scholarly journals Safety of a Novel Dialyzer Containing a Fluorinated Polyurethane Surface-Modifying Macromolecule in Patients with End-Stage Kidney Disease

2021 ◽  
pp. 1-9
Author(s):  
Jill M. Meyer ◽  
Dylan Steer ◽  
Lisa A. Weber ◽  
Abeer A. Zeitone ◽  
Mayuri Thakuria ◽  
...  
Keyword(s):  
Complement Activation ◽  
Removal Rate ◽  
The Novel ◽  
Open Label ◽  
Serious Adverse Events ◽  
Flow Rates ◽  
Dialysate Flow ◽  
Fluorinated Polyurethane ◽  
End Stage

<b><i>Background:</i></b> By inhibiting the adsorption of protein and platelets, surface-modifying macromolecules (SMMs) may improve the hemocompatibility of hemodialyzers. This trial aims to assess the performance and safety of a novel dialyzer with a fluorinated polyurethane SMM, Endexo™. <b><i>Methods:</i></b> This prospective, sequential, multicenter, open-label study (NCT03536663) was designed to meet regulatory requirements for clinical testing of new hemodialyzers, including assessment of the in vivo ultrafiltration coefficient (Kuf). Adults prescribed thrice-weekly hemodialysis were eligible for enrollment. After completing 12 hemodialysis sessions with an Optiflux® F160NR dialyzer, patients received 38 sessions with the dialyzer with Endexo. Evaluated parameters included the in vivo Kuf of the dialyzer with Endexo extent of removal of urea, albumin, and β2-microglobulin (β2M), as well as complement activation. <b><i>Results:</i></b> Twenty-three patients received 268 hemodialysis treatments during the Optiflux period, and 18 patients received 664 hemodialysis treatments during the Endexo period. Three serious adverse events were reported, and none of them were considered device related. No overt complement activation was observed with either dialyzer. Both dialyzers were associated with comparable mean increases in serum albumin levels from pre- to posthemodialysis (Optiflux: 7.9%; Endexo: 8.0%). These increases can be viewed in the context of a mean increase in hemoglobin of approximately 5% and a mean ultrafiltration volume removed of approximately 2.2 L. The corrected mean β2M removal rate was 47% higher during the Endexo period (67.73%). Mean treatment times (208 vs. 205 min), blood flow rates (447.7 vs. 447.5 mL/min), dialysate flow rates (698.5 vs. 698.0 mL/min), urea reduction ratio (82 vs. 81%), and spKt/V (2.1 vs. 1.9) were comparable for the Endexo and Optiflux periods, respectively. The mean (SD) Kuf was 15.85 (10.33) mL/h/mm Hg during the first use of the dialyzer with Endexo (primary endpoint) and 16.36 (9.92) mL/h/mm Hg across the Endexo period. <b><i>Conclusions:</i></b> The safety of the novel dialyzer with Endexo was generally comparable to the Optiflux dialyzer, while exhibiting a higher β2M removal rate.

scholarly journals Performance of a novel dialyzer containing a fluorinated polyurethane surface-modifying macromolecule in patients with end-stage kidney disease

2020 ◽  
Author(s):  
Jill M Meyer ◽  
Dylan Steer ◽  
Lisa A Weber ◽  
Abeer A Zeitone ◽  
Mayuri Thakuria ◽  
...  
Keyword(s):  
Removal Rate ◽  
The Novel ◽  
Open Label ◽  
Serious Adverse Events ◽  
Flow Rates ◽  
Dialysate Flow ◽  
Fluorinated Polyurethane ◽  
End Stage ◽  
To Receive ◽  
Urea Reduction Ratio

Abstract Background By inhibiting the adsorption of protein and platelets, surface-modifying macromolecules (SMMs) may improve the hemocompatibility of hemodialyzers. This trial aims to assess the performance and safety of a novel dialyzer with a fluorinated polyurethane SMM, Endexo™, blended into the membrane during manufacturing. Methods This prospective, sequential, multicenter, open-label study enrolled adults prescribed thrice-weekly hemodialysis. After completing 12 hemodialysis sessions with an Optiflux ® F160NR dialyzer , patients received 38 sessions with the dialyzer with Endexo. Evaluated parameters included the extent of removal of urea, albumin, and β2-microglobulin (β2M), as well as complement activation.Results Twenty-three patients received 268 hemodialysis treatments during the Optiflux period, and 18 patients continued on to receive 664 hemodialysis treatments during the Endexo period. Mean treatment times (208 vs 205 min), blood flow rates (447.7 vs 447.5 mL/min), dialysate flow rates (698.5 vs 698.0 mL/min), urea reduction ratio (82% vs 81%) and spKt/V (2.1 vs 1.9) were comparable for the Endexo and Optiflux periods, respectively. No overt complement activation was observed. Both dialyzers were associated with comparable mean increases in serum albumin levels from pre- to post- hemodialysis (Optiflux: 7.9%; Endexo: 8.0%). The corrected mean β2M removal rate was 47% higher during the Endexo period (67.73%). Three serious adverse events were reported, none of them device-related. Conclusions The performance of the novel dialyzer with Endexo was generally comparable to the Optiflux dialyzer, while exhibiting a higher β2M removal rate. Additional studies are needed to determine whether this novel dialyzer can be incorporated into heparin-free hemodialysis approaches.

An open-label, pharmacokinetic study to determine the bioavailability, safety and tolerability of single dose oral docetaxel in metastatic prostate cancer (mPC) patients treated with IV docetaxel.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5050-5050
Author(s):  
Christopher G. C. A. Jackson ◽  
Yen-chuan Ou ◽  
Meng En ◽  
Tsu-Yi Chao ◽  
Noelyn Anne Hung ◽  
...  
Keyword(s):  
New Combination ◽  
Absolute Bioavailability ◽  
The Novel ◽  
Open Label ◽  
Serious Adverse Events ◽  
P Glycoprotein ◽  
Docetaxel Treatment ◽  
Dose Oral ◽  
Improve Patient ◽  
Clinical Trial Information

5050 Background: Docetaxel has poor oral bioavailability in part due to extrusion by intestinal p-glycoprotein. To improve IV solubility, it is fomulated with the nonionic surfactant polysorbate 80, requiring steroid premedication to manage hypersensitivity type reactions. Oral administration has the potential to improve tolerability, reduce day-stay utilization and improve patient convenience and allows investigation of alternative dosing schedules. Oradoxel is a new combination of oral docetaxel capsules plus the novel gut-selective P-glycoprotein inhibitor encequidar (HM30181A). Methods: Patients with mPC receiving IV docetaxel were enrolled in 3 cohorts with a dose escalation schedule of Oradoxel 75 mg/m2 in Cohort 1, 150 mg/m2 in Cohort 2, 300mg/m2 in Cohort 3. Oradoxel was given 3 weeks before or after IV docetaxel treatment. Intensive PK samples were taken on days 1-5 for Oradoxel and days 1-4 for IV docetaxel. Dose limiting toxicity (DLT) or serious adverse events (SAE) were assessed per CTCAE v4.03. Results: 3 evaluable patients in each Cohort were studied. No DLT, MTD, or drug-related SAE were observed. PK parameters of Oradoxel vs IV docetaxel are summarized in the table below. Mean absolute bioavailability of Oradoxel was 15.9% (range 8-25%). PK became non linear at 300mg/m2. Conclusions: Oradoxel was well tolerated. Based on the results of this and related studies, Oradoxel 300mg/m2 in divided doses is being further evaluated in phase 2 studies. Clinical trial information: 12616000983404. [Table: see text]

Acceleration of Dabigatran Elimination by Activated Charcoal Perfusion and Hemodialysis in a Pig Model.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2272-2272 ◽  
Author(s):  
Jessica Lange ◽  
Christian Thiel ◽  
Karolin Thiel ◽  
Wilfried Klingert ◽  
Kathrin Klingert ◽  
...  
Keyword(s):  
Steady State ◽  
Activated Charcoal ◽  
Plasma Levels ◽  
Binding Capacity ◽  
Flow Rates ◽  
Dialysate Flow ◽  
Maximum Binding Capacity ◽  
Set Up

Abstract Abstract 2272 Background and Aim: Dialysis based approaches can provide rapid removal of dabigatran in cases of emergency due to its low protein binding of ∼35%. However the in vitro properties of these filtration devices have not yet been characterized in detail. This study in the porcine system (both in vitro and in vivo) was performed to evaluate dabigatran elimination by hemodialysis and activated charcoal perfusion as compared to normal renal elimination. Methods: Porcine blood (5L) was supplemented with 1000 ng/mL dabigatran and circulated through an circuit of tubing allowing attached to an activated charcoal filter (Absorba 300 C, Gambro). Further supplementation of dabigatran allowed the determination of maximum binding capacity of the filter. A similar set up was used to also test dialysis (Polyflux 140H, Gambro) and determine the dependence of the flow rate on dabigatran removal. Dialysate flow rates were increased up to 500 ml/min. Anesthetized pigs (Domestic swine, female, ∼60 kg) were attached to an activated charcoal column or a High-Flux hemodialysis filter with a blood flow rate of 200 ml/min. Animals were given an initial i.v. infusion of dabigatran (7.5 mg in 15 min) and then reduced to 5 mg/hr to achieve steady state dabigatran over 1hr. Infusion was then stopped and elimination methods were applied over 4 hrs. An observation time of 1 hr followed. Dabigatran plasma levels were quantitated with diluted thrombin time. Preliminary settings/flow rates were obtained in vitro using 5L citrated porcine whole blood exposed to different AC or HD conditions. Results: Activated charcoal completely removed dabigatran within 1 hr from the 5L whole blood supplemented with 1000 ng/mL dabigatran, with a clearance rate of 100%. By repeatedly reapplying dabigatran, it was shown the active charcoal filter had a maximum binding capacity of ∼30 mg drug. Upon saturation there was no further clearance of dabigatran. Hemodialysis removed dabigatran with increasing clearance rates depending on dialysate flow rates (100 ml/min-35%, 200 ml/min-60%, 300 ml/min-65%) reaching a plateau of ∼65%. Further increases of dialysate flow to 500 ml/min had no further effect on drug clearance. Initial plasma levels of dabigatran ranged between 200–450 ng/mL after 60 min infusion in pigs. Exposure to activated charcoal or hemodialysis (dialysate flow 300 ml/min) resulted in 75–80% reduction in circulating dabigatran after 1 hr as compared to ∼25% reduction untreated controls after 1 hr. After 2 hrs dabigatran levels were below the detection limit using both elimination methods. Conclusions: Dabigatran can effectively be removed from the circulation in this in vivo porcine model using dialysis based approaches, which results in a restoration of blood coagulation. Active charcoal perfusion was fast and effectively removed dabigatran, but may be saturated if dabigatran plasma levels are too high (human body load for 150 mg dose in steady state is ∼14g). Stationary hemodialysis with sufficiently high dialysate flows achieves similar results in this model without saturation limitations; however, the set up for dialysis is much more specialized than the simpler approach of activated charcoal filtration. Disclosures: Formella: Boehringer Ingelheim: Employment. Clemens:Boehringer Ingelheim (Anticoagulant Therapy): Employment. van Ryn:Boehringer Ingelheim: Employment. Schenk:Boehringer Ingelheim: Research Funding.

In vitro hydrodynamics of the Embol-X cannula

Perfusion ◽  
2002 ◽  
Vol 17 (2) ◽  
pp. 153-156 ◽  
Author(s):  
Anja Gerdes ◽  
Thorsten Hanke ◽  
Hans-H Sievers
Keyword(s):  
In Vivo Studies ◽  
Clinical Effects ◽  
Pressure Gradients ◽  
The Novel ◽  
Flow Rates ◽  
Mock Circulation ◽  
Aortic Cannula ◽  
Novel Concept

Background: Prevention of intraoperative plaque dislodgement in patients with atherosclerotic ascending aorta by development of innovative aortic cannula designs gains growing interest in cardiac surgery. To increase knowledge about the hydrodynamics of the innovative Embol-X™ cannula, which includes an intra-aortic filter device targeting at atheromatous emboli capture, was the aim of the present study. Methods: Pressure gradients and back pressures of the Embol-X™ cannula were measured at varying flow rates in a mock circulation and compared with two commonly used single-stream cannulae. Results: At a flow rate of 5.5 l/min, pressure gradients across the Argyle™ and the RMI cannulae were 48% and 62% and back pressures 25% and 47% lower than the corresponding values across the Embol-X™ cannula. Conclusions: The novel concept of integrating a filter device may provide clinical advantages concerning neurologic outcome. Further in vivo studies seem to be desirable to obtain more information concerning the clinical effects of the Embol-X™ cannula hydrodynamics.

scholarly journals Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis

Blood ◽  
2010 ◽  
Vol 116 (4) ◽  
pp. 631-639 ◽  
Author(s):  
Ioannis Kourtzelis ◽  
Maciej M. Markiewski ◽  
Michael Doumas ◽  
Stavros Rafail ◽  
Konstantinos Kambas ◽  
...  
Keyword(s):  
Renal Disease ◽  
Complement Activation ◽  
End Stage Renal Disease ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Anaphylatoxin C5a ◽  
Stage Renal Disease ◽  
End Stage ◽  
Stimulating Factor

Abstract Thrombosis is a common complication of end-stage renal disease, particularly in patients on hemodialysis. Although substantial progress has been made in preventing thrombotic complications in various other groups of patients, the mechanisms of thrombosis during hemodialysis require clarification. In this report, we demonstrate that complement activation triggered by hemodialysis biomaterials, and the subsequent generation of the complement anaphylatoxin C5a, results in the expression of functionally active tissue factor (TF) in peripheral blood neutrophils. Because TF is a key initiator of coagulation in vivo, we postulate that the recurring complement activation that occurs during long-term hemodialysis contributes to thrombosis in dialyzed end-stage renal disease patients. Furthermore, we found that complement contributed to the induction of granulocyte colony-stimulating factor, which has been implicated in the pathogenesis of thrombosis in patients treated with the recombinant form of this molecule. Importantly, the inhibition of complement activation attenuated the TF expression and granulocyte colony-stimulating factor induction in blood passing through a hemodialysis circuit, suggesting that the complement system could become a new therapeutic target for preventing thrombosis in patients with chronic renal failure who are maintained on hemodialysis.

scholarly journals In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Benjamin Xiaoyi Li ◽  
Xiangrong Dai ◽  
Xiaohong Ruby Xu ◽  
Reheman Adili ◽  
Miguel Antonio Dias Neves ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Platelet Aggregation ◽  
Phase I ◽  
Human Platelet ◽  
Open Label ◽  
Serious Adverse Events ◽  
Open Label Phase ◽  
Deinagkistrodon Acutus

AbstractThe interaction of platelet GPIbα with von Willebrand factor (VWF) is essential to initiate platelet adhesion and thrombosis, particularly under high shear stress conditions. However, no drug targeting GPIbα has been developed for clinical practice. Here we characterized anfibatide, a GPIbα antagonist purified from snake (Deinagkistrodon acutus) venom, and evaluated its interaction with GPIbα by surface plasmon resonance and in silico modeling. We demonstrated that anfibatide interferds with both VWF and thrombin binding, inhibited ristocetin/botrocetin- and low-dose thrombin-induced human platelet aggregation, and decreased thrombus volume and stability in blood flowing over collagen. In a single-center, randomized, and open-label phase I clinical trial, anfibatide was administered intravenously to 94 healthy volunteers either as a single dose bolus, or a bolus followed by a constant rate infusion of anfibatide for 24 h. Anfibatide inhibited VWF-mediated platelet aggregation without significantly altering bleeding time or coagulation. The inhibitory effects disappeared within 8 h after drug withdrawal. No thrombocytopenia or anti-anfibatide antibodies were detected, and no serious adverse events or allergic reactions were observed during the studies. Therefore, anfibatide was well-tolerated among healthy subjects. Interestingly, anfibatide exhibited pharmacologic effects in vivo at concentrations thousand-fold lower than in vitro, a phenomenon which deserves further investigation.Trial registration: Clinicaltrials.gov NCT01588132.

An open-label, multicenter, phase I/II study of AT-101 in combination with docetaxel (D) and prednisone (P) in men with castrate-resistant prostate cancer (CRPC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5062-5062
Author(s):  
G. R. MacVicar ◽  
A. Greco ◽  
J. Reeves ◽  
J. Maleski ◽  
J. Holmlund ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase 1 ◽  
Single Agent ◽  
Safety Data ◽  
Preliminary Evidence ◽  
Open Label ◽  
Serious Adverse Events ◽  
Vein Thrombosis

5062 Background: Antiapoptotic Bcl-2 family proteins are overexpressed in CRPC and contribute to resistance to therapy. The oral pan-Bcl-2 inhibitor AT-101 (Bcl-2, Bcl-XL, Bcl-W, Mcl-1) is active as a single agent and in combination in in vitro and in vivo tumor models and as a single agent in CRPC. The Phase 1 portion of the study determined the recommended dose for phase II to be D (75mg/m2 q3weeks) in combination with P (5mg b.i.d. on days 1–21), and AT-101 at 40mg b.i.d. on days 1–3 of each 21-day cycle, and was previously reported. Methods: Men ≥18 years of age with chemotherapy-naïve CRPC (N = 36). Safety (NCI CTCAE v3.0) and efficacy (Bubley Criteria for PSA) were assessed at 3-wk intervals. Radiological assessments were performed at 6-wk intervals for pts with soft tissue disease and bone scans were performed after cycle 6 and at the completion of therapy. Results: 36 patients (pts) have been enrolled in the study. Twenty-four (67%) pts achieved a partial response (PR) (>50% PSA decline), and 26 (72%) pts treated had at least a 30% decrease in PSA level. Nine of 19 pts (47%) with measurable disease had a PR. One PR was unconfirmed per RECIST. Thirteen pts (36%) completed >10 cycles of therapy (range 2–24) thus far. Four pts remains active. Safety data is available for 31 pts. The most common (>20%) Adverse Events (AEs) include: fatigue (68%), nausea (52%), diarrhea (45%), alopecia (32%), constipation and dysgeusia (26%), and neutropenia and vomiting (26%). Neutropenia was the only gr. 4 event occurring in more than one pt (3pts). Serious Adverse Events (SAEs) considered related were reported in 5 pts (16%). The only SAEs reported in 2 or more pts were urinary tract infection (3 pts) and deep vein thrombosis (2 pts) and none were considered related. No ileus has been reported. Conclusions: AT-101 when given in combination with D/P is well tolerated and shows preliminary evidence of efficacy in pts with CRPC. A randomized trial is ongoing. [Table: see text]

Phase 1a/b Study of Monoclonal Antibody CAEL-101 (11-1F4) in Patients with AL Amyloidosis

Blood ◽  
2021 ◽  
Author(s):  
Camille V Edwards ◽  
Nisha Rao ◽  
Divava Bhutani ◽  
Markus Y Mapara ◽  
Jai Radhakrishnan ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Light Chain ◽  
Amyloid Fibrils ◽  
Maximum Tolerated Dose ◽  
Al Amyloidosis ◽  
Open Label ◽  
Serious Adverse Events ◽  
Amyloid Deposits ◽  
Soft Tissue Involvement

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by pathologic deposition of immunoglobulin light chains as amyloid fibrils in vital organs, leading to organ impairment and eventual death. That the process is reversible was evidenced in an in vivo experimental model in which fibril-reactive chimeric monoclonal antibody (mAb) 11-1F4 directly targeted human light-chain amyloid deposits and effected their removal via a phagocyte-mediated response. To determine tolerability and potential amyloidolytic effect of this agent (now designated mAb CAEL-101), we conducted a phase 1a/b study involving 27 patients, most of whom had manifestations of organ involvement. This was an open label study in which phase 1a patients received mAb CAEL-101 as a single intravenous infusion, with escalating dose levels from 0.5 mg/m2 to 500 mg/m2 to establish the maximum tolerated dose (MTD). In phase 1b, the antibody was administered as a graded series of four weekly infusions. For both phases, there were no drug-related serious adverse events or dose-limiting toxicities among recipients and the MTD was not reached. Majority of patients had deep hematologic responses but persistent organ disease prior to treatment. Fifteen of 24 patients (63%) who manifested cardiac, renal, hepatic, gastrointestinal, or soft tissue involvement had a therapeutic response to mAb CAEL-101 as evidenced by serum biomarkers or objective imaging modalities with median time to response of 3 weeks. Infusions of mAb CAEL-101 were well-tolerated and, for the majority, resulted in improved organ function, notably for those with cardiac impairment. This trial was registered at www.clinicaltrials.gov as NCT02245867.

Evidence for an Increased Generation of Prostacyclin in the Microvasculature and an Impairment of the Platelet α-Granule Release in Chronic Renal Failure

1988 ◽  
Vol 60 (02) ◽  
pp. 205-208 ◽  
Author(s):  
Paul A Kyrle ◽  
Felix Stockenhuber ◽  
Brigitte Brenner ◽  
Heinz Gössinger ◽  
Christian Korninger ◽  
...  
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Blood Clotting ◽  
Normal Subjects ◽  
Chronic Uraemia ◽  
Wall Interaction ◽  
End Stage ◽  
Granule Release

SummaryThe formation of prostacyclin (PGI2) and thromboxane A2 and the release of beta-thromboglobulin (beta-TG) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the micro vasculature made to determine bleeding time, was studied in patients with end-stage chronic renal failure undergoing regular haemodialysis and in normal subjects. In the uraemic patients, levels of 6-keto-prostaglandin F1α (6-keto-PGF1α) were 1.3-fold to 6.3-fold higher than the corresponding values in the control subjects indicating an increased PGI2 formation in chronic uraemia. Formation of thromboxane B2 (TxB2) at the site of plug formation in vivo and during whole blood clotting in vitro was similar in the uraemic subjects and in the normals excluding a major defect in platelet prostaglandin metabolism in chronic renal failure. Significantly smaller amounts of beta-TG were found in blood obtained from the site of vascular injury as well as after in vitro blood clotting in patients with chronic renal failure indicating an impairment of the a-granule release in chronic uraemia. We therefore conclude that the haemorrhagic diathesis commonly seen in patients with chronic renal failure is - at least partially - due to an acquired defect of the platelet a-granule release and an increased generation of PGI2 in the micro vasculature.

Uptake, Internalization and Degradation of the Novel Plasminogen Activator Reteplase (BM 06.022) in the Rat

1995 ◽  
Vol 74 (06) ◽  
pp. 1501-1510 ◽  
Author(s):  
J Kuiper ◽  
H van de Bilt ◽  
U Martin ◽  
Th J C van Berkel
Keyword(s):  
Plasminogen Activator ◽  
Liver Cells ◽  
The Novel ◽  
Uptake Mechanism ◽  
Liver Uptake ◽  
Lysosomal Compartment ◽  
Β Phase ◽  
Α Phase ◽  
Parenchymal Liver

SummaryThe catabolism of the novel plasminogen activator reteplase (BM 06.022) was described. For this purpose BM 06.022 was radiolabelled with l25I or with the accumulating label l25I-tyramine cellobiose (l25I-TC).BM 06.022 was injected at a pharmacological dose of 380 μg/kg b.w. and it was cleared from the plasma in a biphasic manner with a half-life of about 1 min in the α-phase and t1/2of 20-28 min in the β-phase. 28% and 72% of the injected dose was cleared in the α-phase and β-phase, respectively. Initially liver, kidneys, skin, bones, lungs, spleen, and muscles contributed mainly to the plasma clearance. Only liver and the kidneys, however, were responsible for the uptake and subsequent degradation of BM 06.022 and contributed for 75% to the catabolism of BM 06.022. BM 06.022 was degraded in the lysosomal compartment of both organs. Parenchymal liver cells were responsible for 70% of the liver uptake of BM 06.022. BM 06.022 associated rapidly to isolated rat parenchymal liver cells and was subsequently degraded in the lysosomal compartment of these cells. BM 06.022 bound with low-affinity to the parenchymal liver cells (550 nM) and the binding of BM 06.022 could be displaced by t-PA (IC50 5.6 nM), indicating that the low-density lipoprotein receptor-related protein (LRP) could be involved in the binding of BM 06.022. GST-RAP, which is an inhibitor of LRP, could in vivo significantly inhibit the uptake of BM 06.022 in the liver.It is concluded that BM 06.022 is metabolized primarily in the liver and the kidneys. These organs take up and degrade BM 06.022 in the lysosomes. The uptake mechanism of BM 06.022 in the kidneys is unknown, while LRP is responsible for a low-affinity binding and uptake of BM 06.022 in parenchymal liver cells.

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