SAFETY PHARMACOLOGY STUDIES final .pptx

toxicology Screening methods
Gastrointestinal tract

1. SAFETY PHARMACOLOGY STUDIES : GI Presented by : Rushikesh S Tidake M.PHARM II SEM Pharmacology RSCP , BULDANA 1

2. Safety Pharmacology Study Objectives of the guidelines – These guidelines were developed to help protect clinical trails participants & patients receiving marketed products from potential adverse effects of pharmaceutical , while avoiding unnecessary use of animal & other resources . 2

3. Gastrointestinal Safety Pharmacology 2-3% discontinuation of drug project Related ADRs & AEs are not life threatening but hampers quality of life for patients 18% of total ADRs Overuse of NSAIDs in US is a reason behind >1,00,000 hospitalization & 17000 deaths in year (2003) Hence there is a need for improved & more extensive GI screening 3

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5. Methods to asses drugs effects on GI function Assessment of gastric emptying & intestinal motility Assessment of Gastric Secretions Models of Nausea & Emesis Models of Gastrointestinal Absorption 5

6. Assessment of gastric Emptying & intestinal Motility In Vitro mode ls : subcellular , cellular, tissue, or whole organ to study the pharmacological effects and mechanism of action of drugs on GIT Stomachs or isolated segments of GIT from small laboratory animals can be suspended in organ baths to investigate the mechanisms underlying a novel drug target and to validate physiological or pharmacological responses. Typically muscular strips or whole segments from the GIT are suspended in organ baths containing a suitable nutrient solution held at 37⁰ C and gassed with carbogen study the enteric nerves is done by measuring changes in motility caused by electrical field stimulation (EFS) 6

7. In Silico Organ Modeling : Computational fluid dynamic (CFD) techniques ( Ferrua and Singh 2010) predict the dynamic effects of luminal contents on Gl motility, luminal content mixing, and propulsion This model showed a complex and highly three-dimensional flow profile during gastric contraction 7

8. In Vivo Models In rodents by administering meals containing markers such as phenol red, barium sulfate (BaSO4), or charcoal, subsequent to the administration of the test compound. The test meals can be used either as an indicator of liquid (phenol red) or solid transport (charcoal, BaSO4). For gastric emptying assessment, the stomach is weighed, after definite time as its weight directly correlates with its content. Any difference in the gastric weight between treatment groups indicates altered gastric emptying. 8

9. For intestinal motility assessment, the intestines are removed (usually from duodenum to ileum) and the length of intestine filled with charcoal or BaSO4 is measured and compared to the full gut length by visual inspection. The percentage of intestinal length filled by the test meal is proportional to the intestinal transit. Any difference between treatment groups indicates an alteration in the intestinal motility (increase or decrease). With phenol red, the intestinal transit is evaluated by measuring the spectral absorbance in specific subparts of the gut. 9

10. Assessment of Gastric Secretion In Vitro Models performed on mucosal cell preparation from stomach mucosa obtained by enzyme dispersion and separated by centrifugation to separate parietal cells (H+ secreting cells) Measures the H+ concentration and pepsin secretion in the gastric effluent 10

11. In Vivo Models Pyloric ligation method Rats fasted for 24hrs prior ligation Randomly divided into 5 groups of 3 animal 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. 11

12. Models of Nausea and Emesis In vivo models assessed in conscious animal models Ferrets and dogs are typically considered to be the best species for the evaluation of emesis, dogs being usually more sensitive to emetic stimuli compared to humans Rats and mice are not able to vomit, but can display some behavioural reactions that can represent nausea, such as gasping or pica Emesis evaluation in dogs, ferrets, or nonhuman primates usually consists of visual recordings of retching and vomiting events, and possibly premonitory signs such a licking, during a defined period following compound administration The number of events and the latency are the most frequent parameters reported. 12

13. Models of Gastrointestinal Absorption In vitro models Cell culture-based permeability screening models are used for the rapid assessment intestinal permeability of drug candidates The human monolayer of colon adenocarcinoma cells (Caco-2) model used to predict the intestinal absorption of orally administered drugs or measurement of flux of a marker molecule or active ion transport across epithelial cells. NSAID-induced mucosal damage has been demonstrated in gastric mucosa 13

14. In vivo models In situ absorption models have been used in the anesthetized rat, with intraluminal administration of the test drug and collection of inflow and outflow of an isolated segment of the gut In parallel, arterial blood is sampled and the disappearance rate of the substance is evaluated 14

15. THANK YOU 15