scholarly journals How Does In Vivo Biliary Elimination of Drugs Change with Age? Evidence from In Vitro and Clinical Data Using a Systems Pharmacology Approach

2016 ◽  
Vol 44 (7) ◽  
pp. 1090-1098 ◽  
Author(s):  
T. N. Johnson ◽  
M. Jamei ◽  
K. Rowland-Yeo
Keyword(s):  
Clinical Data ◽  
Systems Pharmacology ◽  
Biliary Elimination

HOW DOES THE IN VIVO BILIARY ELIMINATION OF DRUGS CHANGE WITH AGE? EVIDENCE FROM CLINICAL DATA USING A SYSTEMS PHARMACOLOGY APPROACH

2015 ◽  
Vol 101 (1) ◽  
pp. e1.34-e1
Author(s):  
Trevor Johnson ◽  
Karen Rowland-Yeo ◽  
Masoud Jamei ◽  
Amin Rostami-Hodjegan
Keyword(s):  
Clinical Data ◽  
Biliary Excretion ◽  
Pharmacokinetic Model ◽  
Systems Pharmacology ◽  
Biliary Elimination ◽  
Physiologically Based Pharmacokinetic ◽  
Age Related ◽  
Canalicular Transporters ◽  
Age Range

There is little information on the development of biliary drug elimination (BE) with age. The aims of this study were to collate literature data on the pharmacokinetics of biliary excreted drugs used in paediatrics and to apply a Physiologically Based Pharmacokinetic model to predict their systemic clearance (CLiv) across this age range.Drug parameters for azithromycin, ceftriaxone and digoxin were collated from the literature and validated against adult clinical data in Simcyp (V14R1). The change in CLiv with age was simulated in the paediatric model and compared to the observed data; the ontogeny function associated with BE was optimised in order to recover the age-related CLiv.For azithromycin (79% BE) a fraction of adult biliary excretion activity of 15% had to be assumed to be able to predict accurately the CL of the drug in neonates (24 to 28 weeks GA) whilst 100% activity was apparent by 7 months. For ceftriaxone (51% BE) full biliary excretion activity appeared to be present at full term birth. Finally, for digoxin (25% BE), a fraction of adult biliary excretion activity of 10% had to be assumed to predict the CL of the drug at birth whilst 100% activity was present by The ontogeny of BE for all three drugs appears to be rapid and reach adult levels at birth or in the first few months of postnatal age. More research is required in this area particularly on the ontogeny of specific canalicular transporters in humans.

scholarly journals Bisphosphonates: from preclinical evidence to survival data in the oncologic setting

2011 ◽  
pp. 141-151
Author(s):  
Daniele Santini ◽  
Maria Elisabetta Fratto ◽  
Bruno Vincenzi ◽  
Silvia Angeletti ◽  
Giordano Dicuonzo ◽  
...  
Keyword(s):  
Clinical Data ◽  
Survival Data ◽  
Clinical Evidence ◽  
Bisphosphonate Therapy ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Phase Iii Trial ◽  
Skeletal Disease

Bisphosphonate therapy has become a standard of therapy for patients with malignant bone disease. In vivo pre-clinical data suggest that bisphosphonates may exert an antitumor effect and preliminary clinical data show promising activity on metastatic disease in cancer patients. This review will describe the pre-clinical evidence of action of bisphosphonates on osteoclasts and tumor cells, in both in vitro and animal models. In addition, the effects of principal bisphosphonates on skeletal disease progression in patients with cancers in different sites, including breast cancer, prostate cancer and non-small cell lung cancer will be reported. The preliminary clinical data from retrospective trials on the effect of bisphosphonates on survival will be described and the ongoing adjuvant phase III trial will be analyzed. This review will describe the preliminary clinical evidences from prospective studies on the effect of zoledronic acid treatment on the prevention of bone metastases.

GNG5 is a novel oncogene associated with cell migration, proliferation, and poor prognosis in glioma

2021 ◽  
Author(s):  
Wang Zhang ◽  
Zhendong Liu ◽  
Binchao Liu ◽  
Miaomiao Jiang ◽  
Shi Yan ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Clinical Data ◽  
Poor Prognosis ◽  
Glioma Cells ◽  
Diagnosis And Treatment ◽  
And Migration ◽  
The Relationship ◽  
Proliferation And Migration

Abstract Background: Although many biomarkers have been reported for detecting glioma, the prognosis for the disease remains poor, and therefore, new biomarkers need to be identified. GNG5, which is part of the G-protein family, has been associated with different malignant tumors, though the role of GNG5 in glioma has not been studied. Therefore, we aimed to identify the relationship between GNG5 and glioma prognosis and identify a new biomarker for the diagnosis and treatment of gliomas.Methods: We used data on more than a thousand gliomas from multiple databases and clinical data to determine the expression of GNG5 in glioma. Based on clinical data and CGGA database, we identified the correlation between GNG5 and multiple molecular and clinical features and prognosis using various analytical methods. Co-expression analysis and GSEA were performed to detect GNG5-related genes in glioma and possible signaling pathways involved. ESTIMATE, ssGSEA, and TIMER were used to detect the relationship between GNG5 and the immune microenvironment. Functional experiments were performed to explore the function of GNG5 in glioma cells.Results: GNG5 is highly expressed in gliomas, and its expression level is positively correlated with pathological grade, histological type, age, and tumor recurrence and negatively correlated with isocitrate dehydrogenase mutation, 1p/19 co-deletion, and chemotherapy. Moreover, GNG5 as an independent risk factor was negatively correlated with the overall survival time. GSEA revealed the potential signaling pathways involved in GNG5 function in gliomas, including cell adhesion molecules signaling pathway. The ssGSEA, ESTIMATE, and TIMER based analysis indicated a correlation between GNG5 expression and various immune cells in glioma. In vivo and in vitro experiments showed that GNG5 could participate in glioma cell proliferation and migration.Conclusions: Based on the large data platform and the use of different databases to corroborate results obtained using various datasets, as well as in vitro and in vivo experiments, our study reveals for the first time that GNG5, as an oncogene, is overexpressed in gliomas and can inhibit the proliferation and migration of glioma cells and lead to poor prognosis of patients. Thus, GNG5 is a potential novel biomarker for the clinical diagnosis and treatment of gliomas.

scholarly journals A putative biomarker signature for clinically effective AKT inhibition: correlation of in vitro, in vivo and clinical data identifies the importance of modulation of the mTORC1 pathway

Oncotarget ◽  
2015 ◽  
Vol 6 (39) ◽  
pp. 41736-41749 ◽  
Author(s):  
Azadeh Cheraghchi-Bashi ◽  
Christine A. Parker ◽  
Ed Curry ◽  
Jean-Frederic Salazar ◽  
Hatice Gungor ◽  
...  
Keyword(s):  
Clinical Data ◽  
Mtorc1 Pathway ◽  
Biomarker Signature

scholarly journals Requirements for multi-level systems pharmacology models to reach end-usage: the case of type 2 diabetes

2016 ◽  
Vol 6 (2) ◽  
pp. 20150075 ◽  
Author(s):  
Elin Nyman ◽  
Yvonne J. W. Rozendaal ◽  
Gabriel Helmlinger ◽  
Bengt Hamrén ◽  
Maria C. Kjellsson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Large Scale ◽  
Whole Body ◽  
Current Status ◽  
Systems Pharmacology ◽  
Cellular Origin ◽  
Multi Level

We are currently in the middle of a major shift in biomedical research: unprecedented and rapidly growing amounts of data may be obtained today, from in vitro , in vivo and clinical studies, at molecular, physiological and clinical levels. To make use of these large-scale, multi-level datasets, corresponding multi-level mathematical models are needed, i.e. models that simultaneously capture multiple layers of the biological, physiological and disease-level organization (also referred to as quantitative systems pharmacology—QSP—models). However, today's multi-level models are not yet embedded in end-usage applications, neither in drug research and development nor in the clinic. Given the expectations and claims made historically, this seemingly slow adoption may seem surprising. Therefore, we herein consider a specific example—type 2 diabetes—and critically review the current status and identify key remaining steps for these models to become mainstream in the future. This overview reveals how, today, we may use models to ask scientific questions concerning, e.g., the cellular origin of insulin resistance, and how this translates to the whole-body level and short-term meal responses. However, before these multi-level models can become truly useful, they need to be linked with the capabilities of other important existing models, in order to make them ‘personalized’ (e.g. specific to certain patient phenotypes) and capable of describing long-term disease progression. To be useful in drug development, it is also critical that the developed models and their underlying data and assumptions are easily accessible. For clinical end-usage, in addition, model links to decision-support systems combined with the engagement of other disciplines are needed to create user-friendly and cost-efficient software packages.

scholarly journals In silico identification of natural products from Traditional Chinese Medicine for cancer immunotherapy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chuipu Cai ◽  
Qihui Wu ◽  
Honghai Hong ◽  
Liying He ◽  
Zhihong Liu ◽  
...  
Keyword(s):  
Natural Products ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Cancer Immunotherapy ◽  
Functional Enrichment ◽  
Literature Mining ◽  
Systems Pharmacology ◽  
Scutellaria Baicalensis Georgi

AbstractAdvances in immunotherapy have revolutionized treatments in many types of cancer. Traditional Chinese Medicine (TCM), which has a long history of clinical adjuvant application against cancer, is emerging as an important medical resource for developing innovative cancer treatments, including immunotherapy. In this study, we developed a quantitative and systems pharmacology-based framework to identify TCM-derived natural products for cancer immunotherapy. Specifically, we integrated 381 cancer immune response-related genes and a compound-target interaction network connecting 3273 proteins and 766 natural products from 66 cancer-related herbs based on literature-mining. Via systems pharmacology-based prediction, we uncovered 182 TCM-derived natural products having potential anti-tumor immune responses effect. Importantly, 32 of the 49 most promising natural products (success rate = 65.31%) are validated by multiple evidence, including published experimental data from clinical studies, in vitro and in vivo assays. We further identified the mechanism-of-action of TCM in cancer immunotherapy using network-based functional enrichment analysis. We showcased that three typical natural products (baicalin, wogonin, and oroxylin A) in Huangqin (Scutellaria baicalensis Georgi) potentially overcome resistance of known oncology agents by regulating tumor immunosuppressive microenvironments. In summary, this study offers a novel and effective systems pharmacology infrastructure for potential cancer immunotherapeutic development by exploiting the medical wealth of natural products in TCM.

Noninvasive Dentistry: A Dream or Reality?

2015 ◽  
Vol 49 (Suppl. 1) ◽  
pp. 11-17 ◽  
Author(s):  
B.H. Clarkson ◽  
R.A.M. Exterkate
Keyword(s):  
Clinical Data ◽  
Surface Integrity ◽  
Clinical Studies ◽  
Pathogenic Bacteria ◽  
Caries Prevention

Various caries prevention and repair strategies are reviewed in this article ranging from the use of fluoride to nanohydroxyapatite particles. Several of the strategies which combine fluoride and calcium and phosphate treatments have both in vitro and in vivo data showing them to be efficacious if the surface integrity of the lesion is not breached. Once this has occurred, the rationale for cutting off the nutrient supplies to the pathogenic bacteria without the removal of the infected dentine, a noninvasive restorative technique, is discussed using existing clinical studies as examples. Finally two novel noninvasive restorative techniques using fluorohydroxyapatite crystals are described. The need for clinical data in support of emerging caries-preventive and restorative strategies is emphasized.

scholarly journals Predicting In Vivo Efficacy from In Vitro Data: Quantitative Systems Pharmacology Modeling for an Epigenetic Modifier Drug in Cancer

2020 ◽  
Vol 13 (2) ◽  
pp. 419-429
Author(s):  
Mehdi Bouhaddou ◽  
Li J. Yu ◽  
Serena Lunardi ◽  
Spyros K. Stamatelos ◽  
Fiona Mack ◽  
...  
Keyword(s):  
Systems Pharmacology ◽  
Quantitative Systems Pharmacology ◽  
In Vivo Efficacy ◽  
Epigenetic Modifier ◽  
Vitro Data ◽  
In Vitro Data

scholarly journals Systems Pharmacology-Based Precision Therapy and Drug Combination Discovery for Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3586
Author(s):  
Ze-Jia Cui ◽  
Min Gao ◽  
Yuan Quan ◽  
Bo-Min Lv ◽  
Xin-Yu Tong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Discovery ◽  
High Throughput Sequencing ◽  
High Reliability ◽  
Animal Experiments ◽  
Common Disease ◽  
Biomedical Data ◽  
Systems Pharmacology

Breast cancer (BC) is a common disease and one of the main causes of death in females worldwide. In the omics era, researchers have used various high-throughput sequencing technologies to accumulate massive amounts of biomedical data and reveal an increasing number of disease-related mutations/genes. It is a major challenge to use these data effectively to find drugs that may protect human health. In this study, we combined the GeneRank algorithm and gene dependency network to propose a precision drug discovery strategy that can recommend drugs for individuals and screen existing drugs that could be used to treat different BC subtypes. We used this strategy to screen four BC subtype-specific drug combinations and verified the potential activity of combining gefitinib and irinotecan in triple-negative breast cancer (TNBC) through in vivo and in vitro experiments. The results of cell and animal experiments demonstrated that the combination of gefitinib and irinotecan can significantly inhibit the growth of TNBC tumour cells. The results also demonstrated that this systems pharmacology-based precision drug discovery strategy effectively identified important disease-related genes in individuals and special groups, which supports its efficiency, high reliability, and practical application value in drug discovery.

scholarly journals GNG5 is a novel oncogene associated with cell migration, proliferation, and poor prognosis in glioma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wang Zhang ◽  
Zhendong Liu ◽  
Binchao Liu ◽  
Miaomiao Jiang ◽  
Shi Yan ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Clinical Data ◽  
Poor Prognosis ◽  
Glioma Cells ◽  
Diagnosis And Treatment ◽  
And Migration ◽  
The Relationship ◽  
Proliferation And Migration

Abstract Background Although many biomarkers have been reported for detecting glioma, the prognosis for the disease remains poor, and therefore, new biomarkers need to be identified. GNG5, which is part of the G-protein family, has been associated with different malignant tumors, though the role of GNG5 in glioma has not been studied. Therefore, we aimed to identify the relationship between GNG5 and glioma prognosis and identify a new biomarker for the diagnosis and treatment of gliomas. Methods We used data on more than a thousand gliomas from multiple databases and clinical data to determine the expression of GNG5 in glioma. Based on clinical data and CGGA database, we identified the correlation between GNG5 and multiple molecular and clinical features and prognosis using various analytical methods. Co-expression analysis and GSEA were performed to detect GNG5-related genes in glioma and possible signaling pathways involved. ESTIMATE, ssGSEA, and TIMER were used to detect the relationship between GNG5 and the immune microenvironment. Functional experiments were performed to explore the function of GNG5 in glioma cells. Results GNG5 is highly expressed in gliomas, and its expression level is positively correlated with pathological grade, histological type, age, and tumor recurrence and negatively correlated with isocitrate dehydrogenase mutation, 1p/19 co-deletion, and chemotherapy. Moreover, GNG5 as an independent risk factor was negatively correlated with the overall survival time. GSEA revealed the potential signaling pathways involved in GNG5 function in gliomas, including cell adhesion molecules signaling pathway. The ssGSEA, ESTIMATE, and TIMER based analysis indicated a correlation between GNG5 expression and various immune cells in glioma. In vivo and in vitro experiments showed that GNG5 could participate in glioma cell proliferation and migration. Conclusions Based on the large data platform and the use of different databases to corroborate results obtained using various datasets, as well as in vitro and in vivo experiments, our study reveals for the first time that GNG5, as an oncogene, is overexpressed in gliomas and can inhibit the proliferation and migration of glioma cells and lead to poor prognosis of patients. Thus, GNG5 is a potential novel biomarker for the clinical diagnosis and treatment of gliomas.

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