A SYSTEMS PHARMACOLOGY MODEL TO EXPLAIN DEVELOPMENTAL DIFFERENCES IN SENSITIVITY TO DRUG-INDUCED QT PROLONGATION

2015 ◽  
Vol 101 (1) ◽  
pp. e1.17-e1
Author(s):  
Verena Gotta ◽  
Marc Pfister ◽  
John van den Anker ◽  
Piet van der Graaf
Keyword(s):  
Ion Channel ◽  
Developmental Change ◽  
Qtc Interval ◽  
Receptor Density ◽  
Qtc Prolongation ◽  
Drug Induced ◽  
Channel Density ◽  
Adults And Children

BackgroundNeonates have been reported to be more sensitive to drugs prolonging the QT-interval than adults. As explanation a developmental change in myocardial ion-channel density has been proposed. Here we explore changes in ion-channel density using a mechanistic pharmacodynamic model and clinical sotalol literature data.Materials and MethodsThe applied model relates in vitro and in vivo drug potency (regarding IKr-receptor occupancy and QTc-prolongation, respectively) by a system-specific transducer function. We characterized this function first for preclinical dog and in vitro data (moxifloxacin, sotalol, dofetilide). From a corresponding dofetilide model in adults we derived scaling factors for the system-specific parameters (maximal in vivo QTc-effect Em,dog/Em,adults, transducer ratio τ,dog/τ,adults; τ is proportional to the receptor density in vivo). The derived relationship was used to predict clinical sotalol pharmacodynamics in adults. Literature data was used to evaluate this scaling approach. Simulations of different τ values were performed to explore pharmacodynamic differences in neonates.ResultsIn adults, the agonistic activity of dofetilide was higher than in dogs (τ,adults≈2x τ,dogs), while the estimated maximal in vivo QTc-prolongation was similar (Em≈27% from baseline). This relationship could also predict clinical sotalol pharmacodynamics in adults and children. The steeper PD profile in neonates could be explained by a higher IKr-receptor density (τ, neonates≈2x τ, adults).ConclusionThis model-based approach allowed to integrate and scale in vitro and in vivo (preclinical, clinical adult and neonate) drug effects on the QTc-interval. The preliminary results confirm the hypothesis that IKr-receptor density is higher (≈2 times) in neonates than in adults and children.

scholarly journals Can We Panelize Seizure?

2020 ◽  
Author(s):  
Ruth Roberts ◽  
Simon Authier ◽  
R Daniel Mellon ◽  
Michael Morton ◽  
Ikuro Suzuki ◽  
...  
Keyword(s):  
Ion Channel ◽  
New Drugs ◽  
Detection Methods ◽  
In Vivo Studies ◽  
Design Stage ◽  
Early Screening ◽  
Drug Induced ◽  
Abnormal Movements

Abstract Seizure liability remains a significant cause of attrition in drug discovery and development, leading to loss of competitiveness, delays, and increased costs. Current detection methods rely on observations made in in vivo studies intended to support clinical trials, such as tremors or other abnormal movements. These signs could be missed or misinterpreted; thus, definitive confirmation of drug-induced seizure requires a follow-up electroencephalogram study. There has been progress in in vivo detection of seizure using automated video systems that record and analyze animal movements. Nonetheless, it would be preferable to have earlier prediction of seizurogenic risk that could be used to eliminate liabilities early in discovery while there are options for medicinal chemists making potential new drugs. Attrition due to cardiac adverse events has benefited from routine early screening; could we reduce attrition due to seizure using a similar approach? Specifically, microelectrode arrays could be used to detect potential seizurogenic signals in stem-cell-derived neurons. In addition, there is clear evidence implicating neuronal voltage-gated and ligand-gated ion channels, GPCRs and transporters in seizure. Interactions with surrounding glial cells during states of stress or inflammation can also modulate ion channel function in neurons, adding to the challenge of seizure prediction. It is timely to evaluate the opportunity to develop an in vitro assessment of seizure linked to a panel of ion channel assays that predict seizure, with the aim of influencing structure-activity relationship at the design stage and eliminating compounds predicted to be associated with pro-seizurogenic state.

scholarly journals Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3through CYP3A4 induction in vitro and in vivo: Implications for drug-induced osteomalacia

2013 ◽  
Vol 28 (5) ◽  
pp. 1101-1116 ◽  
Author(s):  
Zhican Wang ◽  
Yvonne S Lin ◽  
Leslie J Dickmann ◽  
Emma-Jane Poulton ◽  
David L Eaton ◽  
...  
Keyword(s):  
Drug Induced ◽  
Cyp3a4 Induction

Imidazolidinyl urea activates mast cells via MRGPRX2 to induce non-histaminergic allergy

2021 ◽  
Author(s):  
Jiapan Gao ◽  
Delu Che ◽  
Xueshan Du ◽  
Yi Zheng ◽  
Huiling Jing ◽  
...  
Keyword(s):  
Contact Dermatitis ◽  
Mast Cells ◽  
Pharmaceutical Products ◽  
Drug Induced ◽  
Inflammatory Infiltration ◽  
Local Inflammatory Response ◽  
Allergic Contact ◽  
G Protein Coupled

Abstract Imidazolidinyl urea (IU) is used as an antimicrobial preservative in cosmetic and pharmaceutical products. IU induces allergic contact dermatitis, however, the mechanism has not yet been elucidated. Mas-related G protein-coupled receptor-X2 (MRGPRX2) triggers drug-induced pseudo-allergic reactions. The aims of this study were to determine whether IU activated mast cells through MRGPRX2 to further trigger contact dermatitis. Wild-type (WT) and KitW-sh/HNihrJaeBsmJNju (MUT) mice were treated with IU to observe its effects on local inflammation and mast cells degranulation in vivo. Laboratory of allergic disease 2 cells were used to detect calcium mobilization and release of inflammatory mediators in vitro. WT mice showed a severe local inflammatory response and contact dermatitis, whereas only slight inflammatory infiltration was observed in MUT mice. Thus, MRGPRX2 mediated the IU-induced activation of mast cells. However, histamine, a typical allergen, was not involved in this process. Tryptase expressed by mast cells was the major non-histaminergic inflammatory mediator of contact dermatitis. IU induced anaphylactic reaction via MRGPRX2 and further triggering non-histaminergic contact dermatitis, which explained why antihistamines are clinically ineffective against some chronic dermatitis.

scholarly journals In Vivo and In Vitro Toxicodynamic Analyses of New Quinolone-and Nonsteroidal Anti-Inflammatory Drug-Induced Effects on the Central Nervous System

1999 ◽  
Vol 43 (5) ◽  
pp. 1091-1097 ◽  
Author(s):  
Hideki Kita ◽  
Hirotami Matsuo ◽  
Hitomi Takanaga ◽  
Junichi Kawakami ◽  
Koujirou Yamamoto ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Threshold Concentration ◽  
Current Response ◽  
Drug Induced ◽  
Inhibition Ratio ◽  
New Quinolones ◽  
The Central Nervous System ◽  
Anti Inflammatory

ABSTRACT We investigated the correlation between an in vivo isobologram based on the concentrations of new quinolones (NQs) in brain tissue and the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) for the occurrence of convulsions in mice and an in vitro isobologram based on the concentrations of both drugs for changes in the γ-aminobutyric acid (GABA)-induced current response in Xenopus oocytes injected with mRNA from mouse brains in the presence of NQs and/or NSAIDs. After the administration of enoxacin (ENX) in the presence or absence of felbinac (FLB), ketoprofen (KTP), or flurbiprofen (FRP), a synergistic effect was observed in the isobologram based on the threshold concentration in brain tissue between mice with convulsions and those without convulsions. The three NSAIDs did not affect the pharmacokinetic behavior of ENX in the brain. However, the ENX-induced inhibition of the GABA response in the GABAA receptor expressed in Xenopus oocytes was enhanced in the presence of the three NSAIDs. The inhibition ratio profiles of the GABA responses for both drugs were analyzed with a newly developed toxicodynamic model. The inhibitory profiles for ENX in the presence of NSAIDs followed the order KTP (1.2 μM) > FRP (0.3 μM) > FLB (0.2 μM). These were 50- to 280-fold smaller than those observed in the absence of NSAIDs. The inhibition ratio (0.01 to 0.02) of the GABAA receptor in the presence of both drugs was well-fitted to the isobologram based on threshold concentrations of both drugs in brain tissue between mice with convulsions and those without convulsions, despite the presence of NSAIDs. In mice with convulsions, the inhibitory profiles of the threshold concentrations of both drugs in brain tissue of mice with convulsions and those without convulsions can be predicted quantitatively by using in vitro GABA response data and toxicodynamic model.

Drug-induced liver injury classification model based on in vitro human transcriptomics and in vivo rat clinical chemistry data

2014 ◽  
Vol 2 (4) ◽  
pp. 63-70 ◽  
Author(s):  
Danyel Jennen ◽  
Jan Polman ◽  
Mark Bessem ◽  
Maarten Coonen ◽  
Joost van Delft ◽  
...  
Keyword(s):  
Liver Injury ◽  
Clinical Chemistry ◽  
Classification Model ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Chemistry Data ◽  
Model Based ◽  
Injury Classification

scholarly journals A Tissue-Engineered Tracheobronchial In Vitro Co-Culture Model for Determining Epithelial Toxicological and Inflammatory Responses

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 631
Author(s):  
Luis Soriano ◽  
Tehreem Khalid ◽  
Fergal J. O'Brien ◽  
Cian O'Leary ◽  
Sally-Ann Cryan
Keyword(s):  
Epithelial Cells ◽  
Inflammatory Responses ◽  
Bronchial Epithelial Cells ◽  
Lung Fibroblasts ◽  
Drug Induced ◽  
Bronchial Epithelial ◽  
Culture Model ◽  
Epithelial Cultures

Translation of novel inhalable therapies for respiratory diseases is hampered due to the lack of in vitro cell models that reflect the complexity of native tissue, resulting in many novel drugs and formulations failing to progress beyond preclinical assessments. The development of physiologically-representative tracheobronchial tissue analogues has the potential to improve the translation of new treatments by more accurately reflecting in vivo respiratory pharmacological and toxicological responses. Herein, advanced tissue-engineered collagen hyaluronic acid bilayered scaffolds (CHyA-B) previously developed within our group were used to evaluate bacterial and drug-induced toxicity and inflammation for the first time. Calu-3 bronchial epithelial cells and Wi38 lung fibroblasts were grown on either CHyA-B scaffolds (3D) or Transwell® inserts (2D) under air liquid interface (ALI) conditions. Toxicological and inflammatory responses from epithelial monocultures and co-cultures grown in 2D or 3D were compared, using lipopolysaccharide (LPS) and bleomycin challenges to induce bacterial and drug responses in vitro. The 3D in vitro model exhibited significant epithelial barrier formation that was maintained upon introduction of co-culture conditions. Barrier integrity showed differential recovery in CHyA-B and Transwell® epithelial cultures. Basolateral secretion of pro-inflammatory cytokines to bacterial challenge was found to be higher from cells grown in 3D compared to 2D. In addition, higher cytotoxicity and increased basolateral levels of cytokines were detected when epithelial cultures grown in 3D were challenged with bleomycin. CHyA-B scaffolds support the growth and differentiation of bronchial epithelial cells in a 3D co-culture model with different transepithelial resistance in comparison to the same co-cultures grown on Transwell® inserts. Epithelial cultures in an extracellular matrix like environment show distinct responses in cytokine release and metabolic activity compared to 2D polarised models, which better mimic in vivo response to toxic and inflammatory stimuli offering an innovative in vitro platform for respiratory drug development.

Translating the gap in the evaluation of drug-induced QTc-interval prolongation from in vivo to the clinic

2014 ◽  
Vol 70 (3) ◽  
pp. 324
Author(s):  
Vincent F.S. Dubois ◽  
Piet van der Graaf ◽  
Derek Leishman ◽  
David Gallacher ◽  
Nick McMahon ◽  
...  
Keyword(s):  
Qtc Interval ◽  
Interval Prolongation ◽  
Drug Induced ◽  
Qtc Interval Prolongation

scholarly journals Remodeling tumor microenvironment by liposomal co-delivery of DMXAA and simvastatin inhibits malignant melanoma progression

2021 ◽  
Author(s):  
Valentin Florian Rauca ◽  
Laura Patras ◽  
Lavinia Luput ◽  
Emilia Licarete ◽  
Vlad Alexandru Toma ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Hypoxia Inducible Factor ◽  
Tumor Development ◽  
Novel Therapy ◽  
Drug Induced ◽  
Angiogenic Therapy ◽  
Melanoma Model ◽  
M1 Phenotype

Anti-angiogenic therapies for melanoma have not yet been translated into meaningful clinical benefit for patients, due to development of drug-induced resistance in cancer cells, mainly caused by hypoxia-inducible factor 1α (HIF-1α) overexpression and enhanced oxidative stress mediated by tumor-associated macrophages (TAMs). Our previous study demonstrated synergistic antitumor actions of simvastatin (SIM) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on an in vitro melanoma model via suppression of the aggressive phenotype of melanoma cells and inhibition of TAMs-mediated angiogenesis. Therefore, we took the advantage of long circulating liposomes (LCL) superior tumor targeting capacity to efficiently deliver SIM and DMXAA to B16.F10 melanoma in vivo, with the final aim of improving the outcome of the anti-angiogenic therapy. Thus, we assessed the effects of this novel combined tumor-targeted treatment on s.c. B16.F10 murine melanoma growth and on the production of critical markers involved in tumor development and progression. Our results showed that the combined liposomal therapy inhibited almost totally the growth of melanoma tumors, due to the enhancement of anti-angiogenic effects of LCL-DMXAA by LCL-SIM and induction of a pro-apoptotic state in the tumor microenvironment (TME). These effects were favoured by the partial re-education of TAMs towards a M1 phenotype and maintained via suppression of major invasion and metastasis promoters (HIF-1α, pAP-1 c-Jun, and MMPs). Thus, this novel therapy holds the potential to remodel the tumor microenvironment, by suppressing its most important malignant biological capabilities.

scholarly journals IN VITRO AND IN VIVO EVALUATION OF 2-CHLOROE THYLN ITROSOUREA DERIVATIVES AS ANTITUMOR AGENTS

2015 ◽  
Vol 37 (1) ◽  
pp. 23-29
Author(s):  
A Sen ◽  
K K Goswami ◽  
A Mallick ◽  
A K Saxena ◽  
U Sanyal ◽  
...  
Keyword(s):  
T Cells ◽  
Antitumor Agents ◽  
Malignant Tumors ◽  
Optimum Dose ◽  
Mouse Tumor ◽  
Drug Induced ◽  
In Vivo Evaluation ◽  
Liver And Kidney

Aim: To evaluate potential of Naphthal-NU, Napro-NU and 5-Nitro-naphthal-NU, 2-chloroethylnitrosourea compounds with substituted naphthalimide in the pre-clinical studies. Materials and Methods: In vitro cytotoxicity of three nitrosoureas was determined in human and mouse tumor cell lines by MTT assays. In vivo anti-tumor potential was evaluated in Sarcoma-180 (S-180) and Ehrlich’s carcinoma (EC) solid tumors. Apoptosis in S-180 cells was analyzed by using Annexin V-Propidium Iodide (PI). Histological analysis of liver and kidney was performed at optimum dose (50 mg/kg). Expression status of CD4+, CD8+ and CD25+ cells in treated mouse were also examined. Results: Significant tumor growth retardation by the compounds was noted in early and advanced disease groups, as the life span of drug treated mice increased considerably. Drug induced killing was observed by induction of apoptosis. Naphthal-NU and 5-Nitro-naphthal-NU were effective to normalize the tumor induced structural abnormalities of liver and kidney. The compounds have no immunotoxic effect on CD4+ and CD8+ T cells and down regulate CD4+CD25+ regulatory T cells. Conclusion: Overall data holds promise for the antitumor activity with lower toxicity of the compounds that can be utilized for the treatment of human malignant tumors.

scholarly journals in vitro and in vivo investigation of modulators of hyperactivated ion channel induced necrosis in C. elegans

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Shaunak Kamat ◽  
Laura Bianchi ◽  
Shrutika Yeola ◽  
Monica Driscoll
Keyword(s):  
Ion Channel ◽  
C Elegans
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