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Analysis of pathomechanisms involved in side effects of menthol treatment in respiratory diseases

Authors:
  • Vseobecna zdravotna poistovna, a.s.
Open Journal of Molecular and Integrative Physiology, 2013, 3, 21-26 OJMIP
http://dx.doi.org/10.4236/ojmip.2013.31004 Published Online February 2013 (http://www.scirp.org/journal/ojmip/)
Analysis of pathomechanisms involved in side effects of
menthol treatment in respiratory diseases
Silvia Gavliakova1, Tomas Buday1, V. Manjunath Shetthalli2, Jana Plevkova1*
1Department of Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin, Slovakia
2Royal Gwent Hospital, Newport, UK
Email: *jplevkova@gmail.com, plevkova@jfmed.uniba.sk
Received 25 September 2012; revised 3 November 2012; accepted 20 November 2012
ABSTRACT
Menthol is frequently used in over the counter medi-
cations for common colds and coughs. It was formerly
considered to be under the class of herbal medicine,
but identification of menthol receptor (TRPM8)
moved it from the class of herbal medicine to the mo-
lecular pharmacology. It has been documented that
menthol reduces dyspnoea and nasal obstruction via
stimulation of nasal cold or flow receptors. It has also
antitussive and antiirritative effect. Menthol can also
induce adverse reactions such as airway irritation,
dyspnoea, chest tightness and potentially respiratory
failure, mainly in children. The mechanisms respon-
sible for adverse reactions of menthol are not known
completely. The adverse reactions of menthol could
be due to its effects on TRPA1 channel, relevant to
airway irritation. Higher concentrations of menthol
stimulate TRPA1 channel causing airway irritation.
It also increases mucus production and at the same
time reduces cilliary activity leading to mucus stagna-
tion. As the adverse effects were reported mainly at
the night it is supposed that suppressed cough reflex
during sleep potentiated by menthol induced cough
suppression might be responsible for lack of airway
mucus clearing and obliteration of small airways.
Adverse effects could also be due to consequences of
reflexes induced by the menthol action on trigeminal
afferents, like apnoea or bronchoconstriction. Men-
thol is effective in relieving respiratory symptoms,
but cough and cold medications should be used with
caution. Recommendations are low concentrations of
menthol used locally (intranasal) and not combined
with camphor or cineole, as they may have additive
effects and should be avoided in children under 2
years. Further data are necessary to completely elu-
cidate potential risks of over the counter menthol
medication in children but based on the meta analy-
sis of documented case reports, menthol can be used
safely if its contraindications for use are followed as
with any other over the counter medications.
Keywords: Menthol; TRPM8; Airways; Treatment
1. INTRODUCTION
Recycling of respiratory viruses in the community,
seasonal factors, social factors (collective facilities—
schools, kindergartens) as well as the fact that the
respiratory system is open to environmental influences
lead to a high incidence of respiratory diseases in popu-
lation. Many of these diseases are self limiting viral
infections or common colds and they do not require any
specific treatment. However symptomatic relief may be
necessary in such infections. The most commonly used
drugs for symptomatic relief of common colds are nasal
decongestants and cough medications as nasal conges-
tion, runny nose and cough are the most limiting symp-
toms [1].
Over the last couple of years there has been a great
deal of attention focused on the potential risk of cough
and cold medication in infants and young children,
despite the fact that these medicines are widely used with
little evidence about their effectiveness [2].
Many of these symptomatic drugs contain essential
aromatic volatile substances with a characteristic smell
such as camphor, thymol, cineol, but the most common
of them is menthol. Identification of the molecular me-
chanism of the menthol effects (TRPM8 receptor), suc-
cessfully moved the substance from the class of herbal
medicine into the field of molecular pharmacology.
Extensive study of menthol action and other TRPM8
agonists could have interesting clinical applications [3].
2. MENTHOL AND ITS USE
Menthol is an aromatic substance, a component of pep-
permint extract and it has a characteristic flavor and
smell. Menthol is cyclic terpene alcohol, which has three
asymmetrically situated carbon atoms in the cyclohexane
*Corresponding author.
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S. Gavliakova et al. / Open Journal of Molecular and Integrative Physiology 3 (2013) 21-26
22
ring and the chemical structure allows the existence of
four pairs of optical isomers. L-menthol is the isomer
that has the strongest biological activity. It has typical
peppermint smell and causes cooling sensation when ap-
plied topically to the skin or mucous membranes [4,5].
Cooling effects of menthol are not caused by its rapid
evaporation from the surface as it was previously as-
sumed, but rather through the effect of menthol on ther-
mosensitive nerve endings via TRPM8 channel, as the
receptor for menthol and mild cold are identical [6].
TRPM8 is a non-selective cation channel belonging to
the group of melastine TRP channel super family.
TRPM8 was successfully cloned from dorsal root ganglia
neurons of rats, mice and humans and its expression is
not limited only to the primary sensory neurons, but it is
expressed by other cell types, such as respiratory or
genitourinary epithelium [6,7].
This receptor is sensitive to menthol, eucalyptol, lin-
alol, geraniol, icilin and other substances with cooling
effect. Electrophysiological studies have shown that this
channel is highly permeable to Ca2 + and its activation in
turn leads to increased intracellular Ca2 + due to influx
from the extracellular environment as well as release of
calcium from intracellular reserves as well [8].
Application of menthol at low concentrations causes
pleasant cooling, analgesic and antiirritant effect. Higher
concentrations of menthol can cause irritation, but this
mechanism does not depend only on concentration [9,10].
Sensations of burning and irritation after the application
of menthol can be explained by a dual mechanism of
agonism of menthol, which at higher concentrations
activates TRPA1 along with TRPM8 channel. TRPA1 is
abundantly expressed in nociceptors [11].
Symptom Relief by Menthol
One of the most common indications for the use of
menthol and menthol-containing medicines are the upper
respiratory tract diseases regardless of etiology (viral,
bacterial), because the symptomatology of these diseases
is very similar. They are nasal congestion, impaired
breathing through the nose, feeling of airway irritation,
sneezing, increased secretion from the nose and cough.
For that reason, majority of such medicines are for local
intranasal use in form of the nasal drops, sprays or oral
use—pastilles, candies and finally ointments that are
applied in a thin layer on the front and back of the chest
wall.
Application of menthol in combined products, or even
alone considerably limits the feeling of nasal congestion.
Although menthol/placebo inhalation does not affect
objectively measured nasal resistance, it significantly
increases subjective perception of nasal patency, which
was evaluated by visual analogue scale. So the applica-
tion of menthol reduces subjective discomfort caused by
the presence of this symptom [12,13]. Nerve endings
sensitive to menthol were previously known as cold/flow
receptors, because their activation occurs due to airflow
in upper airways. Each “new” breath of fresh air, colder
than the temperature of the mucosal surface activates
them, so does the menthol. Information from these re-
ceptors is in turn interpreted by brain as “a feeling of
improved airflow in the airways” [3].
Intensity of nasal symptoms is also reduced after nerve
stimulation on the palate—for example, administration of
pastilles or candy containing menthol markedly enhances
the feeling of breathing through the nose, but rhino-
manometric parameters remain unchanged [14]. These
oro-nasal interactions are mediated through palatal
nerves and menthol fumes evaporated to the nasopharynx
and nasal cavity during expiration [15]. Menthol in the
symptomatic treatment of cough is mainly used in the
case of acute cough. Antitussive effect of menthol was
shown in experimental studies as well as in the adult
volunteers, after inhalation of menthol vapors to the
lower airways [16,17]. Houghton and Beardmore also
documented antitussive effect of menthol vapors in
children [18]. However, antitussive activity of menthol is
probably mediated through afferent nerves in the upper
airways, which abundantly express TRPM8 channels
[19]. TRPM8 expression in afferent nerves in animal
airways has shown that afferent nerves in the lower
respiratory tract express TRPM8 channels significantly
less in number than those in the upper respiratory tract,
especially trigeminal endings in the nose [20,21].
In addition, antitussive activity of menthol could be
enhanced by other mechanisms. Menthol is known to
reduce the feeling of irritation and respiratory discomfort.
This finding was documented in the study, where 1% l-
menthol was used as part of premedication before fibro-
bronchoscopic examination [22]. Menthol is also known
to modulate mucociliary transport. Substances modu-
lating mucociliary transport suppress cough by reducing
the feeling of irritation of airways, liquefying mucus and
facilitate its mobilization in the airways. The other me-
chanism is that sucking pastilles or sweets containing
menthol increases production of saliva and stimulate
swallowing. Swallowing is a vagal reflex process that su-
ppresses cough [23].
There are also studies that document the administra-
tion of menthol (0.01 to 1 mM) and other TRPM8 ago-
nist icilin (100 µM) inhibits smooth muscle contraction
of airways in vitro and the effect on smooth muscle is
probably mediated through inhibition of Ca2+ entry into
cells, as was shown by fura 2 fluorescence procedures.
These findings suggest potential use of menthol in
reducing symptoms of respiratory illness caused by
bronchoconstriction [24].
Based on the available data as mentioned above, there
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S. Gavliakova et al. / Open Journal of Molecular and Integrative Physiology 3 (2013) 21-26 23
is pharmacological, clinical and laboratory evidence of
its use is alleviation of respiratory symptoms both in
children and adult population [25].
3. ADVERSE EFFECTS OF MENTHOL
CONTAINING COUGH AND COLD
MEDICINES
Although the administration of menthol containing me-
dicines is considered relatively safe and is used quite
often, it can lead to serious adverse reactions. Such mani-
festations may occur in hypersensitive adults. Young
children may also experience toxicity of menthol which
is underestimated in clinical practice.
It is fully not known about the broad range of cough
and cold medicines as their composition is not always
exactly defined and we do not know effects of all drug
components in detail. There are case reports documen-
ting serious or even life-threatening situations caused by
application of cough and cold medications containing
menthol. Meta analysis of literature and available case
histories suggest that it is not the menthol itself, but the
inappropriate use of medicines ignoring the recom-
mendations on product labels could be causing the ad-
verse incidents.
3.1. Disregulation of Breathing Induced by
Application of Menthol
It is known, that the control of breathing and airway
defensive reflexes in newborns and infants matures pro-
gressively with the development of central nervous
system. Some works indicate that these mechanisms are
not fully functional before reaching the age of 24 months
[26]. It is further known that the application of strong
chemical stimuli and cold to the nasal cavity and face
stimulates the nerve endings of the trigeminal nerve.
Relevant stimuli could be chemical, thermal or mecha-
nical. In response to the application of mentioned stimuli
such as cold and chemical irritants to the area of baby’s
nose and face, there is activation of reflex reactions with
deceleration of respiratory rate or even respiratory arrest
(apnoea) followed by the cardiovascular component of
the response in the form of bradycardia and hypertension
with blood redistribution—Kratschmer apnoeic reflex
[27]. In addition, laryngospasm may occur. These reac-
tions are part of a complex system of airway defensive
and protective reflex mechanisms, whose main function
is to prevent inhalation of potential hazards deeper into
the respiratory tract.
In few cases, all children younger than 1 year, menthol
applied to the nostrils caused reflex apnoea. Clinical
signs were laryngospasm, spasm of the glottis, instant
collapse, dypnoea, unconsciousness, cyanosis and hyper-
extensive extremities [28]. This mechanism—activation
of reflex apnoea, was probably responsible for the situa-
tion documented in case reports, where young children
were given nasal drops containing menthol. In this par-
ticular situation the drops had been stored in refrigerator
and activation of trigeminal afferents was not only
triggered by the chemical composition of the drops but
also by low temperature of it. There have also been
documented cases in which parents applied menthol-
containing chest lining VapoRub just below the nose in
an eighteen months old child and the child immediately
went cyanotic and stopped breathing. Parents responded
to the situation by turning the child upside down and
after a few strokes to back the child coughed out mucus
and then breathing went back to normal [29]. In this case
that VapoRub was used in the child younger than 2 years
(contraindicated according to the product label) and it
was not applied on the chest wall, but directly to the
proximity of trigeminal nerve endings near the nostrils.
It is documented in experimental works that cold and
menthol application directly to the nasal mucosa leads to
drop in respiratory rate in experimental animals [30,31]
and application of menthol crystals below the nose of a
newborn considerably inhibits his/her respiratory rate
[26]. Based on this knowledge we can conclude that is
not just the pharmacology of menthol inducing apnoea in
small children, but the way it is administered contri-
buting to it. Caution should always be taken when app-
lying nose drops or sprays to small children considering
possible reflex interactions and immaturity of breathing
regulation mechanisms in infants.
Searching for adverse effects of menthol nasal drops
also revealed case reports of death of infants who had
been treated with certain cough—cold products, but these
were ones containing decongestant Pseudoephedrine,
which was given in large dose [32], so this result could
not be ascribed to the menthol or other natural products.
3.2. Nasobronchial Reflex
Clinical experiences document that menthol containing
cough and cold medication triggered wheezing or bron-
choconstriction. Exact mechanism of menthol induced
airway narrowing causing wheezing is not known. Appli-
cation of menthol and its superagonist icilin in experi-
mental conditions inhibits bronchial smooth muscle con-
traction and hence the direct effect of inhaled menthol
vapors with the development of bronchoconstriction is
unlikely [24].
If we consider the most common application of men-
thol in the form of nose drops or sprays—the bron-
choconstriction could occur in terms of reflex response
called nasobronchial reflex. This increased resistance of
lower airways caused by bronchoconstriction is by irrita-
tion of the trigeminal afferent nerve endings and it is a
trigemino—vagal reflex mechanism [33]. Although the
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S. Gavliakova et al. / Open Journal of Molecular and Integrative Physiology 3 (2013) 21-26
24
opinions of nasobronchial reflex are often being dis-
cussed, the differences of opinion still do exist [34-36].
Some authors have reported bronchoconstriction after
irritation of nasal trigeminal afferents, some authors re-
ported bronchodilation and in some cases, the lower
airway resistance remained unchanged.
Extensive review by Baraniuk and Merck [33] about
nasal reflexes and their implications share that nasobron-
chial reflex is a component of diving (apnoeic) reflex
whose efferent components include bronchoconstriction
along with apnoea and laryngeal spasm. Nasobronchial
reflex is frequently under debate and it may be elicited
by stimulation of trigeminal nasal afferents by mechani-
cal, thermal or chemical stimuli—therefore application
of menthol—which is both chemical and thermal cha-
nnels agonist, might be responsible for such reactions.
3.3. Modulation of Mucociliary Transport
As it has been shown in animal models, menthol
inhalation leads to increased production of mucus in the
airways, which can be beneficial if the airways contain
thick and viscid mucus that is difficult to cough up.
Increased mucus production and change of its biophy-
sical qualities may not always be beneficial, because
menthol simultaneously inhibits the activity of cilia in
the airways, which can lead to stagnation of the mucus in
small airways [2]. Cough reflex plays important role in
the mucus elimination from the airways, but in case of
menthol treatment, cough is usually inhibited due to its
antitussive action. Application of ointments and rubs
containing menthol on the chest in the night times when
the baby does not move can deteriorate the situation
further. It is known that during sleep the sense of airway
irritation does not occur, cough is inhibited due to sleep
and the child may wake up in a paroxysm of cough, dys-
pnoe, wheezing which may eventually lead to respiratory
failure. Mucus plugs obliterate small airways, leading to
alveolar hypoventilation, ventilation-perfusion misma-
tching with impaired oxygenation and ventilation leading
to respiratory failure.
3.4. Other Problems Related to Menthol
“Toxicity”
Application of menthol on the chest can cause irritation
of the skin of the chest, which manifests as redness of the
skin with presence of blisters. These effects are probably
due to the influence of menthol on TRPA1 channels of
skin somatosensitive nociceptors.
Bioavailability and toxicity of menthol and other
components present in VapoRubs and ointments after
dermal absorbtion is minimal with relatively low syste-
mic exposure to these compounds, even when an unrea-
listically large number of patches are applied onto the
skin for unusually long time [37]. Based on the literature
retrieved via MEDLINE and our review of calls to the
PIC there have been cases of accidental poisonings with
essential oils in children. There have been documented
cases of menthol, euclyptol and camphor poisoning in
small children after unintentional ingestion of drops, oils,
or eating VapoRubs by infants [38].
The main symptoms of poisoning were epigastric pain,
nausea, vomiting, dizziness, muscle weakness, miosis,
tachycardia, and breathing difficulties. Therefore it is
important to be cautious and use common sense when
children are surrounded by products containing the
mentioned substances.
4. CONCLUSION
From the literature review, it is evident that use of
menthol and menthol-containing cough and cold medica-
tions is very common in the symptomatic treatment of
common respiratory diseases. There has been increasing
pharmacological evidence for their use in relief of
respiratory symptoms in recent days. The adverse reac-
tions have occurred mostly in cases when the route and
mode of administration was breached or when it was
used in age range when it was not supposed to be used
(children less than 2 years). Accidental poisonings can
happen as with any other mediations and caution should
be used while these medications are in proximity of
children. Overall it can be concluded that over the
counter menthol and menthol containing components can
be safely used for symptomatic relief in common respira-
tory illness in children and adults guided by manufac-
turer guidance and product labels on route and mode of
administration and avoiding their use in very young
children less than 2 years of age.
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... By the same mechanism, menthol vapour application may exert antitussive effects in the lower respiratory tract 62,113 . Whilst these effects modulate the cough response lower down the respiratory tract, the mechanism of action appears to be related to TRPM8 containing trigeminal ganglia, as opposed to localised tissues 113,145 . ...
... Relatedly, these effects are not seen with either +(-) menthol (inactive isomer) or by icilin, which also targets TRPM8 and TRPA1 receptors 28,78,98 . TRPA1 channels are susceptible to causing airway irritation if higher concentrations of menthol are administered 62 . A further potentially adverse effect of menthol is that it increases mucus production, but also minimises mucus clearance due to ciliary movement reductions 62 . ...
... TRPA1 channels are susceptible to causing airway irritation if higher concentrations of menthol are administered 62 . A further potentially adverse effect of menthol is that it increases mucus production, but also minimises mucus clearance due to ciliary movement reductions 62 . In clinical populations suffering from conditions that are associated with coughing e.g. ...
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Mint and to a lesser extent menthol have been used since antiquity for medicinal purposes. Key components of mint and menthol use such as composition and intake, safety and traditional uses are discussed prior to a review of clinical and human performance outcomes in the areas of digestive and respiratory health; antibacterial and anti-fungal properties, nocioception, migraine and headache and emerging evidence regarding COVID 19. Evidence suggests benefit for patients with irritable bowel syndrome and related digestive issues, with analgesic and respiratory effects also noted. Perceptual characteristics relating to thermal comfort and sensation, taste sensitivity and alertness are also considered; these effects are predominantly driven by stimulation of transient receptor potential melastatin 8 (TRPM8) activity resulting in sensations of cooling and freshness, with lesser influence on thirst. Finally, sport performance is considered as a domain that may further elucidate some of the aforementioned underpinning outcomes due to its systemic and dynamic nature, especially when performed in hot environmental conditions.
... Both Strepsils® and Halls® lozenges are effective antiseptics and pain-reliefers but rely on artificial sweeteners and flavours to construct a candy-like medication far more palatable and easier to take than traditional pills or capsules, for both adults and children (Choursiya and Andheriya 2018;Oxford and Leuwer 2011). Additionally, the active substances used in these lozenges have been reported to cause mild adverse effects on occasion, such as headaches and ulceration of the oral cavity for AMC and DCBA, and airway irritation and shortness of breath in the case of menthol (Gavliakova et al. 2013;Weckmann et al. 2017). In this work, it is provided the conceptualization and design of natural throat lozenges bearing active components from olive leaf extract. ...
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This work presents the conceptualization and design of throat lozenges bearing active components from olive leaf extract as a means of valorizing olive leaves. This novel product is a vegan alternative to conventional lozenges and its natural formulation avoids the adverse effects of amylmetacresol, 2,4-dichlorobenzyl alcohol, and menthol, which are common ingredients of Strepsils® and Halls® lozenges. A reliable and straightforward methodology for the preparation of natural throat lozenges is herein described. Additionally, this product is compatible with the use of other leaf extracts, allowing the expansion and diversification of the production line. The manufacture process was simulated using Aspen Custom Modeler software and the energy required for the production of the lozenges was determined to be 0.28 kWh per kilogram of product. A preliminary economic analysis revealed that the industrial implementation of this product is viable, and the payback time was estimated at 4 years.
... Menthol is known to have inhibitory effect on mucociliary transport system. It has been reported that menthol increases mucus production in the airways of mammals, which may not always be beneficial (31,32). Mucociliary system acts as a non-specific defense mechanism against respiratory pathogens. ...
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Introduction: Despite the extensive use of herbal preparations for treatment of viral respiratory diseases in poultry, few studies have analyzed the effectiveness of these products. This study aimed to evaluate the effects of three different herbal respiratory symptom relieving agents in broiler chickens experimentally infected with H9N2 avian influenza (AI) and infectious bronchitis (IB) viruses. Methods: A total of 175 broiler chickens were randomly assigned into 5 equal groups. Negative control (NC) group remained intact while others received H9N2-AI and IB viruses. Treatment groups (G1-G3) but not positive control (PC) birds were treated with three different herbal agents containing menthol. Clinical and pathological aspects were evaluated during the experiment. Results: Administration of these agents to challenged chickens not only did not notably decrease clinical severity, gross and histopathological lesions, but also markedly increased mortality rate in treated groups. In dead cases, cast/plug formation was a prominent feature in the trachea. Treatment with herbal agents induced an increase of more than twofold in the number of goblet cells compared to PC group. Significant ciliostasis was observed in all challenged groups regardless of treatment, while ciliary activity was not changed statistically in comparison with the mean values of PC. Conclusion: In this study administration of herbal preparations adversely affected the tracheal epithelium via enhancement of goblet cell hyperplasia. It appears that hyper-secretion of mucosa along with ciliary incompetence causes mucus stagnation followed by tracheal or bronchial obstruction and death. These findings necessitate cautious use of these products.
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Background Upper respiratory tract infections (URTIs) impact all age groups and have a significant economic and social burden on society, worldwide. Most URTIs are mild and self-limiting, but due to the wide range of possible causative agents, including Rhinovirus (hRV), Adenovirus, Respiratory Syncytial Virus (RSV), Coronavirus and Influenza, there is no single and effective treatment. Over-the-counter (OTC) remedies, including traditional medicines and those containing plant derived substances, help to alleviate symptoms including inflammation, pain, fever and cough. Purpose This systematic review focuses on the role of the major plant derived substances in several OTC remedies used to treat cold symptoms, with a particular focus on the transient receptor potential (TRP) channels involved in pain and cough. Methods Literature searches were done using Pubmed and Web of Science, with no date limitations, using the principles of the PRISMA statement. The search terms used were ‘TRP channel AND plant compound’, ‘cough AND plant compound’, ‘cough AND TRP channels AND plant compound’, ‘cough AND P2X3 AND plant compound’ and ‘P2X3 AND plant compound’ where plant compound represents menthol or camphor or eucalyptus or turpentine or thymol. Results The literature reviewed showed that menthol activates TRPM8 and may inhibit respiratory reflexes reducing irritation and cough. Menthol has a bimodal action on TRPA1, but inhibition may have an analgesic effect. Eucalyptus also activates TRPM8 and inhibits TRPA1 whilst down regulating P2X3, aiding in the reduction of cough, pain and airway irritation. Camphor inhibits TRPA1 and the activation of TRPM8 may add to the effects of menthol. Activation of TRPV1 by camphor, may also have an analgesic effect. Conclusions The literature suggests that these plant derived substances have multifaceted actions and can interact with the TRP ‘cough’ receptors. The plant derived substances used in cough and cold medicines have the potential to target multiple symptoms experienced during a cold.
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The temporal characteristics of the oral perception of menthol solutions were explored in two experiments. In Experiment 1, 10 samples of either 0.03% or 0.30% menthol were presented at 1 min intervals and rated for the perceived intensity of cooling and irritation. Reports of sensation quality (burning, tingling, stinging and numbing) and pain were also collected. At the higher concentration, a significant decrease in perceived intensity was observed over time for irritation, but not for cooling. Experiment 2 was designed to explore further the nature of the decline in irritation observed in Experiment 1. Employing 1-min and 5-min inter-stimulus intervals between solutions, it was found that the decrease in menthol irritation more closely resembled desensitization than adaptation. Decreases in the frequency of reports of the burning and stinging qualities, but not the tingling, numbing or cooling qualities, suggested that menthol has a specific desensitizing effect on a population of mucosal nociceptive fibers.
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Background Cough, the most important airways defensive mechanism is modulated by many afferent inputs either from respiratory tussigenic areas, but also by afferent drive from other organs. In animal models, modulation of cough by nasal afferent inputs can either facilitate or inhibit the cough response, depending on the type of trigeminal afferents stimulated. Methods In this study we addressed the question of possible bidirectional modulation of cough response in human healthy volunteers by nasal challenges with TRPA1 and TRPM8 agonists respectively. After nasal challenges with isocyanate (AITC), cinnamaldehyde, (−) menthol and (+) menthol (all 10-3 M) nasal symptom score, cough threshold (C2), urge to cough (Cu) and cumulative cough response were measured). Results Nasal challenges with TRPA1 relevant agonists induced considerable nasal symptoms, significantly enhanced urge to cough (p<0.05) but no statistically significant modulation of the C2 and cumulative cough response. In contrast, both TRPM8 agonists administered to the nose significantly modulated all parameters including C2 (p<0.05), Cu (p<0.01) and cumulative cough response (p <0.01) documenting strong anti irritating potential of menthol isomers. Conclusions In addition to trigeminal afferents expressing TRP channels, olfactory nerve endings, trigemino – olfactoric relationships, the smell perception process and other supramedullar influences should be considered as potential modulators of the cough response in humans.
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Cough due to upper respiratory tract infections (URIs) is one of the most frequent complaints encountered by pediatric health-care providers, and one of the most disruptive symptoms for children and families. Despite the frequency of URIs, there is limited evidence to support the few therapeutic agents currently available in the United States (US) to treat acute cough due to URI. Published, well-designed, contemporary research supporting the efficacy of narcotics (codeine, hydrocodone) and US Food and Drug Administration (FDA)-approved over-the-counter (OTC) oral antitussives and expectorants (dextromethorphan, diphenhydramine, chlophedianol, and guaifenesin) is absent for URI-associated pediatric cough. Alternatively, honey and topically applied vapor rubs may be effective antitussives.
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The Urge-To-Cough has recently been recognised as a significant factor in understanding the pathophysiology of cough. The principles in the urge to cough model are relevant to the behavioural management of laryngeal conditions including chronic non-specific cough, cough due to paradoxical vocal fold movement, aspiration and reflux. This paper analyses the pathophysiology and behavioural management of these conditions according to the urge to cough model (Tab. 3, Ref. 28). Full Text in free PDF www.bmj.sk.
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TRPM8 is a non-selective cation channel that belongs to the melastatin subfamily of the transient receptor potential (TRP) ion channels. TRPM8 is activated by voltage, cold and cooling compounds such as menthol. Despite its essential role for cold temperature sensing in mammals, the pharmacology of TRPM8 is still in its infancy. Recently, tyrosine 745 (Y745) was identified as a critical residue for menthol sensitivity of the channel. In this report, we study the effect of mutating this residue on the action of several known TRPM8 antagonists: BCTC, capsazepine, SKF96365, and clotrimazole as well as two new inhibitor candidates, econazole and imidazole. We show that Y745 at the menthol binding site is critical for inhibition mediated by SKF96365 of cold- and voltage-activated TRPM8 currents. In contrast, the inhibition by other antagonists was unaffected by the mutation (BCTC) or only partially reduced (capsazepine, clotrimazole, econazole), suggesting that additional binding sites exist on the TRPM8 channel from where the inhibitors exert their negative modulation. Indeed, a molecular docking model implies that menthol and SKF96365 interact readily with Y745, while BCTC is unable to bind to this residue. In summary, we identify structural elements on the TRPM8 channel that are critical for the action of channel antagonists, providing valuable information for the future design of new, specific modulator compounds.
Article
Menthol, known as a cold receptor agonist, has widely been used in the relief of respiratory symptoms such as coughing and chest congestion. Previous studies have demonstrated that menthol reduces bronchoconstriction and airway hyperresponsiveness. The aim of this study was to examine the effects of menthol and icilin, another cold receptor agonist, on airway smooth muscle contraction. Isometric force was monitored using epithelium-denuded tracheal smooth muscle tissues isolated from guinea pigs. Intracellular Ca(2+) concentrations were assessed by fura-2 fluorescence. (-)Menthol (0.01-1mM) inhibited contraction induced by methacholine (MCh, 0.01-10microM) and high extracellular K(+) concentrations (20-60mM) in a concentration-dependent manner. Moreover, the increases of intracellular Ca(2+) concentrations induced by MCh or high K(+) were significantly reduced by (-)menthol. Icilin (100microM) also significantly attenuated contraction induced by MCh or high K(+). The inhibitory effect of 1mM (-)menthol on MCh-induced contraction was significantly higher at cool temperature (24-26 degrees C) than at 37 degrees C. The present results demonstrate that inhibition of Ca(2+) influx plays an important role in the menthol-mediated inhibition of contraction in airway smooth muscle. Furthermore, our findings indicate that stimulation of unknown cold receptors may be involved in these mechanisms. These findings suggest that the use of menthol is beneficial for reducing respiratory symptoms because of its inhibitory effects on airway smooth muscle contraction.
Article
Essential oils, such as camphorated and eucalyptus oils, are volatile oils that can be absorbed by mouth and through the skin; if ingested orally by children, they can be harmful, even life-threatening. To determine the frequency of essential oil ingestion among children in Toronto, Ontario. Charts from December 1995 through March 1997 at the Ontario Regional Poison Information Centre, The Hospital for Sick Children, Toronto were reviewed to collect information on calls about essential oil ingestion, and a search of MEDLINE articles from 1966 to 1998 was conducted using the key words: 'camphor', 'eucalyptus', 'paediatric', and 'poisoning'. Callers to the Poison Information Centre reported that 251 children had ingested an essential oil or product: eucalyptus oil 50 children; camphorated oil 18 children; VapAir (Drug Trading, Canada) vaporizing liquid 93 children; and Vicks VaporRub (Procter & Gamble, Canada) 90 children. The most common symptoms were cough, vomiting and cough associated with vomiting. Two children had seizures but recovered. The MEDLINE search found 18 reports of paediatric ingestion of the oils or oil products. The main symptoms were vomiting, lethargy, coma and seizures. One child died. Although widely used by health care consumers, essential oils and the products that contain them can be harmful when ingested by children. Further education for parents and other caregivers about the risks involved in exposure to these products is required.
Article
Vicks VapoRub (VVR) [Proctor and Gamble; Cincinnati, OH] is often used to relieve symptoms of chest congestion. We cared for a toddler in whom severe respiratory distress developed after VVR was applied directly under her nose. We hypothesized that VVR induced inflammation and adversely affected mucociliary function, and tested this hypothesis in an animal model of airway inflammation. [1] Trachea specimens excised from 15 healthy ferrets were incubated in culture plates lined with 200 mg of VVR, and the mucin secretion was compared to those from controls without VVR. Tracheal mucociliary transport velocity (MCTV) was measured by timing the movement of 4 microL of mucus across the trachea. Ciliary beat frequency (CBF) was measured using video microscopy. [2] Anesthetized and intubated ferrets inhaled a placebo or VVR that was placed at the proximal end of the endotracheal tube. We evaluated both healthy ferrets and animals in which we first induced tracheal inflammation with bacterial endotoxin (a lipopolysaccharide [LPS]). Mucin secretion was measured using an enzyme-linked lectin assay, and lung water was measured by wet/dry weight ratios. [1] Mucin secretion was increased by 63% over the controls in the VVR in vitro group (p < 0.01). CBF was decreased by 35% (p < 0.05) in the VVR group. [2] Neither LPS nor VVR increased lung water, but LPS decreased MCTV in both normal airways (31%) and VVR-exposed airways (30%; p = 0.03), and VVR increased MCTV by 34% in LPS-inflamed airways (p = 0.002). VVR stimulates mucin secretion and MCTV in the LPS-inflamed ferret airway. This set of findings is similar to the acute inflammatory stimulation observed with exposure to irritants, and may lead to mucus obstruction of small airways and increased nasal resistance.
Article
Menthol is a natural herbal compound. Its isomer l-menthol presents the characteristic peppermint scent and is also responsible for the cooling sensation when applied to nasal mucosal surfaces because of stimulation of trigeminal cold receptors. The aim of this study was to assess the effect of menthol inhalation on end-inspiratory nasal mucosa temperature and nasal patency. Eighteen healthy volunteers with a mean age of 30 years were enrolled in this study. Objective measurements included the septal mucosal temperature within the nasal valve area by using a miniaturized thermocouple as well as active anterior rhinomanometry before and after inhalation of l-menthol vapor. All subjects completed a visual analog scale (VAS; range, 1-10) evaluating nasal patency before and after menthol. The mean end-inspiratory mucosal temperature ranged from 27.7 degrees C (+/-4.0) before menthol inhalation to 28.5 degrees C (+/-3.5) after menthol inhalation. There were no statistically significant differences between the temperature values before and after menthol inhalation (p > 0.05). In addition, no statistically significant differences between the rhinomanometric values before and after menthol inhalation were observed. Sixteen of the 18 subjects reported an improvement of nasal breathing after menthol inhalation by means of the VAS. Menthol inhalation does not have an effect on nasal mucosal temperature and nasal airflow. The subjective impression of an improved nasal airflow supports the fact that menthol leads to a direct stimulation of cold receptors modulating the cool sensation, entailing the subjective feeling of a clear and wide nose.
Article
Cooling of the upper airway, which stimulates specific cold receptors and inhibits laryngeal mechanoreceptors, reduces respiratory activity in unanesthetized humans and anesthetized animals. This study shows that laryngeal cooling affects the pattern of breathing in the guinea pig and assesses the potential role of cold receptors in this response by using a specific stimulant of cold receptors (l-menthol). The response to airflows (30 ml/s, 10-s duration) through the isolated upper airway was studied in 23 anesthetized (urethan, 1 g/kg ip) guinea pigs breathing through a tracheostomy. Respiratory airflow, tidal volume, laryngeal temperature, and esophageal pressure were recorded before the challenges (control), during cold airflows (25 degrees C, 55% relative humidity), and during warm airflows (37 degrees C, saturated) with or without the addition of l-menthol. Whereas warm air trials had no effect, cold air trials, which lowered laryngeal but not nasal temperature, reduced ventilation (VE) to 85% of control, mainly by prolonging expiratory time (TE, 145% of control), an effect abolished by laryngeal anesthesia. Addition of l-menthol to the warm airflow caused a greater reduction in VE (41% of control) by prolonging TE (1,028% of control). Nasal anesthesia markedly reduced the apneogenic effect of l-menthol but did not affect the response to cold air trials. In conclusion, both cooling of the larynx and l-menthol in the laryngeal lumen reduce ventilation. Exposure of the nasal cavity to l-menthol markedly enhances this ventilatory inhibition; considering the stimulatory effect of l-menthol on cold receptors, these results suggest a predominant role of nasal cold receptors in this response.