Human Reproduction, Vol. 16, No. 8, 1732-1735,
August 2001
© 2001 European Society of Human Reproduction and Embryology
Prevention of postoperative adhesion formation in rat uterine horn model by nimesulide: a selective COX-2 inhibitor
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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BACKGROUND: Pelvic surgery is one of the main causes of intraperitoneal (i.p.) adhesions that create various medical problems including pelvic pain, bowel obstructions and female infertility. A rat model was used to investigate the efficacy of nimesulide, a selective cyclooxygenase-2 inhibitor, in the prevention of adhesion formation. METHODS: Fifty Wistar-Albino rats underwent bilateral uterine horn injury with a unipolar cautery. Study groups were as follows: (i) control group, no adjuvant therapy; (ii) i.p. Ringer's lactate group, 2 ml Ringer's lactate solution was instilled i.p.; (iii) i.p. Ringer's lactate plus nimesulide group, 1 ml Ringer's lactate plus 1 ml nimesulide (0.5 mg/ml) were given i.p.; (iv) intramuscular (i.m.) nimesulide group, 1 ml i.m. nimesulide (0.5 mg/ml) was given preoperatively for 5 days; and (v) i.p. nimesulide group, 1 ml nimesulide (0.5 mg/ml) was instilled i.p. At the end of the study all animals were killed, and a standard adhesion scoring system was applied by a blinded examiner. RESULTS: The mean adhesion extent in study groups was as follows: 1.33 ± 0.76 in control group, 1.40 ± 0.90 in i.p. Ringer's lactate group, 0.75 ± 0.70 in i.p. Ringer's lactate plus nimesulide group, 0.25 ± 0.44 in i.m. nimesulide group and 0.31 ± 0.70 in i.p. nimesulide group. The mean ± SD adhesion severities of control, i.p. Ringer's lactate, i.p. Ringer's lactate plus nimesulide, i.m. nimesulide, and i.p. nimesulide groups were 0.58 ± 0.35, 0.30 ± 0.41, 0.27 ± 0.3, 0.12 ± 0.28 and 0.15 ± 0.35 respectively. The lowest adhesions were found in the groups treated with nimesulide i.m. and nimesulide i.p. ( P < 0.05). CONCLUSIONS: This study showed that preoperative i.m. or postoperative i.p. administration of nimesulide to the site of injury reduced the formation of postoperative adhesions in a rat uterine horn model.
Key words: adhesion / nimesulide / postoperative / rat / surgery
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Introduction |
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Postoperative pelvic adhesions are a significant cause of morbidity among women of reproductive age. These adhesions create various medical problems including infertility and chronic pelvic pain, and increase health expenses (Diamond and Schwartz, 1998
). Adhesion formation and reformation are still an unavoidable event in reproductive pelvic surgery in spite of modern surgical techniques. In order to prevent postoperative adhesions, many adjuvants have been used in animal models and in the clinical trials (DeCherney and diZerega, 1997). Today barrier methods are the only widespread intervention in clinical use with supporting data. (diZerega-1996; Keckstein et al., 1996; Haney and Doty, 1998; Sawada et al., 2000). In addition to the barrier methods, separating injured peritoneal surfaces physically, several agents have been tested for their ability to modify the inflammatory–coagulation cascade of events following peritoneal injury. These agents include glucocorticoids, non-steroidal anti-inflammatory drugs (NSAID), procoagulant solutions, heparin, and fibrinolytics such as the tissue plasminogen activator. Up to now, no agent has been shown to consistently block adhesion formation.
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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Fifty female Wistar-Albino rats, weighing 200–220 g, were used. They were housed five animals to a cage, with the appropriate diet and water provided ad libitum . All rats were observed for several days to ascertain health before operations. All procedures were approved by the Animal Care and Use Committee of the Cumhuriyet University.
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 4–0 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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Five of the rats died 2 days after the operation and were excluded from the study: one of them in the control group and two in the i.m. nimesulide group and two in i.p. nimesulide group. The remaining 45 rats recovered without incident after operation and resumed preoperative physical activity and feeding patterns postoperatively.
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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The mean ± SD extent score of adhesions in control, i.p. Ringer's lactate, i.p. Ringer's lactate plus nimesulide, i.m. nimesulide and i.p. nimesulide groups was recorded as 1.33 ± 0.76, 1.40 ± 0.90, 0.75 ± 0.70, 0.25 ± 0.44 and 0.31 ± 0.70 respectively. As shown in Table I
, the extent score of adhesions was significantly lower in i.m. and i.p. nimesulide groups than those of control and i.p. Ringer's lactate groups. Although i.p. Ringer's lactate plus nimesulide group appeared to have decreased extent score of adhesions more than those of the control and i.p. Ringer's lactate groups, the difference was not significant. The mean ± SD severity score of adhesions in the study groups was as follows: 0.58 ± 0.35 in control group, 0.30 ± 0.41 in i.p. Ringer's lactate group, 0.27 ± 0.30 in i.p. Ringer's lactate plus nimesulide group, 0.12 ± 0.28 in i.m. nimesulide group, and 0.15 ± 0.35 in i.p. nimesulide group. The severity score of adhesions was significantly lower in i.m. and i.p. nimesulide groups than those of control group (Table I ). Although the severity score of adhesions was lower in i.p. Ringer's lactate and i.p. Ringer's lactate plus nimesulide groups than that of the control group, there was no statistically significant difference. |
Discussion |
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Nimesulide is a non-acidic NSAID and exerts its pharmacological activity through various mechanisms of action. The most important mechanism concerns the selective inhibition of COX-2. This selective inhibition of COX-2 reduces the production of pro-inflammatory prostaglandins, and may provide beneficial effects in inflammation (Bernareggi, 1998
). Inflammation is the initial response to peritoneal injury that leads to extravasations of serum and cellular elements. The site of peritoneal injury is covered predominantly by polymorphonuclear cells entangled in fibrin strands, which are soon outnumbered by macrophages. When normal fibrinolysis occurs, islands of mesothelial cells proliferate throughout the injury site and completely cover the defect within 4–5 days (Raftery, 1973). If normal fibrinolysis is inhibited by several factors, macrophages persist and fibroblasts proliferate at this site. Within 5 days, the fibrin network between adherent structures is replaced by fibrous adhesions of bundles of collagen and fibroblasts (Milligan and Raftery, 1974). It has been found that various inflammatory mediators such as prostaglandins (PGF 2
and PGE 2 ) might play an important role in the process of adhesion formation (Golan et al., 1990, 1991). In another study (Golan et al., 1995) it was observed that systemic administration of aspirin during the 8–96 h of acute adhesion-inducing abdominal surgery in their rat models was effective in limiting postoperative adhesion formation. They suggest that this effect might be attributed to the ability of aspirin to selectively inhibit thromboxane A 2 production. However, the use of aspirin during the intra- or postoperative period is not advised, since it may induce bleeding due to its prolongation of bleeding time by inhibiting platelet aggregation. Inhibition of adhesion formation was observed when meclofenamate (NSAID) was used in combination with a 32% dextran-70 solution in the animal model (Cofer et al., 1994). In one study (Siegler, 1980), ibuprofen appeared to inhibit the formation of significant adhesions as compared with adhesion formation in untreated control animals.
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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3 To whom correspondence should be addressed. E-mail: tguvenal{at}ttnet.net.tr
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Submitted on January 9, 2001; accepted on April 17, 2001.
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