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Mechanistic studies of the metabolic chiral inversion of (R)-ibuprofen in humans.

Baillie TA, Adams WJ, Kaiser DG, Olanoff LS, Halstead GW, Harpootlian H, Van Giessen GJ.

Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle.

The metabolic chiral inversion of R-(-)-ibuprofen has been studied in human subjects by means of specific deuterium labeling and stereoselective gas chromatography-mass spectrometry methodology. After simultaneous p.o. administration of a mixture of R-(-)-ibuprofen (300 mg) and R-(-)-[3,3,3-2H3]ibuprofen (304 mg) to four adult male volunteers, the enantiomeric composition and deuterium content of the drug in serum, and of the drug and its principal metabolites in urine, were followed over a period of 24 hr. The results of these analyses indicated that: 1) conversion of R-(-)- to S-(+)-ibuprofen takes place with complete retention of deuterium at the beta-methyl (C-3) position; 2) chiral inversion of R-(-)-[2H3]ibuprofen is not subject to a discernible deuterium isotope effect; and 3) replacement of the beta-methyl hydrogen atoms by deuterium has no effect on any of the serum pharmacokinetic parameters for R-(-)- or S-(+)-ibuprofen. These data indicate that the process whereby R-(-)-ibuprofen undergoes metabolic inversion in human subjects does not involve 2,3-dehydroibuprofen as an intermediate, and that the underlying mechanism cannot, therefore, entail a desaturation/reduction sequence.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2724138&dopt=Abstract ibuprofen Motrin



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Influence of ibuprofen on renal function in acutely endotoxemic dogs.

Beck RR, Abel FL, Papadakis E.

Department of Physiology, School of Medicine, University of South Carolina, Columbia 29208.

Dogs were anesthetized with pentobarbital and instrumented to measure renal function. An inulin infusion was started; after an appropriate equilibration period one group was infused with endotoxin only (ETOX), a second group was pretreated with ibuprofen before (PRET) endotoxin, and a third group was post-treated with ibuprofen after (POST) endotoxin. Renal blood flow decreased in all animals, but renal vascular resistance increased only in the POST group animals. Urine flow and osmolar clearance decreased and free water clearance increased in the post-treated animals. Glomerular filtration rate as well as electrolyte excretion decreased in both the ETOX and POST group animals. Renal glucose output was unchanged in the ETOX and POST groups, but in the ibuprofen-pretreated animals there was significant net uptake, indicating increased utilization. Ibuprofen alone had no significant effect on blood flow, renal resistance, filtration rate, or solute and water handling. However, when ibuprofen was given 30 min after the induction of endotoxemia, the changes brought about by endotoxin alone were further intensified.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2731320&dopt=Abstract ibuprofen Motrin



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Comparison of home occult blood tests and interaction of tests with ibuprofen.

Collins CL, DeTullio PL, Berardi RR, Elta GH, Patterson RW.

University of Michigan College of Pharmacy, Ann Arbor 48109.

The interaction of ibuprofen with home tests for occult blood was evaluated, and the accuracy of these tests was determined by validating the results with a specific quantitative assay of stool blood. Three home occult blood tests were evaluated: Early Detector, Fleet Detecatest, and CS-T Coloscreen Self Test. Fourteen men 19 to 35 years of age were instructed on how to use the tests and to record each day their dietary intake and stool consistency, the color of test control areas, the results, and the times of ibuprofen administration. The study consisted of a control period (days 0-5) and short-term (days 6-9) and long-term (days 10-14) ibuprofen periods. Each subject took two 200-mg tablets of ibuprofen three times daily beginning on day 6 and ending on day 14. During each study period, one stool sample was collected on each of three consecutive days. All three tests were performed on each sample, in addition to specific quantitative analysis with HemoQuant. All samples in the control period were negative for occult blood. Three positive results were reported by subject 4 in the short-term ibuprofen period, one with Fleet Detecatest and two with Early Detector. Subject 6 reported two positive Fleet Detecatest results and three positive Early Detector results during the long-term drug period. No positive results were detected with CS-T Coloscreen Self Test. The HemoQuant values showed that Early Detector produced one false-negative and two false-positive results.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2752699&dopt=Abstract ibuprofen Motrin



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A direct role of endogenous prostaglandins in reperfusion-induced cardiac arrhythmias.

Moffat MP, Ferrier GR, Karmazyn M.

Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.

The possible role of prostaglandins (PG) in arrhythmias associated with ischemia and reperfusion was studied in isolated, superfused canine Purkinje tissues. Ischemic conditions caused partial depolarization and decrease of excitability. Neither inhibition of PG synthesis (ibuprofen, 30 micrograms/mL) nor addition of exogenous PGF2 alpha (1 ng/mL) modified responses to "ischemia." Reperfusion with normal Tyrode's solution stimulated PG production (measured as 6-keto-PGF1 alpha) and induced a series of electrophysiological events. Under control conditions, Purkinje fibres rapidly repolarized. Subsequently, these tissues began to depolarize and oscillatory afterpotentials appeared. Purkinje tissues depolarized further and became temporarily inexcitable. Return of activity was associated with depolarization-induced automaticity. Ibuprofen prevented reperfusion-stimulated PG release. Ibuprofen also increased the magnitude of early repolarization and greatly attenuated subsequent depolarization. Depolarization-induced automaticity was not observed under these conditions; however, oscillatory afterpotentials were not abolished by ibuprofen. Addition of PGF2 alpha to "ischemic" and reperfusion solutions in the presence of ibuprofen restored the arrhythmogenic responses. We conclude that release of endogenous prostaglandins contributes to electrophysiological changes elicited by reperfusion in canine Purkinje fibres.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2766109&dopt=Abstract ibuprofen Motrin



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Therapeutically relevant differences in the pharmacokinetical and pharmaceutical behavior of ibuprofen lysinate as compared to ibuprofen acid.

Geisslinger G, Dietzel K, Bezler H, Nuernberg B, Brune K.

Department of Pharmacology and Toxicology, University of Erlangen-Nuremberg, FRG.

The pharmacokinetic properties of ibuprofen p.o. given either as a lysine salt or as acid to eight young, healthy male volunteers was investigated. Ibuprofen lysinate, administered after overnight fasting, produced peak plasma concentrations significantly earlier and higher than ibuprofen acid. A similar difference was observed when the drugs were given following a standardized breakfast. Under these conditions the lat-time was significantly shorter for the lysine salt than for the acid. The pharmacokinetic differences are likely to result from the faster dissolution rate of ibuprofen lysinate. They indicate that the administration of ibuprofen as lysine salt before meals may be advantageous if rapid and reliable onset of pain relief is required.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2777420&dopt=Abstract ibuprofen Motrin



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Mechanisms of late hemodynamic and airway dynamic responses to endotoxin in awake sheep.

Wright PE, Bernard GR.

Department of Medicine, Vanderbilt University, Nashville, Tennessee.

The mechanism of sustained alterations in pulmonary hemodynamics and lung mechanics after endotoxin infusion in sheep remains unclear. We examined the effects of metaproterenol, propranolol, atropine, and ibuprofen on pulmonary artery pressure (Ppa), dynamic compliance (Cdyn), resistance to airflow across the lungs (RL), specific airway conductance (SGaw), and alveolar-arterial oxygen difference (delta AaPO2) (room air) given 2.5 h after endotoxemia (except for propranolol, which was given 1 h after metaproterenol) in awake sheep. Atropine infusion had no effect on any of the variables measured. Ibuprofen infusion immediately reduced mean Ppa from 31 +/- 2 (mean +/- SEM) to 24 +/- 2 cm H2O (p less than 0.05). Metaproterenol and ibuprofen immediately increased Cdyn and SGaw and decreased RL to near baseline (p less than 0.05). No intervention affected delta AaPO2 (p greater than 0.05). In sheep treated with metaproterenol, propranolol immediately returned lung mechanics (p less than 0.05) to premetaproterenol levels without affecting delta AaPO2 (p greater than 0.05). Ibuprofen reduced lung lymph thromboxane-B2 towards baseline levels (p less than 0.05). We conclude that endotoxemia causes prolonged bronchoconstriction and pulmonary hypertension in sheep, which is largely mediated by constrictor prostanoids rather than by cholinergic mechanisms and is reversible with ibuprofen given 2.5 h after endotoxin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2782739&dopt=Abstract ibuprofen Motrin



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Interaction of ibuprofen and warfarin on primary haemostasis.

Schulman S, Henriksson K.

Department of Internal Medicine, Karolinska Hospital, Stockholm, Sweden.

It has been stated that ibuprofen can be safely prescribed with concomitant warfarin. The effect of ibuprofen on primary haemostasis was investigated in 20 patients on warfarin for venous thromboembolism. Ibuprofen, 600 mg orally t.i.d., was added for 1 week. Bleeding time, prothrombin time, platelet count and urinalysis for haemoglobin were performed before and 90 minutes after the first dose and after 1 week. The bleeding time was significantly prolonged after 90 minutes (p less than 0.01) and after 1 week (p less than 0.05) and in four cases it was prolonged above the normal range. No clinical side-effects were observed apart from microscopic haematuria and haematoma. Thus, ibuprofen may cause clinical problems in some patients treated with warfarin, particularly in the elderly on complex drug regimens. It is advisable to check the bleeding time a few days after treatment with ibuprofen has been started in patients already on oral anticoagulation, and discontinue the former if the bleeding time is prolonged above the normal range.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2783873&dopt=Abstract ibuprofen Motrin



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Ibuprofen causes reduced toxic effects of interleukin 2 administration in patients with metastatic cancer.

Eberlein TJ, Schoof DD, Michie HR, Massaro AF, Burger U, Wilmore DW, Wilson RE.

Division of Surgical Oncology, Brigham & Women's Hospital, Boston, MA 02115.

Metastatic cancer was treated with interleukin 2 and lymphokine-activated killer cells with the addition of the cyclooxygenase inhibitor ibuprofen in an attempt to reduce side effects in 13 patients (eight male and five female). Twenty-six patients treated with only interleukin 2 and lymphokine-activated killer cells formed the control group. After interleukin 2 administration, a significantly increased number of lymphokine-activated killer cells were transfused in ibuprofen-treated patients. Cytotoxic effects were not significantly different in the treated and untreated groups. With regard to cell phenotype, both groups of patients manifested significant activation of the immune system as measured by T10 and OK1a. Symptom scores were dramatically reduced in patients treated with ibuprofen. Temperature above 37 degrees C were rare. Ibuprofen did not significantly alter rate of response in this immunotherapy trial (38% vs 42%). Ibuprofen is now routinely used in all of our current immunotherapy trials.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2785376&dopt=Abstract ibuprofen Motrin