Received: 6 July 2018 Revised: 6 June 2019 Accepted: 10 June 2019

DOI: 10.1111/bcp.14046

REVIEW

Management of peripheral vertigo with antihistamines:

New options on the horizon

Jonas Dyhrfjeld‐Johnsen | Pierre Attali

Sensorion SA, Montpellier, France

Vertigo is associated with a wide range of vestibular pathologies. It increasingly
Correspondence
affects the elderly, with a high cost to society. Solutions include vestibular
Jonas Dyhrfjeld‐Johnsen, Sensorion, 375 rue
du Professeur Joseph Blayac, 34080, suppressants and vestibular rehabilitation, which form the mainstay of therapy. Anti-
Montpellier, France.
histamines represent the largest class of agents used to combat vestibular vertigo
Email: jonas.dyhrfjeld‐johnsen@sensorion‐
pharma.com symptoms. Agents targeting the H1 and H3 receptors have been in clinical use for
several decades as single agents. Nonetheless, effective management of vertigo
Funding information
Sensorion proves elusive as many treatments largely address only associated symptoms, and
with questionable efficacy. Additionally, the primary and limiting side effect of
sedation is counterproductive to normal functioning and the natural recovery process
occurring via central compensation. To address these issues, the timing of administra-
tion of betahistine, the mainstay H3 antihistamine, can be fine‐tuned, while bioavail-
ability is also being improved. Other approaches include antihistamine combination
studies, devices, physical therapy and behavioural interventions. Recently demon-
strated expression of H4 receptors in the peripheral vestibular system represents a
new potential drug target for treating vestibular disorders. A number of novel
selective H4 antagonists are active in vestibular models in vivo. The preclinical poten-
tial of SENS‐111 (Seliforant), an oral first‐in‐class selective H4 antagonist is the only
such molecule to date to be translated into the clinical setting. With an excellent
safety profile and notable absence of sedation, encouraging outcomes in an induced
vertigo model in healthy volunteers have led to ongoing clinical studies in acute uni-
lateral vestibulopathy, with the hope that H4 antagonists will offer new effective
therapeutic options to patients suffering from vertigo.

K E Y W OR D S

antihistamine, betahistine, SENS‐111, type‐4 histamine receptor, vertigo

1 | B E H I N D T H E SC E N E S OF V E RT I G O positional vertigo (BPPV), vestibular migraine, Ménière's disease, acute

Vertigo is principally characterised by an erroneous sensation of
spinning motion, frequently accompanied by vestibulo‐oculomotor
symptoms of oscillopsia, nystagmus, postural imbalance, and falling,1
along with neurovegetative effects, notably nausea and vomiting.
The 12‐month prevalence of vertigo ranges from 2 to 5%, with
incidence linked to age.2 Vertigo is associated with a wide range of
pathologies, including inner ear diseases such as benign paroxysmal
unilateral vestibulopathy (AUV) and labyrinthitis.3,4 While the occupa-
tional impact is poorly qualified, it represents a substantial economic
cost to society.5
Vertigo may arise centrally following injury to the balance centres
of the central nervous system (CNS), or be of peripheral origin linked
to disorders of the vestibule located in the inner ear. Sense of balance
and position are derived from input from the 3 semicircular canals and
otolith organs in the peripheral vestibular system, integrated with

Br J Clin Pharmacol. 2019;85:2255–2263. wileyonlinelibrary.com/journal/bcp © 2019 The British Pharmacological Society 2255
2256
proprioceptive and visual information in the vestibular nuclei. Sensory
hair cell damage, synaptic uncoupling and neuronal damage disturb the
balance of vestibular signalling. This highly complex process is orches-
trated by peripheral and central neurons, which rely on a range of
neurotransmitters (glutamate, acetylcholine, γ‐aminobutyric acid and
glycine), further modulated by histamine, adrenaline and noradrena-
line.6,7 Nonetheless, in‐depth knowledge of the pathophysiology of
vertigo is lacking and a thorough understanding is currently hampered
by nonstandardised definitions.
While vestibular rehabilitation is recommended by many interna-
tional clinical practice guidelines,8-10 pharmacological approaches form
the backbone of vertigo management, composed of agonists and
antagonists of neurotransmitters and neuromodulators that modulate
vestibular afferent/efferent synaptic input. They are primarily repre-
sented by vestibular suppressants which reduce vertigo and nystag-
mus evoked by vestibular imbalance or motion sickness, while
antiemetics are used to combat nausea and vomiting.11 Vestibular
suppressants cover 3 main drug groups, anticholinergics, antihista-
mines and benzodiazepines. The nonselective nature of many of these
agents imposes clinical limitations, with most antivertigo agents
acting principally through sedation or reduction of nausea rather than
addressing the cause of the vertigo itself. Here, we review current
antihistamine use in managing vertigo, focusing on efficacy, side
effects and impact on central compensation. We also discuss a new
area of research targeting vertigo via the type‐4 (H4) histamine
receptor, and present a novel histamine antagonist clinical candidate,
SENS‐111 (Seliforant, 6‐[3‐(methylamino)azetidin‐1‐yl]‐2‐(2‐
methylpropyl)pyrimidin‐4‐amine; Sensorion).
2 T HE V ES TI B U L A R H I S T A M I N E
| eral vestibular insult in rats was developed by inducing transient
RECEPTOR LANDSCAPE
The 4 known histamine receptors—type‐1 (H1), type‐2 (H2), type‐3
(H3) and H4—belong to the large G‐protein coupled receptor (GPCR)
family, consisting of 7 transmembrane‐spanning helices. The struc-
ture, functioning and mechanisms of action of these receptors is
beyond the scope of this review and have been described in depth
elsewhere.12 In the nervous system, histamine is involved in signalling
at several levels, and histamine receptors are present heteroge-
neously on pre‐ and postsynaptic nerve terminals throughout the
CNS. Histamine is known to be involved in many CNS activities
including wakefulness and cognition, and histamine antagonists form
part of the treatment arsenal for many CNS disorders, including
somnolence.13
Histaminergic ligands also act in the vestibular system, both
peripherally and centrally, and there is accumulating evidence for
the involvement of multiple histamine receptors in modulating vestib-
ular function. To reach the central parts of the vestibular system,
antihistamines must pass the blood–brain barrier, while the peripheral
parts of the vestibular system are also protected by the similarly
14
restrictive blood–labyrinth barrier. In the inner ear, protein expres-
sion of all 4 histamine receptors has been reported in mice and rats,
DYHRFJELD‐JOHNSEN AND ATTALI
including in the organ of Corti, the spiral ganglion, vestibular gan-
glion, vestibular sensory epithelium and the endolymphatic sac.15,16
The H1 and H3 receptors have also been identified in human endo-
lymphatic sac tissue.17 Functional in vitro and in vivo studies per-
formed over the last 3 decades further support a role for histamine
in the context of vertigo.18-22 These studies demonstrated its excit-
atory effect on the vestibular system in rats and guinea pigs, with
membrane depolarisation and transient increased neuronal firing
activity in the central vestibular nuclei (inferior, medial, lateral and
superior), which controls the vestibulo‐ocular reflex. Furthermore,
this activity was selectively blocked by H1, H2 and H3 receptor
antagonists, although not by an H4 receptor antagonist. Unilateral
electrical and caloric stimulation of the inner ear in rats increases
CNS production of histamine,23 confirming that sensory mismatch
signals activate the histaminergic neuron system in the brain. Preclin-
ical studies have also shown that the H1 receptor is upregulated in
vestibular neurons during motion stimulation24 and that symptoms
of motion sickness in the house musk shrew can be alleviated via this
receptor.25
3 | TRANSLATING IN VIVO
A N T I H I S TA M I N E M O D E L S I N T O T H E C L I N I C
Validated predictive preclinical models are essential for ensuring the
translational success from the preclinical setting to the clinic. Such
models have been slow to emerge for vestibular diseases, in part
due to the lack of understanding of their pathophysiology, and the
subjective nature of symptoms. A mechanism‐based model of unilat-
excitotoxicity from transtympanic injections of kainic acid in 1 ear
resulting in swelling of the primary vestibular neuronal terminals and
synaptic uncoupling. This model generates a number of established
vertigo‐associated symptoms such as spontaneous nystagmus,
postural deviations, reflex deficits and gastric paresis, all of which
can be quantified.26
Adequately evaluating antivertigo treatments in humans requires
identification of objective clinical variables accurately reflecting
vertigo. Earlier studies tended to focus on improvements in the
neurovegetative symptoms of nausea and vomiting, while more recent
studies focus on vertigo symptom‐rating for specific symptoms along
with frequency and severity of attacks, often using validated
questionnaires (e.g. Dizziness Handicap Inventory), as well as quality
of life scores. As 1 of the few translationally measurable symptoms
of vertigo, nystagmus can be recorded—typically by electro‐ or
videonystagmography of spontaneous or calorically evoked nystag-
mus, with infrared videonystagmography being considered a gold
standard. As technology has improved, caloric testing with maximum
slow phase velocity (SPV) is increasingly considered a reliable means
of evaluating vestibular function imbalance, despite intrapatient varia-
tion,27 with higher SPV levels reflecting greater imbalance between
the 2 labyrinths.28
DYHRFJELD‐JOHNSEN AND ATTALI 2257

4 | AN HISTORICAL SNAPSHOT OF H1, H2
AND H3 ANTAGONIST USE IN VERTIGO
Histamine antagonists have been reported to be of value to individuals
29
suffering from vertigo since the 1940s, preventing motion sickness
and/or reducing the severity of symptoms, including when taken
postonset. Nonetheless, insights into their role in central and periph-
eral vestibular processing have only emerged relatively recently.
The value of antihistamines in treating vertigo was reported in a
recent meta‐analysis evaluating 13 randomised placebo‐controlled
studies using single‐agent antihistamines (primarily betahistine)
published between 1977 and 2006, including a total of nearly 900
patients. This confirmed a clear benefit for antihistamines, with an
odds ratio of 5.37, 95% confidence interval (3.26–8.84).31
Several H1, H2 and H3 receptor antagonists have been approved
for vertigo and/or motion sickness by international health authorities,
although availability varies by region. All antihistamines currently in
clinical use for vertigo are H1 and H3 antagonists, the most common
of which are summarised in Table 1, while there are currently no H2
receptor blockers available. Current agents include the H1 antagonists
diphenhydramine (typically administered as dimenhydrinate in combi-
nation with 8‐chlorotheophylline), meclizine and its derivate cyclizine,
cinnarizine, and promethazine. Diphenhydramine, a first‐generation
H1 antagonist is widely used. Current evaluations include its comple-
mentary pharmacotherapy role in rehabilitation and recovery, as well
as in combination with other agents. In a recent randomised controlled
study in patients with BPPV, dimenhydrinate was administered after
successful canalith repositioning manoeuvres to evaluate its effect
on residual symptoms.32 A significant reduction in light‐headedness
was observed compared to placebo, although not in Dizziness Handi-
cap Inventory questionnaire scores. Meclizine, which was first shown
33
to be superior than placebo in 1972 for the treatment of vertigo
widely used in the USA, was recently shown to be equivalent to
diazepam for effectiveness in relief of symptoms in acute peripheral
vertigo in a randomised double‐blind study.34 The value of single
agent cinnarizine for improving vertigo has been reported in both pro-
spective and retrospective studies,35,36 and an advantage in combina-
tion with dimenhydrinate is seen compared to betahistine in
randomised clinical studies and routine practice.37-41
Among the H3 antagonists used today, betahistine is the best‐
known. It acts as both a H3 presynaptic antagonist and a weak H1
postsynaptic agonist.42 A thorough review of its preclinical and clinical
30
status was published recently.43 While today betahistine is the most
widely‐used agent for the treatment of Ménière's disease and vestib-
ular drop attacks in Europe, Canada and Latin America,44-46 contro-
versy still exists over the validity of its use. In the USA, betahistine
has a chequered history with approval initially attributed but subse-
quently withdrawn, and today it remains unapproved. Many studies
support its positive impact on vertigo symptoms, with several meta‐
analyses all reporting a favourable outcome, including randomised
controlled studies comparing betahistine to placebo published over 3
decades leading up to 2006.31,47-49 Similarly, the post‐marketing
surveillance OSVaLD study collected data from over 2000 patients
on dizziness and quality of life,50 and confirmed a significant improve-
ment compared to baseline in patients with peripheral vestibular
vertigo. Nonetheless, the heterogeneity in the methodologies used
(assessment of outcome, including investigator vs patient perspective)
and pathologies included, call for caution to be exercised when
interpreting these meta‐analyses. A recent Cochrane review by
Murdin et al. highlighted the poor quality of the evidence in their
meta‐analysis.49 Further doubts are raised by the outcome of the
recent double‐blind, randomised, placebo‐controlled BEMED study in
221 patients which failed to show a significant difference in incidence
rates of Ménière's attacks with either low or high‐dose betahistine vs
placebo after 9 months of treatment.51 The interpretation of the clin-
ical data is further complicated by questions around the mechanism of
is action, since even plasma concentrations of betahistine associated
efficacy in a preclinical vertigo model were in the nanomolar range,
while H1 and H3 receptor affinities are in the micromolar range.42,52
This raises questions around a direct effect through the histaminergic

TABLE 1 Antihistamines currently used to manage vertigo

Receptor Principal adverse reactions in

Drug Other activity the vertigo setting Regional specificities

Betahistine H3/H1 Headache, nausea, upset stomach, Not authorised in the USA due to lack of
vomiting, diarrhoea evidence of activity
Cinnarizine H1 Drowsiness, depression and Not authorised in the USA and Canada
Calcium channel blocker parkinsonism
Cyclizine H1 Drowsiness, dry mouth, constipation,
(meclizine derivative) Anticholinergic visual troubles
Diphenhydramine H1 Drowsiness, poor coordination,
Anticholinergic stomach upset
Flunarizine H1 Weight gain, somnolence, Not authorised in the USA and Japan due to
(cinnarizine derivative) Calcium channel blocker depression, rhinitis lack of evidence of activity
Promethazine H1 anticholinergic Drowsiness, akathisia, lethargy
Meclizine H1 anticholinergic Drowsiness, headache, dry mouth,
stomach upset
2258
receptors, and even about another potential mechanism of action
by increased histamine turnover through upregulated histidine decar-
boxylase in the tuberomammillary nuclei and blockade of H3 receptors
in the vestibular nuclei and tuberomammillary nuclei after very high
preclinical doses of betahistine.53,54
5 | R E TH I N K I N G T H E U S E O F B ET A H I S T I N E
The long history of a lack of clarity over the use of betahistine has led
to the emergence of new approaches for optimising its use. Combina-
tion therapy may improve outcomes over single agent. In a small study
in patients with Ménière's disease, when betahistine was combined
with cinnarizine as a prophylactic measure, vertigo attacks decreased
in patients poorly responsive to betahistine alone.55 Similarly, the
addition of flunarizine to betahistine significantly decreased the fre-
quency of vertigo episodes in a small randomised controlled study.56
The addition of high‐dose betahistine to intratympanic dexametha-
sone improved vertigo control compared to dexamethasone alone.57
Large‐scale controlled studies are required to confirm the usefulness
of this approach.
Bioavailability may pose limitations on the effective implementa-
tion of betahistine. Preclinical studies in cats have demonstrated a link
between betahistine plasma concentrations and both reduced persis-
tent vertigo symptoms and improved balance.52,53 In humans, the oral
betahistine molecule is rapidly and almost completely metabolised into
2‐pyridylacetic acid, which is pharmacologically inactive,58 resulting in
very low bioavailability and limited clinical utility. A nasal formulation
of betahistine, AM‐125, demonstrated improved bioavailability over
the oral formulation in a phase 1 clinical study reported by Auris Med-
ical in October 2018,59 and a phase 2 randomised controlled study
evaluating AM‐125 as treatment for acute peripheral vertigo is
planned (TRAVERS; NCT03908567).
Various in vitro and in vivo models point towards a role for
histamine in modulating vestibular plasticity during the process of ves-
tibular central compensation. This innate spontaneous functional
recovery mechanism triggered after vestibular damage, has been well
described.60,61 It is a complex, multi‐factorial process in which
feedback from the vertigo episode triggers different types of central
plasticity to compensate for peripheral lesions. The time course and
ultimate extent of recovery vary considerably between individuals,
and failure of this process results in chronic vertigo or dizziness/
imbalance.
Several studies have shown that H1, H2 and H3 receptors are
upregulated in the central vestibular system during the first few days
of vestibular compensation following labyrinthectomy.30,62-64 The
sedative side effect of antihistamines, notably H1 antagonists, proba-
65
bly plays a role in delaying this process in vivo. Betahistine has been
shown to facilitate behavioural recovery in cats and reduce H3 recep-
tor binding in vestibular nuclei.66 The effect of betahistine on the time
course of vestibular compensation was investigated in the clinic in
terms of the effect on various symptoms including postural and oculo-
motor disorders, in a double‐blind study in patients who underwent a
DYHRFJELD‐JOHNSEN AND ATTALI
unilateral vestibular neurotomy for Ménière's disease. In this setting,
betahistine reduced the time to reach compensation by a month.67
Likewise, the authors of the VIRTUOSO study suggested that the
use of betahistine for 2 months in patients with vestibular vertigo
could improve compensation.68 However, the data are difficult to
interpret, given that only 40% of patients had peripheral vertigo,
including patients with BPPV, and compensation was only measured
in terms of lasting symptom control.
For compensation to be fully effective, vertigo symptoms and ves-
tibular imbalances must be actively experienced. Patients should
undergo interventions to stimulate plasticity and allow the brain to
substitute alternative information in lieu of the lost peripheral input.69
The use of vestibular suppressants both sedates the brain and sup-
presses vertigo centrally, and, in consequence, reduces the feedback
to the brain indicating a sensory mismatch. Thus the use of suppres-
sants comes at the cost of decreasing or slowing this natural recovery
process.70 It is thus generally considered that vestibular suppressants,
including antihistamines, should only be administered during the acute
phase of vertigo and for a maximum of 3 consecutive days.71-73 None-
theless, Kiroglu et al. recently reported a randomised controlled clinical
study in patients with vertigo and dizziness suggesting a deleterious
effect of betahistine compared to dimenhydrinate when administered
during acute episodes of vertigo, based on higher mean SPV values.72
The authors consequently recommend that betahistine not be used
during the acute phase, to avoid its H1 agonist effects, cautioning
against the concomitant use of dimenhydrinate with betahistine due
to their paradoxical effects in terms of compensation.
A recent preclinical publication delved into the molecular mecha-
nism behind vestibular compensation, providing supporting evidence
of the role of the H1 receptor. Chen et al. used a rat model to demon-
strate that the H1 receptor selectively mediates asymmetric activation
of the commissural inhibitory system in ipsilesional medial ventricular
nuclei, with the H1 antagonists diphenhydramine and mepyramine
both slowing vestibular compensation and blocking the beneficial
effect of betahistine H1 agonism on central compensation.74 This
study further emphasizes an additional potential direct negative impact
of H1 receptor antagonists such as meclizine, dimenhydrinate and
cinnarizine on central compensation, in addition to their established
sedative effect.
6 | NEW DIRECTIONS FOR MANAGING
VERTIGO
In currently active interventional clinical trials for vestibular problems,
vestibular vertigo and dizziness, 23 of 31 studies identified on
Clinicaltrials.gov are testing devices or exercise/physical therapy‐based
and behavioural interventions, while only 8 are testing drug‐based
interventions. Despite the many antihistamines used in the manage-
ment of vertigo, with a general lack of robustness in many trials in this
domain (nonrandomised, uncontrolled and single‐centre studies, an
absence of proven reference treatment and small sample sizes), along
with the negative impact associated with sedation both in terms of
DYHRFJELD‐JOHNSEN AND ATTALI
quality of life and central compensation, new pharmacotherapeutic
options for alleviating vertigo and avoiding long‐term complications
are needed. H1 antagonists can exhibit functional plurality complicating
the understanding of their mechanism of action in vertigo, having
calcium channel blocking effects in addition to their antihistamine
activity,75 further complicating clarification of the antivertigo mecha-
nism of action and the potential efficacy of antihistamines. The antihis-
tamines cinnarizine and flunarizine are both classed as calcium channel
antagonists.70 Anticholinergic properties of promethazine and diphen-
hydramine have also been reported in vivo.76
In terms of H1, H2 or H3 antivertigo agents, recent research is
limited to combination studies of betahistine or dimenhydrinate
with cinnarizine, and investigation of an intranasal formulation of
betahistine, and new clinical candidates under investigation in vertigo
are lacking. However preclinical and clinical investigations have
recently opened up a promising new therapeutic avenue targeting
the H4 receptors.
6.1 | Preclinical evidence for the potential of H4
antagonism in vertigo
The H4 receptor is the most recent member of the histamine receptor
family to have been identified. H3 and H4 receptors share significant
homology,77 although less is known about the intracellular signalling
cascade for the H4 receptor across tissues and cell types. Involvement
of the H4 receptor in inner ear pathologies has recently been raised,
with evidence supporting a potential role in the vestibular system. In
rodents, H4 receptors have been immunolocalised in vestibular pri-
mary neurons, with preferential sub‐membranous and cytoplasmic
expression, along with in the organ of Corti, spiral ganglions, vestibular
ganglions, vestibular sensory epithelium and endolymphatic sac
cells.16,78-80 H4 receptor expression has been found in the CNS of
humans and rats,81 although it is reported to be sparse or absent in
the cortex of humans, guinea pigs and rats.82,83
Emerging H4 antagonists have shown activity in preclinical vestib-
ular models.78,79 A pronounced inhibitory effect on vestibular neuron
activity was seen in vitro and ex vivo in the presence of the selective
H4 antagonist JNJ7777120 and its derivate JNJ10191584. When
administered in 2 rat vestibular lesion models—1 bilateral and 1 unilat-
eral—both agents rapidly improved scored behavioural abnormalities
associated with vestibular deficits, whereas neither betahistine nor
the dual H3/H4 antagonist thioperamide had significant acute effects.
Improvement occurred rapidly (within the first hour) and, in the case
of JNJ7777120, lasted for up to 24 hours. Beneficial treatment effects
on vestibular deficit syndrome, locomotor activity and exploratory
behaviour in the acute phase after unilateral or bilateral vestibular
lesions in a rat model were independently reported for JNJ7777120
administration by another research group.84
Another novel antagonist has shown promising results in vivo.
SENS‐111, a novel oral small molecule, is a first‐in‐class H4 antagonist,
binding with high affinity to both human and animal receptors. Preclin-
ical evaluations show it to be selective for the H4 receptor over the
2259
H1, H2 and H3 receptors as well as a wide panel of receptors, enzymes,
ion channels and bioamine transporters.85 Similar H4 receptor binding
affinity was seen with the main pharmacological and toxicological spe-
cies (mouse, rat and monkey), and it is a potent antagonist in primary
vestibular neurons. Administration of SENS‐111 in a rat model during
the acute phase of peripheral vertigo induced with kainic acid, gave a
bell‐shaped dose/efficacy relationship.86 At the optimal dose, a 20–
30% reduction in symptoms was seen within 1 hour of administration
compared to placebo, while higher doses resulted in a loss of efficacy.
SENS‐111 concentrations in blood plasma, cerebrospinal fluid and the
perilymph had equilibrated 1‐hour postadministration.
6.2 | Clinical evaluation of H4 antagonists
A number of H4 antagonists have reached clinical evaluation in
nonvestibular indications87; however, concerns over potentially
associated, compound‐specific toxicities have seen development
programmes prematurely terminated.88,89 To date, SENS‐111 is the
only H4 antagonist with ongoing clinical evaluation. Oral SENS‐111
has been administered in nearly 200 healthy volunteers and allergic
rhinitis patients in pharmacokinetic and single and repeat dosing
studies90,91 (NCT03110458; NCT01260753). A recent randomised,
double‐blind, placebo‐controlled and meclizine‐calibrated crossover
phase 2a trial, confirmed that unlike, meclizine, SENS‐111 was not
associated with sedation or impairment of memory or cognitive perfor-
mance in healthy volunteers (unpublished data). In an early‐stage first‐
in‐man phase 1 study, H4 receptor antagonism of SENS‐111 (then
called UR‐63325) in humans was confirmed in preliminary findings, as
demonstrated by reduced histamine‐induced eosinophil cell shape
change ex vivo.92 The effect of SENS‐111 on nystagmus and vertigo
induced via caloric irrigation has been evaluated in a randomised
double‐blind dose escalation study in healthy volunteers.91 Latency
of vertigo appearance improved by 10 to 30% with an exposure–
response relationship, with a similar pattern of improvement for
vertigo duration. The bell‐shaped response seen in the preclinical
model was also observed clinically; this probably reflects a dual site
of action, with an initial positive peripheral vestibular response at low
exposure, while at higher exposures with loss of selectivity, efficacy
is reduced due to a central effect on vestibular nuclei neurons in the
brainstem. The effect of SENS‐111 on vertigo symptoms in patients
suffering from AUV is currently being evaluated in a phase 2 clinical
trial (NCT03110458).
7 | COMPARING ANTIVERTIGO EFFECTS
OF ANTIHISTAMINES IN THE CLINIC
While the first clinical comparison of SENS‐111 with the H1 antihista-
mine meclizine was recently completed confirming that it does not
impact vigilance or cognitive performance (unpublished data), with
the AUV clinical trial still ongoing, SENS‐111 efficacy vs other antihis-
tamines in patients is awaited. Studies of vestibular modulation by
current antihistamines in healthy volunteers are limited, with very
2260
few trials specifically evaluating vertigo itself rather than other associ-
ated parameters (vertigo sensation intensity, frequency and duration;
associated symptoms such as nausea and vomiting, quality of life).
Evaluation of calorically‐induced vertigo sensation in healthy
volunteers showed that the magnitude of SENS‐111 treatment effects
fell within the realm of those seen with other agents used to treat
vertigo, albeit with differences in vertigo induction methodology.
Using cold caloric tests in healthy volunteers, dimenhydrinate signifi-
cantly prolonged the time to onset and duration of nystagmus (by
~20%) compared to controls.93 Cinnarizine (albeit at a much higher
dose than normally administered for vertigo) was compared to placebo
in healthy volunteers using parallel swing tests evaluated by
electronystagmography. The duration of nystagmus and of the sensa-
tion of the test were significantly reduced with cinnarizine (~27 and
19% in cupolometric tests respectively) with intra‐subject variability
94
significantly complicating pharmacodynamic measurements. In a
study evaluating Antivert (meclizine combined with nicotinic acid),
bithermic caloric tests in healthy volunteers did not show a significant
change in SPV vs baseline for either Antivert or placebo‐treated
patients (−2.2 and − 0.5% °/s, respectively) 1 hour after treatment. 95
However, studies with torsion and parallel swing challenge in healthy
volunteers showed that Antivert significantly decreased eye move-
ment frequency (by up to 13.4%, torsion swing) and amplitude (by
up to 20.8%, parallel swing) 1.5–2 hours post‐treatment, compared
to minimal changes in patients receiving placebo.
8 | S I D E E F F E C T S OF A N T I H I S T A M I N E S I N
VERTIGO
Sedation and drowsiness are by far the most common side effects
characterising antihistamines. While they can be considered manage-
able, they can have a large impact on daily and professional function-
ing, notably in the context of the workplace and driving. More
importantly, sedation poses a contradiction for optimal vertigo
management in the context of vestibular compensation as part of
the natural recovery process, as demonstrated for betahistine.
Second‐ and third‐generation molecules with lower brain permeability
were developed in an attempt to overcome this effect as well as to
96
improve efficacy. These drugs do indeed have lower levels of drows-
iness; however, as most do not pass the blood–brain barrier or blood–
labyrinth barrier and thus cannot modulate central or peripheral
vestibular activity, they are of limited value in vertigo. It should also
be borne in mind that patients taking antihistamines may poorly
evaluate their sedative effect,97 and that the patient may feel that this
effect diminishes with longer‐duration administration.
In addition to sedation and drowsiness, common H1 antagonist
side effects including somnolence, lethargy, other neural side effects
(headache and insomnia) and gastrointestinal effects (dry mouth,
nausea and stomach upset).98-100 The H3 antagonist betahistine was
considered well tolerated in clinical studies with no differences in side
effects or treatment discontinuation compared to placebo in several
randomised studies.43 There is notably no apparent effect on driving
DYHRFJELD‐JOHNSEN AND ATTALI
motor skills, supporting the absence of drowsiness.101 Associated side
effects include headache and mild gastric alterations such as nausea,
vomiting, dyspepsia, abdominal pain and abdominal distension, which
are typically mild to moderate and can be managed with dose modifi-
cations. Post‐marketing surveillance reported gastrointestinal symp-
toms and headaches as the principal side effects.50
The safety profile associated with SENS‐111, the first H4 antago-
nist to be evaluated clinically, in clinical investigations is extremely
encouraging, with the maximal tolerated dose not reached and
adverse events being nonspecific (headache, back pain), mild to mod-
erate, transient and comparable to placebo.90,91 Importantly, neither
sedation nor drowsiness has been reported—a key finding allowing
treatment of the acute vertigo symptoms while permitting vestibular
compensation.
Combination of 2 antihistamines does not appear to impact the
antihistamine safety profile. No difference was seen when flunarizine
was added to betahistine, with weight gain and somnolence being
the most common side effects in both arms.56 Analysis of cinnarizine
combined with dimenhydrinate in a real‐life setting of over 1250
patients suffering from vertigo, showed that the most common adverse
events were gastrointestinal and neurological (both in <2% of
patients), in particular somnolence, dry mouth, nausea and headache.39
9 | CO NC LUSIO N
Despite a paucity of robust evidence of efficacy, antihistamines have
played a primary role in vertigo management for over half a century.
Clear progress has been made since the initial treatments used, with
widespread administration of betahistine in Europe as well as various
H1 receptor antagonists depending on the geographical region. Our
understanding of the molecular mechanisms affecting vertigo modula-
tion has advanced, and the quality and sensitivity of measures has
improved. The principal burden associated with antihistamines today
remains their sedative side effects which have a strong impact on
optimal central compensation and daily functioning, in addition to
their direct modulation of central vestibular signalling. Although
later‐generation H1 and H3 antihistamines show fewer side effects in
terms of sedation, they do not achieve significant local target expo-
sure, limiting their clinical value for treating vertigo. While betahistine
may not be an appropriate choice for managing acute vertigo symp-
toms, it has potential for use in the recovery phase of vertigo manage-
ment by enhancing central compensation via its H1 agonism
properties, thus reducing chronic symptoms. This will be contingent
on current efforts on improving betahistine bioavailability to increase
exposure.
New approaches in clinical management include behavioural
studies and also combination studies with agents targeting different
histamine receptors, to date, primarily betahistine combinations. More
recently, preclinical evaluations of different H4 antagonists have
shown promise for a potential role of this drug class as new potential
treatments for vertigo, with the first clinical evaluations of the novel
H4 antagonist agent SENS‐111 in patients suffering from AUV
DYHRFJELD‐JOHNSEN AND ATTALI
currently ongoing. The clinical effect of the H4 antagonist SENS‐111
on vertigo induced in healthy volunteers compares favourably to the
magnitude reported for other antihistamines. The benefits of SENS‐
111 demonstrated in animal models of severe acute vertigo support
a role for symptomatic treatment of vertigo of peripheral origin such
as in AUV, Ménière's disease and migraine‐associated vertigo, which
would allow patients to maintain the ability to function normally and
benefit fully from the natural processes of central compensation.
ACKNOWLEDGEMEN TS
Sensorion is the sponsor of SENS‐111. We thank Sarah MacKenzie,
PhD for medical writing support (funded by Sensorion).
COMPETING INTER ESTS
J.D.‐J. and P.A. are shareholders and current/former employees of
Sensorion.
ORCID
Jonas Dyhrfjeld‐Johnsen https://orcid.org/0000-0003-0875-909X
RE FE R ENC E S
1. Bisdorff A, Von Brevern M, Lempert T, Newman‐Toker DE. Classifica-
tion of vestibular symptoms: towards an international classification of
vestibular disorders. J Vestib Res. 2009;19:1‐13.
2. Murdin L, Schilder AGM. Epidemiology of balance symptoms and
disorders in the community: a systematic review. Otol Neurotol.
2015;36(3):387‐392.
3. Neuhauser HK, Lempert T. Vertigo: epidemiologic aspects. Semin
Neurol. 2009;29(05):473‐481.
4. Strupp M, Brandt T. Peripheral vestibular disorders. Curr Opin Neurol.
2013;26(1):81‐89.
5. Neuhauser HK. The epidemiology of dizziness and vertigo. Handb Clin
Neurol. 2016;137:67‐82.
6. Guth PS, Perin P, Norris CH, Valli P. The vestibular hair cells: post‐
transductional signal processing. Prog Neurobiol. 1998;54(2):193‐247.
7. Soto E, Vega R, Seseña E. Neuropharmacological basis of vestibular
system disorder treatment. J Vestib Res. 2013;23(3):119‐137.
8. Bhattacharyya N, Gubbels SP, Schwartz SR, et al. Clinical practice
guideline: benign paroxysmal positional vertigo (update). Otolaryngol
Head Neck Surg. 2017;156(3_suppl):S1‐S47.
9. Hall CD, Herdman SJ, Whitney SL, et al. Vestibular rehabilitation for
peripheral vestibular hypofunction: an evidence‐based clinical
practice guideline: from the American Physical Therapy Association
neurology section. J Neurol Phys Ther. 2016;40(2):124‐155.
10. Imai T, Takeda N, Ikezono T, et al. Classification, diagnostic criteria
and management of benign paroxysmal positional vertigo. Auris Nasus
Larynx. 2017;44(1):1‐6.
11. Hain T. Drug treatment of vertigo. 2017 [cited 2017 Sep 8]; https://
www.dizziness‐and‐balance.com/treatment/drug/drugrx.html.
Accessed Sept 2017.
12. Panula P, Chazot PL, Cowart M, et al. International Union of Basic and
Clinical Pharmacology. XCVIII histamine receptors. Pharmacol Rev.
2015;67(3):601‐655.
13. Panula P, Nuutinen S. The histaminergic network in the brain: basic
organization and role in disease. Nat Rev Neurosci. 2013;14(7):
472‐487.
2261
14. Nyberg S, Abbott NJ, Shi X, Steyger PS, Dabdoub A. Delivery of ther-
apeutics to the inner ear: the challenge of the blood‐labyrinth barrier.
Sci Transl Med. 2019;11(482):eaao0935.
15. Azuma H, Sawada S, Takeuchi S, Higashiyama K, Kakigi A, Takeda T.
Immunohistochemical localization of histamine receptors in rat
cochlea. Laryngoscope. 2004;114(12):2249‐2251.
16. Takumida M, Takumida H, Anniko M. Localization of histamine
(H1, H2, H3 and H4) receptors in mouse inner ear. Acta Otolaryngol.
2016;136(6):537‐544.
17. Møller MN, Kirkeby S, Vikeså J, Nielsen FC, Caye‐Thomasen P.
Expression of histamine receptors in the human endolymphatic sac:
the molecular rationale for betahistine use in Menieres disease.
Eur Arch Otorhinolaryngol. 2016;273(7):1705‐1710.
18. Housley GD, Norris CH, Guth PS. Histamine and related substances
influence neurotransmission in the semicircular canal. Hear Res.
1988;35(1):87‐97.
19. Peng S‐Y, Zhuang Q‐X, He Y‐C, Zhu J‐N, Wang J‐J. Histamine excites
neurons of the inferior vestibular nucleus in rats by activation of H1
and H2 receptors. Neurosci Lett. 2013;541:87‐92.
20. Serafin M, Khateb A, Vibert N, Vidal PP, Mühlethaler M. Medial
vestibular nucleus in the Guinea‐pig: histaminergic receptors. I. an
in vitro study. Exp Brain Res. 1993;93(2):242‐248.
21. Yabe T, de Waele C, Serafin M, et al. Medial vestibular nucleus in the
Guinea‐pig: histaminergic receptors. II. An in vivo study. Exp Brain Res.
1993;93(2):249‐258.
22. Zhuang Q‐X, Wu Y‐H, Wu G‐Y, Zhu J‐N, Wang J‐J. Histamine excites
rat superior vestibular nuclear neurons via postsynaptic H1 and H2
receptors in vitro. Neurosignals. 2013;21(3‐4):174‐183.
23. Horii A, Takeda N, Matsunaga T, et al. Effect of unilateral vestibular
stimulation on histamine release from the hypothalamus of rats
in vivo. J Neurophysiol. 1993;70(5):1822‐1826.
24. Huang L‐G, Wang E‐T, Chen W, Gong W. Role of histamine H1
receptors in vestibular nucleus in motion sickness. Journal of Otology.
2011;6:20‐25.
25. Tu L, Lu Z, Dieser K, et al. Brain activation by H1 antihistamines
challenges conventional view of their mechanism of action in motion
sickness: a behavioral, c‐Fos and physiological study in Suncus
murinus (house musk shrew). Front Physiol. 2017;8:412.
26. Dyhrfjeld‐Johnsen J, Gaboyard‐Niay S, Broussy A, Saleur A,
Brugeaud A, Chabbert C. Ondansetron reduces lasting vestibular
deficits in a model of severe peripheral excitotoxic injury. J Vestib
Res. 2013;23(3):177‐186.
27. Luxon L. Comparison of assessment of caloric nystagmus by observa-
tion of duration and by electronystagmographic measurement of
slow‐phase velocity. Br J Audiol. 1995;29(2):107‐115.
28. Strupp M, Brandt T. Vestibular neuritis. Semin Neurol. 2009;29(05):
509‐519.
29. Witzeman LA. A new treatment for vertigo. Eye Ear Nose Throat Mon.
1949;28:272.
30. Bergquist F, Dutia MB. Central histaminergic modulation of vestibular
function ‐ a review. Sheng li Xue Bao. 2006;58(4):293‐304.
31. Amini A, Heidari K, Kariman H, et al. Histamine antagonists for
treatment of peripheral vertigo: a meta‐analysis. J Int Adv Otol.
2015;11(2):138‐142.
32. Kim M‐B, Lee HS, Ban JH. Vestibular suppressants after canalith
repositioning in benign paroxysmal positional vertigo. Laryngoscope.
2014;124(10):2400‐2403.
33. Cohen B, DeJong JM. Meclizine and placebo in treating vertigo of
vestibular origin. Relative efficacy in a double‐blind study. Arch
Neurol. 1972;27(2):129‐135.
2262
34. Shih RD, Walsh B, Eskin B, et al. Diazepam and meclizine are equally
effective in the treatment of vertigo: an emergency department
randomized double‐blind placebo‐controlled trial. J Emerg Med.
2017;52(1):23‐27.
35. Pianese CP, Hidalgo LOV, González RH, et al. New approaches to the
management of peripheral vertigo: efficacy and safety of two calcium
antagonists in a 12‐week, multinational, double‐blind study. Otol
Neurotol. 2002;23(3):357‐363.
36. Taghdiri F, Togha M, Razeghi Jahromi S, Refaeian F. Cinnarizine for
the prophylaxis of migraine associated vertigo: a retrospective study.
Springerplus. 2014;3(1):231.
37. Cirek Z, Schwarz M, Baumann W, Novotny M. Efficacy and tolera-
bility of a fixed combination of Cinnarizine and Dimenhydrinate
versus Betahistine in the treatment of Otogenic vertigo: a double‐
blind, randomised clinical study. Clin Drug Investig. 2005;25(6):
377‐389.
38. Hahn A, Sejna I, Stefflova B, Schwarz M, Baumann W. A fixed combina-
tion of cinnarizine/dimenhydrinate for the treatment of patients with
acute vertigo due to vestibular disorders: a randomized, reference‐
controlled clinical study. Clin Drug Investig. 2008;28(2):89‐99.
39. Scholtz A‐W, Steindl R, Burchardi N, Bognar‐Steinberg I, Baumann W.
Comparison of the therapeutic efficacy of a fixed low‐dose combina-
tion of cinnarizine and dimenhydrinate with betahistine in vestibular
neuritis: a randomized, double‐blind, non‐inferiority study. Clin Drug
Investig. 2012;32(6):387‐399.
40. Scholtz A‐W, Ilgner J, Loader B, Pritschow BW, Weisshaar G.
Cinnarizine and dimenhydrinate in the treatment of vertigo in medical
practice. Wien Klin Wochenschr. 2016;128(9‐10):341‐347.
41. Otto V, Fischer B, Schwarz M, Baumann W, Preibisch‐Effenberger R.
Treatment of vertebrobasilar insufficiency‐‐associated vertigo with a
fixed combination of cinnarizine and dimenhydrinate. Int Tinnitus
J. 2008;14:57‐67.
42. Arrang JM, Garbarg M, Quach TT, Dam Trung Tuong M, Yeramian E,
Schwartz JC. Actions of betahistine at histamine receptors in the
brain. Eur J Pharmacol. 1985;111(1):73‐84.
43. Ramos Alcocer R, Ledezma Rodríguez JG, Navas Romero A, et al. Use
of betahistine in the treatment of peripheral vertigo. Acta Otolaryngol.
2015;135(12):1205‐1211.
44. Huppert D, Strupp M, Mückter H, Brandt T. Which medication do I
need to manage dizzy patients? Acta Otolaryngol. 2011;131(3):
228‐241.
45. Lacour M, van de Heyning PH, Novotny M, Tighilet B. Betahistine in
the treatment of Ménière's disease. Neuropsychiatr Dis Treat.
2007;3:429‐440.
46. Smith WK, Sankar V, Pfleiderer AG. A national survey amongst UK
otolaryngologists regarding the treatment of Ménière's disease. J
Laryngol Otol. 2005;119(2):102‐105.
47. Della Pepa C, Guidetti G, Eandi M. Betahistine in the treatment of
vertiginous syndromes: a meta‐analysis. Acta Otorhinolaryngol Ital.
2006;26(4):208‐215.
48. Nauta JJP. Meta‐analysis of clinical studies with betahistine in
Ménière's disease and vestibular vertigo. Eur Arch Otorhinolaryngol.
2014;271(5):887‐897.
49. Murdin L, Hussain K, Schilder AGM. Betahistine for symptoms of ver-
tigo. Cochrane Database Syst Rev. 2016;2016:CD010696.
50. Benecke H, Pérez‐Garrigues H, Bin Sidek D, Uloziene I, Sondag E,
Theeuwes A. Effects of betahistine on patient‐reported outcomes in
routine practice in patients with vestibular vertigo and appraisal of
tolerability: experience in the OSVaLD study. Int Tinnitus J.
2010;16(1):14‐24.
DYHRFJELD‐JOHNSEN AND ATTALI
51. Adrion C, Fischer CS, Wagner J, Gürkov R, Mansmann U, Strupp M.
Efficacy and safety of betahistine treatment in patients with
Meniere's disease: primary results of a long term, multicentre, double
blind, randomised, placebo controlled, dose defining trial (BEMED
trial). BMJ. 2016;352:h6816.
52. Tighilet B, Léonard J, Watabe I, Bernard‐Demanze L, Lacour M.
Betahistine treatment in a cat model of vestibular pathology: pharma-
cokinetic and Pharmacodynamic approaches. Front Neurol.
2018;9:431.
53. Tighilet B, Trottier S, Lacour M. Dose‐ and duration‐dependent
effects of betahistine dihydrochloride treatment on histamine turn-
over in the cat. Eur J Pharmacol. 2005;523(1‐3):54‐63.
54. Tighilet B, Trottier S, Mourre C, Chotard C, Lacour M. Betahistine
dihydrochloride interaction with the histaminergic system in the cat:
neurochemical and molecular mechanisms. Eur J Pharmacol.
2002;446(1‐3):63‐73.
55. Teggi R, Gatti O, Sykopetrites V, Quaglieri S, Benazzo M, Bussi M.
Association of cinnarizine and betahistine in prophylactic therapy
for Ménière's disease with and without migraine. Acta
Otorhinolaryngol Ital. 2014;34:349‐353.
56. Lepcha A, Amalanathan S, Augustine AM, Tyagi AK, Balraj A.
Flunarizine in the prophylaxis of migrainous vertigo: a randomized
controlled trial. Eur Arch Otorhinolaryngol. 2014;271(11):2931‐2936.
57. Nagy A, Doros C, Marceanu L, et al. Treatment of Meniere's disease
with intratympanic dexamethazone plus high dosage of betahistine.
Am J Otolaryngol. 2016;37(3):225‐230.
58. Chen XY, Zhong DF, Duan JL, Yan BX. LC‐MS‐MS analysis of 2‐
pyridylacetic acid, a major metabolite of betahistine: application to a
pharmacokinetic study in healthy volunteers. Xenobiotica.
2003;33(12):1261‐1271.
59. AM‐125 for Vertigo. Betahistine spray for intranasal use. Fact sheet.
Auris medical. October 2018. https://aurismedical.com/product‐can-
didates/am‐125. Accessed February 2019.
60. Dutia MB. Mechanisms of vestibular compensation: recent advances.
Curr Opin Otolaryngol Head Neck Surg. 2010;18(5):420‐424.
61. Lacour M, Helmchen C, Vidal P‐P. Vestibular compensation: the
neuro‐otologist's best friend. J Neurol. 2016;263(Suppl 1):S54‐S64.
62. Bergquist F, Ruthven A, Ludwig M, Dutia MB. Histaminergic and
glycinergic modulation of GABA release in the vestibular nuclei of
normal and labyrinthectomised rats. J Physiol (Lond). 2006;577(3):
857‐868.
63. Zhou L, Zhou W, Zhang S, et al. Changes in histamine receptors (H1,
H2, and H3) expression in rat medial vestibular nucleus and Flocculus
after unilateral Labyrinthectomy: histamine receptors in vestibular
compensation. PLoS ONE. 2013;8(6):e66684.
64. Tighilet B, Mourre C, Lacour M. Plasticity of the histamine H3 recep-
tors after acute vestibular lesion in the adult cat. Front Integr Neurosci.
2014;7:87.
65. Peppard SB. Effect of drug therapy on compensation from vestibular
injury. Laryngoscope. 1986;96(8):878‐898.
66. Tighilet B, Mourre C, Trottier S, Lacour M. Histaminergic ligands
improve vestibular compensation in the cat: behavioural, neuro-
chemical and molecular evidence. Eur J Pharmacol. 2007;568(1‐3):
149‐163.
67. Redon C, Lopez C, Bernard‐Demanze L, et al. Betahistine treatment
improves the recovery of static symptoms in patients with unilateral
vestibular loss. J Clin Pharmacol. 2011;51(4):538‐548.
68. Parfenov VA, Golyk VA, Matsnev EI, et al. Effectiveness of betahistine
(48 mg/day) in patients with vestibular vertigo during routine prac-
tice: the VIRTUOSO study. PLoS ONE. 2017;12(3):e0174114.
DYHRFJELD‐JOHNSEN AND ATTALI
69. Goudakos JK, Markou KD, Psillas G, Vital V, Tsaligopoulos M.
Corticosteroids and vestibular exercises in vestibular neuritis. Single‐
blind randomized clinical trial. JAMA Otolaryngol Head Neck Surg.
2014;140(5):434‐440.
70. Rascol O, Hain TC, Brefel C, Benazet M, Clanet M, Montastruc JL.
Antivertigo medications and drug‐induced vertigo. A pharmacological
review. Drugs. 1995;50(5):777‐791.
71. Kaski D, Bronstein AM. Making a diagnosis in patients who present
with vertigo. BMJ. 2012;345(sep03 1):e5809.
72. Kiroglu MM, Dagkiran M, Ozdemir S, Surmrlioglu O, Tarkan O. The
effects of Betahistine and Dimenhydrinate on caloric test parameters;
slow‐phase velocity of nystagmus. J Int Adv Otol. 2014;10(1):68‐71.
73. Walker MF. Treatment of vestibular neuritis. Curr Treat Options
Neurol. 2009;11(1):41‐45.
74. Chen Z‐P, Zhang X‐Y, Peng S‐Y, et al. Histamine H1 receptor contrib-
utes to vestibular compensation. J Neurosci. 2019;39(3):420‐433.
75. Timmerman H. Pharmacotherapy of vertigo: any news to be
expected? Acta Otolaryngol Suppl. 1994;513:28‐32.
76. Orzechowski RF, Currie DS, Valancius CA. Comparative anticholiner-
gic activities of 10 histamine H1 receptor antagonists in two
functional models. Eur J Pharmacol. 2005;506(3):257‐264.
77. Liu C, Ma X, Jiang X, et al. Cloning and pharmacological characteriza-
tion of a fourth histamine receptor (H(4)) expressed in bone marrow.
Mol Pharmacol. 2001;59(3):420‐426.
78. Desmadryl G, Gaboyard‐Niay S, Brugeaud A, et al. Histamine H4
receptor antagonists as potent modulators of mammalian vestibular
primary neuron excitability. Br J Pharmacol. 2012;167(4):905‐916.
79. Wersinger E, Gaboyard‐Niay S, Travo C, et al. Symptomatic treatment
of vestibular deficits: therapeutic potential of histamine H4 receptors.
J Vestib Res. 2013;23(3):153‐159.
80. Zhang X‐Y, Yu L, Zhuang Q‐X, Peng S‐Y, Zhu J‐N, Wang J‐J.
Postsynaptic mechanisms underlying the excitatory action of hista-
mine on medial vestibular nucleus neurons in rats. Br J Pharmacol.
2013;170(1):156‐169.
81. Strakhova MI, Nikkel AL, Manelli AM, et al. Localization of histamine
H4 receptors in the central nervous system of human and rat. Brain
Res. 2009;1250:41‐48.
82. Feliszek M, Speckmann V, Schacht D, von Lehe M, Stark H, Schlicker
E. A search for functional histamine H4 receptors in the human,
Guinea pig and mouse brain. Naunyn Schmiedebergs Arch Pharmacol.
2015;388(1):11‐17.
83. Petri D, Schlicker E. A search for presynaptic inhibitory histamine
receptors in Guinea‐pig tissues: further H3 receptors but no evidence
for H4 receptors. Neuropharmacology. 2016;106:129‐134.
84. Pan L, Qi R, Wang J, Zhou W, Liu J, Cai Y. Evidence for a role of
orexin/Hypocretin system in vestibular lesion‐induced locomotor
abnormalities in rats. Front Neurosci. 2016;10:355.
85. Alfon J, Sanchez‐Gomez S, Salcedo C, et al. Efficacy of UR‐63325, a
new histamine H4 receptor antagonist, in house dust mite‐induced
mouse asthma models. Abstract 1302. Am J Respir Crit Care Med.
2011;183:A1302.
86. Dyhrfjeld‐Johnsen J, Wersinger E, Petremann M, et al. Translational
predictivity of preclinical studies of the anti‐vertigo drug SENS‐111
for clinical PK/PD relationships. Abstract PD170. Association for
Research in Otolaryngology (ARO), 40th MidWinter Meeting, Febru-
ary 11–15 2017, Baltimore MD, USA. 2017.
2263
87. Thurmond RL, Venable J, Savall B, et al. Clinical development of hista-
mine H4 receptor antagonists. Handb Exp Pharmacol. 2017;241:
301‐320.
88. Murata Y, Song M, Kikuchi H, et al. Phase 2a, randomized, double‐
blind, placebo‐controlled, multicenter, parallel‐group study of a H4
R‐antagonist (JNJ‐39758979) in Japanese adults with moderate
atopic dermatitis. J Dermatol. 2015;42(2):129‐139.
89. Thurmond RL, Greenspan A, Radziszewski W, et al. Toreforant, a his-
tamine H4 receptor antagonist, in patients with active rheumatoid
arthritis despite methotrexate therapy: results of 2 phase II studies.
J Rheumatol. 2016;43(9):1637‐1642.
90. Salcedo C, Pontes C, Merlos M. Is the H4 receptor a new drug target
for allergies and asthma? Front Biosci (Elite Ed). 2013;5:178‐187.
91. Venail F, Attali P, Wersinger E, Gomeni R, Poli S, Schmerber S.
Safety, tolerability, pharmacokinetics and pharmacokinetic‐
pharmacodynamic modelling of the novel H4 receptor inhibitor
SENS‐111 using a modified caloric test in healthy subjects. Br J Clin
Pharmacol. 2018;84(12):2836‐2848.
92. Vives R, Cebrecos J, Huguet J, et al. First into man administration of
UR‐63325, a new H4R antagonist for the treatment of allergic
respiratory diseases. 29th European Academy of Allergy and Clinical
Immunology (EAACI) Congress. 2010.
93. Gutner LB, Gould WJ, Batterman RC. Action of dimenhydrinate
(dramamine) and other drugs on vestibular function. AMA Arch
Otolaryngol. 1951;53(3):308‐315.
94. Philipszoon AJ. Influence of cinnarizine on the labyrinth and on
vertigo. Clin Pharmacol Ther. 1962;3(2):184‐190.
95. Martin N, Oosterveld WJ. The vestibular effects of meclizine
hydrochloride‐niacin combination (Antivert). Acta Otolaryngol.
1970;70(1):6‐9.
96. Carson S, Lee N, Thakurta S. Drug class review: newer antihistamines:
final report update 2. Portland (OR): Oregon Health & Science Univer-
sity; 2010. http://www.ncbi.nlm.nih.gov/books/NBK50558/
97. Kay G. The effects of antihistamines on cognition and performance.
J Allergy Clin Immunol. 2000;105(6):S622‐S627.
98. Amini A, Heidari K, Asadollahi S, et al. Intravenous promethazine
versus lorazepam for the treatment of peripheral vertigo in the emer-
gency department: a double blind, randomized clinical trial of efficacy
and safety. J Vestib Res. 2014;24(1):39‐47.
99. Marill KA, Walsh MJ, Nelson BK. Intravenous lorazepam versus
dimenhydrinate for treatment of vertigo in the emergency depart-
ment: a randomized clinical trial. Ann Emerg Med. 2000;36(4):310‐319.
100. Ozdemir H, Akinci E, Coskun F. Comparison of the effectiveness of
intravenous piracetam and intravenous dimenhydrinate in the treat-
ment of acute peripheral vertigo in the emergency department.
Singapore Med J. 2013;54(11):649‐652.
101. Betts T, Harris D, Gadd E. The effects of two anti‐vertigo drugs
(betahistine and prochlorperazine) on driving skills. Br J Clin
Pharmacol. 1991;32(4):455‐458.
How to cite this article: Dyhrfjeld‐Johnsen J, Attali P.
Management of peripheral vertigo with antihistamines: New
options on the horizon. Br J Clin Pharmacol.
2019;85:2255–2263. https://doi.org/10.1111/bcp.14046