Browsing by Subject "Drugs"

Now showing 1 - 10 of 21
  • Thumbnail Image
    Item
    Alcohol exposure disrupts mu opioid receptor-mediated long-term depression at insular cortex inputs to dorsolateral striatum
    (Nature Publishing group, 2018-04-03) Muñoz, Braulio; Fritz, Brandon M.; Yin, Fuqin; Atwood, Brady K.; Psychiatry, School of Medicine
    Drugs of abuse, including alcohol, ablate the expression of specific forms of long-term synaptic depression (LTD) at glutamatergic synapses in dorsal striatum (DS), a brain region involved in goal-directed and habitual behaviors. This loss of LTD is associated with altered DS-dependent behavior. Given the role of the µ-opioid receptor (MOR) in behavioral responding for alcohol, we explored the impact of alcohol on various forms of MOR-mediated synaptic depression that we find are differentially expressed at specific DS synapses. Corticostriatal MOR-mediated LTD (mOP-LTD) in the dorsolateral striatum occurs exclusively at inputs from anterior insular cortex and is selectively disrupted by in vivo alcohol exposure. Alcohol has no effect on corticostriatal mOP-LTD in dorsomedial striatum, thalamostriatal MOR-mediated short-term depression, or mOP-LTD of cholinergic interneuron-driven glutamate release. Disrupted mOP-LTD at anterior insular cortex–dorsolateral striatum synapses may therefore be a key mechanism of alcohol-induced neuroadaptations involved in the development of alcohol use disorders., µ-opioid receptors (MOR) are known to modulate the reward effects of drugs of abuse, and MOR activation induces long-term depression (LTD) at striatal synapses. Here the authors show that alcohol exposure disrupts MOR-induced LTD only at specific cortical inputs to the striatum.
  • Thumbnail Image
    Item
    Biosimilars—Emerging Role in Nephrology
    (American Society of Nephrology, 2019-09-01) Wish, Jay B.; Medicine, School of Medicine
    The Food and Drug Administration (FDA) defines a “biosimilar” agent as a biologic that is highly similar to the reference or originator biologic product notwithstanding minor differences in clinically inactive components with no clinically meaningful differences in terms of the safety, purity, and potency. The advantage of biosimilars is that they are usually about 15%–30% less expensive than the reference product, which results in system-wide cost savings and increased patient access. Because biologic drugs are produced by living organisms, they are by nature heterogeneous and identical copies cannot be made, unlike generic versions of small-molecule drugs. Proposed biosimilars must undergo a rigorous evaluation process to demonstrate a high degree of structural and functional similarity with the reference biologic. Once that is confirmed, a stepwise process of comparison with the reference agent with regard to animal trials, pharmacokinetics/pharmacodynamics, immunogenicity, and human efficacy/safety is conducted. The experience with biosimilars in other highly regulated markets where patent protection for originator biologics is not as robust as in the United States has been favorable in terms of safety, efficacy, and cost savings. An FDA approval pathway was created in 2009 to expedite the approval of biosimilars; as of early 2018 nine agents had been approved through that pathway, none in nephrology. The first United States biosimilar epoetin was approved on May 15, 2018, but does not have an interchangeability designation, meaning that prescribers must specifically write for the biosimilar product for patients to receive it. Given the unfamiliarity of biosimilars within the nephrology community it is recommended that educational programs be developed to address this unmet need and for research to be conducted addressing the perceptual, clinical, and economic effect of biosimilars on our patients.
  • Thumbnail Image
    Item
  • Thumbnail Image
    Item
    Daily Situational Brief, January 29, 2015
    (MESH Coalition, 1/29/2015) MESH Coalition
  • Thumbnail Image
    Item
    The Demographics of Non-motor Vehicle Associated Railway Injuries Seen at Trauma Centers in the United States 2007 - 2014
    (Cureus, 2019-10) Raymond, Jodi; Loder, Randall T.; Schneble, Christopher A.; Orthopaedic Surgery, School of Medicine
    Introduction The majority of railway injury studies are limited by small sample size, restricted to a small geographical distribution, or located outside the United States (US). The aim of our study was to assess the demographic patterns associated with non-motor vehicle railway injuries in the US using a national trauma center database. Materials and Methods Data from the National Trauma Data Bank data from 2007 - 2014 were used; 3,506 patients were identified. For all statistical analyses, a p-value < 0.05 was considered significant. Results The patients were 81% male with an average age of 38.6 + 17.1 years and an Injury Severity Score (ISS) of 16.8 + 13.8. Males compared to females were younger (37.7 vs 42.5 years, p = 0.000002), had greater length of stays (12.7 vs 9.8 days, p = 0.000006), and higher ISS scores (17.1 vs 15.4, p = 0.0007). The geographic distribution within the US was most common in the South (32.0%) and least in the Northeast (18.9%). The racial composition was 67.5% White, 19.1% Black, 11.5% Hispanic/Latino, and 1.9% others. The most common mechanisms of injury were hitting/colliding with rolling stock (38.6%), followed by a fall in or from a train (19.5%), and collision with an object (13.5%). The majority of patients were pedestrians or passengers (68.5%); employees accounted for 12.5%. Although the majority were pedestrian/passengers for all regions, the Midwest had a greater proportion of employees (22.0%) compared to the other regions (7.8% to 12.2%) (p < 10-6), and thus injuries were more commonly work-related (24.6% vs 6.7% - 13.7%, p < 10-6). Work-related injuries were less severe (ISS 11.2 vs 17.3 - p < 10-6) and more commonly occurred due to a fall (32.8% vs 17.9%, p < 10-6). Alcohol and/or drug involvement was present in 40.7% and was less in those with work-related injuries (2.2%). Overall mortality was 6.4% and was less in those having a work-related injury (2.0 vs 6.6% p = 0.000004). Conclusion For non-motor vehicle USA railway injuries, the average age was 38.5 years; 80.6% were male. The injuries were least common in the Northeast and most common in the South. Racial distribution mirrored that of the US population. Alcohol involvement was present in 29%, lower than in previous studies. Mortality was 6.4%, also lower than previously reported.
  • Thumbnail Image
    Item
    Design and implementation of gas chromatography-mass spectrometry (GC-MS) methodologies for the analysis of thermally labile drugs and explosives
    (2016-11-18) Ash, Jordan R.; Goodpaster, John V.
    Gas Chromatography/Mass Spectrometry (GC/MS) is an analytical technique that sees frequent use in labs across the world. It is also one of the most common instruments found in forensic science laboratories. This technique can efficiently and accurately separate and identify a broad range of compounds that may be present in evidence submitted for analysis. In this work, the versatility of this instrument was applied to new methodologies for the detection of explosives and illicit drugs. The analysis of explosives by GC/MS is common but can be problematic. The thermally sensitive nature of some explosives can cause them to degrade when introduced to the high temperatures of a GC/MS inlet. This project looked at the design and implementation of a way to separate and detect a variety of nitrate ester explosives in a short amount of time. In addition to this, a new technique known as Total Vaporization-Solid Phase Microextraction (TV-SPME) was utilized as a pre concentration technique. The parameters for TV-SPME were statistically optimized for a low level of detection. The combination of these areas allowed for the separation of ethylene glycol dinitrate, nitroglycerin, erythritol tetranitrate, and pentaerythritol tetranitrate with a detection limit as low as 50 parts per trillion (ppt). Degradation products such as 1-mononitroglycerin, 1-3-dinitroglycerin, and 2-mononitroglycerin were also successfully identified. The problem of thermally labile compounds extends to the world of illicit drugs. In the second project, several derivatization schemes were developed for common controlled substances. N,O-Bis(trimethylsilyl)trifluoroacetamide (BSTFA) with 1% trimethylchlorosilane (TMCS) was used for silylation, trifluoroacetic anhydride (TFAA) was sued for acylation, and (N,N-Dimethylformamide dimethyl acetal (DMF-DMA) for alkylation. Three different compound classes totaling 15 different drugs were investigated. N,N-Dimethylformamide dimethyl acetal (DMF-DMA) is presented as a novel way of derivatizing several drugs of interest. Primary amines and zwitterions were derivatized with this reagent to much success, specifically: amphetamine, 2-(4-Iodo-2,5-dimethoxyphenyl)ethan-1-amine (2C-I), pregabalin, and gabapentin.
  • Thumbnail Image
    Item
    Detection of Illicit Drugs in Various Matrices Via Total Vaporization Solid-Phase Microextraction
    (2019-08) Davis, Kymeri Elizabeth; Goodpaster, John; Manicke, Nicholas; Deiss, Frédérique
    In Headspace Solid-Phase Microextraction (Headspace SPME), a sample is heated to encourage a portion of the analyte into the headspace of a vial. A coated fiber is introduced into the sample headspace and the analyte is adsorbed onto the fiber coating. Total Vaporization Solid-Phase Microextraction (TV-SPME) is a technique that is derived from this technique. In TV-SPME, liquid samples are completely vaporized allowing for better adsorption and fewer matrix effects. This method does not require any sample preparation, utilizes minimal supplies and can be automated, making it both an efficient and cost-effective method. Chapter 1 will discuss the theory of SPME and TV-SPME. In Chapter 2, the detection of ɣ-hydroxybutyric acid (GHB) and ɣ-butyrolactone (GBL) in beverages is discussed. The detection of these compounds in beverages is of importance because these drugs may be used to facilitate sexual assault. This crime utilizes substances that cause sedation and memory loss. The derivatization of GHB as well as the properties that make GHB difficult to detect will be discussed. Chapter 3 will discuss the detection of methamphetamine and amphetamine (as their trifluoroacetyl derivatives), GBL, and the trimethylsilyl derivative of GHB in human urine. Amphetamine is a metabolite of methamphetamine, therefore, both drugs should be identified within biological samples. GHB and GBL are metabolites of one another and interconvert when in aqueous solution. This interconversion will be discussed. Chapter 4 will cover method optimization of the Total Vaporization Solid-Phase Microextraction method. Analytes of interest for these analyses were methamphetamine, amphetamine, GHB, and GBL. The optimal extraction temperature ranging from 60-160°C of each drug will be discussed as well as why higher temperatures may not be suitable for this method. A limit of detection study for methamphetamine and amphetamine will also be covered. Chapter 5, the future work chapter, will discuss future analyses using the Total Vaporization Solid-Phase Microextraction method including the analysis of powder materials, plant material, and toxicological samples. Powder material will include the analysis of individual powdered drugs as well as realistic drug mixtures. Some analyses on individual powder samples has already been completed and will be shown. Plant material will include the analysis of naturally occurring compounds found in marijuana plants as well as synthetic cannabinoids. Toxicological samples will expand on previously mentioned urine samples to include drugs such as benzoylecgonine and THC-COOH.
  • Thumbnail Image
    Item
  • Thumbnail Image
    Item
    Effects of PERK eIF2α Kinase Inhibitor against Toxoplasma gondii
    (American Society for Microbiology, 2018-10-24) Augusto, Leonardo; Martynowicz, Jennifer; Staschke, Kirk A.; Wek, Ronald C.; Sullivan, William J., Jr.; Biochemistry and Molecular Biology, School of Medicine
    Toxoplasma gondii is an obligate intracellular parasite that has infected one-third of the population. Upon infection of warm-blooded vertebrates, the replicating form of the parasite (tachyzoite) converts into a latent form (bradyzoite) present in tissue cysts. During immune deficiency, bradyzoites can reconvert into tachyzoites and cause life-threatening toxoplasmosis. We previously reported that translational control through phosphorylation of the α subunit of T. gondii eukaryotic initiation factor 2 (eIF2α) (TgIF2α) is a critical component of the parasite stress response. Diverse stresses can induce the conversion of tachyzoites to bradyzoites, including those disrupting the parasite's endoplasmic reticulum (ER) (ER stress). Toxoplasma possesses four eIF2α kinases, one of which (TgIF2K-A) localizes to the parasite ER analogously to protein kinase R-like endoplasmic reticulum kinase (PERK), the eIF2α kinase that responds to ER stress in mammalian cells. Here, we investigated the effects of a PERK inhibitor (PERKi) on Toxoplasma Our results show that the PERKi GSK2606414 blocks the enzymatic activity of TgIF2K-A and reduces TgIF2α phosphorylation specifically in response to ER stress. PERKi also significantly impeded multiple steps of the tachyzoite lytic cycle and sharply lowered the frequency of bradyzoite differentiation in vitro Pretreatment of host cells with PERKi prior to infection did not affect parasite infectivity, and PERKi still impaired parasite replication in host cells lacking PERK. In mice, PERKi conferred modest protection from a lethal dose of Toxoplasma Our findings represent the first pharmacological evidence supporting TgIF2K-A as an attractive new target for the treatment of toxoplasmosis.
  • Thumbnail Image
    Item