Background and Purpose: The benefit of endovascular treatment (EVT) for large vessel occlusion in clinical practice in developing countries like China needs to be confirmed. The aim of the study was to determine whether the benefit of EVT for acute ischemic stroke in randomized trials could be generalized to clinical practice in Chinese population. Methods: We conducted a prospective registry of EVT at 111 centers in China. Patients with acute ischemic stroke caused by imaging-confirmed intracranial large vessel occlusion and receiving EVT were included. The primary outcome was functional independence at 90 days defined as a modified Rankin Scale score of 0 to 2. Outcomes of specific subgroups in the anterior circulation were reported and logistic regression was performed to predict the primary outcome. Results: Among the 1793 enrolled patients, 1396 (77.9%) had anterior circulation large vessel occlusion (median age, 66 [56–73] years) and 397 (22.1%) had posterior circulation large vessel occlusion (median age, 64 [55–72] years). Functional independence at 90 days was reached in 45% and 44% in anterior and posterior circulation groups, respectively. For anterior circulation population, underlying intracranial atherosclerotic disease was identified in 29% of patients, with higher functional independence at 90 days (52% versus 44%; P =0.0122) than patients without intracranial atherosclerotic disease. In the anterior circulation population, after adjusting for baseline characteristics, procedure details, and early outcomes, the independent predictors for functional independence at 90 days were age <66 years (odds ratio [OR], 1.733 [95% CI, 1.213–2.476]), time from onset to puncture >6 hours (OR, 1.536 [95% CI, 1.065–2.216]), local anesthesia (OR, 2.194 [95% CI, 1.325–3.633]), final modified Thrombolysis in Cerebral Infarction 2b/3 (OR, 2.052 [95% CI, 1.085–3.878]), puncture-to-reperfusion time ≤1.5 hours (OR, 1.628 [95% CI, 1.098–2.413]), and National Institutes of Health Stroke Scale score 24 hours after the procedure <11 (OR, 9.126 [95% CI, 6.222–13.385]). Conclusions: Despite distinct characteristics in the Chinese population, favorable outcome of EVT can be achieved in clinical practice in China. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03370939.

Background and Purpose: A recent randomized controlled trial DIRECT-MT (Direct Intra-Arterial Thrombectomy to Revascularize AIS Patients With Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals) compared the safety and efficacy of mechanical thrombectomy (MT) versus combined intravenous thrombolysis (IVT) and MT for acute large vessel occlusion. The current study utilized a prospective, nationwide registry to validate the results of the DIRECT-MT trial in a real-world practice setting. Methods: Subjects were selected from a prospective cohort of acute large vessel occlusion patients undergoing endovascular treatment at 111 hospitals from 26 provinces in China (ANGEL-ACT registry [Endovascular Treatment Key Technique and Emergency Work Flow Improvement of Acute Ischemic Stroke]) between November 2017 and March 2019. All patients eligible for IVT and receiving MT were reviewed and then grouped according to whether prior IVT or not (MT and combined IVT+MT). After a 1:1 propensity score matching, the outcome measures including the 90-day modified Rankin Scale, successful recanalization, door-to-puncture time, symptomatic intracranial hemorrhage, and intraprocedural embolization were compared. Results: A total of 1026 patients, 600 in the MT group and 426 in the combined group, were included. Among 788 patients identified after matching, there were no significant differences in the 90-day modified Rankin Scale (median, 3 versus 3 points; P =0.82) and successful recanalization (86.6% versus 89.3%; P =0.23) between the two groups; however, patients of the MT group had a shorter door-to-puncture time (median, 112 versus 136 minutes; β=−45.02 [95% CI, −68.31 to −21.74]), lower rates of symptomatic intracranial hemorrhage (5.5% versus 10.1%; odds ratio, 0.52 [95% CI, 0.30–0.91]), and embolization (4.6% versus 8.1%; odds ratio, 0.54 [95% CI, 0.30–0.98]) than those of the combined group. Conclusions: This matched-control study largely confirmed the findings of the DIRECT-MT trial in a real-world practice setting, suggesting that MT may carry similar effectiveness to combined IVT+MT for acute large vessel occlusion patients, despite MT alone seems to be associated with a shorter in-hospital delay until procedure, lower risks of symptomatic intracranial hemorrhage, and embolization. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03370939.

Rationale: Chronic amphetamine treatment reduces cocaine self-administration in pre-clinical and clinical settings, and amphetamine has been proposed as a candidate medication for treatment of cocaine abuse. Objectives: Investigate whether chronic amphetamine treatment can decrease the abuse-related cocaine effects in an assay of intracranial self-stimulation (ICSS). Methods: Thirteen adult male Sprague-Dawley rats were equipped with intracranial electrodes targeting the medial forebrain bundle and trained to lever press for pulses of brain stimulation in a “frequency-rate” ICSS procedure. Cocaine (10 mg/kg) was administered before (Day 0), during (Days 7 and 14) and after (post-treatment days 1 and 3) two weeks of continuous treatment with either amphetamine (0.32mg/kg/hr, n=7) or saline (n=6) via osmotic pump. Results: Prior to treatment, cocaine facilitated ICSS in all rats. Saline treatment had no effect on baseline ICSS or cocaine-induced facilitation of ICSS at any time. Conversely, amphetamine produced a sustained though sub-maximal facilitation of baseline ICSS, and cocaine produced little additional facilitation of ICSS during amphetamine treatment. Termination of amphetamine treatment produced a depression of baseline ICSS and recovery of cocaine-induced facilitation of ICSS. Conclusions: These data suggest that chronic amphetamine treatment blunts expression of abuse-related cocaine effects on ICSS in rats.

d-Amphetamine selectively promotes release of both dopamine (DA) and norepinephrine (NE) vs. serotonin (5HT), and chronic d-amphetamine treatment decreases cocaine-taking behavior in rats, nonhuman primates, and humans. However, abuse liability limits the clinical utility of amphetamine maintenance for treating cocaine abuse. One strategy to improve safety and efficacy of monoamine releasers as candidate anti-cocaine medications has been to develop dual DA/5HT releasers like 1-napthyl-2-aminopropane (PAL-287), but the pharmacology of this class of compounds has not been extensively examined. In particular, PAL-287 has similar potencies to release DA, 5HT and NE, and the role of manipulating NE release potency on abuse-related or anti-cocaine effects of dual DA/5HT releasers is not known. To address this issue, the present study compared effects of four novel DA/5HT releasers that varied >800-fold in their selectivities to release DA/5HT vs NE: [1-(5-chloro-1H-indol-3-yl)propan-2-amine (PAL-542), 1-(5-fluoro-1H-indol-3-yl)propan-2-amine (PAL-544), 1-(1H-indol-5-yl)propan-2-amine (PAL-571), and (R)-1-(1H-indol-1-yl)propain-2-amine (PAL-569). Abuse-related effects of all four compounds were evaluated in assays of intracranial self-stimulation (ICSS) in rats and cocaine discrimination in rats and monkeys, and none of the compounds reliably facilitated ICSS or substituted for cocaine. Anti-cocaine effects of the compound with highest selectivity to release DA/5HT vs. NE (PAL-542) were tested in an assay of cocaine vs. food choice in rhesus monkeys, and PAL-542 failed to reduce cocaine choice. These results suggesst that potency to release NE has minimal influence on abuse liability of dual DA/5HT releasers, and reducing relative potency to release NE vs. DA/5HT does not improve anti-cocaine efficacy.

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