Decoding Ca2+ Signals as a Non-electrophysiological Method for Assessing Drug Toxicity in Stem Cell-Derived Cardiomyocytes

2016 ◽  
pp. 173-190 ◽  
Author(s):  
Christopher H. George ◽  
David H. Edwards
Keyword(s):  
Stem Cell ◽  
Drug Toxicity ◽  
Electrophysiological Method

scholarly journals Combining stem cell-derived hepatocytes with impedance sensing to better predict human drug toxicity

2018 ◽  
Vol 15 (1) ◽  
pp. 77-83 ◽  
Author(s):  
Wenli Zhou ◽  
Karen Graham ◽  
Baltasar Lucendo-Villarin ◽  
Oliver Flint ◽  
David C. Hay ◽  
...  
Keyword(s):  
Stem Cell ◽  
Drug Toxicity ◽  
Impedance Sensing

Application of human pluripotent stem cells and pluripotent stem cell-derived cellular models for assessing drug toxicity

2018 ◽  
Vol 15 (1) ◽  
pp. 61-75 ◽  
Author(s):  
Ágota Apáti ◽  
Nóra Varga ◽  
Tünde Berecz ◽  
Zsuzsa Erdei ◽  
László Homolya ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Pluripotent Stem Cells ◽  
Drug Toxicity ◽  
Pluripotent Stem Cell ◽  
Human Pluripotent Stem Cells ◽  
Cellular Models

scholarly journals Skin Immune Stimulation By Infections and Drug Toxicities during Induction and/or Consolidations Increases Incidence of Skin Acute Graft Versus Host Disease in Acute Myeloid Leukemia: A Study on Behalf of SFGM-TC and ALFA

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1946-1946
Author(s):  
Lining Wang ◽  
Emmanuel Raffoux ◽  
Xavier Thomas ◽  
Ibrahim Yakoub-Agha ◽  
Jean Henri Bouhris ◽  
...  
Keyword(s):  
Stem Cell ◽  
Clinical Data ◽  
Graft Versus Host Disease ◽  
Drug Toxicity ◽  
Research Funding ◽  
International Congress ◽  
Immune Stimulation ◽  
Continuous Variables ◽  
Host Disease ◽  
Graft Versus Host

Abstract Introduction: 60-70% of AML patients have an indication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) during their treatment. Among those who undergo allo-HSCT, prognosis and quality of life depended on presence or absence of graft versus host disease (GvHD). Immune stimulation supports the principle of GvHD and graft versus leukemia (GvL) after allo-HSCT. The impact of immune activation prior to allo-HSCT on the pathogenesis of GvHD has never been evaluated. The aim of this study was to determine whether immune stimulation induced by infection or drug toxicity before transplantation increased the incidence of acute GvHD (aGvHD) in AML patients. Materials and methods: 345 AML patients were transplanted in first complete remission (CR) in 21 French centers from 2009 to 2013 after prospectively enrollment in the ALFA-0702 trial (patients aged 18-60y, de novo AML, favorable-risk AML excluded). Clinical data (skin, gut and liver infections or drug toxicities) before allo-HSCT were collected from the ALFA database and clinical data (skin, gut and liver aGvHD) after allo-HSCT were collected from the SFGM-TC database (ProMise). GvHD grading was defined according to Glucksberg criteria. Infection and drug toxicity grading was defined according to CTCAE v4.0. Mann-Withney and Kruskall-Wallis tests were used for continuous variables. Chi-square test was used for non-continuous variables. Overall survival (OS) and progression free survival (PFS) were assessed by Kaplan Meier method. Results: Median age at transplant and M/F sex ratio were 45 years (range, 19-61) and 195/150, respectively. Cytogenetics was intermediate-1, intermediate-2 and unfavorable in 24, 164, 144 patients according to ELN classification, respectively. 82.5% of the patients had reached CR after one cycle of induction. 193 (53%) patients presented infections during induction and 46 (17%) during consolidations. Moreover, 110 (30%) patients suffered from drug toxicity during induction and 36 (10%) during consolidations. Allo-HSCT was performed in all patients after one to three cycles of consolidation. 132 (36%) patients received reduced intensity conditioning. Sex matching was female in male for 74 (21%) patients. ABO matching was matched for 187 and mismatched for 158 patients. HLA matching was related for 138 and unrelated for 198 patients. Source of graft was bone marrow, peripheral stem cell and cord blood in 108, 217 and 12 patients, respectively. 181 (47%) patients underwent aGvHD, most frequently skin aGvHD (stage 1-2: 27.5%; stage 3-4: 9.5%). First, we observed a significant increase of incidence of aGvHD (all grades) if skin toxicities occurred during induction (45/57% for no toxicity and toxicities all grades, respectively p=0.07) or consolidations (46/70% for no toxicity and toxicities all grades, respectively p=0.04). Secondly, we observed a significant increase of skin aGvHD in cases of skin toxicities during induction [stage 0/1-2/3-4 skin aGvHD: 66/27/7% and 47/32/21% for no toxicity and toxicities all grades, respectively (p=0.001)] or consolidations [stage 0/1-2/3-4 skin aGvHD: 64/28/8% and 35/35/30% for no toxicity and toxicities all grades, respectively (p<0.003)]. Thirdly, we observed a correlation between infections and skin aGvHD during consolidations [stage 0/1-2/3-4 skin aGVHD: 64/28/8% vs 49/27/24% for no infection and infections, respectively (p=0.002)], and more particularly between skin infections and skin aGVHD [stage 0/1-2/3-4 skin aGVHD: 63/29/8% vs 44/23/33% for no infection and infections, respectively (p=0.003)]. No correlation was found between others types of infections or toxicities and aGvHD. Finally, we observed no impact of infections and/or toxicities on OS and PFS. Conclusion: Skin immune stimulation induced either by infections during consolidations or by drug toxicity during induction and/or consolidations significantly increased the incidence of skin aGvHD. Nevertheless, we found no impact on OS and PFS in our cohort. Our results confirm the participation of inflammatory process in the physiopathology of GvHD. These data should be confirmed in a larger study to determine whether patients with prior infection and/or drug toxicity to allo-HSCT should receive different GvHD prophylaxis strategies. Disclosures Deconinck: PFIZER: Research Funding; ALEXION: Other: Travel for international congress; JANSSEN: Other: Travel for international congress; NOVARTIS: Other: Travel for international congress; LFB loboratory: Consultancy; ROCHE: Research Funding; CHUGAI: Other: Travel for international congress.

Life-Threatening Complications Suspected Due to Clinical Pharmacokinetic Interaction Between Cyclosporine A and Triazole Antifungal Agents in Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) Recipients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4319-4319
Author(s):  
Ting Yang ◽  
Danhui Fu ◽  
Jianda Hu ◽  
Xiaoyun Zheng ◽  
Xiaofeng Luo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Transplantation ◽  
Drug Toxicity ◽  
Drug Exposure ◽  
Antifungal Agents ◽  
Hematopoietic Stem ◽  
Life Threatening ◽  
Trough Levels ◽  
Trough Plasma ◽  
Acute Graft

Abstract Abstract 4319 Background It is well documented that the co-medication with the triazole antifungal agents is associated with a flattening of the CSA blood concentration profile via the cytochrome P450 3A4 dependent metabolic pathway in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Then it raises the question if the therapeutic monitoring of CsA trough levels is sufficient enough to reflect the drug exposure and to assess the transplant-related complications such as transplant rejection and drug toxicity. Objectives To evaluate the tolerability, toxicity and clinical outcome of the co-administration of CSA and triazole antifungal agents in allo-HSCT recipients. Patients and methods A retrospective review of the medical records of 104 consecutive patients undergoing allo-HSCT for hematologic malignancies at our transplant center over past 5 years was conducted. The causality of administration of CSA in combination with triazole in 12 cases with life-threatening complications experiencing supratherapeutic trough levels of CSA were identified and analyzed. Results In all these 12 patients, the CSA trough levels remained highly than therapeutic range even after gradual tapering of CSA dosage. Shortly after the engraftment, 6 patients (50 %) developed acute graft-versus-host disease (aGVHD) and non-infectious pulmonary complication, and 2 patient (16.66 %) acute graft rejection. Which indicates the trough plasma concentration might be inadequately reflect CSA absorption profile. Whereas, 4 (33.33 %) patients were evaluated with neurological complications, 1 (8.33%) patient cardiovascular complication accompanied by acute renal failure and liver dysfunction, that might be ascribed to CSA-related adverse effects. 10 (83.33 %) out of the 12 patients eventually died, 2 (16.66 %) patient are still alive after graft rejecting. The major causes of death were GVHD related pulmonary injury with fungi infection Conclusion Although preemptive CSA dosage reduction and the close monitoring of its whole blood trough levels may minimize the drug-toxicity when co-administration with triazole antifungal agents, the different clinical spectrum and different disease evolution post transplant in this group warn that in the set of hematopoietic cell transplantation with CSA as immunosuppression agent the individual variables influence the drug-exposure and drug-toxicity. Thereof, as clinicians we should not be mislead by trough plasma concentrations as a routine therapeutic drug monitoring in terms of CSA exposure related efficacy or toxicity, especially when CSA in combination with triazole. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The use of Jelonet dressings in the treatment of drug toxicity in autologous stem cell transplantation in children. Clinical case presentation

2021 ◽  
Vol 8 (3) ◽  
pp. 97-101
Author(s):  
T. Z. Aliev ◽  
T. S. Belysheva ◽  
K. A. Sergeenko ◽  
E. B. Machneva ◽  
N. V. Sidorova ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Drug Toxicity ◽  
Clinical Case ◽  
Skin Lesions ◽  
Hematopoietic Stem ◽  
Case Presentation ◽  
Negative Effect ◽  
Therapeutic Problem

One of the complications arising at the stage of hematopoietic stem cell transplantation (HSCT) is skin lesions. This complication is quite common and represents an important diagnostic and therapeutic problem. The main cause of skin lesions in HSCT is drug toxicity, but also infectious lesions. Each of the complications can manifest itself in varying degrees, as well as be combined with others, having a significant negative effect on the patient’s condition, in severe cases posing a threat to the patient’s life. This paper presents a clinical case of a patient with treosulfan toxicoderma who was treated with JELONET dressings.

Role of stem-cell-derived hepatic endoderm in human drug discovery

2010 ◽  
Vol 38 (4) ◽  
pp. 1033-1036 ◽  
Author(s):  
Claire N. Medine ◽  
Sebastian Greenhough ◽  
David C. Hay
Keyword(s):  
Stem Cells ◽  
Cell Culture ◽  
Stem Cell ◽  
Drug Discovery ◽  
Pluripotent Stem Cells ◽  
Drug Toxicity ◽  
Human Liver ◽  
Human Hepatocytes ◽  
Cell Populations

Accurate prediction of human drug toxicity is a vital part of the drug discovery process. However, the safety evaluation process is hindered by the availability and quality of primary human liver models with which to study drug toxicity. In an attempt to overcome this limitation, research has focused on deriving human hepatocytes from a number of sources, including progenitors from fetal and adult liver, human cell lines derived from liver tumours, immortalized human hepatocytes and pluripotent stem cells. The major hurdles in developing scalable and high-fidelity human hepatocytes from hepatic cell lines and fetal and adult progenitors have been limited organ availability, homogeneous cell purification, short-term cell culture, and the rapid loss of hepatocyte phenotype and function in culture. Therefore it has been necessary to find alternative sources of human hepatocytes which circumvent these issues. The research in our group has focused on generating human hepatic endoderm from the scalable pluripotent stem cell populations, human embryonic stem cells and induced pluripotent stem cells. We have developed efficient and scalable models of human hepatocyte differentiation from these cell populations. Moreover, stem-cell-derived hepatic endoderm displays many of the functional attributes of primary human hepatocytes. Our research is now focused on developing defined culture systems and improving cell culture microenvironments in order to improve our understanding of the mechanisms regulating human liver development. This will in turn facilitate the generation of broad-range functioning hepatic endoderm in vitro. By taking these approaches, we believe that it will be possible to improve the predictive nature of our in vitro models, revolutionizing the manner in which industry measures human drug toxicity and having an impact on drug attrition.

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