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Biomedical subjects

E Middleton

Publications and source records attributed to E Middleton.

At least 73 records · Page 4Linked to original sources
PubMed1985

Newer drugs in management. Calcium antagonists.

Ca2+ ions are critical to the functions of the various cells involved in the pathogenesis of asthma. Interest has developed regarding the potential use of Ca2+ antagonists in the management of asthma and allergic diseases. The information accumulated to date suggests that Ca2+ entry blockers may decrease airway smooth muscle responses to contractile agonists and may also reduce chemical mediator release from mast cells. Both processes would be expected to modify favorably the pathophysiology of asthma. This seems to have been demonstrated with the findings that certain Ca2+ entry blockers may inhibit exercise-induced bronchospasm and cold air- and antigen-induced airway narrowing. In several but not all experiments a direct bronchodilating effect of nifedipine was found in some subjects. In asthmatic patients with coexistent cardiovascular disease requiring beta-blocker therapy, it would be appropriate to use drugs such as the currently available Ca2+ entry blockers in place of the contraindicated beta-blocking agents. It appears that the currently available Ca2+ entry blockers have not provided a breakthrough class of therapeutic agents for the treatment of asthma. However, it seems highly likely that new Ca2+ antagonist drugs can be expected which will have greater specificity for airway smooth muscle and perhaps other cell types involved in the pathogenesis of asthma.

Animals↗
PubMed1984

Flavonoid inhibition of human basophil histamine release stimulated by various agents.

Eleven naturally occurring flavonoids representing five different chemical classes were studied for their effects on human basophil histamine release triggered by six different stimuli. The flavonoids included flavone, quercetin, taxifolin, chalcone, apigenin, fisetin, rutin, phloretin, tangeretin, hesperetin, and naringin. The stimuli were antigen, anti-IgE, concanavalin A, ionophore A23187, formylmethionylleucylphenylalanine, and tetradecanoyl phorbol acetate. Concentration-effect relationships were established for each flavonoid (5-50 microM) at concentrations of stimuli which produced near optimal histamine release. Variable degrees of inhibition were noted depending on the nature of the stimulus and flavonoid structure. The flavonols, quercetin and fisetin, and the flavone, apigenin, exhibited a predilection to inhibit histamine release stimulated by IgE-dependent ligands (antigen, anti-IgE, and con A). The flavanone derivatives, taxifolin and hesperetin, were inactive, as were the glycosides, rutin and naringin. The open chain congeners, chalcone and phloretin, also possessed inhibitory activity. Thus, the flavonoids may be useful probes in comparative analysis of secretory phenomena. The findings suggest that the biochemical pathways leading to secretion differ subtly from one stimulus to another. The differences are detectable with flavonoids of different structures and possibly reflect distinct pathways of Ca2+ mobilization or other unique mechanisms of action.

Arachidonic Acid↗
PubMed1984

Airway smooth muscle, asthma, and calcium ions.

The intracellular concentration of free Ca2+ ions regulates many functions of cells including secretion, contraction, transport processes, and motility, among others. All of the pathogenetic processes in asthmatic airways are Ca2+-dependent phenomena: excitation-contraction coupling in smooth muscle, stimulus-secretion coupling in mast cells and mucous glands, nerve impulse initiation and conduction, and the development of inflammatory infiltration. Ca2+ entry blockers such as nifedipine and verapamil may affect exercise-induced asthma, airway tone, mast cell mediator release, and experimental anaphylaxis. Calmodulin-active drugs can inhibit smooth muscle contraction and mediator release. A new generation of Ca2+ antagonists may find a role in the management of asthma.

Asthma↗
PubMed1984

Flavonoid modulation of human neutrophil function.

Flavonoids are naturally occurring plant compounds that have been demonstrated to possess a variety of anti-inflammatory effects. We studied the effects of flavonoids on three aspects of neutrophil function that are commonly considered to be associated with inflammation: the release of lysosomal enzymes, the chemiluminescence (CL) response, and the production of superoxide anion. Quercetin and eight other flavonoids at a 10(-5)M concentration inhibited the neutrophil CL response to opsonized zymosan particles by approximately 60% or more. In contrast, the release of lysosomal beta-glucuronidase from neutrophils stimulated with opsonized zymosan was only inhibited by two flavonoids, quercetin and chalcone, and only at concentrations of 1.5 X 10(-4)M to 2 X 10(-4)M. Quercetin also inhibited the generation of superoxide anion by neutrophils but to a lesser degree than its effect on CL. The present studies demonstrated that certain flavonoids are not uniformly active in inhibiting neutrophil CL, beta-glucuronidase release, or superoxide generation. The effects of flavonoids on neutrophil functions probably depend on many variables including the response measured, the activating stimulus, and specific flavonoid structural features.

Cyclic AMP↗
PubMed1984

Comparison of the effects of quercetin with those of other flavonoids on the generation and effector function of cytotoxic T lymphocytes.

In previous studies (Schwartz et al., 1982) we showed that the naturally occurring plant flavonoid quercetin can inhibit both the in vitro generation and effector function of alloantigen specific cytotoxic T lymphocytes (CTL). In the present studies, several additional flavonoids of different chemical classes were tested similarly to determine whether structure-function relationships exist. We have found that some other flavonoids, e.g. apigenin , fisetin , hesperetin and chalcone also can inhibit both CTL generation and effector function, with the effective concentration varying with the specific flavonoid tested. On the other hand, flavonoids such as rutin, naringin and catechin were inactive in both systems. Taxifolin ( dihydroquercetin ) differed from all the other flavonoids in that it was a relatively active inhibitor of CTL generation, but was essentially unable to inhibit CTL effector function. The presence of a double bond at position C-2-3 in the flavone and flavonol aglycones, a keto group at C-4, B ring hydroxylation and/or a free hydroxyl group at C-3 may be associated with activity. We also show that the effects of some, but not all, of the flavonoids active in our systems can be blocked by Cu2+ ions. Therefore, chelation of divalent cations such as Cu2+ cannot explain the function of all flavonoids in these systems.

Animals↗
PubMed1984

Effect of carbohydrates on estimated hepatic blood flow.

Recent experiments suggest that propranolol taken orally with a carbohydrate-rich meal increases its apparent bioavailability by reducing first-pass metabolism. It has been postulated that this increase in bioavailability may be secondary to a transient increase in hepatic blood flow (QH). To examine this hypothesis, we examined the effect of one of the carbohydrate meals (potato) tested in other propranolol studies on QH by measuring blood clearance (ClB) of indocyanine green (ICG). Ten minutes after eating 200 gm cooked potato, mean ICG blood clearance (ClB) in six subjects rose by 12% (range -13% to +41%). There also was a 10% mean increase (range -13% to +23%) in ICG ClB 60 min after the meal. It was then postulated that a larger carbohydrate meal might induce a more consistent and substantial increase in ICG ClB; therefore, five of the subjects were restudied after 400 gm potato. The increase in ICG ClB was of the order of that after 200 gm. Changes in QH of this magnitude would be expected to make a negligible contribution to the mean 50% increase in propranolol bioavailability reported by several investigators. It thus appears that factors other than change in QH play a dominant role in the reduced first-pass metabolism of propranolol after a meal rich in carbohydrates.

Adult↗
PubMed1983

Multi-center, double-blind, placebo-controlled trial of fluocortin butyl in perennial rhinitis.

Fluocortin butyl (FCB) is a newly synthesized corticosteroid with a high ratio of topical to systemic activity. FCB was studied in a multi-center, double-blind, placebo-controlled trial of therapy of perennial rhinitis. The study was conducted between January and May 1981. Patients evaluated suffered from either chronic allergic or chronic nonallergic rhinitis or both. A total of 306 patients from 16 investigative centers were evaluated by comparing FCB to placebo. Three separate dosage regimens were employed. Patients received a total daily dose of 2, 4, or 8 mg. FCB was found to be an effective therapeutic agent. It reduced symptoms of nasal congestion, rhinorrhea, postnasal drainage, and sneezing. It also markedly reduced the use of concomitant medications (chlorpheniramine maleate and/or pseudoephedrine). Relief of symptoms was noted as early as the first week of therapy, and the degree of improvement increased progressively during the study. There was little difference between the relief produced by the 4 mg and 8 mg regimens. Both of these were superior to the 2 mg regimen. The drug was well tolerated; no significant side effects were noted.

Adult↗
PubMed1983

Inhibition by quercetin of thyroid hormone stimulation in vitro of human red blood cell Ca2+-ATPase activity.

Human red blood cell membrane Ca2+-ATPase activity is stimulated in vitro by physiological concentrations of thyroid hormone. Quercetin, a flavonoid that inhibits several membrane-linked ATPases, suppressed thyroid hormone action on red cell Ca2+-ATPase activity and also interfered with binding of the hormone by red cell membranes. These effects of quercetin were dose-dependent over a range of concentrations (1-50 microM). In contrast, in the absence of thyroid hormone, quercetin at low concentrations stimulated Ca2+-ATPase activity and at 50 microM inhibited the enzyme. The effects of quercetin at low concentrations (1-10 microM), namely, stimulation of Ca2+-ATPase and inhibition of membrane-binding of thyroid hormone, mimic those of thyroid hormone and are consistent with the thyronine-like structure of quercetin. At high concentrations, quercetin is generally inhibitory of Ca2+-ATPase activity. Chalcone, fisetin, hesperetin and tangeretin are other flavonoids shown to reduce susceptibility of membrane Ca2+-ATPase to hormonal stimulation.

Calcium-Transporting ATPases↗
PubMed1983

Effect of food on hepatic blood flow: implications in the "food effect" phenomenon.

It has been suggested that alteration in the apparent oral bioavailability of propranolol taken with food may be due to a transient increase in QH. To investigate this hypothesis more closely, the time course of effect of a high-protein meal on QH was examined with the model compound ICG. Forty minutes postprandial, the mean increase in estimated QH was 69% above the control. QH was still elevated a mean of 36% at 100 min but by 280 min had decreased to a value that did not differ from control. Computer simulations were performed to predict the magnitude of change in the apparent oral bioavailability of propranolol that would be expected based on the observed QH changes. These simulations suggest that simple changes in QH alone cannot account for the increase in apparent oral bioavailability when propranolol is taken with food.

Adult↗
PubMed1983

Quercetin inhibits anaphylactic contraction of guinea pig ileum smooth muscle.

Certain flavonoids inhibit antigen-induced release of histamine from mast cells and basophils and also inhibit contraction of guinea pig ileum induced by histamine, acetylcholine, and PGE2. We examined the effect of one flavonoid, quercetin, on anaphylactic smooth muscle contraction of ileum from guinea pigs sensitized to egg albumin. Quercetin inhibited both the phasic and tonic components of anaphylactic contraction in a concentration-dependent fashion (IC50 approximately 10 microM). Whether this is primarily an effect on mast cell mediator release or inhibition of mediator effects on smooth muscle has not been established.

Anaphylaxis↗
PubMed1983

Role of calcium and calcium antagonists in airway function.

Airway caliber is primarily under the control of cholinergically innervated smooth muscle but it is also effected in pathological states by the tissue effects of chemical mediators released from mast cells, the hypersecretion of mucous glands, and the aggravation of airway narrowing by the vagus-mediated bronchoconstrictor reflex, and also by the ingress of inflammatory cells into the bronchial wall. The function of each of these cell types (smooth muscle, mast cells, mucous glands, vagus nerve, and inflammatory cells) is dependent upon Ca2+ ions. That is, agonist-induced smooth muscle contraction, antigen-induced mediator release from mast cells, mucous gland secretion, vagus nerve impulse initiation and conduction, and the movement of inflammatory cells are all Ca2+-dependent phenomena in which Ca2+ serves as the coupling agent between excitation and contraction and stimulus and secretion. Normally, all cells in the body maintain a very high inside-to-outside Ca2+ concentration gradient, the maintenance of which involves several mechanisms that pump calcium out of the cell. Calcium antagonists may inhibit the ingress of Ca2+ ions from the extracellular environment or may influence the availability of calcium ions from plasma membrane or subcellular organelles. Calcium antagonists have been shown to exert a beneficial effect in exercise-induced asthma and may possibly affect the release of chemical mediators from mast cells. The future of calcium antagonist therapy in the management of asthma remains to be determined.

Animals↗
PubMed1982

Effect of quercetin on human polymorphonuclear leukocyte lysosomal enzyme release and phospholipid metabolism.

Quercetin inhibited in a concentration-dependent manner the release of beta-glucuronidase from human polymorphonuclear leukocytes stimulated with zymosan-activated serum. 3H-arachidonic acid-prelabelled polymorphonuclear leukocytes released 3H-arachidonic acid upon stimulation with zymosan-activated serum and this was associated with a decrease of radioactivity in the phospholipid fraction as determined by thin layer chromatography. Quercetin inhibited the release of 3H-arachidonic acid. These observations suggest that the zymosan-activated serum stimulus activates phospholipase A2 and that phospholipase A2 is inhibited by quercetin. Thus, quercetin alters polymorphonuclear leukocyte phospholipid metabolism and responses to stimulation.

Arachidonic Acid↗
PubMed1982

Quercetin inhibition of the induction and function of cytotoxic T lymphocytes.

Quercetin is a naturally occurring flavonoid, chemically related to cromolyn. Quercetin has been shown to inhibit antigen- and mitogen-induced histamine release from rat mast cells and basophils of subjects with hay fever, to increase cyclic adenosine monophosphate (AMP) in Ehrlich ascites tumor cells and to inhibit phosphodiesterase and certain adenosine triphosphatase (ATPase) systems. We have studied the effect of quercetin on mouse T cell responses. When 5 x 10(-6) to 5 x 10(-5) M quercetin is present throughout either allogeneic mixed leukocyte culture (MLC) or cytotoxic T lymphocyte (CTL) assay culture, inhibition of in vitro CTL generation or effector function results, respectively (inhibition is 75-100% at 2 x 10(-5) M and 100% at 5 x 10(-5) M). Quercetin also inhibits concanavalin A-induced DNA synthesis. Addition of Cu2+ strongly blocks the effects of quercetin in all systems tested, in a concentration dependent fashion, while Mg2+ and Ca2+ have little or no effect and Mn2+ and Co2+ have a significant but slight blocking effect on quercetin-mediated inhibition of both CTL generation and function. In kinetic studies, evidence was obtained for the existence of a major quercetin-sensitive step in CTL induction, between 3 and 24 hr of the MLC.

Animals↗