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Biomedical subjects

F E Simons

Publications and source records attributed to F E Simons.

At least 19 recordsLinked to original sources
PubMed1992

Bronchodilator and bronchoprotective effects of salmeterol in young patients with asthma.

BACKGROUND: In adults with asthma, the selective beta 2-adrenergic agonist salmeterol has a prolonged bronchodilator and bronchoprotective effect. To date, there are few published studies of salmeterol in children. METHODS: We compared the bronchodilator and bronchoprotective effects of salmeterol, 25 and 50 micrograms, with salbutamol, 200 micrograms, and with placebo, administered via metered-dose inhaler, in a randomized, double-blind, within-patient, four-way crossover, single-dose study in 20 children. RESULTS: Mean baseline forced expiratory volume in 1 second (FEV1) and PC20 methacholine were not significantly different (p > 0.05) on the 4 study days, and did not change significantly after placebo. FEV1 increased significantly from 5 to 30 minutes after salbutamol, and from 5 minutes to 12 hours after 25 micrograms or 50 micrograms salmeterol, compared with placebo. After 25 micrograms or 50 micrograms salmeterol, FEV1 was significantly lower than after salbutamol at 5 and 10 minutes, did not differ from salbutamol at 30 minutes, and was significantly greater than after salbutamol from 3 to 12 hours. No significant difference occurred between the effect of 25 micrograms salmeterol and the effect of 50 micrograms salmeterol on FEV1. After salbutamol, there was a significant increase in PC20 only at 30 minutes. After 25 micrograms or 50 micrograms salmeterol, PC20 increased significantly from 30 minutes to 12 hours. Salmeterol, 25 micrograms and 50 micrograms provided significantly greater bronchoprotection than salbutamol from 3 to 12 hours and from 30 minutes to 12 hours, respectively. Salmeterol, 50 micrograms, provided significantly better bronchoprotection than 25 micrograms salmeterol from 30 minutes to 12 hours. The amount of change in PC20 accounted for by change in FEV1 varied from 14% to 28%, indicating that protection against bronchoconstriction was not entirely dependent on bronchodilation. CONCLUSIONS: Salmeterol is a potent, long-acting bronchodilator, with a slower onset of bronchodilation than salbutamol. It provides significantly greater and longer-lasting protection against bronchoconstriction than salbutamol.

Adrenergic beta-Agonists↗
PubMed1992

The antiallergic effects of antihistamines (H1-receptor antagonists).

Most first-generation and second-generation H1-receptor antagonists have readily demonstrable antiallergic effects in vitro, although high concentrations of some of the medications are required to inhibit mediator secretion from mast cells or basophils. These antiallergic effects can also be seen in vivo in skin, nasal, lung, and ocular challenge studies. Some H1-receptor antagonists appear to have an antiallergic effect in one organ but not in another. In many in vivo studies, doses of H1-receptor antagonists three or more times higher than those required for H1 blockade must be given to achieve the antiallergic effect. It would be premature to attempt to reclassify the H1 antagonists according to their antiallergic properties because these properties have not been investigated fully and their relative contribution to the overall therapeutic effectiveness of each H1 receptor antagonist is unknown.

Basophils↗
PubMed1991

Differential binding properties of protein A and protein G for dog immunoglobulins.

We studied the binding of dog immunoglobulins G, A, M and E to protein A and protein G. Passive cutaneous anaphylaxis (PCA) testing was used for the measurement of dog IgE and enzyme-linked immunosorbent assays (ELISA) were used for the measurements of dog IgG, IgA and IgM. Protein A from lyophilized cells of Staphylococcus aureus bound 97% of IgE, 98% of IgG, 81% of IgA, and 97% of IgM. Protein A-Sepharose CL-4B bound 87% of IgE, 100% of IgG and IgA, and 98% of IgM. In a stepwise elution with varying pH, a small amount of IgE was eluted at pH 5 and pH 6 and all the remaining Igs were eluted at pH 3 from the protein A column. In contrast to protein A, dog IgE was not bound to Protein G-Sepharose, while 100% of IgG, 95% of IgA, and 44% of IgM were bound to Protein G-Sepharose.

Animals↗
PubMed1991

Pharmacokinetic optimisation of histamine H1-receptor antagonist therapy.

Second-generation, relatively nonsedating histamine H1-receptor antagonists (H1-RA) are extensively used worldwide for the symptomatic treatment of allergic rhinoconjunctivitis and chronic urticaria. Information about the pharmacokinetics and pharmacodynamics of these medications, while still incomplete, is now sufficient to permit optimisation of therapy. Published pharmacokinetic and pharmacodynamic information on these H1-RA is summarised here, and areas where more data are required are delineated. Serum concentrations of most second-generation H1-RA are relatively low, and are usually measured by radioimmunoassay. After oral administration, peak concentrations are observed within 2 or 3 h. Bioavailability has not been well studied, due to the lack of intravenous formulations. Most H1-RA are metabolised in the hepatic cytochrome P450 system: terfenadine, astemizole, loratadine, azelastine, and ebastine have 1 or more active metabolites which are present in serum in higher concentrations than the respective parent compound, and therefore can be measured by high performance liquid chromatography. Cetirizine, an active metabolite of the first generation H1-receptor antagonist hydroxyzine, is not further metabolised to any great extent in vivo, and is eliminated via renal excretion. Levocabastine is also eliminated primarily by excretion. Serum elimination half-life values differ greatly from 1 H1-RA to another, and are 24 h or less for terfenadine, astemizole, loratadine, cetirizine, azelastine and ebastine, and the active metabolites of terfenadine, loratadine and ebastine. The active metabolite of azelastine (demethylazelastine) has a serum elimination half-life value of about 2 days, while that of astemizole (demethyl-astemizole) has a value of 9.5 days. From the few published studies in which the apparent volumes of distribution of the second-generation H1-RA have been calculated, it appears that tissue distribution is extensive. In children, the half-lives of H1-RA are generally shorter than are found in adults; there is no published information on the pharmacokinetics of astemizole, loratadine, azelastine, or ebastine in children. In some elderly adults, terfenadine, loratadine and cetirizine may have longer half-lives than in young healthy adults. There is little published data on the pharmacokinetics of the second-generation H1-RA in patients with impaired hepatic function. The half-life of cetirizine is prolonged in those with impaired renal function. There is a paucity of information on the pharmacokinetics of H1-RA in neonates, in pregnancy or during lactation.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1991

Second-generation H1-receptor antagonists.

The second-generation H1-receptor antagonists do not penetrate into the central nervous system as readily as the first-generation H1-receptor antagonists do. They bind preferentially to peripheral rather than central H1-receptors. They cause no more sedation than placebo does. These medications differ considerably from one another in some aspects of basic pharmacology and in pharmacokinetics and pharmacodynamics. An understanding of these differences will facilitate their optimal clinical usage. The second-generation H1-receptor antagonists are replacing the first generation H1-receptor antagonists in the symptomatic treatment of allergic rhinoconjunctivitis, and in relieving pruritus in patients with urticaria. They have a mild beneficial effect in patients with chronic asthma. They have not supplanted the first generation H1-receptor antagonists in atopic dermatitis treatment or as adjunctive treatment of pruritus and other symptoms in patients with anaphylaxis.

Asthma↗
PubMed1990

Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children.

The pharmacokinetics and pharmacodynamics of the H1-receptor antagonist diphenhydramine were studied in 21 fasting subjects divided into three age groups: elderly, (mean age 69.4 +/- 4.3 years), young adults, (mean age 31.5 +/- 10.4 years), and children, (mean age 8.9 +/- 1.7 years). All subjects ingested a single dose of diphenhydramine syrup 1.25 mg/kg, in mean doses of 86.0 +/- 7.3 mg, 87.9 +/- 12.4 mg, and 39.5 +/- 8.4 mg, respectively. Blood samples were collected hourly for 6 hours, every 2 hours until 12 hours, at 24 hours, and, in the adults, up to 72 hours after diphenhydramine administration. At these times, histamine skin tests were performed and wheal and flare areas were computed. The mean serum elimination half-life values for diphenhydramine differed significantly in elderly adults, young adults, and children, with values of 13.5 +/- 4.2 hours, 9.2 +/- 2.5 hours, and 5.4 +/- 1.8 hours being found respectively in each age group. Clearance rates for diphenhydramine also differed significantly with age, being 11.7 +/- 3.1 mL/min/kg in elderly adults, 23.3 +/- 9.4 mL/min/kg in young adults and 49.2 +/- 22.8 mL/min/kg in children. Diphenhydramine produced a maximum wheal suppression of 39.6 +/- 22.5% and a maximum flare suppression of 46.5 +/- 32.1% at 5 and 6 hours respectively in the elderly; a maximum wheal suppression of 45.5 +/- 25.0% and a maximum flare suppression of 53.4 +/- 16.9% at 6 and 4 hours respectively in young adults; and a maximum wheal suppression of 68.4 +/- 10.2% and a maximum flare suppression of 87.2 +/- 4.2% at 2 hours in children.

Administration, Oral↗
PubMed1990

Formoterol, a new long-acting selective beta 2-agonist, decreases airway responsiveness in children with asthma.

We compared the protective effect and duration of action of inhaled formoterol with salbutamol and placebo in 16 asthmatic children in a double-blind, cross-over study. All had an FEV1 greater than or equal to 70% predicted normal and a provocative concentration of methacholine (MCh) required to decrease their FEV1 by 20% (PC20) less than or equal to 4 mg/ml. On each study day, FEV1 was within 10% and PC20 within one doubling-dose of the initial visit. Patients received either placebo, salbutamol 200 micrograms, formoterol 12 micrograms, or formoterol 24 micrograms by metered-dose inhaler. FEV1 and PC20 were measured repeatedly over 12 h. After salbutamol, peak FEV1 was 120% of baseline at 30 min and returned to baseline in 3 h. After formoterol (12 or 24 micrograms) peak FEV1 was 118% at 3 h and remained above baseline for at least 12 h. Protection from MCh by both doses of formoterol was significantly better than by salbutamol. Protection from formoterol 12 and 24 micrograms at 12 h was equivalent to that from salbutamol at 3 h. The PC20 of four children 48 h after formoterol 24 micrograms was more than twice their baseline PC20. Formoterol by inhalation is potent and long-acting and provides significantly better antiasthma protection than salbutamol.

Adolescent↗
PubMed1990

Pharmacokinetics and pharmacodynamics of terfenadine and chlorpheniramine in the elderly.

In a double-blind, randomized, crossover study, the H1-receptor antagonists, terfenadine and chlorpheniramine, were investigated in eight healthy, fasting female subjects, aged 67.8 +/- SD 0.8 years, who ingested single doses of terfenadine, 1 mg/kg (mean dose, 69.6 +/- 11.2 mg), and chlorpheniramine, 0.12 mg/kg (mean dose, 8.4 +/- 1.3 mg). The mean serum-elimination half-life of terfenadine metabolite I was 8.7 +/- 3.7 hours. After terfenadine ingestion, significant wheal suppression occurred from 2 to 24 hours compared to predose wheal size, with maximum wheal suppression, 42 +/- 13% to 60 +/- 16% from 2 to 12 hours. Significant flare suppression occurred from 2 to 24 hours, with maximum flare suppression, 75 +/- 15% to 78 +/- 13% from 4 to 8 hours. The mean serum-elimination half-life of chlorpheniramine was 22.6 +/- 11.0 hours. After chlorpheniramine ingestion, significant wheal suppression occurred from 1 to 10 hours, inclusive, compared to predose wheal size, with maximum wheal suppression, 36 +/- 11% to 37 +/- 11% from 5 to 6 hours. Significant flare suppression occurred from 1 to 12 hours, with maximum flare suppression of 43 +/- 14% to 46 +/- 19% at 2, 5, and 6 hours (p less than 0.01). Adverse effects, chiefly sedation, occurred in five of eight patients after receiving terfenadine, and in all eight patients after receiving chlorpheniramine; but, since no placebo control was administered, these adverse effects could not be definitely attributed to H1-receptor-antagonist ingestion.

Aged↗
PubMed1990

Recent advances in H1-receptor antagonist treatment.

The second-generation H1-receptor antagonists terfenadine, astemizole, loratadine, and cetirizine are important first-line drugs for the relief of symptoms in patients with allergic rhinoconjunctivitis or chronic urticaria and may eventually supplant the potentially sedating first-generation H1-receptor antagonists in the treatment of these disorders. Terfenadine, astemizole, loratadine, and cetirizine produce an incidence of central nervous system and anticholinergic adverse effects similar to that produced by placebo. Our ability to use H1-receptor antagonists optimally has been greatly enhanced by recent pharmacokinetic and pharmacodynamic studies of these medications.

Astemizole↗
PubMed1990

New H1-receptor antagonists: clinical pharmacology.

The non-sedating, second-generation H1-receptor antagonists such as terfenadine, astemizole, loratadine and cetirizine differ considerably from each other in their pharmacokinetics and pharmacodynamics. They are generally well absorbed when administered orally. They have extremely variable serum elimination half-life values. The maximum antihistaminic effect of these medications occurs several hours later than peak serum concentrations do. The duration of the antihistaminic effect is much longer than would be predicted from the serum elimination half-life values. The relative incidence of anticholinergic and central nervous system adverse effects caused by these medications is similar to that produced by placebo. The introduction of the second-generation H1-receptor antagonists represents a major advance in symptomatic therapy of allergic disorders such as allergic rhinitis and urticaria.

Histamine H1 Antagonists↗
PubMed1990

A double-blind, single-dose, crossover comparison of cetirizine, terfenadine, loratadine, astemizole, and chlorpheniramine versus placebo: suppressive effects on histamine-induced wheals and flares during 24 hours in normal subjects.

We objectively tested the relative antihistaminic effects of cetirizine, 10 mg; terfenadine, 120 mg; terfenadine, 60 mg; loratadine, 10 mg; astemizole, 10 mg; chlorpheniramine, 4 mg; and placebo in healthy, male volunteers, mean age 25 +/- 4 years, and mean weight, 73 +/- 9 kg. The wheal areas and flare areas produced by epicutaneous tests with histamine phosphate, 1 mg/ml, before ingestion of the H1-receptor antagonist or placebo, and afterward, at 0.3 and 0.7 hours, then hourly from 1 to 12 hours and at 24 hours, were traced at 10 minutes and measured with an IBM-PC digitizer and stereometric software. In this experimental model, the H1-receptor antagonists differed significantly with regard to time of onset of action, amount of suppression of the histamine-induced wheal and flare, and duration of action. The rank order was, from most effective to least effective, cetirizine, 10 mg; terfenadine, 120 mg; terfenadine, 60 mg; loratadine, 10 mg; astemizole, 10 mg; chlorpheniramine, 4 mg; and placebo.

Adult↗
PubMed1989

The pharmacokinetics and pharmacodynamics of hydroxyzine in patients with primary biliary cirrhosis.

Hydroxyzine, a potent H1-receptor antagonist often used for relief of pruritus in patients with hepatic dysfunction, was studied in eight patients, mean age 53.4 +/- SD 11.2 years, with primary biliary cirrhosis. The patients ingested a single dose of hydroxyzine, 0.7 mg/kg (mean dose 43.9 +/- 6.6 mg). Before the dose, then hourly for 6 hours, every 2 hours from 6-12 hours, at 24 hours, and every 24 hours for 6 days, serum hydroxyzine and cetirizine were measured and an intradermal injection of 0.01 mL of a 0.1 mg/mL solution of histamine phosphate was performed. Wheals and flares were traced at 10 minutes and the areas were calculated. Mean peak hydroxyzine levels of 116.5 +/- 60.6 ng/mL occurred at 2.3 +/- 0.7 hours and mean peak cetirizine levels of 500.4 +/- 302.0 ng/mL occurred at 4.8 +/- 2.8 hours. The mean serum elimination half-life of hydroxyzine was 36.6 +/- 13.1 hours, and the mean serum elimination half-life of cetirizine was 25.0 +/- 8.2 hours. The mean hydroxyzine clearance rate was 8.65 +/- 7.46 mL/min/kg, and the mean volume of distribution was 22.7 +/- 13.3 L/kg. The mean wheal area was suppressed (P less than 0.01) from 1 to 120 hours, with maximal suppression from 2 to 48 hours. The mean flare area was suppressed from 1 to 144 hours, with maximal suppression from 3 to 24 hours (P less than 0.01). All patients became sleepy from 0.5 to 6 hours. Blurred vision, dizziness and dry mouth each occurred in two patients. Hydroxyzine elimination is impaired in patients with primary biliary cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Cetirizine: a pharmacokinetic and pharmacodynamic evaluation in children with seasonal allergic rhinitis.

In a double-blind, randomized, parallel-group 5-week study, cetirizine, 5 mg or 10 mg daily, was ingested by 10 and nine children, respectively. Cetirizine was rapidly absorbed with mean peak cetirizine concentrations of 427.6 +/- SD, 144.2 ng/ml, 1.4 +/- 1.1 hours after the 5 mg dose, and 978.4 +/- 340.6 ng/ml, 0.8 +/- 0.4 hours after the 10 mg dose. The dose-independent serum-elimination half-life of cetirizine was 7.1 +/- 1.6 hours after cetirizine, 5 mg, and 6.9 +/- 1.6 hours after cetirizine, 10 mg. Urinary excretion of unchanged cetirizine during 24 hours after the initial dose of cetirizine, 5 mg, was 40 +/- 15%, and after cetirizine, 10 mg, it was 39 +/- 14%. The mean histamine-induced wheal-and-flare areas were significantly suppressed from 1 to 24 hours after the first dose of cetirizine, 5 mg, and from 1/2 to 24 hours after the first dose of cetirizine, 10 mg, compared to the mean predose wheal-and-flare areas (p less than 0.01). During daily dosing with cetirizine, 5 mg or 10 mg at bedtime for 35 days, serum cetirizine concentrations and suppression of histamine-induced wheals and flares were monitored every 7 days, 12 hours after the cetirizine dose. The mean serum cetirizine concentrations remained relatively stable during this time, and the mean wheal-and-flare areas remained significantly suppressed (p less than 0.01) compared to baseline wheal-and-flare areas measured before the first dose of cetirizine. The symptoms and signs of allergic rhinitis were suppressed throughout the study by cetirizine, 5 mg and 10 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Cetirizine↗
PubMed1989

H1-receptor antagonists: clinical pharmacology and therapeutics.

Each H1-receptor antagonist has unique pharmacokinetic and pharmacodynamic properties, and each H1-antagonist has unique potency and potential for causing adverse effects. Some of the first-generation H1-receptor antagonists should no longer be used because their relative lack of efficacy is combined with a high potential for causing adverse effects. Some of the new H1-receptor antagonists, in manufacturers' recommended doses, seldom cause sedation but may have only modest potency. The choice of optimal H1-receptor antagonist treatment for each patient should be based on up-to-date clinical pharmacology information.

Chemical Phenomena↗