Lyophilized Cyclamen europaeum tuber extract in the treatment of rhinosinusitis

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Lyophilized Cyclamen europaeum tuber extract in the treatment

of rhinosinusitis

Dariusz Jurkiewicz

^1ABDEF

, Elżbieta Hassmann-Poznańska

^2ABDEF

, Henryk Kaźmierczak

^3ABDEF

, Jacek Składzień

^4ABDEF

, Wioletta Pietruszewska

^5ABDEF

, Paweł Burduk

^3ABDEF

, Piotr Rapiejko

^1ABDEF

1 Department of Otolaryngology with Division of Cranio-Maxillo-Facial Surgery in Military Institute of Medicine, Warsaw, Poland

2Department of Paediatric Otolaryngology, Faculty of Medicine, Medical Univeristy of Białystok, Poland

3 Department of Otolaryngology and Oncological Laryngology, Collegium Medicum, Faculty of Medicine, Nicolaus Copernicus University, Torun, Poland

4Department of Otolaryngology Head and Neck Surgery, Jagiellonian University, Cracow, Poland

5Department of Otolaryngology and Oncological Laryngology, Medical University of Lodz, Poland

Article history: Received: 05.01.2016 Accepted: 10.02.2016 Published: 29.02.2016

ABSTRACT: Nasal and sinus mucositis is a significant health problem associated with significant organizational and financial burden for the health care system. In recent years, several important guidelines and positions of expert groups and scientific associations have been published with regard to the diagnostics and treatment of rhinosinusitis, including European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS 2012) and Polish Standards for the Treatment of Rhinitis (PoSLeNN 2013). The management of viral and postviral rhinosinusitis involves systemic treatment including administration of plant origin products.

The goal of this article is to present the current knowledge on the use of intranasal preparations containing natural saponin fractions from the rhizomes of Alpine cyclamen (Cyclamen europaeum).

Saponins contained in the extract of Alpine cyclamen (Cyclamen europaeum) rhizomes are surface-active compounds that reduce the surface tension on the nasal mucosal cells while simultaneously stimulating the trigeminal nerve receptors leading to increased production of seromucous secretion and extensive drainage of the nasal and sinus cavities.

The analysis of published studies on the efficacy and safety of intranasal products containing lyophilized extracts from Cyclamen europaeum tuber warrants the conclusion that these products are useful in the management of nasal and sinus mucositis due to their beneficial impact on the course of the treatment of acute rhinosinusitis. When used in patients with acute rhinosinusitis, an intranasal preparation containing lyophilized extracts from Cyclamen europaeum tuber efficiently reduces the symptoms, particularly the feeling of pressure and pain in the face. Accord- ing to the authors of PROSINUS study, single-agent treatment using Cyclamen europaeum extracts is more efficient (in terms of the percentage of success) than other monotherapy or combination regimens.

KEYWORDS: rhinosinusitis, treatment, phytotherapy, saponins, Cyclamen europaeum

Authors’ Contribution:

A – Study Design B – Data Collection C – Statistical Analysis D – Data Interpretation E – Manuscript Preparation F – Literature Search G – Funds Collection

Rhinosinusitis is a condition commonly encountered in laryngological practice and, at the same time, one of the most common causes of visits at primary care physicians’

practices [1]. According to a review published in 2012 by the International Rhinologic Society, global rhinosinusitis morbidity rates range from 6% to 15%, with secondary bacterial infection developing in 0.5-2% of patients [2].

According to EPOS 2912, rhinosinusitis morbidity rate in

Europe and the US is estimated at 5-15%. In Poland, an- nual incidence is estimated at 4 to 8 million patients, with chronic rhinosinusitis possibly affecting as much as 15% of the overall population [3,4].

Acute rhinosinusitis is an inflammatory condition involving the mucosal membranes of both nasal cavities and parana- sal sinuses [1,4]. The condition has a sudden onset. The in-

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tensity of symptoms as assessed using a visual analog scale (VAS) may be mild, moderate, or severe [1,3].

According to the EPOS 2012 guidelines, rhinosinusitis symptoms lasting not longer than 10 days are referred to as common cold or acute rhinosinusitis while symptoms lasting longer than 10 days but shorter than 12 weeks, or exacerbation of symptoms after 5 days is referred to as acute postviral rhinosinusitis [1,4]. About 98 to 99.5% of the cases of acute rhinosinusitis are caused by a viral infection [4]. Predominant agents responsible for viral infections are rhinoviruses, coronaviruses, paraflu and flu viruses, and adenoviruses [4,5]. Secondary bacterial infections are observed in about 0.5-2% of cases [1,4,5].

Acute rhinosinusitis is associated with a complex pathophys- iological mechanism with a predominant role of inflammatory mucosal swelling, narrowing of natural sinus outlets and impaired mucociliary transport [6]. Risk factors that impair drainage and ventilation of sinuses, thus predisposing the patient to acute rhinosinusitis include mainly allergic rhinitis, anatomical defects of nasal septum and lateral nasal cavity walls, tobacco smoke and environmental pollution [1,3,4]. Ostiomeatal complex is the key region which, when obstructed, leads to the development of inflammatory conditions [6,7]. As the sinus outlet is blocked, oxygen is resorbed by the mucosal membrane from the sinus lumen, leading to reduced pH. Hypoxia and acidic environment contribute to ciliary damage and impaired ciliary epithelial function. Viral infections, particularly infections with flu viruses or adenoviruses, impair the ciliated mucosal cells. This results in secretion of inflammatory mediators including interleukin 1, interleukin 6, and TNF alpha which, as acute phase cy- tokines, activate neutrophil chemotactic agents, and initiate the release of bradykinin, histamine, and leukotrienes. This in turn leads to vessel dilation and more extensive swelling with simultaneous impairment of the excretory glandular function. Transudate from dilated vessels and mucous secretion accumulate within the sinuses due to damaged function of the ciliary apparatus and the obstruction of outlets.

These conditions favor the development of aerobic and an- aerobic bacteria which release toxins to enhance inflammation, thus leading to a vicious circle effect [1,4].

Acute rhinosinusitis has a sudden onset and is most commonly due to primary rhinitis. Most commonly, rhinosinusitis is accompanied by systemic symptoms including elevated temperature, malaise, and anorexia. Predominant symptoms include facial pain, maxillary tooth pain, mucop- urulent nasal discharge with impaired nasal patency. Diag- nosis of acute rhinosinusitis is based on medical interview and physical examination [1,4].

However, the symptoms of sinusitis are not specific or sen- sitive, and therefore at least two of these symptoms are required for the diagnosis [1]. One of the symptoms must consist of a primary symptom including

•

nasal blockage/obstruction/congestion and/or

•

nasal discharge (anterior/posterior nasal drip).

The additional symptoms include:

•

facial pain/pressure

•

reduction/loss of smell in adults and cough in children.

The onset and intensity of local symptoms are related to mucosal swelling and the degree of obstruction of sinus outlets which might indicate the sinus being affected by the inflammatory process. In case of maxillary sinus involvement, pain is located within the region of the cheeks, teeth, or ocular or- bits. Tenderness of the frontal wall of the maxillary sinus may be detected upon palpation. Isolated frontal sinusitis presents with pain in the forehead region with tenderness on palpation of the frontal or the bottom wall of the sinus. Patients with ethmoid sinusitis report pain and a feeling of expansion along with tenderness on palpation within the medial eye canthus.

Multifocal pain or pain localized within the occipital region radiating towards the forehead, temples, medial eye corner or ocular orbit is characteristic for sphenoid sinusitis. In acute rhinosinusitis, inflammation of several sinuses is more common than isolated inflammation of single sinuses, and therefore the clinical presentation of symptoms is by far less characteristic.

Differentiation between the viral, postviral and bacterial acute rhinosinusitis is difficult due to the lack of symptoms specific for any of the etiologies. The character of nasal discharge, e.g.

the purulent character of the discharge, is not a differentiating criterion. In line with the EPOS consensus [1], acute rhinosinusitis (ARS) is classified into:

•

viral ARS/common cold;

•

postviral ARS;

•

bacterial ARS.

The most common acute viral rhinosinusitis usually lasts for up to 10 days. Postviral acute rhinosinusitis is diagnosed in case of symptoms being exacerbated after 5 days or lack of improvement after 10 days. Among these, cases of bacterial acute rhinosinusitis should be differentiated when patients present with three out of the following five symptoms: changed secretion color (purulent nasal discharge predominant in one of the nasal cavities), strong localized facial pain predominant on one side, fever of above 38°C, elevated levels of acute phase markers (CRP>10) or exacerbation of hitherto mild course of the disease. Local symptoms may be accompanied by irritation of the throat, pharynx and trachea leading to dry

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above 38 °C persisting for 3 days or strong pain is diagnosed as severe disease [1,4].

Acute rhinosinusitis is diagnosed on the basis of symptoms and results of physical examination by primary care physicians or on the basis of specialized laryngological examination supported by endoscopic assessment as part of specialist treatment [1].

According to the EPOS 2012 recommendations [1], radiolog- ical examinations (X-ray, CT, MRI) or bacteriology assays are cough, disturbed voice, sleepiness, malaise and overall weak-

ness. These symptoms may persist for up to 12 weeks [4,8].

Determination of symptom intensity using a VAS scale is very important for initiation of appropriate treatment. Patients in- dicating their symptoms’ score to be from 0 to 3 are diagnosed with mild rhinosinusitis.

Symptoms in the score range of 4 to 7 are diagnosed as moderate rhinosinusitis while the score of 8 to 10 with fever of Fig. 1. Management scheme for primary care for adults with acute rhinosinusitis (EPOS 2012) [1]

ACUTE RHINOSINUSITIS IN ADULTS MANAGEMENT SCHEME OF PRIMARY CARE 2 symptoms: one of which should be na-

sal obstruction

or discoloured discharge +/- frontal pain, headache +/- smell disturbance

examination: anterior rhinoscopy X-ray/CT not recommended

symptoms less than 5 days or improving thereafter

Common cold

no effect after 10 days of treatment

symptoms persistent after 10 days or increasing after 5 days

moderate (post viral) severe* (including bacterial)

= at least 3 of:

Discoloured discharge severe local pain fever elevated ESR/CRP do-

uble sickening

topical steroid consider antibiotics

no effect in 48 h

refer to specialist + topical steroid

no effect after 14 of

treatment effect in 48 h

Continue treatment For 7 – 14 days

Immediate referral:

• periorbital oedema/erythema

• displaced globe;

• double vision;

• opthalmophlegia;

• reduced vision acuity;

• severe unilateral or bilateral frontal headache;

• frontal swelling;

• signs of meningitis or neurologic sings

consider referal to specialist Symptomatic relief:

analgesics, nasal saline, irrigation, decongestants, selected herbal compounds

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should be effective against the most common pathogens, including their potential resistance profiles [5].

In case of complications of acute rhinosinusitis, additional surgical treatment may be required [1].

Intranasal glucocorticosteroids as well as antibiotics should be included while standard symptomatic treatment is being continued [1,2,4,9]. Due to the fact that rhinosinusitis of bacterial origin is often associated with bacterial coloniza- tion in the form of biofilms, the extracts of Alpine cyclamen support the efficacy of antibiotics by means of surface-active saponins that destroy these biofilms [12-14].

In case no improvement is achieved after 14 days in the treatment of mild to moderate rhinosinusitis and after 48 hours in the treatment of severe rhinosinusitis, patient should be referred for specialist treatment; bacteriological assays, and, in some cases, hospitalization should also be considered [1].

SAPONINS IN THE TREATMENT OF ACUTE RHINOSINUSITIS

The EPOS 2012 reports recommend the use of substances of plant origin as a supportive treatment [1]. Among the products of plant origin, preparations containing lyophilized powder obtained from fresh tubers of Alpine Cyclamen (Cyclamen europaeum L.) are particularly noteworthy. As surface active substances, saponins interact with mucosa to facilitate the removal of the secretion [14]. By stimulating trigeminal nerve endings, they increase the production of seromucous secretion, thus facilitating the ciliary move- ments and leading to more effective of evacuation sinuses [14,15]. Saponin-containing products used as single agents or in combination regimens significantly remove evacuation of the discharge from nasal and sinus cavities and reduce mucosal swelling thus improving patient’s satisfaction with the treatment [12,13].

Cyclamen (Cyclamen L.) is a genus of plants from family Primulaceae. The genus includes about 20 species from the Mediterranean basin and South-West Asia. One of the rep- resentative species is Alpine cyclamen (Cyclamen europae- um). The extract from the tubers of Alpine cyclamen was used for several centuries as a medicinal agent. The extract from the tubers of Alpine cyclamen is administered as intranasal solution in symptomatic treatment of rhinosinusitis.

Saponins are eliminated along with the mucus rather than being absorbed at the mucosal surface. The extract from the tubers of Alpine cyclamen (Cyclamen europaeum) in not used in the diagnostics of acute rhinosinusitis. The need to

broaden the diagnostic scope occurs upon the failure of treatment, exacerbation of symptoms or suspicion of sinusogenic complications.

TREATMENT OF ACUTE RHINOSINUSITIS

Considering the causes of acute rhinosinusitis such as the blockage of natural sinus outlets and infection, the treatment consists in symptomatic pharmacological treatment.

Conservative treatment should be modified according to the nature of infection, i.e. viral, bacterial, or fungal infection as well as to its intensity, i.e. whether the disorder is mild, moderate, or severe. Surgical treatment of acute rhinosinusitis is recommended in case of sinusogenic complications. In Poland as well as in other countries, there is a predominant trend toward premature initiation of antibiotic treatment which significantly and unnecessarily increases treatment costs on one hand and leads to increased drug resistance on the other [4,5]. Therefore, the adherence to the treatment regimens included in the treatment recommendations of both acute and chronic rhinosinusitis is very important. Cur- rently, binding guidelines include EPOS 2012 [1], PoSLeNN [2] and the Recommendations for the management of extra- mural respiratory tract infections [5] as well as recommendations for family physicians based on the aforementioned guidelines [9]. Management of acute rhinosinusitis depends on the form and the intensity of the condition.

In viral sinusitis lasting less than 10 days, symptomatic treatment is recommended including antipyretics and analgesics and close monitoring strategy [1,2,5,9].

In postviral infections persisting beyond day 10, presenting with mild to moderate symptoms, additional inclusion of intranasal glucocorticosteroids is recommended [1,2,5,9].

In both forms of inflammation, recommendations include the lavage of nasal cavities with isotonic solutions of physiological saline that flushes out the accumulated secretion containing proinflammatory agents or hypertonic solutions of physiological saline that additionally increase water re- sorption and reduce swelling, thus contributing to the improved patency of nasal and sinus cavities [1,10,11].

Antibiotic therapy combined with local steroid therapy is recommended in acute bacterial rhinosinusitis or severe postviral rhinosinusitis, lack of improvement after 14 days of treating moderate disease as well as in case of suspected complications [1]. Antibiotics used in acute rhinosinusitis

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Efficacy and tolerance endpoints were assessed on the basis of average score of rhinosinusitis symptoms (including nasal obstruction, mucous secretion, facial pain/pressure and loss of the sense of smell), endoscopic assessment of symptom resolution, satisfaction with the treatment and incidence of adverse effects as assessed both by the patient and the physician.

Intranasal spray containing Cyclamen europaeum (CE) ex- tract led to reduction (resolution) of symptoms as compared to placebo although the differences in total mean score did not reach the statistical significance level (CE -3.2 ± 2.3;

placebo -2.7 ± 2.2). However, facial pain after 5-7 days of treatment was significantly lower in patients treated with intranasal spray containing the CE extract as compared to the placebo group (p=0.04). Mucosal swelling/nasal obstruction as assessed by endoscopic examination on day 7 was also significantly improved in the CE group (p<0.03). The authors [16] also point to the higher percentage of patients and investigators being satisfied with the reduction of rhinosinusitis symptoms in the CE group as compared to the placebo group (patients: p=0.027, investigators: p=0,035). In this trial, the CE-containing spray significantly reduced the symptoms and was associated with significant reduction in facial pressure/pain, high success rates compared to endoscopic examinations and higher satisfaction with treatment as compared to the placebo group.

In their article titled “An exploratory trial of Cyclamen europaeum extract for acute rhinosinusitis” [17], Ponikau JU et al., presented the results of a study conducted at 25 US- based clinical sites in 29 patients with acute rhinosinusitis confirmed by endoscopic examination and CT scans. Pa- tients received intranasal spray containing CE extract or placebo once daily for 7 days. The trial was designed as a proof-of-concept study. Treatment results were assessed on the basis of reduction of changes in CT scans and patient symptoms (scale 1-6). The results of the trial are indicative of statistically significant reduction in CT changes in patients receiving CE. The percentage of sinus shading was lower in acute rhinosinusitis patients treated with CE while no improvement was observed in the placebo group.

The Cyclamen europaeum extract did not lead to signifi- cant improvement of total symptom score as compared to placebo. In both groups, significant improvement against the baseline level was observed. No safety-related concerns were reported in the trial. Adverse effects were in line with the mechanism of action and observations from previous clinical trials. However, the authors concluded that further studies are required with respect to the safety and efficacy of the treatment of acute rhinosinusitis using the CE extract.

the intranasal spray formulation is available as a medicinal product under multiple trade names in numerous countries worldwide.

AN OVERVIEW OF CLINICAL TRIALS

Clinical efficacy, safety, tolerance and pharmacoeconomic assessment of lyophilized extracts of Cyclamen europaeum in the intranasal spray formulation were demonstrated in several clinical trials.

These trials assessed both subjective and objective symptoms of rhinosinusitis (on the basis of endoscopic examinations, CT scans, rhinomanometric measurements and smell examination).

Below is the summary of the results of the most important trials. Most trials were designed as randomized, placebo-controlled trials; some were randomized trials and two [16,17]

were randomized, double-blind, placebo-controlled trials.

In some trials, Cyclamen europaeum extract was assessed in monotherapeutic setting or in combination with antibiotic treatment. In most trials, the primary efficacy endpoint consisted in the percentage of patients with resolution or reduction of symptoms as well as in the result of physical examination (endoscopy of nasal cavities). Changes in CT scans or X-ray images of the sinuses were also assessed in some trials. The trials were conducted in both adult patients as well as in children and adolescents.

Most studies were conducted in patients with acute rhinosinusitis; some of them were also conducted in patients with chronic rhinosinusitis and in children with exudative otitis. One trial was also conducted in patients with drug-in- duced rhinitis.

In 2012, an article titled „Cyclamen europaeum in the treatment of acute rhinosinusitis: a randomized, double-blind, placebo-controlled trial” was published in Rhinology by Pfaar O, Mullol J, Anders C et al. [16]. The authors conducted a randomized, double-blind, placebo-controlled trial. The trial was conducted at 13 German sites. Included in the study was the population consisting of 99 male and female patients aged 18 through 65 with moderate to severe acute rhinosinusitis. Forty-eight patients received single intrana- sal doses of 1.3 mg of Cyclamen europaeum into each nos- tril for 15 days. The second group of 51 patients received placebo as intranasal spray. All patients received antibiotic treatment for 8 days (amoxicillin 500 mg every 8 hours or another antibiotic in case of hypersensitivity amoxicillin).

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Clinical studies reported good tolerance and absence of un- expected or severe adverse effects. The observed adverse effects were usually associated with the mechanism of action of CE extract or were the regular rhinosinusitis symptoms. These included irritation/burning of the nasal mucosa. Clinical benefits of CE-based nasal sprays combined with its good tolerance profiles are indicative of its positive benefit-to-risk ratio in patients with rhinosinusitis.

Other studies were designed as comparative studies (involving comparisons to standard treatments), partially ret- rospective in character.

In three clinical studies, CE-based nasal sprays were administered as monotherapy compared to standard combination treatment [15,8,19]. The studies showed that complete success rates on day 8 of CE treatment were the same as in the case of standard treatment.

Two other studies were conducted including the use of CE- based nasal sprays in combination with antibiotics or other drugs [20,21]. The study conducted by Ovchinnikov [21] re- vealed that CE-based combination treatments increased the efficacy of standard treatments. Nasal patency improved on day 3 (44.3%), day 6 (73.7%) and day 8 (93.6%) in the group receiving standard treatment + CE as compared to the group that received standard treatment only (23.9%, 57.2%, and 80.2%, respectively; p<0.01). The intensity of nasal secretion was reduced by 48.2% on day 6, 74.6% on day 6, and 92.7% on day 8 in the CE group as compared to 27.5%, 57.9%, and 80.8%, respectively (p<0.01) in the group that received standard treatment only. Reduced headache and restored sense of smell were reported in both groups with no significant differences (p>0.05).

ADVERSE EFFECTS

In the selected clinical studies, the most frequently reported adverse effects included lachrymation, burning sensation in the nose, and sneezing. These effects were associated with the mechanism of action, mild, and lasted not more than 20 minutes after administration. No severe adverse effects were reported [15,16 ]. In the study conducted by Pfaar [16], mild to moderate irritation/burning of the nasal mucosa were reported in both groups. These effects were more common in CE (50%) than in the placebo group (4%). Other reported adverse effects included mild nasal hemorrhage in more than one case (27% CE vs. 14% placebo). Nearly all adverse effects were spontaneous. Good tolerance of the CE treatment was reported in most patients (80%). In studies conducted in the pediatric population, CE was well tolerated The efficacy of treatment of acute rhinitis using the extract

of Cyclamen europaeum was assessed in its pharmacoeco- nomic aspects by Mullol J, Crespo C, Carré C, and Brosa M.

in an article titled ”Pharmacoeconomics of Cyclamen europaeum in the management of acute rhinosinusitis” published in Laryngoscope [13].

Pharmacoeconomic analysis of the use of Cyclamen europae- um (CE) in the treatment of acute rhinosinusitis was carried out in Spain on the basis of data collected in the PROSINUS (PROspective epidemiological study of the diagnosis and treatment of acute rhinoSINUSitis) study [13]. The study involved an overall assessment of the use of health care re- sources, productivity losses and health outcomes in an ob- servational study in comparison to costs representative for the Spanish health care system. According to the authors, single-agent treatment using Cyclamen europaeum extracts is more efficient (in terms of the percentage of success) than other monotherapy or combination regimens. Inclusion of CE with other monotherapies or combination treatments re- vealed a statistically significant improvement of success rates when CE was added to two-drug regimens while the addition of CE to three-drug regimens led to no additional effect.

Treatment including CE monotherapy was EUR 98 cheaper than other monotherapeutic regimens (EUR 584 vs. EUR 682) and EUR 61 cheaper than combination regimens (EUR 584 vs. EUR 645). The cost of CE-based therapies per cured patient was lower in all comparisons with the exception of cases when CE was used in combination with three or more other drugs. Addition of CE to a single antibiotic with or without an intranasal corticosteroid increased the success rates and reduced the total costs due to significant reduction of indi- rect costs. Addition of CE led to reduced cost of treatment per success rate as compared to both antibiotic monotherapy and antibiotic combined with intranasal glucocorticoid. The authors also claimed that the extract of Cyclamen europae- um reduced the risk of acute rhinosinusitis developing into chronic condition. Considering the above, the use of CE both as a single agent and in combination regimens may lead to better clinical outcomes including treatment success rates.

According to the authors [13], nasal sprays containing CE extracts are an efficient and well-tolerated treatment of patients with acute rhinosinusitis. The CE extract should be recommended for use in monotherapy; it was also shown to increase the efficacy of standard treatments that usually involve an an- tibacterial drug and/or intranasal corticosteroid, reducing the time to symptom resolution and complete recovery. The use of CE-containing nasal sprays was also shown to be beneficial in terms of the reduction of symptoms as compared to painful and invasive procedures, including maxillary sinus puncture.

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from Cyclamen europaeum tuber warrants the conclusion that the preparation is useful in the management of nasal and sinus mucositis due to their beneficial impact on the course of the treatment of acute rhinosinusitis. The saponin fraction has surface-active properties and facilitates evacuation of the secretion from nasal and sinus cavities. Irri- tation of trigeminal nerve receptors within the nasal mucosa leads to increased secretion of mucus and extensive drainage of nasal and sinus cavities. When used topically in patients with acute rhinosinusitis, the saponin-containing preparation efficiently reduces the symptoms, particularly the feeling of pressure and pain in the face. According to the authors of PROSINUS study, single-agent treatment using Cyclamen europaeum extracts is more efficient (in terms of the percentage of success) than other monotherapy or combination regimens.

by most patient [16,22]. In the study conducted by Karpov [12], 3 patients (9.3%) reported burning sensation during the treatment. In another study conducted by Bogomilsky et al., the patients receiving CE extract reported their tolerance to the product as “satisfactory”. [22]

SUMMARY

Effective treatment of acute rhinosinusitis reduces the risk of development of the chronic form of the disease. The management of viral and postviral rhinosinusitis involves systemic treatment including administration of plant-origin products . The analysis of published studies of the efficacy and safety of intranasal preparation containing lyophilized extracts

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Access the article online: DOI: 10.5604/00306657.1195609 Full-text PDF: www.otolaryngologypl.com/fulltxt.php?ICID=1195609 Corresponding author: Piotr Rapiejko, Wojskowy Instytut Medyczny, ul. Szaserów 128, 04-141 Warszawa, e-mail: piotr@rapiejko.pl

Competing interests: The authors declare that they have no competing interests.

Cite this article as: Jurkiewicz D. Hassmann-Poznańska E, Kaźmierczak H., Składzień J., Pietruszewska W., Burduk P., Rapiejko P.: Lyophilized Cyclamen europaeum tuber extract in the treatment of rhinosinusitis; Otolaryngol Pol 2016; 70 (1): 1-9

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