Combined Hemoperfusion and Continuous Veno-Venous Hemofiltration for Carbamazepine Intoxication

2021 ◽  
pp. 1-5
Author(s):  
Simon Baylis ◽  
Rahul Costa-Pinto ◽  
Sarah Hodgson ◽  
Rinaldo Bellomo ◽  
Ian Baldwin
Keyword(s):  
Combined Treatment ◽  
Drug Clearance ◽  
Free Drug ◽  
Low Molecular Weight ◽  
Serum Protein Binding ◽  
Drug Levels ◽  
Mass Removal ◽  
In Series ◽  
Extracorporeal Removal ◽  
Massive Overdose

<b><i>Introduction:</i></b> Carbamazepine (CBZ) is a widely used anticonvulsant with a low molecular weight that allows for extracorporeal removal of free drug by both dialytic and hemoperfusion techniques, particularly in a massive overdose where serum protein binding is saturated. This report presents a case of CBZ intoxication where we were able to compare the mass removal of CBZ using hemoperfusion, with the mass removal of CBZ achieved with continuous renal replacement therapy (CRRT) during combined treatment. <b><i>Methods:</i></b> The Jafron HA230 resin hemoperfusion cartridge was applied in series with the continuous veno-venous hemofiltration (CVVH) circuit. Baseline and ongoing serum drug levels along with further samples from pre- and post-hemoperfusion cartridges and from CVVH effluent were collected. <b><i>Results:</i></b> Combined CVVH and resin hemoperfusion therapy in series was associated with a 50% reduction in the CBZ level from 16 mg/L to 8 mg/L over 3 h, far more rapid than that observed with CVVH alone or in the absence of extracorporeal drug clearance in the preceding hours. The combination therapy removed close to 35 mg/h of CBZ. <b><i>Conclusion:</i></b> The combination of CRRT and hemoperfusion can be easily deployed, appears safe, and is able to combine the CBZ mass removal achieved with each technique, thus to maximize CBZ extraction.

scholarly journals N-Acetyltransferase Genotypes and the Pharmacokinetics and Tolerability ofpara-Aminosalicylic Acid in Patients with Drug-Resistant Pulmonary Tuberculosis

2015 ◽  
Vol 59 (7) ◽  
pp. 4129-4138 ◽  
Author(s):  
Sherwin K. B. Sy ◽  
Lizanne de Kock ◽  
Andreas H. Diacon ◽  
Cedric J. Werely ◽  
Huiming Xia ◽  
...  
Keyword(s):  
Mass Function ◽  
Drug Clearance ◽  
Enzyme Analysis ◽  
Restriction Enzyme Analysis ◽  
Probability Mass Function ◽  
Aminosalicylic Acid ◽  
Open Label ◽  
Once Daily ◽  
In Series ◽  
Disposition Model

ABSTRACTThe aim of this study was to examine the relationships betweenN-acetyltransferase genotypes, pharmacokinetics, and tolerability of granular slow-releasepara-aminosalicylic acid (GSR-PAS) in tuberculosis patients. The study was a randomized, two-period, open-label, crossover design wherein each patient received 4 g GSR-PAS twice daily or 8 g once daily alternately. The PAS concentration-time profiles were modeled by a one-compartment disposition model with three transit compartments in series to describe its absorption. Patients'NAT1andNAT2genotypes were determined by sequencing and restriction enzyme analysis, respectively. The number of daily vomits was modeled by a Poisson probability mass function. Comparisons of other tolerability measures by regimens, gender, and genotypes were evaluated by a linear mixed-effects model. The covariate effects associated with efavirenz, gender, andNAT1*3,NAT1*14, andNAT2*5alleles corresponded to 25, 37, −17, −48, and −27% changes, respectively, in oral clearance of PAS. TheNAT1*10allele did not influence drug clearance. The time above the MIC of 1 mg/liter was significantly different between the two regimens but not influenced by theNAT1orNAT2genotypes. The occurrence and intensity of intolerance differed little between regimens. Four grams of GSR-PAS twice daily but not 8 g once daily ensured concentrations exceeding the MIC (1 mg/liter) throughout the dosing interval; PAS intolerance was not related to maximum PAS concentrations over the doses studied and was not more frequent after once-daily dosing. We confirm that the slow phenotype conferred by theNAT1*14andNAT1*3alleles resulted in higher PAS exposure but found no evidence of increased activity of theNAT1*10allele.

Expression of P-Selectin on Hepatic Endothelia and Platelets Promoting Neutrophil Removal by Liver Macrophages

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 520-528
Author(s):  
Jialan Shi ◽  
Yoshihiro Kokubo ◽  
Kenjiro Wake
Keyword(s):  
Molecular Weight ◽  
Endothelial Cells ◽  
Kupffer Cells ◽  
Polymorphonuclear Leukocyte ◽  
Low Molecular Weight Heparin ◽  
Acute Inflammation ◽  
Combined Treatment ◽  
Gadolinium Chloride ◽  
Low Molecular Weight

The role of P-selectin on polymorphonuclear leukocyte (PMN) adhesion-induced PMN elimination in the liver is unclear. Our objectives were to show the expression and distribution of P-selectin in rat liver, as well as to evaluate the changes in the modulation of the expression of P-selectin and its role in the accumulation and sequestration of PMNs. The intravenous administration of endotoxin markedly increased the expression of P-selectin on the venous and sinusoidal endothelial cells, as well as on the platelets trapped in the liver. Its expression peaked at 6 hours postinjection and was associated with a rapid increase in the aggregation and elimination of PMNs in the hepatic sinusoids. Combined treatment with an antibody to P-selectin or with low molecular weight heparin, a P-selectin antagonist, blocked the P-selectin, significantly reduced the arrest of PMNs, and delayed their removal in the liver. Pretreatment with gadolinium chloride inhibited phagocytosis of PMNs by the Kupffer cells, decreased the expression of P-selectin, and limited the hepatic accumulation of PMNs. Thus, P-selectin played a role in accumulation and elimination of PMNs from the liver. Results also suggest that activated Kupffer cells can modulate the expression of P-selectin in the liver and influence the homeostasis of PMNs in the circulation during acute inflammation.

Intratumoral drug distribution of adavosertib in patients with glioblastoma: Interim results of phase I study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2568-2568
Author(s):  
Carlos G Romo ◽  
Brian Michael Alexander ◽  
Nathalie Agar ◽  
Manmeet Singh Ahluwalia ◽  
Arati Suvas Desai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Geometric Mean ◽  
Extracellular Fluid ◽  
Maximum Tolerated Dose ◽  
Brain Regions ◽  
Free Drug ◽  
Total Drug ◽  
Drug Levels ◽  
Drug Concentrations

2568 Background: Wee1 is a key regulator of the G2/M checkpoint and is frequently overexpressed in glioblastoma (GB). Adavosertib is a first-in-class oral, small molecule inhibitor of Wee1 that acts primarily as a DNA damage sensitizer. A phase I clinical trial was conducted to evaluate its safety and establish the recommended phase II dosing. Studies were undertaken to evaluate whether potentially therapeutic concentrations of the drug are achieved in recurrent tumor and adjacent non-enhancing brain regions with presumed intact blood-brain barrier (BBB). Methods: Twelve patients received five daily doses of adavosertib pre-operatively at either the maximum tolerated dose (MTD) for concurrent radiation or adjuvant temozolomide. Tissue from contrast enhancing (CE) and non-enhancing (NE) brain regions was obtained for analysis during surgical resection. A second stage is being conducted using microdialysis (MD) to facilitate continuous sampling of extracellular fluid (ECF) and measuring free drug concentrations in: normal-appearing brain, contrast enhancing tumor, and a peritumoral T2 hyperintense area. The concentration of total adavosertib in plasma and tissue homogenates and free drug in ECF were determined by validated LC/MS/MS methods. Results: Geometric mean concentrations of adavosertib after a 200 mg dose were 644 ng/mL and 119 ng/mL in CE and NE tissue specimens, respectively (6 patients). At the 425 mg dose, the mean concentrations were 3,576 ng/mL in CE tissue and 885 ng/mL in NE tissue (6 patients). MD was performed in 2 patients. Samples from functional MD catheters were collected from NE brain in patient no. 1 and from two NE areas and a FLAIR hyperintense region in patient no. 2, with the following results in the table. Conclusions: The total drug concentration in tissue samples was notably lower in regions of the brain with a relatively intact BBB as compared to contrast enhancing tissue. Concentrations of adavosertib measured by MD vary markedly depending on catheter location. Free drug levels in ECF within brain with a functional BBB, although considerably lower than total drug levels in tissue, were 2-10 times below the previously reported IC50 for antiproliferative activity against sensitive GB cell lines (127 ng/mL). Whether or not the target of the drug is effectively inhibited at these concentrations remains to be demonstrated. Clinical trial information: NCT01849146 . [Table: see text]

Metallothionein alone or in combination with Prussian blue attenuates acute thallium systemic toxicity in rats.

2020 ◽  
Author(s):  
Laura Anaya-Ramos ◽  
Araceli Díaz-Ruíz ◽  
Camilo Ríos ◽  
Sergio Montes ◽  
Yoshajandith Aguirre-Vidal ◽  
...  
Keyword(s):  
Prussian Blue ◽  
Renal Damage ◽  
Combined Treatment ◽  
Brain Regions ◽  
Sublethal Dose ◽  
Low Molecular Weight ◽  
Renal Markers ◽  
Male Wistar Rats ◽  
Weight Protein ◽  
Low Molecular Weight Protein

Abstract Background: Acute Thallium (Tl) toxicosis is still a health problem, worldwide. Oral administration of Prussian blue (PB) is the antidotal treatment of election. On the other hand, metallothionein (MT) is a low-molecular-weight protein, with high content of cysteines (25–30%). MT is able to chelate metals as an efficient endogenous mechanism of detoxification. It is also a potent antioxidant. Methods: In this study, we tested the ability of MT at two doses (100 and 600 µg/rat), administered alone or in combination with Prussian blue (PB) (50 mg/kg) to decrease thallium (Tl) toxicity. A sublethal dose of Tl (16mg/kg) was injected i.p. to male Wistar rats. Antidotes were administered twice-daily, starting 24h after Tl injection, for 4 days. Tl concentrations were analyzed in body organs and brain regions, 5 days after Tl injection. Results: Results showed a diminution (p<0.05) of Tl concentrations in all organs by effect of PB alone or in combination with MT-100 and MT-600, whereas MT-100 only decreased Tl concentrations in testis, spleen, lung and liver. Likewise, Tl in brain regions was also diminished (p<0.05) by effect of PB and both MT-100 alone or in combination in most of the regions analyzed (p<0.05). The greatest diminution of Tl was achieved when the antidotes were combined. Plasma markers of renal damage, increased after Tl administration. Both PB and MT, either alone or in combination, prevented the raise of renal markers of Tl Toxicity. Conclusions: Our findings demonstrate that the combined treatment of PB + MT is a good antidotal option against thallotoxicosis.

scholarly journals Immunomodulatory Functions of Low-Molecular Weight Hyaluronate in an Acute Rat Renal Allograft Rejection Model

1999 ◽  
Vol 10 (5) ◽  
pp. 1059-1066
Author(s):  
ANDREAS KNOFLACH ◽  
HARUHITO AZUMA ◽  
COLM MAGEE ◽  
MARK DENTON ◽  
BARBARA MURPHY ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Allograft Rejection ◽  
Renal Allograft ◽  
Combined Treatment ◽  
Interferon Γ ◽  
Low Molecular Weight ◽  
Renal Allograft Rejection ◽  
Reverse Transcription Pcr ◽  
Acute Renal Allograft Rejection

Abstract. Low molecular weight hyaluronate (LMW-HA) blocks interactions between T lymphocyte CD44 and hyaluronate (HA), a heteropolysaccharide that is expressed on the surface of endothelial cells and ubiquitously in the extracellular matrix. This study was undertaken to assess the ability of LMW-HA to modify the course of experimental acute renal allograft rejection. Lewis (LEW) rats were bilaterally nephrectomized and received an orthotopic, fully MHC-mismatched, Wistar-Furth (WF) kidney transplant. Animals received either no treatment, low doses of cyclosporin A (CsA) on days 0 to 5, LMW-HA on days 0 to 5, or CsA plus LMW-HA on days 0 to 5 after transplantation. With no treatment, CsA monotherapy, or HA monotherapy, animals rejected their allografts at a median of 15, 13, and 7.5 d, respectively (P = NS). In contrast, combined CsA plus LMW-HA therapy prevented acute rejection and significantly prolonged graft survival (P = 0.008) to a median of 49.0 d. CsA/LMW-HA-treated grafts also demonstrated better preservation of renal function at day 30 (serum creatinine level, 1.38 ± 0.8 mg/dl), compared with surviving animals treated with CsA alone (2.9 ± 0.55 mg/dl, P < 0.05). Histologic graft analysis of CsA/LMW-HA-treated animals at day 7 after transplantation showed minimal rejection and leukocyte infiltration, compared with all other groups. Intragraft gene expression analysis, using semiquantitative reverse transcription-PCR, at the same time point showed reductions of CD4, CD8, and interferon-γ transcript levels in the combined-treatment group. This is the first study demonstrating the immunomodulatory functions of LMW-HA in vivo in the setting of organ transplantation. Defining the exact mechanisms that underlie this immunomodulation may provide the rationale to develop novel strategies for use in clinical transplantation.

Clinical utility of monitoring free drug levels

2020 ◽  
pp. 27-42
Author(s):  
Amitava Dasgupta ◽  
Matthew D. Krasowski
Keyword(s):  
Clinical Utility ◽  
Free Drug ◽  
Drug Levels
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