The Experts below are selected from a list of 33219 Experts worldwide ranked by ideXlab platform
Charles C Horn - One of the best experts on this subject based on the ideXlab platform.
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post anesthesia vomiting impact of isoflurane and morphine on ferrets and musk shrews
Physiology & Behavior, 2012Co-Authors: Charles C Horn, Kelly Meyers, Diana Pak, Allysa Nagy, Christian C Apfel, Brian A WilliamsAbstract:Although partially controlled with antiemetic drugs, postoperative nausea and vomiting (PONV) continues to be a problem for many patients. Clinical research suggests that opioid analgesics and volatile anesthetics are the main triggers of PONV. The aim of this study was to develop an animal model for post-anesthesia vomiting for future studies to further determine mechanisms and preclinical drug efficacy. Ferrets (N=34) were initially used because they have served as a gold standard for emesis research. Ferrets were tested with several doses of morphine, inhaled isoflurane, and a positive control injection of cisplatin (a Chemotherapy Agent) to induce emesis. Musk shrews (a small animal model; N=36) were also tested for emesis with isoflurane exposure. A control injection of cisplatin produced emesis in ferrets (ip, 129.8±22.0 retches; 13.7±2.3 vomits; mean ± SEM). Morphine produced a dose-response on emesis in ferrets, with maximal responses at 0.9 mg/kg (sc, 29.6±12.6 retches; 1.8±0.9, vomits). Isoflurane exposure (2–4% for 10 min to 6 h exposure) failed to induce vomiting, was not associated with an increased frequency in emesis when combined with a low dose of morphine (0.1 mg/kg, sc), and failed to produced consistent effects on food and water intake. In contrast to ferrets, musk shrews were very sensitive to isoflurane-induced emesis (0.5 to 3%, 10 min exposure; up to 11.8±2.4 emetic episodes). Overall, these results indicate that ferrets will not be useful for delineating mechanisms responsible for isoflurane-induced emesis; however, musk shrews may prove to be a model for vomiting after inhalation of volatile Agents.
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computerized detection and analysis of cancer Chemotherapy induced emesis in a small animal model musk shrew
Journal of Neuroscience Methods, 2011Co-Authors: Dong Huang, Kelly Meyers, Severine Henry, Fernando De La Torre, Charles C HornAbstract:Vomiting is a common side effect of cancer Chemotherapy and many drug treatments and diseases. In animal studies, the measurement of vomiting usually requires direct observation, which is time consuming and often lacks temporal precision. Musk shrews have been used to study the neurobiology of emesis and have a rapid emetic episode (∼1 s for a sequence of retching and expulsion). The aim of the current study was to develop a method to automatically detect and characterize emetic episodes induced by the cancer Chemotherapy Agent cisplatin. The body contour in each video frame was tracked and normalized to a parameterized shape basis. The tracked shape was projected to a feature space that maximized the shape variations in the consecutive frames during retching. The resulting one dimensional projection was sufficient to detect most emetic episodes in the acute (peak at 2h) and delayed (peak at 54 h) phases after cisplatin treatment. Emetic episodes were relatively invariant in the number of retches (∼6.2), duration (∼1.2s), inter-retch interval (∼198 ms), and amplitude during the 72 h after cisplatin treatment. This approach should open a new vista into emesis research to permit tracking and analysis of emesis in a small animal model and facilitate the development of new antiemetic therapies. These results also yield a better understanding of the brain's central pattern generator for emesis and indicate that the retching response in the musk shrew (at ∼5.4 Hz) is the fastest ever recorded in a free-moving animal.
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food restriction refeeding and gastric fill fail to affect emesis in musk shrews
American Journal of Physiology-gastrointestinal and Liver Physiology, 2010Co-Authors: Charles C Horn, Liz Still, Christiana Fitzgerald, Mark I FriedmanAbstract:Nausea and emesis are common side effects of gastrointestinal disease. Reports indicate that ghrelin and endocannabinoids, Agents that stimulate appetite, also reduce emesis evoked by Chemotherapy treatment, which suggests that stimulation of feeding inhibits the emetic system. In the following study we conducted a more direct test of this hypothesis by determining the impact of manipulating the motivation to eat on emesis, using food restriction and refeeding. Emesis was induced in musk shrews, a commonly used animal model for emesis research, using the cancer Chemotherapy Agent cisplatin (20 mg/kg ip), nicotine (2 mg/kg sc), or motion (1 Hz, horizontal, 4-cm displacement), because these treatments are known to target separate emetic pathways: gut vagal afferents, area postrema, and vestibular pathways, respectively. Twenty-four hours of food restriction was sufficient to stimulate food intake, and 1 h of refeeding filled the stomach. The results indicate that food restriction, refeeding, and gastric fill had no significant effects on the amount of emesis produced by any of the emetic treatments tested here. This suggests that, although activation of the emetic system might have prominent effects on food intake, neural controls for feeding behavior do not significantly affect the neural pathways for emesis. These results may have implications for how we treat patients who experience a constellation of side effects, including nausea and emesis, since stimulating appetite may not necessarily inhibit emetic pathways.
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Chemotherapy Agent cisplatin induces 48 h fos expression in the brain of a vomiting species the house musk shrew suncus murinus
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2009Co-Authors: Bart C De Jonghe, Charles C HornAbstract:Cancer Chemotherapy drugs, such as cisplatin, potently produce nausea and vomiting. Acute effects of these treatments are partly controlled by antiemetic drugs, but the delayed effects (>24 h), especially nausea, are more difficult to treat. It is unknown what brain pathways produce this delayed sickness. Our prior data show that brain Fos expression is increased for at least 48 h after cisplatin treatment in the rat, a nonvomiting species. Here, we extend these observations by using house musk shrews (Suncus murinus), a species with an emetic response. Compared with saline injection, cisplatin treatment (30 mg/kg ip) induced Fos expression in hindbrain areas known to play a role in the generation of emesis, the dorsal motor nucleus (DMN), the area postrema, and the nucleus of the solitary tract (NTS), for up to 48 h. Cisplatin also stimulated Fos expression in the parabrachial nucleus (PBN) of the midbrain and the central nucleus of the amygdala (CeA) for at least 48 h after treatment. When animals were pretreated with the antiemetic palonosetron, a long-term serotonin type 3 (5-HT3) receptor antagonist, cisplatin-induced Fos expression was significantly attenuated in the NTS, DMN, and CeA at 6 h but not at 48 h. These results indicate that cisplatin activates a neural system that includes the dorsal vagal complex and forebrain in the musk shrew, which is partially suppressed by a 5-HT3 receptor antagonist. Our findings suggest the existence of an extensive neural system that could be targeted to reduce nausea, vomiting, and malaise in cancer patients receiving Chemotherapy.
Mark S Berger - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of gemtuzumab ozogamicin, an antibody-targeted Chemotherapy Agent for the treatment of patients with acute myeloid leukemia in first relapse.
Journal of clinical pharmacology, 2001Co-Authors: James A. Dowell, Joan M. Korth-bradley, S. Peter King, Hanjiu Liu, Mark S BergerAbstract:The purpose of this study was to characterize the pharmacokinetics of gemtuzumab ozogamicin (Mylotarg; Wyeth-Ayerst Laboratories, St. Davids, PA) in patients with acute myeloid leukemia (AML) in first relapse. Gemtuzumab ozogamicin is an antibody-chemotherapeutic conjugate characterized as antibody-targeted Chemotherapy, consisting of an engineered human anti-CD33 antibody (hP67.6) linked to a potent cytotoxic Agent, N-acetyl-gamma calicheamicin DMH. The pharmacokinetics of gemtuzumab ozogamicin was evaluated in 59 adult AML patients in first relapse, enrolled in a phase II study. Plasma was collected following each dose at specified times, and the pharmacokinetics was characterized by measures of hP67.6, total calicheamicin derivatives, and unconjugated calicheamicin derivatives. After administration of the first 9 mg/m2 dose of gemtuzumab ozogamicin, the pharmacokinetic parameters (mean +/- SD) of hP67.6 following the first dose were as follows: peak plasma concentration, 2.86 +/- 1.35 mg/L; AUC, 123 +/- 105 mg x h/L; t 1/2, 72.4 +/- 42.0 hours; and clearance, 0.265 +/- 0.229L/h. Increased concentrations were observed after the second dose and are believed to be due to a decrease in clearance by CD33-positive blast cells, a result of the reduced tumor burden following the first dose. The concentration profiles of calicheamicin followed the same time course as hP67.6, evidence that calicheamicin remained conjugated to the antibody and delivered to leukemic cells. No relationship was found between plasma concentration and response at the recommended dose. The pharmacokinetics of gemtuzumab ozogamicin has been characterized in AML patients receiving doses at the proposed therapeutic level.
Jian Jin - One of the best experts on this subject based on the ideXlab platform.
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trpc5 induced autophagy promotes drug resistance in breast carcinoma via camkkβ ampkα mtor pathway
Scientific Reports, 2017Co-Authors: Peng Zhang, Xiaoyu Liu, Zhen Chen, Xiaoqiang Yao, Jian JinAbstract:Adriamycin is a first-line Chemotherapy Agent against cancer, but the development of resistance has become a major problem. Although autophagy is considered to be an adaptive survival response in response to Chemotherapy and may be associated with chemoresistance, its inducer and the underlying molecular mechanisms remain unclear. Here, we demonstrate that adriamycin up-regulates the both levels of TRPC5 and autophagy, and the increase in autophagy is mediated by TRPC5 in breast cancer cells. Blockade of TRPC5 or autophagy increased the sensitivity to Chemotherapy in vitro and in vivo. Notably, we revealed a positive correlation between TRPC5 and the autophagy-associated protein LC3 in paired patients with or without anthracycline-taxane-based Chemotherapy. Furthermore, pharmacological inhibition and gene-silencing showed that the cytoprotective autophagy mediated by TRPC5 during adriamycin treatment is dependent on the CaMKKβ/AMPKα/mTOR pathway. Moreover, adriamycin-resistant MCF-7/ADM cells maintained a high basal level of autophagy, and silencing of TRPC5 and inhibition of autophagy counteracted the resistance to adriamycin. Thus, our results revealed a novel role of TRPC5 as an inducer of autophagy, and this suggests a novel mechanism of drug resistance in Chemotherapy for breast cancer.
James A. Dowell - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of gemtuzumab ozogamicin, an antibody-targeted Chemotherapy Agent for the treatment of patients with acute myeloid leukemia in first relapse.
Journal of clinical pharmacology, 2001Co-Authors: James A. Dowell, Joan M. Korth-bradley, S. Peter King, Hanjiu Liu, Mark S BergerAbstract:The purpose of this study was to characterize the pharmacokinetics of gemtuzumab ozogamicin (Mylotarg; Wyeth-Ayerst Laboratories, St. Davids, PA) in patients with acute myeloid leukemia (AML) in first relapse. Gemtuzumab ozogamicin is an antibody-chemotherapeutic conjugate characterized as antibody-targeted Chemotherapy, consisting of an engineered human anti-CD33 antibody (hP67.6) linked to a potent cytotoxic Agent, N-acetyl-gamma calicheamicin DMH. The pharmacokinetics of gemtuzumab ozogamicin was evaluated in 59 adult AML patients in first relapse, enrolled in a phase II study. Plasma was collected following each dose at specified times, and the pharmacokinetics was characterized by measures of hP67.6, total calicheamicin derivatives, and unconjugated calicheamicin derivatives. After administration of the first 9 mg/m2 dose of gemtuzumab ozogamicin, the pharmacokinetic parameters (mean +/- SD) of hP67.6 following the first dose were as follows: peak plasma concentration, 2.86 +/- 1.35 mg/L; AUC, 123 +/- 105 mg x h/L; t 1/2, 72.4 +/- 42.0 hours; and clearance, 0.265 +/- 0.229L/h. Increased concentrations were observed after the second dose and are believed to be due to a decrease in clearance by CD33-positive blast cells, a result of the reduced tumor burden following the first dose. The concentration profiles of calicheamicin followed the same time course as hP67.6, evidence that calicheamicin remained conjugated to the antibody and delivered to leukemic cells. No relationship was found between plasma concentration and response at the recommended dose. The pharmacokinetics of gemtuzumab ozogamicin has been characterized in AML patients receiving doses at the proposed therapeutic level.
Gary D Kao - One of the best experts on this subject based on the ideXlab platform.
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the hdac inhibitor panobinostat lbh589 inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer
Molecular Cancer Therapeutics, 2009Co-Authors: Cecilia M Crisanti, Africa F Wallace, Veena Kapoor, Fabian Vandermeers, Melissa L Dowling, Luana Pereira, Kara Coleman, Barbara G Campling, Zvi G Fridlender, Gary D KaoAbstract:Lung cancer is the leading cause of cancer deaths in the United States. Current therapies are inadequate. Histone deacetylase inhibitors (HDACi) are a recently developed class of anticancer Agents that cause increased acetylation of core histones and nonhistone proteins leading to modulation of gene expression and protein activity involved in cancer cell growth and survival pathways. We examined the efficacy of the HDACi panobinostat (LBH589) in a wide range of lung cancers and mesotheliomas. Panobinostat was cytotoxic in almost all 37 cancer cell lines tested. IC(50) and LD(50) values were in the low nmol/L range (4-470 nmol/L; median, 20 nmol/L). Small cell lung cancer (SCLC) cell lines were among the most sensitive lines, with LD(50) values consistently <25 nmol/L. In lung cancer and mesothelioma animal models, panobinostat significantly decreased tumor growth by an average of 62% when compared with vehicle control. Panobinostat was equally effective in immunocompetent and severe combined immunodeficiency mice, indicating that the inhibition of tumor growth by panobinostat was not due to direct immunologic effects. Panobinostat was, however, particularly effective in SCLC xenografts, and the addition of the Chemotherapy Agent etoposide augmented antitumor effects. Protein analysis of treated tumor biopsies revealed elevated amounts of cell cycle regulators such as p21 and proapoptosis factors, such as caspase 3 and 7 and cleaved poly[ADP-ribose] polymerase, coupled with decreased levels of antiapoptotic factors such as Bcl-2 and Bcl-X(L). These studies together suggest that panobinostat may be a useful adjunct in the treatment of thoracic malignancies, especially SCLC.