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Disposition of ibuprofen in patients with liver cirrhosis. Stereochemical considerations.

Li G, Treiber G, Maier K, Walker S, Klotz U.

Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Federal Republic of Germany.

Following a single oral dose of racemic ibuprofen 600mg the stereoselective disposition of its enantiomers was studied in 8 patients with moderate to severe cirrhosis. Compared with the elimination half-life (t1/2) of (-)-R- and (+)-S-ibuprofen in 8 healthy age-matched controls (1.7 +/- 0.3h and 1.8 +/- 0.5h, respectively), t1/2 was prolonged significantly (p < 0.045 and < 0.001, respectively) in patients with cirrhosis (t1/2 = 3.1 +/- 1.7h and 3.4 +/- 1.0h, respectively). Whereas the low amounts excreted unchanged into urine differed slightly in both groups studied, much less (p < 0.01) conjugated ibuprofen was recovered either as the R-enantiomer (0.9 +/- 0.4% vs 4.1 +/- 2.8% of the dose) or the S-enantiomer (6.4 +/- 2.5% vs 26.5 +/- 12.9% of the dose) in patients with cirrhosis. Metabolic inversion of the inactive (-)-R-ibuprofen to the active (+)-S-ibuprofen may be impaired in hepatic dysfunction since the normal ratio of areas under the curve (AUC) for R- and S-enantiomers (0.79 +/- 0.18) was significantly (p < 0.02) higher in patients with cirrhosis (1.10 +/- 0.28). In a second study, a single oral dose of 400mg (+)-S-ibuprofen was administered to 8 healthy volunteers and 8 patients with cirrhosis. Elimination of this enantiomer was slightly impaired as could be seen from the prolonged t1/2 (1.6 +/- 0.1h vs 2.6 +/- 0.5h; p < 0.001) and the increase in AUC (101 +/- 35 vs 144 +/- 41 mg/L.h; p = 0.041). In conclusion, in patients with liver disease, hepatic elimination of ibuprofen is impaired. This should be taken into consideration especially if the racemic drug is used. Direct administration of the active (+)-S-enantiomer seems to offer less vulnerable treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8403739&dopt=Abstract ibuprofen Motrin



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Tumor necrosis factor-induced mortality is reversed with cyclooxygenase inhibition.

Fletcher JR, Collins JN, Graves ED 3rd, Luterman A, Williams MD, Izenberg SD, Rodning CB.

Department of Surgery, University of South Alabama, College of Medicine, Mobile.

OBJECTIVE: The authors hypothesized that TNF would induce eicosanoid synthesis, and a cyclooxygenase inhibitor would attenuate both eicosanoid synthesis and improve survival in an LD90 TNF-induced (150 ng/kg/i.v./5 min) mortality model. SUMMARY BACKGROUND DATA: Tumor necrosis factor is a cardinal mediator in sepsis; however, little is known about its effects on arachidonate metabolism. METHODS: Conscious male rats with carotid arterial and jugular venous catheters were randomized for mortality: group I, TNF alone (150 kg/i.v./15 min, n = 30); group II, ibuprofen (30 mg/kg/i.v. at t = -20 and +240 min), plus TNF, (n = 28); and for hemodynamics, eicosanoid synthesis, blood gases: group III, TNF alone, (n = 8); group IV, ibuprofen + TNF (n = 8); group V, monoclonal antibody to TNF plus TNF (n = 8). Mortality was determined at 4-72 hr. Other parameters determined over 4 hours (0, 5, 60, 120, 240 min). RESULTS: TNF stimulated synthesis of (a) TXB2 (71 +/- 30 pg/ml, mean +/- SE at base vs. 117 +/- 18 at 4 hr, p < 0.02); (b) PGE2 (70 +/- 6 pg/ml at base vs. 231 +/- 68 at 4 hr, p < 0.02); (c) 6PGF (52 +/- 6 pg/ml at base vs. 250 +/- 80 at 4 hr, p < 0.02). Ibuprofen significantly (p < 0.05) inhibited eicosanoid synthesis from TNF. TNF-induced mortality (87%, 26/30) was dramatically decreased with ibuprofen (11%, 3/28), at 4, 24, and 72 hr (p < 0.01). Monoclonal antibody to TNF prevented all abnormalities and had 100% survival. Hemodynamic events were similar in both groups, but metabolic acidosis was attenuated with ibuprofen. CONCLUSIONS: TNF stimulates arachidonic acid metabolism in vivo. A cyclooxygenase inhibitor attenuates eicosanoid synthesis and dramatically improves survival. TNF appears to have different effect on tissues that synthesize certain eicosanoids. Hypotension from TNF is not mediated via the eicosanoids. TNF-induced mortality, like endotoxemia/sepsis may be mediated, in part, via arachidonic acid metabolites. These new findings support the notion that cyclooxygenase inhibitors may be used as adjunctive therapy in clinical sepsis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8507112&dopt=Abstract ibuprofen Motrin



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Role of xanthine oxidase and prostaglandins in inflammatory-induced bacterial translocation.

Mainous MR, Xu D, Deitch EA.

Department of Surgery, LSU Medical Center, Shreveport 71130-3932.

We have previously documented that a nonlethal dose of zymosan causes gut mucosal injury associated with increased xanthine oxidase activity and bacterial translocation. The current study was performed to investigate the role of xanthine oxidase activation and other potential mediators of intestinal injury in an LD50 zymosan model. Specific pathogen-free rats and mice were pretreated with saline, allopurinol, or ibuprofen prior to intraperitoneal injection of either saline or the LD50 dose of zymosan. Bacterial translocation to the mesenteric lymph node and systemic organs was measured at 6 or 24 hr following injection. In addition, separate animals in each group were followed for 7 days for survival. Pretreatment with allopurinol or ibuprofen reduced both the incidence and the magnitude of translocation at 6 hr in rats and mice (P < 0.05). In the rats pretreated with allopurinol or ibuprofen, no reduction in the incidence or magnitude of translocation occurred at 24 hr. In the mice pretreated with allopurinol or ibuprofen, although the incidence of translocation was not reduced at 24 hr, the magnitude of translocation was reduced (P < 0.05). Pretreatment with allopurinol or ibuprofen also resulted in an improvement in survival, when compared to zymosan alone (P < 0.01). Allopurinol and ibuprofen provide protection against bacterial translocation and improvement in survival following challenge with a lethal dose of zymosan.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8508522&dopt=Abstract ibuprofen Motrin



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Stereoselective disposition of ibuprofen in patients with compromised renal haemodynamics.

Chen CY, Chen CS.

Department of Family Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.

1. The primary aim of this study was to assess the impact of renal haemodynamics on the pharmacokinetic behaviour of ibuprofen enantiomers. Thirty-two patients and ten age-matched healthy volunteers participated in this study. These patients had at least one of the following risk factors for cardiovascular disorders: hypertension, diabetes mellitus, hyperlipidaemia and hyperuricaemia with or without consequent complications such as coronary artery disease, congestive heart failure, cerebral vascular disease, and chronic renal failure. Renal function in these patients was thus characterized by unstable renal haemodynamics that might render them susceptible to ibuprofen-incurred renal damage. 2. Each subject received a single oral dose of 800 mg of racemic ibuprofen. The pharmacokinetic parameters of (S)- and (R)-ibuprofen, t 1/2(S), t 1/2(R), AUC(S), AUC(R), V/F(R), and CL/F(R), for each individual were determined from respective plasma concentration-time curves. To assess the effect of individual clinical conditions on the disposition of ibuprofen enantiomers, the arithmetic means of these pharmacokinetic parameters for each disease group were compared with those of the healthy volunteers by a t-test. 3. All of these disease groups showed elevated AUC(S) and higher (S)/(R) AUC ratios. These disease states along with gender and age were analyzed by multiple linear regression to discern significant factors for elevating AUC(S). Of these, advanced age (P = 0.02) and hypertension (P = 0.03) were identified as independent factors contributing to AUC(S) increase in this population. Thus, patients with these two clinical conditions are at particular risk from the adverse renal effect of ibuprofen.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8527270&dopt=Abstract ibuprofen Motrin



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Lack of effect of gender and oral contraceptive steroids on the pharmacokinetics of (R)-ibuprofen in humans.

Knights KM, McLean CF, Tonkin AL, Miners JO.

Department of Clinical Pharmacology, Flinders University of South Australia, Bedford Park.

The effects of gender and oral contraceptive steroids on the pharmacokinetics of (R)-ibuprofen were studied in groups of healthy adult males, females and oral contraceptive steroid (OCS) using females. The values of AUC, CLpo, t1/2 and Vss, app did not differ significantly between the groups. Similarly, the percentage unbound of (R)-ibuprofen in pooled plasma from the three groups was not statistically different. Since chiral inversion is the major determinant of (R)-ibuprofen clearance in humans, it may be inferred from these data that gender and OCS have little or no effect on conversion of (R)-ibuprofen to the pharmacologically active S-enantiomer. Moreover, it is unlikely that hormonal factors influence the activity of the human hepatic long-chain fatty-acid:CoA ligase, the enzyme mediating the rate limiting step of (R)-ibuprofen inversion.

PIP: In Australia, clinical researchers studied the effects of gender and oral contraceptive (OC) steroids on the pharmacokinetics of (R)-ibuprofen in 8 healthy adult males (mean age = 21 years), adult females (24 years), and OC users (22 years). There were no statistically significant differences between males, females, and OC users for any pharmacokinetic parameter for (R)-ibuprofen. These parameters included areas under the plasma total concentration-time curve (AUC), maximal plasma concentration, time to maximal plasma concentration, half-life, CLpo, and apparent steady-state volumes of distribution. The AUC to the last data point observed for (S)-ibuprofen (derived from (R)-ibuprofen) was similar, suggesting that hormonal factors do not affect plasma clearance of (S)-ibuprofen. The average percentages unbound of (R)- and (S)-ibuprofen across the concentration was not statistically different between the groups: 1.82% and 2.84% for males, 1.83% and 3.01% for females, and 2.1% and 2.97% for OC users, respectively. The mean fraction unbound of (S)-ibuprofen was 53.6% greater than that of (R)-ibuprofen. Since chiral inversion may explain 62-92% of (R)-ibuprofen clearance in humans, these data may suggest that gender and OCs do not effect or have only a limited effect on the conversion of (R)-ibuprofen to the pharmacologically active S-enantiomer. These findings indicate that hormonal factors probably do not affect the activity of the human hepatic long-chain fatty-acid:CoA ligase, the enzyme mediating the rate limiting step of (R)-ibuprofen inversion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8562298&dopt=Abstract ibuprofen Motrin



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Use of decimal assay for additivity to demonstrate synergy in pair combinations of econazole, nikkomycin Z, and ibuprofen against Candida albicans in vitro.

Tariq VN, Scott EM, McCain NE.

School of Biology and Biochemistry, Queen's University of Belfast, Northern Ireland, United Kingdom.

Interactions between six compounds (econazole, miconazole, amphotericin B, nystatin, nikkomycin Z, and ibuprofen) were investigated for their antifungal activities against Candida albicans by using pair combinations in an in vitro decimal assay for additivity based on disk diffusion. Additive interactions were observed between miconazole and econazole, amphotericin B and nystatin, and amphotericin B and ibuprofen, while an antagonistic interaction was observed between econazole and amphotericin B. Synergistic interactions were recorded for the combinations of econazole and ibuprofen, econazole and nikkomycin Z, and ibuprofen and nikkomycin Z.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8592989&dopt=Abstract ibuprofen Motrin



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Comparative effects of nabumetone, naproxen, piroxicam, and diclofenac on rat gastric irritancy following acute exposure to OTC non-steroidal anti-inflammatory agents and other gastric irritants.

Carryl OR, Spangler RS.

Procter and Gamble Company, Cincinnati, Ohio, USA.

This study examined the relative effects of equally-effective anti-inflammatory doses of nabumetone, naproxen, piroxicam and diclofenac on gastric irritancy induced by over-the-counter (OTC) non-steroidal anti-inflammatory drugs (NSAIDs) aspirin and ibuprofen and a variety of necrotizing agents (0.6 N HCl, 0.2 N NaOH and 25% NaCl). Within one hour, aspirin 100 and 200 mg/kg and ibuprofen up to 15 mg/kg produced significant gastric mucosal injury. Aspirin 50 mg/kg produced only minimal damage that was enhanced by 5 x ID25 piroxicam and naproxen, but not by nabumetone or diclofenac. 5 x ID25 naproxen, piroxicam, and diclofenac significantly enhanced mucosal damage produced by ibuprofen 2.5 mg/kg. An equivalent anti-inflammatory dose of nabumetone failed to enhance the gastric irritancy produced by ibuprofen 2.5 mg/kg. Similarly, naproxen, piroxicam, and diclofenac enhanced the susceptibility of the gastric mucosa to the necrotizing actions of 0.6 N HCl, 0.2 N NaOH or 25% NaCl. Naproxen, piroxicam, or diclofenac are more likely than nabumetone to enhance gastric mucosal injury produced by OTC NSAIDs (aspirin and ibuprofen) or other gastric irritants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8610216&dopt=Abstract ibuprofen Motrin



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Ibuprofen inhibits pyrogen-dependent expression of VCAM-1 and ICAM-1 on human endothelial cells.

Kapiotis S, Sengoelge G, Sperr WR, Baghestanian M, Quehenberger P, Bevec D, Li SR, Menzel EJ, Muhl A, Zapolska D, Virgolini I, Valent P, Speiser W.

Clin. Inst. of Med., Univ. Vienna, Austria.

Leukocyte adhesion and transmigration through the endothelial cell (EC) layer plays a crucial role in inflammation. IL-1 alpha and TNF alpha increase EC-adhesiveness for leukocytes by stimulating surface expression of ICAM-1 (intercellular adhesion molecule 1, CD54), VCAM-1 (vascular cell adhesion molecule 1, CD106) and E-selectin (CD62E). In this study, the effects of ibuprofen on IL-1 alpha and TNF alpha-induced expression of ICAM-1, VCAM-1 and E-selectin on cultured human umbilical vein EC (HUVEC) were analyzed. Exposure to IL-1 alpha or TNF alpha resulted in an increased expression of VCAM-1, ICAM-1, and E-selectin. Ibuprofen was identified as a potent inhibitor of IL-1 alpha and TNF alpha-induced surface expression of VCAM-1 and a less potent inhibitor of pyrogen-induced expression of ICAM-1, whereas no effect on E-selectin was found. The effects of ibuprofen on VCAM-1 expression were dose-dependent (IC50 [IL-1 alpha]: 0.5 mM; IC50 [TNF alpha]: 0.5 mM) and time-dependent with maximum responses observed after 18 h. Moreover, ibuprofen abrogated pyrogen-dependent adhesion of leukocytes to HUVEC. Ibuprofen also inhibited VCAM-1 mRNA expression in pyrogen activated EC. VCAM-1-downregulation on EC by ibuprofen may contribute to the anti-inflammatory actions of the drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8649201&dopt=Abstract ibuprofen Motrin