Non-compartmental Analysis

Gabrielsson, Johan; Weiner, Daniel

doi:10.1007/978-1-62703-050-2_16

Cited by 193 publications

(150 citation statements)

References 11 publications

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“…Plasma samples were added to HEPES buffer (500 mmol/l, pH 7.4) and assayed for fluorescence (496 nm excitation and 520 nm emission, Safire II, Tecan Austria, Grödig, Austria). The exact FITC-inulin dose was calculated from syringe pre to post weight and FITC-inulin clearance was calculated using non-compartmental pharmacokinetic data analysis [30].…”

Section: Methodsmentioning

confidence: 48%

Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db mice as a model of type 2 diabetes

Persson¹,

Franzén²,

Catrina

et al. 2012

Diabetologia

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Aims/hypothesis Increased oxygen consumption results in kidney tissue hypoxia, which is proposed to contribute to the development of diabetic nephropathy. Oxidative stress causes increased oxygen consumption in type 1 diabetic kidneys, partly mediated by uncoupling protein-2 (UCP-2)-induced mitochondrial uncoupling. The present study investigates the role of UCP-2 and oxidative stress in mitochondrial oxygen consumption and kidney function in db/db mice as a model of type 2 diabetes. Methods Mitochondrial oxygen consumption, glomerular filtration rate and proteinuria were investigated in db/db mice and corresponding controls with and without coenzyme Q10 (CoQ10) treatment. −1 ). UCP-2 protein levels were similar in untreated control and db/db mice (67± 9 vs 67± 4 optical density; OD) but were reduced in CoQ10 treated groups (43±2 and 38±7 OD). Conclusions/interpretation db/db mice displayed oxidative stress-mediated activation of UCP-2, which resulted in mitochondrial uncoupling and increased oxygen consumption. CoQ10 prevented altered mitochondrial function and morphology, glomerular hyperfiltration and proteinuria in db/db mice, highlighting the role of mitochondria in the pathogenesis of diabetic nephropathy and the benefits of preventing increased oxidative stress.

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Section: Methodsmentioning

confidence: 48%

Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db mice as a model of type 2 diabetes

Persson¹,

Franzén²,

Catrina

et al. 2012

Diabetologia

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“…Plasma and homogenized samples were analyzed by means of liquid chromatography with tandem mass spectrometry or highperformance liquid chromatography. The pharmacokinetic parameters of TAS-116 in mice, rats, and dogs were calculated by using noncompartmental methods (25).…”

Section: Histopathologic Examination Of Rat Eye Tissuesmentioning

confidence: 99%

TAS-116, a Highly Selective Inhibitor of Heat Shock Protein 90α and β, Demonstrates Potent Antitumor Activity and Minimal Ocular Toxicity in Preclinical Models

Ohkubo

Kodama

Muraoka

et al. 2015

Molecular Cancer Therapeutics

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The molecular chaperone HSP90 plays a crucial role in cancer cell growth and survival by stabilizing cancer-related proteins. A number of HSP90 inhibitors have been developed clinically for cancer therapy; however, potential off-target and/or HSP90-related toxicities have proved problematic. The 4-(1H-pyrazolo [3,4-b]pyridine-1-yl)benzamide TAS-116 is a selective inhibitor of cytosolic HSP90a and b that does not inhibit HSP90 paralogs such as endoplasmic reticulum GRP94 or mitochondrial TRAP1. Oral administration of TAS-116 led to tumor shrinkage in human tumor xenograft mouse models accompanied by depletion of multiple HSP90 clients, demonstrating that the inhibition of HSP90a and b alone was sufficient to exert antitumor activity in certain tumor models. One of the most notable HSP90-related adverse events universally observed to differing degrees in the clinical setting is visual disturbance. A two-week administration of the isoxazole resorcinol NVP-AUY922, an HSP90 inhibitor, caused marked degeneration and disarrangement of the outer nuclear layer of the retina and induced photoreceptor cell death in rats. In contrast, TAS-116 did not produce detectable photoreceptor injury in rats, probably due to its lower distribution in retinal tissue. Importantly, in a rat model, the antitumor activity of TAS-116 was accompanied by a higher distribution of the compound in subcutaneously xenografted NCI-H1975 non-small cell lung carcinoma tumors than in retina. Moreover, TAS-116 showed activity against orthotopically transplanted NCI-H1975 lung tumors. Together, these data suggest that TAS-116 has a potential to maximize antitumor activity while minimizing adverse effects such as visual disturbances that are observed with other compounds of this class.

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“…In clinical studies, adequate caspofungin peak (11.9 μg/mL) and trough levels (3.7 μg/mL) were maintained during ECMO [72]. However, being more lipophilic, voriconazole was significantly sequestered in the circuit, necessitating higher doses of the drug to maintain adequate trough levels.…”

Section: Antibioticsmentioning

confidence: 40%

“…Unfortunately, PK data in adult patients on ECMO are sparse. Neonatal and animal studies are available but have shown significant variability and unpredictability of antibiotic PK during ECMO [32,35,46,50,[66][67][68][69][70][71][72][73][74][75][76][77][78][79] (Table 1). However, no dosing guidelines exist for this group of patients.…”

Section: Antibioticsmentioning

confidence: 44%

Sick patients, starved circuits and sticky drugs: understanding pharmacokinetics during extracorporeal membrane oxygenation to optimise drug dosing and improve patient outcomes

Shekar¹

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Extracorporeal membrane oxygenation (ECMO) is the final option for patients with acute severe cardiac and/or respiratory failure that is unresponsive to conventional management. ECMO plays a supportive role and its success relies on optimal drug therapy to reverse the underlying disease process and to prevent or treat complications.Vital drugs may be sequestered and/or degraded in the ECMO circuit resulting in altered pharmacokinetics (PK). This may be further complicated by the PK changes that occur in the presence of critical illness and may lead to therapeutic failure and/or drug toxicity.However, much of the currently available PK data is from neonates receiving ECMO and may not be extrapolated to adult patients given the developmental and physiologic differences. Equally, such PK alterations are complex and are challenging to investigate in a critically ill patient on ECMO. The aim of this research was to investigate each of the circuit, drug and critical illness factors affecting PK during ECMO in adult patients. A combination of linear and non-linear mixed effects modelling, compartmental and population methods and dosing simulations was utilised to characterise antibiotic, sedative and analgesic PK. The incremental research plan comprised of; (i) ex vivo experiments for drug stability testing in human blood;(ii) ex vivo drug disposition studies in ECMO circuits primed with fresh whole human blood;(iii) PK studies in healthy and critically ill ovine models of ECMO with appropriate non-ECMO controls and;(iv) an international multi-centre clinical population PK study in critically ill adults on ECMO.The introductory chapter (Chapter 1) outlines the origins of this research based on clinical observations, hypothesis generating preliminary data (Chapter 1.1), summarises the available extracorporeal life support therapies (Chapter 1.2) and provides a clinical context to PK alterations induced by ECMO (Chapter 1.3). This is followed by a literature review on PK alterations during ECMO (Chapter 2). Thus, an understanding of the clinical problem, available extracorporeal therapies, and identifying the gaps in literature (Chapter 3) facilitated the development of a comprehensive research plan (Chapter 4.1). Chapter 4.2 describes the methodology for the development of ex vivo and ovine models of ECMO. The protocol for the international multi-centre population PK study that aims to develop dosing guidelines for 18 key antibiotic, sedative and analgesic drugs is presented in Chapter 4.3.Ex vivo studies identified drug stability, lipophilicity (Chapter 5.1) and protein binding (Chapter 5.2) as the key drug factors determining their sequestration and /or degradation in iii ECMO circuits. An increase in peripheral volume of distribution (Vd) of the highly proteinbound, lipophilic drug midazolam was identified in both healthy and critically ill sheep on ECMO (Chapter 6.1) providing further in vivo evidence of circuit drug sequestration. PK of eight antibiotic drugs that exhibited a wide range of lipophilici...

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Non-compartmental Analysis

Cited by 193 publications

References 11 publications

Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db mice as a model of type 2 diabetes

Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db mice as a model of type 2 diabetes

TAS-116, a Highly Selective Inhibitor of Heat Shock Protein 90α and β, Demonstrates Potent Antitumor Activity and Minimal Ocular Toxicity in Preclinical Models

Sick patients, starved circuits and sticky drugs: understanding pharmacokinetics during extracorporeal membrane oxygenation to optimise drug dosing and improve patient outcomes

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