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Exploring Indian Biodiversity in search of Newer anti Gastric Ulcer Principle(s) - Target Based Mechanistic Study with Identified Lead(s) in Preclinical Experimental Models.

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Title Exploring Indian Biodiversity in search of Newer anti Gastric Ulcer Principle(s) - Target Based Mechanistic Study with Identified Lead(s) in Preclinical Experimental Models.
 
Creator Kar, Sudip Kumar
 
Subject Drug Development/Diagnostics & Biotechnology
 
Description In an effort to make target-based search in preclinical experimental models of gastroduodenal ulcers, a large number of natural products including plant extracts, microbial extracts (both bacterial and fungal) and natural-product-based semisynthetic molecules were screened based on two key etiologies, the bacterium H. pylori and the acid HCl. Employing disc diffusion sensitivity assay for
anti H. pylori activity evaluation, Ussing chamber model in isolated frog gastric mucosa for examining gastric antisecretory potential, and H+,K+-ATPase enzyme rich pig gastric membranes for anti proton pump activity evaluation, three large-scale screening platforms were developed for
assessing the potential of the samples. Upon validation of such methods and protocols, thousands of samples were screened, the best 1% fished out, and such primary observations were revalidated to identify putative lead extracts and/or molecules based on some logically derived selection criteria.Seven samples were finally identified as ‘Revalidated Leads’ for anti H. pylori activity, one for gastric antisecretory potential, and three as proton pump inhibitors. Since the major objective of this
dissertation work is natural-product-based drug discovery for gastric ulcer disease, it was of immense curiosity to look into few such screened leads in greater details for drug development. While the Council of Scientific and Industrial Research through a nationally networked programme has provided generous support in getting access to a large pool of natural-product-based samples,
chemistry and synthesis of natural product molecules and a few other studies were carried out in collaboration with other participating laboratories of this programme. Samples were coded, unless mentioned otherwise, in view of the IPR issues.With a few such anti H. pylori leads from plant and microbial extracts, ‘bioassay-guided fractionation’ approaches were attempted with a view to enriching the activity, monitored in terms of inhibition zone diameters and MIC/MBC values against clinical and standard strains. Active fractions in some cases and a molecule in one case could be identified that exhibited strong anti H. pylori
potential.With gastric antisecretory leads found in two Indian medicinal plants, a ‘Make-Fraction −
Test-Fraction’ approach was followed with a view to searching active principle(s) employing Ussing
chamber model using isolated frog gastric mucosa. Their potentials were evaluated in terms of inhibition of basal- and secretagogue-stimulated acid secretion as well as blocking of reversal of such stimulated acid secretion. In both the cases, the non-polar fractions inhibited basal acid secretion, blocked histamine- and forskolin-stimulated acid secretion in a dose dependent manner, and were
effective against gastric proton pump. Such fractions also exhibited excellent antiulcer activity in vivo. One molecule with potent anti H+ pump activity and gastric antisecretory activity was isolated from the n-hexane fraction of the alcoholic extract of a plant. It is concluded that these two plants contain antisecretory principle(s) that can be exploited in making herbal preparations for the therapeutic management of gastric hypersecretion.
 
Date 2012
 
Type Thesis
NonPeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1677/1/Sudip_K._Kar_(SRF%2DCSIR)._Ph._D._Thesis._Oct._2012.pdf
Kar, Sudip Kumar (2012) Exploring Indian Biodiversity in search of Newer anti Gastric Ulcer Principle(s) - Target Based Mechanistic Study with Identified Lead(s) in Preclinical Experimental Models. PhD thesis, Jadavpur University.
 
Relation http://www.eprints.iicb.res.in/1677/