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Biomedical subjects

K J Simons

Publications and source records attributed to K J Simons.

At least 37 records · Page 2Linked to original sources
PubMed1996

Adverse central nervous system effects of older antihistamines in children.

Although older, potentially sedating, "first-generation" antihistamines (H1-receptor antagonists) are commonly used in childhood, their central nervous system (CNS) effects have not been well-documented in young subjects. We hypothesized that diphenhydramine and hydroxyzine would affect CNS function adversely in this population. Our objective was to evaluate the effects of these medications on central and peripheral histamine H1-receptors in children. Fifteen subjects with allergic rhinitis were tested before and 2-2.5 h after administration of diphenhydramine, hydroxyzine, or placebo in a double-blind, single-dose, three-way crossover study. Impairment of cognitive processing was assessed objectively by the latency of the P300 event-related potential (P300). Somnolence was assessed subjectively by a visual analog scale. Peripheral H1-blockade was assessed by suppression of the histamine-induced wheals and flares. At the central (Cz) and frontal (Fz) electrodes, diphenhydramine and hydroxyzine increased the P300 latency significantly (P < 0.05) compared to baseline. Hydroxyzine increased somnolence, as recorded on the visual analog scale, significantly compared to baseline (P < 0.05), with a similar trend for diphenhydramine (P = 0.07). Both antihistamines reduced histamine-induced wheals and flares significantly compared to baseline and compared to placebo. In children, diphenhydramine and hydroxyzine are effective H1-receptor antagonists, but both these medications cause CNS dysfunction, as evidenced by increased P300 latency, a measure of cognitive function, and by increased subjective somnolence.

Child↗
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

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

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

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↗
PubMed1994

Results of a clinical trial in humans with refractory cancer of the intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine-HCl, in combination with various single antineoplastic agents.

PURPOSE: We assessed N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine-HCl (DPPE) potentiation of chemotherapy in vitro and performed a pharmacokinetic study and phase I/II trial of DPPE, combined with various single agents, in patients with advanced refractory cancer. PATIENTS AND METHODS: In vitro chemopotentiation by DPPE was assessed in drug-sensitive and -resistant (multidrug resistant-positive [MDR+]) human tumor cells using a colony survival assay. The effect of DPPE and verapamil on the intracellular concentration of daunorubicin in MDR+ cells was compared. For the clinical study, subjects with progressive malignancy received a weekly infusion of a maximally tolerated dose of DPPE (240 mg/m2) over 80 or 440 minutes, in conjunction with a single chemotherapy drug to which, in most cases, the patient's tumor was previously resistant. Concentrations of DPPE in blood and urine were determined by high-performance liquid chromatography (HPLC). RESULTS: In vitro, micromolar concentrations of DPPE potentiated (fivefold to 10-fold) chemotherapy cytotoxicity to both drug-sensitive and -resistant cells, but did not inhibit the p-glycoprotein pump; in vivo, serum levels of DPPE were 3 to 5 mumol/L at the end of 80 minutes and 1 to 2 mumol/L after 440 minutes of infusion. Of 48 patients monitored for a minimum of four DPPE/chemotherapy treatment cycles, 16 (33%) progressed, 12 (25%) stabilized, 12 (25%) improved, and eight (17%) responded (one complete and seven partial remissions). Four of 11 subjects who did not respond to the 80-minute infusion regimen improved with the 440-minute infusion; one had a partial remission of melanoma. In more than 600 patient-treatments, bone marrow toxicity was negligible (mean absolute neutrophil count [ANC] > 2.0 x 10(9)/L). Acute CNS symptoms associated with DPPE infusions were of relatively short duration (1 to 4 hours); delayed toxicity attributable to DPPE consisted of mild nausea and/or fatigue (1 to 2 days). CONCLUSION: Although preliminary, the results suggest that more structured trials should be performed to determine whether DPPE may increase the therapeutic index of certain chemotherapy drugs.

Adult↗
PubMed1993

Cetirizine pharmacokinetics and pharmacodynamics in primary biliary cirrhosis.

The new H1-receptor antagonist, cetirizine, is eliminated primarily unchanged by renal excretion and is thus potentially useful for relief of pruritus in patients with hepatic dysfunction, in whom many H1-receptor antagonists are contraindicated. The authors studied the elimination of cetirizine in six patients with primary biliary cirrhosis. In contrast to data obtained in healthy adults with normal hepatic function reported in the medical literature, they found that the mean serum elimination half-life value of cetirizine, 13.8 +/- 1.8 hours, was longer, and the mean clearance rate, 0.44 +/- 0.10 mL/min/kg, was lower (P < .05). The mean peak serum cetirizine concentration, 498 +/- 118 ng/mL, was higher, the mean area under the curve, 6438 +/- 1621 ng/mL/hr, was larger, and the mean fraction of the dose excreted as unchanged cetirizine in the urine, .32 +/- .14, was lower (P < .05). The duration of action of cetirizine was prolonged, as evidenced by significant suppression of the histamine-induced wheal and flare for 48 and 72 hours, respectively, after a single dose. Cetirizine elimination was impaired in patients with hepatic dysfunction.

Aged↗
PubMed1993

Pharmacokinetics and pharmacodynamics of ebastine in children.

Ebastine is a new piperidine-containing, relatively nonsedating second-generation H1-receptor antagonist. In a double-blind, parallel-group study of a single 5 mg or 10 mg dose of ebastine syrup used to treat allergic rhinitis in 20 children aged 6 to 12 years, we tested the hypothesis that the medication would have a duration of action of at least 24 hours. We measured plasma concentrations of carebastine, the pharmacologically active metabolite of ebastine, and the wheals and flares produced by epicutaneous tests with histamine phosphate, 1.0 mg/ml. Ebastine was absorbed well; peak carebastine concentrations occurred approximately 3 hours after dosing. Mean plasma elimination half-life values of carebastine ranged from 10 to 14 hours. The pharmacokinetics of carebastine were linear and dose independent in the dosage range studied. After the 5 or 10 mg dose, there were no significant differences between mean plasma elimination half-life values, mean oral clearance values, or mean apparent volumes of distribution. Mean peak plasma carebastine concentrations and mean areas under the plasma carebastine concentration-time curve after the 10 mg dose were 1.93 and 1.76 times, respectively, the values obtained after the 5 mg dose. Both doses significantly reduced the histamine-induced wheal-and-flare areas for up to 28 hours compared with predose values. The differences in effect between the doses generally were not statistically or clinically significant. No adverse effects were noted. We conclude that ebastine, an effective H1-receptor antagonist with a prompt onset of action and a long duration of action, is suitable for once-daily administration to children.

Butyrophenones↗
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

Pharmacokinetics of the acetylcholinesterase oxime reactivator, HI-6, in rhesus monkeys (Macaca mulatta): effect of atropine, diazepam, and methoxyflurane anesthesia.

The pharmacokinetics of the bispyridinium oxime HI-6 (CAS reg. no. 34433-31-3; 1-(((4-aminocarbonyl)pyridinio)methoxy)methyl)-2-[hydroxy i mino)methyl)- pyridinium dichloride) was investigated in rhesus monkeys (Macaca mulatta). The effects of methoxyflurane anesthesia, administration of atropine with and without diazepam were determined on the serum half-life (t1/2), clearance rate (CL), and the volume of distribution (Vd) following intramuscular (IM) administration of HI-6 (30 mg kg-1). The control t1/2, CL and Vd of HI-offere 27 min, 8.6 ml min-1 kg-1 and 0.34 l kg-1, respectively. These parameters were unaffected by the co-administration of either atropine (0.5 mg kg-1, IM) or atropine and diazepam (0.5 mg kg-1, IM + 0.2 mg kg-1 IV, respectively). Methoxyflurane anesthesia resulted in a significant increase in the HI-6 t1/2 to 61 min concomitant with a decrease in the CL to 4.1 ml min-1 kg-1 with no change in the Vd. The increase in the t1/2 of HI-6 in methoxyflurane anesthetized monkeys is probably the result of a decrease in the clearance rate and, thus, excretion of HI-6 by the kidneys.

Anesthesia↗