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The effectiveness of long-term course of Sterimar

Mn nasal spray for treatment of the recurrence
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rates of acute allergic rhinitis in patients with

chronic allergic rhinitis
This article was published in the following Dove Press journal:
Drug Design, Development and Therapy

Michele Grasso 1 Background: The “cost of illness” of the acute allergic rhinitis (AR) episodes in patients with
Marco de Vincentiis 1 chronic AR is very high in terms of therapy and quality of life. AR represents a worldwide health
For personal use only.

Griselda Agolli 1 problem; despite the fact that many standardized treatments have been proposed and used, the
Francesco Cilurzo 2 recurrence rate of acute rhinitis episodes in springtime is always higher.
Raffaele Grasso 2 Materials and methods: Sixty consecutive patients (13 F and 17 M in group A, 15 F and
15 M in group B; p=0.60) with chronic AR were enrolled in this prospective, controlled clinical
1
ENT Department, Head and Neck
Surgery, University “Sapienza”, trial. Thirty patients were treated daily for the same 5 months of the following year (2013) with
Rome, Italy; 2ENT Department, Head isotonic seawater nasal spray enriched with manganese (Sterimar Mn; 4 puffs/day), whereas 30
and Neck Surgery, Lamezia Terme patients received only the standard care and were used as control group.
Hospital, Calabria, Italy
Results: A 5 months course treatment with the nasal Sterimar Mn was able to decrease, signifi-
cantly ( p0.001), the number of episodes of acute AR (6.33 episodes in the group of treated
patients versus 9.33 episodes in control group). Also, the 5 months quality of life reduced over
time (Visual Analogue Scale 5th month 9.90 in treated group versus Visual Analogue Scale 5th
Video abstract
month 8.72 in control group: p0.001) without the typical adverse effects of the AR standard
care therapy.
Conclusion: This study shows the effectiveness of the use of Sterimar Mn for a 5 months therapy
in terms of reduction of the number of episodes of acute AR and effectiveness of intrasubject
improvement of Visual Analog Scale (quality of life).
Keywords: chronic allergic rhinitis, acute allergic rhinitis, prevention, nasal detersion,
Sterimar Mn

Introduction
Allergic rhinitis (AR) is an inflammatory disease of the nasal mucosa. The typical
symptoms are rhinorrhea, sneezing, nasal congestion, nasal pruritus which could
Point your SmartPhone at the code above. If you have a
QR code reader the video abstract will appear. Or use: extend to eyes, and also redness and lacrimation in many patients. AR can lead to
http://youtu.be/SOQfEP7XX0Q many other consequent diseases including Obstructive Sleep Apnea Syndrome (OSAS)
syndrome, rhinosinusitis, asthma, conjunctivitis, and otitis media, and could affect
the social life, school outcomes, work production.1 AR is the most common chronic
disease in children in USA, one of the most common diseases affecting adults, and
Correspondence: Michele Grasso
ENT Department, Head and Neck the fifth most common chronic disease in the USA overall. It affects nearly one in
Surgery, University “Sapienza”, Rome, six US citizens. It impairs the quality of life (QoL), causes loss of school attendance
via San Silverio, 15, Rome 00165, Italy
Tel +39 333 461 6797
and work, and is responsible for up to $4 billion in lost productivity every year. AR
Email [email protected] generates up to $5 billion in direct health expenditures every year. Therefore, there

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 Grasso et al Dovepress

are a lot of diagnostic tests and treatments used to manage respiratory tract, and has a scavenger activity of promoting
this disorder, with considerable variation between them.2 superoxide dismutase (SOD).
Therapy is tailored to a patient’s symptom burden and QoL The aim of this prospective, controlled clinical trial
and is multimodal.3 was to understand if a 5 months course of application of
The Guidelines of Otolaryngology Development Group, isotonic sea water nasal spray enriched with manganese
AAO-HNSF, recommend intranasal steroids when there is a (Sterimar Mn; Laboratori Baldacci, Italy) could be useful to
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clinical diagnosis of AR the symptoms of which affect QoL. control acute AR attacks in adult patients with chronic AR.
Oral second-generation antihistamines are recommended
when AR is associated with primary complaints of itching Materials and methods
and sneezing. A clinical diagnosis of AR should be made Data collection and study design
when patients present on physical examination and with a Sixty consecutive patients with chronic AR were enrolled
history coherent with an allergic base and one or more of the in this prospective, controlled clinical trial. Inclusion crite-
following symptoms: itchy nose, nasal congestion, sneez- ria were as follows: 1) adult patients (18–99 years of age),
ing, runny nose. Findings of AR coherent with an allergic 2) more than 1 episode of acute AR treated with drugs,
cause include pale discoloration of the nasal mucosa, red such as oral antihistamines, nasal corticosteroids, or nasal
and watery eyes, and clear rhinorrhoea. Physicians should decongestants, 3) patients able to give informed consent and
first give empiric therapy. For those who do not respond, complete a scale assessment. Exclusion criteria were the
when the diagnosis is unclear, and when they need to know following: 1) presence of asthma, and 2) persistent AR (4
For personal use only.

the specific causative allergen to target therapy, it is impor- days/wk, or 4 weeks) according to Allergic Rhinitis and
tant to perform specific IgE (skin or blood) allergy testing. its Impact on Asthma (ARIA) guidelines.5 To ensure a bal-
Physicians should check for the associated conditions such ance in the samples size groups that results in equal sample,
as atopic dermatitis, sleep-disordered breathing, asthma, we used a four (4) blocks randomization method. Participants
rhinosinusitis, conjunctivitis, and otitis media. The allergic were monitored for seasonal allergy between February and
patients who respond inadequately to drug therapy with or June 2012 (spring time) at the Department of Otorhino-
without environmental control measures are candidates for laryngology of the Hospital of Lamezia Terme, Italy. The
sublingual or subcutaneous immunotherapy. The avoidance diagnosis was based on clinical symptoms and on specific
of known allergens and environmental controls (ie, the use of IgE (skin or blood) allergy testing. During the same 5 months
air filtration systems, bed covers, removal of pets, acaricides of the following year (2013), they were randomly divided
[all the devices targeted to kill dust mites]) are indicated in into 2 groups (Table 1). The first group (A), composed of
those who have identified allergens that correlate with clini- 13 F and 17 M, was treated with the standard care and named
cal symptoms. Surgeons should perform inferior turbinate “control group”. The second group (B), composed of 15 F
reduction in patients with AR with nasal airway obstruction and 15 M, was treated with the standard care and Sterimar
and enlarged inferior turbinates with no response to medical enriched with Mn (4 puffs/day) for 5 months, and named
management. Patients with perennial, seasonal, or episodic “treated group” ( p=0.60). The mean age was 39.63±1.96 in
AR can take advantage of intranasal antihistamines.2 The group A, and 46.63±1.46 in group B ( p=0.11). Participants
recurrence rate of acute episodes of rhinitis in springtime is were checked with regard to the following: 1) medication
always higher. These episodes worsen the QoL of the people intake and number of episodes of acute AR, 2) examination
with chronic AR. According to many authors,4 saline nasal by the same ear–nose–throat group, 3) self-assessment using
irrigation produced a 27% improvement in nasal symptoms, a Visual Analog Scale (VAS) score by using a visual scale
a 62% reduction in medicine intake, a 31% improvement in which a rating from 1 (poor) to 10 (high) was given for
of mucociliary clearance time, and a 27% increase in QoL.
Nasal irrigations using isotonic solution are indicated as
complementary therapy in AR. They are well tolerated, inex- Table 1 Patients’ features
pensive, easy to use, and there is no evidence showing that a Demographic Group A Group B
indicators (standard of care) (Sterimar Mn)
regular, daily saline irrigation adversely affects the patient’s
Age 39.63±1.96 46.63±1.46
health or leads to unexpected side effects.4 Manganese is
Sex 13 F–17 M 15 F–15 M
important in the control of allergy, as it manages the release Abbreviations: Sterimar Mn, hysotonic seawater nasal spray enriched with
of proinflammatory mediators, such as histamine in the manganese; F, female; M, male.

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 Dovepress Effectiveness of long-term course of Sterimar Mn nasal spray

QoL during the 3rd, 4th, and 5th month of adjuvant treatment. *URXS$VWDQGDUGRIFDUH *URXS%6WHULPDU0Q
The score changed according to the variation of symptoms

of AR, such as sneezing, nasal itching, rhinorrhea, and the 

degree of satisfaction with adjuvant therapy. During the trial,
every acute rhinitis episode was treated with the standard care
(antihistaminic, nasal decongestants, or/and corticosteroids) 
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in every patient. Written informed consent was obtained from

all study participants.

Outcomes
Primary endpoint was the ability to decrease the number of
0HDQQXPEHURI
episodes of acute AR during the 5 months of observation. HSLVRGHVEHIRUH 0HDQQXPEHURI
The secondary endpoint was the QoL improvement during WKHUDS\ HSLVRGHVGXULQJ
the 5 months course of treatment. PRQWKVFRXUVHV
3

Analysis of data Figure 1 Mean number of episodes before therapy and during 5 months courses,
cross-tabulation.
Statistical analysis was performed with SPSS Version 21 Notes: Significant differences between treated and control groups; p0.001.
(SPSS, Inc., Chicago, IL, USA) for Mac. The comparison of
For personal use only.

treated group versus controls for sex was performed with Fish- significant contribution from the drug on the clinical and
er’s exact test. The comparison of quantitative variables and subjective point of view.
scales in the two groups was performed with one-way analy-
sis of variance with bootstrap. All tests were two tailed, and Discussion
the conventional significance level of 0.05 was adopted. According to ARIA guidelines, the standard care in the treat-
ment of AR includes antihistamines, nasal decongestants or/
Ethical considerations and corticosteroids, cromones, antileucotrienics (if asthma
The research protocol of the study was discussed with and coexists), and specific immunotherapy.5 Great importance
approved by the Ethics Committee of the Hospital of Lame- is given to the removal of allergens and irritants in every
zia Terme. step of AR therapy, from those with mild, intermittent to
those with moderate–severe, persistent disease. Sterimar
Results Mn decreases the number of episodes of acute AR with a
The 30 patients (group B) treated with nasal Sterimar Mn mechanical cleansing, in order to remove antigens, viruses,
showed a significant improvement ( p0.001) in the primary
endpoint compared to the 30 untreated patients (group A)
(Figure 1). The mean number of episodes of acute AR before   
therapy was 9.50±2.64 in group A and 10.67±3.14 in group B.  
 
A 5 months course treatment with nasal Sterimar Mn was 

9$6VFRUH


able to decrease, significantly ( p0.001), the number of 
 
episodes of acute AR during the 5 months (6.33 episodes  
 
in treated patients versus 9.33 episodes in control patients).
 
Also, the 5 months QoL reduced over time (VAS 5th month 
 
9.90 in treated group versus VAS 5th month 8.72 in control
DU $

DU $
0 %

0 %
IF S

IF S

group: p0.001) without the typical adverse events seen in

DU XS

DU XS
H

H
Q

Q
R RX

R RX
ULP UR

ULP *UR
UG *U

UG *U
WH *

the AR standard of care. VAS score showed a statistically

WH
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QG

QG
6

significant improvement in group B patients versus group

WD

WD
V

A patients even after 3 months, and was maintained up to

Figure 2 Mean VAS (QoL) during 3 months courses (left side) and Mean VAS (QoL)
the 5th month of treatment ( p0.001) (Figure 2). No side during 5 months courses (right side).
Notes: The QoL is almost 10,000 after 5 months treatment in the treated group.
effects to treatment, like epistaxis or discomfort, happened Significant differences between treated and control; p0.001.
during the 5 months course of the trial. Group B reached a Abbreviations: QoL, quality of life; VAS, Visual Analog Scale.

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 Grasso et al Dovepress

and bacteria and to improve mucociliary clearance. Results vulnerable to oxidative insults implicated in the generation
of meta-analysis and systematic review stated that mucosal of O2-radicals.9 The mechanism of the inhibitory effect of
function improves with a direct physical cleansing. It flushes Mn2+ ions on mast cell secretion is as follows: Mn inhibits
out debris, allergen, crust, air pollutants, and thick mucus; the intracellular calcium-stimulated calcium current. This
removes inflammatory mediators; and improves ciliary beat intracellular calcium is mobilized by the effect of inositol
frequency leading to a better mucociliary clearance. Nasal triphosphate generated in response to peptides or polyamines
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irrigation with saline solution in AR results in the improve- or, from pathways that are still being studied, in response to
ment of symptoms, QoL, and mucociliary clearance time. The antigenic stimuli.10 Variations of intracellular Ca2+ levels
consumption of antiallergic medication can also be reduced. are key features of secretion processes as well as contractile
Nasal irrigation is safe and inexpensive, and represents a and metabolic occurrences. As strong inhibitors of mast cell
nonpharmacological form of treatment.4 The neutrophil is secretion, Mn2+ and Zn2+ can be accounted for as leaders
considered an important member in the inflammation of the of a new class of putative antiallergic therapies modulating
airways in asthmatics. Neutrophils obtained from asthmatic intracellular Ca2+ levels. Mn2+ inhibits a calcium-activated
patients generate a threefold increase in stimulated super- calcium flow and thus opposes the reconstitution of intracel-
oxide anion generation when compared to healthy controls.6 lular Ca2+ reserves.10 Eosinophils generate large amounts of
The mechanism of action of manganese in the control of oxidant species. The eosinophil-dominant type of chronic
respiratory allergic phenomena is due to its function as a rhinosinusitis with nasal polyps is related to more extensive
Ca channel blocker that prevents the release of proinflam- disease and a decreased likelihood of surgical success.
For personal use only.

matory mediators such as histamine in the respiratory tract, SOD is the first-line and only antioxidant enzyme that
and owing to its scavenging activity of promoting SOD. converts superoxide to hydrogen peroxide. SOD activity in
Sterimar Mn could reduce acute AR episodes due to the the eosinophilic and noneosinophilic groups was signifi-
activities of Mn on respiratory mucosa. Excessive production cantly reduced compared to that of the control groups. The
of superoxide anions causes cytokine release, inflammation, reduction in SOD activity and the downregulation of the
formation of chemotactic factors through many pathways SOD message seems to be related to eosinophil recruitment
such as generation of peroxynitrite, and DNA damage. The and epithelial damage of chronic rhinosinusitis with nasal
mechanism of attenuation of inflammation by SOD mimet- polyps.11 An inappropriate use of the standard of therapy
ics is the reduction of peroxynitrite formation through the in AR could lead to unlikely side effects, such as rhinitis
elimination of superoxide anions before they react with medicamentosa.12 In our study, no side effects were observed
nitric oxide. Because peroxynitrites are numerous and have during the 5 months course of the trial with hysotonic sea-
proinflammatory and cytotoxic effects, administration of water nasal spray.
SOD mimetics is clinically very important.7 VAS is a simple quantitative way that is widely used to
Oxygen radicals are highly chemically reactive sub- enable clinicians to assess the severity of AR and to evalu-
stances. They induce bronchoconstriction, increase mucous ate treatment efficacy. The VAS can show the variations of
secretion, and cause microvascular leakage leading to edema symptoms and QoL of patients with AR with high sensitivity.
formation. Organisms have evolved both enzymatic and We used the VAS as a simple quantitative tool to assess the
nonenzymatic antioxidant protective ways to detoxify bad burden of AR in primary care.13
oxidants. The major intracellular antioxidant enzymes, SOD, Studies of nasal irrigations reported different outcomes
catalase, and glutathione peroxidase, inactivate the oxygen in the management of AR.14,15 According to Nguyen et al14 a
radicals, producing a protective result on the airways. Tekin twice-daily nasal irrigation significantly reduced the scores
et al8 found significantly lower erythrocyte copper–zinc SOD of Mini-Rhino Conjunctivitis Quality of Life Questionnaire
activity in mild asymptomatic asthmatic patients who had at 4 and 8 weeks compared to baseline. In our study, we
never taken any kind of antiasthma therapy when compared used Sterimar enriched with manganese (4 puffs/day) for
to healthy controls. Manganese SOD and copper–zinc 5 months, in order to achieve significant improvement of
SOD were immunohistochemically highly expressed in the symptoms of AR and greater degree of satisfaction of adju-
subepithelial glands of nasal mucosa and in the epithelial vant therapy compared with the standard therapy alone. A
cells. The olfactory vesicles showed positive immunostain- Cochrane review15 found no benefit of saline spray over
ing for manganese SOD and copper–zinc SOD. Epithelial intranasal steroids, and some benefit of saline irrigation
goblet cells and the connective tissue of lamina propria (150 mL) with a hypertonic solution compared to placebo, in
exhibited negative immunostaining for SODs, proving to be patients with chronic rhinosinusitis, because of the different

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 Dovepress Effectiveness of long-term course of Sterimar Mn nasal spray

bias in the two studies considered. In our study, we treated 4. Hermelingmeier KE, Weber RK, Hellmich M, Heubach CP, Mösges R.
Nasal irrigation as an adjunctive treatment in allergic rhinitis: a sys-
only patients with chronic AR, comparing the use of adju- tematic review and meta-analysis. Am J Rhinol Allergy. 2012;26(5):
vant therapy to nonuse. Since Chong et al15 pointed out the e119–e125.
nonactivity of nasal physiological solutions in addition to 5. Allergic Rhinitis and its impact on Asthma (Italian Section). Lombardi C,
Passalacqua G, et al. http://www.progetto-aria.it/materiale/2017/slide-
standard care, it could be that the sum of effects of Sterimar kit-aria-2017.ppt
Mn is responsible for the activity. 6. Joseph BZ, Routes JM, Borish L. Activities of superoxide dismutases
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and NADPH oxidase in neutrophils obtained from asthmatic and normal

donors. Inflammation. 1993;17(3):361–370.
Conclusion 7. Li C, Zhou HM. The role of manganese superoxide dismutase in inflam-
mation defense. Enzyme Res. 2011;2011:387176.
In conclusion, our results demonstrate the effectiveness of 8. Tekin D, Sin BA, Mungan D, Misirligil Z, Yavuzer S. The antioxidative
Sterimar Mn (4 puffs/day for nostril) for 5 months courses defense in asthma. J Asthma. 2000;37(1):59–63.
9. Lai MT, Ohmichi T, Ogawa T, Nishizaki K, Masuda Y. Electron spin
therapy to control the number of episodes of acute AR and to resonance spin trapping assay and immunohistochemical localization
improve QoL. The seawater solution enriched with manga- of superoxide dismutases in the rat nasal mucosa. Acta Otolaryngol.
nese represents a good tool in the management of the acute 1997;117(3):437–446.
10. Landry Y, Bronner C, Gies JP, Mousli M. The inhibitory effect of
AR episode in patients with chronic AR, without the typical divalent cations on mast cell secretion. Rev Fr Allergol. 1993;33(2):
side effects seen with common therapy. 146–150.
11. Ono N, Kusunoki T, Miwa M, Hirotsu M, Shiozawa A, Ikeda K.
Reduction in superoxide dismutase expression in the epithelial mucosa
Disclosure of eosinophilic chronic rhinosinusitis with nasal polyps. Int Arch Allergy
Immunol. 2013;162(2):173–180.
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know. Eur Arch Otorhinolaryngol. 2009;266(5):623–625.
13. Demoly P, Bousquet PJ, Mesbah K, Bousquet J, Devillier P. Visual
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