Recent study drug development for peptic ulcer

1. Peptic Ulcer & Their New
Molecular Target
Presented by:-
Kundlik Harichand Rathod
Roll no.-PC/2017-X/173
M.S.(Pharm) Pharmacology & Toxicology,
1st
Semester
05/06/18
1

2. Contents
05/06/18 2

3. Definition
Peptic Ulcer is a sore on the lining of stomach &
first part of small intestine.
05/06/18 3

4. Why Peptic Ulcer occurs??
05/06/18 4

5. REGULATION OF GASTRIC ACID
SECRETION
05/06/18 5

6. Causes of PUD
05/06/18 6

7. PATHOGENESIS
H. Pylori
Inflammation
Catalases Urease Oxidase Hydrogenase
Urea Ammonia + 2CO2
Ammonium Chloride
Glycoprotein in
gastric mucous
Expose
Epithelium
Superoxide radical
Inflammation
Oxidizing molecular
hydrogen
By Intestinal bacteria
05/06/18 7

8. Biochemical Produced By H. Pylori
 Vacuolating toxin (VacA)
Damage epithelial cells & causes apoptosis
 HCP(Helicobacter cysteine-rich protein)
It triggers immune response & causes Inflammation
 EGFR(epidermal growth factor receptor)
It activated by H. Pylori and altered the signal transduction &gene
expression in host cells
05/06/18 8

9. Genes involved in pathogenesis
 In 2010 studied that it present a comprehensive analysis and it
confirmed that acid induction of major virulence is due to the
gene
A.Cag PAI (Pathogenicity island)
 It contains 30 genes
 Steps
1. Attachment of H. Pylori to epithelium
2. Type IV secretion system expressed by Cag PAI
3. Inject an inflammatory sensor NOD1
4. Stimulation of cytokines & It promote inflammation
B. Cag A (Cytotoxic associated gene A)
 Breaks the cell integrity junction and also stimulate cytokine
production within cell05/06/18 9

10. Diagnosis OfDiagnosis Of HH.. PyloriPylori
05/06/18 10

11. Oxidative stress Induced Ulcer
05/06/18 11
Oxidative
stress
Cholinergic
stimulation
Gastric motility
increases
Muscular
contraction &
vasoconstriction
Muscular
ischemia &
acidosis
Hydroxyl ion
generation
increases
GIT
inflammation

12. NSAID induced ulcer
05/06/18 12
COX
NSAIDNSAID
Arachidonic
acid
Prostaglandin (G2 & I2)
Level decreases
Inflammation
-

13. SmokingSmoking
05/06/1805/06/18 1313

14. Zollinger – Ellison syndrome
 Tumors of the gastrin secreting endocrine cells of the pancreas or, less
frequently, the duodenal wall.
 Leads to excessive acid production by the G.I. tract.
 Development of serious and aggressive peptic ulcers.
 Complications can include perforation, hemorrhage and obstruction.
05/06/18 14

15. Treatment
1. Drugs that inhibit gastric acid secretion
I. H2 receptor blockers: Cimetidine, Ranitidine, Famotidine
II. Proton pump inhibitors: Omeprazole, Pantoprazole, esomeprazole
III. Anticholinergic : Pirenzepine
IV. Prostaglandin analogues: Misoprostol
2. Drugs that neutralize gastric acid (Antacids)
I. Systemic: Sodium bicarbonate, sodium citrate
II. Non systemic: Mag. Trisilicate, Aluminium hydroxide gel, Magaldrate
3. Ulcer protective
I. Sucralfate
II. Colloidal Bismuth Sulfate (CBS)
4. Anti H. Pylori drugs
I. Amoxicillin, Clarithromycin, Metronidazole, Tinidazole, Tetracycline
05/06/18 15

16. New molecular target
 Carbonic anhydrase inhibitors & Sulphonamide drugs
 Calcium channel blocker
 Gastrin receptor antagonist
 Bombesin receptor antagonist
 Urease enzyme target
05/06/18 16

17. Carbonic anhydrase inhibitors & Sulfonamide
drugs
05/06/18 17
 A new target for developing sulfonamide& sulfamate gastric drug
Alpha carbonic anhydrase inhibiter CA-I & CA-IV responsible for HCl secretion
 in vivo results performed in humans shows omeprazole inhibit not only H+/k ATPase but also CA-
I & CA-IV
 further gastric acid secretion is inhibited in humans after oral administration of acetazolamide dose
of 25mg/kg
 acetazolamide exhibits antiulcer action in acute experiments because inhibition of CA, but its
effect on gastric ATPase is not clear.
SULFONAMIDE
It is a wide class inhibiters of the zinc enzyme CA a library sulfonamide are investigated for the
inhibition of H.pylori CA,
Whereas new derivative have been Investigating by attaching 4-tert-butyl-phenylcarboxamido to benzene
sulfonamide.

18. Cont…
 All types of activity for inhibition of hpCA have been detected
• Dorzolamide and simple 4-substituted benzene sulfonamides were weak
Inhibitors (KI 873-4360 nM)
• Sulfanilamide, orthanilamide, and indisulam showed better activity (KI 413-
640 nM)
• Methazolamide, Brinzolamide,Topiramate, Zonisamide, acted as medium-potency
inhibitors (KI 105-378nM).
• Clinically used inhibitors, such as In vivo results with the data obtained it
suggest that gastric mucosa of CA-I&CA-IV inhibition is induced by
sulfonamide and it is active form of omeprazole
• therefore hpCA is essential for the survival of the pathogenic acid, it might be
used as a new pharmacologic tool in the management of drug-resistant H.
Pylori.
05/06/18 18

19. Calcium channel blocker
Hypercalcemia
Increase in release of Histamine, Acetylcholine, Gastrin & HCl Acid
CalciumCalcium
Gastric acid Secretion
Verapamil &
Gallopamil ,
Nifedipine,
Diltiazem
--
05/06/18 19

20. Gastrin Receptor Antagonist
 Gastrin low in fasting & take meal increase in level 15-30min.
 CCK which has the C-terminal penta peptide in common with gastrin in
isolated parietal cells.
 CCK -1 receptor produce somatostatin from D cells .
 Gastrin mainly act on CCK-2 receptor
 CCK -2 non peptide receptor antagonist have been identified includes
 Proglumide
 Spiroglumide
 L-365260
 YM-022
 RP-73870
 S-0509
05/06/18 20

21. Gastrin releasing peptide
Bombesin receptor antagonist
 The receptor found in the smooth muscle cells of the intestinal tract.
 In humans , exogenous administration of these peptides release most GIT
hormones including Gastrin & Somatostatin , therefore the effect of
intravenous GRP on gastric secretion is the sum of direct &indirect
stimulatory as well as inhibitory mechanism.
 BIM-26226
 It is potent and specific antagonist for GRP- Bombesin receptor.
 The potency of BIM-26226 was demonstrated by complete inhibition of gastric acid
output and plasma gastric release stimulated by supramaximal doses of IV GRP.
05/06/18 21

22. Future prospective
 To understand better the physiology of H. Pylori & its pathogenic
interaction with the host , thus the identification of new target for
therapeutic aspects.
 Reversible proton pump antagonist – Timoprazole
 Cytoprotective agent – Rebamipide
 H. Pylori Vaccination
 To identify protective antigenic determinants of known structure, & how to
stimulate the common mucosal immune system.
05/06/18 22

23. References
• Nishimori I, Minakuchi T, Morimoto K, Sano S, Onishi S, Takeuchi H,
Vullo D, Scozzafava A, Supuran CT. Carbonic anhydrase inhibitors: DNA
cloning and inhibition studies of the α-carbonic anhydrase from
Helicobacter pylori, a new target for developing sulfonamide and
sulfamate gastric drugs. Journal of medicinal chemistry. 2006 Mar
23;49(6):2117-26.
• Lehmann FS, Hildebrand P, Beglinger C. New molecular targets for
treatment of peptic ulcer disease. Drugs. 2003 Sep 1;63(17):1785-97.
• Rang & Dale's Pharmacology page no 379
05/06/18 23

24. 05/06/18 24