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Expert Opinion on Drug Metabolism & Toxicology

Ágota Apáti, Nóra Varga, Tünde Berecz, Zsuzsa Erdei, László Homolya, Balázs Sarkadi
Human pluripotent stem cells (hPSCs) are capable of differentiating into all types of cells in the body and so provide suitable toxicology screening systems even for hard-to-obtain human tissues. Since hPSCs can also be generated from differentiated cells and current gene editing technologies allow targeted genome modifications, hPSCs can be applied for drug toxicity screening both in normal and disease-specific models. Targeted hPSC differentiation is still a challenge but cardiac, neuronal or liver cells, and complex cellular models are already available for practical applications...
December 10, 2018: Expert Opinion on Drug Metabolism & Toxicology
Gerhard Hamilton, Barbara Rath
Drug screening assays employing 2D-cultures of cancer cells have been largely replaced by 3D multicellular tumor spheroid (MCTS) models which more closely represent patient's tumors. The predictive power of the different MCTSs depends on source of the cells, techniques of preparation and characteristics of the aggregates. Areas covered: The preparation of MCTSs and a comparison of the spheroids assembled from permanent cancer and patient-derived cell lines in respect to the correlation of their chemosensitivity to clinical responses are discussed...
November 28, 2018: Expert Opinion on Drug Metabolism & Toxicology
Ana Pejčić, Slobodan M Janković, Valentina Opančina, Goran Babić, Miloš Milosavljević
Recipients of hematopoietic stem cell transplantation (HSCT) are exposed to numerous drugs in both pre- and post-transplantation period, which creates an opportunity for drug-drug interactions (DDIs); if clinically relevant DDIs happen, the risk of adverse treatment outcomes is increased. Areas covered: This review is focused on DDIs in recipients of HSCT that were observed and published as clinical trials, case series or case reports. Relevant publications were found by the systematic search of the following online databases: MEDLINE, SCOPUS, EBSCO, and SCINDEX...
November 27, 2018: Expert Opinion on Drug Metabolism & Toxicology
Barbara Deleenheer, Isabel Spriet, Johan Maertens
Letermovir is a new antiviral approved to prevent cytomegalovirus infection in hematopoietic stem cell transplant recipients. It has a distinct mechanism of action as it acts as a terminase complex inhibitor, and shows some advantages compared to the current treatment options for cytomegalovirus infection. Areas covered: This review focuses on the efficacy, safety, pharmacokinetics, pharmacodynamics and drug-drug interactions of letermovir. Expert opinion: Letermovir is a new antiviral to prevent cytomegalovirus infection...
November 27, 2018: Expert Opinion on Drug Metabolism & Toxicology
Fabrizio Stocchi, Laura Vacca, Paola Stirpe, Margherita Torti
Levodopa (LD) in combination with a decarboxylase inhibitor is a mainstay and the most effective therapeutic agent in the treatment of Parkinson's disease (PD). Unfortunately, during chronic treatment with this agent, ON-OFF phenomena and dyskinesia appear. Despite the many medical treatment options available, unpredictable OFF episodes can still occur and be severe and disabling. A rescue therapy that provides a rapid and predictable ON response for patients with OFF periods would be of great value for such patients...
November 27, 2018: Expert Opinion on Drug Metabolism & Toxicology
Mattia Galli, Domenico D'Amario, Carmelo Sofia, Marcello Vaccarella, Filippo Crea, Nadia Aspromonte
Heart failure (HF) affects approximately 2% of the population worldwide, remaining a major cause of hospitalization and mortality despite innovative therapeutic approaches introduced in the past few decades. Type 2 diabetes mellitus (T2D) contributes significantly to end-organ damage and HF-related complications and is associated with worse clinical status and increased all-cause and cardiovascular mortality in patients with HF with reduced (HFrEF) or with preserved ejection fraction (HFpEF), compared to HF patients without T2D...
November 24, 2018: Expert Opinion on Drug Metabolism & Toxicology
Marianna Lucafò, Raffaella Franca, Davide Selvestrel, Debora Curci, Letizia Pugnetti, Giuliana Decorti, Gabriele Stocco
Inflammatory bowel diseases is a chronic inflammation of the gut whose pathogenesis is still unclear. Although no curative therapy is currently available, a number of drugs are used in induction and maintenance therapy; however, for most of these drugs, a high inter-individual variability in response is observed. Among the factors of this variability, genetics plays an important role. Areas covered: This review summarizes the results of pharmacogenetic studies, considering the most important drugs used and in particular aminosalycilates, glucocorticoids, thiopurines, monoclonal antibodies and thalidomide...
November 22, 2018: Expert Opinion on Drug Metabolism & Toxicology
Martyn Howard, Jill Barber, Naved Alizai, Amin Rostami-Hodjegan
While the media is engaged and fascinated by the idea of 'Precision Medicine', the nuances related to 'Precision Dosing' seem to be largely ignored. Assuming the 'right drug' is selected, clinicians still need to decide on the 'right dose' for individuals. Ideally, optimal dosing should be studied in clinical trials; however, many drugs on the market lack evidence-based dosing recommendations, and small groups of patients (orphan disease populations) are dependent on local guidance and clinician experience to determine drug dosage adjustments...
November 22, 2018: Expert Opinion on Drug Metabolism & Toxicology
Alvaro Garcia-Ropero, Juan J Badimon, Carlos G Santos-Gallego
Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder associated with high cardiovascular (CV) risk. Some of the therapeutic strategies are contraindicated in patients with concomitant heart disease. However, the newest antidiabetic medications, sodium-glucose cotransporter 2 (SGLT2) inhibitors, have shown to significantly reduce CV mortality and heart failure (HF) hospitalizations. The mechanism behind these surprising cardiac benefits remains unclear. Areas covered: This article reviews the pharmacokinetic, pharmacodynamics, efficacy and safety data for the different SGLT2 inhibitors...
November 21, 2018: Expert Opinion on Drug Metabolism & Toxicology
Françoise Goirand, Florian Lemaitre, Manon Launay, Camille Tron, Etienne Chatelut, Jean-Christophe Boyer, Marc Bardou, Antonin Schmitt
5-FU is currently used as a chemotherapy in several cancers such as head-and-neck (H&N) and colorectal cancers (CRC). 5-FU dosing is traditionally based on body-surface-area, but this strategy is usually associated with severe toxicities. 5-FU is mainly catabolized by dihydropyrimidine dehydrogenase (DPD), and 5-FU dosage adaptation according to DPD status at the first cycle of treatment is now recommended. To further optimize 5-FU-based chemotherapy, a body of evidences justifies therapeutic drug monitoring (TDM)...
November 19, 2018: Expert Opinion on Drug Metabolism & Toxicology
Rand Ahmad, Samaneh Alaei, Hamid Omidian
Prescription opioid abuse is now an epidemic that has forced the government and industries to take initiatives. These include developing abuse-deterrent formulations (ADFs), issuing regulatory guidances, and allocating massive budgets to ensure the of safety and effectiveness of these medications. Areas covered: This review covers the regulatory guidance on evaluation and labeling of the branded and generic ADFs. It also includes the relevant patents and technologies, the in-vitro, in-vivo, the post-marketing data, the FDA reviews, and the products' labeling of the FDA-approved products with abuse-deterrent features...
November 8, 2018: Expert Opinion on Drug Metabolism & Toxicology
Paul Chan, Li Shao, Brian Tomlinson, Yuzhen Zhang, Zhong-Min Liu
Metformin is recommended as first-line treatment for type 2 diabetes (T2D) by all major diabetes guidelines. With appropriate usage it is safe and effective overall, but its efficacy and tolerability show considerable variation between individuals. It is a substrate for several drug transporters and polymorphisms in these transporter genes have shown effects on metformin pharmacokinetics and pharmacodynamics. Areas covered: This article provides a review of the current status of the influence of transporter pharmacogenomics on metformin efficacy and tolerability...
October 30, 2018: Expert Opinion on Drug Metabolism & Toxicology
Matilde Capi, Giovanna Gentile, Luana Lionetto, Gerardo Salerno, Fabiola Cipolla, Martina Curto, Marina Borro, Paolo Martelletti
Migraine is a common neurological disorder with a complex pathophysiology. It has been estimated that incidence between adults of current headache disorder is about 50%. Different studies show that this condition has an important and complex genetic component in response to drug therapy. Areas covered: This review shows and summarizes the importance of the polymorphisms associated with the major antimigraine drug metabolizing enzymes. The research of bibliographic databases has involved only published peer-reviewed articles from indexed journals...
October 26, 2018: Expert Opinion on Drug Metabolism & Toxicology
Joan Rou-En Choo, Soo-Chin Lee
Aberrant cellular proliferation due to dysregulation of the cyclin-dependent kinase (CDK) retinoblastoma (Rb)-pathway occurs in several cancers. Selective inhibition of CDK4/6 is an attractive target particularly in hormone-receptor positive (HR+) metastatic breast cancer (MBC), where it has transformed the treatment of these cancers in recent years. Three CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have been approved for the treatment of HR+, HER2 negative (HER2-) MBC. Areas covered: We reviewed and compared the pharmacology, clinical efficacy, and toxicity profiles of the three CDK4/6 inhibitors and discussed several challenges in the use of these drugs, particularly in identifying biomarkers, optimizing dosing strategies, and finding best combinations with other therapies...
October 25, 2018: Expert Opinion on Drug Metabolism & Toxicology
Sempastian Filippas-Ntekouan, Vasilios Tsimihodimos, Theodosios Filippatos, Theodora Dimitriou, Moses Elisaf
Type 2 diabetes mellitus is characterized by increased cardiovascular morbidity and mortality. Atherogenic dyslipidemia is common in this population, consisting of the triad of increased triglycerides, increased small dense low-density lipoprotein (LDL) particles and decreased high-density lipoprotein cholesterol (HDL-C) levels, leading to increased cardiovascular risk. Areas covered: Aim of the review is the presentation of pharmacokinetic characteristics of the currently available sodium-glucose cotransporters 2 (SGLT-2) inhibitors and the effects of these drugs on lipid metabolism...
October 25, 2018: Expert Opinion on Drug Metabolism & Toxicology
Rolf Teschke
A list presenting a valid ranking of drugs most commonly implicated is hardly to be found. Areas covered: Published cases of drug-induced liver injury (DILI) with verified causality using RUCAM (Roussel Uclaf Causality Assessment Method) were used for a ranking of drugs most commonly implicated in causing DILI. Expert opinion: RUCAM-based DILI cases were retrieved from 15 reports published by six international databases of DILI registries and three large medical centers, which provided 3312 cases. Overall 48 drugs with the highest number of DILI cases were listed...
October 25, 2018: Expert Opinion on Drug Metabolism & Toxicology
Anne Rodallec, Guillaume Sicard, Raphaelle Fanciullino, Sébastien Benzekry, Bruno Lacarelle, Gerard Milano, Joseph Ciccolini
Immune checkpoint inhibitors have considerably changed the landscape of oncology. However apart from world-acclaimed success stories limited to melanoma and lung cancer, many solid tumors failed to respond to immune checkpoint inhibitors due to limited immunogenicity, unfavorable tumor micro-environments (TME), lack of infiltrating T lymphocytes or increases in Tregs. Areas covered: Combinatorial strategies are foreseen as the future of immunotherapy and using cytotoxics or modulating agents is expected to boost the efficacy of immune checkpoint inhibitors...
October 24, 2018: Expert Opinion on Drug Metabolism & Toxicology
J Pletz, S J Enoch, D M Jais, C L Mellor, G Pawar, J C Madden, S D Webb, C A Tagliati, M T D Cronin
The kidney is a major target for toxicity elicited by pharmaceuticals and environmental pollutants. Standard testing which often does not investigate underlying mechanisms has proven not to be an adequate hazard assessment approach. As such, there is an opportunity for the application of computational approaches that utilise multi-scale data based on the Adverse Outcome Pathway (AOP) paradigm, coupled with an understanding of the chemistry underpinning the molecular initiating event (MIE) to provide a deep understanding of how structural fragments of molecules relate to specific mechanisms of nephrotoxicity...
October 22, 2018: Expert Opinion on Drug Metabolism & Toxicology
Ylenia Ingrasciotta, Salvatore Crisafulli, Valeria Pizzimenti, Ilaria Marcianò, Anna Mancuso, Giuseppe Andò, Salvatore Corrao, Piera Capranzano, Gianluca Trifirò
Since 2008, new oral anticoagulants (NOACs) have been approved for the prevention of venous thromboembolism (VTE) in patients receiving hip or knee replacement surgery, prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF), treatment of deep vein thrombosis (DVT), and pulmonary embolism (PE). Premarketing randomized clinical trials (RCTs) of NOACs demonstrated their non-inferiority in terms of efficacy vs. warfarin (traditional oral anticoagulant - TOA), with lower risk of serious adverse drug reactions, especially cerebral hemorrhages...
October 2018: Expert Opinion on Drug Metabolism & Toxicology
Ramy K Aziz, Shaimaa M Hegazy, Reem Yasser, Mariam R Rizkallah, Marwa T ElRakaiby
Pharmacomicrobiomics and toxicomicrobiomics study how variations within the human microbiome (the combination of human-associated microbial communities and their genomes) affect drug disposition, action, and toxicity. These emerging fields, interconnecting microbiology, bioinformatics, systems pharmacology, and toxicology, complement pharmacogenomics and toxicogenomics, expanding the scope of precision medicine. Areas covered: This article reviews some of the most recently reported pharmacomicrobiomic and toxicomicrobiomic interactions...
October 2018: Expert Opinion on Drug Metabolism & Toxicology
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