Pain-mediated altered absorption and metabolism of ibuprofen: an explanation for decreased serum enantiomer concentration after dental surgery.
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AIMS: Rapid onset of analgesia is essential in the treatment of acute pain. There is evidence that conditions of stress cause delayed and decreased pain relief from oral analgesic products through impaired absorption. The aim was to determine the effect of surgery for removal of wisdom teeth on the plasma concentration-time profile of ibuprofen enantiomers. METHODS: Racemic ibuprofen, 200 mg in one group (n=7) and 600 mg in another group (n=7) was administered 1 week before (control) and again after (test) surgical removal of wisdom teeth. Serum concentrations of ibuprofen enantiomers were measured for 6 h. RESULTS: During the control phase, S- and R-ibuprofen concentrations were within the suggested therapeutic range. Surgery resulted in a 2 h delay in the mean time to peak concentration, significant decreases in serum ibuprofen concentration following both doses, and a fall to sub-optimal serum concentrations following the 200 mg dose. During the first 2 h after the 200 mg dose, dental extraction resulted in a significant reduction of the area under serum drug concentration (AUC (0, 2 h) mg l-1 h) from 5.6+/-2.9 to 1.6+/-1.8 (P<0.01) and from 5.5+/-3.0 to 2.1+/-2.0 (P<0.05) for S and R-ibuprofen, respectively. Similar observations were made following the 600 mg dose for AUC (0, 2 h) of S-ibuprofen (from 14.2+/-6.1 to 7.2+/-5.5 mg l-1 h, P<0.05) with no significant difference for R-ibuprofen (from 14.4+/-9.5 to 5.8+/-7. 1). AUC (0, 6 h) was also significantly reduced by surgery. The pattern of stereoselectivity in serum ibuprofen concentration was reversed by surgery such that the S enantiomer was predominant in the control phase but not in the post-surgery phase, which is suggestive of reduced metabolic chiral inversion. CONCLUSIONS: Surgery for wisdom tooth removal resulted in substantial decreases in the serum concentration of ibuprofen enantiomers and a prolongation in the time to peak concentration. Reduced absorption and altered metabolism are the likely cause of these changes. Thus, dental patients may experience a delayed response and possible treatment failure when taking ibuprofen for pain relief after surgery. Our observation may have implications for the treatment of other diseases. (+info)
Altered reflex control of cutaneous circulation by female sex steroids is independent of prostaglandins.
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We tested the hypothesis that the shift in the cutaneous vasodilator response to hyperthermia seen with elevated female reproductive hormones is a prostaglandin-dependent resetting of thermoregulation to higher internal temperatures, similar to that seen in the febrile response to bacterial infection. Using water-perfused suits to control body temperature, we conducted heat stress experiments in resting women under conditions of low and high progesterone and estrogen and repeated these experiments after an acute dose of ibuprofen (800 mg). In six women the hormones were exogenous (oral contraceptives); three women had regular menstrual cycles and were tested in the early follicular and midluteal phases. Resting oral temperature (Tor) was significantly elevated with high hormone status (P < 0.05); this was not affected by ibuprofen treatment (P > 0.2). The Tor threshold for cutaneous vasodilation was significantly increased by high hormone status (+0.27 +/- 0.07 degrees C, P < 0. 02); the shift was not affected by ibuprofen treatment (with ibuprofen: +0.29 +/- 0.08 degrees C, P > 0.2 vs. control experiments). The Tor threshold for sweating was similarly increased by high hormone status (+0.22 +/- 0.05 degrees C, P < 0.05); this shift was not influenced by ibuprofen (with ibuprofen: +0.35 +/- 0. 05, P > 0.1 vs. control experiments). Thus the shift in thermoregulatory control of skin blood flow and sweating mediated by female reproductive steroids is not sensitive to ibuprofen; it therefore appears that this shift is independent of prostaglandins. (+info)
Down-regulation of nitric oxide production by ibuprofen in human volunteers.
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Ibuprofen has been shown in vitro to modulate production of nitric oxide (NO), a mediator of sepsis-induced hypotension. We sought to determine whether ibuprofen alters NO production and, thereby, vascular tone, in normal and endotoxin-challenged volunteers. Techniques for detecting NO were validated in 17 subjects infused with sodium nitroprusside, a NO donor. Then, endotoxin (4 ng/kg) or saline (vehicle alone) was administered in a single-blinded, crossover design to 12 other subjects randomized to receive either ibuprofen (2400 mg p.o.) or a placebo. Endotoxin decreased mean arterial pressure (MAP; P =.002) and increased alveolar NO flow rates (P =.04) and urinary excretion of nitrite and nitrate (P =.07). In both endotoxemic and normal subjects, ibuprofen blunted the small fall in MAP associated with bed rest (P =.005) and decreased alveolar NO flow rates (P =.03) and urinary excretion of nitrite and nitrate (P =.02). However, ibuprofen had no effect on the decrease in MAP caused by endotoxin, although it blocked NO production to the point of disrupting the normal relationship between increases in exhaled NO flow rate and decreases in MAP (P =.002). These are the first in vivo data to demonstrate that ibuprofen down-regulates NO in humans. Ibuprofen impaired the NO response to bed rest, producing a small rise in blood pressure. Although ibuprofen also interfered with the ability of endotoxin to induce NO production, it had no effect on the fall in blood pressure, suggesting that the hemodynamic response to endotoxin is not completely dependent on NO under these conditions. (+info)
Induction of stromelysin gene expression by tumor necrosis factor alpha is inhibited by dexamethasone, salicylate, and N-acetylcysteine in synovial fibroblasts.
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Proinflammatory cytokines, altered connective tissue metabolism, and overexpression of matrix metalloproteinases (MMPs) such as stromelysin compared to tissue inhibitors of metalloproteinases (TIMPs) result in synovial inflammation and erosion of arthritic cartilage. Tumor necrosis factor alpha (TNF-alpha) is a major synovial inflammatory mediator responsible for inhibiting extracellular matrix (ECM) synthesis and stimulating degradation of cartilage ECM by activated MMPs in arthritic joints. To suppress these effects and to gain insight into the mechanism of TNF-alpha action, we identified the inhibitors of TNF-alpha stimulation of stromelysin gene expression. In bovine synovial fibroblasts, TNF-alpha did not affect a recently identified inhibitor, TIMP-3, but induced stromelysin mRNA expression in a dose- and time-dependent fashion (3- to 5-fold) which required de novo protein synthesis. Stimulation by TNF-alpha was potently inhibited (99-100%) by the synthetic glucocorticoid, dexamethasone. Sodium salicylate dose-dependently inhibited (100%) the TNF-alpha action. Indomethacin and ibuprofen were partially inhibitory. Free radical scavenger antioxidant, N-acetylcysteine (but not other antioxidants) also suppressed the TNF-alpha induction (36-100%) of stromelysin suggesting involvement of reactive oxygen species in the induction process. TNF-alpha induction of stromelysin gene expression can therefore be inhibited at the gene expression level by several pharmacological agents which are likely to function via arachidonic acid metabolites, free radical scavenging or interference with the activator protein 1, polyoma virus enhancer A-binding protein 3, and nuclear factor kappaB classes of transcription factors. Our results may help to elucidate the mechanism of TNF-alpha action and explain the beneficial role of these agents in the treatment of inflammatory diseases. (+info)
Age and renal prostaglandin inhibition during exercise and heat stress.
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Aging is associated with a number of physiological changes that may cause the kidney to rely to a greater extent on vasodilatory PGs for normal functioning. Acute exercise has been shown to cause renal vasoconstriction that may be partially buffered by vasodilatory PGs. To determine the relative importance of renal PGs during exercise in older adults, we compared the renal effects of the PG inhibitor ibuprofen (1.2 g/day for 3 days) vs. a placebo control in a cohort of eight younger (24 +/- 2 yr) and eight older (64 +/- 2 yr) women during treadmill exercise ( approximately 57% maximal oxygen consumption) in the heat (36 degrees C). This over-the-counter dose of ibuprofen reduced renal PG (i.e., PGE2) excretion by 47% (P < 0. 05). Acute exercise in the heat caused dramatic decreases in glomerular filtration rate, renal blood flow, and sodium excretion in both age groups. PG inhibition was associated with greater decreases in urine production and free water clearance (P < 0.05). There were no drug-related declines in glomerular filtration rate or renal blood flow. We conclude that PG inhibition has only modest effects on renal function during exercise. Also, the lack of hemodynamic changes with PG inhibition indicates that healthy well-hydrated older women are not in a renal PG-dependent state. (+info)
Specific inhibition of cyclooxygenase-2 with MK-0966 is associated with less gastroduodenal damage than either aspirin or ibuprofen.
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BACKGROUND: Compared with currently available NSAIDs (which inhibit COX-1 and COX-2 isoforms of cyclooxygenase), MK-0966 (a specific COX-2 inhibitor) is expected to cause less gastrointestinal toxicity. AIM: To compare the effect on the upper gastrointestinal mucosae of a high dose of MK-0966 with that of conventional doses of ibuprofen and aspirin. METHODS: Healthy subjects (n = 170; age range 18-54 years) with endoscopically normal gastric and duodenal mucosa were randomized to either MK-0966 250 mg q.d. (n = 51), ibuprofen 800 mg t.d.s. (n = 51), aspirin 650 mg q.d.s. (n = 17), or placebo (n = 51) in this 7-day, double-blind, parallel-group study. The mucosae were evaluated by endoscopy using a predefined scale; scores could range from 0 to 4. The primary end-point was the percentage of subjects who developed a mucosal score >/= 2 (i.e. the development of one or more erosions). To evaluate COX-1 activity, serum thromboxane B2 levels were determined in a subset of the population. RESULTS: The percentage of subjects who developed a mucosal score >/= 2 in the MK-0966 group (12%) was significantly lower (P < 0.001) than that in the ibuprofen (71%) and aspirin (94%) groups, and was similar to that in the placebo group (8%). Only ibuprofen and aspirin significantly (P < 0.0001) reduced baseline thromboxane B2 levels. All treatments were generally well tolerated. CONCLUSIONS: In this acute short-term endoscopic study, MK-0966 250 mg q.d. (a dose at least 10 times higher than that demonstrated to reduce the signs and symptoms of osteoarthritis) produced significantly less gastrointestinal mucosal damage than either ibuprofen 800 mg t.d.s. or aspirin 650 mg q.d.s. and was comparable to placebo in this regard. (+info)
Gastrointestinal safety and tolerance of ibuprofen at maximum over-the-counter dose.
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BACKGROUND: Delineation of non-steroidal anti-inflammatory drug (NSAID) gastrointestinal toxicity has largely depended on retrospective epidemiologic studies which demonstrate that lower doses of NSAIDs pose a lower risk of gastrointestinal toxicity. Ibuprofen, a propionic acid NSAID, has, in most such studies, exhibited a favourable profile in terms of gastrointestinal bleeding. Since 1984, ibuprofen has been available as a non-prescription analgesic/antipyretic with a limit of 1200 mg/day for 10 days of continuous use. Trials and spontaneously reported adverse experiences suggest that gastrointestinal symptoms and bleeding are rare. METHODS: This study prospectively evaluated the gastrointestinal tolerability, as compared to placebo, of the maximum non-prescription dose and duration of ibuprofen use in healthy subjects representative of a non-prescription analgesic user population. RESULTS: Gastrointestinal adverse experiences were similar in the placebo and ibuprofen groups (67 out of 413, 16% with placebo vs. 161 out of 833, 19% with ibuprofen). There was no difference between the two groups in the proportion discontinuing due to a gastrointestinal event. Gastrointestinal adverse experiences reported by >/= 1% of subjects were: dyspepsia, abdominal pain, nausea, diarrhoea, flatulence, and constipation. Seventeen (1.4%) subjects had positive occult blood tests: their frequency was comparable between treatments. CONCLUSIONS: When used as directed to treat episodic pain, non-prescription ibuprofen at the maximum dose of 1200 mg/day for 10 days, is well-tolerated. (+info)
The efficacy of a novel adenosine agonist (WAG 994) in postoperative dental pain.
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AIMS: To determine the comparative efficacy of a new novel adenosine agonist (WAG 994) in postoperative pain after third molar surgery. METHODS: One hundred and twenty-two patients with postoperative pain after third molar surgery were randomised in a placebo double-blind trial with an active control group. In the early postoperative period patients received either a single dose of WAG 994 1 mg, ibuprofen 400 mg or matched placebos. Pain intensity score was recorded on serial visual analogue scales over a 6 h investigation period. Similarly, pain relief was completed on a 4 point categorical scale at each evaluation point. Patients had access to escape analgesic and if these were taken, the time and dosage were recorded. A sparse sampling technique was used to investigate the relationship between analgesic effects and plasma concentrations of WAG 994. RESULTS: All three treatment groups were matched for various demographic variables. For all efficacy measures, WAG 994 was not significantly different from placebo (P >0.05), whereas ibuprofen 400 mg was significantly superior to placebo (P<0.001). No significant relationships (P<0.05) were found between WAG 994 pharmacokinetic variables and efficacy measures. Conclusion WAG 994, an adenosine agonist, did not show efficacy in the management of postoperative pain after third molar surgery. Although this pain responds well to nonsteroidal anti-inflammatory drugs, it appears to be resistant to compounds that interact with purinergic receptors. (+info)