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K J Simons

Publications and source records attributed to K J Simons.

At least 55 records · Page 3Linked to original sources
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

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

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

Histamine is an intracellular messenger mediating platelet aggregation.

Inhibition of human platelet aggregation by N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine-HCl (DPPE), a novel antagonist of histamine binding, suggested that histamine might serve a critical role in cell function. Phorbol-12-myristate-13-acetate (PMA) or collagen was found to increase platelet histamine content in parallel with promotion of aggregation. Inhibitors of histidine decarboxylase (HDC) suppressed both aggregation and the elevation of histamine content, whereas DPPE inhibited aggregation only. In saponin-permeabilized platelets, added histamine reversed the inhibition by DPPE or HDC inhibitors on aggregation induced by PMA or collagen. The results indicate a role for histamine as an intracellular messenger, which in platelets promotes aggregation.

Blood Platelets↗
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

Pharmacokinetic and pharmacodynamic studies of the H1-receptor antagonist hydroxyzine in the elderly.

The pharmacokinetics and pharmacodynamics of the antipruritic H1-receptor antagonist hydroxyzine hydrochloride were studied in nine healthy, fasting subjects (mean age 69.5 +/- 3.7 years) who ingested a single dose of hydroxyzine syrup, 0.7 mg/kg (mean dose 49.0 +/- 6.7 mg). Blood samples were collected hourly for 6 hours, every 2 hours from 6 to 12 hours, at 24 hours, and then every 24 hours for 144 hours. At these times an intradermal injection of 0.01 ml of a 0.1 mg/ml histamine phosphate solution was performed, and wheal and flare areas were computed. The serum elimination t1/2 of hydroxyzine was 29.3 +/- 10.1 hours; the volume of distribution was 22.5 +/- 6.3 L/kg; the clearance rate was 9.6 +/- 3.2 ml/min/kg, and the AUC was 1383.1 +/- 1039.0 ng.hr/ml. The mean serum elimination t1/2 of cetirizine, the active metabolite of hydroxyzine generated in vivo, was 24.8 +/- 7.7 hours, not significantly different from that of the parent compound (p = 0.05). After a single dose of hydroxyzine the mean wheal and flare areas were significantly suppressed from 1 to 144 hours, compared with the mean predose wheal and flare sizes (p less than 0.01). Maximum wheal suppression, compared with all other wheals measured during the study, occurred from 4 to 10 hours, inclusive, and maximum flare suppression occurred from 2 to 72 hours, inclusive (p less than 0.01). Hydroxyzine has a long t1/2 and a large volume of distribution in the elderly. The suppressive effect on the wheal and flare after a single dose of hydroxyzine is also extremely prolonged, suggesting the possibility of enhanced H1-receptor activity in old age.

Age Factors↗
PubMed1989

Development of chronic airway hyperresponsiveness in ragweed-sensitized dogs.

We studied dogs neonatally sensitized to ragweed and their littermate controls at 4, 6, 8, 10, 12, and 15 mo of age. Acute allergic airway response to inhalation of ragweed in the sensitized dogs was marked (greater than 12-fold increase from base line) and reproducible at all times. Nonallergic airway responsiveness, measured as the concentration of acetylcholine required to increase airway resistance by 5 cmH2O.l-1.s (PC5), increased in sensitized and decreased in nonsensitized dogs from 4 to 15 mo of age (P less than 0.01). Before antigen, at 12 and 15 mo, sensitized dogs were significantly (P less than 0.05) more responsive to acetylcholine than controls. Six hours after antigen, sensitized dogs were 11-fold more responsive (P less than 0.005) than controls at those times. More eosinophils and mast cells and fewer macrophages (P less than 0.05) were present in bronchoalveolar lavage (BAL) from 12- and 15-mo-old sensitized dogs than their controls. BAL fluid histamine was higher (P less than 0.05) in sensitized than control dogs. Regression analysis revealed r = -0.75 (P = 0.003) between BAL mast cells and PC5 in sensitized dogs and R2 = 0.89 for PC5 and BAL mast cells, macrophages, and eosinophils. Neonatally sensitized dogs represent an excellent animal model in which to study the pathophysiology of asthma.

Airway Resistance↗
PubMed1989

Optimum pharmacological management of chronic rhinitis.

Pharmacological treatment of chronic rhinitis has greatly improved with the introduction of the relatively non-sedating H1-receptor antagonists such as terfenadine, astemizole, loratadine, and cetirizine, and the safe, highly efficacious topical glucocorticosteroids such as beclomethasone dipropionate, flunisolide, budesonide, fluocortin butyl, and triamcinolone acetonide. In patients whose chief complaint is rhinorrhoea, topical ipratropium bromide may be of value. Patients whose major symptom is nasal congestion will benefit from intermittent use of topically or orally administered decongestants. In patients with allergic rhinitis, sodium cromoglycate (cromolyn sodium) or nedocromil sodium applied topically intranasally have a moderate beneficial effect and are associated with a low incidence of adverse effects. Non-pharmacological treatment of chronic rhinitis cannot be ignored. Patients must avoid inhalation of cigarette smoke and other irritants. Patients with chronic allergic rhinitis should avoid antigens to which they have known sensitivity: in addition, selected patients with allergic rhinitis may benefit from immunotherapy with the offending antigen(s).

Chronic Disease↗
PubMed1988

Lack of subsensitivity to terfenadine during long-term terfenadine treatment.

Eleven healthy male volunteers ingested terfenadine, 60 mg, every 12 hours for 56 days. Compliance was monitored strictly throughout the study. Before the first terfenadine dose on day 0, and 12 hours after the evening terfenadine dose every seventh day and on randomly selected "unscheduled" days, wheal-and-flare areas were measured after intradermal injections of 0.01 ml of histamine phosphate (1.0 mg/ml and 0.1 mg/ml). On days 0, 28, and 56, six volunteers had skin tests hourly for 12 hours after the morning terfenadine dose. On all study days, serum terfenadine metabolite I concentrations were measured each time histamine skin tests were performed. On days 7, 14, 21, 28, 35, 42, 49, and 56, the mean areas of the histamine-induced wheals did not differ significantly from each other but were significantly decreased compared to the mean wheal area on day 0 (p less than 0.01). On these days, the mean areas of the histamine-induced flares also did not differ significantly from each other but remained significantly suppressed compared to the mean flare areas on day 0 (p less than 0.01). Wheal-and-flare suppression was noted in all unscheduled histamine skin tests performed 12 hours after the evening terfenadine dose. In the subgroup of volunteers who had hourly tests, on day 0, the mean wheal-and-flare areas were significantly suppressed from 2 to 12 hours after the dose, with maximal wheal suppression occurring at 5 hours (p less than 0.05) and maximal flare suppression occurring from 3 to 9 hours (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

H1 receptor antagonist treatment of chronic rhinitis.

In patients with chronic rhinitis, H1 receptor antagonists play an important role in relieving the symptoms of sneezing, itching, and rhinorrhea. New information about the pharmacokinetics and pharmacodynamics of first-generation H1 receptor antagonists such as chlorpheniramine has become available in the past few years. Comprehensive pharmacokinetic and pharmacodynamic studies of new relatively nonsedating H1 receptor antagonists such as terfenadine, astemizole, loratadine, and cetirizine are appearing. An understanding of the differences in pharmacokinetics and pharmacodynamics among H1 receptor antagonists is required for optimal use of these drugs.

Asthma↗
PubMed1988

Pharmacokinetics of enprofylline administered intravenously and as a sustained-release tablet at steady state in children with asthma.

The pharmacokinetics of enprofylline (3-propylxanthine) were studied in 10 children with asthma (mean age 7.9 years), after enprofylline 1 mg/kg given intravenously and after enprofylline 7.5 +/- 1.3 mg/kg given as a sustained-release tablet after 8 days of oral dosing twice daily. The mean +/- SD enprofylline serum elimination half-life was 1.06 +/- 0.20 hours, considerably shorter than the half-life reported in adults. The mean steady-state volume of distribution was 0.55 +/- 0.05 L/kg. The mean clearance rate was 0.44 +/- 0.06 L/hr/kg. The mean enprofylline serum concentration at steady state was 1.7 +/- 0.5 mg/L. The mean peak to trough ratio was 3.02 +/- 1.31. On the first and ninth study days, 87% +/- 8% and 90% +/- 16%, respectively, of the dose of enprofylline was recovered as unchanged drug in the urine. Enprofylline has a short half-life in children, but the sustained-release formulation provides stable serum concentrations and satisfactory relief of asthma throughout the 12-hour dosing interval.

Asthma↗
PubMed1987

The effect of chronic administration of hydroxyzine on hydroxyzine pharmacokinetics in dogs.

Subsensitivity to H1-receptor antagonists has been attributed to autoinduction of enzyme systems and increased clearance rates during chronic drug administration. We studied the changes in serum half-life values and clearance rates in dogs who were administered hydroxyzine, 0.7 mg/kg, intramuscularly, daily, for 150 days. Pharmacokinetic studies were performed on the first day of drug administration, and on days 30, 60, 90, 120, and 150. The mean serum half-life value on day 30, 60, and 120 was significantly longer (p less than 0.05) than that of 2.4 +/- 0.3 hours obtained on day 1. The mean clearance values obtained on days 30, 60, 90, 120, and 150 were significantly slower (p less than 0.05) than the value of 25.12 +/- 4.13 ml/min/kg obtained on day 1 but were not significantly different from each other. Mean serum hydroxyzine concentrations were often significantly higher on the later study days than on day 1. The mean apparent volume of distribution values obtained on days 30, 60, 90, 120, and 150 did not differ significantly from the value of 5.0 +/- 1.5 L/kg obtained on day 1. This study adds to the mounting evidence that subsensitivity to the effects of an H1-receptor antagonist is not due to autoinduction of enzyme systems, more rapid clearance of the drug, and lower concentrations of the drug in serum and tissue.

Animals↗
PubMed1987

The pharmacokinetics and pharmacodynamics of terfenadine in children.

The pharmacokinetics and pharmacodynamics of terfenadine were studied in 13 children with allergic rhinitis, mean age 7.45 +/- 0.54 SEM years. Serum concentrations of the active carboxylic acid metabolite of terfenadine (terfenadine metabolite I) were measured before and hourly for 8 hours after administration of a single dose of terfenadine suspension. The mean maximum serum concentration of terfenadine metabolite I, 242 +/- 28 ng/ml, occurred at 2.3 +/- 0.2 hours; the mean serum half-life value was 2.0 +/- 0.1 hours. Wheals and flares after epicutaneous tests with histamine phosphate, 1.0 mg/ml and 0.2 mg/ml, were significantly suppressed from 1 to 8 hours after the terfenadine dose compared to predose values. Maximum wheal suppression occurred at from 3 to 6 hours. Itching was completely suppressed for 8 hours. No serious adverse effects occurred. Terfenadine in children appears to be well absorbed, and its carboxylic acid metabolite has a short serum elimination half-life. The duration of its suppressive effect on the histamine-induced wheal and flare greatly exceeds that expected from consideration of serum terfenadine metabolite I concentrations.

Benzhydryl Compounds↗
PubMed1987

The comparative pharmacokinetics of H1-receptor antagonists.

H1-receptor antagonists appear to be absorbed rapidly after oral administration, with peak serum concentrations being reached one to three hours after a dose. For most of these drugs, the absolute bioavailability is unknown because no intravenous formulations are available for comparative purposes. The serum elimination half-life values of these agents are variable: a few hours for terfenadine and triprolidine; about 9 hours for cetirizine, azatadine, and loratadine; from 20 to 25 hours for hydroxyzine, chlorpheniramine, and brompheniramine; and from 5 to 14 days for astemizole. Few pharmacokinetic studies of H1-receptor antagonists in children have been reported. However, it is known that chlorpheniramine, hydroxyzine, cetirizine, and terfenadine have shorter elimination half-life values in children than in adults. Regardless of the age of patients, for most of the H1-receptor antagonists the apparent volumes of distribution and total body clearances appear to be large (3.4 to 18.5 L/kg and 4.4 to 32.1 mL/min/kg, respectively). Cetirizine is an exception, with values of 0.8 L/kg and 0.5 mL/min/kg. Urinary excretion of unchanged antihistamine is higher after cetirizine (60% of dose) than any other H1 blocker. For H1-receptor antagonists with long half-life values, steady state may not be reached for several days (chlorpheniramine and brompheniramine) or several weeks (astemizole), and significant accumulation of drug occurs if the dosing interval is more frequent than every half-life. There is no evidence for the introduction of metabolism of H1-receptor antagonists, even after months of treatment.

Adult↗
PubMed1986

An investigation of the H1-receptor antagonist triprolidine: pharmacokinetics and antihistaminic effects.

A single oral dose of triprolidine hydrochloride, 0.04 mg/kg (mean dose 2.7 +/- SD 0.4 mg) was administered to seven healthy, fasting adult volunteers who had never been treated previously with H1-receptor antagonists. Blood sampling and intradermal tests with 0.01 ml of histamine phosphate (0.1 mg/ml) were performed at -0.25, 1, 2, 3, 4, 5, 6, 7, 8, and 12 hours after the dose. Wheal-and-flare circumferences were traced, and the areas were measured by planimetry. Pruritus was quantitated by use of a clinical score. Urine was collected in 6-hour pooled aliquots for a total of 24 hours. Serum and urine triprolidine concentrations were measured by high-performance liquid chromatography. Wheal-and-flare areas and pruritus decreased after the triprolidine dose. Suppression of mean flare size was statistically significant at 2, 3, 6 and 8 hours. Suppression of mean wheal size was not statistically significant at any time compared to predose values. The mean triprolidine serum half-life was 2.1 +/- 0.8 hours. The mean peak serum triprolidine concentration of 15.4 +/- 8.3 ng/ml occurred 2 hours after ingestion. No triprolidine was detected in the serum after 12 hours. The mean urinary excretion of unchanged triprolidine during 24 hours was 1.3 +/- 1.0% of the dose administered.

Adult↗
PubMed1986

Comparison of the suppressive effect of astemizole, terfenadine, and hydroxyzine on histamine-induced wheals and flares in humans.

Thirty-two healthy volunteers completed a 14-day, double-blind, noncrossover study comparing the efficacy and adverse effects of astemizole, terfenadine, and hydroxyzine. The subjects received either astemizole (load), 30 mg once daily for 1 week and then 10 mg once daily for 1 week, or astemizole (no load), 10 mg once daily for 2 weeks, or terfenadine, 60 mg twice daily for 2 weeks, or hydroxyzine, 50 mg once daily for 2 weeks. Before and on days 7 and 14 of treatment, five intradermal tests with various amounts of histamine phosphate (range 0.3 to 40 micrograms) were performed. Wheal-and-flare responses were traced, and the areas were computed by use of a graphics tablet. All four H1-receptor antagonist treatment regimens were equally effective in reducing the flare response to histamine. Astemizole (load) and hydroxyzine were significantly more effective than terfenadine and astemizole (no load) in reducing wheal size. The incidence of adverse effects, including sedation, was low overall and lowest in the astemizole (no load) and terfenadine groups, although this difference was not statistically significant.

Adult↗