant in cocoa, as a novel and
promising therapy for the treatment of cough. Theobromine was developed alongside other
methylxanthines for respiratory disorders, but disappeared from clinical use because of its low
potency as a bronchodilator (12). Recent studies, however, demonstrate a unique antitussive
effect, unlike the other methylxanthines, in a series of pharmacological studies in the guinea pig
cough model using a synthetic analog (13, 14).
We, therefore, sought to investigate the action of theobromine in the guinea pig cough model in
vivo, and in isolated human and guinea-pig vagus nerve preparations in vitro. We observed
theobromine inhibited cough in our human trial at concentrations that do not have central side
effects in man and thus is unique in the field of cough therapy. Furthermore, our data show the
antitussive mechanism of action is probably due to direct inhibition of sensory nerve activation.
Our study reveals a promising prospect for a potentially new antitussive that is acutely needed in
the clinical arena for treatment of patients with both acute and chronic cough.
In vivo animal experiments were carried out according to the Institutional Guidelines for Care
and Use of Experimental Animals and approved by the animal Ethics Committee of Chinoin
(Chinoin Co. Ltd., Budapest, Hungary). For the human studies, written informed consent was
obtained from all patients, and approved by the Ethics Committee of the Royal Brompton and
Harefield Hospital National Health Service Trust (London, United Kingdom).
Citric acid-induced cough in the guinea pig
Cough was induced in conscious guinea pigs by a previously described method (14). Briefly,
female Dunkin Hartley guinea pigs (250–300 g) were individually placed in transparent
chambers and exposed to 0.78 M citric acid aerosol solution for 3 min. Coughs were counted by
a trained observer and recognized from the characteristic opening of the mouth and posture of
the animal. Animals with six or more coughs were selected and orally dosed with theobromine or
codeine in a suspension of 0.1% methylcellulose vehicle (treatment groups) or with 0.1%
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methylcellulose alone (control group). A second citric acid exposure was evoked one hour after
dosing in dose–response experiments, and at 0.5, 1, 2, 3, 4, and 6 h in time-duration experiments.
The antitussive activity was calculated as the percentage decrease of the number of coughs
between the second and the first challenge. The drug-treated groups were compared with the
control group using the Kruskal-Wallis test followed by the Conover Inman test for pair-wise
comparisons in the dose–response experiments, or by using the Student's t test in the time-
duration experiments (Graph Pad Prism Software, San Diego, CA). Statistical significance was
taken at P < 0.05.
Capsaicin cough challenge in human subjects
Ten healthy nonsmoking subjects (mean age (±
SD) 38 ± 8.1 year, six females) participated in a
randomized double-blind crossover study. The antitussive effect of a single-dose of theobromine
(1000 mg) was compared with codeine phosphate (60 mg) and placebo during three study visits,
each separated by a washout period of a week. The dose of theobromine was determined in a
pilot study. Interestingly, a previous study documented a bronchodilator effect of theobromine
within a similar dose range (at 500–1000 mg) in patients with asthma (12). The main outcome
measure was the capsaicin concentration required to induce five coughs (C5). The capsaicin
inhalation challenge was performed according to a modified version of our previously published
protocol (15). Briefly, subjects inhaled nebulized single-dose doubling concentrations (0.5–500
µM) of capsaicin delivered via a breath-activated dosimeter (P. K. Morgan Ltd., Gillingham,
UK), at one-minute intervals. Capsaicin doses were alternated at random with 0.9% saline doses
to minimize conditioned responses during the study. Coughs were counted for 1 min after the
inhalation by direct observation. The C5 was determined, and the capsaicin dose was repeated
for confirmation. The C5 was obtained on two screening occasions, and subjects were eligible to
enter the study if their C5 was in the middle of the dose response (up to 31 µM) and
reproducible to 1 doubling difference between both screening visits. Subjects were asked to
refrain from tea, coffee, chocolate, and caffeine-like substances 12 h before each visit. At each
treatment visit, the C5 threshold was determined two hours postdosing, which coincides with the
plasma peak of theobromine (16). Subjects were questioned about adverse effects, including
cardiovascular, central nervous, and gastrointestinal symptoms. Individual capsaicin C5 data was
logarithmically transformed to normalize the data, and the means were used to test the null
hypothesis using two-way ANOVA, with factors for subject and treatment (Graph Pad Prism
Software). Modified t tests to compare subsequent groups of interest were undertaken using the
Bonferroni method to adjust for the P values and multiple comparisons. Statistical significance
was taken at P < 0.05.
Measurement of sensory nerve depolarization in isolated vagus nerve preparations
Male Dunkin-Hartley guinea pigs (300–350 g) housed in a temperature-controlled (21°C) room
with food and water freely available, were killed by cervical dislocation, and the vagus nerves
caudal to the nodose ganglion were carefully dissected and placed in oxygenated Krebs–
Henseleit solution (KHS) of the following composition (mM): NaCl - 118; KCl - 5.9; MgSO
1.2; NaH
- 1.2; CaCl
- 2.5; glucose – 6.6; NaHCO
– 25.5
and bubbled with 95% O
5% CO
(BDH, Poole, UK). Human trachea, with branches of the cervical vagus still attached,
was obtained from a patient (male 44 year with emphysema) undergoing heart-lung
transplantation. Both human and guinea pig vagus nerve trunk segments (40–50 mm) were
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placed in oxygenated KHS, carefully desheathed, and mounted in a ‘grease-gap’ recording
chamber as described previously (17, 18). Briefly, each nerve was drawn longitudinally through
a narrow Perspex channel and petroleum jelly applied at the center of the channel creating an
area of high resistance, and electrically isolating the extracellular space between the two ends of
the nerve. Nerves were constantly superperfused with KHS at 37°C. Silver (Ag/AgCl) electrodes
(Mere 2 Flexible reference electrodes, World Precision Instruments, Stevenage, UK), made
contact at each nerve trunk end, and recorded DC potential and nerve depolarization via a DAM
50 differential amplifier (WPI) onto a calibrated pen-chart recorder (Lectromed Multi-Trace 2,
Letchworth, UK). Control sensory nerve depolarizations were induced by perfusion of the vagus
nerve with a pre-established submaximal concentration of capsaicin (1 µM in guinea pig) (18)
and (10 µM in human) (18) applied for 4 min, after which the tissue was washed until the
baseline response of the nerve was regained. After two reproducible control responses were
obtained to capsaicin, preparations were then perfused for 20 min with theobromine (0.01–100
µM), codeine (0.01–100 µM), or the relevant vehicle control (0.1% DMSO), following which
capsaicin (1 µM) was reapplied in the continued presence of the test agents. Experiments were
randomized so that different concentrations of different drugs were tested on vagus nerves from
the same animal on the same day. The data were subjected to a paired two-tailed t test since the
response to a stimulant was measured before and after drug intervention within the same nerve.
values (–log of the EC
defined as the concentration of drug required to elicit 50% of the
maximum inhibition) and statistical significance, taken at P < 0.05, were calculated using
‘GraphPad Instat
’ (Graph Pad Prism Software).
Theobromine as a potential antitussive
Several synthetic antitussives are characterized by the presence of a 1,2,4-oxadiazole ring in their
chemical structure (Fig. 1A
). With the ‘renaissance’ of the methylxanthine, theophylline (19), for
the treatment of asthma in the seventies, a series of novel compounds with an oxadiazolylalkyl
substituent at the N7 atom on the basic xanthine skeleton (Fig. 1B
), were synthesized (Fig. 1C),
and investigated as potential antiasthmatic and antitussive agents.
With two of these compounds selected for preclinical testing, 3,7-dihydro-3-methyl-7-/(5-
methyl-1,2,4-oxadiazol-3yl)methyl/-1H-purine-2,6-dione (Fig. 1D
) (14, 20), and 3,7-dihydro-
1,3-dimethyl-7-/(5-methyl-1,2,4-oxadiazol-3-yl)methyl/-1H-purine-2,6-dione (Fig. 1E) (13),
there was an unexpected correlation between chemical structure and antitussive potency. When
the N1 atom of the xanthine skeleton remained unsubstituted, the antitussive effect of these 1H-
xanthine derivatives increased considerably compared with the corresponding N1-methyl
analogs. The antitussive effect of 3,7-dihydro-3-methyl-7-/(5-methyl-1,2,4-oxadiazol-
3yl)methyl/-1H-purine-2,6-dione was about eightfold stronger than that of 3,7-dihydro-1,3-
dimethyl-7-/(5-methyl-1,2,4-oxadiazol-3-yl)methyl/-1H-purine-2,6-dione (14). This correlation
among the synthetic xanthine derivatives suggests that if the association also applies to the three
natural methylxanthine alkaloids, theobromine (Fig. 1F
), theophylline (Fig. 1G) and caffeine
(Fig. 1H
), then theobromine, which in contrast to theophylline and caffeine is unsubstituted at
N1, should exhibit a therapeutically significant antitussive effect.
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Theobromine inhibits citric acid-induced cough in the guinea pig model
We investigated the antitussive effect of theobromine on citric acid-induced cough in guinea
pigs, using codeine hydrochloride as a positive control. Cough provocation in conscious guinea
pigs is widely used to test the efficacy of new cough treatments (21, 22). Theobromine and
codeine showed a dose-dependent antitussive effect on citric acid-induced cough in guinea pigs
compared with the vehicle-treated control groups (Fig. 2
). The antitussive effect of theobromine
and codeine was similar to each other, but significantly better than vehicle treatment using doses
between 4–64 mg/kg and 8–64 mg/kg, respectively. Vehicle treatment itself caused some
decrease in the numbers of citric acid-induced cough, which were similar within the two
treatment groups (P=0.92) (Fig. 2
). Theobromine at a dose of 32 mg/kg produced a long-lasting
antitussive effect that was statistically significant for up to 4 h after treatment (Fig. 3
). There was
no tachyphylaxis evident in the tussive response elicited by citric acid as can be seen following
repeat exposure to the tussive agent, following vehicle administration, in the time-course
experiment (Fig. 3
Theobromine inhibits capsaicin-induced cough in man
We next examined whether theobromine could inhibit induced cough in human subjects.
Capsaicin is a well-established, reproducible, sensory C-fiber stimulant in vitro, widely used as a
tussive stimulant in clinical research to determine the cough threshold (23). In 10 healthy
volunteers, theobromine significantly increased the capsaicin concentration required to induce
five coughs (C5, cough threshold) when compared with placebo (P<0.01) (Fig. 4
). The log C5
SD) was 1.43 ± 0.65, 1.59 ± 0.74, and 1.86 ± 0.58 for placebo, codeine, and theobromine,
respectively. There was no significant difference between codeine and placebo (P=0.25). No
adverse effects, particularly cardiovascular or central nervous, were observed.
Theobromine inhibits capsaicin-induced sensory nerve depolarization of guinea pig vagus
and human vagus nerves in vitro
To ascertain whether the mechanism of action was peripheral or central, the effect of
theobromine (Fig. 5A
) and codeine (Fig. 5B) on capsaicin-induced guinea pig vagus nerve
depolarization was investigated. Perfusion of guinea pig vagus nerve preparations with
theobromine (0.01–100 µM) inhibited capsaicin-induced nerve depolarization in a concentration-
dependent manner (pD
=5.2). Maximum inhibition of 94.9 ± 3.8% was observed at the highest
concentration used (Fig. 5A
). Similarly, nerve preparations treated with codeine (0.01–100 µM)
showed markedly reduced sensory nerve depolarization induced by capsaicin in a concentration-
dependent manner (pD
=5.6), and complete inhibition of induced nerve depolarization was
achieved at 100 µM (Fig. 5B
We also studied the effects of theobromine on depolarization of a human vagus nerve preparation
by capsaicin. Human vagus preparations were used to confirm the observations seen with guinea
pig vagus nerves to provide the appropriate validation of the target in man and confirm clinical
relevance. Theobromine (100 µM) inhibited capsaicin (10 µM)-induced nerve depolarization of
the human vagus by 66.7% (Fig. 6
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We have demonstrated for the first time that theobromine, a methylxanthine derivative present in
cocoa, effectively inhibited citric acid-induced cough in conscious guinea pigs in vivo, and using
a randomized double-blind study in healthy human volunteers, we showed that theobromine
inhibited capsaicin-induced cough. We also established by using isolated guinea pig vagus in
vitro that the antitussive mechanism of action probably involves direct inhibition by theobromine
of capsaicin-induced sensory nerve activation. Furthermore, we demonstrated the inhibitory
action of theobromine on capsaicin-induced nerve depolarization using an isolated human vagus
nerve preparation, providing in vitro proof of concept for this action in man. However, further
confirmation of this observation is needed as it was only possible to study one human vagus
sample in the course of these studies.
Even in their recognized clinical role as bronchodilators, the underlying mechanism of action by
methylxanthines is unclear, but is most likely related to their phosphodiesterase inhibitory
activity, and also antagonism of bronchoconstrictor adenosine A
receptors (20, 24).
Prostaglandins PGI
and PGE
cause cyclic AMP accumulation in peripheral nerves (25) and
although cAMP-elevating drugs have recently been shown to activate sensory C-fibers in the
isolated rat vagus in vitro (26) little is known regarding the neuromodulatory role of cyclic
nucleotides and adenosine on human sensory nerve function. Interestingly, methylxanthines have
recently been shown to activate human intermediate-conductance, Ca
-activated K
(hIK) (27). We have previously proposed that activation of large conductance Ca
potassium channels might be a common mechanism of G-protein coupled receptor activation
leading to inhibition of afferent and efferent vagal activity (28), but a role for the hIK channel in
the modulation of sensory nerve activity has not yet been demonstrated.
To determine the mechanism of action of theobromine, we determined the effect of theobromine
on the isolated guinea pig vagus nerve preparation, which is a validated in vitro model that
allows evaluation of compounds on sensory nerve depolarization and appears predictive of data
obtained in single sensory fiber recording experiments (18, 28). We previously demonstrated that
both guinea pig and human vagus isolated nerve preparations respond similarly to a variety of
tussive sensory nerve stimulants, including capsaicin, suggesting that human vagal afferent fibers
react to and show similar responses to afferent stimulants acting on guinea pig nerves (M.
Belvisi, unpublished data). Our data demonstrate that guinea pig and human vagus nerves
respond similarly to theobromine inhibition of capsaicin-induced depolarization. We have
previously demonstrated the utility of the isolated vagus preparation as a preclinical in vitro
screen, which can be used to predict the efficacy of test compounds before evaluation in the in
vivo guinea pig cough model. Furthermore, the data obtained in the guinea pig cough model was
similar to that obtained in the clinical studies in agreement with published studies describing
similarities in the responsiveness of the cough reflex between the two species (22). Taken
together, the findings with theobromine in the guinea pig and human cough models in vivo, as
well as in the guinea pig and human nerve preparations in vitro, are consistent with the
hypothesis that the antitussive action was suggestive of a direct inhibition of sensory nerve
activation rather than by a centrally mediated mechanism. Although the evidence presented
suggests that theobromine may inhibit sensory nerve function via a peripheral mechanism, no
evidence has been presented suggesting the absence of a centrally mediated effect and as such,
this remains to be confirmed. However, although the isolated vagus preparation presents us with
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the ideal opportunity to conduct a comprehensive pharmacological assessment, data using this
preparation should be interpreted with some caution as the pharmacological agents are applied to
the axon of the isolated vagus nerve in vitro. Thus, the depolarization signal recorded
extracellularly represents a summation of the changes in membrane potential of all the axons via
activation of receptors expressed in the neuronal membrane of the axon. Conduction velocities of
the fibers are not recorded and action potentials per se are not measured, so identification of the
activation/inhibition of specific populations of sensory nerve fiber is not possible. Furthermore,
the receptor expression and signal transduction mechanisms in the axon may not necessarily
represent the behavior of those elements in the peripheral endings.
In our human study, no adverse effects were observed of the cardiovascular or central nervous
system, and these data support the use of theobromine as an effective antitussive agent in man,
with a safe therapeutic index. We compared theobromine to codeine phosphate, often used as a
benchmark against which new cough treatments are compared (29), and although systemic
opiates suppress capsaicin-induced cough (30), they are associated with many unacceptable
adverse effects when used in effective antitussive doses (7). To achieve maximum sensitivity in
the capsaicin cough challenge methodology, we controlled the capsaicin variability in our study
population by selecting individuals with no more than one difference in the doubling
concentration of capsaicin (31). Subjects in the middle of the cough dose–response were
selected, and those with attenuated or hyperresponsive effects were excluded to obtain
reproducible results. Our population was biased toward women, supported by previous studies
observing greater capsaicin sensitivity in healthy women (32).
In conclusion, the data described demonstrate a significant antitussive effect of theobromine in
healthy subjects when compared with placebo. Further studies are needed to see whether these
effects can be extrapolated to patients with chronic persistent cough, who, interestingly, have
previously been demonstrated to exhibit increased sensitivity to the tussive effect of the inhaled
irritant, capsaicin (33, 34). These data suggest that theobromine could form the basis for
development of novel and safe antitussive agents for the treatment of a very common and
troublesome symptom.
We are grateful for the help of Endre G. Mikus, Péter Arányi, and István Jelinek (Chinoin Co.
Ltd., Budapest, Hungary).
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29. Eccles, R. (1996) Codeine, cough and upper respiratory infection. Pul. Pharmacol. 9, 293–
30. Fuller, R. W., Karlsson, J. A., Choudry, N. B., and Pride, N. B. (1998) Effect of inhaled and
systemic opiates on responses to inhaled capsaicin in humans. J. Appl. Physiol. 65, 1125–
31. Morice, A. H. (1996) Inhalation cough challenge in the investigation of the cough reflex and
antitussives. Pulm. Pharm. 9, 281–284
32. Fujimura, M., Kasahara, K., Kamio, Y., Naruse, M., Hashimoto, T., and Matsuda, T. (1996)
Female gender as a determinant of cough threshold to inhaled capsaicin. Eur. Resp. J. 9,
33. O’Connell, F., Thomas, V. E., Pride, N. B., and Fuller, R. W. (1994) Capsaicin cough
sensitivity decreases with successful treatment of chronic cough. Am. J. Respir. Crit. Care
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34. Karlsson, J. A. (1993) A role for capsaicin sensitive, tachykinin containing nerves in chronic
coughing and sneezing but not in asthma: a hypothesis. Thorax 48, 396–400
Received June 25, 2004; accepted October 12, 2004.
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Fig. 1
Figure 1.
Chemical structures of the xanthine derivatives. Synthetic antitussives have a characteristic 1,2,4-oxadiazole
ring (A), and incorporating this into the N7 atom of the basic xanthine skeleton (B), a series of novel compounds were
synthesized (C–E). The antitussive activity of the N1 unsubstituted compound, 3,7-dihydro-3-methyl-7-/(5-methyl-1,2,4-
oxadiazol-3-yl)methyl/-1H-purine-2,6-dione (D), was about eightfold stronger than that of the corresponding N-1-methyl
analog, 3,7-dihydro-1,3-dimethyl-7-/(5-methyl-1,2,4-oxadiazol-3-yl)methyl/-1H-purine-2,6-dione (E)(14)
. The naturally
occurring methylxanthines are shown; theobromine, 3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione (F), theophylline, 3,7-
dihydro-1,3-dimethyl-1H-purine-2,6-dione (G), and caffeine, 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (H).
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Fig. 2
Figure 2.
Dose–response antitussive effect of theobromine () and codeine () on citric acid-induced cough in
conscious guinea pigs. Theobromine (n=8) and codeine (n=6) significantly inhibited citric acid-induced cough;
theobromine at 4, 8, 16, 32, and 64 mg/kg, and codeine at 8, 16, 32, and 64 mg/kg when individually compared with the
vehicle- (V) treated control groups. The antitussive effect with vehicle was 28.5% and 28% for theobromine and codeine,
respectively. Logarithmic dose values shown represent mean ± SEM, where *** denotes P < 0.001.
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Fig. 3
Figure 3.
Time dependency of the antitussive effect of theobromine () on citric acid-induced cough in conscious
guinea pigs. Theobromine at a dose of 32 mg/kg (n=8) significantly inhibited citric acid-induced cough after 1, 2, 3, and 4
h compared with vehicle control (). Values shown represent mean ± SEM, where *** denotes P < 0.001.
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Fig. 4
Figure 4.
The effect of theobromine, codeine, and placebo on the capsaicin concentration required to induce five
coughs (C5) in 10 healthy volunteers. Values shown represent mean ± SEM, where ** denotes P < 0.01.
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Fig. 5
Figure 5.
Inhibition of nerve depolarization by theobromine (A) and codeine (B). The inhibitory action of theobromine
and codeine on capsaicin-induced nerve depolarization in isolated guinea pig vagus nerve preparations occurs in a
concentration-dependent manner. Nerve depolarization responses were expressed as mV depolarization before (control
response) and after drug additions and then expressed as a percentage change. V represents vehicle. *P < 0.05, **P < 0.01,
***P < 0.001 denote statistical significance compared with control responses in the same tissue before drug treatment.
Values shown represent mean ± SEM percentage change of n = 4 determinations in depolarizations compared with control
response. The pD
values (–log
of the EC
defined as the concentration of drug required to elicit 50% of the maximal
response) are shown.
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Fig. 6
Figure 6.
Theobromine mediated inhibition on capsaicin-induced nerve depolarization of isolated human vagus
nerve. Tracing shows the inhibitory effect of theobromine on human vagus nerve depolarization induced by capsaicin.
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... persistent cough arising from a wide range of respiratory conditions such as chronic obstructive pulmonary disease, lung cancer and pulmonary fibrosis 6 . Types of antitussives 7 . ...
Full-text available
Background: Many plants are known by people to be used traditionally as medicinal plants among those known some are investigated for their medicinal activities whereas some have not been evaluated. Houttuynia cordata is a plant most commonly found in Southeast Asian countries, it is known tradionally in many countries to be used for various diseases like diarrhea, cough and many others depending on the country find outs. Objective: To study the Pharmacognostical, phytochemical characteristics of Houttuynia cordata and to investigate its anti-tussive activity on guinea pigs. Methods: The plant Houttuynia cordata was collected, dried and powdered. The powdered plant was carried out for extraction using various solvents based on their polarity; the extracts obtained are carried out for phytochemical screening and pharmacological investigation for its medicinal activity. Results: Sub-fraction extraction of the plant was carried by various solvents from the most polar to the least using Soxhlet apparatus; Petroleum ether 10.07%, Benzene 2.27%, Chloroform 1.06%, Acetone 3.34%, Ethanol 6.27%, Aqueous extract 26.21%. Phytochemical screening of H. cordata showed the presence of Alkaloids, carbohydrates, flavonoids, glycosides, Saponins and organic acids; the phytochemical screening results determine the extract that can be used to investigate the pharmacological activity. The pharmacological activity of the plant extracts showed that the Ethanol extract of the plant showed comparatively better results than the aqueous extract when compared to the baseline and standard drug Ambroxol on guinea pigs. Conclusion: The plant Houttuynia cordata has the potential anti-tussive activity when studied on chemically cough-induced guinea pigs; the plant can be studied more in detail for the activity and other activities that have not been explored.
... Theophylline, a type of methylxanthine, possesses anti-inflammatory effects on chronic obstructive pulmonary disease and asthma [103,104]. Moreover, theobromine, another type of methylxanthine, has an obvious anticough effect without side effects [105], and paraxanthine can be used in the treatment of Parkinson's disease [106]. 7-methylxanthine can also prevent the development of myopia and slow axial growth in children [107]. ...
Full-text available
Caffeine is a metabolite derived from purine nucleotides, typically accounting for 2-5% of the dry weight of tea and 1-2% of the dry weight of coffee. In the tea and coffee plants, the main synthesis pathway of caffeine is a four-step sequence consisting of three methylation reactions and one nucleosidase reaction using xanthine as a precursor. In bacteria, caffeine degradation occurs mainly through the pathways of N-demethylation and C-8 oxidation. However, a study fully and systematically summarizing the metabolism and application of caffeine in microorganisms has not been established elsewhere. In the present study, we provide a review of the biosynthesis, microbial degradation, gene expression, and application of caffeine microbial degradation. The present review aims to further elaborate the mechanism of caffeine metabolism by microorganisms and explore the development prospects in this field.
... This metabolite is found in food and is endogenously metabolized from caffeine. Sickness behavior is characterized by reduced food ingestion, which affects host responses to infections (71), and theobromine levels might indicate improved nutritional status upon recovery or even contribute to the resolution of symptoms such as cough (72). Importantly, data integration revealed that metabolite clusters better explain differences in individuals who recovered from mild/moderate and severe disease. ...
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Severe manifestations of coronavirus disease 2019 (COVID-19) and mortality have been associated with physiological alterations that provide insights into the pathogenesis of the disease. Moreover, factors that drive recovery from COVID-19 can be explored to identify correlates of protection. The cellular metabolism represents a potential target to improve survival upon severe disease, but the associations between the metabolism and the inflammatory response during COVID-19 are not well defined. We analyzed blood laboratorial parameters, cytokines, and metabolomes of 150 individuals with mild to severe disease, of which 33 progressed to a fatal outcome. A subset of 20 individuals was followed up after hospital discharge and recovery from acute disease. We used hierarchical community networks to integrate metabolomics profiles with cytokines and markers of inflammation, coagulation, and tissue damage. Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) promotes significant alterations in the plasma metabolome, whose activity varies according to disease severity and correlates with oxygen saturation. Differential metabolism underlying death was marked by amino acids and related metabolites, such as glutamate, glutamyl-glutamate, and oxoproline, and lipids, including progesterone, phosphocholine, and lysophosphatidylcholines (lysoPCs). Individuals who recovered from severe disease displayed persistent alterations enriched for metabolism of purines and phosphatidylinositol phosphate and glycolysis. Recovery of mild disease was associated with vitamin E metabolism. Data integration shows that the metabolic response is a hub connecting other biological features during disease and recovery. Infection by SARS-CoV-2 induces concerted activity of metabolic and inflammatory responses that depend on disease severity and collectively predict clinical outcomes of COVID-19. IMPORTANCE COVID-19 is characterized by diverse clinical outcomes that include asymptomatic to mild manifestations or severe disease and death. Infection by SARS-CoV-2 activates inflammatory and metabolic responses that drive protection or pathology. How inflammation and metabolism communicate during COVID-19 is not well defined. We used high-resolution mass spectrometry to investigate small biochemical compounds (<1,500 Da) in plasma of individuals with COVID-19 and controls. Age, sex, and comorbidities have a profound effect on the plasma metabolites of individuals with COVID-19, but we identified significant activity of pathways and metabolites related to amino acids, lipids, nucleotides, and vitamins determined by disease severity, survival outcome, and recovery. Furthermore, we identified metabolites associated with acute-phase proteins and coagulation factors, which collectively identify individuals with severe disease or individuals who died of severe COVID-19. Our study suggests that manipulating specific metabolic pathways can be explored to prevent hyperinflammation, organ dysfunction, and death.
... Recent studies have identified theobromine as an inhibitor of PARP-1 [27], tooth enamel strengthening [28] and an antitussive agent [29], suggesting that there are opportunities in the future to use theobromine as a drug, be it for prevention or treatment [30]. ...
Conference Paper
The theobromine content in cacao is believed to have health benefits for humans. This study aims to determine the theobromine content of non-fermented cacao powder with hot steam roasting treatment. The raw material for this research is cacao pods from Bantaeng district, South Sulawesi with seeds that are blanched, not fermented, dried in the sun, then roasted using low temperature hot steam at 80 °C, stirring for 30 minutes. Cacao beans are processed into powdered cacao which is rich in flavonoids as raw material for functional food or beverages. Tests were carried out using chromameter for color test, organoleptic test with trained panelists, and HPLC tool to measure theobromine levels. The results showed that color test of cacao powder is pale brown because it comes from unfermented cacao beans, organoleptic scores in general there is no difference in taste between cacao powder that is roasted and not roasted, and the theobromine content in ground roasted cacao (2.41%) was higher than that given unroasted powdered cacao (2.31%). Roasting with heating will evaporate the water in the cacao beans so that the detected theobromine content increases. These results support the function of theobromine in cacao powder as a bioactive component that plays an important role in health.
... Although lately substituted by more efficient compounds, theophylline was also used in the treatment of COPD [26]. Finally, theobromine and theophylline have shown promising antitussive capabilities [27,28]. Interestingly, it has been demonstrated that theophylline inhibits activation of single C-fiber afferents in vivo, impedes depolarization of human and guinea pig vagus in vitro and inhibits calcium influx in specific airway neurons in vitro, producing in consequence its antitussive effects [29]. ...
Because of its benefic effects on alertness, mood and sense of wellbeing, caffeine in its many presentations, is widely consumed. This alkaloid is mainly contained in coffee plants (Coffea spp.), particularly in the seeds known as coffee beans. Caffeine is also naturally present in guarana fruit, mate tea, etc.; when artificially synthesized it is used in beverages, foods, weight loss supplements, over the counter preparations against flu symptoms, etc. Besides its well-recognized consequences on the central nervous system, coffee consumption has also been associated to an improvement in lung function, even though such upgrading could not be undoubtedly related to the caffeine content of the consumed coffee or to other compounds in the brew. In this regard, a study using eucapnic voluntary hyperventilation, established that FEV1 after exercise was about 10 percent greater when 10 mg/kg of caffeine were consumed. Conceivably, caffeine benefits in respiratory function seen in people with exercise-induced bronchoconstriction ought to be explored further. In contrast, caffeine-containing products used by asthmatics as self-treatment seem to increase illness severity, probably because conventional asthma medication intake deferral, interruption or avoidance. As this was not a clinical trial, effect or causality of caffeine association to worse asthma control could not be proven. Seemingly, caffeine capabilities have not been thoroughly understood. Therefore, the aim of the present review was to analyze available data regarding its effects on airways and lung function and to discuss how effects in vitro and in vivo might be due to divergent pathways.
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Xanthine is a versatile nitrogenous alkaloid. The pharmaceutical active nature of xanthine derivatives is widely known for treating various diseases. Therefore, xanthine can act as structurally rigid scaffold which provides enormous possibility for molecular diversity in drug development process. Xanthine based compounds are reported for their non-specific phosphodiesterase inhibition, however, xanthine based inhibitors have not been reported for PDE9A inhibition. With introduction of “xanthine” as a scaffold, the present study was an attempt to bring molecular diversification in PDE9A research. The current study was emphasized on two approaches – one was virtual screening to find out the possibilities of existing xanthine based derivatives to regulate the catalytic action of PDE9A and the second approach was to use the xanthine as scaffold for designing new xanthine derivatives and again the same xanthine was used as ‘starting material’ for synthesizing selected xanthine derivatives. Two schemes were developed based on getting clear understanding over the molecular structure of xanthine. The biological studies were carried out to understand the biological affinity of the selected virtual screened compounds and chemically synthesized new compounds by using spectrophotometric inhibition studies for structural activity relationship (SAR) analysis and thermal shift assay for stability studies of protein-ligand complex. The biological studies showed chemically synthesized xanthine derivatives as better inhibitors than virtual screened compounds.
Background: We previously reported in an uncontrolled study that tiotropium alleviated chronic cough in asthma refractory to inhaled corticosteroids and long-acting β2 agonists (ICS/LABA) by modulating capsaicin cough reflex sensitivity (C-CRS). Objective: We sought to demonstrate the antitussive effects of tiotropium for refractory cough in asthma in a randomized, parallel, open-label, trial. Methods: Fifty-eight asthmatics with chronic cough refractory to ICS/LABA were randomized in a 2:1 ratio to add tiotropium 5 μg (39 patients) or theophylline 400 mg (19 patients) for 4 weeks. Patients underwent workup, including capsaicin cough challenge test and subjective measures such as cough severity visual analog scales (VAS). We adopted C5, the lowest capsaicin concentration to induce at least 5 coughs, as an index of C-CRS. We also performed a post hoc analysis to identify factors predicting tiotropium responders, who showed an improvement of ≥15 mm in cough severity VAS. Results: Fifty-two patients (tiotropium; 38, theophylline; 14) completed the study. Both tiotropium and theophylline significantly improved cough severity VAS and cough-specific quality of life. Tiotropium, but not theophylline, significantly increased C5 values, whereas pulmonary function did not change in either group. Additionally, changes in cough severity VAS correlated with changes in C5 values in the tiotropium group. A post hoc analysis revealed that heightened C-CRS (C5 ≤1.22 µM) before the addition of tiotropium was an independent predictor for tiotropium responders. Conclusion: Tiotropium may alleviate chronic cough in asthma refractory to ICS/LABA by modulating C-CRS. Heightened C-CRS may predict responsiveness to tiotropium for refractory cough in asthma.
This study aims to investigate the chemical components and biological activities such as antioxidant, antibacterial, expectorant, and antitussive activities of essential oils (EOs) from raw and stir-frying Citri Reticulatae Pericarpium (ORP and OSP, respectively). The process for EOs extraction by hydrodistillation was optimized by response surface methodology. The optimized condition included soaking time of 7.20 h, liquid–solid ratio of 17.22:1, and extraction time of 4.18 h. The extraction rates of EOs from ORP and OSP were 2.11 % and 1.58 %, and 34 and 32 chemical components were identified by gas chromatography–mass spectrometry (GC-MS) with the highest proportion of monoterpene hydrocarbons (83.61 % and 93.64 %), respectively. The main components of ORP and OSP were limonene (69.43 % and 75.04 %) and γ-terpinene (8.93 % and 9.94 %). In the antitussive and expectorant tests, OSP significantly promoted tracheal secretion and inhibited cough. The cough frequency of OSP at low dose (100 mg/kg) was lower than that of theobromine. The phenol red secretion and cough incubation period of OSP at a high dose (400 mg/kg) was close to that of the positive control theobromine and ambroxol. ORP and OSP demonstrated strong antitussive and expectorant activities and also possessed certain antioxidant and antibacterial activities. These activities of OSP were significantly better than those of ORP. Hence, OSP shows great application potential in food, medicine, and chemical industries. The traditional processing technology plays a very important role in improving activities.
Objectives: The antitussive, expectorant, and anti-inflammatory effects of Mahwangyounpae-tang (MHYPT) aqueous extracts were observed in appropriate animal models of various respiratory disorders.Methods: MHYPT aqueous extracts were orally administered once a day for 11 days at dose levels of 400, 200, and 100 mg/kg. The effect of MHYPT was determined by comparing its antitussive effect with theobromine (TB), its expectorant effect with ambroxol (AM), and its anti-inflammatory effect with dexamethasone (DEXA).Results: MHYPT aqueous extracts (400 mg/kg) showed favorable antitussive effects comparable to those of TB (50 mg/kg) in the NH4OH-exposure coughing mouse model and expectorant effects comparable to those of AM (250 mg/kg) in the phenol red-secretion mouse model, but MHYPT (400 mg/kg) showed less anti-inflammatory activity compared to DEXA (1 mg/kg) in the xylene-induced acute inflammatory mouse ear model under the experimental conditions used.Conclusion: MHYPT aqueous extracts administered at dosage levels of 400, 200, and 100 mg/kg induced dose-dependent and favorable antitussive, expectorant, and anti-inflammatory activities that occurred by simultaneous modulation of the activity of mast cells and respiratory mucous production under the experimental conditions used in this study.
Study objective: To psychometrically evaluate a cough-specific quality-of-life questionnaire (CQLQ) in adults. Design: Prospective evaluation of CQLQ using three different cohorts of adult subjects with cough. Setting: Academic tertiary-care ambulatory medical facilities. Participants: One hundred fifty-four subjects complaining of chronic cough, 30 of acute cough, and 31 smokers with cough. Interventions: Self-administration of the CQLQ in acute coughers, smokers, and chronic coughers before and after therapy. Measurements: Psychometric analyses including factor analysis (FA), and assessments of reliability and validity. Results: Acute and chronic cough data were subjected to FA, and the Cronbach and interitem correlations were computed. FA of chronic and acute cough data (n 184) revealed six subscales. The Cronbach for the total CQLQ was 0.92, and it was 0.62 to 0.86 (mean, 0.76) for the six subscales. Interitem correlations for the total CQLQ ranged from 0.06 to 0.72, with a mean of 0.28. Test-retest reliability in 52 chronic coughers demonstrated nonsignificant changes with readministration of the questionnaire, and the intraclass correlation for total CQLQ was 0.89, and for the subscales the range was 0.75 to 0.93. Analysis of variance followed by tests of contrasts among all possible pairings of chronic coughers, acute coughers, and smokers showed significant differences (p < 0.001) among the groups. Posttreatment cure scores were significantly lower (p < 0.001) than pretreatment scores in 24 chronic coughers. Conclusions: The 28-item CQLQ has dimensionality that is consistent with a cough-specific quality-of-life instrument. It is a valid and reliable method by which to assess the impact of cough on the quality of life of chronic and acute coughers, and the efficacy of cough therapies in chronic coughers. (CHEST 2002; 121:1123–1131)
Objective. —To estimate the prevalence of recent over-the-counter (OTC) medication use in a national sample of preschool-age children.Design. —Follow-up survey of a nationally representative sample of 3-year-old children in the US population by telephone or personal interview.Participants. —A total of 8145 children whose mothers were interviewed for the 1991 Longitudinal Follow-up to the National Maternal and Infant Health Survey.Main Outcome Measures. —Report of any OTC medications given in the past 30 days and the type of medications that the child received.Results. —During the past 30 days, 53.7% of all 3-year-old children in the United States were given some OTC medications. Among OTC medication users, the most common medications reported were Tylenol (66.7%) and cough or cold medicine (66.7%). Most respondents reported that recent child illness episodes (70%) were treated with OTC medications. After adjustment for recent child illness, women who were white (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.13 to 1.55), were more educated (OR, 1.58; 95% CI, 1.24 to 2.00), and had higher incomes (OR, 1.75; 95% CI, 1.33 to 2.30) were more likely to have given their child OTC medications. Women without health insurance were also more likely to have given OTC medications (OR, 1.27; 95% CI, 1.04 to 1.55). Provider visits, but not telephone calls, were associated with a reduction in OTC medication usage.Conclusions. —Over-the-counter medications are an important component of health care for treating illness in US preschool-age children. The high prevalence of use has occurred despite the dearth of scientific proof for the effectiveness of certain classes of OTC medications and the risks associated with improper use.(JAMA. 1994;272:1025-1030)
We have evaluated the properties of capsaicin as a selective cough-inducing agent in healthy human subjects. Despite frequent coughing, the subjects could inhale repeated breaths of capsaicin aerosol during 60 s without difficulty. Cough started immediately on inhalation and was most intense during the first 30 s. Cough always disappeared promptly when the capsaicin inhalation was terminated. The cough response was well reproducible and concentration-dependent up to 10 microM; at higher concentrations there was a distinct plateau of the cough response. Specific airway conductance was not changed 3 min after 50 microM capsaicin. Capsaicin (> or = 10 microM) had a burning taste, but there were no visual signs of pharyngitis or laryngitis. Citric acid (nebulized solutions 0.125 to 32%) had a choking effect and could be administered only as single breaths. There was no correlation between the cough response to citric acid and to capsaicin. Inhaled lidocaine (20 and 80 mg from nebulized solutions) caused a dose-dependent inhibition of capsaicin-induced cough. Lidocaine suppressed citric acid-induced cough as effectively as capsaicin-induced cough. In conclusion, we have characterized capsaicin-induced cough and demonstrated that it can be a useful tool in the study of cough reactivity and for evaluation of antitussive agents in humans. Capsaicin may be complementary to citric acid and may offer experimental advantages over this traditional tussive stimulus.
Inhalation cough challenge has become an accepted method of investigating antitussive agents. It is, therefore, important to examine the degree of tachyphylaxis seen with repeated cough challenge. In addition, different types of challenge may reveal important differences in the neuronal pathways involved in the cough reflex. Citric acid, distilled water and capsaicin were examined to determine adaptation of the cough response during acute and long-term inhalation studies in healthy subjects. To study acute tachyphylaxis two separate one minute continuous inhalation challenges (n = 13) were performed. Long-term tachyphylaxis (n = 10) was examined using citric acid and capsaicin inhalation at 10 min intervals for 40 min, and at 4 and 6 h. Cross-tachyphylaxis to citric acid and capsaicin was examined in a separate randomized crossover study (n = 10). Highly significant adaptation occurred between the first and last 10 s of the one minute challenge with citric acid (90-100%) and distilled water (74-84%), but was less pronounced with capsaicin (37-49%, at 2 microM). Cough during the whole of the second test was significantly reduced for citric acid (50%). During long-term challenge cough was attenuated over 40 min both with citric acid (100 mM, p less than 0.05; 300 mM, p less than 0.001; 1 M, p less than 0.001) and with capsaicin (3 microM, p less than 0.01; 10, 30, 100 microM, p less than 0.001 each). With higher doses, tachyphylaxis was still present at 180 min with both citric acid (300 mM, p less than 0.05) and capsaicin (100 microM, p less than 0.008).(ABSTRACT TRUNCATED AT 250 WORDS)
To determine the site of action of opiates in humans, we have studied the effect of systemic and inhaled opiates on cough and increase in respiratory resistance (Rrs) caused by inhaled capsaicin. In 13 subjects, a range of doses of capsaicin inhaled in single breaths given in random order produced a reproducible dose-cough response. Inhalation of a dose of capsaicin that caused fewer than two coughs increased Rrs by 28% (21-35, mean 95% confidence interval). Inhaled codeine (50 mg) and morphine (10 mg) did not alter the cough response. In contrast, both drugs increased base-line Rrs by 24% (16-44) and 13% (3-23), respectively, and significantly reduced the increase in Rrs after inhaled capsaicin (P less than 0.05). Oral codeine (60 mg) significantly (P less than 0.05) reduced the number of coughs at 1 and 2 h but did not alter base-line Rrs or its increase after capsaicin. Intravenous morphine (0.15 mg/kg) significantly reduced the sensitivity of the cough response (P less than 0.05), which was reversed by naloxone. However, there was no significant drug effect on either the base-line Rrs or its increase after capsaicin. Systemic dosing of opiates is therefore required to reduce the cough reflex, whereas inhaled opiates may reduce the increase in Rrs after inhaled capsaicin.
The bronchodilator effect of a 10 mg/kg dose of theobromine (3,7-dimethylxanthine) was compared with that of 5 mg/kg of theophylline (1,3-dimethylxanthine) in young patients with asthma. Bronchodilation, as assessed by forced vital capacity, forced expiratory volume in the first second, forced expiratory flows at 25%, 50%, and 75% of vital capacity, and percent of forced expiratory volume in the first second/forced vital capacity did not differ significantly between the two drugs. After each drug bronchodilation peaked at 2 hours and lasted for 6 hours, although it was not always statistically significant for theobromine. The mean peak serum concentrations of both drugs, the time at which peak serum concentrations occurred, and elimination half-life values were similar for theobromine and theophylline.
We have attempted in this review to give an account of an afferent vagal input from the lower respiratory tract that has still to be explored fully, and to present experimental evidence that this fine fibre afferent system plays a significant role in the neural control of respiratory function in both normal and pathological circumstances. We have made a distinction between the afferent C fibres that innervate the lung parenchyma adjacent to the pulmonary capillary bed and those that innervate the conducting airways, even though the afferent C fibres in the two locations appear to have reflex properties that are at least qualitatively similar. We believe that the functional significance of these lower respiratory tract C fibres is determined not simply by their location but also by certain differences in afferent properties that should not be overlooked. Douglas and Ritchie (1962) suggested, in their review of mammalian non-myelinated nerve fibres, that the teleological advantage of the finefibre afferent system, especially in the case of a visceral input where speed of impulse transmission was not of primary importance, was that it allows fibres of a variety of sensory modalities to be accommodated in a small cross-sectional area of nerve trunk. There is no reason to think that the full range of sensory modalities of the afferent C fibres in the lungs and airways has yet been explored. The custom of injecting certain chemicals to identify the presence of lower respiratory tract C fibres when recording the activity in vagal strands is highly selective, so that even now our view of this afferent fibre system may be unnecessarily narrow. Some of the conclusions arrived at in these pages are either purely speculative or derived from experimental evidence that is at best indirect. Whether they prove to be correct or incorrect — and some are sure to fall into the latter category — their purpose will have been served if they are put to the test of experiment.