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Platelet-activating factor (PAF) is an anaphylactic mediator that is degraded in the blood by the enzyme PAF acetylhydrolase. In this study, patients with anaphylactic reactions were found to have higher levels of circulating PAF and lower levels of PAF acetylhydrolase activity than were patients without anaphylaxis. PAF-acetylhydrolase levels were low in patients who died as a result of an anaphylactic reaction to peanuts. Patients with anaphylactic reactions were found to have higher levels of circulating platelet-activating factor (PAF) and lower levels of PAF acetylhydrolase activity than were patients without anaphylaxis. Anaphylaxis is a rapid, potentially fatal, immediate hypersensitivity reaction characterized by laryngeal edema, bronchoconstriction, systemic hypotension, and vascular leakage. 1 Factors that predispose persons to anaphylaxis include age, atopy, asthma, mastocytosis, and activating mutations of mast cells. 2 – 4 Preformed and newly formed biochemical mediators, including histamine, tryptase, carboxypeptidase A, prostaglandin D 2 , leukotrienes, and platelet-activating factor (PAF), are released systemically during the degranulation of mast cells and basophils. 5 PAF is a proinflammatory phospholipid synthesized and secreted by mast cells, monocytes, and fixed tissue macrophages. 6 Circulating levels of PAF are, in part, controlled by the activity of PAF acetylhydrolase, which is . . .

Epinephrine is a life-saving treatment in anaphylaxis. In community settings, a first-aid dose of epinephrine is injected from an auto-injector (EAI). Needle phobia highly contributes to EAI underuse, leading to fatalities—especially in children. A novel rapidly-disintegrating sublingual tablet (RDST) of epinephrine was developed in our laboratory as a potential alternative dosage form. The aim of this study was to evaluate the sublingual bioavailability of epinephrine 30 mg as a potential pediatric dose incorporated in our novel taste-masked RDST in comparison with intramuscular (IM) epinephrine 0.15 mg from EAI, the recommended and only available dosage form for children in community settings. We studied the rate and extent of epinephrine absorption in our validated rabbit model (n = 5) using a cross-over design. The positive control was IM epinephrine 0.15 mg from an EpiPen Jr®. The negative control was a placebo RDST. Tablets were placed under the tongue for 2 min. Blood samples were collected at frequent intervals and epinephrine concentrations were measured using HPLC with electrochemical detection. The mean ± SEM maximum plasma concentration (Cmax) of 16.7 ± 1.9 ng/mL at peak time (Tmax) of 21 min after sublingual epinephrine 30 mg did not differ significantly (p > 0.05) from the Cmax of 18.8 ± 1.9 ng/mL at a Tmax of 36 min after IM epinephrine 0.15 mg. The Cmax of both doses was significantly higher than the Cmax of 7.5 ± 1.7 ng/mL of endogenous epinephrine after placebo. These taste-masked RDSTs containing a 30 mg dose of epinephrine have the potential to be used as an easy-to-carry, palatable, non-invasive treatment for anaphylactic episodes for children in community settings.

The H 1 -receptor antagonists are among the most widely used medications in the world. We review here the molecular basis of their action and their clinical pharmacology, efficacy in allergic disorders, and adverse effects. Although we will discuss the first-generation, relatively sedating H 1 -receptor antagonists briefly, we will emphasize the role of the second-generation, relatively nonsedating H 1 antagonists (Figure 1) and will identify future directions for research of these agents. Molecular Basis of Action Histamine mediates a variety of physiologic and pathologic responses in different tissues and cells and is an important chemical mediator of inflammation in . . .

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.

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.

We compared the bronchodilator effects and pharmacokinetics of orally administered caffeine (10 mg per kilogram of body weight) and theophylline (5 mg per kilogram) in a double-blind, single-dose study in asthmatic patients 8 to 18 years of age. After 48 hours of withdrawal of all methylxanthines, 13 patients received caffeine and 10 received theophylline. Significant improvements in forced vital capacity, forced expiratory volume in one second, and forced expiratory flow rates occurred from one to six hours after administration of either caffeine or theophylline. The bronchodilator effect of caffeine did not differ significantly from that of theophylline and was maximal two hours after ingestion of each drug. Peak serum levels of caffeine (13.5±2.9 mg per liter) occurred at one hour, and peak levels of theophylline (8.4±1.7 mg per liter) at 2.2±0.8 hours. The mean serum half-time for caffeine was 3.9±1.4 hours and that for theophylline was 5.8±1.7 hours. All patients receiving caffeine metabolized it to paraxanthine, theobromine, and theophylline. Mild, transient side effects were seen after both caffeine and theophyl-line. Vital signs did not change significantly after either drug. We conclude that caffeine, a commonly available chemical, is an effective bronchodilator in young patients with asthma. (N Engl J Med 1984; 310:743–6.) IN 1859, Dr. Hyde Salter stated, \"One of the commonest and best reputed remedies of asthma, one that is almost sure to have been tried in any case that may come under our observation, and one that in many cases is more efficacious than any other, is strong coffee.\" 1 Caffeine is a ubiquitous chemical in our environment and is frequently ingested in food, beverages, or proprietary medication. 2 There is no information in the literature about either the pharmacokinetics or the bronchodilator effects of caffeine in children with asthma. We compared caffeine and theophylline in a single-dose, double-blind study in young . . .

To the Editor: In their fine review of histamine H 1 -receptor-antagonist drugs (June 9 issue), 1 Simons and Simons do not mention doxepin, a potent and useful H 1 -receptor antagonist. Although it is not typically placed in this pharmacologic group, doxepin binds with high affinity to brain H 1 receptors. 2 This agent is clinically useful when delivered by either the systemic or topical route. 3 , 4 Like many of the other agents discussed in the review, doxepin has a wide variety of side effects, including xerostomia and postural hypotension. Nevertheless, because of its high potency, it deserves to be included . . .