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2 I Himalaya update Volume 18 Number 8 I 2010 MEDICINE UPDATE Clinical study to evaluate the safety and efficacy of Septilin tablets in respiratory tract infection: An open clinical study Authors *Corresponding Author: Dr. Kavitha Rajarathna MBBS., MD., Dr. D.Palaniyamma, M.D. Lecturer, Department of pharmacology Medical Advisor Bangalore Medical College, R&D Center K.G.Halli, Bangalore The Himalaya Drug Company Makali, Bangalore, India Dr. Suprabha Hegde MS (Ayu), Research associate, The Himalaya Drug company, Makali, Bangalore, India ABSTRACT Respiratory tract infection includes both upper and lower respiratory tract which range from the common cold typically a mild, self-limited, catarrhal syndrome of the nasopharynx to life threatening illnesses such as epiglottitis. Aim: To evaluate the of role of septilin in the treatment of respiratory tract infection. Materials and Methods: The present study comprised of 148 cases suffering from upper and lower respiratory tract infections. Septilin tablet was given to all the patients at a dose of 2 tablets, twice daily for a period of 6 weeks. All the patients were evaluated at intervals of 2 weeks for a period of 6 weeks for the presenting symptoms. Results: The control of symptoms and gradual improvement noticed after 2 weeks of treatment which further improved with continued treatment. Out of 148 patients treated only two patients experienced mild abdominal discomfort effects and all the patients tolerated the drug well. None of the patients were withdrawn due to adverse effects. Conclusion: This study showed that septilin tablets showed statistically significant improvement in the symptoms of upper and lower respiratory tract infections and also Septilin was safe in the dose administered and well tolerated by the patients. KEY WORDS: Respiratory tract infection, Septilin INTRODUCTION Respiratory tract infection includes infections of both upper and lower respiratory tract. Upper respiratory tract infections (URTIs) comprising tonsillitis, pharyngitis, laryngitis, sinusitis, otitis media, and the common cold are frequent presenting conditions in primary care. The majority of URTIs are of viral origin, due to rhinovirus, parainfluenza virus, coronavirus, adenovirus, Coxsackie virus, and influenza virus. However, pharyngitis and the common cold have the greatest probability of being of viral origin. Only 10% of URTIs has been attributable to bacterial aetiology, with the three most common organisms being Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Of these conditions, those that present with sore throat (tonsillitis, pharyngitis, laryngitis) are responsible for just over 50% of presentations, with otitis media adding another 25%.1 These conditions are frequently treated with antibiotics, and rates of antibiotic prescribing have been increased.2 Transmission of organisms causing URIs occurs by aerosol, droplet, or direct hand-to-hand contact with infected secretions, with subsequent passage to the nares or eyes. Thus, transmission occurs more commonly in crowded conditions. Direct invasion of the respiratory epithelium results in symptoms corresponding to the area(s) involved. Lower respiratory tract infection includes pneumonia, lung abscess, acute bronchitis, and emphysema. The two most common infections are bronchitis and pneumonia. Influenza affects both the upper and lower respiratory tracts. Symptoms of Lower respiratory tract infection include shortness of breath, weakness, high fever, coughing and fatigue. MEDICINE UPDATE I Volume 18 Number 8 I 2010 Respiratory tract infections are frequently treated with antibiotics, and rates of antibiotic prescription have been increased. Interview studies 3,4 have shown that general practitioners (GPs) have a range of reasons why they prescribe antibiotics for sore throats. These include the feeling that patients ‘want something done’ or expect to receive a prescription; beliefs that, despite the evidence, antibiotics may help some patients and could do little harm; a concern to preserve and build relationships with patients; and workload factors. Other studies have found that GPs often feel uncomfortable about prescribing antibiotics5, and that antibiotics are ten times more likely to be prescribed if the doctor perceives that a patient expects them6. The development of antimicrobial resistance has occurred predominantly among Streptococcus pneumoniae, Haemophilus influuenzae, and Moraxella catarrhalis. In the United States, the respiratory tract infection accounts for 75 to 100 million physician visits annually at a conservative cost estimate of $7.7 billion per year. Americans spend $2.9 billion on over-the-counter drugs and another $400 million on prescription medicines for symptomatic relief.7,8 More than one-third of patients who saw a doctor received an antibiotic prescription, which has implications for antibiotic resistance from overuse of such drugs.8 An estimated 22 to 189 million school days are missed annually due to a cold. As a result, parents missed 126 million workdays to stay home to care for their children. When added to the 150 million workdays missed by employees suffering from a cold, the total economic impact of cold-related work loss exceeds $20 billion per year.7,8 This accounts for 40% of time lost from work.9 Patients with recurrent upper respiratory tract infections receive various combinations of potent antibacterial agents, which are not only expensive but also potentially toxic, producing unwanted adverse effects and hence not safe for frequent long term use. Indiscriminate use of an antibiotic also produces drug-resistance, creating problem for further use in future when such use may be genuinely life saving. Septilin, reported to have effective antibacterial and anti-inflammatory properties in the management of acute and or recurrent upper and lower respiratory tract infections based on the extensive clinical trials conducted on this herbal medicine. It is an economical and safe drug, free from side-effects when used for a longer period. This prompted us to try Septilin in our cases of respiratory tract infections. The principal herbs of Septilin include Tinospora cordifolia, Emblica officinalis, Glycyrrhiza glabra, Moringa pterygosperma, Balsamodendron mukul and Rubia cordifolia. Aim: To evaluate the efficacy and safety of Septilin tablets in upper and lower respiratory tract infection. MATERIALS AND METHODS Study design An open clinical evaluation was conducted on 148 cases presenting with signs and symptoms of upper and lower respiratory tract Himalaya update 3 Table 1. Demographic data Total number of patients 148 Mean age in years (Mean ± SD) 40.20 ± 8.60 Mean weight in kgs (Mean ± SD) 57.30 ± 2.80 Sex ratio (M:F) 78:70 infection who attended the Outpatient Department of Medicine, Bangalore Medical College, Bangalore, Karnataka, India. Inclusion criteria Adult patients presenting with upper and lower respiratory tract infections of either sex aged between 18-50 years, were included in the study. Exclusion criteria Patients with severe infections like pneumonia, tuberculosis, status asthamaticus, severe bronchospasm were not included in the study. Patients with evidence of pregnancy, lactation, any patients with severe psychiatric/cardiac, metabolic, gastrointestinal disorders or metabolic disorders were excluded from the study. Study procedure The present study comprised of 148 cases suffering from upper and lower respiratory tract infections. At entry demographic details are listed in table 1. Detailed history of the duration, frequency, severity of the infection and history of smoking, allergic/atopic details and occupation related risks of the illness were elicited. A thorough examination of ear, nose, throat, and chest examination, physical examination and vitals including respiratory rate were also conducted and recorded in case report form. Patients entered into the study after signing the voluntary informed consent form. Septilin tablets were given to all the patients at a dose of 2 tablets twice daily for a period of 6 weeks. Adverse effects if any were noted down. The protocol of the study was as per the ICH-GCP guidelines and the patients were free to withdraw from the study Table 2. Break-up of respiratory tract infection Indication No. of patients Duration of illness (days) Respiratory tract infections 148 - Upper respiratory tract infection 112 - Tonsillitis 28 5.26±2.5 Pharyngitis 24 7.23±4.4 Laryngitis 08 7.58±5.1 Sinusitis 20 5.3±1.26 Rhinitis 32 7.47±3.22 Lower respiratory tract infection 36 Bronchitis 36 9.42±3.41 4 Himalaya update if they so desired. No other medication was allowed for these patients. The break-up of respiratory tract infection and the duration of the illness are listed in table 2. Out of the 148 patients suffering from Respiratory tract infections, 112 patients suffered from upper respiratory tract infection presenting with tonsillitis, pharyngitis, rhinitis, laryngitis and sinusitis and remaining 36 cases suffered from bronchitis. Follow up and assessment All the patients were evaluated at intervals of 2 weeks at the end of 2nd week, 4th week and 6th week for the presence of the symptoms. Primary and secondary outcome measure The primary outcome measures were clinical recovery from the presenting symptoms of upper and lower respiratory tract infections. Secondary end points were clinical safety and toxicity profile of Septilin tablets. Adverse events All adverse events reported or observed by patients were recorded with information about severity, date of onset, duration and action taken regarding the study drug. Relation of adverse events to study medication was predefined as “Unrelated” (a reaction that does not follow a reasonable temporal sequence from the administration of the drug), “Possible” (follows a known response pattern to the suspected drug, but could have been produced by the patient’s clinical state or other modes of therapy administered to the patient), “Probable” (follows a known response pattern to the suspected drug that could not be reasonably explained by the known characteristics of the patient’s clinical state) and “Certain” (the adverse events must have definitive relationship to the study drug, which cannot be explained by concurrent disease or any other agent). Patients were allowed to voluntarily withdraw from the study if they had experienced serious discomfort during the study or sustained serious clinical events requiring specific treatment. For patients withdrawing from the study, efforts were made to ascertain the reason for dropout. Non-compliance (defined as failure to take less than 80% of the medication) was not regarded as treatment failure, and reasons for non-compliance were noted. Statistical analysis Statistical analysis was carried out using Fisher’s Exact Test using GraphPad Prism, Version 4.03 for windows, Graphpad Software, San Diego, California, USA. for presence or absence of various signs and symptoms. RESULTS The effect of septilin treatment in respiratory tract infection is shown in table 3. All the cases responded by 2 weeks of treatment and continued to respond with further treatment. Among the 28 I Volume 18 Number 8 I 2010 MEDICINE UPDATE Table. 3 Effect of Septilin tablets on respiratory tract infection Parameters At entry 2 weeks 4 weeks 6 weeks Tonsillitis 28 17 8* 03 Pharyngitis 24 8* 2** 00 Laryngitis 08 00 00 00 Sinusitis 20 12 07* 02** Rhinitis 32 2** 00 00 Bronchitis 36 20 11* 04** *p<0.01 compared to at entry values ** p<0.001 compared to at entry values cases suffering from tonsillitis, at the end of 2 weeks only 17 cases and at the end of 4 weeks 8 cases (p<0.01 ) and at the end of 6 weeks only 3 cases (p<0.001) presented with tonsillitis. The 3 cases who didn’t respond were further treated with antibiotics. Twenty four patients with pharyngitis treated with septilin were additionally advised salt water gargling 2-3 times daily. Patients showed a significant response by 2 weeks of treatment where only 8 patients (p<0.01) and at 4 weeks only 2 patients presented with pharyngitis. At the end of 6 weeks of treatment all the patients responded to the treatment ( p<0.001). Of the 8 laryngitis cases treated with septilin, all the cases responded by 2 weeks of treatment but is not considered as statistically significant because of the small sample size. Among the 20 patients with sinusitis, patients treated with septilin additional steam inhalation was advised. At the end of 2 weeks only 12 cases, at 4 weeks 07 cases (p<0.01), and at the end of 6 weeks only 2 patients (p<0.001) had symptoms of sinusitis. Of the thirty two patients of rhinitis, patients were treated with septilin along with steam inhalation and symptoms reduced significantly by 2 weeks with a significance of p<0.001 and by 4 weeks all the patients responded. In lower respiratory tract infection, 36 bronchitis cases treated with septilin, by 2 weeks 20 cases, by 4 weeks 11 cases (p<0.01) and at the end of 6 weeks 4 cases presented with symptoms who required additional medications. Out of 148 patients treated only two patients experienced mild abdominal discomfort effects and all the patients tolerated the drug well. None of the patients were withdrawn due to adverse effects. In 3 patients suffering from tonsillitis, 2 patients suffering from sinusitis and 4 patients suffering from bronchitis, there was no improvement in symptoms as well as signs. They were advised further treatment specific to the disease. DISCUSSION Upper respiratory tract infection represents the most common acute illness evaluated in the outpatient setting. The upper respiratory tract affects the sinuses, nasal passages, pharynx, and larynx, which serve as gateways to the trachea, bronchi, and pulmonary alveolar spaces and presents as rhinitis, pharyngitis, sinusitis, epiglottitis, laryngitis, tracheitis and bronchitis. MEDICINE UPDATE I Volume 18 Number 8 I 2010 Management of certain chronic and recurrent infections is often unsatisfactory and frustrating to the patient and physician alike. This study demonstrates the efficacy of Septilin in the treatment of such infections. Septilin has immunomodulatory, antioxidant, anti-inflammatory, anti-allergic, antimicrobial actions. Septilin has short and long term safety. Septilin is a multi-herbal preparation and the effect of the formulation is due to synergistic action of the ingredients. Tinospora cordifolia has potent immunomodulatory and immunostimulatory actions, which increases the levels of antibodies and activate macrophages.10-13 Tinospora cordifolia improves the phagocytic and intracellular bactericidal capacities of neutrophils.14 Emblica officinalis enhances cell survival, increases phagocytosis and γ-IFN production.15 Glycyrrhizin from Glycyrrhiza glabra potentiates the reticuloendothelial system,16 enhances immunostimulation,17 and acts on macrophage function in vitro, leading to stimulation of macrophages de novo,18 Betaglycyrrhetinic acid from Glycyrrhiza glabra is a potent inhibitor of the classical complement pathway19 and antiviral activity.20 Emblica officinalis has antibacterial properties, especially against Escherichia coli, Klebsiella pneumoniae, Klebsiella ozaenae, Proteus mirabilis, Pseudomonas aeruginosa, Salmonella typhi, Salmonella paratyphi A & B, and Serratia marcescens21 Rubia cordifolia22 has antibacterial properties. Moringa pterygosperma possesses antibacterial and antiviral properties, and inhibits the growth of gram-positive and gramnegative bacteria like Escherichia coli, Salmonella typhi, Salmonella paratyphi etc.23 Tinospora cordifolia24 and Emblica officinalis25 possess antipyretic properties. Balsamodendron mukul,26-29 Rubia cordifolia30, Emblica officinalis31, Glycyrrhiza glabra32, and Moringa pterygosperma33 have potent antioxidant actions. Balsamodendron mukul 34 have strong anti-inflammatory potential. Glycyrrhiza glabra35 and Moringa pterygosperma36 have also been reported for its antiinflammatory properties. SUMMARY AND CONCLUSION This study demonstrated that septilin tablets used in patients suffering from upper and lower respiratory tract infection showed significant improvement in the presenting symptoms. All the symptoms started improving by 2nd week of treatment and further improved with continued treatment. Out of 148 patients treated only two patients experienced mild abdominal discomfort effects and all the patients tolerated the drug well. None of the patients were withdrawn due to adverse effects. Septilin is not only cheap but a safe drug, well tolerated by the patients and can be used over long-periods without any side-effects. Septilin, a multiherbal formula, provides immunomodulatory activity that enhances natural immunity. Therefore, it may be concluded that Septilin is effective and safe in the treatment of respiratory tract infections. Himalaya update 5 References 1. McCormick A, Fleming D, Charlton J. Morbidity statistics from general practice Fourth national study 1991-1992. London, OPCS, HMSO; 1995. 2. Davey P, Bax R, Newey J. Growth in the use of antibiotics in the community in England and Scotland in 1980-1993. BMJ 1996;312:613613. 3. Butler CC, Rollnick S, Pill R, Maggs-Rapport F, Stott N. 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