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Biomedical subjects

F E Simons

Publications and source records attributed to F E Simons.

At least 37 records · Page 2Linked to original sources
PubMed1999

Allergic rhinobronchitis: the asthma-allergic rhinitis link.

Allergic rhinitis and asthma are linked by epidemiologic, histologic, physiologic, and immunopathologic characteristics and by a common therapeutic approach. Epidemiologically, the disorders often coexist. Histologically, the upper and lower airways are lined, and linked, by the respiratory epithelium. Physiologically, they may be linked by the nasobronchial reflex. Pathologically, they are linked by similar early- and late-phase allergic responses throughout the airways and by the systemic immunologic response to airborne allergens. Uncontrolled allergic rhinitis may be associated with worsening of coexisting asthma, and optimal treatment of allergic rhinitis may improve coexisting asthma. The key to managing both disorders is prevention and relief of chronic allergic inflammation in both the upper and lower airways. The similarities between allergic rhinitis and asthma outweigh the differences. To facilitate appropriate recognition and treatment of the common inflammatory process throughout the airways, consideration should be given to introducing the new term "allergic rhinobronchitis."

Animals↗
PubMed1999

Prospective, long-term safety evaluation of the H1-receptor antagonist cetirizine in very young children with atopic dermatitis. ETAC Study Group. Early Treatment of the Atopic Child.

BACKGROUND: In very young children, H(1 )-receptor antagonists have not been adequately studied, although they are widely used and assumed to be safe. OBJECTIVE: Our objective was to test the hypothesis that cetirizine would be as safe as placebo for long-term use in this population. METHODS: In the prospective, double-blind, parallel-group, 18-month-long Early Treatment of the Atopic Child (ETAC) study, 817 children with atopic dermatitis who were 12 to 24 months old at study entry were randomized to receive either cetirizine 0.25 mg/kg or placebo twice daily. Safety was assessed by using the reports of all adverse events, diary cards, physical examinations, developmental assessments, electrocardiograms, blood hematology and chemistry tests, and urinalyses. RESULTS: The population evaluated for safety consisted of 399 children receiving cetirizine and 396 children receiving placebo. Drop-outs and serious events, including hospitalizations, occurred infrequently and were less common in the children receiving cetirizine than in those children receiving placebo, although the differences were not statistically significant. Most reported symptoms and events were mild and were attributed to intercurrent respiratory or gastrointestinal infections, exacerbations of allergic disorders, or age-related concerns rather than to medication-related adverse effects. There were no clinically relevant differences between the groups for neurologic or cardiovascular symptoms or events, growth, behavioral or developmental assessments, laboratory test results, or electrocardiograms, and no child receiving cetirizine therapy had prolongation of the QTc interval. CONCLUSIONS: The safety of cetirizine has been confirmed in this prospective study, the largest and longest randomized, double-blind, placebo-controlled safety investigation of any H(1 )-antagonist ever conducted in children and the longest prospective safety study of any H(1 )-antagonist ever conducted in any age group.

Cetirizine↗
PubMed1999

The clinical pharmacology of brompheniramine in children.

BACKGROUND: Brompheniramine has been widely used in the treatment of allergic rhinitis and other disorders during the past 4 decades. There are no published studies of its clinical pharmacology in children. OBJECTIVES: This study was performed to test the hypothesis that brompheniramine would have a prompt onset of action and a 24-hour duration of action in children. METHODS: Before brompheniramine 4 mg was ingested, and at intervals from 0.5 to 30 hours thereafter, blood samples were obtained for quantitation of plasma brompheniramine concentrations by means of HPLC. Concurrently, epicutaneous tests with histamine phosphate were performed; wheals and flares were traced at 10 minutes, and the areas were measured by using a computerized digitizing system. RESULTS: In 14 children, mean age 9.5 +/- 0.4 years (SEM), the peak brompheniramine concentration was 7.7 +/- 0.7 ng/mL, and the time at which peak concentrations occurred was 3.2 +/- 0.3 hours. The terminal elimination half-life was 12.4 +/- 1.1 hours, and the oral clearance was 20.2 +/- 2.1 mL/min/kg. Compared with predose areas, the wheals and flares produced by histamine phosphate 1 mg/mL were significantly decreased from 0.5 to 30 hours and from 1 to 30 hours, respectively (P <.05), with mean maximum inhibition at 12 (52% +/- 9%) and 6 hours (72% +/- 10%), respectively. CONCLUSIONS: In children a single dose of brompheniramine produces prompt, long-lasting peripheral H1 -blockade. Revised dosage regimens may be needed in this population.

Adolescent↗
PubMed1999

Production and characterization of monoclonal antibodies to two new mosquito Aedes aegypti salivary proteins.

Mosquito salivary proteins, which are fundamental to the process of blood feeding, also facilitate disease transmission and cause allergic reactions. The identification and characterisation of these proteins have been hampered by the difficulty of obtaining them in purified form. In this report, we describe the production of mouse monoclonal antibodies (mAbs) against mosquito salivary proteins. BALB/c mice were immunised with Aedes aegypti saliva proteins. Hybridomas were produced by fusion of spleen cells with a mouse myeloma cell line. Positive clones were selected using a saliva-capture ELISA and further identified using immunoblotting. Three mAbs reacted with a 44 kDa protein (Aed a X1) in the saliva-immunoblotting, and did not react with 2 recombinant salivary proteins, rAed a 1 (apyrase) and rAed a 2 (D7), in both immunoblotting and ELISA. Two other mAbs reacted with a 37 kDa protein in saliva-immunoblotting, but failed to react with the 37 kDa rAed a 2 in either immunoblotting or ELISA, suggesting that there is a second 37 kDa protein (Aed a X2) which is recognised by the two mAbs. The 44 kDa and 37 kDa proteins have not been previously identified. These mAbs provide a means to purify proteins, to isolate new genes from the salivary gland cDNA library, and to standardise mosquito extracts, facilitating studies of disease transmission by mosquitoes and of mosquito allergy.

Aedes↗
PubMed1999

Central nervous system effects of H1-receptor antagonists in the elderly.

BACKGROUND: The potential adverse central nervous system effects of H1-receptor antagonists have not been optimally studied in the elderly. OBJECTIVE: We hypothesized that newer H1-receptor antagonists such as cetirizine and loratadine would cause less central nervous system dysfunction than the older H1-receptor antagonists diphenhydramine and chlorpheniramine in this population, as they do in younger subjects. METHODS: We performed a randomized, double-blind, single-dose, placebo-controlled, 5-way crossover study in 15 healthy elderly subjects (mean age 71 +/- SD 5 years). On study days at least 1 week apart, they received cetirizine 10 mg, loratadine 10 mg, diphenhydramine 50 mg, chlorpheniramine 8 mg, or placebo. Outcome measures, recorded before and 2 to 2.5 hours after dosing were latency of the P300 event-related potential in which increased latency reflects a decreased rate of cognitive processing, visual analogue scale for subjective somnolence, and histamine skin tests for measurement of peripheral H1-blockade. RESULTS: The changes in P300 following each treatment yielded variances that were not equal (P > .05), precluding usual statistical analysis of the means. These variances were ranked: chlorpheniramine > diphenhydramine > loratadine > placebo > cetirizine. The rank of mean differences in the visual analogue scale increase from pre-dose baseline was: diphenhydramine > chlorpheniramine > cetirizine > loratadine > placebo. All H1-receptor antagonists suppressed the histamine-induced wheal and flare significantly compared to baseline. CONCLUSION: In the elderly, the new H1-receptor antagonists cetirizine and loratadine are less likely to cause adverse central nervous system effects than the old H1-antagonists chlorpheniramine or diphenhydramine, but this requires confirmation using additional objective tests of central nervous system function.

Aged↗
PubMed1999

Is antihistamine (H1-receptor antagonist) therapy useful in clinical asthma?

Airway hyperresponsiveness to histamine is a hallmark of asthma, and histamine inhalation reproduces asthma symptoms. Plasma histamine concentrations are elevated during the early and late responses to inhaled allergens, and may also increase during spontaneous acute asthma episodes. Ordinary doses of currently available antihistamines (H1-receptor antagonists) have minimal bronchodilator and bronchoprotective activity. In severe persistent asthma, H1 antagonists have no significant clinical effect. In moderate persistent asthma, clinical benefits of H1 antagonists are apparent, but may not be worth the potential risks of the higher-than-usual doses required. When mild seasonal asthma and allergic rhinitis coexist, however, relief of rhinitis symptoms with H1 antagonists administered in ordinary dose is associated with significant improvement in asthma symptoms.

Asthma↗
PubMed1999

Non-cardiac adverse effects of antihistamines (H1-receptor antagonists).

Antihistamines, available without prescription in many countries, are generally considered to be safe medications; however, the old first-generation H1 antagonists commonly cause adverse central nervous system (CNS) effects, even when administered in usual doses. Patients may not be aware of these effects and do not necessarily develop tolerance to them. In contrast, the new, second-generation H1 antagonists are relatively free from adverse effects in the CNS, primarily because they do not cross the blood-brain barrier and block the important neurotransmitter function of histamine. Most of the H1 antagonists in current use are unlikely to cause cardiac toxicity. There is no evidence that H1 antagonists, which have been approved by regulatory agencies, have carcinogenic, tumour-promoting, or teratogenic effects in humans.

Animals↗
PubMed1999

Induction of IgE responses using a recombinant mosquito salivary allergen rAed a 2 without adjuvant in mice.

BACKGROUND: Reactions to mosquito bites are a global problem. Several salivary proteins from Aedes (Ae.) aegypti, the most common mosquito species, have been cloned and expressed. Plasmid DNA vaccination has been shown to be effective in the downregulation of IgE responses. To investigate the in vivo antigenicity of these recombinant proteins and to study the mechanisms underlying plasmid DNA vaccination, a mouse model sensitized with a recombinant antigen has been developed. METHODS: BALB/c and C57BL/6 mice were injected intradermally with a 37-kD recombinant Ae. aegypti salivary allergen (rAed a 2) in the absence of adjuvant twice weekly for 8 weeks and then challenged twice with rAed a 2 at weeks 10 and 12. Serum rAed a 2-specific IgE, IgG1 and IgG2a were measured by ELISA. Intradermal tests were performed every 4 weeks. The binding capacity of rAed a 2-specific IgE to the native Aed a 2 was examined by immunoblotting. RESULTS: In both strains, sensitization with rAed a 2 induced a significant increase in IgE and IgG1, but not IgG2a. In all sensitized mice, a positive immediate skin reaction was apparent, while delayed-type hypersensitivity reactions were not observed. BALB/c mice produced significantly higher levels of IgE and IgG1 and larger wheals than C57BL/6 mice. The IgE antibodies elicited by rAed a 2 bound to not only rAed a 2 but also its natural form in mosquito saliva. CONCLUSION: (1) Repeated injections of rAed a 2 without adjuvant induce predominant Th2-type responses in mice. (2) BALB/c mice are better responders for IgE production than C57BL/6 mice. (3) rAed a 2 has identical allergenicity to its natural form.

Adjuvants, Immunologic↗
PubMed1999

Clinical pharmacology of new histamine H1 receptor antagonists.

The recently introduced H1 receptor antagonists ebastine, fexofenadine and mizolastine, and the relatively new H1 antagonists acrivastine, astemizole, azelastine, cetirizine, levocabastine and loratadine, are diverse in terms of chemical structure and clinical pharmacology, although they have similar efficacy in the treatment of patients with allergic disorders. Acrivastine is characterised by a short terminal elimination half-life (t1/2 beta) [1.7 hours] and an 8-hour duration of action. Astemizole and its metabolites, in contrast, have relatively long terminal t1/2 beta values; astemizole has a duration of action of at least 24 hours and is characterised by a long-lasting residual action after a short course of treatment. Azelastine, which has a half-life of approximately 22 hours, is primarily administered intranasally although an oral dosage formulation is used in some countries. Cetirizine is eliminated largely unchanged in the urine, has a terminal t1/2 beta of approximately 7 hours and a duration of action of at least 24 hours. Ebastine is extensively and rapidly metabolised to its active metabolite; carebastine, has a half-life of approximately 15 hours and duration of action of at least 24 hours. Fexofenadine, eliminated largely unchanged in the faeces and urine, has a terminal t1/2 beta of approximately 14 hours and duration of action of 24 hours, making it suitable for once or twice daily administration. Levocabastine has a terminal t1/2 beta of 35 to 40 hours regardless of the route of administration, but is only available as a topical application administered intranasally or ophthalmically in patients with allergic rhinoconjunctivitis. Loratadine is rapidly metabolised to an active metabolite descarboethoxyloratadine and has a 24-hour duration of action. Mizolastine has a terminal t1/2 beta of approximately 13 hours and duration of action of at least 24 hours. Most orally administered new H1 receptor antagonists are well absorbed and appear to be extensively distributed into body tissues; many are highly protein-bound. Most of the new H1 antagonists do not accumulate in tissues during repeated administration and have a residual action of less than 3 days after a short course has been completed. Tachyphylaxis, or loss of peripheral H1 receptor blocking activity during regular daily use, has not been found for any new H1 antagonist. Understanding the pharmacokinetics and pharmacodynamics of these new H1 antagonists provides the objective basis for selection of an appropriate dose and dosage interval and the rationale for modification in the dosage regimen that may be needed in special populations, including elderly patients, and those with hepatic dysfunction or renal dysfunction. The studies cited in this review provide the scientific foundation for using the new H1 antagonists with optimal effectiveness and safety.

Area Under Curve↗
PubMed1999

Mizolastine: antihistaminic activity from preclinical data to clinical evaluation.

Mizolastine, a new H1-receptor antagonist, is highly selective for histamine H1 receptors and has no anticholinergic, antiadrenergic, or antiserotonin activity. It is rapidly absorbed after oral ingestion, with peak plasma concentrations occurring at 1.5 h. The distribution and terminal elimination half-life values are 2 and 13 h, respectively, in healthy young adult volunteers. Half-life values are longer in the elderly and in subjects with chronic renal insufficiency; however, the differences are not large enough to be clinically relevant or to necessitate a dose adjustment in these populations. Mizolastine produces prompt, sustained, peripheral blockade of histamine H1 receptors in the skin. Suppression of the histamine-induced wheal and flare begins 40-60 min after ingestion of a 10-mg dose, peaks at 3-4 h, lasts for at least 24 h, and does not decrease during regular once-daily dosing. The amount of wheal suppression is comparable to that produced by other leading new H1-receptor antagonists. These pharmacokinetic and pharmacodynamic studies of mizolastine provide its clinical pharmacology 'signature'. They also provide the scientific rationale for recommending a once-daily 10-mg dose and suggest that the efficacy and effectiveness of mizolastine will be widely confirmed in allergic disorders, especially rhinitis and urticaria.

Adult↗
PubMed1998

Environmental antigen-induced IL-13 responses are elevated among subjects with allergic rhinitis, are independent of IL-4, and are inhibited by endogenous IFN-gamma synthesis.

Human immediate hypersensitivity diseases represent the most common example of chronic excessive Th2-like activation in developed nations. While IL-13 shares many functional properties with IL-4, the intensity and regulation of environmental Ag-stimulated IL-13 synthesis by allergic vs nonallergic individuals remain ill defined. Here, we examine the intensity of polyclonally and Ag-stimulated IL-13 production by PBMC of 20 subjects with seasonal allergic rhinitis and 20 healthy controls. Polyclonally driven IL-13 responses did not differ significantly (Mann-Whitney U test, p = 0.68). In contrast, the median CD4-dependent IL-13 response among atopics was markedly stronger than nonatopics in Ag-stimulated primary culture (p = 0.0031) and exhibited a strong correlation with IL-5 (r = 0.76, p = 0.0009), but not IL-4 (r = 0.14, p > 0.05), responses. IL-13 production was unaffected by blocking endogenous IL-4 or IL-5 activity or by addition of rIL-4 or rIL-5. In contrast, it was inhibited by low levels of rIFN-gamma and strongly enhanced upon addition of neutralizing anti-IFN-gamma mAb. Collectively, the data are consistent with a negative regulatory role for endogenous IFN-gamma synthesis in controlling the intensity of systemic IL-13 responses evoked in both atopic and nonatopic populations following exposure to common Ags. They also suggest that the elevated levels of IL-4 and IL-5 characteristic of type 2-dominated responses in vivo are without detectable impact on the maintenance of recall Ag-stimulated IL-13 production.

Adolescent↗
PubMed1998

Benefits and risks of inhaled glucocorticoids in children with persistent asthma.

In children, an inhaled glucocorticoid is currently the medication of choice for the long-term control of persistent asthma. Inhaled glucocorticoids are significantly more effective than nonsteroidal medications on all outcome measures of asthma treatment. They reduce the frequency of symptoms and of acute asthma exacerbations, decrease the need for "rescue" medications, improve airway patency, and reduce airway hyperresponsiveness. These considerable long-term benefits are worth the minimal risks of clinically significant local or systemic adverse effects. An inhaled glucocorticoid should be used in the lowest dose that prevents symptoms and eliminates the need for supplemental courses of ingested glucocorticoids. Pulmonary function and height velocity of children receiving an inhaled glucocorticoid should be monitored at regular intervals.

Administration, Inhalation↗
PubMed1998

Epinephrine absorption in children with a history of anaphylaxis.

BACKGROUND: Prompt injection of epinephrine is the cornerstone of systemic anaphylaxis treatment. The rate of epinephrine absorption has not been reported previously in allergic children. OBJECTIVE: Our objective was to study the clinical pharmacology of epinephrine in this population. METHODS: We performed a prospective, randomized, blinded, parallel-group study in 17 children with a history of anaphylaxis to food, Hymenoptera venom, or other substances. We injected 0.01 ml/kg epinephrine solution (maximum 0.3 ml [0.3 mg]) subcutaneously, or 0.3 mg epinephrine intramuscularly from an autoinjector. Plasma epinephrine concentrations, heart rate, blood pressure, and adverse effects were monitored. RESULTS: In nine children who received epinephrine subcutaneously, the mean maximum plasma epinephrine concentration (+/- SEM) was 1802 +/- 214 pg/ml, achieved at a mean time of 34 +/- 14 minutes (range, 5 to 120 minutes). Only two of the nine children achieved maximum plasma concentrations by 5 minutes. In eight children who received epinephrine intramuscularly, the mean maximum plasma concentration was 2136 +/- 351 pg/ml, achieved at a mean time of 8 +/- 2 minutes, which was significantly faster than the mean time at which maximum plasma concentrations were achieved after subcutaneous epinephrine injection (p < 0.05). Six of the eight children achieved maximum plasma concentrations by 5 minutes. The terminal elimination half-life was 43 +/- 15 minutes. No serious adverse effects were noted in any child. CONCLUSIONS: In children, recommendations for subcutaneous epinephrine injection are based on anecdotal experience, and should be reevaluated in view of our finding of delayed epinephrine absorption when this route is used. This delay might have important clinical implications during an episode of systemic anaphylaxis. The intramuscular route of injection is preferable.

Absorption↗
PubMed1998

Immunoblot analysis of salivary allergens in 10 mosquito species with worldwide distribution and the human IgE responses to these allergens.

BACKGROUND: Most people develop skin reactions to mosquito bites, however, little is known about mosquito salivary allergens and the IgE responses to them. OBJECTIVES: We sought to identify these allergens and the specific IgE responses they elicit. METHODS: Saliva or salivary gland extracts were prepared from 10 mosquito species, including seven species with worldwide distribution: Aedes (Ae.) aegypti, Ae. vexans, Ae. albopictus, Ae. togoi, Ae. triseriatus, Culex (Cx.) quinquefasciatus, Cx. pipiens, Cx. tarsalis, Anopheles (An.) sinensis, and Culiseta (Cs.) inornata. Proteins from these preparations were separated by sodium dodecylsulfate-polyacrylamide gel electrophoresis and transferred to nitrocellulose membranes, which were immunoblotted by sequential incubations with human serum, monoclonal anti-human IgE, and enzyme-conjugated goat anti-mouse IgG. Salivary allergens were analyzed by using a pooled serum from subjects allergic to mosquitos. Individual IgE responses to each allergen were evaluated in 12 subjects allergic to mosquitos living in Canada, the United States, and China, as well as in five subjects not allergic to mosquito bites. To study species-shared allergens, the membranes were immunoblotted with two rabbit antibodies specific to recombinant mosquito salivary proteins. RESULTS: Three to sixteen salivary allergens with molecular masses ranging from 16 to 95 kd were found in each species. Both species-shared and species-specific allergens were identified by molecular masses, binding to the two rabbit antibodies, and individual IgE responses to species indigenous to and absent from the regions where the subjects lived. Salivary allergens, especially from Ae. aegypti, Ae. vexans, and Ae. albopictus, elicited higher IgE responses in subjects allergic to mosquitos than in nonallergic subjects. CONCLUSIONS: Species-shared and species-specific allergens that cause IgE responses in subjects allergic to mosquitos are immunologically identified. Species-shared allergens are the most important for potential use in diagnosis and immunotherapy.

Allergens↗
PubMed1998

Highly sensitive and specific ELISA with monoclonal antibody capture to measure Dermatophagoides farinae 1-specific IgE.

BACKGROUND: Dermatophagoides farinae (Der f) is a major allergen in Der f extract. Measurement of Der f I-specific IgE has not been commonly used, because of the difficulty in obtaining large amounts of purified Der f 1. OBJECTIVES: To improve the diagnosis of dust mite allergy, we wanted to develop an ELISA to measure Der f 1-specific IgE in which purified Der f 1 is not required. METHODS: Using a monoclonal antibody (mAb) against Der f 1, a mAb-capture ELISA was developed. Microplates coated with the mAb were sequentially incubated with crude Der f extract, serum samples, goat anti-human IgE, and conjugated rabbit anti-goat IgG. A conventional ELISA using purified Der f 1 as capture (Der f 1-ELISA) was developed to compare it with the mAb-capture ELISA. RESULTS: There was a significant correlation between the two ELISAs (r = 0.89, P < .001) with a sensitivity of 0.8 U/mL. Both the assays were inhibited by the crude Der f extract in a dose-dependent manner. Using the two ELISAs, serum Der f 1-specific IgE was evaluated in 12 allergic patients with positive skin tests to Der f extract, 14 allergic patients with negative skin tests to Der f extract, and 15 healthy subjects. The mean Der f 1-IgE and the positivity rate of Der f I-IgE were higher in the mite-allergic group and lower in the healthy group when the mAb-ELISA was used (P < .01) than when the Der f 1-ELISA was used (P < .05). CONCLUSIONS: Der f 1-specific IgE can be measured by mAb-capture ELISA using crude Der f extract. The mAb-ELISA is more sensitive and specific than the conventional Der f 1-capture ELISA in diagnosing dust mite allergy.

Adolescent↗