scholarly journals Investigating the importance of individual mitochondrial genotype in susceptibility to drug-induced toxicity

2020 ◽  
Vol 48 (3) ◽  
pp. 787-797
Author(s):  
Sophie L. Penman ◽  
Alice S. Carter ◽  
Amy E. Chadwick
Keyword(s):  
Clinical Data ◽  
Research Effort ◽  
Personalised Medicine ◽  
Current Evidence ◽  
Mitochondrial Genetics ◽  
Drug Induced ◽  
Mitochondrial Haplogroup ◽  
Mtdna Variation ◽  
The Impact

The mitochondrion is an essential organelle responsible for generating cellular energy. Additionally, mitochondria are a source of inter-individual variation as they contain their own genome. Evidence has revealed that mitochondrial DNA (mtDNA) variation can confer differences in mitochondrial function and importantly, these differences may be a factor underlying the idiosyncrasies associated with unpredictable drug-induced toxicities. Thus far, preclinical and clinical data are limited but have revealed evidence in support of an association between mitochondrial haplogroup and susceptibility to specific adverse drug reactions. In particular, clinical studies have reported associations between mitochondrial haplogroup and antiretroviral therapy, chemotherapy and antibiotic-induced toxicity, although study limitations and conflicting findings mean that the importance of mtDNA variation to toxicity remains unclear. Several studies have used transmitochondrial cybrid cells as personalised models with which to study the impact of mitochondrial genetic variation. Cybrids allow the effects of mtDNA to be assessed against a stable nuclear background and thus the in vitro elucidation of the fundamental mechanistic basis of such differences. Overall, the current evidence supports the tenet that mitochondrial genetics represent an exciting area within the field of personalised medicine and drug toxicity. However, further research effort is required to confirm its importance. In particular, efforts should focus upon translational research to connect preclinical and clinical data that can inform whether mitochondrial genetics can be useful to identify at risk individuals or inform risk assessment during drug development.

scholarly journals The Impact of Uremic Toxins on Cerebrovascular and Cognitive Disorders

Toxins ◽  
2018 ◽  
Vol 10 (7) ◽  
pp. 303 ◽  
Author(s):  
Maryam Assem ◽  
Mathilde Lando ◽  
Maria Grissi ◽  
Saïd Kamel ◽  
Ziad Massy ◽  
...  
Keyword(s):  
Animal Experiments ◽  
Cognitive Disorders ◽  
Neurological Complications ◽  
Cerebrovascular Diseases ◽  
Uremic Toxins ◽  
Current Evidence ◽  
Cognitive Disorders And Dementia ◽  
The Impact

Individuals at all stages of chronic kidney disease (CKD) have a higher risk of developing cognitive disorders and dementia. Stroke is also highly prevalent in this population and is associated with a higher risk of neurological deterioration, in-hospital mortality, and poor functional outcomes. Evidence from in vitro studies and in vivo animal experiments suggests that accumulation of uremic toxins may contribute to the pathogenesis of stroke and amplify vascular damage, leading to cognitive disorders and dementia. This review summarizes current evidence on the mechanisms by which uremic toxins may favour the occurrence of cerebrovascular diseases and neurological complications in CKD.

scholarly journals Assessment of the impact of mitochondrial genotype upon drug-induced mitochondrial dysfunction in platelets derived from healthy volunteers

2021 ◽  
Author(s):  
Amy L. Ball ◽  
Katarzyna M. Bloch ◽  
Lucille Rainbow ◽  
Xuan Liu ◽  
John Kenny ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Healthy Volunteers ◽  
Adverse Drug Reactions ◽  
Mitochondrial Function ◽  
Flux Analysis ◽  
Drug Reactions ◽  
Drug Induced ◽  
Mtdna Variation ◽  
Mitochondrial Genotype ◽  
The Impact

AbstractMitochondrial DNA (mtDNA) is highly polymorphic and encodes 13 proteins which are critical to the production of ATP via oxidative phosphorylation. As mtDNA is maternally inherited and undergoes negligible recombination, acquired mutations have subdivided the human population into several discrete haplogroups. Mitochondrial haplogroup has been found to significantly alter mitochondrial function and impact susceptibility to adverse drug reactions. Despite these findings, there are currently limited models to assess the effect of mtDNA variation upon susceptibility to adverse drug reactions. Platelets offer a potential personalised model of this variation, as their anucleate nature offers a source of mtDNA without interference from the nuclear genome. This study, therefore, aimed to determine the effect of mtDNA variation upon mitochondrial function and drug-induced mitochondrial dysfunction in a platelet model. The mtDNA haplogroup of 383 healthy volunteers was determined using next-generation mtDNA sequencing (Illumina MiSeq). Subsequently, 30 of these volunteers from mitochondrial haplogroups H, J, T and U were recalled to donate fresh, whole blood from which platelets were isolated. Platelet mitochondrial function was tested at basal state and upon treatment with compounds associated with both mitochondrial dysfunction and adverse drug reactions, flutamide, 2-hydroxyflutamide and tolcapone (10–250 μM) using extracellular flux analysis. This study has demonstrated that freshly-isolated platelets are a practical, primary cell model, which is amenable to the study of drug-induced mitochondrial dysfunction. Specifically, platelets from donors of haplogroup J have been found to have increased susceptibility to the inhibition of complex I-driven respiration by 2-hydroxyflutamide. At a time when individual susceptibility to adverse drug reactions is not fully understood, this study provides evidence that inter-individual variation in mitochondrial genotype could be a factor in determining sensitivity to mitochondrial toxicants associated with costly adverse drug reactions.

scholarly journals P035 NUDT15 variance increases DNA-incorporated thiopurine metabolites and lymphocyte apoptosis in patients with inflammatory bowel disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S149-S150
Author(s):  
H Kiyohara ◽  
T Toyonaga ◽  
S Kuronuma ◽  
A Ueno ◽  
S Okabayashi ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Japanese Patients ◽  
Lymphocyte Apoptosis ◽  
Drug Induced ◽  
Peripheral Blood Mononuclear ◽  
Inflammatory Bowel ◽  
The Impact ◽  
Cd4 Lymphocytes

Abstract Background A novel thiopurine metabolizing enzyme, nucleotide diphosphate-linked moiety X-type motif 15 (NUDT15) was associated with drug-induced leukopenia in patients with non-synonymous genetic polymorphisms. Thiopurine-induced leukopenia in Japanese patients with genetic variance in NUDT15 (c.415C>T) appears to be independent of the 6-thioguanine nucleotide concentration in red blood cells. However, detailed molecular mechanism how NUDT15 variance causes thiopurine-induced leukopenia remains unclear and NUDT15-associated subcellular thiopurine metabolism has not been investigated in patients with inflammatory bowel diseases (IBD). Methods DNA-incorporated deoxythioguanosine (dTG) was measured in the peripheral blood mononuclear cells (PBMCs) of Japanese patients with IBD under thiopurine treatment. Association of a single-nucleotide polymorphism for NUDT15 (c.415C>T) with dTG in PBMCs (dTGPBMC) was examined. Peripheral blood T lymphocytes were cultured in vitro with 6-thioguanine (6-TG) to examine the Impact of NUDT15 genotypes on incorporation into DNA, cell proliferation and apoptosis. Results NUDT15 variants had significantly higher dTGPBMC per thiopurine dosage than non-variants (homozygous variants (TT) vs. heterozygous variants (CT) vs. non-variants (CC), 4418.0 vs. 663.0 vs. 295.3 dTG mol/106 moles dA per mg/kg/day of 6-MP (Figure A)). dTGPBMC and peripheral lymphocyte counts showed a negative correlation (r = −0.30, p = 0.015) (Figure B). Peripheral blood lymphocytes from patients with NUDT15 variance showed a higher DNA-incorporated dTG associated with increased apoptosis (increase of Annexin V+ PI+ CD4+ lymphocytes; TT vs. CT vs. CC, 158.5 % vs. 80.1 % vs. 57.9 % (p = 0.0427)) (Figure C) and decreased proliferation (decrease of proliferative CD4+ lymphocytes, TT vs. CT vs. CC, 49.0 % vs. 25.0 % vs. 19.1 % (p = 0.0098)) (Figure D) when cultured with 6-thioguanine in vitro. Conclusion DNA-incorporated dTG affected by NUDT15 genotypes induces T lymphocyte apoptosis in patients with IBD.

scholarly journals Hydroxychloroquine as Prophylaxis for COVID-19: A Review

2020 ◽  
Vol 11 ◽  
Author(s):  
Manuela Monti ◽  
Bernadette Vertogen ◽  
Carla Masini ◽  
Caterina Donati ◽  
Claudia Lilli ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Data ◽  
Drug Repositioning ◽  
Methodological Approach ◽  
Standard Of Care ◽  
Weekly Schedule ◽  
Loading Dose ◽  
Prophylactic Use ◽  
The Impact

The impact of the COVID-19 pandemic worldwide has led to a desperate search for effective drugs and vaccines. There are still no approved agents for disease prophylaxis. We thus decided to use a drug repositioning strategy to perform a state-of-the-art review of a promising but controversial drug, hydroxychloroquine (HCQ), in an effort to provide an objective, scientific and methodologically correct overview of its potential prophylactic role. The advantage of using known drugs is that their toxicity profile is well known and there are fewer commercial interests (e.g., expired patents), thus allowing the scientific community to be freer of constraints. The main disadvantage is that the economic resources are almost always insufficient to promote large multinational clinical trials. In the present study, we reviewed the literature and available data on the prophylactic use of HCQ. We also took an in-depth look at all the published clinical data on the drug and examined ongoing clinical trials (CTs) from the most important CT repositories to identify a supporting rationale for HCQ prophylactic use. Our search revealed a substantial amount of preclinical data but a lack of clinical data, highlighting the need to further assess the translational impact of in vitro data in a clinical setting. We identified 77 CTs using a multiplicity of HCQ schedules, which clearly indicates that we are still far from reaching a standard of care. The majority of the CTs (92%) are randomized and 53% are being conducted in a phase 3 or 2/3 setting. The comparator is placebo or control in 55 (77%) of the randomized studies. Forty-eight (62%) CTs expect to enroll up to 1,000 subjects and 50 (71%) plan to recruit healthcare workers (HCW). With regard to drug schedules, 45 (58.5%) CTs have planned a loading dose, while 18 (23.4%) have not; the loading dose is 800 mg in 19 trials (42.2%), 400 mg in 19 (42.2%), 600 mg in 4 (8.9%) and 1,200 mg in 1 (2.2%). Forty trials include at least one daily schedule, while 19 have at least one weekly schedule. Forty-one (53.2%) will have a treatment duration of more than 30 days. Awaiting further developments that can only derive from the results of these prospective randomized CTs, the take-home message of our review is that a correct methodological approach is the key to understanding whether prophylactic HCQ can really represent an effective strategy in preventing COVID-19.

scholarly journals Metabolic Aspects of Anthracycline Cardiotoxicity

2021 ◽  
Vol 22 (2) ◽  
Author(s):  
Michele Russo ◽  
Angela Della Sala ◽  
Carlo Gabriele Tocchetti ◽  
Paolo Ettore Porporato ◽  
Alessandra Ghigo
Keyword(s):  
Heart Failure ◽  
Anticancer Agents ◽  
Energy Demand ◽  
Cardiac Metabolism ◽  
Current Evidence ◽  
Anthracycline Cardiotoxicity ◽  
Cardiac Side Effects ◽  
The Impact

Opinion statementHeart failure (HF) is increasingly recognized as the major complication of chemotherapy regimens. Despite the development of modern targeted therapies such as monoclonal antibodies, doxorubicin (DOXO), one of the most cardiotoxic anticancer agents, still remains the treatment of choice for several solid and hematological tumors. The insurgence of cardiotoxicity represents the major limitation to the clinical use of this potent anticancer drug. At the molecular level, cardiac side effects of DOXO have been associated to mitochondrial dysfunction, DNA damage, impairment of iron metabolism, apoptosis, and autophagy dysregulation. On these bases, the antioxidant and iron chelator molecule, dexrazoxane, currently represents the unique FDA-approved cardioprotectant for patients treated with anthracyclines.A less explored area of research concerns the impact of DOXO on cardiac metabolism. Recent metabolomic studies highlight the possibility that cardiac metabolic alterations may critically contribute to the development of DOXO cardiotoxicity. Among these, the impairment of oxidative phosphorylation and the persistent activation of glycolysis, which are commonly observed in response to DOXO treatment, may undermine the ability of cardiomyocytes to meet the energy demand, eventually leading to energetic failure. Moreover, increasing evidence links DOXO cardiotoxicity to imbalanced insulin signaling and to cardiac insulin resistance. Although anti-diabetic drugs, such as empagliflozin and metformin, have shown interesting cardioprotective effects in vitro and in vivo in different models of heart failure, their mechanism of action is unclear, and their use for the treatment of DOXO cardiotoxicity is still unexplored.This review article aims at summarizing current evidence of the metabolic derangements induced by DOXO and at providing speculations on how key players of cardiac metabolism could be pharmacologically targeted to prevent or cure DOXO cardiomyopathy.

Acupuncture and in vitro fertilisation research: Current and future directions

2018 ◽  
Vol 36 (2) ◽  
pp. 117-122 ◽  
Author(s):  
Lee E Hullender Rubin ◽  
Belinda J Anderson ◽  
LaTasha B Craig
Keyword(s):  
Stress Reduction ◽  
Endometrial Thickness ◽  
Current Evidence ◽  
In Vitro Fertilisation ◽  
Future Directions ◽  
Acupuncture Intervention ◽  
Related Stress ◽  
The Impact ◽  
Improve Patient

Background Acupuncture is a common adjuvant treatment to support patients undergoing in vitro fertilisation (IVF). However, the impact of acupuncture and the different roles it can play in IVF remain unclear. Objective In this paper, we present an overview and critique of the current evidence on acupuncture's impact on IVF-related stress, describe harms, and propose future directions for investigation. Conclusion Two to three acupuncture sessions performed on or around the day of embryo transfer are insufficient interventions to improve IVF birth outcomes but provide significant IVF-related stress reduction. Research investigating acupuncture to support IVF is heterogeneous and confounded by the lack of an appropriate comparator. However, evidence suggests several acupuncture sessions improve endometrial thickness, reduce stress, and improve patient satisfaction. Observational studies suggest more sessions are associated with increases in clinical pregnancy and live birth rates. An optimised acupuncture intervention with a reasonable comparator is necessary for future studies, with evidence-based guidance on technique and number of sessions. Acupuncture should not be rejected as an adjuvant therapy for IVF, but more studies are needed to clarify acupuncture's role in supporting IVF cycles.

The impact of EPA and DHA on ceramide lipotoxicity in the metabolic syndrome

2020 ◽  
pp. 1-13
Author(s):  
Chelsey Walchuk ◽  
Yidi Wang ◽  
Miyoung Suh
Keyword(s):  
Metabolic Syndrome ◽  
High Fat Diet ◽  
Animal Studies ◽  
Sphingolipid Metabolism ◽  
Current Evidence ◽  
The Metabolic Syndrome ◽  
Epa And Dha ◽  
The Impact

Abstract The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including obesity, insulin resistance (IR) and dyslipidaemia. Consumption of a high-fat diet (HFD) enriched in SFA leads to the accumulation of ceramide (Cer), the central molecule in sphingolipid metabolism. Elevations in plasma and tissue Cer are found in obese individuals, and there is evidence to suggest that Cer lipotoxicity contributes to the MetS. EPA and DHA have shown to improve MetS parameters including IR, inflammation and hypertriacylglycerolaemia; however, whether these improvements are related to Cer is currently unknown. This review examines the potential of EPA and DHA to improve Cer lipotoxicity and MetS parameters including IR, inflammation and dyslipidaemia in vitro and in vivo. Current evidence from cell culture and animal studies indicates that EPA and DHA attenuate palmitate- or HFD-induced Cer lipotoxicity and IR, whereas evidence in humans is greatly lacking. Overall, there is intriguing potential for EPA and DHA to improve Cer lipotoxicity and related MetS parameters, but more research is warranted.

scholarly journals Prediction of Drug-Induced Hyperbilirubinemia by In Vitro Testing

Pharmaceutics ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 755
Author(s):  
Péter Tátrai ◽  
Péter Krajcsi
Keyword(s):  
Organic Anion ◽  
The Body ◽  
In Vitro Assays ◽  
Current Evidence ◽  
Drug Induced ◽  
Organic Anion Transporting Polypeptide ◽  
Resistance Protein ◽  
Clinically Significant ◽  
Uptake Transporters

Bilirubin, the end product of heme catabolism, is produced continuously in the body and may reach toxic levels if accumulates in the serum and tissues; therefore, a highly efficient mechanism evolved for its disposition. Normally, unconjugated bilirubin enters hepatocytes through the uptake transporters organic anion transporting polypeptide (OATP) 1B1 and 1B3, undergoes glucuronidation by the Phase II enzyme UDP glucuronosyltransferase 1A1 (UGT1A1), and conjugated forms are excreted into the bile by the canalicular export pump multidrug resistance protein 2 (MRP2). Any remaining conjugated bilirubin is transported back to the blood by MRP3 and passed on for uptake and excretion by downstream hepatocytes or the kidney. The bile salt export pump BSEP as the main motor of bile flow is indirectly involved in bilirubin disposition. Genetic mutations and xenobiotics that interfere with this machinery may impede bilirubin disposition and cause hyperbilirubinemia. Several pharmaceutical compounds are known to cause hyperbilirubinemia via inhibition of OATP1Bs, UGT1A1, or BSEP. Herein we briefly review the in vitro prediction methods that serve to identify drugs with a potential to induce hyperbilirubinemia. In vitro assays can be deployed early in drug development and may help to minimize late-stage attrition. Based on current evidence, drugs that behave as mono- or multispecific inhibitors of OATP1B1, UGT1A1, and BSEP in vitro are at risk of causing clinically significant hyperbilirubinemia. By integrating inhibition data from in vitro assays, drug serum concentrations, and clinical reports of hyperbilirubinemia, predictor cut-off values have been established and are provisionally suggested in this review. Further validation of in vitro readouts to clinical outcomes is expected to enhance the predictive power of these assays.

scholarly journals Effects of endocrine disruptors on fetal testis development, male puberty, and transition age

Endocrine ◽  
2020 ◽  
Author(s):  
Francesco Cargnelutti ◽  
Andrea Di Nisio ◽  
Francesco Pallotti ◽  
Iva Sabovic ◽  
Matteo Spaziani ◽  
...  
Keyword(s):  
Endocrine Disruptors ◽  
Reproductive System ◽  
Current Evidence ◽  
Transition Age ◽  
Testis Development ◽  
Fetal Testis ◽  
Male Puberty ◽  
The Impact ◽  
Harmful Effects

Abstract Purpose Endocrine disruptors (EDs) are exogenous substances able to impair endocrine system; consequently, they may cause numerous adverse effects. Over the last years, particular focus has been given to their harmful effects on reproductive system, but very little is known, especially in males. The aim of this review is to discuss the detrimental effects of EDs exposure on fetal testis development, male puberty, and transition age. Methods A search for the existing literature focusing on the impact of EDs on fetal testis development, male puberty, andrological parameters (anogenital distance, penile length, and testicular volume), and testicular cancer with particular regard to pubertal age provided the most current information available for this review. Human evidence-based reports were given priority over animal and in vitro experimental results. Given the paucity of available articles on this subject, all resources were given careful consideration. Results Information about the consequences associated with EDs exposure in the current literature is limited and often conflicting, due to the scarcity of human studies and their heterogeneity. Conclusions We conclude that current evidence does not clarify the impact of EDs on human male reproductive health, although severe harmful effects had been reported in animals. Despite controversial results, overall conclusion points toward a positive association between exposure to EDs and reproductive system damage. Further long-term studies performed on wide number of subjects are necessary in order to identify damaging compounds and remove them from the environment.

scholarly journals Alternating electric tumor treating fields for treatment of glioblastoma: rationale, preclinical, and clinical studies

2018 ◽  
Vol 128 (2) ◽  
pp. 414-421 ◽  
Author(s):  
Sandeep Mittal ◽  
Neil V. Klinger ◽  
Sharon K. Michelhaugh ◽  
Geoffrey R. Barger ◽  
Susan C. Pannullo ◽  
...  
Keyword(s):  
Electric Fields ◽  
Clinical Data ◽  
Combined Treatment ◽  
Current Evidence ◽  
Newly Diagnosed ◽  
Tumor Treating Fields ◽  
Alternating Electric Fields ◽  
Recurrent Gbm

OBJECTIVETreatment for glioblastoma (GBM) remains largely unsuccessful, even with aggressive combined treatment via surgery, radiotherapy, and chemotherapy. Tumor treating fields (TTFs) are low-intensity, intermediate-frequency, alternating electric fields that have antiproliferative properties in vitro and in vivo. The authors provide an up-to-date review of the mechanism of action as well as preclinical and clinical data on TTFs.METHODSA systematic review of the literature was performed using the terms “tumor treating fields,” “alternating electric fields,” “glioblastoma,” “Optune,” “NovoTTF-100A,” and “Novocure.”RESULTSPreclinical and clinical data have demonstrated the potential efficacy of TTFs for treatment of GBM, leading to several pilot studies, clinical trials, and, in 2011, FDA approval for its use as salvage therapy for recurrent GBM and, in 2015, approval for newly diagnosed GBM.CONCLUSIONSCurrent evidence supports the use of TTFs as an efficacious, antimitotic treatment with minimal toxicity in patients with newly diagnosed and recurrent GBM. Additional studies are needed to further optimize patient selection, determine cost-effectiveness, and assess the full impact on quality of life.

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