FDA approval summary: Dalteparin for the treatment of symptomatic venous thromboembolism in pediatric patients.

On May 16, 2019, the U.S. Food and Drug Administration (FDA) approved dalteparin sodium for the treatment of symptomatic venous thromboembolism (VTE) to reduce the risk of recurrence in pediatric patients 1 month of age and older.

Insights into Doxorubicin-induced Cardiotoxicity: Molecular Mechanisms, Preventive Strategies, and Early Monitoring.

Doxorubicin (DOX) is one of the most effective anticancer drugs to treat various forms of cancers; however, its therapeutic utility is severely limited by its associated cardiotoxicity. Despite the enormous amount of research conducted in this area, the exact molecular mechanisms underlying DOX toxic effects on the heart are still an area that warrants further investigations. In this study, we reviewed literature to gather the best-known molecular pathways related to DOX-induced cardiotoxicity (DIC).

Combining Multiscale Experimental and Computational Systems Pharmacological Approaches to Overcome Resistance to HER2-targeted Therapy in Breast Cancer.

The emergence of human epidermal growth factor receptor type-2 (HER2) therapy resistance in HER2-positive (HER2+) breast cancer (BC) poses a major clinical challenge. The primary mechanisms of resistance include aberrant activation of the HER2 and phosphatidylinositol 3-kinase/mammalian target of rapamycin/AKT8 virus oncogene cellular homolog (PI3K/Akt/mTOR) pathways. The existence of feedback loops in this pathway may engender resistance to targeted therapies such as everolimus, an mTOR inhibitor, resulting in a more aggressive form of refractory HER2+ BC.

Utility of a Novel Three-Dimensional and Dynamic (3DD) Cell Culture System for PK/PD Studies: Evaluation of a Triple Combination Therapy at Overcoming Anti-HER2 Treatment Resistance in Breast Cancer.

Emergence of Human epidermal growth factor receptor 2 (HER2) therapy resistance in HER2-positive (HER2+) breast cancer (BC) poses a major clinical challenge. Mechanisms of resistance include the over-activation of the PI3K/mTOR and Src pathways. This work aims to investigate a novel combination therapy that employs paclitaxel (PAC), a mitotic inhibitor, with everolimus (EVE), an mTOR inhibitor, and dasatinib (DAS), an Src kinase inhibitor, as a modality to overcome resistance.

Multiscale systems pharmacological analysis of everolimus action in hepatocellular carcinoma.

Dysregulation of mTOR pathway is common in hepatocellular carcinoma (HCC). A translational quantitative systems pharmacology (QSP), pharmacokinetic (PK), and pharmacodynamic (PD) model dissecting the circuitry of this pathway was developed to predict HCC patients' response to everolimus, an mTOR inhibitor. The time course of key signaling proteins in the mTOR pathway, HCC cells viability, tumor volume (TV) and everolimus plasma and tumor concentrations in xenograft mice, clinical PK of everolimus and progression free survival (PFS) in placebo and everolimus-treated patients were extracted from literature.

Systems pharmacological analysis of mitochondrial cardiotoxicity induced by selected tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) are targeted therapies rapidly becoming favored over conventional cytotoxic chemotherapeutics. Our study investigates two FDA approved TKIs, DASATINIB; indicated for IMATINIB-refractory chronic myeloid leukemia, and SORAFENIB; indicated for hepatocellular carcinoma and advanced renal cell carcinoma. Limited but crucial evidence suggests that these agents can have cardiotoxic side effects ranging from hypertension to heart failure.

Advancing Cancer Therapy with Present and Emerging Immuno-Oncology Approaches.

Immuno-oncology (I-O) is a young and growing field on the frontier of cancer therapy. Contrary to cancer therapies that directly target malignant cells, I-O therapies stimulate the body's immune system to target and attack the tumor, which is otherwise invisible to, or inhibiting the immune response. To this end, several methods have been developed: First, passive therapies that enable T-cells to fight the tumor without direct manipulation, typically through binding and modifying the intracellular signaling of surface receptors.

Effects of Cigarette Smoke Condensate on Oxidative Stress, Apoptotic Cell Death, and HIV Replication in Human Monocytic Cells.

While cigarette smoking is prevalent amongst HIV-infected patients, the effects of cigarette smoke constituents in cells of myeloid lineage are poorly known. Recently, we have shown that nicotine induces oxidative stress through cytochrome P450 (CYP) 2A6-mediated pathway in U937 monocytic cells. The present study was designed to examine the effect of cigarette smoke condensate (CSC), which contains majority of tobacco constituents, on oxidative stress, cytotoxicity, expression of CYP1A1, and/or HIV-1 replication in HIV-infected (U1) and uninfected U937 cells.

Effect of Methamphetamine on Spectral Binding, Ligand Docking and Metabolism of Anti-HIV Drugs with CYP3A4.

Cytochrome P450 3A4 (CYP3A4) is the major drug metabolic enzyme, and is involved in the metabolism of antiretroviral drugs, especially protease inhibitors (PIs). This study was undertaken to examine the effect of methamphetamine on the binding and metabolism of PIs with CYP3A4. We showed that methamphetamine exhibits a type I spectral change upon binding to CYP3A4 with δAmax and KD of 0.

Enhanced oxidative stress by alcohol use in HIV+ patients: possible involvement of cytochrome P450 2E1 and antioxidant enzymes.

Background: Alcohol consumption is prevalent amongst HIV positive population. Importantly, chronic alcohol use is reported to exacerbate HIV pathogenesis. Although alcohol is known to increase oxidative stress, especially in the liver, there is no clinical evidence that alcohol increases oxidative stress in HIV positive patients.

Effect of mild-to-moderate smoking on viral load, cytokines, oxidative stress, and cytochrome P450 enzymes in HIV-infected individuals.

Mild-to-moderate tobacco smoking is highly prevalent in HIV-infected individuals, and is known to exacerbate HIV pathogenesis. The objective of this study was to determine the specific effects of mild-to-moderate smoking on viral load, cytokine production, and oxidative stress and cytochrome P450 (CYP) pathways in HIV-infected individuals who have not yet received antiretroviral therapy (ART). Thirty-two human subjects were recruited and assigned to four different cohorts as follows: a) HIV negative non-smokers, b) HIV positive non-smokers, c) HIV negative mild-to-moderate smokers, and d) HIV positive mild-to-moderate smokers.

Enhanced nicotine metabolism in HIV-1-positive smokers compared with HIV-negative smokers: simultaneous determination of nicotine and its four metabolites in their plasma using a simple and sensitive electrospray ionization liquid chromatography-tandem mass spectrometry technique.

Smoking is approximately three times more prevalent in HIV-1-positive than HIV-negative individuals in the United States. Nicotine, which is the major constituent of tobacco, is rapidly metabolized mainly by cytochrome P450 (CYP2A6) to many metabolites. In this study, we developed a simple, fast, and sensitive electrospray ionization liquid chromatography-tandem mass spectrometry method using a strong cation solid phase extraction, and determined the concentration of nicotine and its four major metabolites (cotinine, nornicotine, norcotinine, and trans-3'-hydroxycotinine) in the plasma of HIV-1-positive and HIV-negative smokers.

Tobacco smoking effect on HIV-1 pathogenesis: role of cytochrome P450 isozymes.

Introduction: Tobacco smoking is highly prevalent among the HIV-1-infected population. In addition to diminished immune response, smoking has been shown to increase HIV-1 replication and decrease response to antiretroviral therapy, perhaps through drug-drug interaction. However, the mechanism by which tobacco/nicotine increases HIV-1 replication and mediates drug-drug interaction is poorly understood.

Alcohol consumption effect on antiretroviral therapy and HIV-1 pathogenesis: role of cytochrome P450 isozymes.

Introduction: Alcohol consumption, which is highly prevalent in HIV-infected individuals, poses serious concerns in terms of rate of acquisition of HIV-1 infection, HIV-1 replication, response to highly active antiretroviral therapy (HAART) and AIDS/neuroAIDS progression. However, little is known about the mechanistic pathways by which alcohol exerts these effects, especially with respect to HIV-1 replication and the patient's response to HAART.

Areas Covered: In this review, the authors discuss the effects of alcohol consumption on HIV-1 pathogenesis and its effect on HAART.

An LC-MS/MS method for concurrent determination of nicotine metabolites and the role of CYP2A6 in nicotine metabolite-mediated oxidative stress in SVGA astrocytes.

Background: Nicotine is known to generate oxidative stress through cytochrome P450 2A6 (CYP2A6)-mediated metabolism in the liver and other organs, including macrophages. This study has been designed to examine the role of CYP2A6 in nicotine metabolism and oxidative stress in SVGA cells, an immortalized human astrocyte cell line.

Methods: SVGA astrocytes were treated with 1 μM nicotine, followed by determination of mRNA and protein levels of several CYPs using quantitative RT-PCR and western blot analyses, respectively.