Olopatadine 0.

6% nasal spray protects from vasomotor challenge in patients with severe vasomotor rhinitis
Peter K. Smith, M.B.B.S., Ph.D. and Joel Collins, M.B.B.S.
ABSTRACT

Background: Vasomotor rhinitis (VMR) is a hypersensitivity syndrome with heightened reactivity to environmental triggers. Methods: Twenty-two patients with severe VMR were treated nasally with either normal saline or 0.6% olopatadine and challenged nasally with a hyperosmolar mannitol solution. Results: Treatment with 0.6% olopatadine resulted in an improvement in instantaneous nasal symptom scores at 5 and 30 minutes (p 0.01) compared with baseline and at 30 minutes after hyperosmolar challenge compared with saline-pretreated individuals (p 0.01). There was also an improvement in nasal peak inspiratory flow rate at 30 minutes after hyperosmolar challenge compared with saline-pretreated individuals (p 0.01). Conclusion: In this patient population 0.6% olopatadine appears to be efficacious in symptom reduction in VMR and protects from hyperosmolar challenge. (Am J Rhinol Allergy 25, e149 e152, 2011; doi: 10.2500/ajra.2011.25.3620) asomotor rhinitis (VMR) is a nasal hypersensitivity syndrome that has many names (nonallergic noninfective rhinitis, nonallergic rhinitis, idiopathic rhinitis, and nonallergic VMR [NAVMR]) and suggested mechanisms. Nasal hypersensitivity can occur in conjunction with patients with allergic rhinitis (mixed rhinitis) or in the absence of IgE allergen-specific reactivity.13 Triggers for VMR have been well described but may not be present in all individuals, frustrating those wishing to define, study, and treat the condition.1,3,4 The most useful differentiating factor in diagnosing VMR is sensitivity to cold dry air; however, other reported triggers include barometric and temperature change, volatile fumes, strong smells, smoke, chlorine, and dietary triggers such as spicy foods and alcohol.18 Olfactory hypervigilance is also recognized in patients with VMR. VMR tends to occur more in women 35 years of age4 but is recognized in children.8 The disease burden impact of patients with VMR is considerable with up to 57% of all patients with chronic rhinitis reported as having either mixed (allergic and VMR) or nonallergic VMR.3 Consistently effective treatment options are limited in nonallergic rhinitis.8,9 Capsaicin has been used as a tool for diagnostic challenge in patients with VMR9 and also for treatment.1014 Capsaicin has a highly specific receptor, the transient receptor potential vanilloid 1 (TRPV1), which belongs to a superfamily of 28 chemical, thermal, and nociceptors.15,16 TRPV1 is expressed on sensory nerves, mucous glands, mast cells, and epithelial cells in humans.17 Animal studies indicate that TRPV1 is present in up to 60% of trigeminal sensory neurons.18 The TRPV1 receptor can be activated by multiple stimuli including heat, acidosis, capsaicin, allicin (in garlic), ethanol, lipo-oxygenase products, and intracellular lipid mediators such as anandamide.15,1924 TRP channels gate calcium and sodium ion currents into cells, which can cause depolarization of sensory nerves. Activation by the aforementioned factors is dependent on sensitization of the TRPV1 receptor that is controlled by intrinsic kinases such as protein kinases A and C, calcium calmodulindependent kinase II, or Srk kinase, which phosphorylate components of the transmembrane protein.2529 An

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inhibitor of TRPV1 activation phosphatidylinositol 4,5-bisphosphate (PIP2) binds to the N terminus and stabilizes the channel.30 Challenging to the airways with capsaicin causes itch, pain, irritation, rhinorrhea, mucous hypersecretion, cough, bronchoconstriction, and, in some cases, death.31 Olopatadine is an antihistamine and mast cell stabilizer with rapid effects.32 It is efficacious in allergic rhinitis.33,34 Japanese animal studies have shown efficacy of olopatadine in a capsaicin challenge model, with an action outside the histamine receptor blockade.35 Hyperosmolar challenge has been unequivocally established to work through the TRPV1 channel in sensory neurons in a knockout mouse model.36 Mannitol is used as a challenge tool for challenging airways in asthma.37,38 This study examines the effect of olopatadine 0.6% nasal spray on symptoms in patients with VMR and determines if this medication delivered a protective effect when challenging the TRPV1 (capsaicin) receptor with a hyperosmolar challenge.

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METHODS
Twenty-two adult patients (aged 1672 years; 18 female and 4 male patients) with severe rhinitis vasomotor triggers were consented and enrolled in the double-blind placebo-controlled crossover study. Ethics Committee approval was obtained via Griffith University, Queensland, Australia. Randomization was performed at www.randomizer. com. Patients were screened with skin testing, specialist allergist review, and completed previously published questionnaire criteria.5 Rhinitis medications were stopped for 48 hours and patients were given either normal saline (Narium; Hamilton Laboratories, Adelaide, Australia) or 0.6% olopatadine spray (Alcon, Fort Worth, TX), 2 sprays in each nostril, and monitored for 30 minutes. Patients were then challenged with 130 L of pharmacist-compounded mannitol at a concentration of 400 mOsm (room temperature) in each nostril. Instantaneous total nasal symptom score (iTNSS) in four domains (0to 3-point scale of congestion, rhinorrhea, itch, and sneezing) and peak inspiratory nasal flow rates were recorded at baseline and at 5and 30-minute intervals, using an In-Check inspiratory flow meter (Clement Clarke, Harlow, United Kingdom). Data were analyzed in a homoscedastic paired two-tailed analysis using Microsoft Excel database software (Microsoft Corp., Redlands, CA).

From Department of Clinical Medicine, Griffith University, Southport, Australia This is an investigator-initiated study and P. Smith received partial support from Alcon in terms of materials and nursing support for the pilot part of this study and self-funded thereafter. P. Smith has participated in Speaker Bureau and Advisory Boards for Alcon, GSK, and Schering Plough. J. Collins has no conflicts to declare pertaining to this article Address correspondence and reprint requests to Prof. Peter K. Smith, Department of Clinical Medicine, Griffith University, High Street, Southport, Queensland 4215, Australia E-mail address: pksm@mac.com Copyright 2011, OceanSide Publications, Inc., U.S.A.

RESULTS
Olopatadine showed efficacy compared with baseline iTNSS (1.36 1.39 versus 2.91 2.24) at 5 and 30 minutes (1.00 1.41 versus 2.91 2.24; p 0.01), whereas saline placebo did not show a difference before mannitol challenge. Results are shown in Table 1 and Fig. 1. In the challenge phase, olopatadine 0.6%pretreated patients had less symptoms at 30 minutes than saline-pretreated patients

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Table 1 Instantaneous nasal symptom scores in saline- and olopatadine-treated patients Treatment Baseline Saline Olopatadine 2.59 2.04 2.91 2.24 5 min 2.09 1.82 1.36 1.40* 30 min 1.77 1/45 1.00 1.41* 5 min 3.50 2.20 2.63 2.12 Mannitol Challenge 30 min 3.86 2.25 1.95 1.81

* Compared to baseline score. Compared to time paired score.

when challenged with mannitol in terms of iTNSS (1.95 1.81 versus 3.86 2.25, shown in Table 1 and Fig. 1; p 0.01) and peak inspiratory nasal flow rate (110 38.7 versus 81.8 26.7; p 0.01).

DISCUSSION

Olopatadine pretreatment resulted in protection from an experimental hyperosmolar challenge, a well-defined trigger of the capsaicin TRPV1 receptor.37,38 Mannitol does have mechanical effects on airway mucosal transport, so this model of hyperosmolar challenge is likely to have effects outside TRPV1 activation. Symptom improvement was rapid in the initial treatment phase with olopatadine 0.6% nasal spray, compared with using saline placebo in patients with severe VMR. Olopatadine nasal spray has been shown to be faster and more efficacious than oral antihistamine therapy in the treatment of pollen-induced rhinitis.39 The speed of olopatadine in symptom relief has been noted by several research series.33,34,3942 Olopatadine, although being an antihistamine, is structurally similar to the antidepressant doxepin, and its effect in VMR may be occurring via neurogenic pathways, which would explain the rapid improvement in iTNSS observed in the prechallenge phase of this study. In an animal model of rhinitis, olopatadine has been shown to reduce sneezing with capsaicin challenge, an effect beyond the antihistamine actions of this medication.35 In lower airway studies, olopatadine has demonstrated capacity to significantly reduce tachykinin effects.43 Olopatadine appears to be particularly potent in this action and the effect on SKCa does not appear to be a class effect to antihistamines. Olopatadine has been reported to inhibit phospholipases.44 The phosphorylation of TRPV1 primes this receptor and enables it to be activated by physical or chemical stimuli to gate calcium into the cell. TRPV1 can be phosphylated and thus sensitized by a wide range of mediators including lymphokines, neurokinins, histamine, prostaglandin tyrosine kinase, and hormones such as prolactin, which are regulated via phospolipases and kinases.4557 It is by the TRPV1 mechanism that hista-

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Figure 1. Instantaneous nasal symptom scores in saline and olopatadine-treated patients. Olopatadine patients had reductions in instantaneous total nasal symptom score (iTNSS) at 5 and 30 minutes compared with baseline. In the challenge phase of the study the olopatadine-pretreated patients had a reduced iTNSS compared with those with saline pretreatment.

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mine results in depolarization of sensory neurons to cause itching.48 Blocking the TRPV1 receptor with an antagonist or in TRPV1 knockout mice, causes abolition of TRPV1 activation by histamine.49 PIP2, which reportedly stabilizes the TRPV1 receptor,30 can be hydrolyzed by phospholipase C.57 Ololpatadine has been shown to inhibit the inhibition of PIP2,58 which could potentially reestablish stability to the cation gate of TRPV1 expressing sensory neurons and other TRPV1 expressing cells in the upper airways. The speculative action, to stabilize sensory nerve release of neurokinins on stimulation, could account for the speed of action of olopatadine 0.6%, and relative protection of sensory nerves to a TRPV1 challenge as observed in the aforementioned patient series. Olopatadine 0.6% nasal spray appears to have rapid efficacy in terms of symptom control in patients with severe VMR and protects from osmotic challenge.

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