1 Departments of Obstetrics and Gynecology and 2 Pharmacology, Cumhuriyet University School of Medicine, 58140 Sivas, Turkey
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Abstract |
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Key words: adhesion / nimesulide / postoperative / rat / surgery
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Introduction |
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Adhesions are the results of the inflammatory response to tissue trauma, infection, haemorrhage, or foreign materials in the peritoneal space. In virtually all models studied, cyclo-oxygenase-2 ( COX-2 ) expression increases in response to inflammatory stimuli and other types of tissue damage and causes elevated levels of local prostaglandins. NSAID, which inhibit prostaglandin production, have been shown to decrease adhesion formation (Siegler et al., 1980; Cofer et al., 1994
; Rodgers et al., 1997
, 1998
). All currently available NSAID inhibit both cyclo-oxygenase-1 (COX-1) and COX-2 isoforms. The efficacy of new COX-2-selective anti-inflammatory drugs was not established for adhesion prevention.
In the present study, we investigated the effect of nimesulide (4-nitro-2-phenoxymethanesulphonanilide), a selective COX-2 inhibitor, on the adhesion prevention in a rat uterine horn model.
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Materials and methods |
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Before operations, rats were randomly assigned into five groups each consisting of ten rats. Each rat was anaesthetized with ketamine hydrochloride (40 mg/kg intravenously). Before surgery, the abdomen was shaved and prepared with a povidone iodine solution. Using sterile technique, a 3 cm vertical midline incision was made and both uterine horns were exposed, and then a 2 cm segment of each uterine horn was traumatized in ten spots on the antimesenteric surface using unipolar cautery. Care was taken to avoid gross bleeding from injured sites. Handling of other tissues was minimized. The incision was closed in a single layer, excluding the peritoneum, with a running 40 monofilament delayed absorbable suture. Before the final throw of the abdominal closure, no adjuvant therapy was given to the rats in control group; and immediately after injury, 2 ml of Ringer's lactate solution was instilled onto each uterine horn of the rats in intraperitoneal (i.p.) Ringer's lactate group; 1 ml of Ringer's lactate solution plus 1 ml of nimesulide (Sigma, St Louis, MO, USA) (0.5 mg/ml) was instilled onto each uterine horn of the rats in i.p. Ringer's lactate plus nimesulide group; 1 ml of nimesulide (0.5 mg/ml) was given intramuscularly (i.m.) two times daily for 5 days before operation to the rats in i.m. nimesulide group and no i.p. adjuvant was used after injury in this group; and only 1 ml of nimesulide was instilled onto each uterine horn immediately after injury to the rats in i.p. nimesulide group.
The total operative time was less than 10 min. Rats were allowed to recover for 3 weeks. On postoperative day 21 the animals were killed by cervical dislocation. The previous midline abdominal incisions were visually inspected for integrity. A transverse subcostal incision was made above the cephalad extent of the midline laparotomy site, and the abdominal cavity was inspected for the presence of adhesions. The extent and severity of adhesions in the operation site for each uterine horn were evaluated with a published scoring system (Linsky et al., 1987) and recorded by an investigator blinded to the treatment groups. The extent of adhesions was evaluated as follows: 0, no adhesion; 1, 25% of traumatized area; 2, 50% of traumatized area; 3, total involvement. The severity of adhesions was measured as follows: 0, no resistance to separation; 0.5, some resistance (moderate force required); 1, sharp dissection needed.
The extent and severity scores of adhesions were compared between left and right uterine horns of each study group with a dependent t -test. Analysis of the extent and severity scores of adhesions of all uterine horns was performed using a one-way analysis of variance (ANOVA) to detect significant differences among study groups. Post-hoc comparisons on parameters found to be significant by ANOVA were performed by using the Bonferroni procedure (pairwise comparisons of all medications). The level of significance was set at P < 0.05 and with Bonferroni correction it was adjusted to P < 0.025.
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Results |
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We found no significant difference between adhesions scores of left and right uterine horns of each study group. Table I shows the extent and severity of adhesions in control, i.p. Ringer's lactate, i.p. Ringer's lactate plus nimesulide, i.m. nimesulide and i.p. nimesulide groups.
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Discussion |
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During peritoneal repair, the cellular events appear to be coordinated at least in part by cytokines that function as chemoattractants and immunostimulants. Interleukin-6 (IL-6) (Saba et al., 1996), transforming growth factor-
, epidermal growth factor (Chegini et al., 1994a
), transforming growth factor-ß (Williams et al., 1992
; Chegini et al., 1994b
), and interleukin-1
(McBride et al., 1989
; Hershlag et al., 1991
) have been found to be adhesiogenic, whereas antibodies to IL-6 (Saba et al., 1996
), tumour necrosis factor-
(TNF-
) and interleukin-1 (IL-1) (Kaidi et al., 1995
) reduce postoperative adhesion formation. It has been demonstrated that COX-2 expression is highly induced by a number of cytokines, including IL-1, TNF-
, and other stimuli associated with inflammation and growth (Crofford et al., 1994
, 1997
). Nimesulide at therapeutic concentrations is a potent inhibitor of IL-6 production (Henrotin, 1999). Inhibitor effect of nimesulide on TNF-
production may also contribute to its anti-inflammatory properties.
In this study, we found a significant reduction in postoperative adhesion formations in rats treated with i.m. or i.p. nimesulide administration. There may be multiple mechanisms by which nimesulide can reduce adhesion formation. First, the reduction in adhesion formation with nimesulide can be related to its anti-prostaglandin activity. Second, nimesulide can reduce the production of adhesiogenic cytokines. The effect of nimesulide is possibly working systemically, not through local action, because the preventive effect is the same in both methods of i.m. and i.p. administration. With these combined effects, nimesulide can be used to prevent adhesion formation after peritoneal surgical procedures. Also, there is no effect of nimesulide on bleeding time, platelet count and platelet aggregation, thromboplastin time (prothrombin time), activated partial thromboplastin time and coagulation factors in humans (Marbet et al., 1998). We found no specific cause for postoperative deaths in control, i.m. nimesulide, and i.p. nimesulide groups. It is not clear whether these deaths are caused by toxic effect of nimesulide because it has been previously demonstrated that nimesulide has a low toxicity by many animal and human studies (Fusetti et al., 1993
; Warrington et al., 1993
; Davies et al., 2000
; Grigsby et al., 2000
).
Rats treated with i.p. Ringer's lactate plus nimesulide had fewer adhesions than those of the control and i.p. Ringer's lactate groups, but the reduction of adhesion formation was not significantly different. The instillation of crystalloid solution such as Ringer's lactate in the peritoneal cavity at the end of surgical procedures to prevent adhesions is debated. Ringer's lactate instillation has been found to be effective in decreasing adhesion formation in rat models (Pagidas and Tulandi, 1992; Ustun et al., 1998
). Despite these findings, it has been shown that this solution has no beneficial effect in reducing postoperative adhesions (Naether and Fischer, 1993
; Gurgan et al., 1996
). The possible causes of its lack of anti-adhesive effect are rapid absorption from peritoneal cavity and dilution of opsonic protein in peritoneal cavity (DeCherney and diZerega, 1997
).
To the best of our knowledge, this study is the first in prevention of postoperative adhesion by a selective COX-2 inhibitor. In summary, these experimental results suggest that nimesulide has promise as a clinical anti-adhesion agent and should be evaluated further in experimental animal models and human trials.
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Notes |
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References |
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Submitted on January 9, 2001; accepted on April 17, 2001.