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Biomedical subjects

E Middleton

Publications and source records attributed to E Middleton.

At least 55 records · Page 3Linked to original sources
PubMed1987

A dose-response study of the bronchodilator action of azelastine in asthma.

Azelastine is an orally effective inhibitor of mediator activity in allergic reactions and has also been demonstrated to have bronchodilator activity. In this randomized, double-blind, placebo-controlled, multicenter study, 150 patients, aged 12 to 60 years, with moderate to severe asthma, received a single oral dose of 2, 4, 8, 12, or 16 mg of azelastine or placebo. Theophylline was stopped 24 hours and other bronchodilators at least 8 hours before the study day. Patients were evaluated for 8 hours after dose by spirometry and were monitored for adverse effects. All doses of azelastine produced bronchodilation with 4 mg greater than 2 mg greater than placebo; higher doses did not increase magnitude or duration of effect. We conclude that azelastine produces significant bronchodilation of long duration. The optimal dose appears to be 4 mg for adolescent and adult patients with asthma.

Adolescent↗
PubMed1987

Intraindividual variability in theophylline pharmacokinetics in subjects with mild/moderate asthma.

Intrasubject variability in theophylline pharmacokinetics was assessed in six subjects with mild/moderate asthma. On four occasions, each separated by a minimum of 3 weeks, a 6 mg/kg intravenous aminophylline dose was infused during 30 minutes, and multiple blood samples were obtained thereafter. The pharmacokinetic parameters of clearance (Cl), volume of distribution, and half-life were determined by noncompartmental analysis. There was evidence for within-subject variability in these parameters. In comparison to the first study day, Cl changed by greater than 15% in all but one subject and by greater than 25% in two of six subjects. Changes in half-life exceeding 25% of the value observed on the first study day occurred in three of six subjects. Within-subject coefficient of variation for Cl was 14.9% (range 3.9% to 33.3%) and 14.4% (range 5.8% to 24.3%) for half-life. Volume of distribution, however, was a more stable parameter with a within-subject coefficient of variation of 7.2% (range 2.3% to 11.1%). Thus, within-subject changes in the pharmacokinetics of theophylline do exist over time. These data suggest that close monitoring of patients receiving theophylline is warranted, particularly when theophylline concentrations are maintained at either extreme of the therapeutic range.

Adult↗
PubMed1986

Effects of flavonoids on enzyme secretion and endocytosis in normal and mucolipidosis II fibroblasts.

The effect of flavonoids on beta-hexosaminidase transport and endocytosis has been studied in cultured human skin fibroblasts. In mucolipidosis II fibroblast cultures, characterized by their preferential secretion of most newly synthesized hydrolases, quercetin and phloretin (200 microM) inhibited beta-hexosaminidase synthesis as well as total culture-associated enzyme activity. Taxifolin induced a 2.4-fold increase in the total enzyme activity without altering the intra- and extracellular distribution of the enzyme. Rutin, although less effective, also stimulated an overall increase in total enzyme. The flavonoid effects were all concentration-dependent. Very little effect was observed in either the distribution or the total beta-hexosaminidase activity in normal fibroblast cultures. Taxifolin and hesperitin inhibited receptor-mediated endocytosis of beta-hexosaminidase by fibroblasts up to 50% of control uptake. Naringin, quercetin, and phloretin moderately inhibited uptake by 30% while rutin and fisetin had no effect. The results demonstrate that certain naturally occurring flavonoids affect the secretion of lysosomal enzymes as well as their endocytosis by fibroblasts. Since most individuals ingest up to one gram per day of these substances, flavonoids may prove to have significant effects on normal lysosomal enzyme physiology.

Acetylglucosaminidase↗
PubMed1986

The role of hydrogen peroxide in basophil histamine release and the effect of selected flavonoids.

Studies on hydrogen peroxide (H2O2)-induced histamine release from human basophils indicate that H2O2 is a weak stimulus of histamine release, that the release process is Ca2+ and energy-dependent, and that histamine release is not influenced by theophylline (in keeping with previous observations with rat mast cells). Low concentrations of H2O2 appeared to augment and high concentrations to inhibit histamine release induced by anti-IgE. However, the inhibitory effect of high concentrations of H2O2 were completely abrogated by catalase, which destroys H2O2, and thus indicates that basophils retain immunologic responsivity and are not irreversibly effected by high concentrations of H2O2. Leukocyte suspensions relatively enriched in monocytes, lymphocytes, basophils, neutrophils, and neutrophils plus eosinophils were prepared by Percoll-gradient centrifugation. Anti-IgE stimulated H2O2 formation only in the fraction richest in basophils. Opsonized zymosan, on the other hand, stimulated H2O2 generation in both the basophil and monocyte fractions, indicating activation of both monocytes and basophils by this stimulus. Mixtures of basophil-containing leukocyte suspensions plus purified neutrophils and opsonized zymosan stimulated histamine release in proportion to concomitant generation of H2O2. Addition of catalase reduced histamine release under these conditions, whereas scavengers of other toxic oxygen derivatives (superoxide dismutase, alpha-tocopherol, D-mannitol) had little or no effect on histamine release. These findings suggest that neutrophil-derived H2O2 can cause basophil histamine release in mixed populations of activated leukocytes. Three naturally occurring flavonoids, quercetin, apigenin, and taxifolin (dihydroquercetin) were examined for their effect on anti-IgE-induced histamine release and H2O2 generation in basophil-containing leukocyte suspensions.(ABSTRACT TRUNCATED AT 250 WORDS)

Basophils↗
PubMed1986

Some effects of flavonoids on lymphocyte proliferative responses.

A number of representative flavonoids reversibly inhibit human lymphocyte proliferative responses in a concentration-dependent manner. The flavonoids quercetin and tangeretin are most effective when added during the early phase of exposure of lymphocytes to the mitogenic stimuli but become progressively less effective when added after increasing lengths of time following stimulation, suggesting an early flavonoid-sensitive step(s) in cell activation. In the proliferative response to phytomitogens, they do not act by inhibiting the early increase in calcium influx. They do not augment cellular cyclic-AMP concentration in basal or phytomitogen-stimulated lymphocytes nor reduce its increment in the presence of inhibitors of phosphodiesterase. At concentrations inhibitory to the proliferative response, quercetin (but not tangeretin) inhibits the calcium-activated, phospholipid-dependent protein kinase (C kinase). Certain flavonoids powerfully inhibit the uptake of thymidine into phytomitogen-stimulated lymphocytes but do not directly affect incorporation of already transported thymidine into newly synthesized DNA.

Calcium↗
PubMed1986

The effects of flavonoids on human lymphocyte proliferative responses.

Flavonoids reversibly inhibit lymphocyte proliferative responses to phytomitogens, soluble antigens and phorbol esters by blocking an early event or events that follow stimulation. Quercetin and tangeretin inhibit thymidine transport in stimulated lymphocytes. These flavonoids reversibly inhibit antigen processing by monocytes and inhibit the expression of class II histocompatibility (DR) antigens in PBM cells.

Antigen-Presenting Cells↗
PubMed1985

Antiviral effect of flavonoids on human viruses.

The effect of several naturally occurring dietary flavonoids including quercetin, naringin, hesperetin, and catechin on the infectivity and replication of herpes simplex virus type 1 (HSV-1), polio-virus type 1, parainfluenza virus type 3 (Pf-3), and respiratory syncytial virus (RSV) was studied in vitro in cell culture monolayers employing the technique of viral plaque reduction. Quercetin caused a concentration-dependent reduction in the infectivity of each virus. In addition, it reduced intracellular replication of each virus when monolayers were infected and subsequently cultured in medium containing quercetin. Preincubation of tissue culture cell monolayers with quercetin did not affect the ability of the viruses to infect or replicate in the tissue culture monolayers. Hesperetin had no effect on infectivity but it reduced intracellular replication of each of the viruses. Catechin inhibited the infectivity but not the replication of RSV and HSV-1 and had negligible effects on the other viruses. Naringin had no effect on either the infectivity or the replication of any of the viruses studied. Thus, naturally occurring flavonoids possess a variable spectrum of antiviral activity against certain RNA (RSV, Pf-3, polio) and DNA (HSV-1) viruses acting to inhibit infectivity and/or replication.

Animals↗
PubMed1985

Theophylline and fibrocystic breast disease.

After literature reports linking fibrocystic breast disease (FBD) to methylxanthine ingestion, a pilot study was undertaken to investigate the possible contribution of theophylline to this effect. The major goal of this project was to measure the effect of theophylline therapy on FBD in asthmatic women. All women attending an allergy clinic or an obstetrics/gynecology clinic over a 9-month period were examined to clinically assess FBD and were asked to complete a detailed questionnaire covering health history, other risk factors, and drug and dietary methylxanthines. The sample included 62 asthmatic women, 66 allergic but not asthmatic women, and 72 nonallergic and nonasthmatic women. By use of the FBD clinical taxonomy with its 19-point scale going from 0 to 18 that was developed for this study, the three groups did not differ significantly in terms of mean severity of FBD. On analyzing the effect of each of the methylxanthines on FBD severity, there is clear evidence that total methylxanthines was a contributing factor in FBD severity with or without adjustment for relevant variables, such as age, menopause, pregnancies, and groups. Theophylline was significant only when adjustments were made for age, pregnancy, and menopause in contrast to caffeine that was only significant with no adjustments.

Adult↗
PubMed1985

Calcium antagonists and asthma.

Calcium ions participate in the pathogenesis of asthma. Increased cytosolic concentrations of free Ca2+ must develop to trigger smooth muscle contraction, mast cell mediator release, mucous gland secretion, vagal nerve activity, and the movement of inflammatory cells into the walls of the airways. Recent interest has centered on the possibility that Ca2+ antagonists might be useful in the treatment of asthma. Evidence now exists that airway smooth muscle contraction and mast cell and basophil mediator release may be inhibited by the calcium channel blockers nifedipine and verapamil. Other experiments indicate that these drugs may interfere with EIA and bronchoconstriction provoked by cold air and methacholine, for example. CaM antagonists may also interfere with smooth muscle contraction and mediator release. It is possible that more specific calcium antagonists, both Ca2+ channel blockers and CaM-active compounds, will be developed and find use as effective antiasthmatic agents.

Asthma↗
PubMed1985

Effects of hydralazine, nitroglycerin, and food on estimated hepatic blood flow.

Several recent studies have shown that hydralazine and nitroglycerin may increase the apparent oral bioavailability of high-clearance drugs. It has been postulated that the mechanism responsible may be a vasodilator-induced transient increase in hepatic blood flow with an associated reduction in first-pass metabolism. To test this hypothesis, we examined the effect of hydralazine (25 mg) and sublingual nitroglycerin (2 doses of 0.6 mg separated by 30 minutes) on indocyanine green (ICG) blood clearance (ClB). Forty minutes after the start of nitroglycerin therapy, ICG ClB fell from a baseline of 648 +/- 98 to 607 +/- 151 ml/min, and was further decreased to 578 +/- 98 ml/min 80 minutes after dosing. Hydralazine induced no consistent effect on ICG ClB. ICG ClB was 744 +/- 376, 721 +/- 218, and 763 +/- 195 ml/min at baseline, 40 minutes, and 80 minutes after dosing. As a positive control, ICG ClB was assessed after a high-protein meal. After this meal, ICG ClB increased from 656 +/- 107 to 811 +/- 141 and 801 +/- 132 ml/min at 40 and 80 minutes after dosing. These data suggest that one or more mechanism(s) other than changes in hepatic blood flow are involved in the vasodilator-induced increase in the apparent oral bioavailability of high-clearance drugs.

Administration, Oral↗
PubMed1985

Allergy-related diseases and cancer: an inverse association.

This paper presents the results of a retrospective study that examines the association of cancer with a history of asthma, hay fever, hives, and other allergy-related diseases. This study is based on interview data collected from 13,665 cancer cases and 4,079 nonneoplastic controls who were admitted to Roswell Park Memorial Institute from 1957 to 1965. Although there is a general tendency for the age- and cigarette smoking-adjusted odds ratios associated with a history of asthma and hay fever to be less than 1, for both males and females, there is stronger evidence for a decreased risk of cancer associated with a history of hives and other allergy-related diseases. Decreased risks associated with a history of hives and other allergies are seen in males for oral cancer, cancers of the lung, larynx, digestive system, urinary system, and cancers of all sites combined and in females for cancers of the digestive system, reproductive system, in particular, cancer of the cervix, and cancers of all sites combined. None of the few odds ratios over 1 associated with a history of any allergy-related condition are statistically significant (alpha = 0.05). These findings suggest that individuals with allergy-related disorders may be at decreased risk of cancer, although reasons for cautious interpretation of the findings are emphasized. Prospective studies of carefully defined allergic disease cohorts are needed.

Asthma↗
PubMed1985

Naturally occurring flavonoids and human basophil histamine release.

Naturally occurring plant flavonoids, normal dietary constituents, affect a variety of cell activation phenomena including the secretion of histamine from human basophils stimulated by a variety of agents (antigen, anti-IgE, concanavalin A, ionophore A23187, formyl-Met-Leu-Phe and tetradecanoyl phorbol acetate). Variable profiles of inhibition are seen depending on the nature of the stimulus and the chemical structure of flavonoids.

Basophils↗
PubMed1985

The treatment of asthma--beyond bronchodilators.

I have attempted to indicate the importance of Ca2+ ions in the various pathogenetic processes that contribute to the development of asthma and to show how both Ca2+ entry blockers and calmodulin-active compounds may alter the function of mediator releasing cells and smooth muscle contractility in vitro as well as their effects in various experimental animal situations and on airway function in man. It would appear that the currently available cardiovascular-active Ca2+ entry blockers are not very specific with regard to either airway smooth muscle or mast cell function but their observed activities certainly warrant the search for new Ca2+ antagonists that might have greater specificity for airway smooth muscle, for example, and might facilitate therapy of asthma. There have been remarkably few studies of the effects of calmodulin-active compounds on allergic processes or in asthma. The activity of these compounds in various experimental models demands that they should be further studied with respect to their possible clinical usefulness in the management of asthma and other allergic disorders.

Airway Resistance↗