Wednesday, November 28, 2018

Screening Method of Anti Ulcer Drugs on Animal Model

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Peptic ulcer  is one of the most prevalent  chronic  gastrointestinal disorder.
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Ulcer imbalance chart 

Regulation of Acid Secretion

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Regulation of acid secretion

Approaches to Treatment Ulcer 

  • Reduction of gastric acid secretion
  • Neutralization of gastric acid 
  • Ulcer protective
  • Anti H. Pylori drugs

Screening of Anti Ulcer Agents

Requirements of an ideal model

  • Should be simple, reproducible & allow for easy quantification of results.
  • Should induce characteristic ulceration in specific locations.
  • Should involve different mechanisms by which ulceration is produced.
  • Ulcers produced should not spontaneously heal during observation period. 
  • Ideal animal for screening anti ulcer agents…..?
  • Continuous secretion of acid
  • Glandular portion of rat stomach analogous to body of stomach in man both anatomically and functionally.
  • Being omnivorous resembles man nutritionally
Guinea pigs are used when histamine is used to induce ulcers.

Animal Models for Screening

  1. Pylorus ligation induced gastric ulcers in rats (Shay rat)
  2. Drug (NSAID ) induced gastric ulcers in rats
  3. Ethanol induced gastric ulcers in rats
  4. Acetic acid induced  gastric ulcers in rats
  5. Stress induced ulcers in rats
  6. Histamine induced duodenal ulcers in guinea pigs.

Pylorus Ligation Induced Ulcers in Rats

Pyloric ligation  in rats leads to accumulation of gastric acid in the stomach leading to acute gastric ulceration. First demonstrated by Shay and co-workers in 1945.

Requirements

  • Albino Wistar Rats (150-200 g)

  • Drugs :       
                           Ether (Anesthetic)
                          Saline (control) 
                          Omeprazole (standard) 
                          Test drug (3 different concentrations x, 2x, 4x)
  • Reagents :  
                          NaOH (0.01N)
                          Topfer’s reagent (dimethyl amino azo benzene)
                          Phenolphthalein

  • Dissecting microscope (10x magnification), pH meter, burette, surgical instruments.

Procedure of pylorus ligation 

  • Rats fasted for 24 hrs prior to pyloric ligation. 
  • Randomly divided into 5 groups of 3 animals each.

                                     Group I   : Control vehicle
                                     Group II  : Standard drug (Omeprazole)
                                     Group III : ‘x’ concentration of test drug
                                     Group IV : ‘2x’ concentration of test drug
                                     Group V : ‘ 4x’ concentration of test drug
  • Drugs administered once for 2 days and 30 mins prior to ligation
  • Rats anesthetized with ether.
  • Pyloric ligation procedure done.
  • Rats  placed in separate cages and allowed to recover.
  • 19 hrs after pyloric ligation, animals sacrificed by decapitation.

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Isolated rat stomach 
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  • Ulcer index is calculated.


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Ulcer index formula 

Intensity of ulcers is scored as below :-


          0 – normal stomach
          1 – superficial mucosal erosion
          2 – deep ulcer
          3 – penetrated or perforated ulcer


Contents of the stomach analyzed for ulcer  

  • Volume 
  • pH : pH of it is noted with pH meter.
  • Free acidity  and total acidity : Titration of the solution against 0.01N NaOH done using Topfer’s reagent and phenolphthalein as indicators. Volume of NaOH which turns the solution to yellowish orange corresponds to free acidity. Titration is continued  till solution turns pink. The total volume of NaOH used up corresponds to total acidity. 

                              Acidity(meq/l/100g) =  (Vol of NaOH X Normality x 100)/0.1

  • Mucin and prostaglandin levels can be estimated to detect cytoprotective effects.           

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Inference

Ulcer index of test drug  compared with control group to detect anti-ulcer effect of test drug. If present, it is compared with that of standard group.

Other parameters help to infer the mechanism of ulcer protection. Examples are given below - 
  •  Decrease in vol, free & total acidity    :  antisecretory action 
  •  Rise in pH                                           :    acid neutralizing action
  •  Increase in mucin, PGs                      :   cytoprotective effect.

Drug induced ulcers in rats

Gastric ulceration is produced in rats by certain drugs. The ability of the test drug to protect against the ulceration is observed.

NSAIDs  like Aspirin, Indomethacin, Ibuprofen

Inhibition of endogenous prostaglandin production and consequent loss of gastric mucosal defence. Important model for identifying drugs that could be effective in NSAIDs induced gastropathy.

Procedure of drug induced ulcer 

  • Rats fasted for 24 hours in separate cages and randomly divided into 5 groups
  • The control, standard, test drug are administered once daily for 2 days and 30 mins prior to administration of ulcerogenic agent.
  • Ulcerogens administered by oral gavage. 

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Oral gavage
  • Rats sacrificed  4 - 6 hours later
  • Ulcer index, analysis of stomach contents done.

Ethanol induced gastric ulcer in rats

Ethanol damages superficial epithelial layers & inhibits prostaglandin release. An agent that protects against ethanol induced ulcers might be cytoprotective & exert its action by stimulating release of endogenous prostaglandins & mucin. However, anti secretory agents also are effective in this model.

Acetic acid induced gastric ulcers in rats

Model mimics the chronic pattern seen with peptic ulcer.

Procedure of acetic acid induced ulcer

  • Overnight fasted rats operated under ether anesthesia
  • Anterior & posterior walls of stomach clamped with forceps
  • 0.2 ml of 40% acetic acid injected into clamped portion.
  • After 45 secs , acid removed.
  • Deep round ulcers develop on the anterior & posterior walls.
  • Respective treatments( control, standard, test) started from 3rd to 10 th day. Rats sacrificed on 10th day.
  • Ulcers respond well to most  anti ulcer drugs like PPI, H2 blockers, cytoprotectives.

Stress induced ulcer in rats

Model of restraint ulcer - 
Drugs (control, standard, test) administered once daily for 2 days & 30 mins prior to applying restraint. Fasted & lightly anesthetized rats placed on galvanized steel window screen. Limbs are held together in pairs & tightened with adhesives. After 24 hrs, animal removed, sacrificed and degree of ulceration noted.

 Modified method - Water immersion induced restraint ulcer.

Histamine induced duodenal ulcers in guinea pigs

  • Guinea pigs fasted for 48 hrs.
  • Drugs (control, standard, test) once daily for 2 days & 30 mins before administration of histamine.
  • Ulceration induced by injecting 1 ml of histamine solution intraperitoneally.
  • Promethazine 5mg injected intraperitoneally  15 mins before and after histamine .
  • Animals sacrificed after 4 hrs
  • Degree of ulceration & gastric contents assessed. 

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