Rescue stenting after the failure of intravenous thrombolysis and bridging thrombolysis: an initial Vietnamese report.

OBJECTIVE: Intravenous (IV) recombinant tissue plasminogen activator is the standard of care for patients with acute ischemic stroke (AIS) who present to the hospital within 4.5 hours of symptom onset. However, IV thrombolysis, even bridging thrombolysis (combining intravenous thrombolysis and mechanical thrombectomy) has limited efficacy among patients who had occlusive lesions associated with high-grade arterial stenosis requiring revascularization to improve neurological deficits. We evaluated whether rescue stenting results in good outcomes among patients after the failure of intravenous thrombolysis and bridging thrombolysis. PATIENTS AND METHODS: We retrospectively analyzed patients with AIS who underwent rescue stenting for large vessel occlusion with severe atherosclerotic stenosis between May 2020 and August 2022 at Can Tho S.I.S General Hospital. Primary outcomes included the incidence of hemorrhagic transformation and the rate of good outcomes (modified Rankin Scale < 3) at 3-month follow-up. RESULTS: We identified 13 patients who received rescue stenting after the failure of IV alteplase and bridging thrombolysis, but only 11 patients met the inclusion criteria. All patients experienced successful recanalization, and 1 (9.1%) patient experienced new infarcts. Of these 11 patients, 10 (90.9%) had good outcomes 3 months after rescue stenting. Additionally, a loading dose of dual antiplatelet therapy (DAPT) applied concurrently with IV alteplase improved the recanalization rate for large target arteries but had no significant effect on the incidence of symptomatic intracranial hemorrhage. CONCLUSIONS: Rescue stenting appears to represent an additional therapeutic option in cases that fail to resolve with IV alteplase, which may improve clinical outcomes.

Rescue intracranial stenting in acute ischemic stroke: a preliminary Vietnamese study.

OBJECTIVE: In cases of acute ischemic stroke (AIS) caused by intracranial large vessel occlusion, rescue intracranial stenting (RIS) has recently emerged as a treatment option for achieving recanalization when mechanical thrombectomy (MT) fails. However, few studies to date have reported on the beneficial outcomes of RIS. Our goal was to analyze whether RIS use can improve prognosis in patients 3 months post-treatment. PATIENTS AND METHODS: A retrospective analysis was performed on a prospective cohort of patients with AIS treated with RIS at Can Tho S.I.S General Hospital. The study inclusion criteria were evidence of intracranial large vessel occlusion, absence of intracranial hemorrhage (ICH), and severe stenosis or reocclusion after MT. Patients with tandem occlusions, failure to follow up after discharge, or severe or fatal illness concomitant with AIS were excluded from the study. The primary outcome was the "non-poor" prognosis status rate at 3 months after RIS and post-procedural symptomatic ICH (sICH). RESULTS: The post-treatment outcomes of 85 eligible patients who received RIS between August 2019 and May 2021 were assessed. Of the 85 included patients, 82 (96.5%) achieved successful recanalization, and 4 (4.7%) experienced sICH. At 3-months post-treatment, 47 (55.3%) patients had "non-poor" outcomes, whereas 35 (41.2%) had good outcomes. The use of dual antiplatelet therapy was associated with new infarcts (relative risk [RR]: 0.1; 95% confidence interval [CI]: 0.01-0.7) and sICH occurrence (RR: 0.1; 95% CI: 0.01-0.9). CONCLUSIONS: Our study suggests that despite the occurrence of post-procedural sICH in a small proportion of cases, RIS could serve as a useful alternative or additional treatment in the event of MT failure.

Discovery of a selective, state-independent inhibitor of NaV1.7 by modification of guanidinium toxins.

The voltage-gated sodium channel isoform NaV1.7 is highly expressed in dorsal root ganglion neurons and is obligatory for nociceptive signal transmission. Genetic gain-of-function and loss-of-function NaV1.7 mutations have been identified in select individuals, and are associated with episodic extreme pain disorders and insensitivity to pain, respectively. These findings implicate NaV1.7 as a key pharmacotherapeutic target for the treatment of pain. While several small molecules targeting NaV1.7 have been advanced to clinical development, no NaV1.7-selective compound has shown convincing efficacy in clinical pain applications. Here we describe the discovery and characterization of ST-2262, a NaV1.7 inhibitor that blocks the extracellular vestibule of the channel with an IC50 of 72 nM and greater than 200-fold selectivity over off-target sodium channel isoforms, NaV1.1-1.6 and NaV1.8. In contrast to other NaV1.7 inhibitors that preferentially inhibit the inactivated state of the channel, ST-2262 is equipotent in a protocol that favors the resting state of the channel, a protocol that favors the inactivated state, and a high frequency protocol. In a non-human primate study, animals treated with ST-2262 exhibited reduced sensitivity to noxious heat. These findings establish the extracellular vestibule of the sodium channel as a viable receptor site for the design of selective ligands targeting NaV1.7.

Nerve growth factor acts through the TrkA receptor to protect sensory neurons from the damaging effects of the HIV-1 viral protein, Vpr.

Distal sensory polyneuropathy (DSP) with associated neuropathic pain is the most common neurological disorder affecting patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Viral protein R (Vpr) is a neurotoxic protein encoded by HIV-1 and secreted by infected macrophages. Vpr reduces neuronal viability, increases cytosolic calcium and membrane excitability of cultured dorsal root ganglion (DRG) sensory neurons, and is associated with mechanical allodynia in vivo. A clinical trial with HIV/AIDS patients demonstrated that nerve growth factor (NGF) reduced the severity of DSP-associated neuropathic pain, a problem linked to damage to small diameter, potentially NGF-responsive fibers. Herein, the actions of NGF were investigated in our Vpr model of DSP and we demonstrated that NGF significantly protected sensory neurons from the effects of Vpr. Footpads of immunodeficient Vpr transgenic (vpr/RAG1(-/-)) mice displayed allodynia (p<0.05), diminished epidermalinnervation (p<0.01) and reduced NGF mRNA expression (p<0.001) compared to immunodeficient (wildtype/RAG1(-/-)) littermate control mice. Compartmented cultures confirmed recombinant Vpr exposure to the DRG neuronal perikarya decreased distal neurite extension (p<0.01), whereas NGF exposure at these distal axons protected the DRG neurons from the Vpr-induced effect on their cell bodies. NGF prevented Vpr-induced attenuation of the phosphorylated glycogen synthase-3 axon extension pathway and tropomyosin-related kinase A (TrkA) receptor expression in DRG neurons (p<0.05) and it directly counteracted the cytosolic calcium burst caused by Vpr exposure to DRG neurons (p<0.01). TrkA receptor agonist indicated that NGFacted through the TrkA receptor to block the Vpr-mediated decrease in axon outgrowth in neonatal and adult rat and fetal human DRG neurons (p<0.05). Similarly, inhibiting the lower affinity NGF receptor, p75, blocked Vpr's effect on DRG neurons. Overall, NGF/TrkA signaling or p75 receptor inhibition protects somatic sensory neurons exposed to Vpr, thus laying the groundwork for potential therapeutic options for HIV/AIDS patients suffering from DSP.