Abilifright: A Case Report of Massive Aripiprazole Overdose in a Toddler.

INTRODUCTION: Aripiprazole is an atypical antipsychotic with unique receptor-binding properties that has a favorable safety profile in therapeutic doses compared to other antipsychotics. Massive aripiprazole overdose in children, however, presents with profound lethargy and may have neurologic, hemodynamic, and cardiac effects, often requiring admission to a high level of care. CASE REPORT: We describe a case of a 21-month-old male with a reported 52-milligram aripiprazole ingestion. Initial vital signs were remarkable for tachycardia and hypertension, which rapidly resolved. The patient did not develop hypotension throughout hospitalization. He experienced 60 hours of lethargy. Irritability associated with upper extremity spasms and tremors occurred from 36-72 hours post ingestion, which resolved without intervention. The initial electrocardiogram demonstrated ST-segment depressions in the anteroseptal leads; further cardiac workup was normal. Concurrent medical workup was unrevealing. Aripiprazole and dehydro-aripiprazole serum concentrations sent 46 hours after reported exposure were 266.5 nanograms per milliliter (ng/mL) and 138.6 ng/mL, respectively. He returned to neurologic baseline and was discharged 72 hours after ingestion. CONCLUSION: Antipsychotics, including aripiprazole, should be considered as a potential toxicological cause of persistent central nervous system depression; ingestion of a single dose has the potential to cause significant toxicity.

Self-Complementary Adeno-Associated Virus-Mediated Interleukin-1 Receptor Antagonist Gene Delivery for the Treatment of Osteoarthritis: Test of Efficacy in an Equine Model.

The authors are investigating self-complementary adeno-associated virus (scAAV) as a vector for intra-articular gene-delivery of interleukin-1 receptor antagonist (IL-1Ra), and its therapeutic capacity in the treatment of osteoarthritis (OA). To model gene transfer on a scale proportional to the human knee, a frequent site of OA incidence, studies were focused on the joints of the equine forelimb. Using AAV2.5 capsid and equine IL-1Ra as a homologous transgene, a functional ceiling dose of ∼5 × 1012 viral genomes was previously identified, which elevated the steady state levels of eqIL-1Ra in synovial fluids by >40-fold over endogenous production for at least 6 months. Here, using an osteochondral fragmentation model of early OA, the functional capacity of scAAV.IL-1Ra gene-delivery was examined in equine joints over a period of 12 weeks. In the disease model, transgenic eqIL-1Ra expression was several fold higher than seen previously in healthy joints, and correlated directly with the severity of joint pathology at the time of treatment. Despite wide variation in expression, the steady-state eqIL-1Ra in synovial fluids exceeded that of IL-1 by >400-fold in all animals, and a consistent treatment effect was observed. This included a 30-40% reduction in lameness and ∼25% improvement in total joint pathology by both magnetic resonance imaging and arthroscopic assessments, which included reduced joint effusion and synovitis, and improved repair of the osteochondral lesion. No vector-related increase in eqIL-1Ra levels in blood or urine was noted. Cumulatively, these studies in the equine model indicate scAAV.IL-1Ra administration is reasonably safe and capable of sustained therapeutic IL-1Ra production intra-articularly in joints of human scale. This profile supports consideration for human testing in OA.

Gene Therapy for Osteoarthritis: Pharmacokinetics of Intra-Articular Self-Complementary Adeno-Associated Virus Interleukin-1 Receptor Antagonist Delivery in an Equine Model.

Toward the treatment of osteoarthritis (OA), the authors have been investigating self-complementary adeno-associated virus (scAAV) for intra-articular delivery of therapeutic gene products. As OA frequently affects weight-bearing joints, pharmacokinetic studies of scAAV gene delivery were performed in the joints of the equine forelimb to identify parameters relevant to clinical translation in humans. Using interleukin-1 receptor antagonist (IL-1Ra) as a secreted therapeutic reporter, scAAV vector plasmids containing codon-optimized cDNA for equine IL-1Ra (eqIL-1Ra) were generated, which produced eqIL-1Ra at levels 30- to 50-fold higher than the native sequence. The most efficient cDNA was packaged in AAV2.5 capsid, and following characterization in vitro, the virus was injected into the carpal and metacarpophalangeal joints of horses over a 100-fold dose range. A putative ceiling dose of 5 × 1012 viral genomes was identified that elevated the steady-state eqIL-1Ra in the synovial fluids of injected joints by >40-fold over endogenous levels and was sustained for at least 6 months. No adverse effects were seen, and eqIL-1Ra in serum and urine remained at background levels throughout. Using the 5 × 1012 viral genome dose of scAAV, and green fluorescent protein as a cytologic marker, the local and systemic distribution of vector and transduced cells following intra-articular injection scAAV.GFP were compared in healthy equine joints and in those with late-stage, naturally occurring OA. In both cases, 99.7% of the vector remained within the injected joint. Strikingly, the pathologies characteristic of OA (synovitis, osteophyte formation, and cartilage erosion) were associated with a substantial increase in transgenic expression relative to tissues in healthy joints. This was most notable in regions of articular cartilage with visible damage, where foci of brilliantly fluorescent chondrocytes were observed. Overall, these data suggest that AAV-mediated gene transfer can provide relatively safe, sustained protein drug delivery to joints of human proportions.

Steroid-Induced Psychosis in the Pediatric Population: A New Case and Review of the Literature.

OBJECTIVES: Iatrogenic steroid-induced psychosis is a rare but serious adverse side effect seen largely in the adult population that less commonly affects children and adolescents. Given the significant distress steroid-induced psychosis may cause, recommendations are needed for effective management. Here we conducted a systematic review of the literature and report a new case of steroid-induced psychosis in a 12-year-old patient. METHODS: We performed a systematic search using Embase, PubMed, Scopus, and PsychInfo. Key terms included ("steroid induced" or "corticosteroid induced" or "glucocorticoid induced") and ("psychosis" or "hallucinations" or "delusions") and ("child" or "adolescent" or "pediatric"). A total of 15 articles of steroid-induced psychosis in children and adolescents were found in the scientific literature. This report includes those articles and a novel case of steroid-induced psychosis. RESULTS: Children with asthma, autoimmune diseases, and cancer have been reported to experience steroid-induced psychosis. The mean age of children with steroid-induced psychosis was 12 ± 3.6 years. Our team presents a report of steroid-induced psychosis in a 12-year-old patient with discoid-type lupus erythematosus. Within days of treatment with 40 mg prednisone daily, this patient began to drool, became mute, and was responding to internal stimuli. Treatment was difficult secondary to the acute exacerbation of lupus, requiring ongoing therapy. It was initially unclear whether the acute psychosis was a manifestation of lupus, a side effect of medication, or a combination of the two risk factors. Neurology consultation ruled out lupus cerebritis. Psychosis was treated with haloperidol 5 mg. Psychosis did not resolve until the steroid taper was complete and the patient was no longer taking any prednisone. CONCLUSIONS: Given the common use of glucocorticoid therapy in children, it is important that physicians and parents recognize the signs of steroid-induced psychosis and are aware of the data on treating this complication.