Impact of obesity-related indicators on first-pass effect in patients with ischemic stroke receiving mechanical thrombectomy.

PURPOSE: The first-pass effect (FPE), defined as complete revascularization after a single thrombectomy pass in large vessel occlusion, is a predictor of good prognosis in patients with acute ischemic stroke (AIS) receiving mechanical thrombectomy (MT). We aimed to evaluate obesity-related indicators if possible be predictors of FPE. METHODS: We consecutively enrolled patients with AIS who were treated with MT between January 2019 and December 2021 at our institution. Baseline characteristics, procedure-related data, and laboratory test results were retrospectively analyzed. A multivariable logistic regression analysis was performed to evaluate the independent predictors of FPE. RESULTS: A total of 151 patients were included in this study, of whom 47 (31.1%) had FPE. After adjusting for confounding factors, the independent predictors of achieving FPE were low levels of body mass index (BMI) (OR 0.85, 95% CI 0.748 to 0.971), non-intracranial atherosclerotic stenosis (OR 4.038, 95% CI 1.46 to 11.14), and non-internal carotid artery occlusion (OR 13.14, 95% CI 2.394 to 72.11). Patients with lower total cholesterol (TC) (< 3.11 mmol/L) were more likely to develop FPE than those with higher TC (≥ 4.63 mmol/L) (OR 4.280; 95% CI 1.24 to 14.74) CONCLUSION: Lower BMI, non-intracranial atherosclerotic stenosis, non-internal carotid artery occlusion, and lower TC levels were independently associated with increased rates of FPE in patients with AIS who received MT therapy. FPE was correlated with better clinical outcomes after MT.

First pass effect in patients undergoing endovascular treatment for posterior circulation acute ischemic stroke.

OBJECTIVE: This study aims to investigate the impact of first pass effect (FPE) on outcomes in the posterior circulation acute ischemic stroke (PC-AIS) and the independent predictors of FPE. METHODS: This was a multicenter, retrospective study. PC-AIS patients who underwent endovascular treatment were reviewed. The cohort achieving complete or nearly complete reperfusion (defined as expanded treatment in cerebralischemia [eTICI] ≥ 2c) was categorized into the FPE and multiple pass effect (MPE) groups. FPE was defined as achieving eTICI ≥ 2c with a single pass and without the use of rescue therapy. Modified FPE (mFPE) was defined as meeting the criteria for FPE but with eTICI ≥ 2b. The association of FPE with 90-day clinical outcomes and predictors for FPE were both investigated. RESULTS: The study included a total of 328 patients, with 69 patients (21 %) in the FPE group. For primary outcome, FPE had a significant higher favorable outcome (mRS ≤ 3) rate than MPE (65.2 % vs. 44.8 %, p = 0.003). Similar outcomes were observed in the mFPE. Furthermore, FPE was significantly associated with favorable outcome (adjusted OR 2.23, 95 % CI 1.06-4.73, p = 0.036). Positive predictors for FPE included occlusion in the distal basilar artery, the first-line aspiration or combination, and cardioembolic etiology. Negative predictors for FPE included hypertension and general anesthesia. CONCLUSION: For PC-AIS patients due to large or medium vessel occlusion, FPE is associated with favorable clinical outcomes. The first-line techniques of aspiration or combination, as well as avoiding general anesthesia, contribute to a better realization of FPE.

Dose-dependent pharmacokinetics of midazolam in rats: influence of hepatic first-pass metabolism.

To characterise the dose-dependent pharmacokinetics of midazolam and evaluate the intestinal and hepatic first-pass effects on midazolam in Sprague-Dawley rats, the concentrations and area under the concentration-time curve (AUC) of midazolam in the portal and systemic plasma were simultaneously determined with a double cannulation method.It was found that about 75% of the dose was left in the portal blood with different oral administration doses, while the bioavailability in the liver was 37.86% at 20 mg/kg, significantly higher than 9.16% at 2 mg/kg.The disproportional increase in AUC of midazolam and significant decrease in exposure of metabolites were observed in systemic plasma after hepatic portal vein administration. And in the in vitro study, the formation rate of the metabolites of midazolam significantly decreased when midazolam was at 300 µM compared with 100 µM.These results indicated that not only the saturation of first-pass metabolism but also the inhibition of hepatic metabolism is responsible for the nonlinear PK of midazolam. Thus, a rational dose should be chosen when midazolam is used as a probe in the drug-drug interaction study, particularly for orally administered drugs that undergo hepatic first-pass metabolism.

First-pass effect in posterior acute ischemic stroke undergoing endovascular thrombectomy: A systematic review and meta-analysis.

OBJECTIVES: First-pass effect (FPE) has been shown to be a predictor of favorable clinical outcomes following endovascular thrombectomy (EVT) for acute ischemic stroke (AIS) in the anterior circulation. Literature regarding FPE for posterior circulation AIS is sparse; we conducted a systematic review and meta-analysis to explore FPE in posterior circulation stroke undergoing EVT. MATERIALS AND METHODS: We conducted a systematic review of the English literature in PubMed, Embase, Scopus, and Web of Science. FPE was defined as thrombolysis in cerebral infarction (TICI) 2c-3 and modified FPE (mFPE) was defined as TICI 2b-3 in one pass. Definitions of non-FPE and non-mFPE varied among studies. The primary outcome of interest was modified Rankin Scale (mRS) 0-2. Secondary outcomes of interest were mRS 0-3, symptomatic intracranial hemorrhage (sICH), and mortality. We calculated odds ratios (OR) and corresponding 95% confidence intervals (CI). Heterogeneity was assessed with Q statistic and I2 test. RESULTS: Seven studies with 417 patients in the mFPE group, 942 in the non-mFPE group, 545 in the FPE group, and 1023 in the non-FPE group were included. Overall, FPE was associated with greater rates of 90-day mRS 0-2 (OR= 2.78, 95% CI= 2.11-3.65; P-value< 0.001) and mRS 0-3 (OR= 2.67, 95% CI= 1.98-3.60; P-value< 0.001); however, there was significant heterogeneity among studies for both mRS 0-2 (I2= 69%; P-value< 0.001) and mRS 0-3 (I2= 69%; P-value< 0.001). FPE and non-FPE were associated with similar rates of sICH (OR= 0.65, 95% CI= 0.40-1.07; P-value= 0.09), and no heterogeneity was observed (I2= 0%; P-value= 0.95). FPE was associated with lower rates of mortality (OR= 0.44, 95% CI= 0.33-0.58; P-value< 0.001), although heterogeneity was observed (I2= 58%; P-value= 0.01). CONCLUSIONS: FPE is associated with favorable clinical outcomes in patients undergoing EVT for posterior circulation AIS. Future studies should work to further quantify the impact of FPE on outcomes in the posterior circulation.

Intravenous Thrombolysis Is Associated with Less Disabling Stroke and Lower Mortality in Multiple-Pass Endovascular Thrombectomy.

BACKGROUND AND PURPOSE: The benefit of bridging intravenous thrombolysis (IVT) in acute ischaemic stroke patients eligible for endovascular thrombectomy (EVT) is unclear. This may be particularly relevant where reperfusion is achieved with multiple thrombectomy passes. We aimed to determine the benefit of bridging IVT in first and multiple-pass patients undergoing EVT ≤6 h from stroke onset to groin puncture. METHODS: We compared 90-day modified Rankin Scale (mRS) outcomes in 187 consecutive patients with large vessel occlusions (LVOs) of the anterior cerebral circulation who underwent EVT ≤6 h from symptom onset and who achieved modified thrombolysis in cerebral ischaemia (mTICI) 2c/3 reperfusion with the first pass to those patients who required multiple passes to achieve reperfusion. The effect of bridging IVT on outcomes was examined. RESULTS: Significantly more first-pass patients had favourable (mRS 0-2) 90-day outcomes (68 vs. 42%, p = 0.001). Multivariate analysis showed an association between first-pass reperfusion and favourable outcomes (OR 2.25; 95% CI 1.08-4.68; p = 0.03). IVT provided no additional benefit in first-pass patients (OR 1.17; CI 0.42-3.20; p = 0.76); however, in multiple-pass patients, it reduced the risk of disabling stroke (mRS ≥4) (OR 0.30; CI 0.10-0.88; p = 0.02) and mortality (OR 0.07; CI 0.01-0.36; p = 0.002) at 90 days. CONCLUSION: Bridging IVT may benefit patients with anterior circulation stroke with LVO who qualify for EVT and who require multiple passes to achieve reperfusion.

Influence of first-pass effect on recanalization outcomes in the era of mechanical thrombectomy: a systemic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis summarized the current literature to compare the safety and efficacy between first-pass effect (FPE) and multiple-pass effect (MPE) for thrombectomy in treatment of acute ischemic stroke (AIS). METHODS: Major databases were searched for studies which reported clinical outcomes regarding successful or complete recanalization after first pass of mechanical thrombectomy in AIS. The assessment of bias was performed using different scales. I2 statistic was used to evaluate heterogeneity between reviewers. Subgroup, meta-regression, and sensitivity analyses were conducted to explore the source of heterogeneity. Visualization of funnel plots was used to evaluate publication bias. RESULTS: A total of 9 studies were eligible for final analysis. For successful recanalization (mTICI 2b-3), favorable outcomes were seen in 49.7% (95% confidence interval (CI): 40.5-58.9%) and 34.7% (95% CI: 26.8-42.7%) of FPE and MPE patients, respectively. Mortality at 3 months was 13.8% (95% CI: 10.8-16.9%) and 26.0% (95% CI: 17.7-34.2%), respectively. For complete recanalization (mTICI 2c-3), proportion of favorable outcomes were 62.7% (95% CI: 51.2-74.2%) and 47.7% (95% CI: 37.4-58.0%) in FPE and MPE; mortality was seen in 11.5% (95% CI: 4.9-18.2%) and 17.0% (95% CI: 5.2-28.7%), respectively. For AIS with successful recanalization, FPE had more favorable outcome (odds ratio (OR): 1.85, 95% CI: 1.48-2.30; p < 0.01; I2 = 0%) and lower mortality than MPE (OR: 0.58, 95% CI: 0.42-0.79; p = 0.001; I2 = 61.9%). Similar results were seen in a subgroup analysis of patients with complete recanalization, with FPE having better outcome (OR: 1.79, 95% CI: 1.40-2.28; p < 0.01; I2 = 0%) and lower mortality risk (OR: 0.61, 95% CI: 0.44-0.86; p = 0.005; I2 = 0%) compared to MPE. CONCLUSION: FPE is associated with better outcomes than MPE after achieving successful or complete recanalization.

Ovarian Folliculogenesis and Uterine Endometrial Receptivity after Intermittent Vaginal Injection of Recombinant Human Follicle-Stimulating Hormone in Infertile Women Receiving In Vitro Fertilization and in Immature Female Rats.

The uterine first-pass effect occurs when drugs are delivered vaginally. However, the effect of vaginally administered recombinant human follicle-stimulating hormone (rhFSH) on ovarian folliculogenesis and endometrial receptivity is not well established. We aimed to compare the efficacy of rhFSH administered vaginally and abdominally in clinical in vitro fertilization (IVF) treatment, pharmacokinetic study, and animal study. In IVF treatment, the number of oocytes retrieved, endometrial thickness and uterine artery blood perfusion were not different between women who received the rhFSH either vaginally or abdominally. For serum pharmacokinetic parameters, significantly lower Tmax, clearance, and higher AUC and T1/2_elimination of rhFSH were observed in women who received rhFSH vaginally, but urine parameters were not different. Immature female rats that received daily abdominal or vaginal injections (1 IU twice daily for 4 days) or intermittent vaginal injections (4 IU every other day for two doses) of rhFSH had more total follicles than the control group. In addition, the serum progesterone and progesterone receptors in the local endometrium were significantly higher in the groups treated with intermittent abdominal or vaginal injection of rhFSH, compared with those who recieved daily injection. In summary, vaginal administration of rhFSH may provide an alternative treatment regimen in women receiving IVF.

A Translational Hepatic Artery Infusion (HAI) Model for Hepatocellular Carcinoma in Woodchucks.

BACKGROUND: Woodchucks (Marmota monax) are a well-accepted animal model for the investigation of spontaneous hepatocellular carcinoma (HCC). As HCC tumors obtain nutrient blood supply exclusively from the hepatic artery, hepatic artery infusion (HAI) has been applied to HCC. However, there is a scarcity of experimental animal models to standardize drug regimens and examine novel agents. The purpose of this study was to establish an HAI model in woodchucks. MATERIALS AND METHODS: HAI ports were placed in the gastroduodenal artery (GDA) of 11 woodchucks. The ports were infused with either a vehicle (dextrose 5% in water) or an experimental drug, CBL0137, once a week for 3 wk. Technical success rates, anatomical variation, morbidity and mortality, and tumor responses between groups were analyzed. RESULTS: The GDA access was feasible and reproducible in all woodchucks (11/11). The average operation time was 95 ± 20 min with no increase in the levels of liver enzymes detected from either infusate. The most common morbidity of CBL0137 therapy was anorexia after surgery. One woodchuck died due to hemorrhage at the gallbladder removal site from hepatic coagulopathy. Significantly higher CBL0137 concentrations were measured in the liver compared with blood after each HAI. Tumor growth was suppressed after multiple CBL0137 HAI treatments which corresponded to greater T cell infiltration and increased tumor cell apoptosis. CONCLUSIONS: HAI via GDA was a feasible and reproducible approach with low morbidity and mortality in woodchucks. The described techniques serve as a reliable platform for the identification and characterization of therapeutics for HCC.

Effect of manual aspiration thrombectomy using large-bore aspiration catheter for acute basilar artery occlusion: comparison with a stent retriever system.

BACKGROUND: A large-bore aspiration catheter can be employed for recanalization of acute basilar artery occlusion. Here we compare the results of mechanical thrombectomy using a stent retriever (SR) and manual aspiration thrombectomy (MAT) using a large-bore aspiration catheter system as a first-line recanalization method in acute basilar artery occlusion (BAO). METHODS: The records of 50 patients with acute BAO who underwent mechanical thrombectomy were retrospectively reviewed. Patients were assigned to one of two groups based on the first-line recanalization method. The treatment and clinical outcomes were compared. RESULTS: Sixteen (32%) patients were treated with MAT with a large-bore aspiration catheter and 34 (68%) with a SR as the first-line treatment method. The MAT group had a shorter procedure time (28 vs. 65 min; p = 0.001), higher rate of first-pass recanalization (68.8% vs. 38.2%, p = 0.044), and lower median number of passes (1 vs 2; p = 0.008) when compared with the SR group. There was no significant difference in the incidence of any hemorrhagic complication (6.3% vs. 8.8%; p = 0.754) between the groups. However, there were four cases of procedure-related subarachnoid hemorrhage (SAH) in the SR group and one death occurred due to massive hemorrhage. CONCLUSIONS: Selection of MAT using a large-bore aspiration catheter for acute BAO may be a safe and effective first-line treatment method with higher first-pass recanalization rate and shorter procedure time than SR.

Characterization of osthenol metabolism in vivo and its pharmacokinetics.

Osthenol, a prenylated coumarin, is a C8-prenylated derivative of umbelliferone isolated from the root of Angelica koreana and Angelica dahurica, an intermediate and is known as a major metabolite of desmethyl-osthole.The various pharmacological effects of osthenol have been reported. In previous studies, we investigated five hydroxylated metabolites by cytochromes P450 (CYP) and glucuronide conjugates of osthenol by uridine diphosphate-glucuronosyltransferases (UGTs). However, osthenol have very few studies have been reported on its pharmacokinetic (PK) profiling, we reported the PK parameters in mouse of osthenol through this study.After oral (5 and 20 mg/kg) and intravenous (5 mg/kg) administration, the concentration of osthenol in plasma was determined by LC-MS/MS. The quantitative method was validated in terms of linearity, accuracy, and precision. When 5 and 20 mg/kg of osthenol were orally administered, the bioavailability (BA) was found to be very low at 0.43 and 0.02%, respectively.In fact, osthenol was mostly metabolized to a two-Phase II conjugates, a sulfonyl and glucuronyl-osthenol, in the blood, which was determined by LC-HR/MS analysis of the blood sample. Because osthenol is rapidly metabolized to two conjugates by first-pass effect the BA of osthenol is low after oral administration.

Optimization of lipid materials in the formulation of S-carvedilol self-microemulsifying drug-delivery systems.

OBJECTIVES: The blocking effect of S-carvedilol (S-CAR) on the beta-adrenoceptor is about 100 times stronger than that of the right-handed conformation. However, further development is restricted because of its poor bioavailability caused by its low solubility and high first-pass effect. In the study, S-CAR self-microemulsifying drug-delivery systems (SMEDDSs) were established, and the effects of different lipid materials on the absorption and metabolism of S-CAR were investigated. METHODS: Six kinds of lipid materials with different chemical structures including oleic acid, glycerol monooleate, glycerol trioleate, oleoyl macrogol-6 glycerides, soybean lecithin, and α-tocopherol were selected to be the oil phase. The S-CAR SMEDDSs were prepared by the same ratio. In vitro characteristics, in vitro release, in situ intestine absorption, and bile excretion, as well as the in vivo characteristic of relative bioavailability, were determined. KEY FINDINGS: The lipid structure significantly affected physical characteristics, the absorption and excretion rates of S-CAR SMEDDSs. The findings of rat-intestine perfusion experiments showed that the S-CAR SMEDDSs decreased the bile-excretion rate of S-CAR. Compared with the S-CAR group, the oleic acid and soybean lecithin groups decreased the bile excretion to 32% and 45%, respectively. Pharmacokinetic studies showed that the AUCs of these two groups were about 1.9 and 1.7 times more than that of the S-CAR group, and the mean retention time was extended. CONCLUSION: The SMEDDS using ionic lipids (oleic acid or soybean lecithin) as oil phase can increase the oral bioavailability of S-CAR by increasing the solubility and reducing the first-pass effect.

Impact of Reperfusion for Nonagenarians Treated by Mechanical Thrombectomy: Insights From the ETIS Registry.

Background and Purpose- Nonagenarians represent a growing stroke population characterized by a higher frailty. Although endovascular therapy (ET) is a cornerstone of the management of acute ischemic stroke related to large vessel occlusion, the benefit of reperfusion among nonagenarians is poorly documented. We aimed to assess the impact of ET-related reperfusion on the functional outcome of reperfusion in this elderly population. Methods- A retrospective analysis of clinical and imaging data from all patients aged over 90 included in the ETIS (Endovascular Treatment in Ischemic Stroke) registry between October 2013 and April 2018 was performed. Association between post-ET reperfusion and favorable (modified Rankin Scale [0-2] or equal to prestroke value) and good (modified Rankin Scale [0-3] or equal to prestroke value) outcome were evaluated. Demographic and procedural predictors of functional outcome, including the first-pass effect, were evaluated. Results were adjusted for center, admission National Institutes of Health Stroke Scale, and use of intravenous thrombolysis. Results- Among the 124 nonagenarians treated with ET, those with successful reperfusion had the lowest 90-day modified Rankin Scale (odds ratio, 3.26; 95% CI, 1.04-10.25). Only patients with successful reperfusion after the first pass (n=53, 56.7%) had a reduced 90-day mortality (odds ratio, 0.15; 95% CI, 0.05-0.45) and an increased rate of good outcome (odds ratio, 4.55; 95% CI, 1.38-15.03). No increase in the rate of intracranial hemorrhage was observed among patients successfully reperfused. Conclusions- Successful reperfusion improves the functional outcome of nonagenarians who should not be excluded from ET. The first-pass effect should be considered in the procedural management of this frail population.

Impact of collagen-induced arthritis on the pharmacokinetic disposition of voriconazole, a widely used antifungal agent: in vitro and in vivo investigations in DBA/1J mice.

Pharmacokinetics of voriconazole, an anti-fungal agent, was determined in collagen-induced arthritic (CIA) and healthy DBA/1J mice. CIA was confirmed in DBA/1J mice by clinical scoring and histological analysis. In vivo oral pharmacokinetic study (3 mg/kg) and in vitro stability assessment in liver microsomes were performed in CIA vs. healthy DBA/1J mice. Additionally, hepatic portal vein cannulated (HPVC) CIA and healthy mice were used to clarify the role of gut first-pass effect. Voriconazole/N-oxide metabolite was measured in plasma and in vitro samples using liquid chromatography tandem-mass spectrometry method. Voriconazole exposure was reduced in CIA by 27% as compared to healthy mice. Formation of voriconazole N-oxide was higher in CIA mice as evidenced by higher molar Cmax ratio (i.e. metabolite/parent) of 2.08 vs. 1.66 in healthy mice. Because voriconazole was stable in microsomes, involvement of presystemic gut metabolism was suspected for decreased voriconazole exposure and formation of higher molar ratio of metabolite. HPVC work revealed higher formation of voriconazole N-oxide in CIA relative to healthy mice resulting in Cmax/AUC ratios of 0.41/0.54 and 0.08/0.17, respectively, confirming first-pass effect. The findings may have implications in the clinical therapy of arthritis patients who are concomitantly given voriconazole for the management of fungal infections.

Investigating the bioavailabilities of olerciamide A via the rat's hepatic, gastric and intestinal first-pass effect models.

Olerciamide A (OA) is a new alkaloid isolated from Portulaca oleracea L. that has been proved to possess a low bioavailability (F) after oral administration in rats in our previous study. Hence, to clarify the reasons for its low bioavailability, hepatic, gastric and intestinal first-pass effect models were established, and a rapid, sensitive UHPLC method was validated and applied for the determination after dosing via the femoral, portal, gastric and intestinal routes. As inhibitors of CYP3A and P-gp, verapamil, midazolam and borneol in low and high dose groups were selected to improve the low bioavailability of olerciamide A. Moreover, a rectal administration method was also carried out to improve the bioavailability of olerciamide A. The results showed that the bioavailability of olerciamide A using hepatic, gastric and intestinal routes were 92.16%, 84.88% and 5.76%, respectively. The areas under the plasma concentration-time curve from zero to infinity (AUC0 → ∞ ) were increased a little after being dosed with 10 and 30 mg/kg verapamil (p > 0.05), but markedly increased after being dosed with 0.4 and 1.2 mg/kg midazolam as well as 8 and 24 mg/kg borneol (p < 0.05). Besides, the AUC0 â†’ ∞ values after the lower and upper rectal administrations were separately similar to the intravenous and intraportal administrations. Our study showed that the intestinal first-pass effect mainly contributed to the low bioavailability of olerciamide A in rats due to it being a substrate of CYP3A and P-gp as well as to its poor intestinal absorption.

Novel mouse models of hepatic artery infusion.

BACKGROUND: The liver has unique anatomy in that most blood flow to normal hepatocytes is derived from the portal venous system, whereas liver tumors obtain their nutrient blood supply exclusively from the hepatic artery. The focused arterial delivery of anticancer agents to liver tumors has been performed for decades; however, preclinical models to standardize drug regimens and examine novel agents have been lacking. The purpose of this study was to establish preclinical hepatic artery infusion (HAI) models in a mouse and to evaluate the safety and delivery capability of the models. MATERIAL AND METHODS: C57BL/6 and BALB/c mice were used to develop models of HAI via the hepatic artery (HA), superior pancreaticoduodenal artery (SPDA), or lienogastric artery (LGA). Success rates, distribution of perfusion, and associated morbidity and mortality were analyzed between groups. RESULTS: All three models were feasible and reproducible in mice, and there was no statistical difference on body weight change between models. The HA model had a 13.3% mortality from acute liver failure, and the SPDA model demonstrated duodenal and pancreatic toxicity. SPDA and LGA routes had the highest success rates (96.7% and 91.4%, respectively) with low mortality, better drug delivery, and preserved physiologic liver function compared with the HA model. CONCLUSIONS: The optimal route of HAI was mouse breed specific; SPDA access in BALB/c mice, and the LGA access in C57BL/6 mice. The described techniques serve as a reproducible platform for the identification and characterization of therapeutics for diverse metastatic liver tumors.

Hepatic, gastric and intestinal first-pass effects of vitexin-2''-O-rhamnoside in rats by ultra-high-performance liquid chromatography.

Previous research in our laboratory found that the absolute bioavailability of vitexin-2''-O-rhamnoside (VR) was quite low at 4.89%. A rapid and sensitive UHPLC method using hesperidin as an internal standard was therefore developed and validated to investigate the reasons for this by determining VR in rat plasma after administering intravenously, intraportally (5 mg/kg), intraduodenally and intragastrically (40 mg/kg) to the rat model of the hepatic, gastric and intestinal first-pass effects. As only a high intestinal first-pass effect of VR was found, that is, there existed a low bioavailability of VR (2.40%), inhibitors of P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A), including verapamil, cyclosporin A and midazolam, and absorption enhancers, including bile salts and borneol, combined with VR, were instilled into duodenum to evaluate the effects on bioavailability of VR. The results demonstrated that area under the concentration-time curve (AUC) values of VR slightly increased after administration of verapamil, cyclosporin A and midazolam, indicating that CYP3A and P-gp do not play an important role in the first-pass effect in the intestine. AUC values of VR significantly increased after administering bile salts or borneol, indicating that the low bioavailability of VR was mainly related to its poor absorption in the intestine.

Predictive Factors of First-Pass Effect in Patients Who Underwent Successful Endovascular Thrombectomy for Emergent Large Vessel Occlusion.

OBJECTIVE: The primary treatment goal of current endovascular thrombectomy (EVT) for emergent large-vessel occlusion (ELVO) is complete recanalization after a single maneuver, referred to as the 'first-pass effect' (FPE). Hence, we aimed to identify the predictive factors of FPE and assess its effect on clinical outcomes in patients with ELVO of the anterior circulation. METHODS: Among the 129 patients who participated, 110 eligible patients with proximal ELVO (intracranial internal carotid artery and proximal middle cerebral artery) who achieved successful recanalization after EVT were retrospectively reviewed. A comparative analysis between patients who achieved FPE and all others (defined as a non-FPE group) was performed regarding baseline characteristics, clinical variables, and clinical outcomes. Multivariate logistic regression analyses were subsequently conducted for potential predictive factors with p<0.10 in the univariate analysis to determine the independent predictive factors of FPE. RESULTS: FPE was achieved in 31 of the 110 patients (28.2%). The FPE group had a significantly higher level of functional independence at 90 days than did the non-FPE group (80.6% vs. 50.6%, p=0.002). Pretreatment intravenous thrombolysis (IVT) (odds ratio [OR], 3.179; 95% confidence interval [CI], 1.025-9.861; p=0.045), door-to-puncture (DTP) interval (OR, 0.959; 95% CI, 0.932-0.987; p=0.004), and the use of balloon guiding catheter (BGC) (OR, 3.591; 95% CI, 1.231-10.469; p=0.019) were independent predictive factors of FPE. CONCLUSION: In conclusion, pretreatment IVT, use of BGC, and a shorter DTP interval were positively associated with FPE, increasing the chance of acquiring better clinical outcomes.

Radially adjustable stent retriever for mechanical thrombectomy in acute ischemic stroke: Improved first-pass effect with rapid-inflation deflation technique.

INTRODUCTION: Evidence for improved first-pass effect with the novel radially adjustable radio-opaque stent retriever Tigertriever is lacking. OBJECTIVE: To compare improvement in first pass success with Tigertriever using two different techniques-rapid inflation deflation (RID) and suction thrombectomy (ST). METHODS: Retrospective analysis of patients with acute ischemic stroke who underwent mechanical thrombectomy with Tigertriever at a single comprehensive stroke center. RESULTS: Thirty patients were included. Mean age was 72.8 years. Twelve patients (48%) experienced successful first passes with Tigertriever. Successful revascularization (modified thrombolysis in cerebral infarction (mTICI) 2b/3) was achieved in all (100%) patients who received RID or ST technique for thrombectomy. Good clinical outcome (modified Rankin score = 0-2) was noted in 40% (n = 10). Total mortality in the cohort was 8% (n = 2). RID and ST groups comprised of 10 and 15 patients, respectively. Five patients underwent MT with Tigertriever as a rescue device. RID VS ST: No difference was noted in mean age (p = 0.27), gender (p = 0.29), location of occlusion (p = 0.46), and device used for first pass (p = 0.57). A 70% first-pass success rate in RID group and 37.5% in ST group was noticed (p = 0.06). Mean time from groin puncture to reperfusion (TICI 2b//3) was statistically similar (p = 0.29, RID: 19.9 min vs ST: 25 min). Both groups noted a 100% complete recanalization rate. The rate of mortality between the two groups were not statistically different (p = 0.46). CONCLUSION: The preliminary first-pass success rates of RID technique with Tigertriever compared to ST technique, are encouraging. Longitudinal studies with longer follow up are needed to elucidate the smaller learning curve with this device.

Pre-navigation balloon technique: Distal emboli protection during stent retriever thrombectomy.

OBJECTIVE: During stent retriever thrombectomy, a balloon guide catheter reduces distal emboli and consequently improves clinical outcomes. Because balloons are usually used before stent retrieval, these can affect the thrombus including the distal emboli while performing microcatheter navigation. This study aimed to evaluate the usefulness and safety of the pre-navigation balloon technique during microcatheter and microwire navigation. METHODS: Patients who underwent stent retriever thrombectomy secondary to an anterior circulation large-artery occlusion were retrospectively evaluated. The pre-navigation balloon technique was used, and the number of retrievals, procedure time, final recanalization, presence of distal emboli, first-pass effect (FPE), symptomatic intracranial hemorrhage including procedure-related complications, and clinical outcomes at 3 months were evaluated. RESULTS: In total 123 patients were analyzed, and occurrence of distal emboli was lesser in the pre-navigation balloon than in the non-preballoon group (4.4% vs. 11.5%, p = 0.02). No statistical difference was found in successful recanalization, mortality, and procedure-related complications. Moreover, the pre-navigation balloon group had a higher FPE than the non-balloon group (37.8% vs. 20.5%, p = 0.004). Although no statistical difference was found in the pre-navigation balloon group, a trend toward a higher rate of good clinical outcomes was observed (mRS 0-2 at 3 months, 55.6% vs. 48.7%, p = 0.09). For ICA occlusion(n = 35), significant effects were seen in decreasing distal embolism (0(0%) vs 3(16%), p = 0.01), increasing FPE (8(50%) vs 6(32%), p = 0.003), and improving clinical outcomes (mRS 0-2 at 3 months, 9(56%) vs 7(37%), p = 0.03) in the pre-navigation balloon group. In the multivariate analysis, lesser distal embolism (0.91 [0.80-1.00], p = 0.02), higher successful recanalization (3.52 [1.11-7.03], p = 0.016), and higher FPE (3.17 [1.83-7.37], p = 0.001) secondary to the procedure was a predictor of favorable clinical outcomes. CONCLUSIONS: The pre-navigation balloon technique significantly reduced occurrence of distal embolism and increased the FPE.

Electrical impedance measurements can identify red blood cell-rich content in acute ischemic stroke clots ex vivo associated with first-pass successful recanalization.

Background: Electrochemical impedance spectroscopy can determine characteristics such as cell density, size, and shape. The development of an electrical impedance-based medical device to estimate acute ischemic stroke (AIS) clot characteristics could improve stroke patient outcomes by informing clinical decision making. Objectives: To assess how well electrical impedance combined with machine learning identified red blood cell (RBC)-rich composition of AIS clots ex vivo, which is associated with a successfully modified first-pass effect. Methods: A total of 253 clots from 231 patients who underwent thrombectomy in 5 hospitals in France, Japan, Serbia, and Spain between February 2021 and October 2023 were analyzed in the Clotbase International Registry. Electrical impedance measurements were taken following clot retrieval by thrombectomy, followed by Martius Scarlet Blue staining. The clot components were quantified via Orbit Image Analysis, and RBC percentages were correlated with the RBC estimations made by the electrical impedance machine learning model. Results: Quantification by Martius Scarlet Blue staining identified RBCs as the major component in clots (RBCs, 37.6%; white blood cells, 5.7%; fibrin, 25.5%; platelets/other, 30.3%; and collagen, 1%). The impedance-based RBC estimation correlated well with the RBC content determined by histology, with a slope of 0.9 and Spearman's correlation of r = 0.7. Clots removed in 1 pass were significantly richer in RBCs and clots with successful recanalization in 1 pass (modified first-pass effect) were richer in RBCs as assessed using histology and impedance signature. Conclusion: Electrical impedance estimations of RBC content in AIS clots are consistent with histologic findings and may have potential for clinically relevant parameters.