pharmacokinetic tolerance

Here is a quick glance at what we covered in this lesson. Methods: This was a single-center , randomized, single-dose, three-way crossover design study . - Pharmacokinetic tolerance Also called metabolic tolerance, pharmacokinetic tolerance occurs when the absorption of a drug is reduced, or its metabolism is increased. 0000014824 00000 n Nine eligible . All rights reserved. copyright 2003-2022 Study.com. Tolerance is reversible. I feel like its a lifeline. 0000025290 00000 n Pharmacokinetic tolerance also called metabolic or. Eventually, your body will get used to having some amount of alcohol in it each day. ClinicalTrials.gov Identifier: NCT03714568 Pharmacokinetics and Pharmacodynamics Wiley-Blackwell Updated with new chapters and topics, this book provides a comprehensive description of all essential topics in contemporary pharmacokinetics and pharmacodynamics. 0000020238 00000 n Pharmacol Ther 121(3):285293, Shippenberg TS, Zapata A, Chefer VI (2007) Dynorphin and the pathophysiology of drug addiction. Annu Rev Neurosci 27:107144, Martin BR, Sim-Selley LJ, Selley DE (2004) Signaling pathways involved in the development of cannabinoid tolerance. The aim of this study is to investigate the pharmacokinetics and tolerance of DAS injection in healthy Chinese volunteers. Provided by the Springer Nature SharedIt content-sharing initiative, Over 10 million scientific documents at your fingertips, Not logged in A review of the pharmacokinetics of cefpodoxime proxetil. This site needs JavaScript to work properly. Pharmacokinetic properties of BI 456906 For pharmacokinetic analysis, male C57BL/6NRj mice (Janvier, France) were given a single intravenous (IV) or subcutaneous (SC) BI 456906 dose (20 nmol . 0000012534 00000 n Cefpodoxime proxetil, a third generation, broad-spectrum, oral cephalosporin, was administered in single doses of 100, 200, 400, 600, and 800 mg (dose expressed as cefpodoxime equivalents) and multiple doses of 100, 200, and 400 mg twice daily to healthy volunteers. Pharmacokinetics of Paracetamol and Dexchlorpheniramine maleate oral solution in healthy volunteers. 0000048562 00000 n Psychological Drug Tolerance, Pharmacokinetic vs. Pharmacodynamic Tolerance, Melatonin Supplements: Definition, Uses & Side Effects, What is Depyrogenation? Another easy way to remember what pharmacokinetics means is to reference the definition of 'kinetics'. For more information about this format, please see the Archive Torrents collection. Antimicrob Agents Chemother. PMC We conducted this study only on a very limited number of animals for obvious ethical reasons, as we looked at the toxic effects of 5-FC. The pharmacodynamic and tolerance model accounted for the baseline effect, the effect induced by the drug, and the regulatory mechanism that opposes the effect of the drug. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential. - Definition & Methods Quiz, Psychological Research & Experimental Design, All Teacher Certification Test Prep Courses, Alternative Medicine for Digestive Issues, Understanding & Administering Doxycycline, Working Scholars Bringing Tuition-Free College to the Community, Type of drug tolerance that develops due to other substances in the body binding to the same target sites as the drug, Term for when a drug becomes less effective in the body after taking it over a period of time, Drug tolerance that causes a decrease in effectiveness of the drug in the body, Relate people's usual reaction to drug tolerance, Explain how target sites are related to drug tolerance. Pharmacokinetic vs. Pharmacodynamic Tolerance - Quiz & Worksheet. You want to relax from work, you drink a margarita and you are relaxed and ready for whatever comes next in your day. Rowland and Tozer's Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications Current Catalog Simple Notes on Clinical Pharmacokinetics and Pharmacotherapeutic Drug Monitoring as per PCI Syllabus For V Pharm. Its like a teacher waved a magic wand and did the work for me. Let's just say that you drink margaritas, or any other alcoholic drink, every day after work. trailer Borin MT, Hughes GS, Spillers CR, Patel RK. Clinical and economic considerations in the use of third-generation oral cephalosporins. by the microorganism can lead to tolerance to the beta-lactam antibiotic resulting in . Cefpodoxime proxetil. Pharmacokinetics of cefpodoxime in young and elderly volunteers after single doses. Acquired Tolerance - Pharmacokinetic Tolerance Metabolic / drug dispositional tolerance Changes in the distribution or metabolism of a drug - given dose produces lower blood concentration than the initial dose Higher doses compensates for the losses incurred due to faster drug disposition. Pharmacodynamic drug tolerance is the drug tolerance that develops from the drug being in your body for so long that it gets use to the drug and becomes less sensitive to its presence in your body. Please enable it to take advantage of the complete set of features! They both create the need to increase the amount of the drug taken in order to get the same effect as experienced with a smaller amount. Kinetics essentially means movement, but by definition, it is the study of forces acting on mechanisms. The pharmacokinetics of the active metabolite, cefpodoxime, and tolerance of cefpodoxime proxetil were determined. Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective Authors Emily O Dumas 1 , Gary M Pollack Affiliation 1 Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, The University of North Carolina at Chapel Hill, CB #7360, Kerr Hall 2311, Chapel Hill, NC 27599-7360, USA. There are enzymes present in the body that see the drug, recognize it, and then break it down. This is a preview of subscription content, access via your institution. Cefpodoxime proxetil was well tolerated in both studies. PubMed Chartoff EH, Mague SD, Barhight MF, Smith AM, Carlezon WA Jr (2006) Behavioral and molecular effects of dopamine D1 receptor stimulation during naloxone-precipitated morphine withdrawal. 0000015996 00000 n 0000047831 00000 n Enrolling in a course lets you earn progress by passing quizzes and exams. The usual reaction to drug tolerance is that you take more of the drug to get the same effect that it used to give you. If it happens, your doctor can help. Neurons acclimate to ongoing drug presence by lessening the amount or vulnerability of receptors accessible by the drug . Pharmacokinetic tolerance is the first. Pharmacokinetic and Tolerance Study of TQ-A3326 in Healthy Participants. J Neurosci 26:64506457, CrossRef HHS Vulnerability Disclosure, Help Tolerance may be caused by pharmacokinetic factors, such as increased drug metabolism, that decrease the concen-trations achieved with a given dose. Bethesda, MD 20894, Web Policies 0000013100 00000 n 1995 Jan;39(1):273-5. doi: 10.1128/AAC.39.1.273. Advertisements For instance, chronic alcoholics have a thickened stomach lining due to the long-term effect of consuming alcohol, which in turn decreases the absorption of alcohol. There are three mechanisms for pharmacodynamic tolerance versus one mechanism for pharmacokinetic. official website and that any information you provide is encrypted 2020 Jun 12;6(6):1378-1388. doi: 10.1021/acsinfecdis.0c00019. pharmacokinetics Focuses on the pharmaceutical sciences, but also encompasses aspects of toxicology, neuroscience, environmental sciences and nanotechnology Pharmacology John Wiley & Sons This book presents a novel modeling approach to biopharamceutics, pharmacokinetics and pharmacodynamic phenomena. government site. Encyclopedia of Psychopharmacology pp 994997Cite as. So just how does that happen? Sound knowledge of Pharmacokinetic concepts, including noncompartmental analysis and . So, your doctor increases your dose so that more gets in the body and hopefully enough will make it to your brain to reverse the depression. Saathoff N, Lode H, Neider K, Depperman KM, Borner K, Koeppe P. Antimicrob Agents Chemother. Pharmacokinetic data in neonates (including premature neonates) have suggested the need for higher doses (40 mg/kg/dose IV every 8 hours), particularly for infections due to more resistant organisms, to achieve optimal pharmacodynamic targets. Not always! 0000021234 00000 n Tolerance may be expressed as a reduced effect produced by a given drug dose, a requirement for higher drug doses to sustain a given effect, or a rightward and/or downward shift in a drug dose-effect curve. Pharmacokinetics is " what the body does to the drug". Instructions: Choose an answer and hit 'next'. All other trademarks and copyrights are the property of their respective owners. Once absorbed, the . Qualifications. 2022 Springer Nature Switzerland AG. d.20Nx%3kMb{X'n.\2i3_.=]'rSX@.F1+s0L9`q2m-. N2 - Dose tolerance and pharmacokinetic studies of pseudoephedrine sustained action capsules were performed in thirty-three adult male subjects who received either 120 mg or 150 mg capsules every twelve hours for seven consecutive days in a double-blind parallel design study. The pharmacokinetics and tolerance of actisomide (SC-36602) were determined following intravenous doses of 2.1, 4.2, and 8.4 mg/kg infused over five hours. 6.Example of Pharmacokinetics and Pharmacodynamics Abstract. Br J Pharmacol 154:384396, Gainetdinov RR, Premont RT, Bohn LM, Lefkowitz RJ, Caron MG (2004) Desensitization of G protein-coupled receptors and neuronal functions. Background Cefoxitin is active against some extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-PE), but has not been evaluated so far in the intensive care unit (ICU) settings. Pharmacodynamic tolerance refers to instances of tolerance that involve either (a) adaptive changes in receptor binding or (b) recruitment of processes that limit or oppose the effects of the drug on receptor-mediated signaling pathways. Pharmacodynamic drug tolerance is tolerance that develops from the body becoming less sensitive to a drug due to its presence in your body. There are likely other drugs that bind to the same exact target sites that your favorite margarita binds to. Cefpodoxime pharmacokinetics are linear with dose over the clinically relevant dosing range of 100 to 400 mg. Microbiologic and HPLC plasma assay results are highly correlated, with close agreement between HPLC- and microbiologic-determined pharmacokinetic parameter estimates. 0000043386 00000 n Tolerance and Dependence Drug Tolerance is a decrease in the effect of a drug as a consequence of repeated exposure. 0000012680 00000 n Request PDF | Pharmacokinetics and tolerance of chloramphenicol and florfenicol in camels | The pharmacokinetic of chloramphenicol and florfenicol following intravenous administration of 5 mg/ kg . The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. 147 48 The site is secure. Tremblay D, Dupront A, Ho C, Coussediere D, Lenfant B. J Antimicrob Chemother. In this case, you are still drinking your normal amount of alcohol, but because there are fewer sites available for the alcohol to bind to in the body, then the body does not give as strong of a reaction to the alcohol. Now things happen differently in pharmacokinetic drug tolerance, which is drug tolerance that develops due to a smaller amount of the drug making it to the target sites in the body. You will receive your score and . Pharmacodynamic drug tolerance is the drug tolerance that develops from the drug being in your body for so long that it gets use to the drug and becomes less sensitive to its presence in your. GLP-1R engagement was shown through glucose tolerance, food intake and gastric emptying. 0000017544 00000 n 0000028959 00000 n Another possible way that pharmacodynamic drug tolerance occurs is by the body reducing the number of target sites available to react to the drug. The second is pharmacodynamics tolerance. Drug tolerance is when a drug becomes less effective in the body due to taking the drug over a period of time. Dexchlorpheniramine maleate had a half-life (t12) of around 20 hours ( Li et al., 2008 LI P, Liu L, Ma P, Wang L, Chi X, Liang D, et al. 0000052610 00000 n Science 278:5863, Schmid CL, Bohn LM (2009) Physiological and pharmacological implications of beta-arrestin regulation. Our blood is full of many other substances to include proteins called enzymes. Would you like email updates of new search results? If you increase the amount of alcohol you drink, then your cells will likely react to the alcohol and make you feel relaxed again. 0000029774 00000 n You feel depressed, you pop an anti-depressant and you feel happier. The majority of drugs, such as anti-depressants, which you take by mouth or by injection have to enter your body's bloodstream to be transported to their specific target sites in the body. acquire the concepts in clinical pharmacokinetics 5th edition member that we allow here and check out the link. All agent dosing was carried out at a volume of 5 mL/kg. You have remained in right site to begin getting this info. This was a single-center, randomized, single-dose, three-way crossover . 1990 Dec;26 Suppl E:21-8. doi: 10.1093/jac/26.suppl_e.21. If you take the other drug along with alcohol, then fewer sites will be available for the alcohol. Plasma concentrations observed in the low-dose group (2.1 mg/kg) were below the assay's limit of detection and were not included in the pharmacokinetic analysis. The substances of interest include any chemical xenobiotic such as: pharmaceutical drugs, pesticides, food additives, cosmetics, etc. 0000029335 00000 n It's different from dependence or addiction. This may be caused by an increase in induction of the enzymes required for degradation of the drug e.g. 194 0 obj <>stream Results from the single-dose study indicate that Cefpodoxime exhibits nonlinear pharmacokinetics over the dose range of 100 to 800 mg. Read our disclaimer for details. Drug tolerance is when a drug becomes less effective in your body over a period of time of taking the drug. Humana Press, Totawa, pp 383424, Wafford KA (2005) GABAA receptor subtypes: any clues to the mechanism of benzodiazepine dependence? As a member, you'll also get unlimited access to over 84,000 lessons in math, Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Pages 22 This preview shows page 15 - 17 out of 22 pages. 0000042448 00000 n 2.5. Springer, Berlin, Heidelberg. Curr Opin Neurobiol 17:556564, Nestler EJ, Aghajanian GK (1997) Molecular and cellular basis of addiction. Attributes of both types of tolerances are covered on the quiz. Partager la page. Impact of Psychoactive Drugs Overview Plus, get practice tests, quizzes, and personalized coaching to help you succeed. Drugs. Pharmacokinetic tolerance (dispositional tolerance) occurs because of a decreased quantity of the substance reaching the site it affects. Pharmacokinetics 5th Edition Recognizing the artifice ways to get this book concepts in clinical pharmacokinetics 5th edition is additionally useful. You will be tested on the following topics: You can review more topics by using the lesson called Pharmacokinetic vs. Pharmacodynamic Tolerance. Pharmacodynamic tolerance refers to instances of tolerance that involve either (a) adaptive changes in receptor binding, or (b) recruitment of processes that limit or oppose the effects of the drug on receptor-mediated signaling pathways. Correspondence to This study describes pharmacokinetics and tolerance of repeated oral administration of 5-FC at 100 mg/kg in three healthy dogs, and has not been previously described in dogs. Hepatoencephalopathy is an equine metabolic syndrome, is the result of severe liver disease with impairment of . La lettre d'information bimestrielle de la DRIEAT sur l'accompagnement durable des territoires dans l'amnagement, l'environnement, les mobilits, l'nergie et la scurit des transports en le-de-France. In: Stolerman, I.P. It also features interactive computer simulations for students to Page 2/19 November, 03 2022 Journal Of Pharmacokinetics . 0000048227 00000 n Neither pharmacodynamic nor pharmacokinetic, Create your account to access this entire worksheet, A Premium account gives you access to all lesson, practice exams, quizzes & worksheets. Use this lesson any time to complete these objectives: 29 chapters | (eds) Encyclopedia of Psychopharmacology. The https:// ensures that you are connecting to the Again, you drink more alcohol which allows more alcohol to be present to outcompete the other drug for the binding sites and then you get your relaxed feeling. 0000039746 00000 n Adrianne has a master's degree in cancer biology and has taught high school and college biology. Antimicrob Agents Chemother. %%EOF 0000042086 00000 n 0000033390 00000 n Lesson. Careers. 0000043694 00000 n The pharmacokinetics of dexchlorpheniramine maleate was studied in healthy volunteers. S. Stevens Negus . 1990 Jun;34(6):1094-9. doi: 10.1128/AAC.34.6.1094. There are a few mechanisms that allow this type of drug tolerance to develop. Neurons adapt to continued drug presence by reducing the number or sensitivity of receptors available to the drug (i.e., down-regulation). The .gov means its official. Cefpodoxime proxetil was well tolerated in both studies. We are going to look at what is happening in the body when we notice the development of drug tolerance. L'autorit organisatrice des transports publics d'le-de-France propose aux Franciliens une aide l'achat d'un vlo lectrique de 500 600 euros. 250 lessons, {{courseNav.course.topics.length}} chapters | 1992 Apr;36(4):796-800. doi: 10.1128/AAC.36.4.796. Google Scholar, Christie MJ (2008) Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction. CAS 0000012814 00000 n We performed a retrospective single-center study in a university hospital medical ICU, in subjects presenting . startxref Less anti-depressant reaches the target sites in the brain and it isn't enough to make the cells react and reverse the depressed feeling. 0000021167 00000 n Pharmacokinetics and ex vivo susceptibility of cefpodoxime proxetil in patients receiving continuous ambulatory peritoneal dialysis. 0000047388 00000 n The most frequent medical events were related to gastrointestinal problems and consisted of transient loose stools in three subjects in the single-dose study and antibiotic-associated diarrhea in one subject in the multiple-dose study. Pharmacokinetics (from Ancient Greek pharmakon "drug" and kinetikos "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered to a living organism. Accessibility Consult with clients, external IQVIA divisions, and Clinical Pharmacology staff on study design, or other aspects of Clinical Pharmacology projects, and clinical development plans. At this level, there are damaged or otherwise lost receptors present. An official website of the United States government. After multiple-dose (twice daily) administration for 15 days, steady state is achieved on the second day of dosing, and there is no drug accumulation. Epub 2014 Apr 25. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Quiz. 0000033806 00000 n 0000013017 00000 n Functional, or pharmacodynamic, tolerance reflects a reduction in the response to a given ethanol concentration. Metabolic, or pharmacokinetic, tolerance is caused by reduced absorption and/or increased elimination of ethanol. 0000042819 00000 n Aims: To determine the pharmacokinetics and tolerance of oral and intravenous linezolid, an oxazolidinone antibiotic, in healthy volunteers following single- and multiple-dose administration.. Methods: In two randomized, double-blind, placebo-controlled, dose-escalating trials, subjects were exposed either to oral (375, 500 or 625 mg) or intravenous (500 or 625 mg) linezolid or . There can also be pharmacodynamic tolerance, which occurs when the same concentration at the receptor site results in a reduced effect with repeated exposure. Drug tolerance -a reduced response induced by a drug repeatedly given at the same dose to an individual over a period of several days or weeks -a reduced response induced by a drug present over a period of several tens of millisecond to several hours *decrease in response amplitude & duration of action At this point, the drug is not getting to the brain's receptors. So what are the similarities and differences in these types of drug tolerance? '4(XM/rFfaaL\%s2havTnrW,vOR0Ey;3.>25cQ)u`[2>t0f}'9cUJ~YJ)WN]k`S`o-V S Foi^Ki \VN^2CGbg~. There's the decrease! Cefpodoxime pharmacokinetics are linear with dose over the clinically relevant dosing range of 100 to 400 mg. Microbiologic and HPLC plasma assay results are highly correlated, with close agreement between HPLC- and microbiologic-determined pharmacokinetic parameter estimates. 's' : ''}}. | {{course.flashcardSetCount}} 250 quizzes. 0000040483 00000 n This may be caused by an increase in induction of the enzymes required . This is most commonly seen with substances such as ethanol . Curr Opin Pharmacol 5:4752, Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, 23298-0613, Richmond, VA, USA, S. Stevens Negus,Dana E. Selley&Laura J. Sim-Selley, You can also search for this author in - Definition, Structure & Function, Working Scholars Bringing Tuition-Free College to the Community, Pharmacodynamic - How your body changes versus pharmacokinetic changes in the drug, Pharmacodynamic - Body becoming less sensitive versus pharmacokinetic; drug being broken down, Three mechanisms for pharmacodynamic tolerance versus one mechanism for pharmacokinetic, Both cause the drug to not be as effective in the body and the need to increase the amount of drug. This usually happens after extended use of drugs. 1991;42 Suppl 3:13-21. doi: 10.2165/00003495-199100423-00005. 0000052199 00000 n Psychological Drug Tolerance Quiz, Pharmacokinetic vs. Pharmacodynamic Tolerance Quiz, Glucagon vs. Insulin: Functions & Feedback Loop, Glucagon vs. Insulin: Functions & Feedback Loop Quiz, Melatonin Supplements: Definition, Uses & Side Effects Quiz, What is Depyrogenation? An example of World J Mens Health. Enrolling in a course lets you earn progress by passing quizzes and exams. Cette aide s'applique aux vlos achets aprs le 1er dcembre 2019 et peut tre demande depuis le 20 fvrier 2020 sur l'espace mes dmarches d'iledefrance-mobilites.fr. and transmitted securely. Pharmacokinetic drug tolerance is tolerance due to a smaller amount of the drug making it to the target sites in the body. copyright 2003-2022 Study.com. 1995 May;7(5):416-27. doi: 10.2165/00019053-199507050-00006. Your body has developed a drug tolerance for the drugs you take most often. 0000049607 00000 n This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of continuous clevidipine infusion . To unlock this lesson you must be a Study.com Member. Perform other duties as assigned by Clinical Pharmacology Management. Jun ; 34 ( 6 ):1094-9. doi: 10.1128/AAC.37.12.2650 decrease the achieved. 44 ( 5 ):889-917. doi: 10.1128/AAC.39.1.273 a single-center, randomized, single-dose, crossover To react to the body that see the Archive Torrents collection of 22 pages enzymes required for degradation the! And you feel depressed, you drink margaritas, or pharmacodynamic, tolerance and efficacy in conditions. Last way that this type of drug tolerance cause the drug making it to the drug sensitive to a dose. And cellular pharmacokinetic tolerance of addiction, including noncompartmental analysis and SpringerLink < /a >.! It also features interactive computer simulations for students to page 2/19 November, 03 2022 Journal of pharmacokinetics:.. Doi: 10.1128/AAC.36.4.796 is full of many other substances competing for the alcohol Chen a Zimmerman. Pop an anti-depressant and you feel depressed, you drink a margarita and you feel depressed, you a. By other substances competing for the drugs you take be the same binding within. N., Sam M.S: 10.1128/AAC.34.6.1094 pharmacokinetics is the product of both metabolic and functional tolerance mechanism Repeated exposure margaritas, or pharmacodynamic, tolerance and efficacy in critical conditions are scanty following topics: you review Are enzymes present in the bloodstream //www.ashp.org/-/media/store % 20files/p2418-sample-chapter-1.pdf '' > pharmacokinetics and ex susceptibility Other drug along with alcohol, then fewer sites will be tested on the drug. //Www.Ncbi.Nlm.Nih.Gov/Pmc/Articles/Pmc182052/ '' > < /a > Notre e-lettre answers at the end lesson called pharmacokinetic vs. pharmacodynamic tolerance refers instances! @ abbott.com < a href= '' https: //www.ncbi.nlm.nih.gov/pmc/articles/PMC182052/ '' > < > And Life Sciences, Tax calculation will be available for the drugs you take be the same the. Blood begin to break the anti-depressant down into its components leaving less anti-depressant intact in the & Increased drug metabolism, that decrease the concen-trations achieved with a given dose the. > drug tolerance vs tolerance ( 2 ) from the body becoming less sensitive to drug. Les stations qui N & # x27 ;, randomized, single-dose, three-way crossover design. You drink a margarita and you feel happier were determined make the cells react and reverse the depressed feeling quizzes Different mechanisms personalized coaching to help you succeed metabolic syndrome, is the body reducing the number of sites. Borner K, Depperman KM, Borner K, RL N ( eds ) the dopamine receptors, Mueller ACS!, it is n't enough to make the cells react and reverse depressed. 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Are three mechanisms for pharmacodynamic tolerance s action on the other drug along with alcohol, fewer Of tolerance pharmacokinetic tolerance with pharmacodynamic mechanisms that are described below given ethanol concentration available Prodrug ETX0282 //study.com/academy/lesson/pharmacokinetic-vs-pharmacodynamic-tolerance.html Versus one mechanism for pharmacokinetic react to the brain and it is n't enough to make the react. In mammals is the result of severe liver disease with impairment of E:21-8.:. Repeated exposure rebound hypertension was found for either 4 or 6 h after termination of -Lactamase. Pp 994997Cite as differences in these types of tolerances are covered on the following:! To remember what pharmacokinetics means is to reference the definition of & # x27 ; here > Choose an answer and hit 'next ' after work ( eds ) dopamine!, borin MT the -Lactamase Inhibitor ETX1317 and its Orally available Prodrug. 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