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Biomedical subjects

R R Osborn

Publications and source records attributed to R R Osborn.

32 records · Page 2Linked to original sources
PubMed1992

SK&F 104353, a selective leukotriene receptor antagonist, inhibits leukotriene D4- and antigen-induced bronchoconstriction in cynomolgus monkeys.

The ability of SK&F 104353 to prevent and reverse leukotriene (LT) D4- and antigen (Ag)-induced bronchoconstriction was examined in anesthetized, spontaneously breathing cynomolgus monkeys. Aerosol administration of LTD4 (10 micrograms/ml; 20 breaths) produced a sustained increase in pulmonary resistance and decrease in dynamic lung compliance. Aerosolized SK&F 104353 (150 breaths, 0.3 or 4.4 mg/ml) administered 15 min prior to LTD4 challenge antagonized these changes in a dose-dependent manner. When given intravenously 6 min after LTD4, SK&F 104353 (5 mg/kg) rapidly and completely reversed the ongoing bronchoconstriction. In mepyramine-pretreated (2 mg/kg i.v.) monkeys sensitive to aerosolized Ascaris suum Ag, intravenously administered SK&F 104353 (5 mg/kg) substantially reversed, but did not abolish, Ag-induced bronchoconstriction when administered 12 min after the Ag challenge. In contrast, SK&F 104353 (5 mg/kg i.v.) did not reverse Ag-induced bronchoconstriction in animals that had not been pretreated with mepyramine. Similar results were obtained when SK&F 104353 (20 mg/kg i.v.) was administered (as a pretreatment) 5 min prior to Ag under these conditions. Thus, SK&F 104353 reduced Ag-induced bronchoconstriction in mepyramine-pretreated monkeys, but had little effect in the absence of mepyramine. The data suggest that LTs, in addition to histamine, play a role in allergic bronchoconstriction in cynomolgus monkeys.

Administration, Inhalation↗
PubMed1991

Pharmacologic and pharmacokinetic profile of SK&F S-106203, a potent, orally active peptidoleukotriene receptor antagonist, in guinea-pig.

In this report the pharmacologic and pharmacokinetic profile of the leukotriene receptor antagonist 3(S)-[(2-carboxyethyl)thio]-3-[2-(8-phenyloctyl)phenyl] propanoic acid (SK&F S-106203) in guinea-pigs is described. In isolated guinea-pig tracheae SK&F S-106203 was a potent, competitive antagonist of leukotriene (LT) D4-induced contractions (pA2 = 7.6). SK&F S-106203 was also a potent antagonist of LTE4-induced contractions (pKB = 7.3), but had little effect on those elicited by LTC4 (pKB = 5.5). SK&F S-106203 (10 microM) had no effect on contractions produced by histamine, carbachol, KCl, U-44069, PGF2 alpha or PGD2. In addition, SK&F S-106203 (10 microM) did not inhibit cyclic nucleotide phosphodiesterase (PDE) activity of several PDE isozymes. In guinea-pig lung membrane preparations, SK&F S-106203 was a potent antagonist of 3H-LTD4 binding with a Ki = 19.4 +/- 2.1 nM (n = 5). The pharmacokinetic profile of SK&F S-106203 was determined in unanesthetized guinea-pigs. Following an i.v. (bolus) dose (25 mg/kg), SK&F S-106203 disappeared from plasma in a biphasic fashion with half-lives of 0.1 h (50% of the area under the plasma concentration-time curve, AUC) and 11 h. The AUC obtained for SK&F S-106203 following i.v. administration was 87.3 +/- 7.5 micrograms-h/ml. Following an oral dose of SK&F S-106203 (100 mg/kg), the maximal plasma concentration (Cmax) and the time Cmax was achieved (Tmax) were 21.62 +/- 2.26 micrograms/ml and 4 +/- 1 h, respectively; the AUC was 279.9 +/- 41.8 micrograms-h/ml. Studies examining the effects of i.v. infusion of SK&F S-106203 revealed that marked inhibition of LTD4-induced bronchospasm was produced with steady-state plasma levels of SK&F S-106203 less than 1 microgram/ml (less than 2 microM). Oral (p.o.) pretreatment with 100 mumol/kg SK&F S-106203 for up to 24 h essentially abolished LTD4-induced bronchospasm; this correlated with sustained plasma concentrations of greater than 2 micrograms/ml. The results indicate that in guinea-pig airways, SK&F S-106203 is a potent and selective LT receptor antagonist that is active via aerosol, oral and i.v. routes of administration. When given orally, SK&F S-106203 is highly bioavailable and has a very long duration of action which correlates with the pharmacokinetic profile of the compound. SK&F S-106203 may be useful therapy in asthma and other disorders in which the LTs are thought to play a prominent pathophysiological role.

Animals↗
PubMed1989

International relations: challenge of the future.

The AHRA has made considerable progress in the past few years in expanding its liaison activities to an international level. Mr. Osborn, the association's Coordinator for International Relations, traces the development of this effort and looks at goals and objectives for the future.

Forecasting↗
PubMed1989

The bronchopulmonary pharmacology of SK&F 104353 in anesthetized guinea pigs: demonstration of potent and selective antagonism of responses to peptidoleukotrienes.

The bronchopulmonary pharmacology of SK&F 104353 [2(S)-hydroxy-3(R)-[2(2-carboxyethyl)thio]-3[2-(8- phenyloctyl)phenyl]-propanoic acid], a potent and selective leukotriene (LT) receptor antagonist in vitro, was assessed in anesthetized, spontaneously breathing guinea pigs. Aerosol administration of SK&F 104353 (5-2000 micrograms/ml x 100 breaths) reduced in a concentration-dependent manner the response to a standard LTD4 challenge (4.33 micrograms/ml x 5 breaths) given 30 min later. Inhalation of a 2000 micrograms/ml solution abolished LTD4-induced bronchoconstriction for at least 2 hr. The i.v. administration of SK&F 104353 10 min before challenge antagonized LTD4-induced bronchoconstriction with an ID50 of 0.55 mumol/kg (0.25 mg/kg). Substantial antagonism of LTD4-induced bronchospasm was observed for at least 60 min after i.v. administration of 5 mumol/kg of SK&F 104353. Infusion of SK&F 104353 at various rates revealed that a steady-state plasma concentration of 0.125 microM (0.06 micrograms/ml) reduced LTD4-induced bronchoconstriction by 60%. In addition to preventing the response to LTD4, i.v. administered SK&F 104353 (10 mumol/kg) rapidly and completely reversed ongoing LTD4-induced bronchoconstriction. SK&F 104353 also was effective when given intraduodenally 1 hr before LTD4 challenge, although the ID50 (32 mumol/kg) was 60-fold greater than the i.v. ID50. Given intragastrically, 100 mumol/kg of SK&F 104353 abolished the response to LTD4 for 1 hr, and reduced the response for 6 hr. SK&F 104353 (20 mumol/kg i.v.) had no effect on the bronchoconstriction induced by aerosolized acetylcholine, histamine or U-44069, but did antagonize the response to LTC4. SK&F 104353 alone did not produce bronchoconstriction when administered by any route or dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗
PubMed1986

Radiology survival in a cost-sensitive environment.

Based on a presentation made at the 1984 RSNA-Associated Sciences Workshop, this paper looks back on a year of change for the radiology community. Mr. Osborn identifies the strategies employed by those organizations that not only survived, but actually improved their financial position during the year.

Cost Control↗
PubMed1983

2-nor-leukotriene analogs: antagonists of the airway and vascular smooth muscle effects of leukotriene C4, D4 and E4.

A structural analog of LTD4, 4R-hydroxy-5S-cysteinylglycyl-6Z-nonadecenoic acid (4R, 5S, 6Z-2-nor-LTD1) has been synthesized and pharmacologically characterized. It significantly antagonized the contractile action of LTD4, LTC4 and LTE4 in guinea pig airways. In addition, this compound antagonized the in vitro vasoconstrictive effects of LTD4 in the guinea pig pulmonary artery. The study of a series of structural analogs of 4R, 5S, 6Z-2-nor-LTD1 suggests that the spatial separation of the C-1 (eicosanoid) carboxyl relative to the hydroxyl is a critical determinant in LTD4 agonist/antagonist activity.

Airway Resistance↗
PubMed1983

Effect of inhibition of thromboxane production on the leukotriene D4-mediated bronchoconstriction in the guinea pig.

Leukotriene D4 (LTD4) administered intravenously to anesthetized, spontaneously breathing guinea pigs elicited decreases in dynamic lung compliance (Cdyn) and airway conductance (GAW) with a maximal response achieved at 0.5 min. Simultaneously, plasma levels of the thromboxane metabolite, TxB2, and the prostacyclin metabolite, 6-keto-PGF1 alpha, increased 10-fold over pre-LTD4 levels. Pretreatment of the guinea pigs with meclofenamic acid delayed the onset of the LTD4-induced bronchoconstriction, antagonized the magnitude of the decreases in Cdyn and GAW, and blocked the increase in plasma TxB2 and 6-keto-PGF1 alpha levels. The thromboxane synthetase inhibitor, UK 37,248, suppressed the LTD4-induced bronchoconstriction, while it completely blocked TxB2 production without significantly affecting 6-keto-PGF1 alpha. The SRS-A end organ antagonist, FPL 55712, blocked both the LTD4-induced bronchoconstriction and the production of the arachidonic acid metabolites. These results suggest that thromboxane A2 plays an important role in mediating part of the bronchoconstriction elicited by intravenously administered LTD4 in the guinea pig.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Antagonism of the pulmonary effects of the peptidoleukotrienes by a leukotriene D4 analog.

4R-hydroxy-5S-cysteinylglycine-6-Z-nonadecenoic acid (4R,5S, 6Z-2-nor-LTD1), a structural analog of leukotriene (LT) D4 (LTD4), significantly antagonized the pulmonary actions of LTD4 in several guinea pig models of LT-mediated bronchoconstriction and edema formation. In vitro, 4R,5S,6Z-2-nor-LTD1 (10(-5) and 10(-4) M) antagonized the LTD4-induced contraction of tracheal spirals and lung parenchymal strips. This antagonist action of 4R,5S,6Z-2-nor-LTD1 was specific for the LTs, in that LTC4- and LTE4-induced contractions of the trachea were also antagonized, whereas the contractions elicited by other spasmogens, e.g., histamine, carbachol, prostaglandin F2 alpha and KCl, were not antagonized. In vivo, the LTD4-induced bronchoconstriction in anesthetized, spontaneously breathing guinea pigs as reflected by decreases in dynamic lung compliance and airway conductance were attenuated significantly by a 1-min pretreatment with 4R,5S,6Z-2-nor-LTD1 at 5 mg/kg i.v. Similarly, the LTD4-induced increase in tracheal microvascular permeability, as assessed by extravasation of [125I]bovine serum albumin, was blocked by pretreatment with 4R,5S,6Z-2-nor-LTD1. These results provide the first demonstration that a structural analog of the peptidoleukotrienes can pharmacologically antagonize the potent actions of these LTs.

Animals↗
PubMedDate not supplied

American Hospital Radiology Administrators: a decade of progress.

The AHRA in ten years has made much progress toward accomplishing its goals. The organization has established standards for professional conduct in hospital radiology department administration, fostered communication with other professional organizations, and expanded educational services to its members.

Hospital Departments↗