MAJOR ARTICLE

Variant Effect of First- and Second-Generation

Antihistamines as Clues to Their Mechanism
of Action on the Sneeze Reflex
in the Common Cold
Philipp S. Muether1 and Jack M. Gwaltney, Jr.2
1
Aachen Medical School, Aachen, Germany; 2Department of Internal Medicine, Division of Epidemiology and Virology, University
of Virginia School of Medicine, Charlottesville, Virginia

Treatment with first-generation antihistamines reduces sneezing, rhinorrhea, nasal mucus weight, and, in some
instances, cough in subjects with experimental or natural colds; however, treatment with second-generation
antihistamines has not been effective for these complaints in trials in subjects with natural colds. This article
reports the negative results of a clinical trial with loratadine, a second-generation antihistamine, in adults in
the rhinovirus challenge model. This finding in the highly controlled setting of the challenge model confirms
the earlier negative studies with second-generation antihistamines in natural colds. First-generation antihis-
tamines block both histaminic and muscarinic receptors as well as passing the blood-brain barrier. Second-
generation antihistamines mainly block histaminic receptors and do not pass the blood-brain barrier. The
effectiveness of first-generation antihistamines in blocking sneezing in colds may be due primarily to neu-
ropharmacological manipulation of histaminic and muscarinic receptors in the medulla.

The individual symptoms of a common cold are due mediators did not [2]. Also, treatment with first-gen-
to multiple and somewhat specific pathways of inflam- eration antihistamines is highly effective in reducing
mation [1]. Sneezing has been generally thought to re- sneezing in subjects with experimental and natural
sult from the release of histamine from nasal mast cells colds [3–5]. It is, therefore, surprising that, unlike with
and basophils, which are activated by a cold virus in- allergic rhinitis, histamine levels are not elevated in na-
fection. Supporting this belief is the finding that in- sal secretions of patients with colds [6–9], although
tranasal challenge with histamine in normal volunteers nasal mucosal sensitivity to histamine has been reported
elicited sneezing whereas intranasal exposure to other
to be increased [10–13].
Both first- and second-generation antihistamines are
competitive antagonists to histamine at the H1-receptor
Received 17 January 2001; revised 18 April 2001; electronically published 4
October 2001. site [14]. An additional pharmacological activity of
Written, informed consent was obtained from each subject, and human first-generation, but not second-generation antihista-
experimentation guidelines of the United States Department of Health and Human
services and those of the University of Virginia Human Investigation Committee mines is the competitive antagonism of acetylcholine
were followed in the conduct of clinical research. at neuronal and neuromuscular muscarinic receptors.
Financial support: Schering-Plough.
First-generation antihistamines also pass the blood-
Reprints or correspondence: Dr. Jack M. Gwaltney, Jr., Dept. of Internal
Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908 brain barrier and thus have a potential for activity in
(jmg3u@[Link]). the brain; second-generation antihistamines do not. In
Clinical Infectious Diseases 2001; 33:1483–8 limited testing, and despite their H1-blocking activity,
 2001 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2001/3309-0006$03.00 second-generation antihistamines have been ineffective

Antihistamines in Colds • CID 2001:33 (1 November) • 1483

 Table 1. Infection and illness rates in adults with experimental rhinovirus colds given loratadine or placebo.

No. (%) with

Mean  SE no. days virus shed
No. of No. (%) who antibody No. (%) No.
a
Agent subjects shed virus All volunteers Infected volunteers titer rise infected (%) ill
Loratadine 30 28 (93) 2.9  .23 3.0  .21 12 (40) 29 (9) 23 (79)
Placebo 30 24 (80) 2.5  .29 3.2  .22 11 (37) 24 (80) 14 (58)
a
Of subjects who were infected.

in suppressing sneezing in patients with natural colds [15–18]. Study medication. Loratadine was administered in 10-mg
These findings raise an interesting question about the mech- tablets. The placebo tablets were identical to the loratadine
anism of action of first-generation antihistamines in reducing tablets but contained pharmacologically inert ingredients.
sneezing in patients with colds and about the ineffectiveness Virus challenge. Intranasal challenge with rhinovirus type
of second-generation antihistamines in this setting. Also, nat- 16 was performed by coarse drops by use of 0.5 mL (0.25 mL
ural cold studies have certain technical problems, such as dif- per nostril) an inoculum pool containing 100 tissue culture
ficulty in enrolling patients in the early stages of a cold, when infection dose 50/mL (TCID50/mL) of virus. The challenge was
treatment effects are most accurately measured [19]. Therefore, performed twice with a 20-min interval between challenges.
it would be desirable to confirm the results of the natural cold The inoculum pool was safety tested for extraneous agents [20].
studies by testing a second-generation antihistamine in the rhi- Measures of infection. Nasal washings were collected 8
novirus challenge model, which provides more precision in the days prior to and immediately before the inoculation of the
measurement of sneezing. This article reports a clinical trial challenge virus to determine whether subjects were infected
using a second-generation antihistamine, loratadine, in adults with a wild-type virus. After virus challenge, nasal washings
with experimental rhinovirus colds and reviews the possible were collected each morning before administration of medi-
sites of action of first-generation and second-generation anti- cation. Washings were cultured for rhinovirus for 5 days after
histamines. Although the study was originally designed to de- challenge in human embryonic lung cells (WI-38). Isolates were
termine whether loratadine by down-regulating expression of identified as rhinovirus type 16 by neutralization with type-
intercellular adhesion molecule-1 (ICAM-1) on nasal epithelial specific antibody. Venous blood was obtained 7 days prior to
cells reduces rhinovirus infection rates, it provides heretofore- treatment and 14–21 days after intranasal inoculation for mea-
missing information on the results of testing a second-gener- surement of homotypic neutralizing antibody [21].
ation antihistamine in the virus challenge mode. Measures of illness. The presence and severity of symp-
toms were determined daily beginning on the first day of treat-
ment, 7 days prior to viral challenge, for a total of 13 days.
MATERIALS AND METHODS
Data on symptoms were collected immediately before admin-
Subjects. A total of 66 adult volunteers from the Charlottes- istration of loratadine or placebo by a nurse who recorded the
ville, Virginia, area with neutralizing antibody titers of ⭐2 to subject’s assessment of the severity of symptoms over the prior
rhinovirus type 16 were enrolled in the study. Subjects were 24 h on a 5-point scale (0, “none”; 1, “mild”; 2, “moderate”;
required to have been free of cold symptoms and fever 3, “severe”; 4, “very severe”) [22]. The symptoms assessed were
(137.8C) for 1 week prior to entering the trial and to have sneezing, runny nose, nasal obstruction, sore throat, cough,
no history of hypersensitivity to antihistamines. In addition, headache, malaise, and chilliness. The total symptom score was
subjects were excluded if they had (or had a history of) allergic determined by adding severity scores for the symptoms over
rhinitis, bronchial asthma, or other lower respiratory tract dis- the 5-day period after viral challenge. The score for each symp-
eases such as chronic obstructive lung disease or emphysema. tom present immediately before challenge was subtracted from
Subjects with a history of alcohol and drug abuse were excluded, each of the daily scores for that symptom.
as were volunteers who had used investigational drugs within Evaluation of illness severity also included daily measure-
30 days, antihistamines and/or cold preparations within 14 ments of nasal secretion weights [23]. Each subject kept a daily
days, monoamine oxidase inhibitors within 7 days, astemizole log of the number of coughs and sneezes. Nasal secretion mea-
within 90 days, or any other medication thought to interfere surements and cough and sneeze counts were started after the
with the study drug. Other exclusion criteria included preg- subjects were cloistered in a hotel after challenge had occurred.
nancy or lactation, glaucoma, and renal, hepatic, endocrine, Before leaving the hotel on the last day, subjects were asked
digestive, genitourinary, neurologic, or psychologic disease. The whether, in their opinion, they experienced a cold. Information
protocol was reviewed by the Human Investigation Committee on the occurrence and severity of any adverse effects was col-
of the University of Virginia. lected daily, graded as “none,” “mild,” “moderate,” or “severe.”

1484 • CID 2001:33 (1 November) • Muether and Gwaltney

 subjects on loratadine and 14 (58%) of 24 infected subjects on
placebo met the modified Jackson criteria for illness (P p .2).
Symptom scores. Mean (SE) sneezing severity scores
were similar for the first 3 days and tended to be lower in the
placebo group on the fourth day (figure 1). Mean (SE) total
symptom scores were similar in the 2 groups (figure 2B). Rhi-
norrhea scores tended to be lower in the placebo group on
days 2 and 3, but the reverse was seen on days 4 and 5 (figure
2D). Mean (SE) nasal obstruction, sore throat, and cough
scores were similar in the 2 groups (figures 2C, 2F, 2G). Mean
(SE) headache and malaise scores tended to be lower in the
loratadine group for the latter days of illness (figures 2H, 2I).
Figure 1. Mean (SE) sneezing severity scores in adults with ex- Nasal mucus weights. There was a consistent trend for
perimental rhinovirus colds given loratadine or placebo. nasal secretion weights to be lower in the placebo group (figure
2C). Total mean  SE nasal mucus weights for 5 days were
27.1  4.0 g for the loratadine group and 19.7  5.2 g for the
Experimental design. The trial was a 13-day, single-center,
placebo group (P p .3).
randomized double-blind, placebo-controlled, parallel group
ICAM-1 levels. Mean (SE) nasal fluid ICAM-1 levels
study in healthy volunteers 18–40 years of age, of either sex.
rose from the baseline on day 2 and peaked on day 3. The
Loratadine or placebo was administered each morning between
levels were similar in both groups (figure 3).
6 a.m. and 8 a.m., on days 1–13 of the study, with viral challenge
Adverse events. One subject in the placebo group had a
given on day 8. The subjects were randomly assigned to receive
migraine headache and vomiting and another had vomiting.
either treatment or placebo and were blinded as to their treatment
Otherwise, no adverse events were reported.
status, as were the observers recording clinical information.
Data analysis. For comparing proportions, Fisher’s exact
test was used. The t test was used for comparing ordinal and DISCUSSION
interval data. The results of probability testing were 2-tailed.
In regard to the original purpose of the study, no differences
were observed between the groups receiving loratadine and
RESULTS
groups receiving placebo for viral shedding rates, viral titers,
Subjects. Of the 66 subjects enrolled, 34 received loratadine overall infection rates, illness rates, or symptom scores. ICAM-
and 32 received placebo. Four subjects in the loratadine group 1 levels in nasal secretions in the 2 groups were also similar.
and 1 in the placebo group were infected with a wild-strain The results also showed no therapeutic effect of loratadine
rhinovirus at the time of entry into the study. They were ex- on sneezing. This supports earlier work in patients with natural
cluded from evaluation, as was 1 subject on placebo who dis- colds in whom second-generation antihistamines were ineffec-
continued medication after developing a migraine headache on tive in reducing sneezing [15–18]. Why first-generation anti-
day 10, leaving 60 evaluable subjects for analysis. histamines are effective in reducing sneezing in colds [3, 5] and
Infection rates. Twenty-eight (93%) of 30 subjects on lor- second-generation antihistamines are not is of interest. First-
atadine and 24 (80%) of 30 subjects on placebo shed the chal- generation antihistamines, beside their ability to block H1-re-
lenge virus in nasal fluid on ⭓1 days (P p .25; table 1). The ceptors, also block muscarinic receptors and pass the blood-
mean number of days on which virus was shed was similar for brain barrier [14]. Second-generation antihistamines are
all challenged volunteers and for all infected volunteers in the specific H1-receptor blockers without other recognized phar-
2 groups. Homotypic antibody responses occurred in 12 (40%) macological properties and do not pass the blood-brain barrier.
of 30 subjects treated with loratadine and 11 (37%) of 30 sub- Information on the neurologic pathways of the sneeze reflex
jects who received placebo. The infection rate (viral shedding comes mainly from work in animals [24, 25]. The sneeze reflex
and/or antibody rise) was 29 (97%) of 30 in the loratadine travels along peripheral nerves and through the medulla ob-
group and 24 (80%) of 30 in the placebo group (P p .1). longata. The neuropharmacology of the sneeze involves H1,
Viral titers. Geometric mean viral titers peaked on the muscarinic, and nicotinic receptors. With colds, the sneeze re-
second day after viral challenge, as expected (figure 2A). Viral flex begins in the nose with the infection of nasal cells by a
titers were similar in the 2 groups, although there was trend cold virus (figure 4). There is no evidence that activation of
for lower titers in the placebo group on day 2. basophils and mast cells with release of histamine occurs in
Occurrence of illness. Twenty-three (79%) of 29 infected colds; however, there is presumed stimulation of free nerve

Antihistamines in Colds • CID 2001:33 (1 November) • 1485

Figure 2. Geometric mean (SE) viral titers, mean (SE) nasal mucus weights, and mean (SE) symptom scores in adults with experimental
rhinovirus colds given loratadine or placebo.

endings of the ethmoidal branch of the trigeminal nerve by the impulse is redirected to the trigeminal nucleus and, sub-
inflammatory mediators known to be present, such as bradyk- sequently, to the sneeze center in the medulla. When the res-
inin [1]. The nerve impulse then travels along the afferent nerve timulation of the sneeze center is sufficient, the impulse is then
fibers to the sensory trigeminal nucleus in the medulla oblon- directed by intramedullary fibers to the synapses of multiple
gata and arrives at the adjacent sneeze center [26–28]. Via respiratory centers in the reticular formation, and from there
another synapse, the impulse then arrives at the parasympath- to the synapses of respiratory neurons of the vagus, phrenic,
etic superior salivary nucleus of the facial nerve. Here, it crosses and intercostal nerves. Then, via nicotinic synapses, the nerve
a synapse and travels via the preganglionic fibers of the greater impulse stimulates the muscular contractions responsible for a
petrosal nerve to the sphenopalatine ganglion. Supporting this sneeze.
route of transmission in sneezing is the finding that injection The nose is the first site at which histamine may be involved
of alcohol into the sphenopalatine ganglion blocks the sneeze in the pathogenesis of sneezing and where an antihistamine
reflex [29]. The impulse then travels across another synapse might inhibit the sneeze reflex. H1-receptors are present on the
(mainly nicotinic, some muscarinic) and proceeds via post- free nerve endings of the trigeminal nerve [30]. Against the
ganglionic fibers to the synapses (muscarinic) of mucus glands possibility that the nasal mucosa is the primary site of action
and blood vessels, which are then stimulated. The resultant of first-generation antihistamines is the finding that histamine
glandular secretion and vascular transudation restimulate the levels have not been found to be elevated in nasal secretions
free nerve endings of the trigeminal nerve by which pathway during colds [6–9]. Also, in earlier natural cold studies and in

1486 • CID 2001:33 (1 November) • Muether and Gwaltney

 This analysis suggests that an important site for the thera-
peutic effect of first-generation antihistamines on sneezing is
in the medulla oblongata, where both H1 and muscarinic re-
ceptors may be involved. H1 receptors are known to be present
in high concentrations in the hypothalamus, where histamine
acts as a neurotransmitter to help regulate the level of wake-
fulness [14]. This accounts for the drowsiness associated with
the use of first-generation antihistamines. Because of the dense
concentration of H1 receptors in the hypothalamus, and be-
cause parasympathetic nerve fibers arise from and are activated
by the hypothalamus, it is probable that histamine plays a role
in signal transmission in this region.
Figure 3. Mean (SE) nasal fluid ICAM-1 levels in adults with ex- First-generation antihistamines are also known to be helpful
perimental rhinovirus colds given loratadine or placebo.
in reducing the nausea associated with motion sickness [31].
Scopolamine, an anticholinergic drug, which passes the blood-
the current study, second-generation antihistamines, despite brain barrier, is an effective treatment for motion sickness,
reaching the nasal mucosa and despite having H1-blocking ac- whereas atropine, which does not pass the blood-brain barrier
tivity, have been ineffective in sneeze reduction [15–18]; how- as readily, is not effective. The antinausea effect of scopolamine
ever, because the nasal mucosa appears to have enhanced sen- depends partially on blocking of muscarinic receptors of the
sitivity to histamine during colds [10–13], the role of the nasal vestibular nuclei and the area postrema of the brain. Other
sites cannot be entirely excluded. nuclei in the brainstem may use the muscarinic receptor system
The next possible site for a first-generation antihistamine to
block sneezing is in the medulla oblongata, where synaptic
junctions are present at several locations. Both H1 and mus-
carinic receptors have been identified in certain areas of the
brain [14, 31]. Such receptors would be potential targets for
the action of first-generation, but not second-generation an-
tihistamines; however, the synaptic mediators that are involved
in the sneeze reflex in the medulla have not been characterized.
The observed failure of the second-generation antihistamines
to reduce sneezing in colds supports the possibility of these
sites being important.
Muscarinic activity is exclusively responsible for parasym-
pathetic stimulation of the glandular secretion and vascular
dilatation with transudation that occurs next. The anticholin-
ergic activity of first-generation antihistamines would be ex-
pected to operate at these sites. This is supported by the well-
documented effect of first-generation antihistamines in
reducing the volume of nasal fluid production during colds [3,
4]. The second afferent impulse to the medulla is again initiated
by stimulation of the free nerve endings of the trigeminal nerve.
Vascular transudation leads to release of kininogen with re-
sultant generation of kinin [14]. This event provides a means
for direct stimulation of free nerve endings by kinins as well
as by histamine released from mast cells by kinin stimulation.
This provides another possible target for the action of an an-
tihistamine. Also, when the nerve impulse is redirected to the
medulla, H1 and muscarinic synaptic sites may be blocked by
first-generation antihistamines as described above. From that
point on, when the motor neurons become involved, nerve
transmission depends on nicotinergic receptors and thus would
not be susceptible to the action of an antihistamine. Figure 4. Pathway of the sneeze reflex

Antihistamines in Colds • CID 2001:33 (1 November) • 1487

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