Autoinjector Research Articles

A double‐blind, randomized, placebo‐controlled trial of a diazepam auto‐injector administered by caregivers to patients with epilepsy who require intermittent intervention for acute repetitive seizures

A diazepam auto‐injector (AI) has been developed for intramuscular administration to treat acute repetitive seizures (ARS). The objective of this study was to evaluate the efficacy and safety of the diazepam AI when administered by caregivers to control an episode of ARS (ClinicalTrials.gov identifier NCT00319501). In this phase III, randomized, double‐blind, parallel‐group, placebo‐controlled, multicenter study, subjects with epilepsy on a stable antiepileptic drug regimen who required intermittent medical intervention to control ARS were randomized 1:1 to the placebo AI or the diazepam AI group. Subjects were stratified according to age (2–5, 6–11, ≥12 years). Dose (5, 10, 15, or 20 mg) was based on age and weight. A single dose of study medication was dispensed to be administered by caregivers in an outpatient setting when required. The primary end point was time to next seizure or rescue from 15 min to 12 h postdose. Secondary end points included rescue medication use, number of seizures postdose, caregiver and physician treatment assessments, and safety measures. Of 234 subjects randomized, 81/110 in the placebo AI group and 82/124 in the diazepam AI group were included in the intent‐to‐treat analysis. Baseline characteristics were similar for both groups. Time to next seizure or rescue was significantly longer in the diazepam AI group compared with the placebo AI group, with a hazard ratio of 0.55 (95% confidence interval [CI] 0.34–0.88; p = 0.012) for diazepam AI versus placebo AI, adjusted for age group. The 25th percentile for time to the next seizure or rescue was 1.18 h (95% CI 0.38–2.03) for placebo AI and 2.70 h (95% CI 0.48–11.42) for diazepam AI; the median was 5.9 h for placebo AI and was inestimable for diazepam AI due to the low number of events experienced by subjects in that group. The proportion of subjects using rescue medication postdose was 30% (24/81) placebo AI versus 17% (14/82) diazepam AI (p = 0.066). An event (seizure or rescue) occurred in 55.6% of subjects in the placebo AI group and 35.4% in the diazepam AI group. The number of seizures experienced during the 12‐h postdose period was significantly lower for diazepam AI (median 0.0) compared with placebo AI (median 1.0; p = 0.010). Treatment‐emergent adverse events (TEAEs) were reported in 44% (35/79) of subjects in the placebo AI group and 42% (34/81) in the diazepam AI group. The most common TEAEs reported were injection site pain (15% placebo AI, 17% diazepam AI) and injection site hemorrhage (6% placebo AI, 5% diazepam AI). The diazepam AI was significantly more effective than placebo AI at delaying the next seizure or rescue. Secondary efficacy end points were generally supportive of the primary outcome. Diazepam AI administered by trained caregivers was effective for the treatment of ARS and was well tolerated, with a safety profile similar to placebo.

Anstrengungsinduzierte Anaphylaxie

Exercise-induced anaphylaxis is a mast cell dependent reaction, which is induced by allergen exposure in combination with physical activity. Typically, the reaction occurs within 2 hours after allergen exposure followed by physical activity. Not only food allergens but all kinds of allergens including drugs can induce this form of anaphylaxis. The clinical symptoms of exercise-induced anaphylaxis are the same as in any other type of anaphylaxis. Thus not only the skin and mucosa but also other organ systems like the lungs, cardiovascular system and gastrointestinal tract can be affected. The diagnostic work up should cover a detailed clinical history including the assessment of symptoms and possible trigger factors including suspected allergens. Besides classical allergy diagnostics like skin prick tests and specific IgE determination, tryptase should be measured for the differential diagnosis to exclude mast cell dependent diseases. The diagnosis of exercise-induced anaphylaxis is made by the means of a double-blind placebo-controlled provocation test. Both, a sufficient amount of allergen and of physical activity must be achieved for a valid test. After the diagnosis is made, patients should be extensively counseled and provided with an emergency kit including an epinephrine auto injector.

Epinephrine (E) for Self-Administration: Autoinjectors and Alternatives

Epinephrine (E) for Self-Administration: Autoinjectors and Alternatives

Prospective Evaluation of an Anaphylaxis Education Mini-Handout: The AAAAI Anaphylaxis Wallet Card

Few anaphylaxis education materials have been prospectively evaluated in randomized controlled trials. Our objective was to evaluate the American Academy of Allergy, Asthma & Immunology Anaphylaxis Wallet Card (AAAAI-AWC) as an anaphylaxis education mini-handout for health care professionals. We performed a randomized controlled study of the AAAAI-AWC with residents in general pediatrics at Miami Children's Hospital. Participants in the intervention group completed a pretest about anaphylaxis, heard a 3-minute PowerPoint presentation based on the AAAAI-AWC, reviewed the AAAAI-AWC, and discussed it with the presenter. After this, participants took a post-test immediately and a follow-up test 4 weeks later. Participants in the control group took the pretest, were handed an AAAAI-AWC, studied it briefly, then took the post-test immediately and the follow-up test 4 weeks later. Fifty-five residents participated. Regardless of the amount of time spent studying the AAAAI-AWC, when the pretests were compared with the post-tests and follow-up tests, residents in both the intervention and control groups were more likely to recognize anaphylaxis symptoms (P < .05), name asthma as the most common comorbid disease in children with fatal or near-fatal anaphylaxis (P < .05), and recall the names of epinephrine auto injectors (P < .05) and the epinephrine doses available in these auto injectors (P < .05). When the pretests were compared with the post-tests and the follow-up tests, residents in the intervention group were more likely than controls to identify the body organ systems involved in severe or fatal anaphylaxis correctly (P < .05). The AAAAI-AWC is a practical, concise anaphylaxis education mini-handout for pediatric residents, a time-challenged group of health care professionals.

P4 Omalizumab: A National Review of Practise Across the United Kingdom

A varied approach to the initiation, assessment and delivery of Omalizumab across the United Kingdom has been observed. To analyse the disparity in practize a questionnaire was disseminated to centres...

Development and Validation of Headspace Method for Determination of Residual Solvents in Diphenoxylate Hydrochloride Bulk Drug

Organic volatile impurities by Headspace GC method was developed and validated for Diphenoxylate hydro- chloride bulk drug for its seven residual solvents. Analysis was performed on Perkin Elmer HS 40 system with auto injector. Carrier gas Helium was used with constant flow rate of 2.5mL/min as carrier gas and the separation of residual solvents were achieved on DB-5 column. The thermostat temperature was 125 °C for 20 minute for each vial and after the equilibration the vials were pressurized and injected on GC column. FID detector was used for detection. The parameter for which the method was validated included specificity, limit of detection and quantification, linearity, precision, accuracy and robustness. The method was successfully used to quantify the levels of specified limit for residual solvents in Diphenoxylate hydrochloride bulk drug.

An open-label trial of a sumatriptan auto-injector for migraine

Patients  Male or female outpatients (18−60 years of age) were eligible for study entry if they met International Headache Society criteria for migraine with or without aura,5 with ≥2 attacks per month, and if they reported use of the traditional SC injectable sumatriptan on ≥2 occasions within the previous 2 months.  Patients were excluded from the study if they reported: – The use of monoamine oxidase inhibitors (in the previous 14 days prior to study entry), ergot-containing drugs (in the previous 30 days), or medication for migraine prophylaxis (unless stable use for the previous 3 months). – A history of hemiplegic or basilar migraine. – A history of seizure disorders. – A history of cardiac arrhythmia, uncontrolled hypertension, or coronary artery disease (CAD) (or two or more risk factors for CAD); myocardial infarction, or any cerebrovascular syndrome or peripheral vascular disease. – Hypersensitivity or known contraindication to treatment with sumatriptan. – Any clinically significant medical illness or laboratory abnormalities. – A history of alcohol or substance abuse, or use of any experimental drug within the past month. An Open-Label Trial of a Sumatriptan Auto-Injector For Migraine Stephen H. Landy, MD1; Stewart J. Tepper, MD2; Theodore Wein, MD3; Edward Schweizer, MD4; Elodie Ramos, MSc, PhD5 1Wesley Neurology Clinic, Memphis, TN, USA; 2Neurological Center for Pain, Cleveland Clinic, Cleveland, OH, USA; 3Division of Neurology, Montreal General Hospital, Montreal, Canada; 4Paladin Consulting Group, Princeton, NJ, USA; 5Pfizer Inc., New York, NY, USA

What happens when the adrenaline rush is over?

<h3>Background</h3> Anaphylaxis is a life-threatening condition that may recur. It is important to evaluate the potential precipitating allergens, provide education, appropriate treatment, training in medication administration and school care plans. Such focusing on “aftercare” on future management during an admission is important to reduce further anaphylaxis. <h3>Aims</h3> To evaluate the aftercare of children presenting with anaphylaxis (airway, breathing or cardiovascular compromise) and admitted to the paediatric ward. <h3>Methods</h3> Cases were identified from coding between 2005 to 2010 and were all analysed. We evaluated the main presenting complaint, treatment given (table 1) and aftercare provision given (table 2) including basic life support, watching Adrenaline Auto injector video, Adrenaline Auto injector training, provision of Epipen, informing school nurse, medic alert bracelet information, documentation of the provision of information provided to families and outpatient follow-up with a consultant with special interest in allergy. <h3>Results</h3> 29 children were admitted to the paediatric ward for further care. There was one death (medication reaction). Exposure to known allergen occurred in 16 (55%). The airway was involved in 17 (57%), breathing 25 (86%), circulation 11 (38%) and skin in 25 (86%). <h3>Conclusions</h3> Most children received adrenaline auto injectors and training although reasons for their apparent non provision in 35% is concerning. Follow-up in specialist outpatients did not occur in all cases. Our study will emphasise the importance of the care beyond the adrenaline.

UV–VIS and HPLC studies on Amphiroa anceps (Lamarck) Decaisne

The present study was aimed to explore phytochemical constituents present in Amphiroa anceps (Lamarck) Decaisne. The extracts of A. anceps were scanned in the wavelength ranging from 200 to 1100nm by using Shimadzu Spectrophotometer. HPLC method was performed on a Shimadzu LC-10 AT VP HPLC system, which was equipped with a model LC-10AT pump, UV–VIS detector SPD-10AT, Rheodyne injector fitted with a 20μl loop and auto injector SIL-10AT. Out of 156 (2×6×13=156) tests for the presence or absence of the above compounds, 42 tests gave positive results and the remaining 114 showed negative results. The 42 positive results showed the presence of alkaloids, steroids, phenolic groups, saponins, tannin, flavonoids, terpenoids, glycosides, proteins and sugars. The results of the ash analysis discovered the existence of sulphur, calcium, magnesium, iron, phosphorous and chlorine in all the extracts of A. anceps. The UV–VIS profile of A. anceps benzene extracts showed peaks at 670, 612, 536, 504, and 412nm with the absorption 2.004, 0.333, 0.417, 0.608 and 3.311. The UV–VIS profile of A. anceps chloroform extracts showed the peaks at 666, 608, 538, 502 and 416nm with the absorption 1.029, 0.39, 0.458, 0.552 and 2.648. The qualitative UV–VIS spectrum profile of A. anceps methanolic extracts showed peaks at 656 and 330nm with the absorption 0.295 and 3.656. The HPLC profile of A. anceps aqueous extracts showed two prominent peaks at a retention time of 1.737 and 2.680min and some moderate peaks were observed with the retention time 4.083, 6.387 and 1.490min. The qualitative HPLC fingerprint profile of isopropanol extract of A. anceps showed one prominent peak at a retention time of 2.673min. The HPLC profile of A. anceps methanolic extracts illustrated two prominent peaks at a retention time of 1.927 and 2.667min and some moderate peaks were also observed with the retention time 2.347, 4.077 and 5.873min, respectively.

Autoinjectors for Adrenalin Products EpiPen, Twinject, and Adrenaclick

Autoinjectors for Adrenalin Products EpiPen, Twinject, and Adrenaclick

Epipen Demographics and Use in a V.A. Population

RATIONALE: Epinephrine auto injector (Epi-pen) use and demographic data have not been studied in a VA population. This study investigates utilization and patient's understanding of Epi-pen use in this population.

Simultaneous Determination of LogD, LogP, and pKa of Drugs by Using a Reverse Phase HPLC Coupled with a 96-Well Plate Auto Injector

For years, the physicochemical properties of drug candidates have been used to predict their in vivo pharmacokinetic behaviors. Several theories and empirical correlations have been established by various researchers with the overall goal of expediting the drug candidate selection process, with greater confidence and faster turnaround. This study describes a 96-well reverse phase HPLC method, simultaneously determining LogD, LogP, and pK(a) values of drugs in a throughput mode. The LogD and LogP values of each compound were determined, based on the octanol-aqueous partitioning behavior of the charged and non-charged species under different pH values. The pK(a) value was determined by using the Polynomial fit between LogP and LogD and the equation LogD (pK(a)) approximately LogP-0.301. The advantages of this method are: low sample consumption, suitability for low solubility compounds, less restriction on compound purity, potential for higher throughput, precise data, and multiple determinations in one assay.

Food Allergy in Adults: An Over- or Underrated Problem? Stringent Elimination Diet

Seitz et al conducted a retrospective analysis of more than 400 patients with suspected allergies and rightly emphasize that a comprehensive allergological evaluation can protect patients from the negative consequences of over- or underestimating the allergy (1). In 66 cases they describe oral provocation tests—following a medical history and standardized skin tests—whose results were negative. The authors diagnose a allergy in more than 50% of their patients—but we don’t know whether in case the situation was not obvious, oral provocation tests were conducted in these patients too. In everyday practice, the proportion of patients with unclear constellations after a medical history has been taken, skin tests have been conducted, or IgE concentrations were measured is high (for example, existing differential diagnoses to allergies and sensitization to several foodstuffs in unequivocal symptoms after a composite meal). The allergy working group of the three German allergy societies (the German Society for Allergology and Clinical Immunology [DGAKI], the Medical Association of German Allergologists [ADA,], and the Society of Pediatric Allergology [GPA]) have compiled position papers and guidelines relevant to clinical practice that can be found at http://www.leitlinien.net by searching for food allergy. The specialist societies are particularly concerned that institutions with allergological experience should extensively offer the option of oral provocation tests for patients whose constellation is unclear. Targeted oral provocation tests can be sufficiently reproduced in hospitals under DRG conditions and are often the only option to confirm a suspected diagnosis of allergy (2, 3). Food allergies can have harmless outcomes but they can also be fatal, albeit rarely. Neither the degree of sensitization nor the extent of a previous systemic reaction are predictive of the outcome of life threatening reactions to foodstuffs. Hence even patients with mild confirmed systemic reactions to foodstuffs should stringently adhere to a strict elimination diet after dietary advice and should carry an emergency kit (adrenaline auto injector, antihistamine, steroid) on their person.

EpiPen training provided to parents of children with food allergies

It has been estimated that food allergy affects 6% of children,1 and occasionally it can be fatal. Optimal management of these children includes prescription of epinephrine auto injector devices (EpiPen)...

A sensitive and selective HPLC/ESI-MS/MS assay for the simultaneous quantification of 16-dehydropregnenolone and its major metabolites in rabbit plasma☆

A sensitive, selective and rapid liquid chromatographic/electrospray ionization tandem mass spectrometric assay was developed and validated for the simultaneous quantification of 16-dehydropregnenolone (DHP) and its five metabolites 4,16-pregnadien-3, 20-dione (M(1)), 5-pregnene-3beta-ol-20-one (M(2)), 5-pregnene-3beta, 20-diol (M(3)), 5-pregnene-3beta-ol-16, 17-epoxi-20-one (M(4)) and 5,16-pregnadien-3beta, 11-diol-20-one (M(5)) in rabbit plasma using dexamethasone as internal standard (IS). The analytes were chromatographed on Spheri-5 RP-18 column (5 microm, 100 mm x 4.6 mm i.d.) coupled with guard column using acetonitrile:ammonium acetate buffer (90:10, v/v) as mobile phase at a flow rate of 0.65 ml/min. The quantitation of the analytes was carried out using API 4000 LC-MS-MS system in the multiple reaction monitoring (MRM) mode. The method was validated in terms of linearity, specificity, sensitivity, recovery, accuracy, precision (intra- and inter-assay variation), freeze-thaw, long-term, auto injector and dry residue stability. Linearity in plasma was observed over a concentration range of 1.56-400 ng/ml with a limit of detection (LOD) of 0.78 ng/ml for all analytes except M(3) and M(5) where linearity was over the 3.13-400 ng/ml with LOD of 1.56 ng/ml. The absolute recoveries from plasma were consistent and reproducible over the linearity range for all analytes. The intra- and inter-day accuracy and precision method were within the acceptable limits and the analytes were stable after three freeze-thaw cycles and their dry residues were stable at -60 degrees C for 15 days. The method was successfully applied to determine concentrations of DHP and its putative metabolites in plasma during a pilot pharmacokinetic study in rabbits.

A sensitive and selective LC–MS–MS method for simultaneous determination of picroside-I and kutkoside (active principles of herbal preparation picroliv) using solid phase extraction in rabbit plasma: Application to pharmacokinetic study

A rapid, sensitive and selective LC–MS–MS method for the simultaneous quantitation of picroside-I and kutkoside (active constituents of herbal hepatoprotectant picroliv) was developed and validated in rabbit plasma. The analytes and internal standard (Amarogentin) were extracted using Oasis ® HLB solid phase extraction cartridges. Analysis was performed on Spheri RP-18 column (10 μm, 100 mm × 4.6 mm i.d.) coupled with guard column using acetonitrile:MilliQ water (50:50, %v/v) as mobile phase at a flow rate of 1 ml/min with a retention time of 1.39, 1.33 and 1.42 min for picroside-I, kutkoside and amarogentin, respectively. The quantitation was carried out using an API-4000 LC–MS–MS with negative electro spray ionization in multiple reaction monitoring (MRM) mode. The precursor to product ion transitions for picroside-I, kutkoside and amarogentin were m/ z 491 > 147, 199; 511 > 167, 235; 585 > 227, respectively. The method was validated in terms of establishing linearity, specificity, sensitivity, recovery, accuracy and precision (within- and between-assay variation), freeze–thaw (f–t), auto injector and dry residue stability. Linearity in plasma was observed over a concentration range of 1.56–400 ng/ml with a limit of detection (LOD) of 0.5 ng/ml for both analytes. The recoveries from spiked control samples were >60 and >70% for picroside-I and kutkoside, respectively. Accuracy and precision of the validated method were within the acceptable limits of <20% at low and <15% at other concentrations. The analytes were stable after three freeze–thaw cycles and their dry residues were stable at −60 °C for 15 days. The method was successfully applied to determine concentrations of picroside-I and kutkoside post i.v. bolus administration of picroliv in rabbit.

Fully automated online multi-dimensional protein profiling system for complex mixtures

For high throughput proteome analysis of highly complex protein mixtures, we have constructed a fully automated online system for multi-dimensional protein profiling, which utilizes a combination of two-dimensional liquid chromatography and tandem mass spectrometry (2D-LC–MS–MS), based on our well-established offline system described previously [K. Fujii, T. Nakano, T. Kawamura, F. Usui, Y. Bando, R. Wang, T. Nishimura, J. Proteome Res. 3 (2004) 712]. A two-valve switching system on a programmable auto sample injector is utilized for online two-dimensional chromatography with strong cation-exchange (SCX) and reversed-phase (RP) separations. The SCX separation is carried out during the equilibration of RP chromatography and the entire sequence of analysis was performed under fully automated conditions within 4 h, based on six SCX fractionations, and 40 min running time for the two-dimensional RP chromatography. In order to evaluate its performance in the detection and identification of proteins, digests of six standard proteins and yeast 20S proteasome have been analyzed and their results were compared to those obtained by the one-dimensional reversed-phase chromatography system (1D-LC–MS–MS). The 2D-LC–MS–MS system demonstrated that both the number of peptide fragments detected and the protein coverage had more than doubled. Furthermore, this multi-dimensional protein profiling system was also applied to the human 26S proteasome, which is one of the highly complex protein mixtures. Consequently, 723 peptide fragments were identified as 31 proteasome components, together with other coexisting proteins in the sample. The identification could be comprehensively performed with a 63% sequence coverage on an average, and additionally, with modifications at the N-terminus. These results indicated that the online 2D-LC–MS–MS system being described here is capable of analyzing highly complex protein mixtures in a high throughput manner, and that it would be applicable to dynamic proteomics.

Anaphylaxis in Schools and Other Child Care Settings

AAAAI Board of DirectorsJ Allergy Clin Immunol.1021998173176This physician's statement is published to better identify the problem of anaphylaxis in schools and other child care settings with an emphasis on avoidance, treatment strategies, and making available emergency health care plans.Do not apply to this review.This critically important statement is an excellent guide for primary care providers to deal with anaphylaxis. The diagnosis of allergy with a risk of anaphylaxis is made based on the patient's history and confirmed with skin or blood tests performed by appropriately trained allergy specialists. It also identifies the fact that school personnel should develop a system of identifying children with life-threatening allergies to prevent anaphylactic reactions, and school personnel should be prepared to deal with these reactions. When prescribed, every student should also have an epinephrine auto injector device clearly labeled with his or her name and classroom number. School personnel should be instructed about the location of the medication and expiration dates should be checked carefully. This physician's statement makes comments about the avoidance of foods, especially dealing with the student who is going to eat from the cafeteria menu. The child's parents should inform the cafeteria staff in writing about foods to be avoided and suggest safe substitutions. All food service personnel should be instructed of the student's allergies. The physician's statement also deals with treatment strategies. Treatment protocols need to be prescribed by a physician. School staff should have written instructions. Epinephrine should be the first drug that should be used in the emergency management. All individuals receiving emergency epinephrine should be immediately transported to a hospital even if symptoms appear to have resolved. Additional epinephrine should be available during transport if necessary. All individuals entrusted with the care of children need to have familiarity with basic first aid and resuscitative techniques. The physician's statement also nicely defines the common symptoms and signs of an allergic reaction, and has an excellent emergency health care plan sample which includes a form that could be readily used by schools and other facilities taking care of children who may have the potential for anaphylaxis.Although not a research paper, this article was included because of its great relevance to pediatricians.

A sensitive method for the determination of 6-nitrochrysene, 2-nitro-fluoranthene and 1-, 2- and 4-nitropyrenes in airborne particulates using high-performance liquid chromatography with chemiluminescence detection

A sensitive method for the determination of 6-nitrochrysene (NC), 2-nitrofluoranthene (NF) and 1-, 2- and 4-nitropyrenes (NP) in airborne particulates is described. After ultrasonic extraction of airborne particulates with benzene/ethanol, the extract was injected into a high-performance liquid chromatographic (HPLC) system. The system consisted of four pumps, an auto injector, two separation columns (ODS), a reduction column (zinc/glass beads), a concentration column (ODS), a switching valve, a column oven, a chemiluminescence detector and an integrator. Nitroarenes were separated on the first separation column and reduced to their corresponding aminoarenes through the reduction column. The elution bands containing the analytes were concentrated selectively onto the concentration column by increasing the water concentration of the mobile phase. By rotating the switching valve, the analytes were introduced into the second separation column, separated and then detected chemilumigenically. Detection limits were in the 0.3–5 fmol range. Utilizing the above method, atmospheric concentrations of the above five nitroarenes in Kanazawa were determined.

Bioanalytical automatlon: history and future plans

Bioanalysis is determining the concentration of drugs and metabolites in biological fluids (i.e. plasma and urine). During the past 15 years tremendous advances in bioanalysis, for example HPLC, auto injectors, data collection systems and robotics has enabled the productivity of the bioanalyst to increase but it still requires considerable manual intervention. This paper describes the rationale, the justification and the plans Bristol-Myers Squibb has to completely automate the entire bioanalytical process.