Keith J. Simons

Platelet-activating factor, PAF acetylhydrolase, and severe anaphylaxis.

BACKGROUND Platelet-activating factor (PAF) is an important mediator of anaphylaxis in animals, and interventions that block PAF prevent fatal anaphylaxis. The roles of PAF and PAF acetylhydrolase, the enzyme that inactivates PAF, in anaphylaxis in humans have not been reported. METHODS We measured serum PAF levels and PAF acetylhydrolase activity in 41 patients with anaphylaxis and in 23 control patients. Serum PAF acetylhydrolase activity was also measured in 9 patients with peanut allergy who had fatal anaphylaxis and compared with that in 26 nonallergic pediatric control patients, 49 nonallergic adult control patients, 63 children with mild peanut allergy, 24 patients with nonfatal anaphylaxis, 10 children who died of nonanaphylactic causes, 15 children with life-threatening asthma, and 19 children with non-life-threatening asthma. RESULTS Mean (+/-SD) serum PAF levels were significantly higher in patients with anaphylaxis (805+/-595 pg per milliliter) than in patients in the control groups (127+/-104 pg per milliliter, P<0.001 after log transformation) and were correlated with the severity of anaphylaxis. The proportion of subjects with elevated PAF levels increased from 4% in the control groups to 20% in the group with grade 1 anaphylaxis, 71% in the group with grade 2 anaphylaxis, and 100% in the group with grade 3 anaphylaxis (P<0.001). There was an inverse correlation between PAF levels and PAF acetylhydrolase activity (P<0.001). The proportion of patients with low PAF acetylhydrolase values increased with the severity of anaphylaxis (P<0.001 for all comparisons). Serum PAF acetylhydrolase activity was significantly lower in patients with fatal peanut anaphylaxis than in control patients (P values <0.001 for all comparisons). CONCLUSIONS Serum PAF levels were directly correlated and serum PAF acetylhydrolase activity was inversely correlated with the severity of anaphylaxis. PAF acetylhydrolase activity was significantly lower in patients with fatal anaphylactic reactions to peanuts than in patients in any of the control groups. Failure of PAF acetylhydrolase to inactivate PAF may contribute to the severity of anaphylaxis.

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.

Histamine and H1-antihistamines: Celebrating a century of progress

In this review we celebrate a century of progress since the initial description of the physiologic and pathologic roles of histamine and 70 years of progress since the introduction of H(1)-antihistamines for clinical use. We discuss histamine and clinically relevant information about the molecular mechanisms of action of H(1)-antihistamines as inverse agonists (not antagonists or blockers) with immunoregulatory effects. Unlike first (old)-generation H(1)-antihistamines introduced from 1942 to the mid-1980s, most of the second (new)-generation H(1)-antihistamines introduced subsequently have been investigated extensively with regard to clinical pharmacology, efficacy, and safety; moreover, they are relatively free from adverse effects and not causally linked with fatalities after overdose. Important advances include improved nasal and ophthalmic H(1)-antihistamines with rapid onset of action (in minutes) for allergic rhinitis and allergic conjunctivitis treatment, respectively, and effective and safe use of high (up to 4-fold) doses of oral second-generation H(1)-antihistamines for chronic urticaria treatment. New H(1)-antihistamines introduced for clinical use include oral formulations (bilastine and rupatadine), and ophthalmic formulations (alcaftadine and bepotastine). Clinical studies of H(3)-antihistamines with enhanced decongestant effects have been conducted in patients with allergic rhinitis. Additional novel compounds being studied include H(4)-antihistamines with anti-inflammatory effects in allergic rhinitis, atopic dermatitis, and other diseases. Antihistamines have a storied past and a promising future.

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.

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.

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,β) [1.7 hours] and an 8-hour duration of action. Astemizole and its metabolites, in contrast, have relatively long terminal t1/2,β 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,β of ∼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 ∼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,β of ∼14 hours and duration of action of 24 hours, making it suitable for once or twice daily administration.Levocabastine has a terminal t1/2,β 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,β of ∼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.

Epinephrine and its use in anaphylaxis: current issues.

Purpose of reviewEpinephrine is a life-saving medication in the treatment of anaphylaxis, in which it has multiple beneficial pharmacologic effects. Here, we examine the evidence base for its primary role in the treatment of anaphylaxis episodes in community settings. Recent findingsWe review the practical pharmacology of epinephrine in anaphylaxis, its intrinsic limitations, and the pros and cons of different routes of administration. We provide a new perspective on the adverse effects of epinephrine, including its cardiac effects. We describe the evidence base for the use of epinephrine in anaphylaxis. We discuss the role of epinephrine auto-injectors for treatment of anaphylaxis in community settings, including identification of patients who need an auto-injector prescription, current use of auto-injectors, and advances in auto-injector design. We list reasons why physicians fail to prescribe epinephrine auto-injectors for patients with anaphylaxis, and reasons why patients fail to self-inject epinephrine in anaphylaxis. We emphasize the primary role of epinephrine in the context of emergency preparedness for anaphylaxis in the community. SummaryEpinephrine is the medication of choice in the first-aid treatment of anaphylaxis in the community. For ethical reasons, it is not possible to conduct randomized, placebo-controlled trials of epinephrine in anaphylaxis; however, continued efforts are needed towards improving the evidence base for epinephrine injection in this potentially fatal disease.

Can Epinephrine Inhalations Be Substituted for Epinephrine Injection in Children at Risk for Systemic Anaphylaxis

Background. For out-of-hospital treatment of anaphylaxis, inhalation of epinephrine from a pressurized metered-dose inhaler is sometimes recommended as a noninvasive, user-friendly alternative to an epinephrine injection. Objective. To determine the feasibility of administering an adequate epinephrine dose from a metered-dose inhaler in children at risk for anaphylaxis by assessing the rate and extent of epinephrine absorption after inhalation. Methods. We performed a prospective, randomized, observer-blind, placebo-controlled, parallel-group study in 19 asymptomatic children with a history of anaphylaxis. Based on the childs weight, 10, 15, or 20 carefully supervised epinephrine or placebo inhalations were attempted. Before dosing, and at intervals from 5 to 180 minutes after dosing, we monitored plasma epinephrine concentrations, blood glucose, heart rate, blood pressure, and adverse effects. Results. Eleven children (mean ± standard error of the mean: 9 ± 1 years and 33 ± 3 kg) in the epinephrine group were able to inhale 11 ± 2 (range: 3–20) puffs, equivalent to 74% ± 7% of the precalculated dose or 0.078 ± 0.009 mg/kg. They achieved a mean peak plasma epinephrine concentration of 1822 ± 413 (range: 230-4518) pg/mL at 32.7 ± 6.2 minutes. Eight children (10 ± 1 years of age and 33 ± 5 kg) in the placebo group were able to inhale 12 ± 2 (range: 8–20) puffs, 89% ± 3% of the precalculated dose, and had a peak endogenous plasma epinephrine concentration of 1316 ± 247 (range: 522-2687) pg/mL at 44.4 ± 16.7 minutes. In the children receiving epinephrine compared with those receiving placebo, mean plasma epinephrine concentrations were not significantly higher at any time, mean blood glucose concentrations were significantly higher from 10 to 30 minutes, mean heart rate was not significantly different at any time, and mean systolic and diastolic blood pressures were not significantly increased at most times. After the inhalations of epinephrine or placebo, the children complained of bad taste and many experienced cough or dizziness. After inhaling epinephrine, 1 child developed nausea, pallor, and muscle twitching. Conclusions. Despite expert coaching, because of the number of epinephrine inhalations required and the bad taste of the inhalations, most children were unable to inhale sufficient epinephrine to increase their plasma epinephrine concentrations promptly and significantly. Therefore, we urge caution in recommending epinephrine inhalation as a substitute for epinephrine injection for out-of-hospital treatment of anaphylaxis symptoms in children.

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.

Epinephrine fails to hasten hemodynamic recovery in fully developed canine anaphylactic shock.

Background: Epinephrine (Epi) is the treatment of choice for reversing cardiovascular collapse in anaphylactic shock (AS). However, there are few data supporting its use in this condition, and most treatment guidelines have been anecdotally derived. In the present study, the time course of hemodynamic recovery from maximal hypotension was investigated in a canine model of AS in which Epi was administered by the intravenous (IV), subcutaneous (SQ) and intramuscular (IM) routes on different occasions. The findings obtained with Epi treatment were compared to those in a nontreatment study. Methods: Ragweed-sensitized dogs were examined in respective studies approximately 5 weeks apart in which Epi was administered by one of the above routes in a randomized design. Either Epi (0.01 mg/kg) or placebo was administered at maximal hypotension, and hemodynamics were followed for 3 h after shock. The animals were studied while ventilated and anesthetized. Mean arterial pressure (MAP), cardiac output, stroke volume (SV), pulmonary wedge pressure (Pwp) and plasma Epi concentrations were obtained at each measurement interval. Results: In the IV study, Epi produced a transient immediate increase in MAP, SV and Pwp as compared to the nontreatment study (144 vs. 52 mm Hg; 32 vs. 12 ml; 9 vs. 5 mm Hg; p < 0.01), but no differences were observed 15 min after shock. Hemodynamics were not different between Epi and no treatment at any intervals when Epi was given by the SQ and IM routes. AS compared with the placebo study, plasma Epi concentrations were higher in the IV and IM studies, but not in the SQ study. Conclusions: Although higher Epi concentrations were observed in the IM and IV studies, a sustained benefit in hemodynamic recovery was not observed in this anesthetized, ventilated canine model. In AS, when administered during maximum shock after mediators have already been released, a single IM, IV or SQ dose of Epi may have limited utility in the treatment of cardiovascular collapse. Earlier administration of Epi, before maximal hypotension occurs, may produce a more beneficial effect.