In Vivo Evaluation of Taste-Masked Fast-Disintegrating Sublingual Tablets of Epinephrine Microcrystals.

In community settings, IM injection of 0.3 mg epinephrine (Epi) using an auto-injector is the drug of choice for treatment of anaphylaxis. Previously, a taste-masking (TM) formulation of fast-disintegrating sublingual tablets (FDSTs) was developed in our lab. Also, Epi was micronized (Epi-MC) successfully and reduced the previously achieved bioequivalent sublingual Epi dose to 0.3 mg IM injection by half using non-taste-masked fast-disintegrating sublingual tablets (TM-FDSTs). Our objective for this study was to evaluate the sublingual absorption of Epi-MC using TM-FDST. These sublingual Epi tablets have potential for out-of-hospital treatment of anaphylaxis and are suitable for human studies. TM-FDSTs containing Epi-MC were manufactured by direct compression. The rate and extent of Epi absorption from our developed 20 mg Epi-MC-TM-FDSTs (n = 5) were evaluated in rabbits and compared to the previous result from 20 mg Epi-MC in non-TM-FDSTs and EpiPen® auto-injector. Blood samples were collected over 1 h, and Epi concentrations were measured using HPLC with electrochemical detection. Mean ± SEM AUC0-1 h and Cmax from 20 mg Epi-MC-TM-FDSTs (733 ± 78 ng/ml/min and 30 ± 8 ng/ml) and 20 mg Epi-MC-non-TM-FDSTs (942 ± 109 ng/ml/min and 38 ± 4 ng/ml) were not significantly different (p > 0.05) from each other or from EpiPen® (592 ± 50 ng/ml/min and 28 ± 3 ng/ml) but were significantly higher (p < 0.05) than endogenous Epi after placebo FDSTs (220 ± 32 ng/ml/min and 8 ± 1 ng/ml). Mean ± SD Tmax was not significantly different (p > 0.05) among all formulations. Epi-MC-TM-FDSTs formulation improved Epi absorption twofold and reduced the required bioequivalent dose by 50%, similar to results obtained using non-TM-FDSTs. The incorporation of TM excipients did not interfere with the absorption of Epi-MC.

Epinephrine doses delivered from auto-injectors stored at excessively high temperatures.

CONTEXT: Prompt injection of epinephrine (adrenaline) from epinephrine auto-injectors (EAIs) is the primary treatment for anaphylaxis in out-of-hospital settings. Storage of EAIs at room temperature (25 °C) is advised; however, storage at excessively high temperatures sometimes occurs. To our knowledge, there are no previous publications on the doses of epinephrine ejected from EAIs after storage at such temperatures. OBJECTIVE: We examined the epinephrine doses delivered from activated EAIs stored constantly or cyclically at 70 °C. METHODS: Twenty-five in-date EAIs were stored constantly or cyclically at 70 °C (excessive heat) or 25 °C (controls) for 5 d or 10 d. EAIs were activated and the epinephrine doses in the ejected solutions were measured using HPLC-UV. The enantiomeric purity of epinephrine was also measured by HPLC-UV. RESULTS: Control EAIs ejected a volume of 0.300 ± 0.006 mL containing 103.7 ± 3.3% of labeled dose (LD). After 5 d or 10 d of constant storage at 70 °C and activation at 70 °C, EAIs ejected a volume of 0.367 ± 0.008 mL containing 96.8 ± 3.8% LD and 0.373 ± 0.007 mL containing 77.7 ± 3.3% LD, respectively. After 5 d of cyclic storage at 70 °C and cooling to 25 °C before activation, EAIs ejected a volume of 0.311 ± 0.008 mL containing 87.2 ± 1.9% LD. Under the experimental conditions of this study, the resultant chromatographic peaks of epinephrine solutions from all EAIs represented only the pure l-enantiomer of epinephrine. CONCLUSION: EAIs should be stored under recommended conditions of the manufacturer. EAIs stored at excessively high temperatures cannot be used to treat humans while still hot, and when cooled, cannot be relied on to deliver the labeled epinephrine dose in anaphylaxis.

Sublingual Diffusion of Epinephrine Microcrystals from Rapidly Disintegrating Tablets for the Potential First-Aid Treatment of Anaphylaxis: In Vitro and Ex Vivo Study.

For the first-aid treatment of anaphylaxis, epinephrine (Epi) 0.3 mg intramuscular (IM) injection in the thigh is the drug of choice. Epi auto-injectors are widely recommended for anaphylaxis treatment in community settings but not necessarily carried or used as prescribed when anaphylaxis occurs. We therefore developed rapidly disintegrating sublingual tablets (RDSTs) as an alternative noninvasive dosage form. Our objective in this study was to evaluate the effect of reducing Epi particle size on its in vitro and ex vivo diffusion, with the goal of enhancing Epi sublingual absorption from Epi RDSTs. Epi particle size was reduced by top-bottom technique using a microfluidizer for one pass at 30,000 Psi. The micronized Epi crystals (Epi-MC) were characterized using Zetasizer, Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Epi RDSTs were formulated and manufactured using our previously developed method. In vitro and ex vivo diffusion of Epi 10, 20, and 40 mg RDSTs and Epi-MC 10 and 20 mg RDSTs (n = 4) were evaluated using Franz cells. Epi 10 mg solution was used as a control. Mean (±standard deviation (SD)) Epi particle size was successfully reduced from 131.8 ± 10.5 to 2.5 ± 0.4 µm. Cumulative Epi diffused and influx from 40 mg Epi RDSTs and 20 mg Epi-MC RDSTs were not significantly different from each other in vitro and ex vivo (p > 0.05). Also, Epi permeability from 20 mg Epi-MC RDSTs was significantly higher than from the rest (p < 0.05). Epi-MC RDSTs improved Epi diffusion twofold and might have the potential to reduce the Epi dose needed in RDSTs by 50%.

Metabolic disposition of the insect repellent DEET and the sunscreen oxybenzone following intravenous and skin administration in rats.

Insect repellent N,N-diethyl-m-toluamide (DEET) and sunscreen oxybenzone have shown a synergistic percutaneous enhancement when applied concurrently. Both compounds are extensively metabolized in vivo into a series of potentially toxic metabolites: 2 metabolites of DEET, N,N-diethyl-m-hydroxymethylbenzamide (DHMB) and N-ethyl-m-toluamide (ET), and 3 metabolites of oxybenzone, 2,4-dihydroxybenzophenone (DHB), 2,2-dihydroxy-4-methoxybenzophenone (DMB), and 2,3,4-trihydroxybenzophenone (THB). In this study, the metabolites were extensively distributed following intravenous and topical skin administration of DEET and oxybenzone in rats. Combined application enhanced the disposition of all DEET metabolites in the liver but did not consistently affect the distribution of oxybenzone metabolites. The DHMB appeared to be the major metabolite for DEET, while THB and its precursor DHB were the main metabolites for oxybenzone. Repeated once-daily topical application for 30 days led to higher concentrations of DEET metabolites in the liver. Hepatoma cell studies revealed a decrease in cellular proliferation from all metabolites as single and combined treatments, most notably at 72 hours. Increased accumulation of DHMB and ET in the liver together with an ability to reduce cellular proliferation at achievable plasma concentrations indicated that simultaneous exposure to DEET and oxybenzone might have the potential to precipitate adverse effects in a rat animal model.

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.

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.

Tissue disposition of the insect repellent DEET and the sunscreen oxybenzone following intravenous and topical administration in rats.

The insect repellent N,N-diethyl-m-toluamide (DEET) and sunscreen oxybenzone (OBZ) have been shown to produce synergistic permeation enhancement when applied concurrently in vitro and in vivo. The disposition of both compounds following intravenous administration (2 mg/kg of DEET or OBZ) and topical skin application (100 mg/kg of DEET and 40 mg/kg of OBZ) was determined in male Sprague-Dawley rats. Pharmacokinetic analysis was also conducted using compartmental and non-compartmental methods. A two-compartment model was deemed the best fit for intravenous administration. The DEET and oxybenzone permeated across the skin to accumulate in blood, liver and kidney following topical skin application. Combined use of DEET and oxybenzone accelerated the disappearance of both compounds from the application site, increased their distribution in the liver and significantly decreased the apparent elimination half-lives of both compounds (p < 0.05). Hepatoma cell studies revealed toxicity from exposure to all treatment concentrations, most notably at 72 h. Although DEET and oxybenzone were capable of mutually enhancing their percutaneous permeation and systemic distribution from topical skin application, there was no evidence of increased hepatotoxic deficits from concurrent application.

Dissolution testing of sublingual tablets: a novel in vitro method.

In the sublingual (SL) cavity, compared with the gastrointestinal tract, tablets are subjected to minimal physiological agitation, and a limited volume of saliva is available to facilitate disintegration and dissolution. None of the official compendial dissolution apparatuses and methods simulate these SL conditions. In this study, a custom-made dissolution apparatus was constructed, and a novel in vitro method that simulates SL conditions was evaluated. Several epinephrine 40 mg SL tablet formulations under development and two commercial SL tablets, isosorbide dinitrate 5 mg and nitroglycerin 0.6 mg, were studied. The dissolution medium was 2 mL of distilled water at 25°C. Dissolution was measured at 60 and 120 s. The novel in vitro method was validated for accuracy, reproducibility, and discrimination capability, and was compared with the official US Pharmacopeia (USP) dissolution method using apparatus 2 (Paddle). The data obtained following the novel in vitro method were accurate and reproducible. This method was capable of detecting minor changes in SL formulations that could not be detected using other in vitro tests. Results from the official USP dissolution method and our novel in vitro method were significantly different (p < 0.05). Results reflecting the dissolution of rapidly disintegrating tablets using simulated SL conditions were obtained using the novel in vitro dissolution method.

An electronic tongue: evaluation of the masking efficacy of sweetening and/or flavoring agents on the bitter taste of epinephrine.

An epinephrine (E) tablet is under development for sublingual (SL) administration for the first-aid treatment of anaphylaxis; however, the inherent bitterness of E may hinder acceptability by patients, especially children. To assess the degree of E bitterness and to predict the masking effects of sweetening and/or flavoring non-medicinal ingredients (NMIs), the potential usefulness of an electronic tongue (e-Tongue) was evaluated. The e-Tongue sensors were conditioned, calibrated, and tested for taste discrimination. Six standard active pharmaceutical ingredients were used to build and validate a bitterness model which was then used to assess E bitartrate (EB) solutions from 0.3-9 mM. Taste-masking efficiency of aspartame (ASP), acesulfame potassium (ASK), and citric acid (CA) each at 0.5 mM was evaluated. Using EB 9 mM, the bitterness score was 20 on a scale of 20 (unacceptable) down to 1 (not detected). When NMIs 0.5 mM were added, neither ASK (17.2, unacceptable) nor was ASP (14.0, limit acceptable) effective in masking the bitter taste. When the combination of ASK and ASP was used, the bitterness score was reduced to 9.2 (acceptable). However, the addition of CA alone resulted in the best reduction of the bitterness score to 3.3 (not detected). Using the e-Tongue, the incorporation of a variety of sweetening and/or flavoring NMIs into a SL tablet of E could be shown to mask its bitter taste by up to 80%. These results should be confirmed by in vivo studies.

Epinephrine in Anaphylaxis: Preclinical Study of Pharmacokinetics after Sublingual Administration of Taste-Masked Tablets for Potential Pediatric Use.

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.

Fast-disintegrating sublingual tablets: effect of epinephrine load on tablet characteristics.

The aim of this study was to evaluate the effect of increasing epinephrine load on the characteristics of fast-disintegrating sublingual tablets for the potential emergency treatment of anaphylaxis. Four tablet formulations, A, B, C, and D, containing 0%, 6%, 12%, and 24% of epinephrine bitartrate, respectively, and microcrystalline cellulose:low-substituted hydroxypropyl cellulose (9:1), were prepared by direct compression, at a range of compression forces. Tablet weight variation, content uniformity, hardness, disintegration time, wetting time, and friability were measured for each formulation at each compression force. All 4 tablet formulations at each compression force were within the United States Pharmacopeia (USP) limits for weight variation and content uniformity. A linear increase in compression force resulted in an exponential increase in hardness for all formulations, a linear increase in disintegration and wetting times of A, and an exponential increase in disintegration and wetting times of B, C, and D. At a mean +/- SD hardness of > or = 2.3 +/- 0.2 kg, all tablet formulations passed the USP friability test. At a mean +/- SD hardness of < or = 3.1 +/- 0.2 kg, all tablet formulations resulted in disintegration and wetting times of <10 seconds and <30 seconds, respectively. Tablets with drug loads from 0% to 24% epinephrine can be formulated with hardness, disintegration times, and wetting times suitable for sublingual administration.

Simultaneous analysis of the H1-antihistamine acrivastine and the decongestant pseudoephedrine hydrochloride by high-performance liquid chromatography.

High-performance liquid chromatography (HPLC) was used for the simultaneous quantification of the H(1)-antihistamine acrivastine and the decongestant pseudoephedrine hydrochloride. Both compounds were detected at the wavelength of 214 nm. The influence of the mobile phase and the detection wavelength was evaluated and optimized. This method was used to assay various samples from studies of the commercial preparation Semprex-D capsules. The method was found to be accurate, specific, selective, rapid, and versatile for use in routine quality control analyses.

Adrenaline (epinephrine) microcrystal sublingual tablet formulation: enhanced absorption in a preclinical model.

OBJECTIVES: For anaphylaxis treatment in community settings, adrenaline (epinephrine) administration using an auto-injector in the thigh is universally recommended. Despite this, many people at risk of anaphylaxis in community settings do not carry their prescribed auto-injectors consistently and hesitate to use them when anaphylaxis occurs.The objective of this research was to study the effect of a substantial reduction in adrenaline (Epi) particle size to a few micrometres (Epi microcrystals (Epi-MC)) on enhancing adrenaline dissolution and increasing the rate and extent of sublingual absorption from a previously developed rapidly disintegrating sublingual tablet (RDST) formulation in a validated preclinical model. METHODS: The in-vivo absorption of Epi-MC 20 mg RDSTs and Epi 40 mg RDSTs was evaluated in rabbits. Epi 0.3 mg intramuscular (IM) injection in the thigh and placebo RDSTs were used as positive and negative controls, respectively. KEY FINDINGS: Epimean (standard deviation) area under the plasma concentration vs time curves up to 60 min and Cmax from Epi-MC 20 mg and Epi 40 mg RDSTs did not differ significantly (P > 0.05) from Epi 0.3 mg IM injection. After adrenaline, regardless of route of administration, pharmacokinetic parameters were significantly higher (P < 0.05) than after placebo RDSTs administration (reflecting endogenous adrenaline levels). CONCLUSION: Epi-MC RDSTs facilitated a twofold increase in Epi absorption and a 50% reduction in the sublingual dose. This novel sublingual tablet formulation is potentially useful for the first-aid treatment of anaphylaxis in community settings.

Hydroxyzine from topical phospholipid liposomal formulations: evaluation of peripheral antihistaminic activity and systemic absorption in a rabbit model.

Hydroxyzine, an effective but sedating H1-antihistamine is given orally to treat allergic skin disorders. This study was performed to assess the peripheral H(1)-antihistaminic activity and extent of systemic absorption of hydroxyzine from liposomes applied to the skin. Using L-alpha-phosphatidylcholine (PC), small unilamellar vesicles (SUVs) and multilamellar vesicles (MLVs) containing hydroxyzine were prepared. Hydroxyzine in Glaxal Base (GB) was used as the control. Using a randomized, crossover design, each formulation, containing 10 mg of hydroxyzine, was applied to the shaved backs of 6 rabbits (3.08 +/- 0.05 kg). Histamine-induced wheal tests and blood sampling were performed at designated time intervals up to 24 hours. Compared with baseline, hydroxyzine from all formulations significantly suppressed histamine-induced wheal formation by 75% to 95% for up to 24 hours. Mean maximum suppression, 85% to 94%, occurred from 2 to 6 hours, with no differences among the formulations. The areas of plasma hydroxyzine concentration versus time area under the curve (AUCs) from PC-SUV and PC-MLV, 80.1 +/- 20.8 and 78.4 +/- 33.9 ng/mL/h, respectively, were lower than that from GB, 492 +/- 141 ng/mL/h (P < or =.05) over 24 hours. Plasma concentrations of cetirizine arising in-vivo as the active metabolite of hydroxyzine, from PC-SUV, PC-MLV, and GB, were similar with AUCs of 765 +/- 50, 1035 +/- 202, and 957 +/- 227 ng/mL/h, respectively (P < or =.05). Only 0.02% to 0.06% of the initial hydroxyzine dose remained on the skin after 24 hours. In this model, hydroxyzine from SUV and MLV had excellent topical H1-antihistaminic activity, and minimal systemic exposure occurred. Cetirizine formed in-vivo contributed to some of H1-antihistaminic activity.

Rapidly-disintegrating sublingual tablets of epinephrine: role of non-medicinal ingredients in formulation development.

Epinephrine is the drug of choice in the management of anaphylaxis. For first-aid treatment in the community, epinephrine autoinjectors (E-autos) are commonly prescribed, but are underutilized. In our laboratory, we developed a series of first-generation rapidly-disintegrating sublingual tablets (RDSTs) containing 40mg of epinephrine. One RDST had similar bioavailability to epinephrine 0.3mg from an auto-injector, as confirmed in a validated rabbit model, while other formulations containing different non-medicinal ingredients (NMIs) and with similar in vitro characteristics demonstrated much lower bioavailability. Subsequently, we evaluated the effect of changing the grade and proportion of NMIs, specifically mannitol and microcrystalline cellulose (MCC), on the in vitro characteristics of second- and third-generation RDSTs. Weight variation, content uniformity, breaking force, and friability were tested using official USP methods. Novel validated methods that simulate ambient conditions of the sublingual cavity were developed to test disintegration time, wetting time, and dissolution. Using these methods, it was possible to measure the effects of making small changes in NMIs on the in vitro characteristics of the formulations. The RDST formulation that resulted in the best in vitro characteristics contained the optimum proportion of mannitol and a specific ratio of coarse and fine particle grades of MCC. Appropriate comparative testing resulted in the selection of the RDST with the optimum in vitro characteristics.

Epinephrine and its use in anaphylaxis: current issues.

PURPOSE OF REVIEW: Epinephrine 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 FINDINGS: We 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. SUMMARY: Epinephrine 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.

Epinephrine (adrenaline) in anaphylaxis.

Epinephrine (adrenaline) is universally recommended as the initial drug of choice for the treatment of anaphylaxis. No other medication has similar life-saving pharmacologic effects in multiple organ systems, including prevention and relief of both upper and lower airway obstruction, and of shock. Failure to inject epinephrine promptly contributes to anaphylaxis fatalities. It is most effective when given immediately after the onset of anaphylaxis symptoms. The initial recommended adult dose is 0.3-0.5 mg, injected intramuscularly in the anterolateral aspect of the mid-thigh. Injected by other routes, epinephrine appears to have a less satisfactory therapeutic window; for example, onset of action is potentially delayed when it is injected subcutaneously, and risk of adverse effects potentially increases when it is injected intravenously. The possibility of randomized, controlled trials of epinephrine in anaphylaxis should be considered. For ethical reasons, these trials will not be placebo-controlled. They might involve comparison of one epinephrine dose versus another, or one route of epinephrine administration versus another. For first-aid treatment of people with anaphylaxis in the community, novel epinephrine formulations are being developed. These include epinephrine autoinjectors that are safer and easier to use, and epinephrine formulations that can be administered through non-invasive routes.