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Relationship between pathophysiology and clinical experiments in Acute Rhinosinusitis and Postoperative Care
POPOVICH, V.
Head of the Otorhinolaryngology Department,
Ivano-Frankivsk State Medical University. Ukraine
New Treatment Approaches to Rhinosinusitis: Less is more.
Crete. Greece. 15-19 June 2008
Keywords New Treatment approaches to Rhinosinusitis - PDF
ABSTRACT
In pathophysiological airway conditions, the body generates reflex reactions that cause an adaptive effect. The lack of such an effect lies at the root of many airway diseases. We sought to determine the effect caused by the cyclamen extract-based product (beyond studying its effectiveness) on the autonomic nervous system and the physiological parameters and functions that are controlled by this system. The most significant conclusions are that the levels of variation are within the normal range and establish the reaction’s adaptive-protective function. The appearance of mild subjective sensations with treatment disappears with adaptation to the preparation’s action.
At present, a clear trend has been observed towards an increased morbidity associated with acute and chronic rhinosinusitis.
The number of patients suffering from this type of disease is increasing year after year in virtually all countries.
In spite of this, there is no effective solution for the treatment of acute rhinosinusitis, Professor Vasil Popovich warned in his lecture. The trend is to prefer non-invasive treatment strategies for patients with rhinosinusitis. The traditional treatment regimens include antibiotics, secretolytics, decongestants and other products, but they are not effective in all cases. Antibiotic therapy is associated with particular problems; this treatment is not always effective and is not even indicated in many cases. Further, as Professor Popovich warned, “in recent years, there has been a significant increase in the average duration of the use of antibiotics in rhinosinusitis, from 3 days to 14-16 days, without any clear improvement in effectiveness being reported.” Furthermore, this also entails an increase in the risk of antibiotic resistance. Hence the need for new studies that enable alternative treatment resources to be used.
STUDIES REQUIRED
It has been considered since time immemorial that adequate functioning of the nose is vital for a person to maintain normal activity. Given this awareness, considerable effort has been made to improve understanding of nasal pathophysiology.
As a result, for example, it has been discovered that the reflex action of the nasal and paranasal cavities plays a significant role in regulating various organ and body functions. These reflexes appear primarily in the mucous membrane. The receptor system in the mucous membrane, nose and nasal cavity consists of the sensory nerve fibres of the trigeminal nerve, which branch extensively in the mucous membrane to form an enormous field for sensory reception. It is the irritation of the sensory endings of the trigeminal nerve that triggers the vascular and secretory reactions.
The autonomic nervous system is also very important for the maintenance of vital functions, as it plays an essential role in the pathogenesis of many diseases (including those of the respiratory system).
Under normal physiological conditions, an appropriate stimulus for the receptors in the airways is an inhaled and exhaled airflow, which acts as a mechanical, physical and chemical stimulant. In pathological conditions (sudden temperature changes, irritants, existence of disease), the reflex reactions lead to an adaptive effect in the body and, in the absence of this adaptive effect, a neuroreflex process is started which is present in many diseases (in particular, diseases affecting the airways).
Consequently, as Prof. Vasil Popovich stated, it was necessary to study the effect that certain substances used intranasally could have, not only because of their local effect on the mucous membrane but also analysing their possible effects on other organs and systems. It is particularly important to study these intranasally administered medicines when they are used in repeated doses and in the presence of respiratory disease.
STUDIES WITH CYCLAMEN EXTRACT
It has been possible to perform such studies with cyclamen extract. In the Ukraine, cyclamen extract has been marketed since 2002 under the brand name Sinuforte®. Since then, a large number of clinical trials have been carried out in that country that have enabled its effectiveness and safety to be established in the treatment of acute and chronic rhinosinusitis, and also for postoperative care.
Post-marketing studies performed by Zabolotny et al. have shown the efficacy of treating patients with sinusitis with Sinuforte®, and studies performed by Bezshapochniy et al. have evaluated the effect of Sinuforte® in the treatment of acute purulent sinusitis. These pioneering studies have been followed by many others: Popovich et al. have confirmed that the transport function of the nasal mucous membrane recovers much more quickly in patients treated with cyclamen extract. For their part, Berezniuk et al. have shown that including Sinuforte® as part of a combined therapy in patients with acute rhinosinusitis, accompanied by secretory otitis, achieves more rapid relief of inflammatory processes in the nasal cavity, paranasal sinuses and middle ear.
The results of these studies have been published in the Journal of Otorhinolaryngological Diseases (Ukraine) and in the journal Rhinology (Ukraine). In general, as Dr. Popovich highlighted, “the results obtained from these studies with cyclamen europaeum show that it is highly effective in the treatment of rhinosinusitis.”
cyclamen extract has been shown to be highly effective in all patients with acute rhinosinusitis, irrespective of the degree of severity of their disease. Compared with traditional therapies, the inclusion of cyclamen extract significantly reduces the time required to cure the disease (8-10 days vs. 14-16 days with the classic therapies). Furthermore, with its complex action, cyclamen europaeum can not only be used concurrently with other medicines but, in many cases, use of other treatment resources can be avoided or, at least, their use can be dramatically reduced.
It has also been observed that during initial postoperative rehabilitation, after surgical resolution of the obstruction of the nasal ostium, treatment with cyclamen europaeum is effective, reducing hyperaemia and, in particular, oedema in the restored mucosa. It is also confirmed that this treatment speeds up the physiological regeneration process and assures rapid recovery of nasal functions; as a result, it is possible to move on to the following stage in postoperative therapy (with corticoids or other drugs) at a much earlier point, with the benefits this entails.
It has also been shown in many studies that cyclamen extract is very well tolerated by patients and does not induce clinically significant adverse effects.
STUDIES PERFORMED
With the aim of gaining further knowledge of the benefits of this product, a number of studies have been performed with cyclamen extract at the Department of Otorhinolaryngology, Ivano-Frankivsk State Medical University, Ukraine.
It is currently known that the action of cyclamen europaeum is associated with a reflex secretory reaction by the mucous membrane in the nasal cavity, triggered by the trigeminal nerve endings. The reflex effect in the nasal cavity and in the paranasal sinuses plays a crucial role in the regulation of important body functions and maintenance of normal activity. The first place where this reflex effect appears is in the nasal membrane. This triggers the vascular and secretory reaction by the nasal mucous membrane. For its part, the autonomic nervous system mediates the cholinergic and adrenergic effect on primary vital functions.
It is also known that in physiological conditions, the nasal reflexes contribute to adapting the human body to the environment. However, in pathological situations these reflexes account for the neuroreflex component of the pathogenesis of many diseases, particularly of the respiratory system. Consequently, as the speaker indicated, “it is increasingly important to study the effect of intranasal drugs on the body.”
Anatomical data and the results of numerous experimental and clinical studies show that the trigeminal and autonomic nervous systems play a key role in vasculomotor and secretory functions, with an adaptive-trophic role. The essential function in this entire process is performed by the autonomic nervous system. However, the data available in this respect are confined to the study of the autonomic nervous system’s influence on reflex reactions in normal situations or where there are difficulties in breathing through the nose.
At present, a large number of drugs delivered intranasally are available in Otorhinolaryngology. It is therefore vital to ascertain their influence on the autonomic nervous system. It is also vitally important to determine the reflex reactions of organs and organ systems after the use of such drugs. Thus, it is known that the parasympathetic system acts as a self-defence mechanism in the respiratory system (its role is particularly important in the presence of upper airway disease which also affects the lower respiratory system).
Given this situation, it has been sought to determine the systemic effect induced by the use of cyclamen europaeum in patients with acute and chronic rhinosinusitis. Summarising these effects, Professor Popovich stated “its use has an interesting influence on the autonomic nervous system.”
Among these effects, he highlights the reduction in the frequency of sensations (such as itching or sneezing) induced by the product during the first days of use and the increase in hearing ability in patients with secretory otitis. In addition, the mucociliary transport function in the nasal cavity returns to physiological levels by the third day of treatment (with statistically significant differences compared with the control group; p<0.001). A positive trend is observed in the temperature of the nasal mucous membrane; thus, the local temperature on the seventh day of treatment was only 0.3ºC higher than in healthy subjects, after falling an average of 2.5ºC during treatment with this product (in the control group, the mean temperature fell 1.2ºC; p<0.001). Treatment with cyclamen extract also accelerates the physiological regeneration process, with rapid recovery of nasal functions.
AN INNOVATIVE STUDY
Given these findings, Professor Popovich presented the results of a study performed by his group which has assessed the effect of cyclamen europaeum on the functions of various organs related with the parasympathetic system and the possible benefits obtained in the lower respiratory tract after single or multiple doses of this product in patients with different types of respiratory diseases (such as COLD or rhinosinusitis).
The results obtained in a study with 30 subjects (10 healthy volunteers and 20 patients with rhinosinusitis) were presented at this forum. The study parameters analysed included the patients’ subjective sensations, blood and urine analyses, blood chemistry, liver, gallbladder and kidney echo-dynamics, and respiratory function (measured by spirometry). The measurements were performed before and 1.5-2 hours after administration of cyclamen europaeum, while the respiratory function was assessed 20 minutes after administration of the product and, in the group of patients who received the preparation, also on treatment days 3 and 7.
As regards the subjective sensations, the findings obtained in previous studies performed with cyclamen extract are confirmed. After the first dose of cyclamen europaeum, the patients experience certain mild subjective sensations (nasal itching, smarting, rhinorrhea, watery eyes) that recede as treatment continues, indicating an adaptation to the preparation’s irritant action.
With administration of the cyclamen extract, a trend is seen towards changes in the clinical data obtained in the laboratory tests, but within an acceptable range of physiological values. For Professor Popovich, “this is a normal reaction that does not lead to any significant changes.”
An ultrasonographic assessment was also performed in this study. The ultrasonographic examination of the internal organs before and after a single daily dose of cyclamen europaeum shows a certain reaction in the gallbladder: in most healthy volunteers, the gallbladder contracts (8 out of 10), while none of the patients show this effect. No significant changes in the status of other organs are documented by ultrasonography.
The bronchial patency indices show varying behaviours in the volunteers and in the patients with acute rhinosinusitis after administration of cyclamen extract. In the volunteers, there is a significant decrease in the bronchial patency indices 20 minutes after administration of this product (p<0.01). However, after 2 hours, these indices return to normal values and are improved in some cases (p<0.01). The baseline bronchial patency indices in the patients with acute rhinosinusitis are lower than in the healthy volunteers (p<0.01), which could suggest the existence of airway hyperreactivity in the patients. However, these indices remain practically unchanged in the patients 20 minutes after administration of cyclamen europaeum, and, after 2 hours, are within the average normal range (p<0.01). In short, during the treatment process of acute rhinosinusitis, the respiratory function indices progressively improve and, by the seventh day of treatment, the peak expiratory flow rates (PEFR) before use of cyclamen extract gave normal values (the PEFR was 535.4). Immediately after use of cyclamen extract, the indices were within the same range, without any tendency to increase or decrease (p<0.05); 2 hours after administration of cyclamen europaeum, bronchial patency is seen to improve by more than 10% (p<0.001).
As this expert insisted, “the local action of cyclamen extract takes place through the trigeminal nervous system and the systemic action takes place by its effect on the autonomic nervous system. The nature of the systemic reaction shows that cyclamen europaeum has a cholinomimetic action, as had already been shown in previous preclinical studies.”
It is also concluded from the study presented by Professor Popovich that the patients with acute rhinosinusitis present airway hyperreactivity, which shows the existence of mechanisms that adapt to certain stress situations. However, the use of cyclamen europaeum does not promote airway hyperreactivity. Furthermore, it has been found that a cycle of treatment with this product helps reduce hyperreactivity and restore normal upper airway function.
As his closing message, the speaker pointed out that “the effects observed during treatment with one cycle of cyclamen europaeum confirm the development of a systemic adaptive reaction. This is seen, as a secondary consequence of the preparation’s effect, when it is used for the treatment of acute rhinosinusitis in patients with a history of airway hyperreactivity and/or obstruction.”
New Treatment Approaches in Rhinosinusitis - Index
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