Simultaneous fitting of R- and S-ibuprofen plasma concentrations after oral administration of the racemate.
(73/808)
AIMS: To assess the pharmacokinetic equivalence of two different formulations of ibuprofen lysinate with special focus on the expected effects. METHODS: Sixteen healthy volunteers received cross-over ibuprofen lysinate as either one tablet of 400 mg ('test') or two tablets of 200 mg ('reference'). Ibuprofen plasma concentrations were followed up for 10 h. Bioequivalence was assessed by standard noncompartmental methods. Ibuprofen plasma concentrations were fitted with a model that took bioinversion of R- to S-ibuprofen into account. RESULTS: Peak plasma concentrations of R- and S-ibuprofen were 18.1 and 20 microg ml(-1) (test), and 18.2 and 20 microg ml(-1) (reference). Areas under the plasma concentration vs. time curves were 39.7 and 67.5 microg ml(-1) h (test), and 41.1 and 68.2 microg ml(-1) h (reference). Clearance of R-ibuprofen was 5.2 (test) and 5 l h(-1) (reference). A specific plasma concentration was reached with the test formulation about 5 min later than with the reference. Parameters from compartmental modelling were (given for R-and then for S-ibuprofen): body clearance: 4.9 and 4.64 l h(-1), central volume of distribution: 2.8 and 4.1 l, intercompartment clearance: 5.1 and 5.45 l h(-1), peripheral volume of distribution: 4.1 and 5.2 l. The absorption rate constant was 1.52 h(-1), and the test but not the reference formulation had a lag time of 0.1 h. Simulations showed similarity between formulations of the expected effects except for a calculated delay of 6 min with the test formulation. CONCLUSIONS: Ibuprofen formulations were bioequivalent. The pharmacokinetic model may serve as a basis for future pharmacokinetic/pharmacodynamic calculations after administration of racemic ibuprofen. (+info)
Vascularization pattern of C6 glioma is modified with medroxyprogesterone acetate and ibuprofen in Wistar rat brain.
(74/808)
Beneficial effects of medroxyprogesterone acetate (MPA) in cancer therapy is partly mediated via its antiangiogenic activity. The same is true for the antitumoral action of non-steroidal antiinflammatory drugs. We have studied two liposoluble drugs, MPA and the analgesic ibuprofen, on glioma vascularization in vivo. In this study we have shown that, until the sacrifice at 27. day after tumor inoculation in the right hemisphere, MPA had a slight though insignificant activity to reduce the fatality of C6 glioma, growing in right cerebral hemisphere of male Wistar rats. But ibuprofen both alone or with MPA had no effect on survival with gavage application of a 30 mg/kg/day dosing regime. On histological analysis, intra- and peritumoral vessels were counted. Progesterone seemed to lower intratumoral, but to increase peritumoral vessels, especially glomeruloids, around the tumor mass. Coadministration of ibuprofen acted to suppress the peritumoral vessel increase, and to enhance lymphomonocytic infiltration around tumor vessels. (+info)
Ibuprofen versus acetaminophen with codeine for the relief of perineal pain after childbirth: a randomized controlled trial.
(75/808)
BACKGROUND: Pain from episiotomy or tearing of perineal tissues during childbirth is often poorly treated and may be severe. This randomized double-blind controlled trial was performed to compare the effectiveness, side effects and cost of, and patient preference for, 2 analgesics for the management of postpartum perineal pain. METHODS: A total of 237 women who gave birth vaginally with episiotomy or a third- or fourth-degree tear between August 1995 and November 1996 at a tertiary-level teaching and referral centre for obstetric care in Vancouver were randomly assigned to receive either ibuprofen (400 mg) (n = 127) or acetaminophen (600 mg) with codeine (60 mg) and caffeine (15 mg) (Tylenol No. 3) (n = 110), both given orally every 4 hours as necessary. Pain ratings were recorded before the first dose and at 1, 2, 3, 4, 12 and 24 hours after the first dose on a 10-cm visual analogue scale. Side effects and overall opinion were assessed at 24 hours. RESULTS: Ibuprofen and acetaminophen with codeine had similar analgesic properties in the first 24 hours post partum (mean pain rating 3.4 and 3.3, mean number of doses in 24 hours 3.4 and 3.3, and proportion of treatment failures 13.8% [16/116] and 16.0% [16/100] respectively). Significantly fewer subjects in the ibuprofen group than in the acetaminophen with codeine group experienced side effects (52.4% v. 71.7%) (p = 0.006). There were no significant differences in overall patient satisfaction between the 2 groups. The major determinant of pain intensity was forceps-assisted delivery. Overall, 78% of the treatment failures were in women with forceps-assisted deliveries. INTERPRETATION: Since the 2 analgesics were rated similarly, ibuprofen may be the preferred choice because it is less expensive and requires less nursing time to dispense. Further studies need to address improved analgesia for women with forceps-assisted deliveries. (+info)
A high level of cyclooxygenase-2 inhibitor selectivity is associated with a reduced interference of platelet cyclooxygenase-1 inactivation by aspirin.
(76/808)
Both nonsteroidal anti-inflammatory drugs, such as ibuprofen, and the prototypical selective cyclooxygenase (Cox)-2 inhibitors DuP-697 and NS-398 block the inhibition of Cox-1 by aspirin in vitro. However, clinical studies have shown that the Cox-2 selective drugs (or coxibs) rofecoxib and etoricoxib, at therapeutic doses, do not interfere with the antiplatelet effect of aspirin, in contrast to ibuprofen. Here, we have evaluated the relative potential of ibuprofen and various coxibs to interfere with the inactivation of Cox-1 by aspirin by using purified enzyme and calcium ionophore-activated human platelets. The irreversible inactivation of Cox-1 by aspirin can be antagonized by ibuprofen and coxibs, albeit with widely different potencies. The rank order of potencies for this process (ibuprofen > celecoxib > valdecoxib > rofecoxib > etoricoxib) parallels that obtained for the inhibition of Cox-1-mediated thromboxane B(2) production by calcium ionophore-stimulated platelets. The antagonism of aspirin therefore likely involves a competition at the enzyme active site. The EC(50) value for the antagonism against 10 microM aspirin for each drug is approximately 10- to 40-fold lower than the corresponding IC(50) value for inhibition of platelet Cox-1 activity, consistent with the much weaker initial binding of aspirin to Cox-1 as compared with arachidonic acid. These results show that a low affinity for Cox-1 and a high degree of Cox-2 selectivity confers a low potential to block aspirin inhibition of platelet Cox-1, consistent with the results of clinical studies. (+info)
Tramadol and acetaminophen tablets for dental pain.
(77/808)
The purpose of this work was to compare the efficacy and time to analgesia of a new tramadol/acetaminophen combination tablet to those of tramadol or acetaminophen (APAP) alone. A meta-analysis was performed of 3 separate single-dose, double-blind, parallel-group trials in patients with moderate or severe pain following extraction of 2 or more third molars. Patients in each study were evenly randomized to a single dose of tramadol/APAP (75 mg/650 mg), tramadol 75 mg, APAP 650 mg, ibuprofen 400 mg, or placebo. Active control with ibuprofen was used to determine model sensitivity. Pain relief (scale, 0-4) and pain intensity (scale, 0-3) were reported at 30 minutes after the dose and then hourly for 8 hours. Total pain relief over 8 hours (TOTPAR8) and the sum of pain intensity differences (SPID8) were calculated from the hourly scores. Time to onset of pain relief was determined by the double-stopwatch technique, and patients were advised to wait at least 2 hours before taking supplemental analgesia. Patients assessed overall efficacy (scale, 1-5) upon completion. In all, 1197 patients (age range, 16-46 years) were evaluable for efficacy; treatment groups in each study were similar at baseline. Pain relief was superior to placebo (P < or = .0001) for all treatments. Pain relief provided by tramadol/ APAP was superior to that of tramadol or APAP alone, as shown by mean TOT-PAR8 (12.1 vs 6.7 and 8.6, respectively, P < or = .0001) and SPID8 (4.7 vs 0.9 and 2.7, respectively, P < or = .0001). Estimated onset of pain relief was 17 minutes (95% CI, 15-20 minutes) for tramadol/APAP compared with 51 minutes (95% CI, 40-70 minutes) for tramadol, 18 minutes (95% CI, 16-21 minutes) for APAP, and 34 minutes (95% CI, 28-44 minutes) for ibuprofen. Median time to supplemental analgesia and mean overall assessment of efficacy were greater (P < .05) for the tramadol/APAP group (302 minutes and 3.0, respectively) than for the tramadol (122 minutes and 2.0) or APAP (183 minutes and 2.7) monotherapy groups. A new combination analgesic, tramadol/APAP, is superior to tramadol or APAP alone with respect to pain relief and duration of action. It is also superior to tramadol alone with respect to time to onset. (+info)
Effect of ibuprofen and warfarin on the allosteric properties of haem-human serum albumin. A spectroscopic study.
(78/808)
Haem binding to human serum albumin (HSA) endows the protein with peculiar spectroscopic properties. Here, the effect of ibuprofen and warfarin on the spectroscopic properties of ferric haem-human serum albumin (ferric HSA-haem) and of ferrous nitrosylated haem-human serum albumin (ferrous HSA-haem-NO) is reported. Ferric HSA-haem is hexa-coordinated, the haem-iron atom being bonded to His105 and Tyr148. Upon drug binding to the warfarin primary site, the displacement of water molecules--buried in close proximity to the haem binding pocket--induces perturbation of the electronic absorbance properties of the chromophore without affecting the coordination number or the spin state of the haem-iron, and the quenching of the 1H-NMR relaxivity. Values of Kd for ibuprofen and warfarin binding to the warfarin primary site of ferric HSA-haem, corresponding to the ibuprofen secondary cleft, are 5.4 +/- 1.1 x 10(-4) m and 2.1 +/- 0.4 x 10(-5) m, respectively. The affinity of ibuprofen and warfarin for the warfarin primary cleft of ferric HSA-haem is lower than that reported for drug binding to haem-free HSA. Accordingly, the Kd value for haem binding to HSA increases from 1.3 +/- 0.2 x 10(-8) m in the absence of drugs to 1.5 +/- 0.2 x 10(-7) m in the presence of ibuprofen and warfarin. Ferrous HSA-haem-NO is a five-coordinated haem-iron system. Drug binding to the warfarin primary site of ferrous HSA-haem-NO induces the transition towards the six-coordinated haem-iron species, the haem-iron atom being bonded to His105. Remarkably, the ibuprofen primary cleft appears to be functionally and spectroscopically uncoupled from the haem site of HSA. Present results represent a clear-cut evidence for the drug-induced shift of allosteric equilibrium(a) of HSA. (+info)
Determinants of renal microvascular response to ACh: afferent and efferent arteriolar actions of EDHF.
(79/808)
The renal microvascular actions of ACh were investigated using the in vitro perfused hydronephrotic rat kidney. ACh reversed ANG II-induced vasoconstriction in the afferent and efferent arteriole by 106 +/- 2 and 75 +/- 5%, respectively. Inhibition of nitric oxide synthase [NOS; 100 micromol/l N(G)-nitro-L-arginine methyl ester (L-NAME)] and cyclooxygenase (COX; 10 micromol/l ibuprofen) prevented the sustained response of the afferent arteriole but did not reduce the magnitude of the initial dilation (97 +/- 7%). However, NOS/COX inhibition abolished the response of the efferent arteriole. The underlying mechanisms mediating this endothelium-derived hyperpolarizing factor (EDHF)-like response were characterized using K channel blockers. Ba (100 micromol/l), tetraethylammonium (1 mmol/l), and ouabain (3 mmol/l) had no effect, arguing against a role of an inward rectifier K channel, large-conductance Ca-activated K channel, or Na,K-ATPase. Charybdotoxin (10 nmol/l) and apamin (1.0micromol/l) attenuated the response when administered alone (63 +/- 7% and 37 +/- 5%, respectively) and abolished the response when coadministered (0.1 +/- 1.0%). These findings indicate that, as in other vascular beds, the renal EDHF-like response to ACh involves K channels that are sensitive to a combination of apamin and charybdotoxin. Our finding that EDHF modulates preglomerular, but not postglomerular, tone is consistent with the evolving concept that vasomotor mechanisms in cortical efferent arterioles do not involve voltage-gated Ca entry. (+info)
Cyclooxygenase inhibitors and the antiplatelet effects of aspirin.
(80/808)
BACKGROUND: Patients with arthritis and vascular disease may receive both low-dose aspirin and other nonsteroidal antiinflammatory drugs. We therefore investigated potential interactions between aspirin and commonly prescribed arthritis therapies METHODS: We administered the following combinations of drugs for six days: aspirin (81 mg every morning) two hours before ibuprofen (400 mg every morning) and the same medications in the reverse order; aspirin two hours before acetaminophen (1000 mg every morning) and the same medications in the reverse order; aspirin two hours before the cyclooxygenase-2 inhibitor rofecoxib (25 mg every morning) and the same medications in the reverse order; enteric-coated aspirin two hours before ibuprofen (400 mg three times a day); and enteric-coated aspirin two hours before delayed-release diclofenac (75 mg twice daily) RESULTS: Serum thromboxane B(2) levels (an index of cyclooxygenase-1 activity in platelets) and platelet aggregation were maximally inhibited 24 hours after the administration of aspirin on day 6 in the subjects who took aspirin before a single daily dose of any other drug, as well as in those who took rofecoxib or acetaminophen before taking aspirin. In contrast, inhibition of serum thromboxane B(2) formation and platelet aggregation by aspirin was blocked when a single daily dose of ibuprofen was given before aspirin, as well as when multiple daily doses of ibuprofen were given. The concomitant administration of rofecoxib, acetaminophen, or diclofenac did not affect the pharmacodynamics of aspirin CONCLUSIONS: The concomitant administration of ibuprofen but not rofecoxib, acetaminophen, or diclofenac antagonizes the irreversible platelet inhibition induced by aspirin. Treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin. (+info)