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Biomedical subjects

F E Simons

Publications and source records attributed to F E Simons.

At least 73 records · Page 4Linked to original sources
PubMed1996

Immunoblot analysis of IgE and IgG binding antigens in extracts of mosquitos Aedes vexans, Culex tarsalis and Culiseta inornata.

Extracts of one globally distributed mosquito species (Aedes vexans) and two North American species (Culex tarsalis and Culiseta inornata) were prepared from heads and thoraxes. Proteins of the three extracts were separated by 12% SDS-PAGE and transferred to nitrocellulose membranes for immunoblotting. Immunoblotting was completed by sequential incubations of the membranes with a pooled human serum from subjects allergic to mosquito bites, monoclonal antibodies to human IgE or IgG, and goat antimouse IgG conjugate. Twelve to sixteen antigens with molecular masses ranging from 18.5 to 160 kDa were found in each extract. Nine antigens were shared by 3 species and 6 were shared by 2 species. Only 3 were species-unique. Most antigens bound to both IgE and IgG antibodies. IgE and IgG antibodies against A. vexans were studied by immunoblotting using individual serum from subjects with or without skin reactions to A. vexans bites. All 3 subjects with severe skin reactions had strong IgE and IgG antibodies to 32.5, 40, and 50 kDa proteins. The patterns and magnitudes of IgE and IgG antibodies to the antigens varied among individuals. Very faint IgE antibodies to these antigens were found in the 2 subjects with no skin reactions, suggesting that IgE plays a role in the development of mosquito allergy.

Aedes↗
PubMed1996

Comparison of the central nervous system effects produced by six H1-receptor antagonists.

BACKGROUND: A comprehensive comparative study of the central nervous system (CNS) properties of newer H1-receptor antagonist is needed. OBJECTIVE: Our objective was to investigate the central nervous system effects of a single manufacturer's recommended dose of six H1-receptor antagonists, using appropriate controls. METHODS: Fifteen healthy subjects received astemizole 10 mg, cetirizine 10 mg, ketotifen 2 mg, loratadine 10 mg, terfenadine 60 mg, diphenhydramine 50 mg or placebo. Before and 2-2.5 h after dosing, cognitive function was assessed using the P300-event-related potential, somnolence was assessed using a subjective score, and histamine skin tests were performed. RESULTS: In rank order from least to greatest effect on the P300 latency, the medications were: terfenadine, placebo, cetirizine, ketotifen, loratadine, astemizole and diphenhydramine. Only diphenhydramine increased the P300 latency significantly compared with baseline and placebo. Subjective somnolence was significantly greater than baseline and placebo after cetirizine, ketotifen and diphenhydramine. All the H1-receptor antagonists suppressed the histamine induced weal significantly compared with baseline. CONCLUSIONS: The H1-receptor antagonist tested affected cognitive functioning and somnolence to different extents, although all produced satisfactory peripheral H1-blockade.

Adolescent↗
PubMed1995

Identification of a dog IgD-like molecule by a monoclonal antibody.

IgD has not been identified in dogs. We produced a monoclonal antibody (mAb) designated 9B during the production of hybridomas to dog IgE. Using Western blot analysis under non-reducing conditions, the mAb (9B) recognized a predominant protein band of 185 kDa which was also recognized by anti-dog IgG F(ab')2, suggesting that this 185 kDa protein is an immunoglobulin (Ig) containing light chains. Under reducing conditions, the mAb (9B) recognized only one protein band of 55 kDa which presented a distinct molecular weight (MW) and immunoreactivity from the dog tau, mu, alpha, and epsilon chains. The 55 kDa band did not react with anti-dog IgE, IgM, IgA, and IgG, but did react with the mAb (9B). The MW was 75 kDa for the epsilon chain, 77.5 kDa for the mu chain, 58 kDa for the alpha chain, and 52 kDa for the tau chain. Further, by immunofluorescent staining, this Ig recognized by the mAb (9B) was found on the surface of dog lymphocytes. Studies of this dog Ig with the mAb revealed that this Ig bound to protein A and protein G-Sepharose, and that its enzyme-linked immunosorbent assay (ELISA) activity as measured by the mAb (9B) did not change after heating at 56 degrees C for 2 h. Ragweed-specific IgG, IgE, and this newly defined Ig significantly increased when dogs were immunized with ragweed extract. These data suggest that this Ig is a previously unrecognized IgD-like molecule in dogs.

Allergens↗
PubMed1995

Effect of the H2-antagonist cimetidine on the pharmacokinetics and pharmacodynamics of the H1-antagonists hydroxyzine and cetirizine in patients with chronic urticaria.

BACKGROUND: Concomitant administration of an H1-receptor antagonist with an H2-receptor antagonist may enhance the wheal and flare suppression produced by the H1-antagonist. This synergism may be due, at least in part, to a pharmacokinetic effect. METHODS: In a randomized, double-blind, parallel-group study in 16 patients with chronic urticaria, we investigated the pharmacokinetics and suppressive effect on the histamine-induced wheal and flare of a single dose of hydroxyzine 25 mg or cetirizine 10 mg, given before and after treatment with cimetidine 600 mg every 12 hours for 10 days. RESULTS: When hydroxyzine was administered with cimetidine, the partial hydroxyzine area under the curve increased significantly (p < 0.05) to 303 +/- 92 ng/ml/hr from 227 +/- 77 ng/ml/hr after administration of hydroxyzine alone, and the concentration of cetirizine arising from hydroxyzine was lower. When hydroxyzine was given with cimetidine, wheal and flare suppression increased compared with when hydrozyzine was given alone, but the differences were not statistically significant (p > 0.05). When cetirizine was administered with cimetidine, the pharmacokinetics of cetirizine did not change significantly, and no enhancement of wheal and flare suppression was observed. CONCLUSIONS: In this study co-administration of hydroxyzine with cimetidine resulted in significantly increased serum hydroxyzine concentrations and increased wheal and flare suppression, thus confirming the rationale for a trial of concomitant administration of these medications in some patients with chronic urticaria unresponsive to treatment with an H1-antagonist alone. We found no therapeutic rationale for co-administration of cetirizine with cimetidine in urticaria treatment. These medications may be co-administered safely without fear of medication interaction.

Adolescent↗
PubMed1995

Quantitation of H1-receptor antagonists in skin and serum.

BACKGROUND: Cetirizine and hydroxyzine produce prompt, long-lasting peripheral H1-blockade in skin. We hypothesized that after oral administration of these H1-receptor antagonists, skin concentrations would be higher than serum concentrations and would correlate with peripheral H1 blockade. METHODS: In a randomized, double-blind, parallel-group study in 13 healthy subjects, skin biopsies, venipunctures, and epicutaneous tests with histamine were performed before ingestion of 10 mg cetirizine or 50 mg hydroxyzine and 1, 3, 6, 9, and 24 hours after administration. Subjects then took 10 mg cetirizine or 50 mg hydroxyzine at 21:00 hours for 6 consecutive days. All tests were repeated at 168 hours (steady state), 12 hours after the last dose. RESULTS: Skin cetirizine concentrations were lower than serum ccetirizine concentrations from 1 to 9 hours but were higher at 24 hours and equivalent at 168 hours (steady state). Skin hydroxyzine concentrations were higher than serum hydroxyzine concentrations at all test times. After hydroxyzine dosing, cetirizine, the active metabolite of hydroxyzine arising in vivo, was found in skin and serum. Single doses of cetirizine or hydroxyzine produced highly significant suppression of wheals and flares from 3 to 24 hours inclusive, and this suppression was maintained at steady state. CONCLUSIONS: Cetirizine and hydroxyzine enter the skin readily, and their sustained high concentrations in skin after single or multiple dosing may contribute to their well-known efficacy in symptomatic treatment of urticaria and other skin disorders in which histamine plays a role.

Administration, Oral↗
PubMed1995

Antigen mediated and polyclonal stimulation of human cytokine production elicit qualitatively different patterns of cytokine gene expression.

Polyclonal activators are widely used as surrogate antigens in analysis of human cytokine gene expression. An implicit assumption is that the T cell activation and cytokine production observed in response to polyclonal activation provides a more intense, but qualitatively identical, reflection of results that would be obtained with antigen. Here we demonstrate that stimulation using accessory cell independent (immobilized anti-CD3 mAb) or dependent [phytohemagglutinin (PHA) or soluble anti-CD3 mAb] polyclonal activators yields different conclusions from those that are obtained in response to antigen-specific T cell activation. Cytokine synthesis in 1-5 day bulk cultures of fresh peripheral blood mononuclear cells (PBMC) from 52 subjects evenly divided between grass pollen sensitive allergic rhinitis subjects and normal, non-atopic controls were examined. Antigen-specific re-stimulation elicited elevated IL-4 and IL-10 production and lower IFN-gamma synthesis among allergic subjects than normal non-atopic control subjects. This commitment of fresh PBMC towards a Th2-like response in atopics and the dominance of the IFN-gamma response seen in non-allergic subjects was reinforced when the ratio of IFN-gamma:IL-4 production in bulk culture was examined. Atopic individuals exhibited median IFN-gamma:IL-4 values of 0.07, whereas grass pollen stimulated cytokine production by normal subjects yielded a ratio of 4.8. In marked contrast, IL-2, IL-4, IL-10 and IFN-gamma production elicited using polyclonal activators, though much more intense, did not differ between allergic and non-allergic subjects (Wilcoxon rank sum test P > > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Antiasthmatic effects of a leukotriene biosynthesis inhibitor (MK-0591) in allergic dogs.

Peptidoleukotrienes may be important mediators of human bronchial asthma. Accordingly, the effects of a selective leukotriene (LT) biosynthesis inhibitor (MK-0591) were assessed in allergic dogs characterized by acute bronchoconstriction and subsequent airway hyperresponsiveness induced by inhaled ragweed allergen. Peak acute increases in airway resistance (Rrs) induced by ragweed were associated with increased bronchoalveolar lavage histamine concentration, and neither parameter was inhibited by MK-0591 (8 micrograms.kg-1.min-1 i.v.). However, the duration of the bronchoconstriction was significantly decreased by MK-0591, with a reduction in the area under the curve of 40% (P < 0.05). Associated with the acute bronchoconstriction in placebo-treated animals was a fivefold increase in urinary LTE4 excretion (as seen with allergic asthmatic patients), which was reduced to < 10% of basal values by MK-0591. Similarly, whole blood LTB4 biosynthesis was abolished in the MK-0591-treated animals. Bronchial hyperresponsiveness preallergen (measured as the percent concentration of acetylecholine required to increase Rrs by 5 cmH2O.l-1.s) tended to improve with MK-0591 (0.41 +/- 0.15 vs. 0.23 +/- 0.05%). Five hours after allergen inhalation, the percent concentration declined substantially in the placebo group (0.07 +/- 0.02%; P < 0.01), revealing an increased airway responsiveness that was significantly blunted by MK-0591 (0.26 +/- 0.07%; P < 0.001). These data suggest that selective inhibition of LT biosynthesis by novel compounds such as MK-0591 may modify the airway changes associated with bronchial hyperresponsiveness, as well as offer symptomatic relief in asthma.

5-Lipoxygenase-Activating Proteins↗
PubMed1995

Allergen-stimulated interleukin-4 and interferon-gamma production in primary culture: responses of subjects with allergic rhinitis and normal controls.

The balance of interleukin-4 (IL-4) to interferon-gamma (IFN-gamma) production that is induced following exposure to common environmental antigens is believed to be instrumental in determining whether hypersensitivity or clinical unresponsiveness results to that antigen. To date, evaluation of cytokine (protein) production has been based predominantly on allergen-reactive CD4 T-cell clones or activation of fresh unselected peripheral blood mononuclear cell (PBMC) populations with non-physiological stimuli such as phorbal myristate acetate (PMA) and calcium ionophore, phytohaemagglutinin (PHA), anti-CD3 or anti-CD2/anti-CD28 monoclonal antibodies (mAb). Here, ultrasensitive IL-4 and IFN-gamma assays were optimized to allow direct analysis of antigen-stimulated cytokine production by fresh human PBMC. Primary cultures of cells from grass pollen-sensitive allergic rhinitis subjects and non-atopic controls were stimulated using a range of grass pollen allergen concentrations in the absence of exogenous cytokines or polyclonal activators. The majority of subjects (45 of 52) exhibited chloroquine-sensitive, CD4-dependent cytokine production in allergen-stimulated, short-term primary culture. Median IL-4 production was substantially greater among atopics (13.0 pg/ml versus < 1 pg/ml, Mann-Whitney U test, P < 0.0000001) and IFN-gamma was lower (P = 0.008), providing direct evidence for an imbalance in both IL-4 and IFN-gamma production among circulating, pollen-reactive cells in individuals with seasonal allergic rhinitis. The distinction in the allergen-driven cytokine responses elicited from normal and atopic donors was underscored by examination of the ratios of IFN-gamma:IL-4 synthesis. Non-atopic individuals exhibited intense IFN-gamma dominance of the T-cell response, in marked contrast to that observed among grass pollen-sensitive individuals (median IFN-gamma:IL-4 ratios of 14.0 versus 0.096, P = 0.000002). The observation that essentially all individuals produced IFN-gamma (+/- IL-4) following antigen stimulation in vitro argues that the most relevant consideration in determining susceptibility to immediate hypersensitivity versus clinical tolerance to environmental allergens is not a genetically defined capacity to recognize the antigen (i.e. if allergen-reactive T cells are present in that individual) but the nature of the cytokine response.

Adolescent↗
PubMed1995

Nasal patency in children with allergic rhinitis: correlation of objective and subjective assessments.

BACKGROUND: Children with allergic rhinitis may have difficulty with self-assessment of nasal symptoms. OBJECTIVE: To correlate objective and subjective assessments of nasal stuffiness in children with seasonal allergic rhinitis. METHODS: Children, aged 6 to 12 years, with seasonal allergic rhinitis recorded their degree of nasal obstruction on two separate occasions using a nasal stuffiness score and a visual analogue scale. Physicians also assessed the degree of nasal obstruction using a visual analogue scale. Anterior rhinometry was performed and saccharin transient time was also measured. Correlations between subjective scores and objective measurements were calculated using Spearman correlation coefficients. RESULTS: Patient's nasal stuffiness scores correlated with their visual analogue assessment (r = .45, P = .0001). Patients visual analogue assessments did not correlate with anterior nasal airflow (r = -.12, P > .05). Physicians' visual analogue assessment correlated better with nasal airflow than childrens' assessment (r = -.41, P = .0001). Saccharin transit time was not helpful in assessment of degree of nasal obstruction. CONCLUSION: Children appear to have difficulty in self-assessment of nasal symptoms, and to be poor judges of the presence or severity of nasal obstruction. In studies of allergic rhinitis in children, objective measurements should be performed, if possible, to facilitate more accurate interpretation of data.

Child↗
PubMed1995

Measurement of mosquito Aedes vexans salivary gland-specific IgE and IgG antibodies and the distribution of these antibodies in human sera.

BACKGROUND: Lack of sensitive, reproducible, and specific immunoassays has hampered the evaluation and immunotherapy of mosquito allergy. OBJECTIVE: We wanted to develop ELISAs for measurement of mosquito-specific IgE and IgG using salivary glands from the mosquito Aedes vexans. METHODS: Microplates coated with the salivary gland antigen were sequentially incubated with serum samples or reference serum, goat antibody to human IgE or IgG, and enzyme-conjugated rabbit anti-goat IgG. RESULTS: The specificity of the assays was demonstrated by the successful inhibition of the ELISA reactions with the mosquito antigens. Reproducible results were obtained; mean coefficients of variation between assays were 0.200 +/- 0.002 for the IgE measurement and 0.114 +/- 0.001 for the IgG measurement. The sensitivity of each assay was 0.39 U/mL. Using these assays, sera from 50 subjects with skin reactions to mosquito bites ranging from negative to strongly positive were analyzed for mosquito-specific IgE and IgG. The mean mosquito-specific IgE and IgG were significantly higher in subjects with skin reactions to mosquito bites than in those without skin reactions (P < .005), higher in females than males (P < .031), and slightly higher in atopics than nonatopics (P > .05). Also, there was a significant correlation between mosquito-specific IgE and IgG levels (r = .77, P < .001). CONCLUSIONS: Specific, reproducible, and sensitive ELISAs have been developed for measurement of antibodies to Aedes vexans. Mosquito-specific IgE and IgG may involved in the development of sensitivity to mosquito bites.

Aedes↗
PubMed1995

Individual differences in central nervous system response to antihistamines (H1-receptor antagonists).

HYPOTHESIS: We hypothesized that the objectively documented central nervous system response to antihistamines (H1-receptor antagonists) could not be predicted reliably by an individual's subjective perception of somnolence after ingestion of these medications. METHODS: In a double-blind, placebo-controlled, single-dose, four-way crossover study, cetirizine 10 mg, hydroxyzine 50 mg, diphenhydramine 50 mg, or placebo were administered to 20 healthy subjects. Before and two to two and one-half hours after dosing, the latency of the P300 event-related potential (P300) at the central (Cz) and parietal (Pz) scalp electrodes, and the visual analogue scale for somnolence were recorded. Epicutaneous tests with histamine were performed, and serum H1-receptor antagonist concentrations were also measured. RESULTS: Neither cetirizine nor placebo significantly increased the mean P300 latency or somnolence as recorded on the visual analogue scale compared with predose baseline (P > .05), although increases were seen in some subjects after each of these treatments. Hydroxyzine and diphenhydramine increased the mean P300 latency and somnolence significantly (P < .05) compared with baseline; increases were observed in most, but not all subjects. Hydroxyzine increased P300 latency and somnolence significantly compared with placebo and with cetirizine. Diphenhydramine increased somnolence significantly compared with placebo. Overall, correlation between the objective test, P300 latency, and the subjective assessment, somnolence as recorded on the visual analogue scale, was statistically significant but clinically unimportant. Identification of central nervous system adverse effects after one potentially sedating H1-receptor antagonist did not predict central nervous system adverse effects after the others. CONCLUSIONS: Inter-individual objective and subjective central nervous system responses to H1-receptor antagonists are wide-ranging. The subjective responses can be misleading and do not necessarily predict the abnormalities that can be documented objectively after the same H1-receptor antagonist or a different H1-antagonist.

Adolescent↗
PubMed1994

Limiting dilution analysis of antigen stimulated IL-4 and IFN-gamma production in human mononuclear cell populations.

Limiting dilution analysis (LDA) of fresh human mononuclear cell populations has previously been used to estimate the frequency of specific B cells, CTL, proliferative T cells, or cells capable of IL-2 production in various clinical situations. Such approaches evaluate the intensity of the response but provide little information concerning the balance between Th1- vs. Th2-like patterns of cytokine gene expression. Here, we describe development of an LDA method to obtain quantitative estimates of the frequency of antigen-specific IFN-gamma or IL-4 producing cells in human peripheral blood. The approach utilizes 3-4 day antigen-mediated restimulation of mononuclear cell populations freshly derived from grass pollen sensitive allergic rhinitis subjects. IFN-gamma and IL-4 production in culture supernatants are determined by ELISA and CT.h4S bioassay. Cytokine production elicited in this assay is CD4 dependent and antigen specific. As such, it provides a useful non-invasive approach for rapid evaluation of low frequency, antigen-induced cytokine production in the circulating repertoire. This method can readily be extended to analysis of other cytokines in other immunologic disorders or in infectious disease states, allowing longitudinal analysis of individuals and facilitating efforts to establish clear correlations between in vivo patterns of cytokine gene expression and disease exacerbation and remission.

Adolescent↗
PubMed1994

The pharmacology and use of H1-receptor-antagonist drugs.

The second-generation H1-antagonist drugs are supplanting their predecessors in the treatment of allergic rhinoconjunctivitis and chronic urticaria. Their use can be justified mainly on the basis of a more favorable risk-benefit ratio, because they are less toxic to the central nervous system. Future research into H1 antagonists should include additional dose-response studies in patients with allergic disorders, especially children and the elderly; objective studies of adverse effects; studies of topical mucosal application of H1 antagonists; and studies of H1-antagonist enantiomers and active metabolites. With the cloning of the gene encoding the H1 receptor and increased understanding of the precise structural requirements for H1-receptor activity, H1 antagonists with an even more favorable therapeutic index may be developed.

Animals↗
PubMed1994

Benefit/risk ratio of the antihistamines (H1-receptor antagonists) terfenadine and chlorpheniramine in children.

There are few objective studies of the benefit/risk ratio of H1-receptor antagonists in children. We hypothesized that terfenadine would provide as effective peripheral H1 blockade as chlorpheniramine in young patients, but would cause less central nervous system dysfunction. We tested this hypothesis with epicutaneous histamine tests to monitor peripheral H1 blockade, P300-event-related potentials as a measure of cognitive processing, and a visual analog scale for somnolence, in a double-blind, single-dose, placebo-controlled, three-way crossover study in 15 children with allergic rhinitis (mean age, 8.5 +/- 1.4 years). On 3 different days the children received terfenadine, 60 mg, chlorpheniramine, 4 mg, or placebo; the tests were performed before and 2 to 2 1/2 hours after dosing. Both terfenadine and chlorpheniramine suppressed the histamine-induced wheal and flare compared with baseline and with placebo; terfenadine was significantly more effective (p < 0.05). Terfenadine did not increase the latency of P300-event-related potentials at the parietal (Pz) or frontal (Fz) scalp electrodes compared with baseline, in contrast to chlorpheniramine and placebo, which did increase P300 latency. Terfenadine and placebo did not increase somnolence compared with baseline, but chlorpheniramine did. In children, as previously documented in adults, terfenadine has a more favorable benefit/risk ratio than chlorpheniramine, as shown by production of significantly greater peripheral histamine blockade and significantly less central nervous system dysfunction.

Action Potentials↗
PubMed1994

Effect of the H2-receptor antagonist cimetidine, on the pharmacokinetics and pharmacodynamics of the H1-receptor antagonists hydroxyzine and cetirizine in rabbits.

The effects of coadministration of the H2-receptor antagonist cimetidine on the pharmacokinetics and pharmacodynamics of the H1-receptor antagonists hydroxyzine and cetirizine were studied in rabbits. A single dose of hydroxyzine, 10 mg (Experiment A), or cetirizine, 10 mg (Experiment B), was given intravenously on three occasions: 2 weeks before cimetidine administration, after cimetidine, 100 mg/kg, had been given every 12 hr for 1 week, and 2 weeks after the cimetidine was discontinued. Serum concentrations of hydroxyzine and cetirizine, the active metabolite of hydroxyzine arising in vivo (Experiment A), or cetirizine (Experiment B) were measured by HPLC. The pharmacologic effects of hydroxyzine and cetirizine were monitored by measuring the suppression of histamine-induced wheals, using an IBM-PC and digitizer. The hydroxyzine and cetirizine half-life and AUC0-->infinity values were significantly increased and the systemic clearance rates were significantly decreased in the presence of cimetidine. Similar results were obtained when cetirizine was administered de novo. Wheal suppression produced by hydroxyzine or cetirizine was increased and prolonged in the presence of cimetidine. The synergism observed between hydroxyzine or cetirizine and cimetidine in suppression of the histamine-induced cutaneous response may be due to a pharmacokinetic interaction.

Alanine Transaminase↗