The effects of methylene blue on renal scarring due to pyelonephritis in rats

The aim of this study was to evaluate the efficiency of methylene blue (MB) in preventing renal scar formation after the induction of pyelonephritis (PNP) in a rat model with delayed antimicrobial therapy. An inoculum of the K-12 strain of Escherichia coli was injected into both kidneys. Control groups received isotonic saline instead of bacterial solution. Four equal groups were then formed: the PNP group was untreated and the PNP ciprofloxacin (CIP) treated group was treated only with CIP intraperitoneally (i.p.) starting on the third day following bacterial inoculation. In the PNP (MB)-treated group, MB was given i.p., and in the PNP MB + CIP-treated group, MB + CIP were administered i.p.. In the sixth week following bacterial inoculation, all rats were sacrificed, and both kidneys of the rats in all groups were examined biochemically and histopathologically for renal scarring. Renal scar was significant in the groups treated with MB alone or MB + CIP combination compared with untreated or antibiotic only groups. Delayed treatment with antibiotics had no effect on scarring. These results suggest that the addition of MB to the delayed antibiotic therapy might be beneficial in preventing PNP-induced oxidative renal tissue damage.     

The role of vitamin A in preventing renal scarring secondary to pyelonephritis.

OBJECTIVE: To evaluate the efficiency of exogenously administered vitamin A in preventing renal scarring caused by experimental pyelonephritis in rats. MATERIALS AND METHODS: Forty Wistar rats were injected with 0.1 mL of solution containing Escherichia coli (1010 /mL) into both renal medullae. Five equal groups were then formed: group 1 was treated only with ciprofloxacin (30 mg/kg per day, twice daily, intraperitoneally) for 5 days, starting 3 days after bacterial inoculation; in group 2, 60 kIU of vitamin A was injected intramuscularly with the bacterial inoculation; in group 3, 60 kIU of vitamin A was injected similarly, but 3 days after bacterial inoculation; in group 4, 60 kIU of vitamin A was given orally with the bacterial inoculation; and group 5 was treated with ciprofloxacin for 5 days and vitamin A intramuscularly from the third day after bacterial inoculation. All the rats were killed 6 weeks after bacterial injection; blood samples were obtained to determine serum vitamin A and beta-carotene levels, and both kidneys were examined pathologically for scarring, graded as 0 (none), 1 (mild), 2 (moderate) and 3 (severe). RESULTS: Serum vitamin A levels were higher in the rats given vitamin A (group 2-5) than in group 1, being highest in group 4, although only this group had significantly higher levels of vitamin A than group 1 (P<0.05). Histopathologically, the fibrosis was mildest in groups 2 and 4 (two of 16 kidneys grade 1), whereas it was most severe in group 1 (all 16 grade 2-3). Fibrosis was significantly less in groups 2-5 than in group 1 (P<0.05). There was a significant negative correlation between vitamin A levels and the sum of the fibrosis, inflammation and tubular atrophy scores of all rats (r=-0.391, P<0.02). beta-carotene levels were unrelated to renal scarring. CONCLUSION: The administration of vitamin A could have a role in preventing renal scar formation from pyelonephritis induced experimentally in rats.     

Preoperative oral rofecoxib and postoperative pain in patients after laparoscopic cholecystectomy: a prospective, randomized, double-blinded, placebo-controlled trial

Cyclooxygenase-2 (COX-2) inhibitors are a class of drugs that may avoid some of the side effects of narcotics and nonsteroidal anti-inflammatory drugs (NSAIDs). We performed a randomized, double-blinded, placebo-controlled trial giving a single oral dose of the COX-2 inhibitor rofecoxib 25 mg or placebo preoperatively to determine the impact upon postoperative pain, complications, narcotic use, and hospital stay after laparoscopic cholecystectomy. Investigators and patients were blinded. Pain was measured on a 10-point visual analogue scale. Eighty patients were randomized: 40 to the rofecoxib group and 40 to the placebo group. The amount of pain between the two groups postoperatively was equivalent. Pain was recorded at 1 hour, 4.03 +/- 1.93 in the rofecoxib group versus 4.38 +/- 1.34 in the placebo group (P = 0.36); at 6 hours, 3.00 +/- 1.12 in the rofecoxib group versus 2.78 +/- 0.78 in the placebo group (P = 0.42); and at 24 hours, 1.64 +/- 0.67 in the rofecoxib group versus 2.68 +/- 1.90 in the placebo group (P = 0.17). The amount of pain medication received and lengths of hospital stay was not significantly different between the two groups. Our data demonstrate no significant benefit of preoperative oral rofecoxib in patients undergoing laparoscopic cholecystectomy.     

The effects of the short-term administration of low therapeutic doses of anti-COX-2 agents on the healing of fractures. An experimental study in rabbits

We have evaluated the effect of the short-term administration of low therapeutic doses of modern COX-2 inhibitors on the healing of fractures. A total of 40 adult male New Zealand rabbits were divided into five groups. A mid-diaphyseal osteotomy of the right ulna was performed and either normal saline, prednisolone, indometacin, meloxicam or rofecoxib was administered for five days. Radiological, biomechanical and histomorphometric evaluation was performed at six weeks. In the group in which the highly selective anti-COX-2 agent, rofecoxib, was used the incidence of radiologically-incomplete union was similar to that in the control group. All the biomechanical parameters were statistically significantly lower in both the prednisolone and indometacin (p = 0.01) and in the meloxicam (p = 0.04) groups compared with the control group. Only the fracture load values were found to be statistically significantly lower (p = 0.05) in the rofecoxib group. Histomorphometric parameters were adversely affected in all groups with the specimens of the rofecoxib group showing the least negative effect. Our findings indicated that the short-term administration of low therapeutic doses of a highly selective COX-2 inhibitor had a minor negative effect on bone healing.     

Plasminogen activator inhibitor-1 regulates neutrophil influx during acute pyelonephritis

Acute pyelonephritis, frequently caused by Escherichia coli, is a substantial health problem. Plasminogen activator inhibitor type-1 (PAI-1) not only inhibits plasminogen activation but is also involved in cell migration. To determine if it has a role in host defense, we induced pyelonephritis in PAI-1 gene knockout and wild-type mice by intravesical inoculation with uropathogenic E. coli 1677. Bacterial growth was determined on blood agar plates in portions of the kidneys homogenized in sterile saline. Kidney levels of PAI-1 were increased in infected compared to control mice, suggesting a physiological role for PAI-1 during pyelonephritis. The knockout mice had significantly more bacterial outgrowth in kidney homogenates compared to the wild-type mice. Strikingly, higher colony-forming units were accompanied by increased levels of the cytokines TNF-alpha, IL-1beta, and IL-6 in the kidneys of knockout mice, but levels of the chemokines KC and MIP-2 were not different. Remarkably, plasma levels of KC were higher, but renal neutrophil influx was significantly lower, in the knockout than in the wild-type mice. Our study shows that PAI-1 is critically involved in host defense against E. coli-induced acute pyelonephritis, in part, by modulating neutrophil influx.     

Treatment of lung cancer using clinically relevant oral doses of the cyclooxygenase-2 inhibitor rofecoxib: potential value as adjuvant therapy after surgery

OBJECTIVE: To investigate the uses and limitations of cyclooxygenase- (COX) 2 inhibition using clinically relevant doses of oral rofecoxib in the treatment of murine models of non-small-cell lung cancer (NSCLC). SUMMARY BACKGROUND DATA: Overexpression of COX-2 has been reported in lung cancer. Several studies have demonstrated that high doses of COX-2 inhibitors could inhibit the growth of rodent and human lung cancer cell lines. The potential uses and limitations of COX-2 inhibition at doses equivalent to those currently approved for use in humans have not been well studied. METHODS: Three murine NSCLC cell lines were injected into the flanks of mice to establish tumor xenografts. Mice were treated orally with low doses of a COX-2 inhibitor (rofecoxib chow, 0.0075%). Mechanisms were evaluated by analysis of tumor-infiltrating lymphocytes. To study rofecoxib as adjuvant therapy, large established tumors (14-18 days after tumor inoculation) were surgically debulked and animals were treated with rofecoxib starting 3 days before surgery. Recurrence of the tumor after debulking was monitored. RESULTS: Rofecoxib significantly slowed the growth of small (0-120 mm) tumors (P < 0.01-0.05) in all 3 cell lines, with higher efficacy in the more immunogenic tumors. Minimal responses were noted in larger tumors. Rofecoxib appeared to augment CD8 T cell infiltration in immunogenic tumors. Rofecoxib significantly reduced the recurrence rate after debulking (P < 0.01). CONCLUSIONS: Clinically relevant doses of the COX-2 inhibitor rofecoxib given orally were effective in inhibiting the growth of small (but not large) tumors in 3 murine NSCLC cell lines tested and in preventing recurrences after surgical debulking. Depending on the immunogenicity of human tumors, COX-2 inhibition might be useful as adjuvant therapy for surgically resectable NSCLC.     

IBUPROFEN COMBINED WITH ANTIBIOTICS SUPPRESSES RENAL SCARRING DUE TO ASCENDING PYELONEPHRITIS IN RATS

PURPOSE: In acute pyelonephritis renal scarring may be decreased by immediate antibiotic therapy. Unfortunately in children there is often a delay in starting treatment, which increases the likelihood of renal scarring. In rodents immediate antibiotic therapy is effective for preventing renal scar formation resulting from experimentally induced pyelonephritis. However, the same treatment beginning 72 hours after infection does not prevent renal scarring in this paradigm. We examined whether delayed administration of the nonsteroidal anti-inflammatory agent ibuprofen only or combined with antibiotics suppresses renal scarring in a model of ascending pyelonephritis in rats. MATERIALS AND METHODS: An inoculum of 5x10(9) organisms per ml. of Escherichia coli strain BH-5 was instilled into the bladder of rats and the urethra was occluded for 4 hours. Groups of animals were and were not treated with 15 mg./kg. cefadroxil or 10 mg./kg. ibuprofen given twice daily for 5 days, or the 2 drugs combined. Treatment began 72 hours after inoculation. In an additional group of rats sterile phosphate buffered saline was instilled into the bladder. In each rat the kidneys were examined grossly and microscopically 6 weeks later. RESULTS: Combined antibiotics and ibuprofen significantly inhibited gross renal scarring compared with no treatment or antibiotics only (p<0.05). No difference in renal scarring was detected in animals that received no treatment versus those that received antibiotics or ibuprofen only (p>0.05). CONCLUSIONS: Renal scarring resulting from acute pyelonephritis in this rat model is not decreased by delayed treatment with antibiotics only. The addition of ibuprofen to antibiotic therapy is effective for decreasing renal scarring due to acute pyelonephritis even when treatment is delayed for 72 hours.     

Prevention of intra-abdominal adhesions using the antiangiogenic COX-2 inhibitor celecoxib

OBJECTIVE: To determine the effects of COX-2 specific inhibitors on postoperative adhesion formation. SUMMARY AND BACKGROUND DATA: Intra-abdominal adhesions are the major cause of intestinal obstruction and secondary infertility after surgical procedures. Because adhesion synthesis requires angiogenesis, and cyclooxygenase-2 enzyme (COX-2) inhibitors have antiendothelial activity, we tested COX-2 inhibitors in a murine model of intra-abdominal adhesion formation. METHODS: A silicone patch was secured to the lateral abdominal wall of groups of C57BL/6 mice, followed by cecal abrasion to promote adhesion formation. Beginning on the day of surgery, mice were treated with the selective COX-2 agents, celecoxib or rofecoxib, and the nonspecific COX inhibitors, aspirin, naproxen, ibuprofen, or indomethacin. Animals were treated for 10 days and killed. A second group (celecoxib, rofecoxib, aspirin) was treated for 10 days and observed for an additional 25 days. After treatment, intra-abdominal adhesions were scored using a standard method. The patch was subjected to immunohistochemistry with the endothelial-specific marker, CD31. RESULTS: Animals treated with selective and nonselective COX-2 inhibitors, except aspirin, had significantly fewer adhesions than control animals. Celecoxib produced a maximal reduction in adhesion formation compared with rofecoxib and the nonselective COX-2 inhibitors at 10 days. After 25 days, celecoxib and rofecoxib, but not aspirin, had fewer adhesions than control mice. Adhesions from mice treated with celecoxib had reduced microvessel density compared with rofecoxib, the nonselective COX inhibitors, and control animals. CONCLUSIONS: Selective COX-2 inhibitors, in particular celecoxib, provide durable inhibition of intra-abdominal adhesions through an antiangiogenic mechanism.     

Effects of high-intensity focused ultrasound in the treatment of experimental neuroblastoma.

This report evaluates the effect of high-intensity focused ultrasound (HIFU) on subcutaneous murine neuroblastoma C1300. HIFU treatment was administered with a focused 4-MHz quartz transducer with a peak intensity of 550 W/cm2. In experiment 1, 60 animals with tumor were divided into four groups. Group I (n = 15) were controls; group II (n = 15) received adriamycin, 5 mg/kg intraperitoneally; group III (n = 15) received HIFU; and group IV (n = 15) received both adriamycin and HIFU. All the animals in groups I and II died of tumor by 35 days. Fifty-three percent (8/15) of mice in group III and 80% (12/15) in group IV were cured with no evidence of tumor (NET) at 200 days. Log-rank statistics showed significant prolongation of survival in the groups III and IV as compared with groups I or II (P less than .05). In experiment 2, 45 animals with tumor were divided into three groups. Group I (n = 15) were controls; group II (n = 15) received HIFU; and group III (n = 15) received repeated HIFU. The results showed 47% (7/15) of mice in group II and 67% (10/15) in group III were NET at 200 days. Significant survival prolongation was achieved in groups II and III in comparison with group I (P less than .05). In experiment 3, 90 mice received either tumor (n = 60) or saline (n = 30) inoculation in the left flank. On day 5, 45 mice with tumor were treated with HIFU (group I), while the other 15 mice with tumor (group II) had a sham procedure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of cyclooxygenase-2 inhibitor and adenosine triphosphate-sensitive potassium channel opener in syngeneic mouse islet transplantation

In the initial days after transplantation, islet grafts may be attacked by cytokines via cyclooxygenase-2 (COX-2), producing primary nonfunction. In addition, chronic overstimulation of β-cells may impair insulin secretion. To enhance the function of transplanted islets, the present study investigated the effects of rofecoxib, a COX-2 inhibitor, and NN414 (6-chloro-3-[1-methylcyclopropyl]amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide), an adenosine triphosphate-sensitive potassium channel opener, on islet transplantation. Male inbred C57BL/6 mice were used as donors and recipients. One hundred fifty islets were isolated via collagenase digestion and density gradient, and syngeneically transplanted under the kidney capsule in mice with streptozotocin-induced diabetes. Recipients were treated with or without rofecoxib, 10 mg/kg/d orally, or with or without NN414, 3 mg/kg/d orally, for 4 weeks. After transplantation, recipient body weight, blood glucose concentration, and intraperitoneal glucose tolerance were measured. The grafted kidney was extracted for determination of insulin content at 4 weeks. In the rofecoxib-treated and NN414-treated groups and both control groups, body weight remained stable, and the blood glucose concentration decreased progressively. However, at 4 weeks after transplantation in the groups treated or not treated with rofecoxib or NN414, no significant difference was observed in recipient body weight, blood glucose concentration, and glucose tolerance or in insulin content of the graft. These data indicate that posttransplantation treatment with rofecoxib or NN414 has no beneficial effect on transplantation outcome in diabetic mouse recipients engrafted with a marginal islet mass.     

Selective COX-2 inhibitor versus indomethacin for the prevention of heterotopic ossification after hip replacement: a double-blind randomized trial of 100 patients with 1-year follow-up

Introduction Recent reports have suggested that selective COX-2 inhibition may be sufficient for the prevention of heterotopic ossification.

Methods We performed a randomized controlled study to evaluate the effect of the selective COX-2 inhibitor rofecoxib compared to that of indomethacin on the incidence and extent of heterotopic ossification in patients who had undergone hip replacement surgery. 50 patients received a daily dose of 25 mg rofecoxib and 50 patients received a daily dose of 100 mg indomethacin (25, 25, and 50 mg).

Results No ossifications were found in 48 patients. Grade-II ossifications were seen in 5/46 patients in the rofecoxib group and in 6/50 patients in the indomethacin group. Grade-III and grade-IV ossifications were seen in 3/46 patients in the rofecoxib group only. The differences were not statistically significant. The study medication had to be discontinued in 2 patients in the indomethacin group, due to dyspepsia.

Interpretation After short-term administration, the selective COX-2 inhibitor rofecoxib was effective in preventing heterotopic ossification after total hip arthroplasty.     

Selective cyclooxygenase-2 inhibitor rofecoxib (vioxx) induces expression of cell cycle arrest genes and slows tumor growth in human pancreatic cancer

Recent studies indicate that cyclooxygenase-2 (COX-2) is overexpressed in pancreatic adenocarcinoma and may play a critical role in this rapidly progressing form of cancer. A human pancreatic adenocarcinoma cell line, Mia PaCa-2, was incubated for 18 hours with 5μ mol/L of rofecoxib (Vioxx), a selective COX-2 inhibitor. Total RNA was isolated and gene expression analyzed by DNA microarray chips. In a separate experiment, athymic mice were orthotopically injected with 7.5 x 10⁵ Mia PaCa-2 cells through a minilaparotomy. After 1 month, laparotomy was repeated to measure tumor size, and mice were randomized to receive reformulated rodent chow containing either 12.5 mg/kg/day of rofecoxib or no drug for 21 days. Tumor growth was assessed by comparing volume before and after treatment. In vitro, rofecoxib decreased gene expression of cyclin D1/PRAD1, a key component of cell cycle progression, while increasing expression of several cell cycle arrest genes, including p21/WAF1, p33/ING, GADD34, and GADD45 (Pμ0.05). In vivo, tumor growth was significantly reduced in treated vs. control mice (Pμ0.05). No systemic toxicity was observed in mice receiving rofecoxib. These data suggest that rofecoxib slows the growth of human pancreatic cancer through changes in gene expression that favor cell cycle arrest. Presented at the Forty-Third Annual Meeting of The Society for Surgery of the Alimentary Tract, San Francisco, California, May 19–22, 2002 (oral presentation).     

Prevention of heterotopic ossification after spinal cord injury with COX-2 selective inhibitor (rofecoxib)

STUDY DESIGN: A randomized, prospective, double-blind, placebo-controlled clinical trial. OBJECTIVES: To determine the effect of COX-2-selective inhibitor on the prevention of heterotopic ossification (HO) after spinal cord injury (SCI). SETTING: County and University Teaching Hospital, Miami, FL, USA. METHODS: A total of 76 patients were enrolled in the study. Among them, 39 patients received placebo, and 37 received COX-2-selective inhibitor rofecoxib 25 mg daily for a period of 4 weeks. Prevention was started 3 weeks after spinal cord injury (SCI). In both groups of patients there was similar age as well as the level of SCI and ASIA impairment scale. Two methods were used to diagnose early HO, clinical symptoms and bone scintigraphy. Radiography was used for diagnosis of late stages of HO development. RESULTS: A significantly lower incidence of HO was found in the rofecoxib group (13.4%) than in the placebo group (33.3%: P<0.05). In patients receiving rofecoxib, there was a 2.5 times lower relative risk of developing HO than in the placebo group (95% CI, 2.3-6). There were no patients who discontinued the study due to adverse effects of medication. CONCLUSION: Our data suggest that COX-2-selective inhibitor rofecoxib is an effective medication in prevention of HO after SCI.     

Antioxidative effects of exogenous nitric oxide versus antioxidant vitamins on renal ischemia reperfusion injury

The objectives of this study were to compare the protective influence of exogenous nitric oxide on renal ischemia reperfusion (I/R) injury with that of the antioxidant vitamins C and E. Sprague-Dawley rats were divided into three groups ( n=12 per group). Normal saline solution was given in group 1, a vitamin C (200 mg/kg/d) plus vitamin E (100 mg/kg/d) combination in group 2 for 3 days before operating and Na-nitroprusside (5 mg/kg/d) in group 3 before reperfusion. The left kidneys were exposed to warm ischemia for 40 min followed by reperfusion for 90 min. The right kidneys were used as internal controls. After both kidneys were removed, histopathological examinations were performed, and oxidative and antioxidative parameters were measured. In the postischemic reperfused rat kidneys, the renal lipid peroxidation level was significantly lower, and the renal GSH level higher in the group given Na-nitroprusside compared with groups 1 and 2. Renal specific xanthine oxidase activity was also significantly lower in the group treated with Na-nitroprusside than in the groups given vitamins or saline. There was a significant, negative correlation between lipid peroxidation and reduced glutathione levels. Our results suggest that the exogenous nitric oxide (Na-nitroprusside) inhibits xanthine oxidase, and has more apparent preventive features for renal I/R injury than the antioxidant vitamins C+E.     

Suppression of adjuvant-induced arthritic bone destruction by cyclooxygenase-2 selective agents with and without inhibitory potency against carbonic anhydrase II.

In vitro assays revealed that COX-2 inhibitors with CA II inhibitory potency suppressed both differentiation and activity of osteoclasts, whereas that without the potency reduced only osteoclast differentiation. However, all COX-2 inhibitors similarly suppressed bone destruction in adjuvant-induced arthritic rats, indicating that suppression of osteoclast differentiation is more effective than that of osteoclast activity for the treatment. INTRODUCTION: Cyclooxygenase (COX)-2 and carbonic anhydrase II (CA II) are known to play important roles in the differentiation of osteoclasts and the activity of mature osteoclasts, respectively. Because several COX-2 selective agents were recently found to possess an inhibitory potency against CA II, this study compared the bone sparing effects of COX-2 selective agents with and without the CA II inhibitory potency. MATERIALS AND METHODS: Osteoclast differentiation was determined by the mouse co-culture system of osteoblasts and bone marrow cells, and mature osteoclast activity was measured by the pit area on a dentine slice resorbed by osteoclasts generated and isolated from bone marrow cells. In vivo effects on arthritic bone destruction were determined by radiological and histological analyses of hind-paws of adjuvant-induced arthritic (AIA) rats. RESULTS: CA II was expressed predominantly in mature osteoclasts, but not in the precursors. CA II activity was inhibited by sulfonamide-type COX-2 selective agents celecoxib and JTE-522 similarly to a CA II inhibitor acetazolamide, but not by a methylsulfone-type COX-2 inhibitor rofecoxib. In vitro assays clearly revealed that celecoxib and JTE-522 suppressed both differentiation and activity of osteoclasts, whereas rofecoxib and acetazolamide suppressed only osteoclast differentiation and activation, respectively. However, bone destruction in AIA rats was potently and similarly suppressed by all COX-2 selective agents whether with or without CA II inhibitory potency, although only moderately by acetazolamide. CONCLUSIONS: Suppression of osteoclast differentiation by COX-2 inhibition is more effective than suppression of mature osteoclast activity by CA II inhibition for the treatment of arthritic bone destruction.     

Rofecoxib inhibits heterotopic ossification after total hip arthroplasty

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) prevent heterotopic ossification but gastrointestinal complaints are frequently. Selective cyclooxygenase-2 (COX-2) inhibiting NSAID produce less gastrointestinal side effects. PATIENTS AND METHODS: A prospective two-stage study design for phase 2 clinical trials with 42 patients was used to determine if rofecoxib (a COX-2 inhibitor) 50 mg oral for 7 days prevents heterotopic ossification. A cemented primary THA was inserted for osteoarthroses. After 6 months heterotopic bone formation was assessed on AP radiographs using the Brooker classification. RESULTS: No heterotopic ossification was found in 81% of the patients, 19% of the patients had Brooker grade 1 ossification. CONCLUSION: Using a two-stage study design for phase 2 clinical trials, a 7-day treatment of a COX-2 inhibitor (rofecoxib) prevents effectively the formation of heterotopic ossification after cemented primary total hip arthroplasty.     

Effect of Euro-Collins' or UW solution on the early graft function following cadaveric kidney transplantation

From November 1985 to March 1990, 55 cadaveric kidney transplants were performed under cyclosporine therapy. All kidneys were harvested from non-heart beating donors and cold stored after being flushed with EC solution (Group I, n = 27) or UW solution (Group II, n = 28). Warm ischemic time (min) in groups I and II were 7.1 +/- 3.3 and 6.9 +/- 2.3, respectively. Cold ischemic times (hr) in groups I and II were 6.9 +/- 2.4 and 8.4 +/- 2.8, respectively. Mean numbers of days for postoperative dialysis were 14.0 +/- 7.9 in group I and 7.9 +/- 5.8 in group II (p less than 0.05). One-month creatinine (mg/dl) was 2.9 +/- 2.8 in group I and 1.75 +/- 1.0 in group II (NS). One-month graft survivals (%) in groups I and II were 81.4% and 92.8%, respectively. In conclusion, UW solution has provided beneficial effect of preservation on ischemic damaged kidney and appears to be method of choice in non-heart beating cadaveric kidney transplantation.     

Effects of a selective cyclo-oxygenase 2 inhibitor on colonic anastomotic and skin wound integrity

BACKGROUND: Selective inhibitors of inducible cyclo-oxygenase (COX-2) are of potential benefit in the perioperative period for both their analgesic and, perhaps, antineoplastic actions. However, their effects on laparotomy and intestinal wound healing are unknown. METHODS: Forty adult Sprague-Dawley rats underwent laparotomy, descending colonic transection and handsewn reanastomosis. The animals were randomized to receive either a selective COX-2 inhibitor (rofecoxib, 10 mg/kg) or an equal volume of water by gavage before operation and then daily after surgery. Animals were killed after 3 or 7 days, and their wounds were evaluated by means of tensiometry (skin and colonic wounds) and bursting pressure measurement (colonic anastomoses). In addition, haematoxylin and eosin-stained intestinal sections were examined and scored by a blinded independent observer. RESULTS: Five animals that received rofecoxib had anastomotic leaks by day 7 compared with none in the control group (P = 0.048). Intact colonic suture lines were also significantly weaker in this group (tensile strength at day 3, P = 0.043; bursting pressure on days 3 and 7, both P = 0.019). Skin wound strengths were similar in the two groups at both time points. CONCLUSION: Although beneficial in the treatment of pathological inflammation, selective COX-2 inhibitors may adversely affect colonic anastomotic healing.     

Ketamine attenuates liver injury attributed to endotoxemia: role of cyclooxygenase-2

BACKGROUND: Endotoxic shock can cause end-organ dysfunction and liver injury. Critically ill patients frequently require surgical intervention under general anesthesia for source control. However, the effects of anesthetics on organ function during sepsis and their influence on inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) remain to be fully elucidated. Because ketamine anesthesia has anti-inflammatory effects in some tissues, we hypothesized that it would attenuate lipopolysaccharide (LPS)-induced liver injury. METHODS: Adult rats were given no anesthesia (saline), continuous isoflurane inhalation, or intraperitoneal (i.p.) injection of ketamine 70 mg/kg. One hour later, the rats received saline or LPS (20 mg/kg i.p.) for 5 hours. The rats were killed, and serum hepatocellular enzymes, liver COX-2, iNOS protein (Western immunoblot), and nuclear factor kappa B (NF-kappaB)-binding activity (electrophoretic mobility shift assay) determined. In a separate study, the role of COX-2 in LPS-induced liver injury was examined by pretreating rats with the selective COX-2 inhibitor NS-398 (3 mg/kg, i.p.) and the role of iNOS examined with the use of the selective inhibitor aminoguanidine (45 mg/kg, i.p.) 1 hour before LPS. RESULTS: LPS increased serum aspartate aminotransferase and alanine aminotransferase levels, hepatic iNOS and COX-2 protein, and nuclear factor NF-kappaB. Ketamine, but not isoflurane, attenuated these effects caused by LPS. COX-2 inhibition with NS-398 as well as iNOS inhibition with aminoguanidine diminished LPS-induced changes in aspartate aminotransferase and alanine aminotransferase levels. CONCLUSIONS: These data indicate that anesthetics differ in their effects on liver injury caused by LPS. Ketamine has hepatoprotective effects, while isoflurane does not. Moreover, the protective effects of ketamine are mediated, at least in part, through a reduction in COX-2 and iNOS protein that could be regulated via changes in NF-kappaB-binding activity.     

诱导性一氧化氮合酶抑制药对感染性休克鼠肝、肺组织学改变的影响

目的　研究诱导性一氧化氮合酶 ( i NOS)抑制药氨基胍 ( AG)和非选择性 NOS抑制药L- N-硝基精氨甲酯 ( L- NAME)对感染性休克鼠肝肺组织学改变的影响。方法　小鼠腹腔内注射 ( i.p.)内毒素 ( L PS,2 0 mg· kg- 1 )后 4小时随机分为 L PS组 ( n=60 ) ,L PS L - NAME组 ( 3 0 mg· kg- 1i.p.,n=60 )。和 L PS AG组 ( 2 0 mg· kg- 1 i.p.,n=60 )。5小时后取受试鼠的肝肺组织进行光镜和电镜检查。并观察 2 4小时内受试鼠的生存率。结果　 L PS组、L PS L- NAME组和 L PS AG组 2 4小时内生存率分别为 3 7.5 % ,5 %和 64 .3 % ( P<0 .0 5 )。光镜下 L PS组和 L PS L- NAME组肝细胞和核肿胀 ;肺间质增厚。电镜下可见 L PS组和 L PS L- NAME组可见肝细胞核、细胞膜和线粒体膜明显破坏 ;肺血气屏障明显增厚。 L PS AG组肝细胞和肺部的改变明显轻于其它两组。结论　感染性休克中 c NOS介导的一定量的 NO对器官有保护作用。以氨基胍选择性抑制 i NOS合成的 NO,疗效好于非选择性 NOS抑制药