Brief Resume of Intended Work: 1: need for the study




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6.0



Brief Resume of Intended Work:

6.1: NEED FOR THE STUDY:

Ulcer has long been recognized as one of the most important problem in developing countries. About 70% population in developing countries relies on traditional medicine for their primary health care needs2

Peptic ulcer disease (PUD) is a serious widespread gastrointestinal disorder affecting millions of people. According to the latest WHO data published in April 2011 Peptic Ulcer Disease Deaths in India reached 108,392 or 1.20% of total deaths. The age adjusted death rate is 12.37 per 100,000 of population and India ranks #5 in the world.27 Peptic ulcer affects 10% of world population. But till now, the extent of etiopathogenesis of peptic ulcer is not completely understood. However, there are reports that the pathophysiology involved in peptic ulcer is a result of imbalance between defensive factors and aggressive factors; the defensive factors viz., mucus, mucosal blood flow, formation of HCO3, and prostaglandins like PGE3 etc., get impaired or overpowered by the aggressive factors viz., acid, pepsin, NSAIDs and Helicobacter pylori infection etc. Peptic ulcer may also be caused by variety of factors such as stress, emotion, anxiety, depression, excessive gastric secretions, smoking, and modern life style. Hence Peptic ulcer is regarded as a multifactorial gastrointestinal disorder which also includes generation of free radicals. It has been now established that oxygen derived free radicals, primarily super oxide (O2) anion and hydroxyl radical (OH) play very important role in pathogenesis of acute experimental gastric lesions induced by stress, ethanol and NSAIDs viz., Indomethacin, Aspirin etc.1 Thus, a major underlining factor of peptic ulcer disorder is the generation of free radicals in addition to increased and prolonged acid secretion, thus it is suggested that the compounds containing antiulcer, antioxidant and antisecretory activities can prove to be effective in PUD.

Acid neutralization is being recognized as effective treatment for many centuries, But with the understanding of pathogeneses of PUD the treatment has become more effective. A number of antiulcer drugs like gastric anti-secretory drugs, H2-receptors antagonists, antimuscarine drugs, proton pump inhibitors and mucosal protective agents are in most common usage as a remedy for peptic ulcer. In addition a large section of the world’s population relies on traditional and medicinal herbs and minerals due to their less cost and easy access. Therefore it is needed to verify and validate the traditional and folklore remedies.in this regard ayurvedic literature prescribes various herbs, minerals and herbal products for the treatment of PUD. It is necessary to evaluate them, so as to put them in to the therapeutic arena. Most of these Ayurvedic preparations are not single components, many of them ARE herbal formulations containing several herbs are herbal or/and herbomineral products.one such formulation is being marketed as HIMCOCID by Himalaya herbal health care.

HIMCOCID contains Varatika (Cyprea monata) and Dugdhapashana (Magnesium silicate) are the natural sources of calcium and magnesium, which act as non-systemic antacids. While relieving the symptoms of dyspepsia, Himcocid does not produce any acid-base or electrolyte imbalance.

Although the effect of Himcocid was short-lived, it provided significant symptomatic relief in a variety of dyspeptic symptoms4. Pre-clinical assessment of its anti-ulcer potential will provide a strong scientific evidence to place this preparation into therapeutic arena. The comparison with second generation proton pump inhibitor will also provide the scientific information regarding the efficacy of it. In addition there is no scientific data available regarding the anti-ulcer potential of Himcocid and its comparative study with proton pump inhibitors. hence it is planned to compare Himcocid with proton pump inhibitors using pylorus ligation, ethanol induced ulcer model and indomethacin induced ulcer models in rats. Since this study helps in finding out an alternative treatment for peptic ulcer, the study is justifiable.



3.2) REVIEW OF LITERATURE:

HIMCOCID Syrup is manufactured by Himalaya herbal health care and it is the herbomineral formulation containing the following Ingredients

Each 5ml of Himalaya Himcocid contains :

Varatika Syn. Cowrie bhasma – 350 mg

Dugdhapashana – 350 mg. Mouktika Sukti Syn. Mouktika bhasma – 75 mg.

The synergistic effect of Himalaya Himcocid Syrup’s constituents produces neutralization of gastric acid and offers relief from the burning pain of hyperacidity. Himalaya Himcocid Syrup relieves gaseous distension and bilious symptoms. Himalaya Himcocid Syrup relieves the symptoms of indigestion and thus improves appetite.24

Prof. S .Rastogi et al reported that Himcocid was reasonably successful in controlling symptoms of non-ulcer dyspepsia during its administration. After 6 weeks of treatment, the majority of the patients in our series were relieved of their dyspeptic symptoms. Since patients with arthritis are on long-term or intermittent NSAID therapy during the period of pain, Himcocid prophylaxis can effectively control the symptoms. Patients who were on long-term treatment with NSAIDs and who had completed the trial of Himcocid, remained symptom-free for more than 4-6 weeks after the end of course.4

Devanathan. R. et al reported that Varatika Bhasma prepared from Varatika, which comes under Sadharana Rasavarga and also under Sudhavarga as per Rasa literature, is taken up and studied from Standardisation point of view. Varatika is the external shell of sea animal Cyprea moneta linn Chemically Varatika is identified as Carbonate of Calcium.5

Anupama reported that Muktashukti Bhasma is preparation of oyster shells which produces pearls. These pearl oysters are found in Indian Ocean. The shells of oyster are processed as per Ayurvedic texts to produce calcinated shells. It is cold in potency, antacid, tonic has anti-pyretic activity. 

Muktashukti Bhasma contains calcium carbonate, calcium phosphate, aluminium oxide, magnesium oxide and organic matter.27

Indications of Himcocid syrup

Useful for symptomatic management of Hyperacidity, Dyspepsia, Flatulence, Heartburn.

Xue-Qing Li et al reported that inhibitory profiles of the five studied PPIs were similar, lansoprazole and pantoprazole are the most potent in vitro inhibitors of CYP2C19 and CYP2C915

C J Hawkey et al reported that improved relief and duodenal ulcer healing with lansopraole a new proton pump inhibitor with ranitidine.7

Raquel et al., reported the anti-ulcerogenic effect of MBI (Methanolic extract of Byrsonima intermedia with different ulcerogenic agents in rodents (mice and rats), such as NSAID, HCl/ethanol, pyloric ligature, absolute ethanol, cysteamine and ischemia–reperfusion.26

Tamara Regina et al., reported the antiulcer activity in Alchornea glandulosa plant extract using HCl/ethanol and by nonsteroidal antiinflammatory drug-induced gastric lesions models in Rats. They have concluded that the potential antiulcer activity Alchornea glandulosa plant extract is due to total phenolic constituents such as myricetin-3-O-a-L-rhamnopyranoside,quercetin-3-O-a-L-rabinopyranoside,quercetin-3-O-b-galactopyranoside, quercetin, amentoflavone, methyl gallate, gallic acid in Alchornea glandulosa plant extract.16

Kam chuen lai et al reported that Lansoprozol prevent the recurrences of ulcer complications from long term low dose aspirin use.8

Kim N et al, reported that lafutidine-clarithromycin-amoxicillin therapy was a safe and effective as Lansoprozol-based triple therapy for the eradication rate of H. pylori, and could be considered as an additional treatment option.12

David Y reported that Proton pump inhibitors such as Lansoprozol are superior to placebo for the prevention of NSAID-induced gastric ulcers but not superior to misoprostol, 800 µg/d. When the poor compliance and potential adverse effects associated with misoprostol are considered, proton pump inhibitors and full-dose misoprostol are clinically equivalent.13

Sampath K. Vemula Amlapitta Misran produces significant antiulcer activity in NSIAD's induced ulcers in rats. According to the present findings, gatroprotective effect of Amlapitta Mishran in prevention of ulcers might be due to production of prostaglandins in the stomach. The results suggest that Amlapitta Mishran having a significant gastroprotective effect in a dose dependent manner.14

6.3 OBJECTIVES OF THE STUDY:


  • To evaluate the gastro protective activity of Himcocid syrup and Lansoprozol against ethanol induced, pylorus ligated and indomethacin induced ulcer in rats.

  • To study, gastro protective activity of combination of Himcocid and Lansoprozol treatment in ethanol induced, pylorus ligated and indomethacin induced ulcer in rats.


7.0 MATERIALS & METHODS

7.1 Source of the data:

Data will be generated by performing experiments on animals. The standard information from

collected from various journals, standard Text books in library of Govt. college of pharmacy,

Indian Institute of Science, RGUHS digital library and from various standard websites.



Web sites: www.sciencedirect.com,

www.pubmed.com,

www.google.com

EXPERIMENTAL ANIMALS:

Adult rats weighing between 200-250 g of either sex will be used in the study. The animals will be kept under standard conditions at ambient temp of 25± 20 C with 12hr light/ 12hr dark cycle with food and water. Animals will be acclimatized to laboratory condition before the test.



Acute toxicity study.

Determination of LD50 of Himcocid as per OECD Guidelines. The guideline described by OECD will be adapted for the determination of LD50 on adult female mice. Female mice will be used as they are more sensitive to toxicity compared to male mice. Hence female rats are taken for acute toxicity study and1/10th & 1/5th of LD50 dose will be taken for the further study.


7.2 EXPERIMENTAL DESIGN

  1. Ethanol induced ulcer model

ii. Pylorus ligation induced ulcer model

  1. Indomethacin induced ulcer model

I) GASTRIC LESIONS INDUCED BY ETHANOL (CYTOPROTECTION STUDIES)

Rats will be randomly divided in to 5 groups of 6 rats in each group and treated as follows.

Group 1: Negative control, receives only vehicle

Group 2: Positive control

Group 3: Proton Pump Inhibitors -(Lansoprozol)

Group 4: Ayurvedic Preparation-HIMCOCID

Group5: Lansoprozol + HIMCOCID

The animals will be administered 1ml of 100% ethanol by gavage. Himcocid or Lansoprozol given by gavage 30 min before the administration of ethanol. One hour after the administration of ethanol the animals will be sacrificed and examined for lesions in the stomach. Patched lesions of the stomach induced by ethanol will be scored according to the method described by the literature17 using the following scale;

0.5= red color

1.0= spot ulcer

1.5= haemorrhagic streaks

2.0= ulcers ≥3 to ≤ 5 (size or diameter)

3.0= ulcers ≥ 5

Percentage protection of ulcer index is calculated by the formula

percentage protection=UC-UT X 100

UT

II) PYLORUS LIGATION INDUCED ULCER MODEL

Rats are divided into 5 groups of 8 animals each and treated as follows:

Group 1: Control Group, Receives only vehicle

Group 2: Positive control

Group 3: Proton Pump Inhibitors -Lansoprozol

Group 4: Ayurvedic Preparation-HIMCOCID

Group5: Lansoprozol + HIMCOCID

Albino rats of either sex weighing 150-200 g will be used. After 18 hours of fasting, ulcer induction will be undertaken. The rats are quickly and mildly anaesthetized with ether and the abdomen will be cut open through a midline incision. The pylorus will be secured and ligated with silk sutures, after which the wound will be closed and the animal are allowed to recover from anesthesia. After ligation of the pylorus, drinking water will be withheld and the gastric examinations will be under-taken 19 hours after pylorus ligation. The animals will be sacrificed with an overdose of ether and the stomach removed after clamping the esophagus. The gastric contents will be collected through the esophagus. The gastric juice will be centrifuged and volume will be recorded.19 20

III) INDOMETHACIN INDUCED ULCER MODEL

Albino wister rats weighing 200-250 gm. are taken for the study.animals are randomly

divided in to five groups of six animals each and are fasted for 24 hour with free access to

drinking water ad libitum. They are housed in single cage with bottoms wide wire mesh in

order to avoid cannibalism and coprophagy.

Rats will be randomly divided in to 5 groups of 6 rats in each group and treated as follows.

Group 1: Negative control, receives only vehicle

Group 2: Positive control

Group 3: Proton Pump Inhibitors -(Lansoprozol)

Group 4: Ayurvedic Preparation-HIMCOCID

Group5: Lansoprozol + HIMCOCID

One hour after the administration of the HIMCOCID or the proton pump inhibitor all the

animals received indomethacin 30mg/kg b.w.p.o the animals the animals are sacrified 4 hrs after indomethacin administration. The stomach were removed opened along the greater curvature. The number of ulcers per stomach was noted and severity of the ulcer was scored microscopically with help of hand and lens (10X) percentage protection calculate by the formula.1

percentage protection=UC-UT X 100

UT

The stomach also used for the glutathione and lipid peroxide estimation.


7.3 PARAMETERS MONITERED

I. Stomach tissue biochemical estimation:

1 Glutathione

2. Lipid peroxidation

II. Stomach histopathological evaluation

7.4 STATISTICAL ANALYSIS

The data obtained from experimentation will be subjected to one way analysis of variance (ANOVA) with suitable post-hoc test



7.5 DOES THE STUDY REQUIRE ANY INVESTIGATION OR INTERVENTIONS

TO BE CONDUCTED ON PATIENTS OR OTHER HUMANS /ANIMALS? IF SO

PLEASE DESCRIBE BRIEFLY.

Yes, the above study requires investigation to be done on the rats for the determination of Gastric ulcers.



7.6 Has ethical clearance been obtained from your institute in case 7.3?

YES, The study has been referred to the ethical committee of the institution and clearance is awaited



.

8. REFERENCES:

  1. Nataraj HN, Murthy RLN, Setty R. Evaluation of gastroprotective ability of Amorphophallus paeoniifolius corms against indomethacin induced gastric ulcers. J Pharm Sci. 2012; 1(2).

  2. Gregory M, Divya B, Mary RA, Viji MMH, Kalaichelvan VK, Palanivel V. Antiulcer activity of ficus religiosa leaf ethanolic extract. Asian Pac J Trop Biomed. 2013 July; 3(7): 554–6.

  3. Sharma P, Vidyasagar G, Bhandari A, Singh S, Ghule S, Agrawal A, et al. Antiulcer Activity of Leaves Extract of Murraya Koenigii In Experimentally Induced Ulcer In Rats. Pharmacol online 2011;2: 818-24.

  4. Rasthogi S, Kulkarni KS. Using Himcocid in the Management of Dyspeptic Symptoms in Patients Receiving Non-steroidal Anti-inflammatory Drugs. Insert in gut. 2002 June.

  5. Devanathan R, Rajalakshmi P, Brindha P. Chemical standardization studies on Varatika bhasma. Int J Current Pharmaceut Res. 2010 July;2(4):975-1491. 

  6. Wallace JL. How do NSAIDs cause ulcer disease. Baillieres Best Pract Res Clin Gastroenterol. 2000 Feb;14(1):147-59

  7. Hawkey CJ, Long RG, Bardhan KD, Wormsley KG, Cochran KM, Christian J et al. Improved symptoms relief and duodenal ulcer healing with lansoprazole a new proton pump inhibitor compared with ranitidine. Gut. 1993 October; 34(10): 1458–62.

  8. Lai KC, Lam SK, Chu KM, Wong BCY, Hui WM, Hu WHC.et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. New Eng J Med. 2002; 346(26): 2033-8.

  9. Pilotto A, Franceschi M, Leandro G, Bozzola L, Fortunato A, Rassu M,.et al. Efficacy of 7 day lansoprazole-based triple therapy for Helicobacter pylori infection in elderly patients. J Gastroenter Hepatol. 2003 Dec;14(5):468–75,

  10. Khandare RA, Gulecha VS, Mahajan MS, Mundada AS, Gangurde HH. Evaluation of antiulcer activity polyherbal formulation. IJPRD. 2009;1(10)

  11. Maity P, Bindu S, Choube V, Alam A, Mitra K, Goyal M.et al. Lansoprazole protects and heals gastric mucosa from non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy by inhibiting mitochondrial as well as Fas-mediated death pathways with concurrent induction of mucosal cell renewal. J Biol Chem. 2008 May;283(21):14391-401.

  12. Kim N, Park SH, Seo GS, Lee SW, Kim JW, Lee KJ et al. Lafutidine versus lansoprazole in combination with clarithromycin and amoxicillin for one versus two weeks for Helicobacter pylori eradication in Korea. Helicobacter. 2008 Dec;13(6):542-9.

  13. Graham DY, Agarwal NM, Campbell DR, Haber MM, collis C, Nancy L, et al. Anti- inflammatory drugs Results of Double-blind, Randomized Ulcer Prevention in Long term users of Nonsteroidal, Multicenter, Active-and Placebo-Controlled study of Misoprostal vs Lansoprazole. Arch intern med. 2002 Jan;162(2):169-75.

  14. Vemula SK, Chawada MB, Thakur KS, Vahalia MK. Antiulcer activity of amlapitta mishrana suspension in rats. Anc Sci Life. 2012 Oct;32(2):112–5

  15. Li XQ, Andersson TB, Ahlström M, Weidolf L. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome p450 activities. Drug Metab Dispos. 2004 Aug;32(8):821-7

  16. Regina T. Constituents and Antiulcer Effect of Alchornea glandulosa: Activation of Cell Proliferation in Gastric Mucosa during the Healing Process. Biol Pharm Bull. 2007;30(3): 451-9.

  17. RodriguesHYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Rodrigues%20LE%5BAuthor%5D&cauthor=true&cauthor_uid=22895918" LE, Galle P, Siry P, Vinhaes A. The protective effect of zinc on gastric ulceration caused by ethanol treatment. Braz J Med Biol Res. 1989;22(1):41-50.

  18. Cho CH, Ogle CW .The effect of Zinc sulphate on vagal-induced mast cell changes and Ulcers in the Rat stomach.european journal of pharmacology. 1977;43:315-22.

  19. Minaiyan, Ghassemi, Mohammadzadeh. Anti-ulcer effect of Tripleurospermum disciforme (C.A. Mey) Shultz Bip on pylorus ligated (Shay) rats. Res Pharmaceut Sci. 2006;1:15-21.

  20. Shay, Komarow, Fels, Meranze, Gryenstein, Siplet. A simple method for the uniform production of gastric ulceration in the rat. Gastroenterol. 1945;5:43-61.

  21. Xu XMD, Xu S, Zheng Y, Xu S. Novel role of Zn (II)–curcumin in enhancing cell proliferation and adjusting proinflammatory cytokine-mediated oxidative damage of ethanol-induced acute gastric ulcers. Chemico-Biological Interactions. 2012;197:31–9.

  22. Odabasoglu F, Cakir A, Aslan HSHA, Bayir Y, Halici M, Kazaz C. Gastroprotective and antioxidant effects of usnic acid on indomethacin-induced gastric ulcer in rats. J Ethnopharmacol. 2006;103:59–65.

  23. World health rankings live longer live better. [Online] [Cited 2013 Nov 16] Available from the URL: http://www.worldlifeexpectancy.com/india-peptic-ulcer-disease.

  24. info@anchorstoreonnet.com

  25. C J HawkeyR G LongK D BardhanK G WormsleyK M CochranJ Christian et al.improved symptoms relief and duodenal ulcer healing with lansoprazole a new proton pump inhibitor compared with ranitidine. Gut. 1993 Oct;34(10):1458–62.

26 Santosa RC, Kushimaa H, Rodriguseb CM, Sannomiyac M, Rochaa LMR, Tais Maria Bauabd T M et al.Byrsonima intermidia A. Juss:Gastric and Duodenal antiulcer, antimicrobial and antidiarrheal effects in experimental rodent models. J. ethnopharmacol.2012;(104)203-212.

27 http://www.bimbima.com/health/post/2013/10/29emuktashukti-bhasma-uses-details.aspx







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