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Biomedical subjects

H G Morris

Publications and source records attributed to H G Morris.

At least 37 records · Page 2Linked to original sources
PubMed1985

Effects of salsalate (nonacetylated salicylate) and aspirin on serum prostaglandins in humans.

Prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and salicylic acid were measured in blood samples from 10 healthy men after administration of antiinflammatory doses of aspirin (3.9 g/day) or salsalate (3.0 g/day). Each medication was given for 3 days, followed by an observation period of 13 days. Plasma salicylate concentrations were slightly, but generally insignificantly, higher during aspirin dosing, although both drugs produced salicylic acid levels in the antiinflammatory range. Serum levels of PGE2 and TXB2, which reflected synthesis of cyclo-oxygenase products by platelets, were minimally affected by salsalate but profoundly suppressed by aspirin. When medication was discontinued, the effects of salsalate on serum PGE2 and TXB2 were readily reversible within 36 h, whereas the recovery from aspirin was still incomplete after 13 days of observation. These results indicate that the two orally administered salicylates have differential effects on prostaglandin synthesis in platelets and may also differ in their therapeutic and adverse effects.

Adult↗
PubMed1985

Mechanisms of glucocorticoid action in pulmonary disease.

This article reviews the multiple mechanisms by which glucocorticoids influence the pathophysiology of pulmonary disease. Particular emphasis is given to the influence of glucocorticoids on the release and action of mediators that promote inflammation and that modulate other pathophysiologic processes in the lung. The time course and mechanisms of action that contribute to glucocorticoid effects on pulmonary function are also discussed.

Animals↗
PubMed1984

Staphylococcus aureus and human platelets cause pulmonary hypertension and thromboxane generation in isolated saline-perfused rabbit lungs.

The potential contributions of bacterial-platelet interactions to the development of acute edematous lung injury, such as that seen in the adult respiratory distress syndrome (ARDS), remains unknown. We found that the addition of Staphylococcus aureus, 502A to isolated rabbit lungs perfused with saline, and human platelets rapidly decreased the number of circulating platelets, increased pulmonary artery perfusion pressures, and generated thromboxane B2, the stable derivative of thromboxane A2. In contrast, increases in perfusion pressures or thromboxane levels did not occur when platelets treated with acetylsalicylic acid (ASA) were used, even though ASA-treated platelets disappeared from the perfusates. The results suggest that activation of platelets by bacteria may account for thrombocytopenia, platelet microemboli, and/or contribute to increases in pulmonary artery pressures seen in some patients with ARDS.

Animals↗
PubMed1984

Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline-perfused rabbit lungs.

Generation of reactive oxygen metabolites, thromboxane increases, and vasoconstriction have been implicated in the pathogenesis of acute edematous lung injury, such as that seen in patients with the Adult Respiratory Distress Syndrome (ARDS), but their interactions are unknown. We hypothesized that reactive O2 products would stimulate arachidonic acid metabolism in lungs and that vasoactive products of arachidonate, such as the potent vasoconstrictor thromboxane A2, might then mediate O2-metabolite-induced pulmonary vasoconstriction. We found that O2 metabolites generated by injection of purine plus xanthine oxidase caused increases in mean pulmonary artery perfusion pressures (27 +/- 4 mmHg) in isolated perfused lungs. In addition, purine plus xanthine oxidase also caused 30-fold increases in perfusate levels of thromboxane B2 (the stable metabolite of thromboxane A2) compared with only twofold increases in 6-keto-PGF1a (the stable metabolite of prostacyclin). Moreover, prior addition of catalase inhibited both vasoconstriction and the thromboxane B2 production seen in isolated lungs following injection of purine plus xanthine oxidase. Similarly, pretreatment with cyclooxygenase inhibitors, either aspirin or indomethacin, also completely blocked thromboxane generation and markedly attenuated pressor responses usually seen after purine plus xanthine oxidase (increase in mean pulmonary artery perfusion pressures, 4.4 +/- 1.5 mmHg). Furthermore, imidazole, a thromboxane synthetase inhibitor, also decreased O2-metabolite-induced thromboxane generation and vasoconstriction. These results suggested that thromboxane generation might participate in O2-metabolite-induced vasoconstriction. However, since a significant correlation between thromboxane levels and the degree of vasoconstriction could not be demonstrated, and since addition of superoxide dismutase reduced thromboxane generation but did not affect the intensity of vasoconstriction, it is possible that thromboxane is not the only vasoactive mediator in this model. We conclude that exposing lungs to O2 metabolites results in thromboxane generation and that thromboxane is a major mediator of oxidant-induced vasoconstriction.

Animals↗
PubMed1983

Timed effects of an oral adrenergic bronchodilator on pulmonary function and measurements of plasma and leukocyte cyclic AMP: divergence in duration of drug action and development of tolerance.

The time course of response to initiation and withdrawal of treatment with terbutaline (5 mg orally, three times daily) was examined in eight normal subjects and 14 asthmatic patients. The various indices of response, examined simultaneously, yielded divergent estimates of the duration of drug action and the development of tolerance during continuous treatment. Bronchodilator responses were observed after each dose of terbutaline, but within 8 hr after a dose, pulmonary functions were similar to those observed in the absence of treatment. There was a suggestion of moderate tolerance to the bronchodilator effects of medication in that areas under the curve for increments in pulmonary function after terbutaline were lower during treatment than after the initial doses of medication; but the variations in magnitude of pulmonary response on different study days did not achieve statistical significance. Measurements of plasma cyclic AMP concentration suggested a much longer duration of drug action, with elevated levels observed 24 hr after a treatment dose; there was a progressive decrease in the plasma cyclic AMP responses to medication during the course of treatment. Conversely, leukocyte cyclic AMP responses to adrenergic stimulation were suppressed within 4 hr after the first dose of medication; the suppression persisted throughout treatment and for 1 to 3 days thereafter. These observations indicated that duration of drug action and induction of tolerance vary in different organ systems.

Administration, Oral↗
PubMed1983

Failure of children with asthma to respond to daily aspirin therapy.

Adverse reactions to aspirin in asthmatic patients have been widely described in the past. In contrast to this more frequent complication, several authors have published reports suggesting that aspirin and other nonsteroidal anti-inflammatory drugs can improve asthma. We studied the effect of long-term aspirin administration in children with moderately severe asthma. Ten children who showed no immediate effect of aspirin challenge (either adverse or beneficial) were placed in a 9 wk, double-blind crossover study, receiving aspirin (10 gr twice daily) or placebo for 4 wk, then a 1 wk washout period, followed by aspirin or placebo for 4 wk. There was no difference between aspirin and placebo periods in number of wheezing episodes, frequency of additional bronchodilator or prednisone use, or daily spirometric measurements. Serum thromboxane B2 levels were significantly reduced during aspirin therapy (p less than 0.001), indicating that the patients had complied with the aspirin therapy. Thus long-term administration of aspirin to asthmatics who show no immediate beneficial or adverse response to aspirin challenge appeared not to influence the clinical course of asthma. In addition, inhibition of the platelet prostaglandin cyclooxygenase pathway in these patients did not modify the clinical course of their asthma.

Adolescent↗
PubMed1983

Acetyl glyceryl ether phosphorylcholine-stimulated human platelets cause pulmonary hypertension and edema in isolated rabbit lungs. Role of thromboxane A2.

Macrophages, neutrophils, and platelets may play a role in acute edematous lung injury, such as that seen in the adult respiratory distress syndrome (ARDS), but their potential actions and interactions are unclear. Because stimulated human macrophages and neutrophils can release acetyl glyceryl ether phosphorylcholine (AGEPC), a potent platelet activator, we hypothesized that in ARDS, leukocyte release of AGEPC might stimulate platelets to release thromboxane A2 (TXA2), which then produces pulmonary hypertension and lung edema. In support of this premise, we found that pulmonary hypertension and edema occurred in isolated rabbit lungs perfused with human platelets and AGEPC, but not with platelets or AGEPC alone. Infusion of a vasodilator (nitroglycerin) to maintain base-line pulmonary artery pressures in lungs perfused with platelets and AGEPC prevented the development of lung edema suggesting that platelet and AGEPC-induced edema was hydrostatic in nature. Additional experiments suggested that the increased pressure was a result of TXA2 release from platelets stimulated by AGEPC. Specifically, preincubation of platelets with imidazole, a thromboxane synthetase blocker, prior to infusion with AGEPC significantly diminished pulmonary hypertension and prevented lung edema. Furthermore, pretreating lung preparations with 13-azaprostanoic acid, a TXA2 antagonist, before infusion of AGEPC and untreated platelets also reduced the pulmonary hypertension and blocked the lung edema. The role of TXA2 was further suggested when perfusates from lungs infused with platelets and AGEPC developed high levels of TXA2, whereas perfusates from controls did not. These results suggest that platelet aggregation induced by AGEPC may contribute to ARDS by releasing TXA2, which raises microvascular pressure and increases edema formation, especially when an underlying permeability defect is present.

Animals↗
PubMed1983

Concepts regarding formation, action, and pharmacologic inhibition of arachidonic acid metabolites in asthma.

Lipid products derived from the metabolism of arachidonic acid have a central role in inflammatory reactions and probably contribute to the pathophysiology of bronchial asthma as well as other obstructive diseases of the lung. Metabolites of arachidonic acid also modulate numerous physiologic responses. The goal of pharmacologic intervention is to enhance the beneficial effects of certain arachidonate metabolites and to inhibit those which are undesirable. Development of new pharmacologic agents which selectively inhibit synthesis or action of certain arachidonic acid metabolites, particularly the bronchospastic leukotrienes, may provide more effective treatment of asthma in the future.

Arachidonic Acids↗
PubMed1981

Variables associated with radioimmunoassay of prostaglandins in plasma.

This study examined a number of variables which influence radio-immunoassay measurements of prostaglandins in plasma. Comparative assays in specimens obtained from normal subjects and processed by different methods demonstrated that prostaglandin measurements were uniformly lower when blood was anticoagulated with EDTA, aspirin or indomethacin was added to inhibit further synthesis or prostaglandins in vitro, samples were centrifuged at 4 degrees C at speeds which removed platelets from the sample, and assays were performed when plasma was thawed for the first time. Examination of assay results also revealed that the presence of unextracted plasma enhanced the binding of labeled ligands to antisera (%Bo) but thereafter, the displacement of ligand by increasing quantities of the reference prostaglandin paralleled the results in buffer throughout the range of the assay. In subsequent studies therefore the %Bo for plasma assays was adjusted on the basis of ligand binding in the presence of comparable volumes of pooled plasma from aspirin-treated subjects. Results of 7 prostaglandin assays in plasma and serum of normal subjects are reported.

Aspirin↗
PubMed1981

Clinical response and serum prostaglandin levels in aspirin idiosyncrasy. Effect of aspirin and a new nonsteroidal anti-inflammatory agent.

Clinical measurements and serum prostaglandin concentrations were monitored in three normal subjects, three asthmatic controls and five asthmatic patients with aspirin (ASA) idiosyncrasy before and after oral challenge with small doses of aspirin. Additionally, in the latter group, the effects of ASA were compared with those of piroxicam, a new nonsteroidal anti-inflammatory agent. Challenge with either agent caused bronchospasm in patients with aspirin idiosyncrasy, but was more severe after piroxicam. Nasal stuffiness and/or rhinorrhea preceded or accompanied the changes in pulmonary function with both agents. Serum prostaglandin concentrations, which reflect synthesis by platelets during the clotting of blood, revealed significant decreases in PGE1, PGE2, and PGF2 alpha and thromboxane B2 within two to four hours after drug administration in all subjects with or without ASA idiosyncrasy. The change in serum PG concentration was presented when bronchospasm developed in patients with ASA idiosyncrasy, but persisted for a longer time, reflecting the irreversible effect of these agents on the cyclo-oxygenase enzyme in platelets. The results demonstrate that administration of minute doses of ASA and other nonsteroidal anti-inflammatory drugs alters prostaglandin synthesis in normal and asthmatic subjects with or without ASA idiosyncrasy. Alteration in arachidonate metabolism may be responsible for the induction of bronchospasm, and cautious use of cyclo-oxygenase inhibitors in patients with known or suspected ASA idiosyncrasy is indicated.

Adult↗
PubMed1980

Morning plasma cortisol levels in infants treated with topical fluorinated glucocorticosteroids.

The plasma cortisol levels of 17 infants of mean age 12.1 months taken at 8 AM were measured before and after application of a topical fluorinated glucocorticosteroid. There was a statistically significant depression of plasma cortisol value in 11 infants at days 3, 7, and 14 after therapy. All of the plasma cortisol levels returned to normal. For the entire group of 17 infants, however, there was no significant depression of plasma cortisol levels. Even in the usual office use of topical glucocorticosteroids, one must be aware of the possiblity of percutaneous absorption.

Absorption↗