Diagnosing and treating pericarditis and myocarditis in the emergency department.

Pericarditis and myocarditis represent a challenging set of diseases to diagnose and treat. These diseases typically present with chest pain and dyspnea in previously healthy young people, often in the weeks following a viral illness, including COVID-19. Nonetheless, the etiologies can be very diverse, including infectious, noninfectious, drug-induced, and autoimmune causes. This review focuses on the evaluation, diagnosis, and management of emergency department patients presenting with pericarditis and myocarditis and summarizes current guidelines and best-practice medical management strategies in order to avoid potential life-threatening cardiac complications.

Performance comparison of intraosseous devices and setups for infusion of whole blood in a cadaveric swine bone model.

OBJECTIVES: Intraosseous (IO) access can provide a critical bridge for blood product infusion when peripheral venous access is not obtainable. Successful pressurized IO infusion requires flow rates sufficient to preserve life, but with infusion pressures low enough to avoid clinical complications (e.g., hemolysis, bone damage, fat emboli). However, the optimal method for pressured IO delivery of blood was unknown. METHODS: Three trained physicians infused 500 mL of whole blood through a 15-gauge, 45 mm IO catheter into fresh, high bone density cadaveric swine proximal humeri. Participants applied eight different pressure infusion strategies: (1) gravity, (2) pressure bag, (3) pressure bag actively maintained at or above 300 mmHg, (4) hand pump, (5) hand pump with pressure bag, (6) push-pull with 10 mL syringe, (7) push-pull with 60 mL syringe, and a (8) Manual Rapid Infuser in a randomized within-subjects design (30 trials per method, 240 trials total). The primary outcomes of flow rates, mean and peak pressures, and user ratings were contrasted using ANOVA at p < 0.05. RESULTS: The Manual Rapid Infuser conferred the highest flow rates (199 ± 3 mL/min) and most favorable user ratings, but also the highest mean and peak pressures. Push-pull conferred the next highest flow rates (67 ± 5 mL/min for 60 mL, 56 ± 2 mL/min for 10 mL) and pressures, with intermediate-to-high user ratings. Hand pump flow rates were essentially identical with (45 ± 4 mL/min) or without (44 ± 3 mL/min) pressure bag, with high user ratings without a pressure bag. Pressure bag and gravity methods conferred low flow rates and user ratings. CONCLUSIONS: Some pressured IO infusion methods can achieve flow rates adequate to serve as a resuscitative bridge in the massively hemorrhaged trauma victim, but flow rates and pressures vary greatly across IO pressurized infusion methods. Manual Rapid Infuser and push-pull methods conferred high flow rates but also relatively high pressures, highlighting the importance of using in vivo models in future research to assess the possible clinical complications of using these promising methods. Combined, present findings highlight the importance of studying pressurized IO methods towards preserving the life of the critically injured trauma victim.

The development and characterization of a long acting anti-thrombotic von Willebrand factor (VWF) aptamer.

BACKGROUND: Thrombus formation involves coagulation proteins and platelets. The latter, referred to as platelet-mediated thrombogenesis, is predominant in arterial circulation. Platelet thrombogenesis follows vascular injury when extracellular von Willebrand factor (VWF) binds via its A3 domain to exposed collagen, and the free VWF A1 domain binds to platelet glycoprotein Ib (GPIb). OBJECTIVES: To characterize the antiplatelet/antithrombotic activity of the pegylated VWF antagonist aptamer BT200 and identify the aptamer VWF binding site. METHODS: BT100 is an optimized aptamer synthesized by solid-phase chemistry and pegylated (BT200) by standard conjugation chemistry. The affinity of BT200 for purified human VWF was evaluated as was VWF inhibition in monkey and human plasma. Efficacy of BT200 was assessed in the monkey FeCl3 femoral artery thrombosis model. RESULTS: BT200 bound human VWF at an EC50 of 5.0 nmol/L and inhibited VWF A1 domain activity in monkey and human plasma with mean IC50 values of 183 and 70 nmol/L. BT200 administration to cynomolgus monkeys caused a time-dependent and dose-dependent effect on VWF A1 domain activity and inhibited platelet function as measured by collagen adenosine diphosphate closure time in the platelet function analyzer. BT200 demonstrated a bioavailability of ≥77% and exhibited a half-life of >100 hours after subcutaneous injection. The treatment effectively prevented arterial occlusion in an FeCl3 -induced thrombosis model in monkeys. CONCLUSIONS: BT200 has shown promising inhibition of human VWF in vitro and prevented arterial occlusion in non-human primates. These data including a long half-life after subcutaneous injections provide a strong rationale for ongoing clinical development of BT200.

Histopathological Findings in Cynomolgus Macaques ( Macaca fascicularis) Consistent with Secondary Immunological Reaction to Biotherapeutics with an Emphasis on the CNS and Eye.

Biotherapeutics are pharmaceutical products derived from or synthesized by biological systems. Such molecules carry the potential for immunogenicity which may lead to adverse immune responses. The cynomolgus macaque ( Macaca fascicularis) is the species of choice in nonclinical safety assessment of biotherapeutics. The main aim of this study was to confirm whether mononuclear cell infiltrates at specific locations represent a generic effect of biotherapeutics, and therefore the result of their immunogenicity. Following a review of microscopic findings in studies conducted over a 10-year period at one test facility, 15% of biotherapeutics were reported to have such findings. The most commonly affected site was the choroid plexus and less frequently the meninges and ciliary body. The reporting of such findings as test article-related becomes more subjective as the severity and incidence decreases. To assess the accuracy of such associations, a mathematical approach was employed to determine the probability of obtaining the observed results by chance. There was good agreement between this approach and the original findings. In addition to an increased number and size of mononuclear cell infiltrates in the brain, biotherapeutic administration was strongly associated with the presence of plasma cells and eosinophils.

Evaluation of the PhysioTel™ Digital M11 cardiovascular telemetry implant in socially housed cynomolgus monkeys up to 16weeks after surgery.

INTRODUCTION: The novel PhysioTel™ Digital M11 telemetry implant was evaluated in socially housed monkeys with respect to both safety pharmacological cardiovascular (arterial blood pressure (BP), heart rate (HR) and electrocardiogram (ECG)) and toxicological (clinical pathology and histopathology) endpoints. METHODS: Telemetry and clinical pathology data were obtained repeatedly up to 16weeks after surgery in four female cynomolgus monkeys, followed by necropsy. Due to postsurgical complications, one spare animal was included and only toxicological endpoints from the affected (fifth animal) were reported. Continuous telemetry recordings were conducted at periods without dosing and after ascending doses of moxifloxacin (0, 10, 30, 100mg/kg) and L-NAME (0, 0.1, 1, 10mg/kg). Additionally, a retrospective power analysis was conducted based on baseline M11 implant data from 32 other animals. RESULTS: During periods without dosing, the cardiovascular endpoints were stable over time and within normal ranges. Moxifloxacin and L-NAME elicited the expected pharmacological responses with dose-dependent increase in QTca (8, 17, 22ms) and BP (mean BP: 12, 21, 34mmHg), respectively. Expected intravascular and tissue reactions were observed at the sites of the BP catheter and the transmitter. Signs of infection (localised to the transmitter implantation site with associated systemic effects) was noted in the fifth animal. No systemic pathologies were seen in any animals. Power analysis (80% power) indicated that the minimal differences which can be detected in a parallel group design (n=6) are 7mmHg (mean BP), 16bpm (HR), 12ms (QTca). DISCUSSION: The M11 implant provided stable, high quality ECG and BP data for a duration covering the length of sub-chronic repeated dose toxicity studies without important impact on toxicological endpoints. Adequate power in order to elucidate major treatment-related cardiovascular effects was demonstrated. However to avoid post-surgical complications the implantation procedures should be carefully considered before using the method.

Vehicle Systems and Excipients Used in Minipig Drug Development Studies.

Minipigs have been used for dermal drug development studies for decades, and they are currently more frequently considered as the second nonrodent species for pivotal nonclinical studies, in lieu of the dog or nonhuman primate, for compounds delivered via standard systemic routes of administration. Little is known about the tolerability of different excipients in minipigs; sharing knowledge of excipient tolerability and compositions previously used in nonclinical studies may avoid testing of inadequate formulations, thereby contributing to reduced animal usage. This article reviews vehicles employed in the Göttingen(®)minipig based on the combined experience from a number of pharmaceutical companies and contract research organizations. The review includes vehicles tolerated for single or multiple dosing by the Göttingen minipig, some of which are not appropriate for administration to other common nonrodent species (e.g., dogs). By presenting these data for dermal, oral, subcutaneous, and intravenous routes of administration, studies to qualify these vehicles in minipigs can be minimized or avoided. Additionally, investigators may more frequently consider using the minipig in place of higher species if the tolerability of a vehicle in the minipig is known.

The minipig as nonrodent species in toxicology--where are we now?

Over the past 3 decades minipigs have moved from being an obscure alternative to dogs and nonhuman primates to being a standard animal model in regulatory toxicity studies. This article covers the use of minipigs as a model in the context of nonclinical drug safety and provides an overview of the minipig's developmental history and relates minipigs to other animal species commonly used in toxicology; and the minipig's translational power is supported by 43 case studies of marketed drug products covered. Special focus is given to criteria for selecting minipigs in nonclinical programs supporting the development of new medicines; the use of swine in the assessment of food additives, agrochemicals, and pesticides; as well as a regulatory perspective on the use of minipigs in Food and Drug Administration (FDA)-regulated products. This article presents the main points conveyed at a symposium held at the 2010 American College of Toxicology meeting in Baltimore, Maryland.