scholarly journals E-018 A novel 8fr aspiration catheter significantly increases the first pass effect in comparison with industry standard 6fr devices in an in-vitro human vasculature model

2020 ◽  
Author(s):  
S Fitzgerald ◽  
D Ryan ◽  
L Mullins ◽  
J Thornton ◽  
R Nogueira
Keyword(s):  
First Pass Effect ◽  
Industry Standard ◽  
First Pass

scholarly journals Comparable Intestinal and Hepatic First-Pass Effect of YL-IPA08 on the Bioavailability and Effective Brain Exposure, a Rapid Anti-PTSD and Anti-Depression Compound

2020 ◽  
Vol 11 ◽  
Author(s):  
You Gao ◽  
Chunmiao Yang ◽  
Lingchao Wang ◽  
Yanan Xiang ◽  
Wenpeng Zhang ◽  
...  
Keyword(s):  
Species Difference ◽  
Binding Activity ◽  
Translocator Protein ◽  
First Pass Effect ◽  
Pharmacokinetic Properties ◽  
Brain Exposure ◽  
First Pass ◽  
Fit For Purpose

YL-IPA08, exerting rapid antidepressant-like and anxiolytic-like effects on behaviors by translocator protein (TSPO) mediation, is a novel compound that has been discovered and developed at our institute. Fit-for-purpose pharmacokinetic properties is urgently needed to be discovered as early as possible for a new compound. YL-IPA08 exhibited low bioavailability (∼6%) during the preliminary pharmacokinetics study in rats after oral administration. Our aim was to determine how metabolic disposition by microsomal P450 enzymes in liver and intestine limited YL-IPA08’s bioavailability and further affected brain penetration to the target. Studies of in vitro metabolic stability and permeability combined with in vivo oral bioavailability, panel CYP inhibitor co-administration via different routes, and double cannulation rats were conducted to elucidate the intestinal and hepatic first-pass effect of YL-IPA08 on bioavailability. Unbound brain-to-plasma ratio (Kp,uu) in rats was determined at steady state. Results indicated that P450-mediated elimination appeared to be important for its extensive first-pass effect with comparative contribution of gut (35%) and liver (17%), and no significant species difference was observed. The unbound concentration of YL-IPA08 in rat brain (6.5 pg/ml) was estimated based on Kp,uu (0.18) and was slightly higher than in vitro TSPO-binding activity (4.9 pg/ml). Based on the onset efficacy of YL-IPA08 toward TPSO in brain and Kp,uu, therapeutic human plasma concentration was predicted to be ∼27.2 ng/ml would easily be reached even with unfavorable bioavailability.

Abstract 1122‐000073: Influence of Catheter Tip Position and Aspiration Technique on ADAPT Revascularization Success with Various Catheters

2021 ◽  
Vol 1 (S1) ◽  
Author(s):  
Seán T Fitzgerald ◽  
Liam Mullins ◽  
Kevin Connolly ◽  
John Thornton ◽  
Raul G Nogueira
Keyword(s):  
Vessel Wall ◽  
Outer Diameter ◽  
Vessel Size ◽  
First Pass Effect ◽  
First Pass ◽  
The Face ◽  
Aspiration Technique ◽  
Catheter Tip ◽  
Tip Position

Introduction : Previous studies demonstrated that both the location of the distal access catheter tip and angle of aspiration have a significant impact on revascularization outcomes 1,2 . A direct aspiration First‐Pass technique (ADAPT) with large‐bore aspiration catheters has emerged as a fast, safe, and effective thrombectomy technique. Maximizing the catheter‐to‐vessel size has previously been shown to enhance distal flow control resulting in improved in‐vitro revascularization rates for aspiration thrombectomy 3 . However, physicians differ in their preference for aspiration catheter tip placement, typically either positioning the catheter tip at the ‘face’ of the clot or advancing the catheter tip into the clot to engage it. We hypothesize that sizing the aspiration catheter outer diameter (OD) to the inner diameter (ID) of the vessel and embedding the catheter tip in the clot may result in ‘pinning’ fragments of clot between the catheter and vessel wall, thereby negatively affecting revascularization outcomes. Withdrawal of the aspiration catheter under continuous aspiration may mitigate this effect. We investigate the influence of catheter tip position and aspiration technique on ADAPT revascularization success with various sizes of aspiration catheters. Methods : Two clot analogues phenotypes (RBC‐Rich and Fibrin/Platelet‐Rich) were created from human blood and used to form occlusions in an In‐vitro thrombectomy model as previously described 4 . Two catheter tip positions and three techniques were investigated; 1). Catheter tip proximal to the face of the clot followed by conventional aspiration, 2). Catheter tip ‘embedded’ into the clot followed by conventional aspiration, and 3). Catheter tip ‘embedded’ into the clot followed by conventional aspiration and aspiration on catheter withdrawal even if clot ingestion occurred. Two aspiration catheters were investigated; Millipede 088’’ (Perfuze Ltd) and SOFIA Plus (Terumo). Multiple replicates of each test were performed. Endpoints were First‐Pass Effect and procedural‐related distal emboli from 200–1000µm. Results : Maximizing the catheter‐to‐vessel size increases success of the ADAPT approach when the tip is located proximal to the clot face (Fig 1 A&B); Millipede 088 achieves a higher First‐Pass Effect rate than SOFIA Plus. Sizing the catheter‐to‐vessel and embedding the catheter tip into the clot (Figure 1C) results in ‘pinning’ of clot fragments between the catheter and vessel wall (Figure 1D) resulting in lower rates of First‐Pass Effect. Withdrawing the catheter under continuous aspiration increases the success of the embedding method by capturing ‘pinned’ fragments. Conclusions : The position of the aspiration catheter tip and aspiration technique used both influence the success of ADAPT procedures. Sizing the catheter‐to‐vessel results in improved revascularization. However, embedding the tip into the clot when the vessel is similar in ID to the catheter OD may reduce First‐Pass Effect rates. To optimize the rates of First‐Pass Effect, aspiration catheters may be positioned at the proximal face of the clot or retracted under continuous aspiration if wedged into the clot.

scholarly journals Pharmacokinetics of mangiferin and its metabolite-Norathyriol, Part 1: Systemic evaluation of hepatic first-pass effect in vitro and in vivo

BioFactors ◽  
2016 ◽  
Vol 42 (5) ◽  
pp. 533-544 ◽  
Author(s):  
Xiaoting Tian ◽  
Yu Gao ◽  
Zhou Xu ◽  
Shan Lian ◽  
Yuanjie Ma ◽  
...  
Keyword(s):  
First Pass Effect ◽  
First Pass

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

Clot imaging characteristics predict first pass effect of aspiration—first approach to thrombectomy

2021 ◽  
pp. 159101992110191
Author(s):  
Muhammad Waqas ◽  
Weizhe Li ◽  
Tatsat R Patel ◽  
Felix Chin ◽  
Vincent M Tutino ◽  
...  
Keyword(s):  
Internal Carotid ◽  
Validation Cohort ◽  
Area Under The Curve ◽  
Large Vessel Occlusion ◽  
Vessel Occlusion ◽  
First Pass Effect ◽  
Imaging Characteristics ◽  
First Pass ◽  
Sensitivity Specificity ◽  
Youden’S Index

Background The value of clot imaging in patients with emergent large vessel occlusion (ELVO) treated with thrombectomy is unknown. Methods We performed retrospective analysis of clot imaging (clot density, perviousness, length, diameter, distance to the internal carotid artery (ICA) terminus and angle of interaction (AOI) between clot and the aspiration catheter) of consecutive cases of middle cerebral artery (MCA) occlusion and its association with first pass effect (FPE, TICI 2c-3 after a first attempt). Results Patients ( n = 90 total) with FPE had shorter clot length (9.9 ± 4.5 mm vs. 11.7 ± 4.6 mm, P = 0.07), shorter distance from ICA terminus (11.0 ± 7.1 mm vs. 14.7 ± 9.8 mm, P = 0.048), higher perviousness (39.39 ± 29.5 vs 25.43 ± 17.6, P = 0.006) and larger AOI (153.6 ± 17.6 vs 140.3 ± 23.5, P = 0.004) compared to no-FPE patients. In multivariate analysis, distance from ICA terminus to clot ≤13.5 mm (odds ratio (OR) 11.05, 95% confidence interval (CI) 2.65–46.15, P = 0.001), clot length ≤9.9 mm (OR 7.34; 95% CI 1.8–29.96, P = 0.005), perviousness ≥ 19.9 (OR 2.54, 95% CI 0.84–7.6, P = 0.09) and AOI ≥ 137°^ (OR 6.8, 95% CI 1.55–29.8, P = 0.011) were independent predictors of FPE. The optimal cut off derived using Youden’s index was 6.5. The area under the curve of a score predictive of FPE success was 0.816 (0.728–0.904, P < 0.001). In a validation cohort ( n = 30), sensitivity, specificity, positive and negative predictive value of a score of 6–10 were 72.7%, 73.6%, 61.5% and 82.3%. Conclusions Clot imaging predicts the likelihood of achieving FPE in patients with MCA ELVO treated with the aspiration-first approach.

scholarly journals Overexpression of P-glycoprotein, MRP2, and CYP3A4 impairs intestinal absorption of octreotide in rats with portal hypertension

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiaoyu Sun ◽  
Shunxiong Tang ◽  
Binbin Hou ◽  
Zhijun Duan ◽  
Zhen Liu ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Portal Hypertension ◽  
Western Blot ◽  
In Vitro Experiments ◽  
Rt Pcr ◽  
P Glycoprotein ◽  
Intestinal Microsomes ◽  
First Pass

Abstract Background Portal hypertension (PH) is the main cause of complications and death in liver cirrhosis. The effect of oral administration of octreotide (OCT), a drug that reduces PH by the constriction of mesenteric arteries, is limited by a remarkable intestinal first-pass elimination. Methods The bile duct ligation (BDL) was used in rats to induce liver cirrhosis with PH to examine the kinetics and molecular factors such as P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2) and cytochrome P450 3A4 (CYP3A4) influencing the intestinal OCT absorption via in situ and in vitro experiments on jejunal segments, transportation experiments on Caco-2 cells and experiments using intestinal microsomes and recombinant human CYP3A4. Moreover, RT-PCR, western blot, and immunohistochemistry were performed. Results Both in situ and in vitro experiments in jejunal segments showed that intestinal OCT absorption in both control and PH rats was largely controlled by P-gp and, to a lesser extent, by MRP2. OCT transport mediated by P-gp and MRP2 was demonstrated on Caco-2 cells. The results of RT-PCR, western blot, and immunohistochemistry suggested that impaired OCT absorption in PH was in part due to the jejunal upregulation of these two transporters. The use of intestinal microsomes and recombinant human CYP3A4 revealed that CYP3A4 metabolized OCT, and its upregulation in PH likely contributed to impaired drug absorption. Conclusions Inhibition of P-gp, MRP2, and CYP3A4 might represent a valid option for decreasing intestinal first-pass effects on orally administered OCT, thereby increasing its bioavailability to alleviate PH in patients with cirrhosis.

Formulation and Characterization of Eplerenone Mucoadhesive Buccal Tablets

2021 ◽  
pp. 3097-3103
Author(s):  
Harini Amballa ◽  
Navaneetha Kaluva ◽  
Sree Giri Prasad Beri ◽  
Krishna Mohan Chinnala ◽  
Mayuri Konda
Keyword(s):  
Drug Delivery ◽  
Drug Release ◽  
Drug Delivery System ◽  
Delivery System ◽  
Release System ◽  
First Pass Metabolism ◽  
First Pass ◽  
Buccal Tablets ◽  
Pass Metabolism

Mucoadhesive drug release system is a preferably unidirectional release system where mucosal epithelial exterior is enclosed by the mucus deposit that interacts with the bio-adhesive drug delivery system and swelling time of the buccal dosage form which is amplified by mucin molecules at the location of administration. Eplerenone is an Anti-hypertensive drug that undergoes hepatic first pass metabolism and shows 69% of bioavailability. In order to bypass the hepatic first pass metabolism the drug is designed to be delivered through buccal cavity to avoid the first pass metabolism. Eplerenone buccal tablets were formulated by using direct compression method with different polymers like HPMC K 100M, Carbopol 934P, Carbopol 974P, Xantham Gum, Eudragit L100 and NaCMC in various concentrations and compositions. Incompatibility complications were not observed from the FTIR spectrums. The formulated and prepared buccal solid dosage forms were evaluated for pre-compressions and post- compression parameters such as hardness, weight variation, thickness, friability, surface pH, swelling index, in-vitro dissolution studies, drug content uniformity, mucoadhesion strength and mucoadhesion time. Evaluation results of formulation F12 are proven to be the optimal formulation showing highest mucoadhesion time, mucoadhesion strength and in-vitro drug release for prolonged period of time about 8 hours. Eplerenone is best delivered through buccal drug delivery system to enhance its oral bioavailability and bypass the hepatic first pass metabolism.

First-Pass Effect in Basilar Artery Occlusions: Insights From the Endovascular Treatment of Ischemic Stroke Registry

Stroke ◽  
2021 ◽  
Author(s):  
Mathilde Aubertin ◽  
David Weisenburger-Lile ◽  
Benjamin Gory ◽  
Sébastien Richard ◽  
Raphael Blanc ◽  
...  
Keyword(s):  
Basilar Artery ◽  
Rescue Therapy ◽  
Strong Predictor ◽  
Artery Occlusion ◽  
Basilar Artery Occlusion ◽  
Anterior Circulation ◽  
Unique Identifier ◽  
First Pass Effect ◽  
Improved Outcomes ◽  
First Pass

Background and Purpose: In the settings of thrombectomy, the first-pass effect (FPE), defined by a complete recanalization after one pass with no rescue therapy, has been shown to be associated with an improved outcome. As this phenomenon has been predominantly described in anterior circulation strokes, we aimed to study the prevalence, outcomes, and predictors of FPE in patients with a basilar artery occlusion. Methods: From a prospective multicentric registry, we collected the data of all consecutive basilar artery occlusion patients who underwent thrombectomy and compared the outcomes of patients who achieved FPE and those who did not. We also compared FPE patients with those who achieved a complete recanalization with >1 pass. Finally, a multivariate analysis was performed to determine the predictors of FPE. Results: Data from 280 patients were analyzed in our study, including 84 of 280 patients (30%) with an atheromatous etiology. An FPE was achieved in 93 patients (33.2%), with a significantly higher proportion of good outcomes (modified Rankin Scale score 0-2 at 3 months) and lower mortality than non-FPE patients. An FPE was also associated with improved outcomes compared with patients who went on to have full recanalization with >1 pass. Contact aspiration as first-line strategy was a strong predictor of FPE, whereas baseline antiplatelets and atheromatous etiology were negative predictors. Conclusions: In our study, an FPE was achieved in approximately one-third of patients with a basilar artery occlusion and was associated with improved outcomes. More research is needed to improve devices and techniques to increase the incidence of FPE. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03776877.

Influence of First-Pass Effect on Availability of Drugs on Oral Administration

1971 ◽  
Vol 60 (9) ◽  
pp. 1338-1340 ◽  
Author(s):  
M. Gibaldi ◽  
R.N. Boyes ◽  
S. Feldman
Keyword(s):  
Oral Administration ◽  
First Pass Effect ◽  
First Pass
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