Lack Of Animal Studies Research Articles

Antithrombotic efficacy and bleeding risks of vaccine-induced immune thrombotic thrombocytopenia treatments

AbstractCurrent guidelines for treating vaccine-induced immune thrombotic thrombocytopenia (VITT) recommend nonheparin anticoagulants and IV immunoglobulin (IVIg). However, the efficacy of these treatments remains uncertain due to case studies involving small patient numbers, confounding factors (eg, concurrent treatments), and a lack of animal studies. A recent study proposed danaparoid and heparin as potential VITT therapies because of their ability to disrupt VITT IgG-platelet factor 4 (PF4) binding. Here, we examined the effects of various anticoagulants (including unfractionated [UF] heparin, danaparoid, bivalirudin, fondaparinux, and argatroban), IVIg, and the FcγRIIa receptor-blocking antibody, IV.3. Our investigation focused on VITT IgG-PF4 binding, platelet activation, thrombocytopenia, and thrombosis. Danaparoid, at therapeutic doses, was the sole anticoagulant that reduced VITT IgG-PF4 binding, verified by affinity-purified anti-PF4 VITT IgG. Although danaparoid and high-dose UF heparin (10 U/mL) inhibited platelet activation, none of the anticoagulants significantly affected thrombocytopenia in our VITT animal model and all prolonged bleeding time. IVIg and all anticoagulants except UF heparin protected the VITT mice from thrombosis. Direct FcγRIIa receptor inhibition with IV.3 antibody is an effective approach for managing both thrombosis and thrombocytopenia in the VITT mouse model. Our results underscore the necessity of animal model investigations to inform and better guide clinicians on treatment choices. This study provides compelling evidence for the development of FcγRIIa receptor blockers to prevent thrombosis in VITT and other FcγRIIa-related inflammatory disorders.

P033 Transcranial direct current stimulation in a mouse model of traumatic brain injury

Introduction Traumatic brain injury (TBI) causes long-term neurological disability in 7% of survivors for which there is no clinically proven therapies. Transcranial direct current stimulation (tDCS) is a prospective treatment currently being clinically tested in TBI patients. However, due to a lack of animal studies, the mechanisms and optimal stimulation parameters for tDCS are unknown. Objectives Our objective is to evaluate mechanisms and the efficacy of tDCS in a mouse model of TBI. We hypothesized that tDCS, applied during recovery phase after TBI, improves long-term neurologic outcome involving a sustained increase in cerebral blood flow (CBF). Materials & methods TBI was induced by controlled cortical impact (CCI) with a Benchmark Controlled Cortical Stereotaxic Impactor using a 3-mm flat-tip impounder deployed at a velocity of 5 m/s and a depth of 2.0 mm from the cortical surface. Pre-trained mice were subjected to TBI and tested at 3 weeks after trauma by Rotarod for neurologic motor deficits. Anodal tDCS (0.1 mA/15 min) or sham stimulation were applied every day for 4 days, starting 2 weeks after TBI. Using in vivo 2-photon laser scanning microscopy over the parietal cortex we monitored changes in microvascular blood flow and tissue oxygenation (NADH) before and after tDCS treatment. Results Anodal tDCS improved motor function in mice after TBI compared to sham treated mice as shown by latency to fall from the rotating rod (75.4 ± 12 s. vs. 55.6 ± 16 s, n = 4, P Conclusions tDCS acutely increases brain microvascular flow and tissue oxygenation that could contribute to neurologic improvement after TBI. The vasodilation observed may be mediated by tDCS-stimulated nitric oxide release. Support NIH-NIGMS P20GM109089-01A1, Rio Grande Neurosciences.

Renal failure increases gastric mucosal blood flow and acid secretion in rats: role of endothelium-derived nitric oxide.

Because of the contradictory findings in clinical studies, and the complete lack of animal studies, the purpose of this investigation was to characterize the changes in gastric mucosal blood flow (GMBF) and acid secretion in an animal model of chronic renal failure. Rats with chronic renal failure induced by partial kidney infarction had a significantly higher basal GMBF and lower gastric vascular resistance than control rats. The gastric acid secretory and mucosal hyperemic response to pentagastrin were markedly enhanced in renal failure rats. Because endothelial-derived nitric oxide (NO) is an endogenous vasodilator that regulates gastric vascular tone, we hypothesized that NO mediates the gastric hyperemia of renal failure rats. The administration of N omega-nitro-L-arginine methyl ester (L-NAME), a specific inhibitor of NO formation, produced a significantly greater decrease in GMBF in renal failure rats than in control rats, including a low dose inhibiting the basal hyperemia in renal failure rats but having no effect in control rats. It also attenuated pentagastrin-stimulated GMBF in both groups. In contrast, L-NAME produced a similar decrease in basal skeletal muscle blood flow in both renal failure and control rats. We conclude that in the renal failure rat 1) there is an increased basal GMBF and pentagastrin-stimulated acid output and GMBF, and 2) this gastric mucosal hyperemia is mediated by NO.

Sodium Phosphate Enemas: How to Kill Cats, Cause Cardiac Arrest, and Cure Eye Rolling at Stanford

To the Editor.— The continuing reports of intoxication following administration of commercial hypertonic sodium phosphate enema solution in both the human1,2and veterinary3literature and the recent comment on the lack of animal studies of sodium phosphate enema intoxication prompt me to write. In a recent study,4we systematically evaluated alterations in acid-base, fluid, and electrolyte balance after administration of hypertonic sodium phosphate enemas to normal adult cats. Study.— Ten awake cats, in whom arterial catheters had been previously implanted, were divided into two groups. Group A received 60 mL (mean dose, 18 mL/kg) of hypertonic sodium phosphate enema solution and group B received 120 mL (mean dose, 32 mL/kg) of hypertonic sodium phosphate enema solution, both with five minutes' forced retention. Abnormalities, noted as early as 15 minutes following administration of enema solution, included severe hyperphosphatemia, mild hypernatremia, hyperglycemia, hypocalcemia, lactic acidosis with an increased anion