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  1. Article ; Online: Exposure-Response Modeling and Simulation of Progression-Free Survival and Adverse Events of Sorafenib Treatment in Patients With Advanced Thyroid Cancer.

    Grevel, Joachim / Jentsch, Garrit / Austin, Rupert / Prins, Nicolaas H / Lettieri, John / Mitchell, David / Huang, Funan / Brose, Marcia S / Schlumberger, Martin / Meinhardt, Gerold / Peña, Carol E A / Ploeger, Bart A

    Clinical and translational science

    2019  Volume 12, Issue 5, Page(s) 459–469

    Abstract: Sorafenib is an oral multikinase inhibitor approved for the treatment of differentiated thyroid carcinoma (DTC), renal cell carcinoma, and hepatocellular carcinoma. In the phase III DECISION trial in patients with DTC, sorafenib exposure and the ... ...

    Abstract Sorafenib is an oral multikinase inhibitor approved for the treatment of differentiated thyroid carcinoma (DTC), renal cell carcinoma, and hepatocellular carcinoma. In the phase III DECISION trial in patients with DTC, sorafenib exposure and the incidence of some adverse events (AEs) were higher than in previous trials; therefore, we analyzed exposure-response relationships, including progression-free survival (PFS) and selected AEs in patients with DTC. A novel, stratified prediction-corrected visual predictive check (pc-VPC) was developed to show robustness of the exposure-response relationships. Time-to-event simulations confirmed the benefit of the recommended dosing schedule of 800 mg/day: initial doses of 800 mg/day were associated with the highest PFS, whereas lower doses (600 or 400 mg/day) were associated with improved tolerability but reduced PFS. A simulated dose-reduction strategy of 800 mg/day for an initial two cycles followed by dose reductions seemed likely to maintain efficacy while possibly mitigating selected AEs (e.g., diarrhea and hand-foot skin reactions).
    MeSH term(s) Cell Differentiation ; Disease Progression ; Female ; Humans ; Kaplan-Meier Estimate ; Male ; Models, Biological ; Neoplasm Staging ; Progression-Free Survival ; Sorafenib/adverse effects ; Sorafenib/pharmacokinetics ; Sorafenib/therapeutic use ; Thyroid Neoplasms/drug therapy ; Thyroid Neoplasms/pathology
    Chemical Substances Sorafenib (9ZOQ3TZI87)
    Language English
    Publishing date 2019-04-12
    Publishing country United States
    Document type Clinical Trial, Phase III ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 2433157-0
    ISSN 1752-8062 ; 1752-8054
    ISSN (online) 1752-8062
    ISSN 1752-8054
    DOI 10.1111/cts.12634
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Population pharmacokinetics of oxaliplatin (85 mg/m2) in combination with 5-fluorouracil in patients with advanced colorectal cancer.

    Kho, Yuhan / Jansman, Frank G A / Prins, Nicolaas H / Neef, Cees / Brouwers, Jacobus R B J

    Therapeutic drug monitoring

    2006  Volume 28, Issue 2, Page(s) 206–211

    Abstract: Pharmacokinetic (PK) studies of oxaliplatin, using a dose regimen of 85 mg/m, are lacking. A PK model may be used in future studies to investigate the relationship between pharmacokinetics and dose limiting toxicity. The purpose of this study was to ... ...

    Abstract Pharmacokinetic (PK) studies of oxaliplatin, using a dose regimen of 85 mg/m, are lacking. A PK model may be used in future studies to investigate the relationship between pharmacokinetics and dose limiting toxicity. The purpose of this study was to construct a population PK model to describe platinum (Pt) concentrations in plasma in 33 patients with colorectal cancer. The secondary objective was to determine the relationship between the amount of Pt in 24-hour urine and the amount of Pt in fractionated urine collection periods. Plasma and urine samples were collected from patients during their first oxaliplatin treatment course. Population PK analysis was performed with WinNonMix. The model that best described the Pt concentrations in plasma was a two-compartment PK model. The elimination clearance (CL) and the elimination clearance of the peripheral compartment (CL2) (median +/- SE) were 25.2 +/- 6.3 L/hr and 68 +/- 24.8 L/hr, respectively. The median volume of distribution (V1) was determined to be 41.6 +/- 9.4 L and the median volume of distribution of the peripheral compartment (V2) was 452.5 +/- 96.4 L. The relationship between the cumulative amount of Pt in urine in the first 12 hours compared with the amount of Pt in 24 hours urine was reflected by a correlation coefficient (r2) of 0.95. The cumulative Pt concentration in urine in the first 10 hours and the first 8 hours compared with 24 hours was reflected by correlation coefficients r2 = 0.93 and r2 = 0.897, respectively. This PK model could be useful in identifying predictors for PK and pharmacodynamic variability to individualize dosing. The results of this study suggest that fractionated urine samples can replace 24-hour urine collection.
    MeSH term(s) Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Colorectal Neoplasms/blood ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/urine ; Creatinine/blood ; Creatinine/urine ; Drug Administration Schedule ; Female ; Fluorouracil/administration & dosage ; Humans ; Infusions, Intravenous ; Leucovorin/administration & dosage ; Male ; Metabolic Clearance Rate ; Middle Aged ; Organoplatinum Compounds/administration & dosage ; Organoplatinum Compounds/pharmacokinetics ; Time Factors ; Vitamin B Complex/administration & dosage
    Chemical Substances Organoplatinum Compounds ; oxaliplatin (04ZR38536J) ; Vitamin B Complex (12001-76-2) ; Creatinine (AYI8EX34EU) ; Leucovorin (Q573I9DVLP) ; Fluorouracil (U3P01618RT)
    Language English
    Publishing date 2006-04
    Publishing country United States
    Document type Clinical Trial ; Journal Article
    ZDB-ID 424443-6
    ISSN 1536-3694 ; 0163-4356
    ISSN (online) 1536-3694
    ISSN 0163-4356
    DOI 10.1097/01.ftd.0000191305.64775.04
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1503: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
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  3. Article: Differential effects of 5-hydroxytryptamine4 receptor agonists at gastric versus cardiac receptors: an operational framework to explain and quantify organ-specific behavior.

    De Maeyer, Joris H / Prins, Nicolaas H / Schuurkes, Jan A J / Lefebvre, Romain A

    The Journal of pharmacology and experimental therapeutics

    2006  Volume 317, Issue 3, Page(s) 955–964

    Abstract: Quantification of different levels of 5-hydroxytryptamine4 (5-HT4) receptor agonism expression across animal species as well as across organs within the same animal species offers substantial potential for the separation of desired gastrointestinal ... ...

    Abstract Quantification of different levels of 5-hydroxytryptamine4 (5-HT4) receptor agonism expression across animal species as well as across organs within the same animal species offers substantial potential for the separation of desired gastrointestinal versus undesired cardiac pharmacological activity of compounds in development. Since a detailed investigation of such properties is lacking to date, we set out to quantify gastric and cardiac effects of 5-HT4 receptor ligands in the pig, a model considered to be representative for the human situation. An in vitro test was developed to study the potentiating effect of 5-HT, prucalopride, tegaserod, R149402 (4-amino-5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid [3-hydroxy-1-(3-methoxy-propyl)-piperidin-4ylmethyl]-amide), and R199715 (4-amino-5-chloro-2,3-dihydro-benzofuran-7-carboxylic acid [3-hydroxy-1-(3-methoxy-propyl)-piperidin-4ylmethyl]-amide) on electrically induced cholinergic contractions in longitudinal muscle strips of the proximal stomach. The results were compared with inotropic and chronotropic effects of these compounds in the electrically paced left atrium and spontaneously beating right atrium, respectively. To quantify the observed tissue-dependent responses, a nonlinear mixed-effects model based on the operational model of agonism was developed and successfully fitted to the data. The model quantified the tissue-dependent partial agonism of the selective 5-HT4 receptor agonists prucalopride, R149402, and R199715, whereas tegaserod and 5-HT were equiefficacious. The model was further extended to incorporate the responses to prucalopride in the presence of the 5-HT4 receptor antagonist GR113808 ([1-[2-[(methylsulphonyl)amino]ethyl]-4-piperidinyl-]methyl 1-methyl-1H-indole-3-carboxylate). The results indicate that these interactions do not follow a simple competitive pattern and that they differ between stomach and left atrium.
    MeSH term(s) Animals ; Heart Atria/drug effects ; Heart Atria/metabolism ; In Vitro Techniques ; Models, Biological ; Muscle Contraction/drug effects ; Muscle, Smooth/drug effects ; Muscle, Smooth/metabolism ; Myocardial Contraction/drug effects ; Myocardium/metabolism ; Organ Specificity ; Serotonin 5-HT4 Receptor Agonists ; Serotonin Antagonists/pharmacology ; Serotonin Receptor Agonists/pharmacology ; Stomach/drug effects ; Stomach/metabolism ; Swine
    Chemical Substances Serotonin 5-HT4 Receptor Agonists ; Serotonin Antagonists ; Serotonin Receptor Agonists
    Language English
    Publishing date 2006-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3106-9
    ISSN 1521-0103 ; 0022-3565
    ISSN (online) 1521-0103
    ISSN 0022-3565
    DOI 10.1124/jpet.106.101329
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uf I Zs.40: Show issues Location:
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  4. Article: Characterization of 5-HT7-receptor-mediated gastric relaxation in conscious dogs.

    Janssen, Pieter / Prins, Nicolaas H / Moreaux, Benoit / Meulemans, Ann L / Lefebvre, Romain A

    American journal of physiology. Gastrointestinal and liver physiology

    2005  Volume 289, Issue 1, Page(s) G108–15

    Abstract: We aimed to evaluate the gastric relaxant capacity of the 5-HT(1/7)-receptor agonist 5-carboxamidotryptamine (5-CT) in conscious dogs and to clarify the mechanism of action by use of selective antagonists, vagotomy, and in vitro experiments. A barostat ... ...

    Abstract We aimed to evaluate the gastric relaxant capacity of the 5-HT(1/7)-receptor agonist 5-carboxamidotryptamine (5-CT) in conscious dogs and to clarify the mechanism of action by use of selective antagonists, vagotomy, and in vitro experiments. A barostat enabled us to monitor the intragastric volume in response to different treatments (intravenously administered) before and after supradiaphragmatic vagotomy [results presented as the maximum volume change after treatment (mean; n = 5-11)]. In vitro experiments were performed with isolated muscle strips cut from four different stomach regions of the vagotomized dogs [results were fitted to the operational model of agonism to determine the efficacy parameter tau (n = 5)]. 5-CT (0.5-10 microg/kg) caused a dose-dependent gastric relaxation (29-267 ml) that was completely blocked by the selective 5-HT(7)-receptor antagonist SB-269970 (50 microg/kg). After vagotomy, the relaxation to 10 microg/kg 5-CT was significantly less pronounced (73 vs. 267 ml; P < 0.05) but still blocked by SB-269970, whereas the response to the nitric oxide donor nitroprusside was similar to that before vagotomy (178 vs. 218 ml). In vitro, 5-CT concentration dependently inhibited the PGF(2alpha)-contracted muscle strips before and after vagotomy. Although before and after vagotomy the response in every region was mediated by 5-HT(7) receptors (apparent affinity dissociation constant: SB-269970, 8.2-8.6 vs. 8.3-8.6, respectively), the response after vagotomy was less efficacious (log tau: 1.9 to 0.5 vs. 1.4 to -0.1). The results indicate that the 5-CT-induced proximal stomach relaxation in conscious dogs before and after vagotomy is mediated via 5-HT(7) receptors. The decreased efficacy of 5-CT in vitro after vagotomy is probably related to vagotomy-induced changes in receptor density or coupling efficiency and provides a possible explanation for the decreased in vivo response to 5-CT after vagotomy.
    MeSH term(s) Animals ; Consciousness ; Dogs ; Female ; In Vitro Techniques ; Models, Biological ; Muscle Relaxation/drug effects ; Muscle Relaxation/physiology ; Muscle, Smooth/innervation ; Muscle, Smooth/physiology ; Phenols/pharmacology ; Receptors, Serotonin/physiology ; Serotonin/analogs & derivatives ; Serotonin/pharmacology ; Serotonin Antagonists/pharmacology ; Serotonin Receptor Agonists/pharmacology ; Stomach/innervation ; Stomach/physiology ; Sulfonamides/pharmacology ; Vagotomy
    Chemical Substances Phenols ; Receptors, Serotonin ; SB 269970 ; Serotonin Antagonists ; Serotonin Receptor Agonists ; Sulfonamides ; serotonin 7 receptor ; Serotonin (333DO1RDJY) ; 5-carboxamidotryptamine (91H76044O0)
    Language English
    Publishing date 2005-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 603840-2
    ISSN 1522-1547 ; 0193-1857
    ISSN (online) 1522-1547
    ISSN 0193-1857
    DOI 10.1152/ajpgi.00012.2005
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    Uc I Zs.89: Show issues Location:
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  5. Article: 5-HT7 receptor efficacy distribution throughout the canine stomach.

    Janssen, Pieter / Prins, Nicolaas H / Peeters, Pieter J / Zuideveld, Klaas P / Lefebvre, Romain A

    British journal of pharmacology

    2004  Volume 143, Issue 3, Page(s) 331–342

    Abstract: This study aimed to determine, quantify and explain regional differences in the relaxant response to the selective 5-HT(1) and 5-HT(7) receptor agonist 5-carboxamidotryptamine (5-CT) throughout the canine stomach. Longitudinal muscle strips from eight ... ...

    Abstract This study aimed to determine, quantify and explain regional differences in the relaxant response to the selective 5-HT(1) and 5-HT(7) receptor agonist 5-carboxamidotryptamine (5-CT) throughout the canine stomach. Longitudinal muscle strips from eight gastric corpus regions and six antrum regions were mounted for isotonic measurement. The 5-CT-induced relaxation was examined on a prostaglandin F(2alpha)-induced submaximal response, expressed as percentage of this response and fitted to the operational model of agonism (OMOA). 5-HT(7) receptor messenger RNA (mRNA) expression was compared by means of quantitative PCR. 5-CT inhibited PGF(2alpha)-induced tonic contraction (corpus) and increase of phasic contraction amplitude (antrum). The consistent antagonism produced by the selective 5-HT(7) receptor antagonist SB-269970 (10 nm, pA(2) estimates 8.2-8.9) confirmed that in every region, the inhibition by 5-CT was 5-HT(7) receptor mediated. However, variation in the maximum effect (61-108%) and pEC(50) (6.4-8.6) was observed throughout the different regions. The OMOA explained these differences as differences in the efficacy parameter tau (ratio of receptor density and coupling efficiency; log tau estimates ranging from 0.1 to 2.1). The log tau gradient decreases going from the lesser to the greater curvature. A proportional difference (68%) in the relative expression of 5-HT(7) receptor mRNA between the lesser and the greater curvature indicates that differences in receptor density contribute to the observed functional differences. This study illustrates that 5-HT(7) receptors are present throughout the ventral wall of the canine stomach, but the efficacy (expressed as log tau) is clearly greater close to the lesser curvature. Differences in 5-HT(7) receptor expression at least partially explain the functional differences.
    MeSH term(s) Alternative Splicing ; Animals ; Dinoprost/pharmacology ; Dogs ; Dose-Response Relationship, Drug ; Female ; Gene Expression ; In Vitro Techniques ; Male ; Molecular Sequence Data ; Muscle Contraction/drug effects ; Muscle Relaxation/drug effects ; Nitroprusside/pharmacology ; Phenols/pharmacology ; Protein Isoforms/genetics ; Protein Isoforms/physiology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Receptors, Serotonin/genetics ; Receptors, Serotonin/physiology ; Reverse Transcriptase Polymerase Chain Reaction ; Serotonin/analogs & derivatives ; Serotonin/pharmacology ; Serotonin Antagonists/pharmacology ; Serotonin Receptor Agonists/pharmacology ; Stomach/drug effects ; Stomach/metabolism ; Stomach/physiology ; Sulfonamides/pharmacology ; Tetrodotoxin/pharmacology
    Chemical Substances Phenols ; Protein Isoforms ; RNA, Messenger ; Receptors, Serotonin ; SB 269970 ; Serotonin Antagonists ; Serotonin Receptor Agonists ; Sulfonamides ; serotonin 7 receptor ; Nitroprusside (169D1260KM) ; Serotonin (333DO1RDJY) ; Tetrodotoxin (4368-28-9) ; 5-carboxamidotryptamine (91H76044O0) ; Dinoprost (B7IN85G1HY)
    Language English
    Publishing date 2004-10
    Publishing country England
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80081-8
    ISSN 1476-5381 ; 0007-1188
    ISSN (online) 1476-5381
    ISSN 0007-1188
    DOI 10.1038/sj.bjp.0705922
    Database MEDical Literature Analysis and Retrieval System OnLINE

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