Browsing by Subject "Pharmacokinetic"

Now showing 1 - 3 of 3
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    Augmented Concentration of Isopentyl-Deoxynyboquinone in Tumors Selectively Kills NAD(P)H Quinone Oxidoreductase 1-Positive Cancer Cells through Programmed Necrotic and Apoptotic Mechanisms
    (MDPI, 2023-12-14) Wang, Jiangwei; Su, Xiaolin; Jiang, Lingxiang; Boudreau, Matthew W.; Chatkewitz, Lindsay E.; Kilgore, Jessica A.; Zahid, Kashif Rafiq; Williams, Noelle S.; Chen, Yaomin; Liu, Shaohui; Hergenrother, Paul J.; Huang, Xiumei; Biochemistry and Molecular Biology, School of Medicine
    Lung and breast cancers rank as two of the most common and lethal tumors, accounting for a substantial number of cancer-related deaths worldwide. While the past two decades have witnessed promising progress in tumor therapy, developing targeted tumor therapies continues to pose a significant challenge. NAD(P)H quinone oxidoreductase 1 (NQO1), a two-electron reductase, has been reported as a promising therapeutic target across various solid tumors. β-Lapachone (β-Lap) and deoxynyboquinone (DNQ) are two NQO1 bioactivatable drugs that have demonstrated potent antitumor effects. However, their curative efficacy has been constrained by adverse effects and moderate lethality. To enhance the curative potential of NQO1 bioactivatable drugs, we developed a novel DNQ derivative termed isopentyl-deoxynyboquinone (IP-DNQ). Our study revealed that IP-DNQ treatment significantly increased reactive oxygen species generation, leading to double-strand break (DSB) formation, PARP1 hyperactivation, and catastrophic energy loss. Notably, we discovered that this novel drug induced both apoptosis and programmed necrosis events, which makes it entirely distinct from other NQO1 bioactivatable drugs. Furthermore, IP-DNQ monotherapy demonstrated significant antitumor efficacy and extended mice survival in A549 orthotopic xenograft models. Lastly, we identified that in mice IP-DNQ levels were significantly elevated in the plasma and tumor compared with IB-DNQ levels. This study provides novel preclinical evidence supporting IP-DNQ efficacy in NQO1+ NSCLC and breast cancer cells.
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    Diabetic Retinopathy in the Aging Population: A Perspective of Pathogenesis and Treatment
    (Dovepress, 2021-07-15) Leley, Sameer P.; Ciulla, Thomas A.; Bhatwadekar, Ashay D.; Ophthalmology, School of Medicine
    The elderly population in the United States is projected to almost double by the year 2050. In addition, the numbers of diabetics are rising, along with its most common complication, diabetic retinopathy (DR). To effectively treat DR within the elderly population, it is essential first to consider the retinal changes that occur due to aging, such as decreased blood flow, retinal thinning, and microglial changes, and understand that these changes can render the retina more vulnerable to oxidative and ischemic damage. Given these considerations, as well as the pathogenesis of DR, specific pathways could play a heightened role in DR progression in elderly patients, such as the polyol pathway and the vascular endothelial growth factor (VEGF) axis. Current ocular treatments include intravitreal corticosteroids, intravitreal anti-VEGF agents, laser photocoagulation and surgical interventions, in addition to better control of underlying diabetes with an expanding range of systemic treatments. While using therapeutics, it is also essential to consider how pharmacokinetics and pharmacodynamics change with aging; oral drug absorption can decrease, and ocular drug metabolism might affect the dosing and delivery methods. Also, elderly patients may more likely be nonadherent to their medication regimen or appointments than younger patients, and undertreatment with anti-VEGF drugs often leads to suboptimal outcomes. With a rising number of elderly DR patients, understanding how aging affects disease progression, pharmacological metabolism, and adherence are crucial to ensuring that this population receives adequate care.
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    Polymorphisms in drug-metabolizing enzymes and steady-state exemestane concentration in postmenopausal patients with breast cancer
    (Springer Nature, 2017-12) Hertz, Daniel L.; Kidwell, Kelley M.; Seewald, Nicholas J.; Gersch, Christina L.; Desta, Zeruesenay; Flockhart, David A.; Storniolo, Ana-Maria; Stearns, Vered; Skaar, Todd C.; Hayes, Daniel F.; Henry, N. Lynn; Rae, James M.; Medicine, School of Medicine
    Discovery of clinical and genetic predictors of exemestane pharmacokinetics was attempted in 246 post-menopausal patients with breast cancer enrolled on a prospective clinical study. A sample was collected two hours after exemestane dosing at a 1 or 3 month study visit to measure drug concentration. The primary hypothesis was that patients carrying the low-activity CYP3A4*22 (rs35599367) SNP would have greater exemestane concentration. Additional SNPs in genes relevant to exemestane metabolism (CYP1A1/2, CYP1B1, CYP3A4, CYP4A11, AKR1C3/4, AKR7A2) were screened in secondary analyses and adjusted for clinical covariates. CYP3A4*22 was associated with a 54% increase in exemestane concentration (p<0.01). Concentration was greater in patients who reported White race, had elevated aminotransferases, renal insufficiency, lower body mass index, and had not received chemotherapy (all p<0.05), and CYP3A4*22 maintained significance after adjustment for covariates (p<0.01). These genetic and clinical predictors of exemestane concentration may be useful for treatment individualization in patients with breast cancer.