ABSTRACT
Large vessel ischemic stroke represents the most disabling subtype. While t-PA and endovascular thrombectomy can recanalize the occluded vessel, good clinical outcomes are not uniformly achieved. We propose that supplementing endovascular thrombectomy with superselective intra-arterial (IA) verapamil immediately following recanalization could be safe and effective. Verapamil, a calcium channel blocker, has been shown to be an effective IA adjunct in a pre-clinical mouse focal ischemia model. To demonstrate translational efficacy, mechanism, feasibility, and safety, we conducted a group of translational experiments. We performed in vivo IA dose-response evaluation in our animal stroke model with C57/Bl6 mice. We evaluated neuroprotective mechanism through in vitro primary cortical neuron (PCN) cultures. Finally, we performed a Phase I trial, SAVER-I, to evaluate feasibility and safety of administration in the human condition. IA verapamil has a likely plateau or inverted-U dose-response with a defined toxicity level in mice (LD50 16-17.5 mg/kg). Verapamil significantly prevented PCN death and deleterious ischemic effects. Finally, the SAVER-I clinical trial showed no evidence that IA verapamil increased the risk of intracranial hemorrhage or other adverse effect/procedural complication in human subjects. We conclude that superselective IA verapamil administration immediately following thrombectomy is safe and feasible, and has direct, dose-response-related benefits in ischemia.
Subject(s)
Anti-Arrhythmia Agents/administration & dosage , Anti-Arrhythmia Agents/therapeutic use , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/therapeutic use , Stroke/prevention & control , Thrombectomy/adverse effects , Verapamil/administration & dosage , Verapamil/therapeutic use , Adult , Aged , Aged, 80 and over , Animals , Anti-Arrhythmia Agents/adverse effects , Brain Ischemia/drug therapy , Brain Ischemia/pathology , Cell Death/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Female , Humans , Hypoxia, Brain/drug therapy , Injections, Intra-Arterial , Male , Mice, Inbred C57BL , Middle Aged , Neurites/drug effects , Neuroprotective Agents/adverse effects , Primary Cell Culture , Stroke/pathology , Treatment Outcome , Verapamil/adverse effectsABSTRACT
PURPOSE: Carcinoid syndrome, characterized by flushing, diarrhea, and valvular heart disease, can occur following carcinoid tumor metastasis to the liver and systemic release of bioactive hormones into the systemic circulation. Treatment of this devastating disease is hampered by the lack of an in vivo model that recapitulates the clinical syndrome. EXPERIMENTAL DESIGN: Here, we have injected BON cells, a novel human carcinoid cell line established in our laboratory, into the spleens of athymic nude mice to establish liver metastases. RESULTS: The majority of mice injected intrasplenically with BON cells developed significant increases in plasma serotonin and urine 5-hydroxyindoleacetic acid, and several mice exhibited mesenteric fibrosis, diarrhea, and fibrotic cardiac valvular disease reminiscent of carcinoid syndrome by both echocardiographic and histopathologic evaluation. Mice pretreated with octreotide, a long-acting somatostatin analogue, or bevacizumab, a vascular endothelial growth factor inhibitor, developed fewer liver metastases and manifestations of carcinoid syndrome, including valvular heart disease. CONCLUSION: We have provided an important in vivo model to further delineate novel treatment modalities for carcinoid syndrome that will also be useful to elucidate the factors contributing to the sequelae of carcinoid disease (e.g., mesenteric fibrosis and valvular heart disease).