الفهرس 
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Abstract
Leflunomide (Avara) is an immunomodulating agent and disease modifying antirheumatic drug with anti-inflammatory and immunosuppressive activity. It is used for treatment of rheumatoid arthritis. It has multiple side effects as diarrhea, nausea, vomiting, mouth ulcers, skin rash, alopecia, minor infections, mild increase in blood pressure and elevated liver enzymes.
Ranitidine, Histamine H2-receptor antagonist, is used to treat gastro –intestinal disorders such as peptic or duodenal ulcers.
This work focuses on the possible protective effect of Ranitidine against the injurious effects of leflunomide on gastric pyloric mucosa of adult male albino rat.
Materials and Methods
Fifty adult male albino rats weighting 100-150gm. were used in this study and were randomly divided into four groups.
• Group I (control):
10 rats received 2ml distilled water by oral route for 4 weeks and served as -ve control.
• Group II (control):
10 rats received ranitidine at a dose of 20mg/kg b.w/ day by I.m injection for 4 weeks and served as + ve control group.
• Group III (Leflunomide treated):
20 rats received leflunomide at a dose of 10 mg/kg b.w/ day dissolved in 2ml distilled water by oral route for 4 weeks.
Rats were divided into 2 equal subgroups:
• Group IIIA: 10 rats were sacrificed after 4 weeks.
• Group IIIB: 10 rats will be kept without treatment for another 2 weeks and served as recovery group.
• Group IV (leflunomide and ranitidine treated) :
10 rats received leflunomide and ranitidine at the same previous doses for 4 weeks.
Leflunomide is available in the form of Avara tablets. It is manufactured by Sanofi Aventis Pharm .The tablet contains 10mg of active drug. Each tablet suspended in 10ml saline and given orally by modified plastic syringe to the animals.
Ranitidine is available in the form of Zantac. It is manufactured by GlaxoSmithKline Company. It is found in the form of tablets (150mg and 300mg) and ampules (2ml contains 50mg). It is given by injection by insulin syringe to the animals.
At the end of each detected period, rats were sacrificed then tissue samples were obtained and prepared for electron microscopy and for histological histochemical and immuno histo-chemical studies.
Results, Discussion and Conclusion
• Group I (control group)
The histological and histochemical studies of the control group showed the normal histological and ultrastructure picture of the pyloric gastric glands. There were minimal collagen fibers in the lamina propria and submucosa. Strong PAS positive reaction was observed in the mucus coat and in the mucus neck cells. While the basal parts of the glands showed negative reaction.
The immune-histochemical study, showed negative immune-reactivity for caspase -3 in the cells lining gastric glands and strong immunoreactivity for PCNA.
2- Groups II (Ranitidine treated group)
A histological and histochemical study, examination of pyloric mucosa of rats of this group was more or less similar to the control group with intact surface epithelium. Also, there were minimal collagen fibers in the lamina propria and submucosa. This group showed strong PAS positive reaction. While the immune histochemical study of these group showed negative immune-reactivity for caspase -3 in the cells lining gastric glands and strong immune-reactivity for PCNA.
3-Group IIIA (Avara treated group)
The histological and histochemical studies of this group revealed the presence of wide areas of epithelial discontinuity with surface cellular loss (ulcer). Some parietal cells appeared degenerated and detached from their basement membrane.
There were marked cellular infiltration in the lamina propria and submucosa. This is due to inhibition of the production of mucus layer by leflunomide, so mucosa became exposed to the effect of acid and proteolytic enzymes with subsequent bacterial invasion of bacteria which were chemotactic for neutrophil, lymphocyte and macrophage.
An increase in collagen fibers in the sub mucosa and lamina propria was observed .
Electron microscopic examination of the gastric pyloric glands of this group confirmed the histological findings and showed the mucus neck cells with highly indented nucleus and their cytoplasm containing heterogeneous mucus secretory granules and cytoplasmic vacuoles.
The parietal cells showed highly shrunken nucleus with irregular nuclear membrane and excessive heterochromatin. Their cytoplasm contained swollen mitochondria and cytoplasmic vacuoles. The intracellular canaliculi showed huge dilatation with disruption of microvilli. Weak PAS reaction in the mucus coat and in the upper part of the glands was observed. These findings attributed to the more damage to the mucus secreting cells of the gastric mucosa by the action of leflunomide. AS regard the immunohistochemical study, sections of this group showed strong positive immunoreactivity for caspase-3 in the cells lining gastric glands, and weak reaction for PCNA.
4-Group IIIB (after two weeks recovery)
Histological and histochemical studies, examination of pyloric mucosa of rats of this group showed small amount of epithelial exfoliation and desquamation .There were slight increase in the amount of collagen fibers in the lamina propria and submucosa. Mild PAS positive reaction was observed in the mucus coat which extends to fill the gastric pits.
Immuno histochemical study of this group showed moderate immunoreactivity for caspase-3 in the cells lining gastric glands and moderate PCNA immunoreactivity for the nuclei.
5-Group IV (avara and ranitidine treated group)
The histological and histochemical studies, examination of sections of the pyloric mucosa of rats of these groups was more or less similar to the control group. There were minimal amounts of collagen fibers in the lamina propria and submucosa. Strong PAS positive reaction for the mucosal coat and mucous neck cells. While the immunohistochemical study of these groups showed negative immunoreactivity for caspase -3 in the cells lining gastric glands and strong PCNA reaction.
We can conclude that any patient taking DMARDs must be made aware of potentially fatal adverse effects, give informed consent, and then be closely monitored for hepatic, gastrointestinal, hematologic, infectious, pulmonary, dermatologic, and neurologic adverse effects.