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Clinical Trial Evaluation of efficacy and safety of Gasex Syrup in functional dyspepsia MAHTO A.K., PRASAD S.R., MITRA S.K. ABSTRACT The present study was planned to evaluate the clinical efficacy and safety of Gasex syrup in functional dyspepsia. Dyspepsia is a symptom complex of upper abdominal pain or discomfort believed to originate in the upper gastrointestinal (GI) tract. The pathogenesis of functional dyspepsia remains uncertain. However, regardless of the cause, the treatment effects have generally not been impressive. The present study was an open clinical trial, conducted as per the ethical guidelines of Declaration of Helsinki. All patients suffering from pain or discomfort centered in the upper abdomen with associated bloating, belching, nausea, and heartburn were included in the study, patients having severe vomiting and diarrhea, and those suffering with gastric or duodenal ulcer, cancer or varices disease were excluded from the study. A thorough history, symptomatic evaluation and clinical examination was done for all patients before treatment and during follow-up visits every week till the end of treatment on Day 28 along with recording the occurrence of any adverse event/s. The predefined primary endpoints were rapid symptomatic relief from upper abdominal pain, heart burn and bloating. The predefined secondary endpoints were short- and long-term safety, and overall compliance to the drug treatment. A total of 50 patients were enrolled into the trial and all the patients completed the study. A significant reduction (p<0.0001) in the mean symptom score of upper abdominal pain, heartburn, abdominal bloating, belching, fullness of stomach after meals, and nausea were observed after 28 days of treatment with Gasex syrup. There were no clinically significant adverse events, either reported or observed, during the entire study period. Therefore, it may be concluded that Gasex syrup is clinically safe and effective in the management of functional dyspepsia. INTRODUCTION Dyspepsia is defined as episodic or persistent symptoms of abdominal pain or discomfort referable to the upper gastrointestinal tract.1 However, actual mucosal lesions, such as erosions or ulcers, are found in as few as 20% of dyspeptic patients.2 In patients without mucosal changes, the dyspepsia is thought to be secondary to a disorder of function, rather than structure, hence the name functional dyspepsia (FD). Typical symptoms of FD include postprandial epigastric pain, early satiety, belching, bloating, and Dr. A.K. Mahto, M.D. (Med.) Professor and Head, Department of Medicine, Rajendra Institute of Medical Sciences, Bariatu, Ranchi, Jharkhand, India. Dr. S.R. Prasad, Medical Advisor, Dr. S.K. Mitra, Executive Director, R&D Center, The Himalaya Drug Company, Bangalore - 562 123, India. Specially Contributed to "The Antiseptic" Vol. 105 No. 1 & P : 35 - 40 January 2008 nausea. The current Rome II criteria for FD are symptoms for at least a 12week duration, which need not be consecutive, within the preceding year of (a) persistent or recurrent dyspepsia, (b) no evidence of organic disease (including at upper gastrointestinal endoscopy) that is likely to explain the symptoms, and (c) no evidence that dyspepsia is exclusively relieved by defecation or associated with the onset of a change in stool frequency or stool form (i.e., not irritable bowel syndrome).3 Several pathophysiological mechanisms underlying FD such as delayed gastric emptying,4,5 abnormal antroduodenal motility,6,7 altered sensitivity to duodenal lipid or acid exposure, 8-10 visceral hypersensitivity11, 12 and impaired fundic accommodation, 13, 14 have been identified. The current knowledge of these pathophysiological mechanisms has not led to a complete understanding of FD. Furthermore, attempts to develop therapeutic THE ANTISEPTIC strategies based on this knowledge have thus far not banned dyspepsia from our midst. However, regardless of the cause of FD the present treatment effects have generally not been impressive. Gasex syrup is a polyherbal formulation containing extracts of Cuminum cyminum, Mentha arvensis, Foeniculum vulgare, Elettaria cardamomum, Apium graveolens, Coriandrum sativum, Curcuma longa, and Trikatu, all of which are recommended for the management of dyspepsia. This study was planned to evaluate the clinical efficacy and safety of Gasex syrup in the management of functional dyspepsia. PATIENTS AND METHODS Inclusion criteria All patients aged between 18 to 70 years, suffering from pain centered in the upper abdomen with associated bloating, belching and nausea, were included in the study. 35 Exclusion criteria Patients having severe vomiting and diarrhea, and those suffering with gastric or duodenal ulcer, cancer or varices disease were excluded from the study. Study procedure The study was an open, nonrandomized and non-comparative, prospective, phase III clinical trial, conducted at Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India, from November 2006 to January 2007 as per the ethical guidelines of Declaration of Helsinki. The study protocol, case report forms (CRFs), regulatory clearance documents, product-related information and informed consent forms (in English, Hindi and Tamil) were submitted to the institutional ethics committee and were approved by the same. The patients who attended the Department of Medicine, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India, were informed about the study drug, its effects, duration of the trial, and overall plan of the study. The patients were included in the clinical study only after written informed consent was obtained from them, and a witness, independent of the clinical trial, signed the informed consent form. The history was noted by interviewing the patient. Thorough clinical examination and symptomatic evaluation was carried out and the details were noted down in the CRF. Patients were advised to take the drug at a dose of 2 teaspoonfuls twice a day after meals for 28 days. All patients were received every week till the end of treatment on Day 28 and symptomatic evaluation and clinical examination was done, along with recording the occurrence of any adverse event/s (either reported or observed). Primary endpoints and secondary The predefined primary endpoints were rapid symptomatic relief from upper abdominal pain, heartburn, bloating, and fullness after meals. The predefined secondary endpoints were short- and long-term safety, and 36 overall compliance to the drug treatment. Adverse events All adverse events, either reported or observed, were recorded in the CRF with information about severity, onset, duration, and action taken regarding the study drug. Relation of adverse events to the study medication was predefined as unrelated (a reaction that does not follow a reasonable temporal sequence from the time of administration of the drug), possible (follows a known response pattern to the suspected drug, but could have been produced by the patients clinical state or other modes of therapy administered to the patient), and probable (follows a known response pattern to the suspected drug that could not be reasonably explained by the known characteristics of the patients clinical state). Patients were allowed to voluntarily withdraw from the study, if they 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. Noncompliance (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 done according to intention-to-treat principles. The changes in various parameters from pre-treatment values to post-treatment values were analyzed by Friedmans test followed by Dunns Multiple Comparison test analysis. The minimum level of significance was fixed at 95% confidence limit and a 2sided p value of <0.05 was considered significant. RESULTS A total of 50 patients suffering from functional dyspepsia were included in the clinical trial and all patients completed the study. The study group had 30 male and 20 female patients. The mean age of the THE ANTISEPTIC patients was 36.8 years. Out of 50 patients, all of them were suffering from upper abdominal pain and heartburn, 42 patients had abdominal bloating, 39 patients had belching, 36 patients had fullness after meals, and 14 patients had nausea. A significant reduction (p<0.0001) in mean symptom score of upper abdominal pain from 1.82 ± 0.133 to 0.24 ± 0.067, heartburn from 1.74 ± 0.164 to 0.38 ± 0.085, abdominal bloating from 1.86 ± 0.149 to 0.44 ± 0.095, belching from 1.76 ± 0.155 to 0.32 ± 0.088, fullness of stomach after meals from 1.280 ± 0.137 to 0.240 ± 0.073, and nausea from 1.140 ± 0.134 to 0.180 ± 0.062 were observed after 28 days of treatment with Gasex syrup. The reduction in these symptoms score started appearing from the Day 7 of treatment itself (Table 1; Figures 1 to 6). Patients global assessment revealed that 22% of them became totally symptom-free, 20% showed marked improvement, 40% had moderate improvement, and 18% had slight improvement after 28 days of therapy with Gasex syrup (Figure 7). Investigators global assessment revealed that 48% patients became totally symptom free, 38% of patients had marked improvement, and 14% of them had moderate improvement at the end of treatment with Gasex syrup (Figure 8). There were no clinically significant adverse events, either reported or observed, during the entire study period. DISCUSSION Although the precise definition of dyspepsia remains debatable, the most widely quoted definition is a chronic, recurrent pain or discomfort centred in the upper abdomen.15 Once an evaluation has been performed and organic etiologies for the dyspeptic symptoms have been excluded, an affected patient is said to be suffering from functional dyspepsia (FD; previously termed non-ulcer dyspepsia).16 Epidemiological studies suggest that approximately 15% of the general population in western countries suffers with FD.17,18 January 2008 Table 1: Reduction in mean symptom score of upper abdominal pain, heartburn, bloating, belching, fullness after meals, and nausea with Gasex syrup treatment Parameter Day 0 Day 7 Day 14 Day 21 Day 28 Upper abdominal pain Heartburn 1.820 ± 0.133 0.820± 0.127* 0.500± 0.112* 0.340± 0.084* 0.240± 0.067* 1.740± 0.164 1.220± 0.147 0.800± 0.137* 0.500± 0.104* 0.380± 0.085* Bloating 1.860± 0.149 1.140± 0.149# 0.900± 0.149* 0.600± 0.121* 0.440± 0.095* Belching 1.760± 0.155 1.100± 0.146 0.740± 0.137* 0.500± 0.100* 0.320± 0.088* Fullness after 1.280± 0.137 0.680± 0.119# meals Nausea 1.140± 0.134 0.540± 0.108# 0.460± 0.104* 0.280± 0.081* 0.240± 0.073* 0.280± 0.081* 0.220± 0.072* 0.180± 0.062* # Friedman Statistic (FS) & Significance FS: 138.3; p<0.0001, Significant FS: 116.6; p<0.0001, Significant FS: 115.9; p<0.0001, Significant FS: 102.5; p<0.0001, Significant FS: 99.27; p<0.0001, Significant FS: 98.47; p<0.0001, Significant p<0.01 and *p<0.001 as compared with Day 0 value Figure 1: Reduction in mean symptom score of upper abdominal pain with Gasex syrup treatment (Mean ± SEM) Figure 2: Reduction in mean symptom score of heartburn with Gasex syrup treatment (Mean ± SEM) Figure 3: Reduction in mean symptom score of bloating with Gasex syrup treatment (Mean ± SEM) Figure 4: Reduction in mean symptom score of belching with Gasex syrup treatment (Mean ± SEM) January 2008 THE ANTISEPTIC 37 Figure 5: Reduction in mean symptom score of fullness after meals with Gasex syrup treatment (Mean ± SEM) Figure 6: Reduction in mean symptom score of nausea with Gasex syrup treatment (Mean ± SEM) Figure 7: Percentage of improvement from patients global assessment Figure 8: Percentage of improvement from investigators global assessment Nearly two-thirds of dyspeptic patients will eventually end up with a diagnosis of FD following an evaluation.19 FD tends to be a chronic condition with long-term studies demonstrating persistent symptoms in >80% of affected patients after 67 years of follow-up.20,21 Other studies have consistently found that FD negatively affects quality of life.22-24 A wide variety of pathophysiological mechanisms have been postulated to contribute to the development of symptoms in patients with FD. Of the abnormalities proposed, alterations in gastroduodenal motor and reflex function have been most extensively studied. Delayed gastric emptying has been reported in 30-40% of FD patients. 25-30 38 At present, it remains unclear if any one or more likely some combination of these abnormalities is responsible for symptoms in FD patients. A wide variety of treatments have been used to manage FD including dietary and lifestyle modifications, Helicobacer pylori eradication, antacids, mucosal protectants, antisecretory agents, prokinetics, antidepressants, and behavioural therapies as well as complementary and alternative medical (CAM) therapies. But the fact is that no single available therapy consistently provides relief to the majority of FD patients . The present clinical study observed a significant relief in the THE ANTISEPTIC symptoms of dyspepsia like upper abdominal pain, heartburn, abdominal bloating, abdominal belching, fullness of stomach after meals, and nausea and vomiting after 28 days of treatment with Gasex syrup. The reduction in these symptoms started appearing from the Day 7 of treatment itself and complete relief by 28 days. There were no clinically significant adverse events, either reported or observed, during the entire study period. Earlier research works on the extracts of individual ingredients of Cuminum cyminum, Mentha arvensis, Foeniculum vulgare, Elettaria cardamomum, Apium graveolens, Coriandrum sativum, Curcuma longa, and Trikatu have proven their carminative, antispasmodic, analgesic, January 2008 anti-inflammatory, and antioxidant activities. Cuminum cyminum, belonging to the family Apiaceae, is widely used in Ayurvedic medicine for the treatment of dyspepsia, diarrhea and jaundice.31 All the herbs tested increased acid secretion in the following declining order: fennel, omum, cardamom, cumin, and coriander; these herbs increased gastric acid secretion, in some by a cholinergic mechanism but by other mechanism(s) as well. 32 Cumin may protect the colon by decreasing the activity of betaglucuronidase and mucinase.33 Trikatu is an Ayurvedic preparation containing black pepper, long pepper and ginger, which is prescribed routinely for a variety of diseases as part of multidrug prescriptions. These herbs along with piperine (alkaloid of peppers) have been shown to possess diverse biological activities in mammalian systems. 34 Peppers and ginger have been commonly used in conjunction in folklore medicines. Modern research, mostly European, has documented the ability of ginger to stimulate gastric motility (efficiency of moving food through the digestive tract) to relieve indigestion and to promote digestion. The main reason that this herbal trio is part of so many Ayurvedic formulations is its proven ability to enhance gastrointestinal absorption of nutrients. Many groups of scientific investigators attribute this bioenhancing property of pepper to its main alkaloid, piperine.35 Mentha arvensis plant has antispasmodic, carminative, cholagogic, and antimicrobial properties. The oil contains 95% of menthol and offers cytotoxic properties. The fruit of Foeniculum vulgare has anti-inflammatory, analgesic and antioxidant activities.36 Elettaria cardamomum has shown gastroprotective property in rats.37 Extract of Apium graveolens contains apiin as the major constituent and exerted significant anti-inflammatory property in in vivo model. 38 The January 2008 antioxidant activity of the aqueous extracts of 3 umbelliferous fruits coriander (Coriandrum sativum), cumin (Cuminum cyminum) and fennel (Foeniculum vulgare) has been demonstrated. 39 Curcuma longa has been commonly used as a traditional remedy for a variety of symptoms such as inflammation, gastritis and gastric ulcer. When Curcuma longa extract was administered per os to pylori-ligated rat stomachs, it reduced gastric acid secretion and protected against the formation of gastric mucosal lesions. Therefore, it was tested whether Curcuma longa extract inhibits gastric ulcers by blocking the H2 histamine receptor. These findings suggest that the extract from Curcuma longa specifically inhibits gastric acid secretion by blocking H2 histamine receptors in a competitive manner.40 REFERENCES 1. Heading, R.C. Definitions of dyspepsia. Scand. J. Gastroenterol. 1991;182:1-6. 2. Health and Public Policy Committee. American College of Physicians. Endoscopy in the evaluation of dyspepsia. Ann. Intern. Med. 1985;102:266-269. 3. Talley N, Stanghellini V, Heading R, et al. Functional gastroduodenal disorders. Gut 1999;45(suppl 2): II37-42. 4. Jian R, Ducrot F, Ruskone A, et al. Symptomatic, radionuclide and therapeutic assessment of chronic idiopathic dyspepsia – A double-blind placebo-controlled evaluation of cisapride. Dig. Dis. Sci. 1989;34: 657–664. 5. Wegener M, Borsch G, Schaffstein J, Schulz-Flake C, Mai U, Leverkus F. Are dyspeptic symptoms in patients with Campylobacter pyloriassociated type B gastritis linked to delayed gastric emptying? Am. J. Gastroenterol. 1988;83:737-740. Therefore, the observed clinical benefits of Gasex syrup might be due to the synergistic actions of its ingredients. 6. Bassotti G, Pelli MA, Morelli A. Duodenojejunal motor activity in patients with chronic dyspeptic symptoms. J. Clin. Gastroenterol. 1990;12:17–21. CONCLUSION 7. Stanghellini V, Ghidini C, Maccarini MR, Paparo GF, Corinaldesi R, Barbara L. Fasting and postprandial gastrointestinal motility in ulcer and nonulcer dyspepsia. Gut 1992;33:184–190. Functional dyspepsia is a commonly encountered condition in medical practice. Being a multifactorial syndrome complex, many therapeutic interventions have been studied. However, there is no clinically effective and safe medication that can be recommended in the management of functional dyspepsia. This study was conducted to evaluate the clinical efficacy and safety of Gasex syrup in FD. This study observed a significant symptomatic relief from upper abdominal pain, heartburn, abdominal bloating, belching, fullness of stomach after meals, and nausea. Symptomatic relief was evident in 7 days of treatment in majority of the patients, while almost all were relieved within 28 days of treatment. There were no clinically significant adverse events, either reported or observed, during the entire study period. Therefore, it may be concluded that Gasex syrup is clinically safe and effective in the management of functional dyspepsia. THE ANTISEPTIC 8. Barbera R, Feinle C, Read NW. Abnormal sensitivity to duodenal lipid infusion in patients with functional dyspepsia. Eur. J. Gastroenterol. Hepatol. 1995;7:1051-1057. 9. Barbera R, Feinle C, Read NW. Nutrient-specific modulation of gastric mechanosensitivity in patients with functional dyspepsia. Dig. Dis. Sci. 1995;40:1636–1641. 10. Samsom M, Verhagen MA, van Berge Henegouwen GP, Smout AJ. 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Impact of functional dyspepsia on quality of life. Dig. Dis. Sci. 1995;40:584-589. 25. Quartero AO, de Wit NJ, Lodder AC, Numans ME, Smout AJ, Hoes AW. 40 33. Nalini N, Sabitha K, Viswanathan P, et al. Influence of spices on the bacterial (enzyme) activity in experimental colon cancer. J. Ethnopharmacol. 1998;62(1):15-24. 34. Johri RK, Zutshi U. An Ayurvedic formulation ‘Trikatu’ and its constituents. J. Ethnopharmacol. 1992;37(2):85-91. 35. James J. Gormley. Ancient art of balancing digestion, nutrient absorption, and metabolism. Better Nutrition 1996;July. 36. Choi EM, Hwang JK. Antiinflammatory, analgesic and antioxidant activities of the fruit of Fitoterapia Foeniculum vulgare. 2004;75(6):557-565. 37. Jamal A, Javed K, Aslam M, et al. Gastroprotective effect of cardamom, Elettaria cardamomum Maton. fruits in rats. J. Ethnopharmacol. 2006;103(2):149-153. 38. Mencherini T, Cau A, Bianco G, et al. An extract of Apium graveolens var. dulce leaves: structure of the major constituent, apiin, and its antiinflammatory properties. J. Pharm. Pharmacol. 2007;59(6):891-897. 39. Satyanarayana S, Sushruta K, Sarma GS, et al. Antioxidant activity of the aqueous extracts of spicy food additives: Evaluation and comparison with ascorbic acid in in-vitro systems. J. Herb. Pharmacother. 2004;4(2): 1-10. 40. Kim DC, Kim SH, Choi BH, et al. Curcuma longa extract protects against gastric ulcers by blocking H2 histamine receptors. Biol. Pharm. Bull. 2005;28(12):2220-2224. v A 31 year old woman who had taken oxytetracycline for three months to treat rosacea attended clinic because of painful finger nails, which had partially lifted off the nail bed and turned yellow. She had noticed this while on holiday in Turkey three weeks earlier. On examination she had onycholysis of all fingernails and toenails, and a yellow discoloration of all nails. Photo-onycholysis is a well documented side effect of tetracyclines within the photosensitivity spectrum. Treatment was stopped and her nails are now returning to normal . (BMJ June 2007) Light's criteria for pleural exudate transudate 1. Ratio of pleural fluid protein to total serum protein is 0.5 or more. 2. Ratio of pleural fluid LDH to total serum LDH is 0.6 or more. 3. Pleural fluid LDH is two-thirds or more of the upper limit for serum LDH. (JMAJ Sep. - Oct. 2006) THE ANTISEPTIC January 2008