The simultaneous, quantitative and rapid analysis of plasma concentrations of multiple drugs is important to determine the clinical decision and to expect the prognosis in patients administered in emergency unit with intoxication. Here, we developed the liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based drug screening method for analyzing 12 drugs (acetaminophen, amitriptyline, chlorpromazine, cimetidine, diazepam, doxylamine, ephedrine, imipramine, metoclopramide, propranolol, tramadol, and zolpidem) with frequent events of intoxication throughout the country and evaluated its clinical applicability. The overall sensitivity (low limit of quantitation, 0.1-0.5 μg/mL), specificity, precision and accuracy for the quantification of 12 drugs were reliable and all drugs can be analyzed within 6 min. Among 12 drugs in samples for quality control, the REMEDi HS-based method detected only 6 drugs with low accuracy, while the LC-MS/MS system was able to precisely quantify all drugs. In addition, pilot analysis of patient samples with unknown drug intoxication was superior to the conventional LC-based drug profiling system, and was rapid and cost effective. In conclusion, LC-MS/MS-based drug screening is a good replacement for conventional LC-based REMEDi analyzer and has the better clinical applicability.Keywords Liquid chromatography mass spectrometry, LC-MS/MS, REMEDi analyzer, Drug screeningThe first priority of the treatment of the poisoned patients arrived in emergency department is clinical stabilization 1,2 . Once the poisoned patients is clinically stabilized, it should be estimated the level of exposure to the poison. However, particularly in the case of intentional self-poisoning, it may be difficult to collect the information about poisons in numerous cases. The quantitative determination of plasma concentration of overdosed drug can often provide both prognostic and therapeutic guidance. For example, the plasma concentration of salicylate or acetaminophen in overdosed patient is useful to determine the therapeutic strategy using nomogram 3 . However, if health providers fail to obtain the information about poisoned drugs or chemicals, the appropriate quantitative analysis method for the determination of unknown materials will be great useful. Several tens of toxins or drugs are commonly poisoned in human. The characteristics of poisons are different according to the country, culture, socioeconomic status, or urbanization. For instance, intoxication by organophosphorus insecticides and herbicides are relatively common in rural area, whereas abused opioids or other clinical drugs are common intoxicants in urban region. The liquid chromatography with ultraviolet detection (LC/UV) platform for screening of poisoned drugs in biologic samples was widely used for several decades 4 . However, there are many limitations are present, including sensitivity, time-consuming of sample preparation, chromatographic separation, and lack of quantification. Therefore, the more efficient and precise method to
Poly(ethylene glycol) diglycidyl ether (PEGDE) is widely used to cross-link polymers, particularly in the pharmaceutical and biomaterial sectors. However, the subcutaneous toxicity of PEGDE has not yet been assessed. PEGDE samples (500–40,000 μg/mouse) were subcutaneously injected into the paraspinal dorsum of BALB/c male mice. Cage-side observations were carried out with measurement of organ weight, body weight variation, and feed intake, as well as histopathological characterization on day 28 post-exposure. Mice that received 40,000 μg of PEGDE showed severe toxic response and had to be euthanized. Subcutaneous injection of PEGDE did not alter feed intake and organ weight; however, the body weight variation of mice injected with 20,000 μg of PEGDE was significantly lower than that of the other groups. Exposure to 10,000 and 20,000 μg of PEGDE induced epidermal ulcer formation and hair loss. The histology of skin tissue in mice administered with 20,000 μg of PEGDE showed re-epithelialized or unhealed wounds. However, the liver, spleen, and kidneys were histologically normal. Collectively, PEGDE, particularly above 10,000 μg/mouse, caused subcutaneous toxicity with ulceration, but no toxicity in the other organs. These results may indicate the optimal concentration of subcutaneously injected PEGDE.
Amplification of human epidermal growth factor receptor 2 (HER2) is an oncogenic driver found in approximately 25% of breast cancer. Despite the arsenal of HER2-directed therapies available to patients, more than 50% of patients with HER2 amplification eventually develop central nervous system (CNS) metastases over the course of their disease indicating a clear medical need for brain penetrant therapies in this patient population. ORIC-114 is a brain penetrant, orally bioavailable, irreversible small molecule inhibitor that was designed to target exon20 insertions in epidermal growth factor receptor (EGFR) and HER2. ORIC-114 is highly selective for the EGFR/HER2 family of receptors, reducing the risk for off-target kinase liabilities. In biochemical assays, ORIC-114 displayed low nanomolar potency on HER2. To explore the application of ORIC-114 in the HER2-amplified tumor setting, a cell viability screen was performed against a panel of human breast cancer lines containing both HER2-amplified and non HER2-amplified cell lines. ORIC-114 demonstrated greater than 100-fold enhanced cellular potency on HER2-amplified cancer cell lines relative to non-amplified cancer cell lines. Notably, ORIC-114 cellular EC50s in HER2-amplified breast cancer cell lines were below 30 nM and more potent than both lapatinib and tucatinib, two FDA-approved tyrosine kinase inhibitors for the treatment of HER2-positive breast cancer. ORIC-114 was designed to incorporate physicochemical properties suitable to cross the blood-brain barrier and has exhibited good brain penetration across multiple preclinical species. To further investigate the brain penetrant attributes of ORIC-114 in the context of HER2-positive breast cancer with brain metastases, key features were assessed relative to tucatinib, which has demonstrated clinical efficacy in this setting. In contrast to tucatinib, ORIC-114 displayed minimal impact on efflux transporters as it was only a weak substrate for P-glycoprotein (P-gp) and was not a substrate for breast cancer associated protein (BCRP) in vitro. In addition, ORIC-114 demonstrated superior in vivo brain penetration relative to tucatinib as measured by free brain-to-plasma ratio in mouse. Consequently, ORIC-114 free brain concentrations in rodents were greater than tucatinib, even when the active metabolites of tucatinib were considered. Taken together, these data further establish ORIC-114 as a selective, irreversible, and brain penetrant EGFR/HER2 inhibitor, making it a promising therapeutic candidate for development in patients with HER2-positive tumors including those with CNS metastases. A Clinical Trial Application for ORIC-114 is anticipated in the second half of 2021. Citation Format: Melissa R. Junttila, Jason E. Long, Robert Warne, Sunghwan Kim, Younho Lee, Hwan Kim, Juhee Kang, Jiyoon Seok, Jihye Yoo, Youngyi Lee, Dong-Hyuk Seo Seo, Jung Beom Son, Daekwon Kim, Hwan Geun Choi, Nam Doo Kim, Tatiana Zavorotinskaya, Chelsea Chan, Matthew Panuwat, Jessica Sun, Jae H. Chang, Lori S. Friedman. ORIC-114, an orally bioavailable, irreversible kinase inhibitor, has superior brain penetrant properties and enhanced potency in preclinical studies of HER2-positive breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P234.
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