Cardiorenal effects of celecoxib as compared with the nonsteroidal anti-inflammatory drugs diclofenac and ibuprofen

The cardiorenal safety database from the Celecoxib Long-term Arthritis Safety Study (CLASS) was analyzed to examine whether supratherapeutic doses of celecoxib are associated with decreased renal function and blood pressure (BP) effects compared with standard doses of diclofenac and ibuprofen in osteoarthritis (OA) and rheumatoid arthritis (RA) patients.In total, 8059 patients were enrolled; 7968 received at least one dose of study drug (RA: N = 2183; OA: N = 5785). Patients received celecoxib, 400 mg twice a day (b.i.d.). (N = 3987); ibuprofen, 800 mg three times a day. (N = 1985); or diclofenac, 75 mg b.i.d. (N = 1996). Effects measured included: investigator-reported hypertension, edema or congestive heart failure, clinically important BP elevations, incidence of patients starting new antihypertensive medication, and increases in serum creatinine or reductions in creatinine clearance. Celecoxib was associated with a similar incidence of hypertension or edema to diclofenac but significantly lower than ibuprofen. The celecoxib group had significantly fewer initiations of antihypertensives versus ibuprofen. Systolic BP increases of >20 mmHg and above 140 mmHg occurred significantly less often with celecoxib compared with ibuprofen or diclofenac. Changes in serum creatinine or estimated creatinine clearance occurred in a similar percentage of patients taking celecoxib or ibuprofen; modest differences were evident against diclofenac. In patients with mild prerenal azotemia, significantly fewer patients taking celecoxib exhibited clinically important reductions in renal function (3.7%), compared with diclofenac (7.3%; P < 0.05) and ibuprofen (7.3%; P < 0.05). A supratherapeutic dose of celecoxib was associated with an improved cardiorenal safety profile compared with standard doses of either ibuprofen or diclofenac.     

Renal physiology of the prostaglandins and the effects of nonsteroidal anti-inflammatory agents on the kidney

The prostaglandins are a series of fatty acid products derived from the cellular metabolism of arachidonic acid. The kidney makes prostaglandins and the endogenous renal prostaglandins appear to play a role in the regulation of renal hemodynamics, renal salt and water excretion, and control of the level of activity of the renin-angiotensin system. The administration of nonsteroidal anti-inflammatory drugs blocks cyclooxygenase activity, an early step in the synthesis of prostaglandins. This class of drugs, under certain circumstances, leads to sodium retention, hyperkalemia and several different forms of acute and chronic renal failure. The potential role of altered prostaglandin synthesis in leading to these clinical syndromes is reviewed.     

Reduction of inflammation following cataract surgery by the nonsteroidal anti-inflammatory drug, flurbiprofen

In this double-masked clinical trial, 72 patients undergoing cataract extraction surgery received a topical loading dose of 0.03% flurbiprofen or vehicle before surgery and one drop four times daily for 2 weeks after surgery. The severity of conjunctival hyperemia, aqueous humor cells, and aqueous humor flare was lower in the flurbiprofen-treated group than in the vehicle-treated group at all follow-up visits; the differences were significant on day 14. Four patients treated with flurbiprofen and two treated with vehicle exhibited postoperative hyphemas. Treatment with flurbiprofen appeared to decrease the severity of inflammation following cataract extraction surgery.     

Influence of diclofenac (group of nonsteroidal anti-inflammatory drugs) on fracture healing

Introduction Nonsteroidal antirheumatics (NSAR; NSAID) are often used in patients with fractured bones for analgetic reasons. This animal experiment was performed to determine the influence of NSAR on the process of fracture healing. As an alternative, tramadol, the centrally acting analgetic without peripheral effects, was included in this experiment.Materials and methods Wistar rats were operated on by a transverse osteotomy of the proximal tibia of the left leg. The fracture was stabilized by intramedullary nailing (healing period 21 days). All drugs were applied orally twice a day. The animals were divided into four groups with 10 rats each: Group 1 was treated with placebo (P), group 2 with tramadol (T; 20 mg/kg body weight/day), group 3 with diclofenac sodium (DS; 5 mg/kg bw/day) for 7 days followed by 14 days of placebo, group 4 with diclofenac sodium (DL; 5 mg/kgbw/day) over 21 days. On day 21 the rats were killed, and each leg was examined by X-ray, then the tibia was examined by CT scan, three-point bending, and histology.Results The results of CT and three-point bending showed that rats treated by diclofenac presented with delayed fracture healing compared with those treated by placebo or tramadol. Bone density in CT was highest in group 1 (mean 611.4±50.1 mg/ml), followed by group 2 (mean 542.5±29.5 mg/ml). Groups 3 (mean 411±34.0 mg/ml; p=0.006) and 4 (mean 395.2±15.4 mg/ml; p=0.009) were significantly lower. The stability of the bones, as measured by the breaking force (F_max), was highest in group 1 (mean 45.8±19.0 N), followed by group 2 (mean 39.0±7.9 N; NS); group 3 (mean 20.6±7.8 N; p=0.01) was significantly lower than the placebo animals, followed by group 4 (mean 26.5±8.3 N; p=0.03). Similar results were shown for bending stiffness: group 1 (mean 1404.6±611.4 Nmm/mm), group 2 (mean 1033.2±232.1 Nmm/mm; NS), group 3 (mean 564.2±457 Nmm/mm; p=0.045), and group 4 (mean 494.8±340.2 Nmm/mm; p=0.028). There were no significant differences between groups 1 and 2 and between groups 3 and 4, respectively. Diclofenac serum levels on day 21 in rats with long-term diclofenac application (mean 301.4±83.3 ng/ml) were comparable to those in humans.Conclusion Oral application of diclofenac significantly delayed fracture healing in rats. This effect might be comparable to other NSAR and fracture healing in humans.     

Comparison of the effects of dexketoprofen trometamol,meloxicam and diclofenac sodium on fibular fracture healing,kidney and liver: An experimental rat model

Objectives

Nonsteroidal anti-inflammatory drugs (NSAIDs) are particularly used in patients with bone fractures, but there are limited studies on whether one NSAID is superior to another. In this study, we used histopathological and biochemical parameters to determine whether there are differences between the effects of the administration of clinical doses of dexketoprofen trometamol (DEXT), meloxicam (MEL) and diclofenac sodium (DIC) on the healing of closed fibular fractures and the toxicity of both the liver and kidney.

Methods

Twenty-eight male Sprague-Dawley rats were randomly divided into four groups of seven each. Closed diaphyseal fractures were formed in the left fibulas of all of the rats. The NSAIDs dexketoprofen trometamol (DEXT) (Arveles^®), meloxicam (MEL) (Melox^®) and diclofenac sodium (DIC) (Voltaren^®) were intramuscularly administered to Groups I, II, and III, respectively, for a period of 10 days after the fibular fractures were performed. No pharmacological agents were administered to Group IV (Control group). Blood samples were collected from all of the rats after the fractures were performed, and the rats were sacrificed on day 28. The histopathological findings were compared, and the blood samples were evaluated to determine any differences between the levels of superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA).

Results

Our results suggest that DEXT and MEL impair the healing of bone fractures and that DIC does not histopathologically affect the healing process of bone fractures. We also found that DEXT, MEL, and DIC impaired the renal histopathology compared with the control group. However, the liver histopathological analysis showed that DEXT and MEL caused a higher degree of parenchymal necrosis compared with DIC.

Conclusion

Based on our results, DIC can be considered a relatively safe medication in patients with fractures.     

Effects of melatonin on diclofenac sodium treated rat kidney: a stereological and histopathological study

Abstract

Objective: In this study, we aimed to investigate the effect of diclofenac sodium (DS) and melatonin (MEL) on kidney of the prenatally administered rats. Materials and methods: Pregnant rats were divided into the control, physiological saline, DS, and DS?+?MEL groups. All injections were given beginning from the 5th day after mating to the 15th day of the pregnancy. Physical dissector and Cavalieri principle were used to estimate the numerical density and total number of glomeruli and the volumetric parameters of kidney, respectively. Results: Our stereological results indicated that DS application during the pregnancy lead to decrease in the mean volume, numerical density, and total number of the glomeruli (p?<?0.05). In addition, we determined that usage of the MEL with the DS caused increases in the mean volume, numerical density, and total number of the glomeruli (p?<?0.05). So, there was no significant difference in terms of the any parameter between the CONT and DS?+?MEL groups (p?>?0.05). Light microscopic investigation showed congestion in blood vessels and shrinkage of the Bowman's space in the DS group. Moreover, there was degeneration in nephrons including glomerulosclerosis and tubular defects, and an increase in the connective tissue in the kidneys of the DS-treated group. However, usage of the MEL with the DS caused preventing of these pathological alterations in the kidney. Discussion: We suggested that DS might lead to adverse effects in the kidneys of the rats that are prenatally subjected to this drug. Fortunately, these adverse effects can be prevented by the melatonin supplementation.     

Effect of nonsteroidal anti-inflammatory drug use on the incidence of erectile dysfunction

PURPOSE: We estimated the effect of nonsteroidal anti-inflammatory drug use on the incidence of erectile dysfunction. MATERIALS AND METHODS: The target population consisted of men 50, 60 or 70 years old residing in the study area in Finland in 1994. Questionnaires were mailed to 3,143 men in 1994 and to 2,864 men 5 years later. The followup sample consisted of 1,683 men who responded to baseline and followup questionnaires. We estimated the effect of NSAIDs on the incidence of ED in men free from moderate or complete ED at baseline (in 1,126). ED was assessed by 2 questions on subject ability to achieve or maintain an erection sufficient for intercourse. Confounding was assessed by stratification and by adjustment in multivariate Poisson regression model. RESULTS: The incidence of ED was 93 cases per 1,000 person-years in men who used and 35 in those who did not use NSAIDs. Among men with arthritis, the most common indication for NSAID use, ED incidence was 97 cases per 1,000 in those using and 52 in men who did not use NSAIDs. Compared with men who did not use NSAIDs and were free from arthritis, the relative risk of ED after controlling for the effects of age, smoking, and other medical conditions and medications was higher in men who used NSAIDs but were free of arthritis (IDR 2.0, 95% CI 1.2-3.5) and in those who used NSAIDs and had arthritis (IDR 1.9, 95% CI 1.2-3.1). The relative risk was only somewhat higher in men who had arthritis but did not use NSAIDs (IDR 1.3, 95% CI 0.9-1.8). CONCLUSIONS: The use of nonsteroidal anti-inflammatory drugs increases the risk of ED and the effect is independent of indication.     

The effect of a new immunosuppressive drug, brequinar sodium, on heart, liver, and kidney allograft rejection in the rat.

Brequinar sodium (BQR) prevents cell proliferation by virtue of its inhibition of de novo pyrimidine biosynthesis. BQR is capable of inhibiting immune responses in vitro and is effective in suppressing the development of contact sensitivity and adjuvant arthritis in rodent models. Based on the antiproliferative and immunosuppressive capacity of BQR, we have evaluated the efficacy of BQR in preventing allograft rejection utilizing experimental models of heterotopic heart and kidney and orthotopic liver transplantation in an MHC and non-MHC mismatched ACI----LEW rat strain combination. The immunosuppressive activity of BQR is illustrated by its ability to inhibit the development of delayed-type hypersensitivity to DNFB in mice. When BQR was administered orally throughout the sensitization and elicitation phases of the DNFB contact sensitivity response, it was found to be a potent immunosuppressant with an ED50 value of 0.5 mg/kg. This immunosuppressive activity is also seen in vitro, where BQR is capable of inhibiting the mixed lymphocyte response between allogeneic ACI and LEW rat strains with an IC50 of 150 ng/ml. The immunosuppressive activity of BQR is highly effective in prolonging heart, liver, and kidney allograft survival in the rat. Cardiac allografts are not rejected during the period of drug treatment at dosage levels of 12 to 24 mg/kg orally three times weekly. The grafts survive until the drug is discontinued (30 days posttransplantation), and the grafts are then rejected approximately 14 days later. Liver and kidney allografts are permanently accepted by approximately 50 to 90% of the recipient rats following 30 days of treatment with BQR at 12 mg/kg. The tolerance that is induced to the liver grafts extends in the majority of animals to greater than 250 days and is specific for the donor ACI strain. Challenge of long-term liver graft survivors with donor cardiac grafts is associated with permanent survival of donor, but not third-party, heart grafts. Combination therapy consisting of suboptimal doses of BQR and CsA demonstrates that the combination of these two immunosuppressive drugs results in an increased efficacy in prolonging graft survival. The results of these allograft experiments demonstrate that this new immunosuppressive agent is highly effective in preventing allograft rejection in the rat. The antiproliferative activity of BQR is effective for inhibiting T-lymphocyte-mediated immune responses, and Brequinar sodium should be an important addition to a polytherapeutic approach in the treatment of organ graft rejection.     

The morphine sparing effects of diclofenac sodium following abdominal surgery

A randomised, double-blind placebo controlled study was undertaken to assess the analgesic efficacy of diclofenac. Following major abdominal surgery and 12 hours later, patients received either placebo or diclofenac 75 mg intramuscularly and their cumulative morphine requirements administered by a patient-controlled system over 24 hours were compared. Pain scores were also measured. Arterial blood gases and coagulation studies were assessed pre- and postoperatively. Morphine consumption was significantly greater in the placebo group (59.5 compared to 38.5 mg, p less than 0.01). Pain scores were significantly lower in the diclofenac group at 4 hours, but not thereafter. Arterial carbon dioxide was significantly increased in the control groups. There was no significant change in platelet count within each group, but a significant difference between the groups (p less than 0.05).     

Effect of a non-steroidal anti-inflammatory drug, diclofenac, on haemostasis in patients undergoing total hip replacement

Haemostasis was studied in patients receiving diclofenac for postoperative pain relief. Intravenous diclofenac 75 mg over 60 min, followed first by an infusion of 5 mg/h for 15 h and then by 50 mg every 8 h orally was administered to 20 patients undergoing total hip replacement. Eighteen patients receiving a placebo infusion and dextropropoxyfen per os served as controls. The results showed no statistically significant differences between the groups in blood loss, bleeding time (IVY), partial activated thromboplastin time and prothrombin complex assay or in platelet count. The measurements were performed preoperatively, 3 h postoperatively and on the fourth and tenth postoperative days. Plasma concentrations were also determined in ten patients undergoing knee arthroscopy. An i.v. diclofenac infusion of 75 mg over a period of 15 min was administered either once (to half of the patients) or twice. The mean diclofenac concentrations were 28 +/- 5 nmol/ml (+/- s.d.) after 15 min and 36 +/- 12 nmol/ml after the second infusion. The bleeding time in the arthroscopy patients receiving one or two bolus infusions of 75 mg diclofenac remained at the control level. It is concluded that diclofenac given as an intravenous infusion of 75 mg in 60 min, then 5 mg/h for 15 h, followed by 50 mg every 8 h orally, is a safe as dextropropoxyfen for pain relief in patients undergoing major orthopaedic surgery as far as coagulation data are concerned.     

The effect of nonsteroidal anti-inflammatory agents on spinal fusion

A large body of information suggests NSAIDS have a negative impact on the healing of bone. Although each clinical healing scenario presents a slightly different level of challenge, the healing of a posterolateral spinal fusion is one of the most difficult challenges in bony healing. Clinically, this results in a relatively high rate of nonunions using traditional fusion techniques. Spinal fusion models have confirmed NSAIDS have a definite inhibitory effect on healing of the fusion. Although data are limited, it appears this effect is most severe when NSAIDS are administered in the early postoperative period. Moreover, the effect may be worse with certain types initial inflammatory, subsequent reparative, and final remodeling phases. Because of the anti-inflammatory activity of NSAIDS, one might assume their effects would be worse when administered in the inflammatory phase. Indeed, the study by Riew et al suggests the inhibitory effects are more significant when NSAIDS are administered earlier following fusion. Other studies conducted with non-spinal models also suggest early administration of NSAIDS results in greater inhibition of bone formation (Goodman et al). Unfortunately, the length of the inflammatory phase in humans is not well known. This leaves the clinician unsure about the safe time to allow resumption of NSAID usage clinically. It appears likely NSAID use following a spinal fusion procedure will increase the rate of pseudarthrosis. The literature suggests that avoidance of NSAIDS in the postoperative period may avoid nonunion. Additionally, we propose that chronic NSAID usage should be addressed in a similar manner to cigarette smoking. While neither are absolute contraindications to elective spinal fusion, patients should be counseled to discontinue the use of NSAIDS in the peri- and postoperative period to maximize their chance for a successful fusion.     

Analgesic and anti-inflammatory efficacy of tenoxicam and diclofenac sodium after third molar surgery.

Tenoxicam and diclofenac sodium were compared with each other for analgesic efficacy following removal of third molars under general anesthesia. Thirty-five healthy patients between the ages of 18 and 28 yr were randomly allocated to two groups to participate in this study. Patients in Group A (n = 17) received a single intravenous injection of tenoxicam 40 mg at induction of anesthesia, followed by a 20-mg tablet given in the evening of the day of the operation and thereafter, one 20-mg tablet daily from days 2 to 7. Group B (n = 18) received a single intramuscular injection of diclofenac sodium 75 mg at induction of anesthesia, followed by a 50-mg tablet 4 to 6 hr after the operation and again, between 2100 hr and 2200 hr the same day. Thereafter, a 50-mg tablet was taken 3 times daily for the next 6 days. Pain was measured hourly for the first 4 hr postoperatively, then at 21 hr, and thereafter in the morning and the evenings on days 2 to 7. The highest pain scores were obtained 1 hr postoperatively for both trial groups. At 1 and 2 hr postoperatively, no statistical significant differences in pain scores could be shown for both groups. However, at 3 and 4 hr postoperatively, patients in the tenoxicam group experienced significantly (P < or = 0.05) less pain than those in the diclofenac sodium group. On the evening of the third postoperative day, the tenoxicam group of patients experienced significantly less pain (P < or = 0.05) than those in the diclofenac sodium group. This was again the case on the morning of the fourth postoperative day. On the fifth, sixth, and seventh postoperative days, the average pain scores for patients in the tenoxicam group were statistically significantly lower, both mornings and evenings, than those in the diclofenac sodium group of patients (P = 0.05).     

The non-steroidal anti-inflammatory drug diclofenac reduces appearance of osteoblasts in bone defect healing in rats

Introduction

Non-steroidal anti-inflammatory drug (NSAID) is well known to significantly delay fracture healing. Results from in vitro studies implicate an impairment of osteoblast proliferation due to NSAIDs during the initial stages of healing. We studied whether diclofenac, a non-selective NSAID, also impairs appearance of osteoblasts in vivo during the early phase of healing (at 10 days).

Materials and methods

Two defects (Ø 1.1 mm) were drilled within distal femurs of 20 male Wistar rats. Ten rats received diclofenac continuously; the other obtained a placebo until sacrificing at 10 days. Osteoblast proliferation was assessed by cell counting using light microscopy, and bone mineral density (BMD) was measured using pQCT.

Results

Osteoblast counts from the centre of bone defect were significantly reduced in the diclofenac group (median 73.5 ± 8.4 cells/grid) compared to animals fed with placebo (median 171.5 ± 13.9 cells/grid). BMD within the defect showed a significant reduction after diclofenac administration (median 111.5 ± 9.3 mg/cm³) compared to the placebo group (median 177 ± 45.4 mg/cm³).

Conclusion

The reduced appearance of osteoblasts in vivo implicates an inhibiting effect of diclofenac on osteoblasts at a very early level of bone healing. The inhibition of proliferation and migration of osteoblasts, or differentiation from progenitor cells, is implicated in the delay of fracture healing after NSAID application.

     

Response of the kidney to furosemide. II. Effect of captopril on sodium balance

We investigated the role of the renin-angiotensin-aldosterone (RAA) system during furosemide (F) administration. The effects of adding captopril (C) (25 mg . 6 hr-1) to F (40 mg daily for 3 days) were studied in six normal subjects equilibrated to a daily sodium (Na) intake of 270 mmoles. Without C, F produced a marked natriuresis but Na+ excretion fell sharply between drug doses. This resulted in neutral Na balance (+22 +/- 58 mmoles . 3 days-1; mean +/- SE). Plasma angiotensin (AII) and aldosterone (Aldo) rose, but mean blood pressure (MBP) was unaltered. C abolished the F-induced increases in AII and Aldo but did not modify the pattern of Na+ excretion. Na+ balance remained neutral (+42 +/- 54 mmoles . 3 days-1). With C alone, Na+ balance was positive (+110 +/- 30 mmoles . 3 days-1; P less than 0.02). In protocols C alone and F + C, MBP fell by a comparable amount. F alone and F + C increased plasma norepinephrine and prostaglandin E2 metabolite; these did not change with C alone. In conclusion, activation of the RAA system by F is not essential for the compensatory increase in Na+ reabsorption that maintains Na+ balance after F.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of furosemide on the obstructed kidney

The effect of furosemide on the obstructed kidney was studied in dogs. In control kidneys (n = 4) the renal blood flow (RBF) was increased transiently after intravenous infusion of 20 mg of furosemide; from 12.9 +/- 1.2 to 14.8 +/- 1.4 ml/min/kg.B.W. No change in the renal pelvic pressure was observed. Urine flow increased from 0.47 +/- 0.12 to 4.98 +/- 1.15 ml/min at 20 minutes after furosemide administration. Increases in the fractional fluid excretion rate (V/GFR), the fractional sodium excretion rate (FENa) and the fractional potassium excretion rate (FEK) were observed and the maximum values were obtained at 20 minutes after furosemide administration. In two-week unilateral incompletely obstructed kidneys (incomplete UUO; n = 5), RBF was lower than that of the control kidney, whereas a tendency of transient increase was also noticed after furosemide administration; from 8.4 +/- 1.9 to 10.5 +/- 2.3 ml/min/kg.B.W. The renal pelvic pressure increased immediately and transiently after furosemide infusion. Increase in the urine flow was significant, but the value was lower than that of control, and the maximum value was marked at 20 minutes after furosemide administration. V/GFR, FENa and FEK were also increased in incomplete UUO, but the peak values were lower than those of control. In two-week unilateral completely obstructed kidneys (complete UUO; n = 5), RBF was markedly decreased (3.14 +/- 0.38 ml/min/kg.B.W.), and no significant increase was noticed after furosemide administration. The renal pelvic pressure was gradually and continuously increased after furosemide infusion. The fractional excretion rate of pelvic urine components was variable. In particular, V/GFR was significantly increased 60 minutes after furosemide administration.(ABSTRACT TRUNCATED AT 250 WORDS)