Lyophilized Cyclamen Europaeum Tuber Extract in the Treatment of Rhinosinusitis

review article

Lyophilized Cyclamen europaeum tuber extract in the treatment of rhinosinusitis

Authors’ Contribution: 1ABDEF 2ABDEF 3ABDEF A – Study Design Dariusz Jurkiewicz , Elżbieta Hassmann-Poznańska , Henryk Kaźmierczak , B – Data Collection 4ABDEF 5ABDEF 3ABDEF 1ABDEF C – Statistical Analysis Jacek Składzień , Wioletta Pietruszewska , Paweł Burduk , Piotr Rapiejko D – Data Interpretation E – Manuscript Preparation 1 F – Literature Search Department of Otolaryngology with Division of Cranio-Maxillo-Facial Surgery in Military Institute of Medicine, Warsaw, Poland G – Funds Collection 2Department of Paediatric Otolaryngology, Faculty of Medicine, Medical Univeristy of Białystok, Poland 3Department 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

Rhinosinusitis is a condition commonly encountered in Europe and the US is estimated at 5-15%. In Poland, an- laryngological practice and, at the same time, one of the nual incidence is estimated at 4 to 8 million patients, with most common causes of visits at primary care physicians’ chronic rhinosinusitis possibly affecting as much as 15% of practices [1]. According to a review published in 2012 by the overall population [3,4]. the International Rhinologic Society, global rhinosinusitis morbidity rates range from 6% to 15%, with secondary Acute rhinosinusitis is an inflammatory condition involving bacterial infection developing in 0.5-2% of patients [2]. the mucosal membranes of both nasal cavities and parana- According to EPOS 2912, rhinosinusitis morbidity rate in sal sinuses [1,4]. The condition has a sudden onset. The in------

OTOLARYNGOL POL 2016; 70 (1): 1-9 DOI: 10.5604/00306657.1195609 1 review article

tensity of symptoms as assessed using a visual analog scale However, the symptoms of sinusitis are not specific or sen- (VAS) may be mild, moderate, or severe [1,3]. sitive, and therefore at least two of these symptoms are required for the diagnosis [1]. One of the symptoms must According to the EPOS 2012 guidelines, rhinosinusitis symp- consist of a primary symptom including toms lasting not longer than 10 days are referred to as common • nasal blockage/obstruction/congestion cold or acute rhinosinusitis while symptoms lasting longer than and/or 10 days but shorter than 12 weeks, or exacerbation of symp- • nasal discharge (anterior/posterior nasal drip). toms after 5 days is referred to as acute postviral rhinosinusitis [1,4]. About 98 to 99.5% of the cases of acute rhinosinusitis are The additional symptoms include: caused by a viral infection [4]. Predominant agents responsible • facial pain/pressure for viral infections are rhinoviruses, coronaviruses, paraflu and • reduction/loss of smell in adults and cough in children. flu viruses, and adenoviruses [4,5]. Secondary bacterial infections are observed in about 0.5-2% of cases [1,4,5]. The onset and intensity of local symptoms are related to mucosal swelling and the degree of obstruction of sinus outlets Acute rhinosinusitis is associated with a complex pathophys- which might indicate the sinus being affected by the inflam- iological mechanism with a predominant role of inflamma- matory process. In case of maxillary sinus involvement, pain tory mucosal swelling, narrowing of natural sinus outlets and is located within the region of the cheeks, teeth, or ocular or- impaired mucociliary transport [6]. Risk factors that impair bits. Tenderness of the frontal wall of the maxillary sinus may drainage and ventilation of sinuses, thus predisposing the be detected upon palpation. Isolated frontal sinusitis presents patient to acute rhinosinusitis include mainly allergic rhi- with pain in the forehead region with tenderness on palpation nitis, anatomical defects of nasal septum and lateral nasal of the frontal or the bottom wall of the sinus. Patients with cavity walls, tobacco smoke and environmental pollution ethmoid sinusitis report pain and a feeling of expansion along [1,3,4]. Ostiomeatal complex is the key region which, when with tenderness on palpation within the medial eye canthus. obstructed, leads to the development of inflammatory condi- Multifocal pain or pain localized within the occipital region tions [6,7]. As the sinus outlet is blocked, oxygen is resorbed radiating towards the forehead, temples, medial eye corner or by the mucosal membrane from the sinus lumen, leading to ocular orbit is characteristic for sphenoid sinusitis. In acute rhi- reduced pH. Hypoxia and acidic environment contribute to nosinusitis, inflammation of several sinuses is more common ciliary damage and impaired ciliary epithelial function. Viral than isolated inflammation of single sinuses, and therefore the infections, particularly infections with flu viruses or ade- clinical presentation of symptoms is by far less characteristic. noviruses, impair the ciliated mucosal cells. This results in Differentiation between the viral, postviral and bacterial acute secretion of inflammatory mediators including interleukin rhinosinusitis is difficult due to the lack of symptoms specific 1, interleukin 6, and TNF alpha which, as acute phase cy- for any of the etiologies. The character of nasal discharge, e.g. tokines, activate neutrophil chemotactic agents, and initiate the purulent character of the discharge, is not a differentiating the release of bradykinin, histamine, and leukotrienes. This criterion. In line with the EPOS consensus [1], acute rhinosi- in turn leads to vessel dilation and more extensive swelling nusitis (ARS) is classified into: with simultaneous impairment of the excretory glandular function. Transudate from dilated vessels and mucous se- • viral ARS/common cold; cretion accumulate within the sinuses due to damaged func- • postviral ARS; tion of the ciliary apparatus and the obstruction of outlets. • bacterial ARS. These conditions favor the development of aerobic and an- The most common acute viral rhinosinusitis usually lasts for aerobic bacteria which release toxins to enhance inflamma- up to 10 days. Postviral acute rhinosinusitis is diagnosed in tion, thus leading to a vicious circle effect [1,4]. case of symptoms being exacerbated after 5 days or lack of improvement after 10 days. Among these, cases of bacterial Acute rhinosinusitis has a sudden onset and is most com- acute rhinosinusitis should be differentiated when patients monly due to primary rhinitis. Most commonly, rhinosi- present with three out of the following five symptoms: changed nusitis is accompanied by systemic symptoms including secretion color (purulent nasal discharge predominant in one elevated temperature, malaise, and anorexia. Predominant of the nasal cavities), strong localized facial pain predomi- symptoms include facial pain, maxillary tooth pain, mucop- nant on one side, fever of above 38°C, elevated levels of acute urulent nasal discharge with impaired nasal patency. Diag- phase markers (CRP>10) or exacerbation of hitherto mild nosis of acute rhinosinusitis is based on medical interview course of the disease. Local symptoms may be accompanied and physical examination [1,4]. by irritation of the throat, pharynx and trachea leading to dry - - - - -

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ACUTE RHINOSINUSITIS IN ADULTS MANAGEMENT SCHEME OF PRIMARY CARE

2 symptoms: one of which should be na- Immediate referral: sal obstruction • periorbital oedema/erythema or discoloured discharge • displaced globe; • double vision; +/- frontal pain, headache • opthalmophlegia; +/- smell disturbance • reduced vision acuity; examination: anterior rhinoscopy • severe unilateral or bilateral frontal headache; • frontal swelling; X-ray/CT not recommended • signs of meningitis or neurologic sings

= at least 3 of: Discoloured discharge symptoms less than 5 days symptoms persistent after 10 days or severe local pain fever or improving thereafter increasing after 5 days elevated ESR/CRP double sickening

Common cold moderate (post viral) severe* (including bacterial)

Symptomatic relief: + topical steroid topical steroid analgesics, nasal saline, consider antibiotics irrigation, decongestants, selected herbal compounds

no effect after 14 of effect in 48 h no effect in 48 h no effect after 10 days treatment of treatment

consider referal Continue treatment refer to specialist to specialist For 7 – 14 days

Fig. 1. Management scheme for primary care for adults with acute rhinosinusitis (EPOS 2012) [1]

cough, disturbed voice, sleepiness, malaise and overall weak- above 38 °C persisting for 3 days or strong pain is diagnosed ness. These symptoms may persist for up to 12 weeks [4,8]. as severe disease [1,4].

Determination of symptom intensity using a VAS scale is very Acute rhinosinusitis is diagnosed on the basis of symptoms and important for initiation of appropriate treatment. Patients in- results of physical examination by primary care physicians or on dicating their symptoms’ score to be from 0 to 3 are diagnosed the basis of specialized laryngological examination supported with mild rhinosinusitis. by endoscopic assessment as part of specialist treatment [1].

Symptoms in the score range of 4 to 7 are diagnosed as mod- According to the EPOS 2012 recommendations [1], radiolog- erate rhinosinusitis while the score of 8 to 10 with fever of ical examinations (X-ray, CT, MRI) or bacteriology assays are - - - - -

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not used in the diagnostics of acute rhinosinusitis. The need to should be effective against the most common pathogens, broaden the diagnostic scope occurs upon the failure of treat- including their potential resistance profiles [5]. ment, exacerbation of symptoms or suspicion of sinusogenic complications. In case of complications of acute rhinosinusitis, additional surgical treatment may be required [1].

TREATMENT OF ACUTE RHINOSINUSITIS Intranasal glucocorticosteroids as well as antibiotics should be included while standard symptomatic treatment is being Considering the causes of acute rhinosinusitis such as the continued [1,2,4,9]. Due to the fact that rhinosinusitis of blockage of natural sinus outlets and infection, the treat- bacterial origin is often associated with bacterial coloniza- ment consists in symptomatic pharmacological treatment. tion in the form of biofilms, the extracts of Alpine cyclamen Conservative treatment should be modified according to the support the efficacy of antibiotics by means of surface-ac- nature of infection, i.e. viral, bacterial, or fungal infection tive saponins that destroy these biofilms [12-14]. as well as to its intensity, i.e. whether the disorder is mild, moderate, or severe. Surgical treatment of acute rhinosinus- In case no improvement is achieved after 14 days in the treat- itis is recommended in case of sinusogenic complications. In ment of mild to moderate rhinosinusitis and after 48 hours Poland as well as in other countries, there is a predominant in the treatment of severe rhinosinusitis, patient should be trend toward premature initiation of antibiotic treatment referred for specialist treatment; bacteriological assays, and, which significantly and unnecessarily increases treatment in some cases, hospitalization should also be considered [1]. 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 SAPONINS IN THE TREATMENT OF ACUTE both acute and chronic rhinosinusitis is very important. Cur- RHINOSINUSITIS rently, binding guidelines include EPOS 2012 [1], PoSLeNN [2] and the Recommendations for the management of extra- The EPOS 2012 reports recommend the use of substanc- mural respiratory tract infections [5] as well as recommen- es of plant origin as a supportive treatment [1]. Among the dations for family physicians based on the aforementioned products of plant origin, preparations containing lyophilized guidelines [9]. Management of acute rhinosinusitis depends powder obtained from fresh tubers of Alpine Cyclamen on the form and the intensity of the condition. (Cyclamen europaeum L.) are particularly noteworthy. As surface active substances, saponins interact with mucosa In viral sinusitis lasting less than 10 days, symptomatic treat- to facilitate the removal of the secretion [14]. By stimulat- ment is recommended including antipyretics and analgesics ing trigeminal nerve endings, they increase the production and close monitoring strategy [1,2,5,9]. of seromucous secretion, thus facilitating the ciliary move- ments and leading to more effective of evacuation sinuses In postviral infections persisting beyond day 10, presenting [14,15]. Saponin-containing products used as single agents with mild to moderate symptoms, additional inclusion of or in combination regimens significantly remove evacuation intranasal glucocorticosteroids is recommended [1,2,5,9]. of the discharge from nasal and sinus cavities and reduce mucosal swelling thus improving patient’s satisfaction with In both forms of inflammation, recommendations include the treatment [12,13]. the lavage of nasal cavities with isotonic solutions of physiological saline that flushes out the accumulated secretion Cyclamen (Cyclamen L.) is a genus of plants from family containing proinflammatory agents or hypertonic solutions Primulaceae. The genus includes about 20 species from the of physiological saline that additionally increase water re- Mediterranean basin and South-West Asia. One of the rep- sorption and reduce swelling, thus contributing to the im- resentative species is Alpine cyclamen (Cyclamen europae- proved patency of nasal and sinus cavities [1,10,11]. um). The extract from the tubers of Alpine cyclamen was used for several centuries as a medicinal agent. The extract Antibiotic therapy combined with local steroid therapy is from the tubers of Alpine cyclamen is administered as intra- recommended in acute bacterial rhinosinusitis or severe nasal solution in symptomatic treatment of rhinosinusitis. postviral rhinosinusitis, lack of improvement after 14 days Saponins are eliminated along with the mucus rather than of treating moderate disease as well as in case of suspected being absorbed at the mucosal surface. The extract from complications [1]. Antibiotics used in acute rhinosinusitis the tubers of Alpine cyclamen (Cyclamen europaeum) in - - - - -

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the intranasal spray formulation is available as a medicinal Efficacy and tolerance endpoints were assessed on the ba- product under multiple trade names in numerous coun- sis of average score of rhinosinusitis symptoms (including tries worldwide. nasal obstruction, mucous secretion, facial pain/pressure and loss of the sense of smell), endoscopic assessment of symptom resolution, satisfaction with the treatment and AN OVERVIEW OF CLINICAL TRIALS incidence of adverse effects as assessed both by the patient and the physician. Clinical efficacy, safety, tolerance and pharmacoeconomic assessment of lyophilized extracts of Cyclamen europaeum Intranasal spray containing Cyclamen europaeum (CE) ex- in the intranasal spray formulation were demonstrated in tract led to reduction (resolution) of symptoms as compared several clinical trials. to placebo although the differences in total mean score did not reach the statistical significance level (CE -3.2 ± 2.3; These trials assessed both subjective and objective symp- placebo -2.7 ± 2.2). However, facial pain after 5-7 days of toms of rhinosinusitis (on the basis of endoscopic exami- treatment was significantly lower in patients treated with nations, CT scans, rhinomanometric measurements and intranasal spray containing the CE extract as compared to smell examination). the placebo group (p=0.04). Mucosal swelling/nasal obstruction as assessed by endoscopic examination on day 7 was Below is the summary of the results of the most important also significantly improved in the CE group (p<0.03). The trials. Most trials were designed as randomized, placebo-con- authors [16] also point to the higher percentage of patients trolled trials; some were randomized trials and two [16,17] and investigators being satisfied with the reduction of rhi- were randomized, double-blind, placebo-controlled trials. nosinusitis symptoms in the CE group as compared to the In some trials, Cyclamen europaeum extract was assessed placebo group (patients: p=0.027, investigators: p=0,035). In in monotherapeutic setting or in combination with antibi- this trial, the CE-containing spray significantly reduced the otic treatment. In most trials, the primary efficacy endpoint symptoms and was associated with significant reduction in consisted in the percentage of patients with resolution or facial pressure/pain, high success rates compared to endo- reduction of symptoms as well as in the result of physical scopic examinations and higher satisfaction with treatment examination (endoscopy of nasal cavities). Changes in CT as compared to the placebo group. scans or X-ray images of the sinuses were also assessed in some trials. The trials were conducted in both adult patients In their article titled “An exploratory trial of Cyclamen eu- as well as in children and adolescents. ropaeum extract for acute rhinosinusitis” [17], Ponikau JU et al., presented the results of a study conducted at 25 US- Most studies were conducted in patients with acute rhinosi- based clinical sites in 29 patients with acute rhinosinusitis nusitis; some of them were also conducted in patients with confirmed by endoscopic examination and CT scans. Pa- chronic rhinosinusitis and in children with exudative oti- tients received intranasal spray containing CE extract or tis. One trial was also conducted in patients with drug-in- placebo once daily for 7 days. The trial was designed as a duced rhinitis. proof-of-concept study. Treatment results were assessed on the basis of reduction of changes in CT scans and pa- In 2012, an article titled „Cyclamen europaeum in the treat- tient symptoms (scale 1-6). The results of the trial are in- ment of acute rhinosinusitis: a randomized, double-blind, dicative of statistically significant reduction in CT changes placebo-controlled trial” was published in Rhinology by Pfaar in patients receiving CE. The percentage of sinus shading O, Mullol J, Anders C et al. [16]. The authors conducted a was lower in acute rhinosinusitis patients treated with CE randomized, double-blind, placebo-controlled trial. The while no improvement was observed in the placebo group. trial was conducted at 13 German sites. Included in the The Cyclamen europaeum extract did not lead to signifi- study was the population consisting of 99 male and female cant improvement of total symptom score as compared to patients aged 18 through 65 with moderate to severe acute placebo. In both groups, significant improvement against rhinosinusitis. Forty-eight patients received single intrana- the baseline level was observed. No safety-related concerns sal doses of 1.3 mg of Cyclamen europaeum into each nos- were reported in the trial. Adverse effects were in line with tril for 15 days. The second group of 51 patients received the mechanism of action and observations from previous placebo as intranasal spray. All patients received antibiotic clinical trials. However, the authors concluded that further treatment for 8 days (amoxicillin 500 mg every 8 hours or studies are required with respect to the safety and efficacy another antibiotic in case of hypersensitivity amoxicillin). of the treatment of acute rhinosinusitis using the CE extract. - - - - -

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The efficacy of treatment of acute rhinitis using the extract Clinical studies reported good tolerance and absence of un- of Cyclamen europaeum was assessed in its pharmacoeco- expected or severe adverse effects. The observed adverse nomic aspects by Mullol J, Crespo C, Carré C, and Brosa M. effects were usually associated with the mechanism of ac- in an article titled ”Pharmacoeconomics of Cyclamen eu- tion of CE extract or were the regular rhinosinusitis symp- ropaeum in the management of acute rhinosinusitis” pub- toms. These included irritation/burning of the nasal mu- lished in Laryngoscope [13]. cosa. Clinical benefits of CE-based nasal sprays combined with its good tolerance profiles are indicative of its positive Pharmacoeconomic analysis of the use of Cyclamen europae- benefit-to-risk ratio in patients with rhinosinusitis. um (CE) in the treatment of acute rhinosinusitis was carried out in Spain on the basis of data collected in the PROSINUS Other studies were designed as comparative studies (in- (PROspective epidemiological study of the diagnosis and volving comparisons to standard treatments), partially ret- treatment of acute rhinoSINUSitis) study [13]. The study rospective in character. involved an overall assessment of the use of health care re- sources, productivity losses and health outcomes in an ob- In three clinical studies, CE-based nasal sprays were admin- servational study in comparison to costs representative for istered as monotherapy compared to standard combination the Spanish health care system. According to the authors, treatment [15,8,19]. The studies showed that complete suc- single-agent treatment using Cyclamen europaeum extracts cess rates on day 8 of CE treatment were the same as in the is more efficient (in terms of the percentage of success) than case of standard treatment. other monotherapy or combination regimens. Inclusion of CE with other monotherapies or combination treatments re- Two other studies were conducted including the use of CE- vealed a statistically significant improvement of success rates based nasal sprays in combination with antibiotics or other when CE was added to two-drug regimens while the addi- drugs [20,21]. The study conducted by Ovchinnikov [21] re- tion of CE to three-drug regimens led to no additional effect. vealed that CE-based combination treatments increased the Treatment including CE monotherapy was EUR 98 cheaper efficacy of standard treatments. Nasal patency improved on than other monotherapeutic regimens (EUR 584 vs. EUR 682) day 3 (44.3%), day 6 (73.7%) and day 8 (93.6%) in the group and EUR 61 cheaper than combination regimens (EUR 584 receiving standard treatment + CE as compared to the group vs. EUR 645). The cost of CE-based therapies per cured pa- that received standard treatment only (23.9%, 57.2%, and 80.2%, tient was lower in all comparisons with the exception of cases respectively; p<0.01). The intensity of nasal secretion was re- when CE was used in combination with three or more other duced by 48.2% on day 6, 74.6% on day 6, and 92.7% on day 8 in drugs. Addition of CE to a single antibiotic with or without the CE group as compared to 27.5%, 57.9%, and 80.8%, respec- an intranasal corticosteroid increased the success rates and tively (p<0.01) in the group that received standard treatment reduced the total costs due to significant reduction of indi- only. Reduced headache and restored sense of smell were re- rect costs. Addition of CE led to reduced cost of treatment ported in both groups with no significant differences (p>0.05). 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- ADVERSE EFFECTS um reduced the risk of acute rhinosinusitis developing into chronic condition. Considering the above, the use of CE both In the selected clinical studies, the most frequently reported as a single agent and in combination regimens may lead to adverse effects included lachrymation, burning sensation in better clinical outcomes including treatment success rates. the nose, and sneezing. These effects were associated with the mechanism of action, mild, and lasted not more than 20 According to the authors [13], nasal sprays containing CE ex- minutes after administration. No severe adverse effects were tracts are an efficient and well-tolerated treatment of patients reported [15,16 ]. In the study conducted by Pfaar [16], mild with acute rhinosinusitis. The CE extract should be recom- to moderate irritation/burning of the nasal mucosa were re- mended for use in monotherapy; it was also shown to increase ported in both groups. These effects were more common the efficacy of standard treatments that usually involve an an- in CE (50%) than in the placebo group (4%). Other report- tibacterial drug and/or intranasal corticosteroid, reducing the ed adverse effects included mild nasal hemorrhage in more time to symptom resolution and complete recovery. The use than one case (27% CE vs. 14% placebo). Nearly all adverse of CE-containing nasal sprays was also shown to be beneficial effects were spontaneous. Good tolerance of the CE treat- in terms of the reduction of symptoms as compared to painful ment was reported in most patients (80%). In studies con- and invasive procedures, including maxillary sinus puncture. ducted in the pediatric population, CE was well tolerated - - - - -

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by most patient [16,22]. In the study conducted by Karpov from Cyclamen europaeum tuber warrants the conclusion [12], 3 patients (9.3%) reported burning sensation during that the preparation is useful in the management of nasal the treatment. In another study conducted by Bogomilsky and sinus mucositis due to their beneficial impact on the et al., the patients receiving CE extract reported their tol- course of the treatment of acute rhinosinusitis. The saponin erance to the product as “satisfactory”. [22] 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 mu- SUMMARY cosa leads to increased secretion of mucus and extensive drainage of nasal and sinus cavities. When used topically Effective treatment of acute rhinosinusitis reduces the risk of in patients with acute rhinosinusitis, the saponin-contain- development of the chronic form of the disease. The manage- ing preparation efficiently reduces the symptoms, particu- ment of viral and postviral rhinosinusitis involves systemic larly the feeling of pressure and pain in the face. According treatment including administration of plant-origin products . to the authors of PROSINUS study, single-agent treatment using Cyclamen europaeum extracts is more efficient (in The analysis of published studies of the efficacy and safety terms of the percentage of success) than other monothera- of intranasal preparation containing lyophilized extracts py or combination regimens.

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Corresponding author: Piotr Rapiejko, Wojskowy Instytut Medyczny, ul. Szaserów 128, 04-141 Warszawa, e-mail: [email protected]

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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