Browsing by Subject "Drug Evaluation, Preclinical"
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Item Open Access An update on the progress of galidesivir (BCX4430), a broad-spectrum antiviral.(Antiviral research, 2021-09-20) Julander, Justin G; Demarest, James F; Taylor, Ray; Gowen, Brian B; Walling, Dennis M; Mathis, Amanda; Babu, YSGalidesivir (BCX4430) is an adenosine nucleoside analog that is broadly active in cell culture against several RNA viruses of various families. This activity has also been shown in animal models of viral disease associated with Ebola, Marburg, yellow fever, Zika, and Rift Valley fever viruses. In many cases, the compound is more efficacious in animal models than cell culture activity would predict. Based on favorable data from in vivo animal studies, galidesivir has recently undergone evaluation in several phase I clinical trials, including against severe acute respiratory syndrome coronavirus 2, and as a medical countermeasure for the treatment of Marburg virus disease.Item Open Access Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation(Expert review of hematology, 2016-01) Ghadimi, K; Welsby, IJ; Levy, JH; Dombrowski, KEAndexanet alfa is a specific reversal agent for Factor Xa inhibitors. The molecule is a recombinant protein analog of factor Xa that binds to Factor Xa inhibitors and antithrombin:LMWH complex but does not trigger prothrombotic activity. In ex vivo, animal, and volunteer human studies, andexanet alfa (AnXa) was able to dose-dependently reverse Factor Xa inhibition and restore thrombin generation for the duration of drug administration. Further trials are underway to examine its safety and efficacy in the population of patients experiencing FXa inhibitor-related bleeding.Item Open Access Anti-inflammatory effects of progesterone in lipopolysaccharide-stimulated BV-2 microglia.(PLoS One, 2014) Lei, Beilei; Mace, Brian; Dawson, Hana N; Warner, David S; Laskowitz, Daniel T; James, Michael LFemale sex is associated with improved outcome in experimental brain injury models, such as traumatic brain injury, ischemic stroke, and intracerebral hemorrhage. This implies female gonadal steroids may be neuroprotective. A mechanism for this may involve modulation of post-injury neuroinflammation. As the resident immunomodulatory cells in central nervous system, microglia are activated during acute brain injury and produce inflammatory mediators which contribute to secondary injury including proinflammatory cytokines, and nitric oxide (NO) and prostaglandin E2 (PGE2), mediated by inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively. We hypothesized that female gonadal steroids reduce microglia mediated neuroinflammation. In this study, the progesterone's effects on tumor necrosis factor alpha (TNF-α), iNOS, and COX-2 expression were investigated in lipopolysaccharide (LPS)-stimulated BV-2 microglia. Further, investigation included nuclear factor kappa B (NF-κB) and mitogen activated protein kinase (MAPK) pathways. LPS (30 ng/ml) upregulated TNF-α, iNOS, and COX-2 protein expression in BV-2 cells. Progesterone pretreatment attenuated LPS-stimulated TNF-α, iNOS, and COX-2 expression in a dose-dependent fashion. Progesterone suppressed LPS-induced NF-κB activation by decreasing inhibitory κBα and NF-κB p65 phosphorylation and p65 nuclear translocation. Progesterone decreased LPS-mediated phosphorylation of p38, c-Jun N-terminal kinase and extracellular regulated kinase MAPKs. These progesterone effects were inhibited by its antagonist mifepristone. In conclusion, progesterone exhibits pleiotropic anti-inflammatory effects in LPS-stimulated BV-2 microglia by down-regulating proinflammatory mediators corresponding to suppression of NF-κB and MAPK activation. This suggests progesterone may be used as a potential neurotherapeutic to treat inflammatory components of acute brain injury.Item Open Access Cost of innovation in the pharmaceutical industry.(J Health Econ, 1991-07) DiMasi, JA; Hansen, RW; Grabowski, HG; Lasagna, LThe research and development costs of 93 randomly selected new chemical entities (NCEs) were obtained from a survey of 12 U.S.-owned pharmaceutical firms. These data were used to estimate the pre-tax average cost of new drug development. The costs of abandoned NCEs were linked to the costs of NCEs that obtained marketing approval. For base case parameter values, the estimated out-of-pocket cost per approved NCE is $114 million (1987 dollars). Capitalizing out-of-pocket costs to the point of marketing approval at a 9% discount rate yielded an average cost estimate of $231 million (1987 dollars).Item Open Access Monosodium urate crystal induced macrophage inflammation is attenuated by chondroitin sulphate: pre-clinical model for gout prophylaxis?(BMC Musculoskelet Disord, 2014-09-27) Orlowsky, EW; Stabler, TV; Montell, E; Vergés, J; Kraus, VBBACKGROUND: Chondroitin Sulphate (CS), a natural glycosaminoglycan of the extracellular matrix, has clinical benefit in symptomatic osteoarthritis but has never been tested in gout. In vitro, CS has anti-inflammatory and positive effects on osteoarthritic chondrocytes, synoviocytes and subchondral bone osteoblasts, but its effect on macrophages is unknown. The purpose of our study was to evaluate the in vitro effects of CS on monosodium urate (MSU)-stimulated cytokine production by macrophages. METHODS: THP-1 monocytes were differentiated into mature macrophages using a phorbol ester, pretreated for 4 hours with CS in a physiologically achievable range of concentrations (10-200 μg/ml) followed by MSU crystal stimulation for 24 hours. Cell culture media were analyzed by immunoassay for factors known to be upregulated during gouty inflammation including IL-1β, IL-8 and TNFα. The specificity of inflammasome activation by MSU crystals was tested with a caspase-1 inhibitor (0.01 μM-10 μM). RESULTS: MSU crystals ≥10 mg/dl increased macrophage production of IL-1β, IL-8 and TNFα a mean 7-, 3- and 4-fold respectively. Induction of IL-1β by MSU was fully inhibited by a caspase-1 inhibitor confirming inflammasome activation as the mechanism for generating this cytokine. In a dose-dependent manner, CS significantly inhibited IL-1β (p = 0.003), and TNFα (p = 0.02) production from macrophages in response to MSU. A similar trend was observed for IL-8 but was not statistically significant (p = 0.41). CONCLUSIONS: CS attenuated MSU crystal induced macrophage inflammation, suggesting a possible role for CS in gout prophylaxis.Item Open Access Monosodium urate crystal induced macrophage inflammation is attenuated by chondroitin sulphate: pre-clinical model for gout prophylaxis?(BMC musculoskeletal disorders, 2014-09-27) Orlowsky, Eric W; Stabler, Thomas V; Montell, Eulàlia; Vergés, Josep; Kraus, Virginia ByersChondroitin Sulphate (CS), a natural glycosaminoglycan of the extracellular matrix, has clinical benefit in symptomatic osteoarthritis but has never been tested in gout. In vitro, CS has anti-inflammatory and positive effects on osteoarthritic chondrocytes, synoviocytes and subchondral bone osteoblasts, but its effect on macrophages is unknown. The purpose of our study was to evaluate the in vitro effects of CS on monosodium urate (MSU)-stimulated cytokine production by macrophages.THP-1 monocytes were differentiated into mature macrophages using a phorbol ester, pretreated for 4 hours with CS in a physiologically achievable range of concentrations (10-200 μg/ml) followed by MSU crystal stimulation for 24 hours. Cell culture media were analyzed by immunoassay for factors known to be upregulated during gouty inflammation including IL-1β, IL-8 and TNFα. The specificity of inflammasome activation by MSU crystals was tested with a caspase-1 inhibitor (0.01 μM-10 μM).MSU crystals ≥10 mg/dl increased macrophage production of IL-1β, IL-8 and TNFα a mean 7-, 3- and 4-fold respectively. Induction of IL-1β by MSU was fully inhibited by a caspase-1 inhibitor confirming inflammasome activation as the mechanism for generating this cytokine. In a dose-dependent manner, CS significantly inhibited IL-1β (p = 0.003), and TNFα (p = 0.02) production from macrophages in response to MSU. A similar trend was observed for IL-8 but was not statistically significant (p = 0.41).CS attenuated MSU crystal induced macrophage inflammation, suggesting a possible role for CS in gout prophylaxis.Item Open Access Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model.(International journal of radiation oncology, biology, physics, 2015-11) Ashcraft, Kathleen A; Boss, Mary-Keara; Tovmasyan, Artak; Roy Choudhury, Kingshuk; Fontanella, Andrew N; Young, Kenneth H; Palmer, Gregory M; Birer, Samuel R; Landon, Chelsea D; Park, Won; Das, Shiva K; Weitner, Tin; Sheng, Huaxin; Warner, David S; Brizel, David M; Spasojevic, Ivan; Batinic-Haberle, Ines; Dewhirst, Mark WPurpose
To test the effects of a novel Mn porphyrin oxidative stress modifier, Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE), for its radioprotective and radiosensitizing properties in normal tissue versus tumor, respectively.Methods and materials
Murine oral mucosa and salivary glands were treated with a range of radiation doses with or without MnBuOE to establish the dose-effect curves for mucositis and xerostomia. Radiation injury was quantified by intravital near-infrared imaging of cathepsin activity, assessment of salivation, and histologic analysis. To evaluate effects of MnBuOE on the tumor radiation response, we administered the drug as an adjuvant to fractionated radiation of FaDu xenografts. Again, a range of radiation therapy (RT) doses was administered to establish the radiation dose-effect curve. The 50% tumor control dose values with or without MnBuOE and dose-modifying factor were determined.Results
MnBuOE protected normal tissue by reducing RT-mediated mucositis, xerostomia, and fibrosis. The dose-modifying factor for protection against xerostomia was 0.77. In contrast, MnBuOE increased tumor local control rates compared with controls. The dose-modifying factor, based on the ratio of 50% tumor control dose values, was 1.3. Immunohistochemistry showed that MnBuOE-treated tumors exhibited a significant influx of M1 tumor-associated macrophages, which provides mechanistic insight into its radiosensitizing effects in tumors.Conclusions
MnBuOE widens the therapeutic margin by decreasing the dose of radiation required to control tumor, while increasing normal tissue resistance to RT-mediated injury. This is the first study to quantitatively demonstrate the magnitude of a single drug's ability to radioprotect normal tissue while radiosensitizing tumor.Item Open Access Otoprotective Effects of Stephania tetrandra S. Moore Herb Isolate against Acoustic Trauma.(Journal of the Association for Research in Otolaryngology : JARO, 2018-12) Yu, Yan; Hu, Bing; Bao, Jianxin; Mulvany, Jessica; Bielefeld, Eric; Harrison, Ryan T; Neton, Sarah A; Thirumala, Partha; Chen, Yingying; Lei, Debin; Qiu, Ziyu; Zheng, Qingyin; Ren, Jihao; Perez-Flores, Maria Cristina; Yamoah, Ebenezer N; Salehi, PezhmanNoise is the most common occupational and environmental hazard, and noise-induced hearing loss (NIHL) is the second most common form of sensorineural hearing deficit. Although therapeutics that target the free-radical pathway have shown promise, none of these compounds is currently approved against NIHL by the United States Food and Drug Administration. The present study has demonstrated that tetrandrine (TET), a traditional Chinese medicinal alkaloid and the main chemical isolate of the Stephania tetrandra S. Moore herb, significantly attenuated NIHL in CBA/CaJ mice. TET is known to exert antihypertensive and antiarrhythmic effects through the blocking of calcium channels. Whole-cell patch-clamp recording from adult spiral ganglion neurons showed that TET blocked the transient Ca2+ current in a dose-dependent manner and the half-blocking concentration was 0.6 + 0.1 μM. Consistent with previous findings that modulations of calcium-based signaling pathways have both prophylactic and therapeutic effects against neural trauma, NIHL was significantly diminished by TET administration. Importantly, TET has a long-lasting protective effect after noise exposure (48 weeks) in comparison to 2 weeks after noise exposure. The otoprotective effects of TET were achieved mainly by preventing outer hair cell damage and synapse loss between inner hair cells and spiral ganglion neurons. Thus, our data indicate that TET has great potential in the prevention and treatment of NIHL.Item Open Access Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) Shows Efficacy Against Osteosarcoma.(Molecular cancer therapeutics, 2020-07) Reddy, Gireesh B; Kerr, David L; Spasojevic, Ivan; Tovmasyan, Artak; Hsu, David S; Brigman, Brian E; Somarelli, Jason A; Needham, David; Eward, William CTherapeutic advances for osteosarcoma have stagnated over the past several decades, leading to an unmet clinical need for patients. The purpose of this study was to develop a novel therapy for osteosarcoma by reformulating and validating niclosamide, an established anthelminthic agent, as a niclosamide stearate prodrug therapeutic (NSPT). We sought to improve the low and inefficient clinical bioavailability of oral dosing, especially for the relatively hydrophobic classes of anticancer drugs. Nanoparticles were fabricated by rapid solvent shifting and verified using dynamic light scattering and UV-vis spectrophotometry. NSPT efficacy was then studied in vitro for cell viability, cell proliferation, and intracellular signaling by Western blot analysis; ex vivo pulmonary metastatic assay model; and in vivo pharmacokinetic and lung mouse metastatic model of osteosarcoma. NSPT formulation stabilizes niclosamide stearate against hydrolysis and delays enzymolysis; increases circulation in vivo with t 1/2 approximately 5 hours; reduces cell viability and cell proliferation in human and canine osteosarcoma cells in vitro at 0.2-2 μmol/L IC50; inhibits recognized growth pathways and induces apoptosis at 20 μmol/L; eliminates metastatic lesions in the ex vivo lung metastatic model; and when injected intravenously at 50 mg/kg weekly, it prevents metastatic spread in the lungs in a mouse model of osteosarcoma over 30 days. In conclusion, niclosamide was optimized for preclinical drug delivery as a unique prodrug nanoparticle injected intravenously at 50 mg/kg (1.9 mmol/L). This increased bioavailability of niclosamide in the blood stream prevented metastatic disease in the mouse. This chemotherapeutic strategy is now ready for canine trials, and if successful, will be targeted for human trials in patients with osteosarcoma.Item Open Access Rapid tissue prototyping with micro-organospheres.(Stem cell reports, 2022-09) Wang, Zhaohui; Boretto, Matteo; Millen, Rosemary; Natesh, Naveen; Reckzeh, Elena S; Hsu, Carolyn; Negrete, Marcos; Yao, Haipei; Quayle, William; Heaton, Brook E; Harding, Alfred T; Bose, Shree; Driehuis, Else; Beumer, Joep; Rivera, Grecia O; van Ineveld, Ravian L; Gex, Donald; DeVilla, Jessica; Wang, Daisong; Puschhof, Jens; Geurts, Maarten H; Yeung, Athena; Hamele, Cait; Smith, Amber; Bankaitis, Eric; Xiang, Kun; Ding, Shengli; Nelson, Daniel; Delubac, Daniel; Rios, Anne; Abi-Hachem, Ralph; Jang, David; Goldstein, Bradley J; Glass, Carolyn; Heaton, Nicholas S; Hsu, David; Clevers, Hans; Shen, XilingIn vitro tissue models hold great promise for modeling diseases and drug responses. Here, we used emulsion microfluidics to form micro-organospheres (MOSs), which are droplet-encapsulated miniature three-dimensional (3D) tissue models that can be established rapidly from patient tissues or cells. MOSs retain key biological features and responses to chemo-, targeted, and radiation therapies compared with organoids. The small size and large surface-to-volume ratio of MOSs enable various applications including quantitative assessment of nutrient dependence, pathogen-host interaction for anti-viral drug screening, and a rapid potency assay for chimeric antigen receptor (CAR)-T therapy. An automated MOS imaging pipeline combined with machine learning overcomes plating variation, distinguishes tumorspheres from stroma, differentiates cytostatic versus cytotoxic drug effects, and captures resistant clones and heterogeneity in drug response. This pipeline is capable of robust assessments of drug response at individual-tumorsphere resolution and provides a rapid and high-throughput therapeutic profiling platform for precision medicine.Item Open Access Reported lifetime aberrant drug-taking behaviors are predictive of current substance use and mental health problems in primary care patients.(Pain Med, 2008-11) Fleming, Michael F; Davis, James; Passik, Steven DBACKGROUND: The aim of this report is to determine the frequency of aberrant drug behaviors and their relationship to substance abuse disorders in a large primary sample of patients receiving opioids for chronic pain. METHODS: The data utilized for this report was obtained from 904 chronic pain patients receiving opioid therapy from their primary care physician. A questionnaire was developed based on 12 aberrant drug behaviors reported in the clinical literature. The diagnosis of a current substance use disorder was determined using Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition(DSM-IV) criteria. RESULTS: The average duration of chronic pain in the sample was 16 years and for opioid therapy, 6.4 years. Of the patients, 80.5% reported one or more lifetime aberrant drug behaviors. The most frequent behaviors reported included early refills (41.7%), increase dose without physician consent (35.7%), and felt intoxicated from opioids (32.2%). Only 1.1% of subjects with 1-3 aberrant behaviors (N = 464, 51.2%) met DSM-IV criteria for current opioid dependence compared with 9.9% of patients with four or more behaviors (N = 264, 29.3%). Persons with positive urine toxicology tests for cocaine were 14 times more likely to report four or more behaviors than no behaviors (14.1% vs 1.1%). A logistic model found that subjects who reported four or more aberrant behaviors were more likely to have a current substance use disorder (odds ratio [OR] 10.14; 3.72, 27.64), a positive test for cocaine (odds ratio [OR] 3.01; 1.74, 15.4), an Addiction Severity Index (ASI) psychiatric composite score >0.5 (OR 2.38; 1.65, 3.44), male gender (OR 2.08: 1.48, 2.92), and older age (OR 0.69; 0.59, 0.81) compared with subjects with three or fewer behaviors. Pain levels, employment status, and morphine equivalent dose do not enter the model. CONCLUSIONS: Patients who report four or more aberrant drug behaviors are associated with a current substance use disorder and illicit drug use, whereas subjects with up to three aberrant behaviors have a very low probability of a current substance abuse disorder. Four behaviors--oversedated oneself, felt intoxicated, early refills, increase dose on own--appear useful as screening questions to predict patients at greatest risk for a current substance use disorders.Item Open Access The price of innovation: new estimates of drug development costs.(J Health Econ, 2003-03) DiMasi, Joseph A; Hansen, Ronald W; Grabowski, Henry GThe research and development costs of 68 randomly selected new drugs were obtained from a survey of 10 pharmaceutical firms. These data were used to estimate the average pre-tax cost of new drug development. The costs of compounds abandoned during testing were linked to the costs of compounds that obtained marketing approval. The estimated average out-of-pocket cost per new drug is 403 million US dollars (2000 dollars). Capitalizing out-of-pocket costs to the point of marketing approval at a real discount rate of 11% yields a total pre-approval cost estimate of 802 million US dollars (2000 dollars). When compared to the results of an earlier study with a similar methodology, total capitalized costs were shown to have increased at an annual rate of 7.4% above general price inflation.