Pathological effect of administration Norfloxacin in stomach, intestine and skin of mice Z. waheed Coll. of Vet.Med./ Unive.

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1 Pathological effect of administration Norfloxacin in stomach, intestine and skin of mice Z. waheed Coll. of Vet.Med./ Unive. of Basrah Abstract The experimental work of this research was contain three groups of white swiss mice, the range of body weight 20-25gm.Each group was had 10 mice.the animals were grouping and the first was administrated 5-7 mg / kg of norfloxacin daily for 14 days.the second group was given semi drug and dose for 30days twice daily by mouth,and third group as a control. This study was contain adverse pathological changes reported after the long period (14/30 days ) administration of norfloxacin in stomach,intestine and skin tissue of mice. The Norfloxacin drug from Quinolone group 1-Ethyl -6 fluoro -1,4 dihydro 4 oxo 7 ( piperazin 1-yl) quinoline -3- carboxylic acid (C1 6 H18FN3O3) (1). Treatment with Norfloxacin given doses of 800 mg /kg reducing to 200mg/kg daily (4 ).In 1965 the first commercial product was nalidixic acid (first generation Quinolone). The structural changes incorporated into these new compounds enhanced pharmacodynamic characteristics and pharmacokinetic profiles. Norfloxacin is the second-generation quinolones group. It, s well absorbed in duodenum and jejunum. They have large volumes of distribution and their penetration in to different tissue and body fluids (5,6,7). The primary target of nalidixic and probably also the fluoroquinolones is 30 white mice were taken and reared in the animal house of veterinary medicine college Basrha university for 2 weeks period of exposure adaptation than we divided it 3 groups. The first group and the second were administrated 400mg /kg Norfloxacin as dissolved one tablet in the 35 ml of distal water for 14 days and 30 days respectively twice daily by the mouth. The third one as control group. During sacrificing period anesthesia was given intramuscularly 15mg/kg b.w. Ketamin followed by 5mg/kg b.w. xylazine. The Macroscopic examination were carried out pruritis and redness skin noted on the face and forearms. There were congestion Introduction Materials and Methods Result inhibit the type 2 topoisomerases,dna gyraes and topoisomerase IV.,as essential bacterial enzyme maintains super helical twist in DNA (3,8, 10 ).The most frequent adverse effects are gastro intestinal disturbances include nausea, vomiting diarrhea,abdomenal pain and dyspnea, pseudo membranous colitis has been reported rarely In addition to rash and pruritus, hyper sensitivity, type reaction affecting the skin have included photo - sensitivity,toxic epidermal necrolysis and anaphylaxis (10,11, 12, 13 ) and Therefore, a few studies on the pathological effects of administration of Norfloxacin in the organs of lab. animals (4,14,15 ). The aim of this study to identify the pathological effect of Norfloxacin after long period of treatment. animal was placed in dorsal recumbence and skin incision on was made the linea alba starting from the umbilicus back to the pubic region. The intestine, stomach and skin were washed with normal saline. Small pieces of these organs were fixed in 10% for 48hr. and trimmed to suitable sizes. Dehydrated,cleared and embedded in paraffin wax. Sectioned at 1 µm thickness stained with hematoxylin & eosin stain and examined by alight microscope (16 ). of blood vessels of the gastrointestinal tract wall especially in the second group (400 mg /kg b. w. of Norfloxacin for 30 22

2 2225 العدد/ 2 days).as well as there are slight redness in group (figer4). (figer5) there are catarrhal the skin tissue increase it s severity in the enteritis in the second group which were second group. The microscopic administration with Norfloxacin for 30 examination reveal erosion area of mucosal days (figer6). And there are atrophy of layer gastrointestinal tract (figer 1,2,3), and epidermis and the dermis had infltrated by there are infiltration of inflammatory plasma cells and eosonophil cells (figer7 ). cell.(pleomorphonuclear mainaly),in first The study was recorded the pathological changes in mice after administration of this drug by mouth {Norfloxacin (Quinolone group)}.there were pruriginous anderythematous eruptions (17,18) due to hypersensitivity reaction after adminstration of Norfloxacin colonisation resistance in a natural mucosa associated defence mechanism which protects against secondary colonisation of the gastrointestinal tract by non-commensal microorganisms the ecological balance of the indigenous oropharyneal and gastrointestinal microflora mostly anaerobic is Discussion subject to disturbance by the adminstration of antibacterial drugs leading to overgrowth of existing microorganism with natural resistance and the establishment of new resistant pathogenic species (3,4,6.19,20). these parthogenic species is resprasiple for erusion in the GIT and inflammatory process characterized by infiltration of neutrophils & mononuclear cells(19).also, there is catarrhal inflammatory lesion resulted from irritation of mucosal glands under long treatment period by Norf loxacin in the second group of mice. Fig.1. Histological section of stomach of mice, administration of Norfloxacin for 30 days. Note the sloughing of mucous layer (erosion) X10 H&E. 23

3 Fig.2. Histological section of mucous layer of mice stomach, administration of Norfloxacin for 14 days. Note erosion X 20 H&E. Fig.3. Histological section of intestine of mice, administration the drug for 30 days. Note Sloughing of mucous layer. For 30 days X10 H&E, X20H &E 24

4 Fig 4. Section of intestine &gastric. Note the infiltration of neutrophils and mononuclear cells in the mice administrated the drug for 14 days. X40 H&E. Fig 5. Histological section of gastric of second group. Note the mononuclear cells infiltration in the wall. X40 H&E 25

5 Fig.6. Histological section of intestine of second group. Note the mucinous material released along the mucosal surface of intestine by the goblet cells X20 H&E. Fig 7. Histological section of skin of second group. Note the atrophy of epidermis and there are Inflammatory cells especially mononuclear cells in the dermis X40 H&E. 26

6 2225 العدد/ 2 Refrenceses 1- British Pharmacopoeia.(1996). 31 resolvase locus in Escherichia coli thedition, London. and is the result of interaction 2- Crumplin, G.C. ; Kenwright. L. and T. Ltirst. (1964). Investigations in to the mechanism of action of the antibacterial agent Norfloxacin. J. Antimicrob. chemother. 13 (supp 1 B ) John S. Wolison J. S. and David C. Hooper. (1985). The fluoroquinolones : Structures, Mechanisms of Action and Resistance, and Spectra of acticity in Vitro. (.28), 4, Kashida, Y. and Kato, M. (1997). Characterization of fluoroquinolone- induced Achilles tendon toxicity in rats : Comparison of toxicity of 10 fluoroquinolones and effects of anti-inflammatory Compounds. Drug safety Reseearch Laboratory, Daiichi Pharmacentical o. td.dogawa, Tokyo, Japan. 5- Rothlin-RP. (1999). Quinolones : historic review, Medicine-B- Aires. 59 supp 1 : Appelbaum-PC. (1995 ). Quinolone activity against anaerobes : Microbiological aspects. Drugs 49 supp 1,2 : Bergan-T. (1995). Quinolones in the eldely. Drugs,49 supp 1,2 : Laurence,D. R. ;Bennett, P. N. andbrown, M. J. (1997). Clinical pharmacology. 8 th edition. Churchill. Livingstone,London. 9- Paton,JH. And Reeves, DS. (1992). Adverse reaction to the fluoroquinolones. Adverse Drug React Bull.,April, : Domagala,JM. (1994 ). Structureactivity and structure-side effect relation ships for the quinolone antibacterial. J. Antimicro. Chem. Other. 33 : Hojgaard,A. ; Szerlong, H. ; Tabor, C. and Kuempel, P. (1999). Norfloxacine-induced DNA cleavage occurs at the Dif 27 with topoisomerase.iv. Mo1 Microbiol. Sep.; 33 (5) : Paton,J. H. and Reeves,DS. (1991). Clinical features and management of advers effects of quinolone anti bacterial Drug Safety, 6 : Holmes, B. Brogden, RN.and Richards, DM. (1985 ). A review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 30 : Krcmery-S. ;Hromec- J. ; Tvrdikova- M. ; Hassan M. and Gulla-D. (1999). Newer quinolones in the long term prophylaxis of recurrent urinary tract infections (U T I ). Drugs, 58 supp 1, 2 : Bjornsson,E. ; Olsson, R. and Remotti, H. (2000). Norfloxacininduced eosinophilic necrotizing granulomatous nepatitis. Am-J. Gastroenterol.Dec; 95 (12) : Hadimeri,H. ;Almroth, G. and Cederbrant, A. (1997 ). Allergic nephropathy associated with Norfloxacin and Ciprofloxacin therapy Scand-J. Urd. Nephrol. Oct ; 31 (5 ) : Luna,L. G. (1968 ). Manual of Histological Staining Method of the Armed Forces Institute of Pathology 3 rd edition. USA :Mcgrew Hill Book Co. 18- Lopitaux, R. ; Hermet, R.; Sirot, J. and Terver, S. (1985 ). Tolerance dela pefloxaine an cours dutraitement d, une serie d, infections osteo- articulaires. Therapie 40 : Appelbaum. PC. (1999 ). Quinolone activity against anaerobs. Drugs,58 supp 1 2 : Huysmans, M-B. and urnidge, J-D. (1997 ). Disc susceptibility testing for thermomphilic campylobacers

7 2225 العدد/ 2. Pathology ; May 29 (2 ) :209- ecology. Drug, 58 supp 1 2 : Edlund, C.;and Nord,C. E. (1999). Effect of quinolones on intestinal التأثيرات المرضية لعقار النورفلوكساسين في المعدة واألمعاء والجلد في الفئران ز نب وح د خض ر كل ة الطب الب طري / جامعة البصرة الخالصة تم تجر ع )02( من الفئران الب ضاء تراوحت أوزانها من غم قسمت الح وانات إلى ثالث مجام ع كل مجموعة تحتوي على 02 فئران ح ث جرعت المجموعت ن األولى والثان ة 7-5 ملغم / كغم من عقار النور فلوكساس ن لمدة 04 وم وشهر على التوال مرت ن بال وم عبرر الفرم والمجموعرة الثالثرة مجموعرة السر طرة. وبعرد قترل الح وانرات المختبر رة جرر دراسة التغ رات المرض ة لنس ج معدة وأمعاء الفئران باالضافة إلى نس ج الجلد. 28