DOCSLIB.ORG

Prodrugs Extend the Half Life and Potency of Cabotegravir Tanmay A

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Prodrugs Extend the Half Life and Potency of Cabotegravir Tanmay A Prodrugs extend the half life and potency of Cabotegravir Tanmay A. Kulkarni1,2*†, Aditya N. Bade2*, Brady Sillman2, Bhagya Laxmi Dyavar Shetty2, Melinda Wojtkiewicz2, JoEllyn McMillan2, Benson Edagwa2 and Howard E. Gendelman1,2 1Department of Pharmaceutical Sciences, 2Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198. Poster# 489 *Authors contributed equally, †Presenting author Abstract Pharmacokinetics Antiretroviral activity of NM2CAB BACKGROUND Prevention of new infections, reduction in transmission and management of chronic infection characterize once a month dosing of cabotegravir (CAB) in its current formulation (CAB LA, referred henceforth as NCAB). We previously demonstrated that the potency, bioavailability and tissue distribution of CAB could be improved by A increasing drug lipophilicity and hydrophilicity.A first generation prodrug (MCAB) nanoformulation (NMCAB) extended the protein adjusted IC90 (PA-IC90) up to 3 months in rhesus macaques after a single 45 mg/kg CAB equivalent intramuscular (IM) injection. We now report modifications of CAB designed to further reduce dosing frequency while improving drug bioavailability. METHODS A second generation CAB prodrug (M2CAB) was synthesized through bioreversible acylation. Poloxamer 407 nanoformulations (abbreviated NM2CAB) were prepared by high-pressure homogenization. Electron microscopy was used to evaluate particle shape and size. Human monocyte derived macrophages (MDM) and CD4+ T cells were the biological platforms employed to measure drug uptake, retention and release. Antiretroviral activity was examined by culture fluid assay for reverse transcriptase activity and cell- based HIV-1p24 antigens recorded by immunohistochemistry. Pharmacokinetic evaluation was performed in humanized NOD/scid-IL-2Rγc null (NSG) mice and rhesus macaques. RESULTS NM2CAB exhibited uniform particle size of 300-350 nm, narrow polydispersity index (PDI) of 0.2, a negative zeta potential and a high drug loading capacity (> 80%). Physical and thermal stability of NM2CAB at 25°C was observed with no particle agglomeration. NM2CAB was retained in MDM (levels of 8 nmol/106 cells) at one month. NM2CAB attenuation of viral replication was observed to 30 days compared to 15 and 1 day for NMCAB and NCAB, respectively. After a single 45 mg/kg CAB equivalent IM injection of NM2CAB in mice, plasma CAB levels were > 4 times the PA-IC90 (664 ng/ml) for > 8 months compared to 2.5 and 1 month for NMCAB and NCAB, respectively and replicated in rhesus macaques in ongoing studies. CONCLUSIONS The hydrophobicity and sustained slow hydrolysis of the M2CAB prodrug facilitate NM2CAB to harness the injection site as a primary drug depot as well as macrophages and other tissues as secondary drug depots for months. This can potentially reduce frequent dosing and injection volume improving patient adherence to B antiretroviral therapy. Days 1 5 10 15 20 25 30 Results HIV-1 Synthesis of M2CAB A NCAB B C + DIEA DMF, 25ºC Acyl CAB chloride M2CAB NMCAB D NM2CAB E F G Figure 3. Pharmacokinetics of NM2CAB. Plasma CAB levels determined over eight months after a single 45 mg/kg CAB equivalent IM injection of NM2CAB, NMCAB and NCAB (a CAB LA equivalent formulation). This study parallels results seen in rhesus macaques and remains ongoing. In vitro characterization of NM2CAB Control A B C Figure 5. Antiretroviral activity of NM2CAB. (A) MDM were treated with 100 μM NM2CAB, NMCAB or NCAB for 8 hrs (drug loading) at the time points listed. MDM were challenged with 0.1 MOI HIV-1ADA after drug loading. Ten days after viral challenge, reverse transcriptase (RT) activity was measured in culture medium and (B) cells were stained for HIV-1 p24 antigen. Figure 1. Synthesis and characterization of M2CAB (A) Synthesis scheme (B) FTIR spectroscopy of CAB and M2CAB (C) Drug concentration for 50% HIV inhibition (IC50) of CAB (20.8 nM), MCAB (7.1 nM) and M2CAB (6.5 nM) in human MDM (D) 1H-NMR spectra of CAB and M2CAB (E) Depletion of M2CAB into active CAB in physiological conditions (plasma of various species) at 37 ºC (F) CAB formation (G) Decreased aqueous solubility of M2CAB at room temperature is shown Conclusions Synthesis and characterization of M2CAB nanoformulation (NM2CAB) NM2CAB B • demonstrated up to 10-fold improvement in pharmacokinetics over unmodified CAB nanoformulation. A C • was found safe for administration in animals and no cytotoxic effects were seen in vitro. • has excellent scalability owing to its simple design and optimized straight forward synthesis. • showed stability over 100 days in terms of particle size, charge and drug content integrity. • is potent with sustained antiretroviral activity. • is retained and released slowly and effectively by macrophages. D Acknowledgements This research was supported by the University of Nebraska Foundation; the Vice Chancellor for Research Office, University of Nebraska Medical Center; and National Institutes of Health grants, P01 DA028555,R01 NS36126,P01 D E NS31492, 2R01 NS034239,P01 MH64570,P01 NS 43985, 1 R56 A1 138613-01A1, 3P30 MH062261,P30 AI078498, 1R24 OD018546, and R01 AG043540. Figure 4. In vitro characterization of NM2CAB (A) Uptake and (B) Retention of NM2CAB in MDM compared with NMCAB and NCAB. For uptake, drug concentration was determined in MDM treated with 100 μM NM2CAB, NMCAB or NCAB for 2-24 hours. Cell drug retention was determined after treatment of MDM for 8 hrs with 100 μM Figure 2. Synthesis and characterization of NM2CAB (A) Synthesis of nanoformulated M2CAB (NM2CAB) (B) SEM of NM2CAB shows rod shaped nanoparticles (C)Stability NM2CAB, NMCAB or NCAB, followed by replacement with fresh medium without drug. Drug concentration determined from 1-30 days. (C) CAB release was determined of NM2CAB in terms of particle size, polydispersity index and zeta potential over 100 days at 25 ºC (D) MTT assay shows no cytotoxicity of NM2CAB in MDM at various for 30 days from MDM treated with 100 μM NM2CAB, NMCAB and NCAB. (D) TEM of MDM at the end of 30 days after treatment for 8 hrs with 100 μM NM2CAB, NMCAB, concentrations (E) X-ray diffraction pattern illustrates that crystallinity of M2CAB is retained in NM2CAB or NCAB. The cells exposed to NM2CAB showed nanocrystals (red arrowheads) while NMCAB and NCAB showed no drug crystals..
Load more

Recommended publications
  • Exploring the Concept of Safety and Tolerability
    SECOND ANNUAL WORKSHOP ON CLINICAL OUTCOME ASSESSMENTS IN CANCER CLINICAL TRIALS April 25, 2017 Bethesda, MD Co-sponsored by Session 1 Exploring the Concepts of Safety and Tolerability: Incorporating the Patient Voice SECOND ANNUAL WORKSHOP ON CLINICAL OUTCOME ASSESSMENTS IN CANCER CLINICAL TRIALS April 25, 2017 Bethesda, MD Co-sponsored by Disclaimer • The views and opinions expressed in the following slides are those of the individual presenters and should not be attributed to their respective organizations/companies, the U.S. Food and Drug Administration or the Critical Path Institute. • These slides are the intellectual property of the individual presenters and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. All trademarks are the property of their respective owners. 3 Session Participants Chair • Bindu Kanapuru, MD – Medical Officer, Division of Hematology Products, OHOP, FDA Presenters • James (Randy) Hillard, MD – Professor of Psychiatry, Michigan State University • Crystal Denlinger, MD, FACP – Associate Professor, Department of Hematology/Oncology; Chief, Gastrointestinal Medical Oncology; Director, Survivorship Program; Deputy Director, Phase 1 Program, Fox Chase Cancer Center • Katherine Soltys, MD – Acting Director, Bureau of Medical Sciences, Therapeutic Products Directorate, Health Products and Food Branch, Health Canada • Karen E. Arscott, DO, MSc – Associate Professor of Medicine-Patient Advocate and Survivor, Geisinger Commonwealth
    [Show full text]
  • Bugs, Drugs, and Cancer: Can the Microbiome Be a Potential
    REVIEWS Drug Discovery Today Volume 24, Number 4 April 2019 Reviews Bugs, drugs, and cancer: can the GENE TO SCREEN microbiome be a potential therapeutic target for cancer management? 1,z 2,z 1 1 Biying Chen , Guangye Du , Jiahui Guo and Yanjie Zhang 1 Department of Oncology, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, 280 Mohe Road, Shanghai, 201999, China 2 Department of Pathology, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, 280 Mohe Road, Shanghai, 201999, China Outnumbering our own cells over ten times, gut microbes can even be considered an additional organ. Several studies have explored the association between microbiomes and antitumor drug response. It has been reported that the presence of specific bacteria might modulate cancer progression and the efficacy of anticancer therapeutics. Bacteria-targeting intervention can provide crucial guidance for the design of next-generation antitumor drugs. Here, we review previous findings elucidating the impact of gut microbiomes on cancer treatment and the possible underlying mechanisms. In addition, we examine the role of microbiome manipulation in controlling tumor growth. Finally, we discuss concerns regarding the alteration of the microbiome composition, and the potential approaches to surpass existing limitations. Introduction cantly during life [5] (Fig. 1). Gut microbial density increases from The microbiota is defined as all microorganisms that are associated the proximal to the distal GI tract and along the tissue–lumen axis. with a specific host cellular environment [1]. These microorganisms Similarly, diversity further increases in the same pattern [6]. More- are identified using 16S ribosomal RNA (rRNA)sequencing.
    [Show full text]
  • Live Biotherapeutic Products, a Road Map for Safety Assessment
    Live Biotherapeutic Products, A Road Map for Safety Assessment Alice Rouanet, Selin Bolca, Audrey Bru, Ingmar Claes, Helene Cvejic, Haymen Girgis, Ashton Harper, Sidonie Lavergne, Sophie Mathys, Marco Pane, et al. To cite this version: Alice Rouanet, Selin Bolca, Audrey Bru, Ingmar Claes, Helene Cvejic, et al.. Live Biotherapeutic Products, A Road Map for Safety Assessment. Frontiers in Medicine, Frontiers media, 2020, 7, 10.3389/fmed.2020.00237. hal-02900344 HAL Id: hal-02900344 https://hal.inrae.fr/hal-02900344 Submitted on 8 Jun 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License POLICY AND PRACTICE REVIEWS published: 19 June 2020 doi: 10.3389/fmed.2020.00237 Live Biotherapeutic Products, A Road Map for Safety Assessment Alice Rouanet 1, Selin Bolca 2†, Audrey Bru 3†, Ingmar Claes 4†, Helene Cvejic 5,6†, Haymen Girgis 7†, Ashton Harper 8†, Sidonie N. Lavergne 9†, Sophie Mathys 10†, Marco Pane 11†, Bruno Pot 12,13†, Colette Shortt 14†, Wynand Alkema 15, Constance Bezulowsky 16, Stephanie Blanquet-Diot 17, Christophe Chassard 18, Sandrine P. Claus 19, Benjamin Hadida 20, Charlotte Hemmingsen 21, Cyrille Jeune 7, Björn Lindman 22, Garikai Midzi 8, Luca Mogna 11, Charlotta Movitz 22, Nail Nasir 23, 24 25 25 26 Edited by: Manfred Oberreither , Jos F.
    [Show full text]
  • Pharmacology Part 2: Introduction to Pharmacokinetics
    J of Nuclear Medicine Technology, first published online May 3, 2018 as doi:10.2967/jnmt.117.199638 PHARMACOLOGY PART 2: INTRODUCTION TO PHARMACOKINETICS. Geoffrey M Currie Faculty of Science, Charles Sturt University, Wagga Wagga, Australia. Regis University, Boston, USA. Correspondence: Geoff Currie Faculty of Science Locked Bag 588 Charles Sturt University Wagga Wagga 2678 Australia Telephone: 02 69332822 Facsimile: 02 69332588 Email: [email protected] Foot line: Introduction to Pharmacokinetics 1 Abstract Pharmacology principles provide key understanding that underpins the clinical and research roles of nuclear medicine practitioners. This article is the second in a series of articles that aims to enhance the understanding of pharmacological principles relevant to nuclear medicine. This article will build on the introductory concepts, terminology and principles of pharmacodynamics explored in the first article in the series. Specifically, this article will focus on the basic principles associated with pharmacokinetics. Article 3 will outline pharmacology relevant to pharmaceutical interventions and adjunctive medications employed in general nuclear medicine, the fourth pharmacology relevant to pharmaceutical interventions and adjunctive medications employed in nuclear cardiology, the fifth the pharmacology related to contrast media associated with computed tomography (CT) and magnetic resonance imaging (MRI), and the final article will address drugs in the emergency trolley. 2 Introduction As previously outlined (1), pharmacology is the scientific study of the action and effects of drugs on living systems and the interaction of drugs with living systems (1-7). For general purposes, pharmacology is divided into pharmacodynamics and pharmacokinetics (Figure 1). The principle of pharmacokinetics is captured by philosophy of Paracelsus (medieval alchemist); “only the dose makes a thing not a poison” (1,8,9).
    [Show full text]
  • Pharmacokinetic Models to Characterize the Absorption Phase and the Influence of a Proton Pump Inhibitor on the Overall Exposure of Dacomitinib
    pharmaceutics Article Pharmacokinetic Models to Characterize the Absorption Phase and the Influence of a Proton Pump Inhibitor on the Overall Exposure of Dacomitinib Ana Ruiz-Garcia 1, Weiwei Tan 2, Jerry Li 2, May Haughey 2, Joanna Masters 2, Jennifer Hibma 2 and Swan Lin 2,* 1 Metrum Research Group, San Diego, CA 92121, USA; [email protected] 2 Department of Pharmacometrics, Pfizer Inc, San Diego, CA 92121, USA; weiwei.tan@pfizer.com (W.T.); jerry.li@pfizer.com (J.L.); may.haughey@pfizer.com (M.H.); joanna.c.masters@pfizer.com (J.M.); jennifer.e.hibma@pfizer.com (J.H.) * Correspondence: swan.lin@pfizer.com; Tel.: +1-(858)-622-7377 Received: 17 March 2020; Accepted: 3 April 2020; Published: 7 April 2020 Abstract: Introduction: Dacomitinib is an epidermal growth factor receptor (EGFR) inhibitor approved for the treatment of metastatic non-small cell lung cancer (NSCLC) in the first line in patients with EGFR activating mutations. Dacomitinib is taken orally once daily at 45 mg with or without food, until disease progression or unacceptable toxicity occurs. Oncology patients often can develop gastroesophageal reflux disease (GERD), which may require management with an acid-reducing agent. Proton pump inhibitors (PPIs), such as rabeprazole, inhibit sodium-potassium adenosine triphosphatase (H+/K+-ATPase) pumps that stimulate acid secretion in the stomach and have a prolonged pharmacodynamic effect that extends beyond 24 h post-administration. The aim of this work was to characterize the absorption of dacomitinib via modeling with a particular interest in quantifying the impact of rabeprazole on the pharmacokinetics (PK) of dacomitinib.
    [Show full text]
  • International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification
    0031-6997/03/5504-597–606$7.00 PHARMACOLOGICAL REVIEWS Vol. 55, No. 4 Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics 30404/1114803 Pharmacol Rev 55:597–606, 2003 Printed in U.S.A International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on Terms and Symbols in Quantitative Pharmacology RICHARD R. NEUBIG, MICHAEL SPEDDING, TERRY KENAKIN, AND ARTHUR CHRISTOPOULOS Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (R.R.N.); Institute de Recherches Internationales Servier, Neuilly sur Seine, France (M.S.); Systems Research, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina (T.K.); and Department of Pharmacology, University of Melbourne, Parkville, Australia (A.C.) Abstract ............................................................................... 597 I. Introduction............................................................................ 597 II. Working definition of a receptor .......................................................... 598 III. Use of drugs in definition of receptors or of signaling pathways ............................. 598 A. The expression of amount of drug: concentration and dose ............................... 598 1. Concentration..................................................................... 598 2. Dose. ............................................................................ 598 B. General terms used to describe drug action ...........................................
    [Show full text]
  • Receptor Af®Nity and Potency of Non-Steroidal Antiandrogens: Translation of Preclinical ®Ndings Into Clinical Activity
    Prostate Cancer and Prostatic Diseases (1998) 1, 307±314 ß 1998 Stockton Press All rights reserved 1365±7852/98 $12.00 http://www.stockton-press.co.uk/pcan Review Receptor af®nity and potency of non-steroidal antiandrogens: translation of preclinical ®ndings into clinical activity GJCM Kolvenbag1, BJA Furr2 & GRP Blackledge3 1Medical Affairs, Zeneca Pharmaceuticals, Wilmington, DE, USA; 2Therapeutic Research Department, and 3Medical Research Department, Zeneca Pharmaceuticals, Alderley Park, Maccles®eld, Cheshire, UK The non-steroidal antiandrogens ¯utamide (Eulexin1), nilutamide (Anandron1) and bicalutamide (Casodex1) are widely used in the treatment of advanced prostate cancer, particularly in combination with castration. The naturally occurring ligand 5a-DHT has higher binding af®nity at the androgen receptor than the non-steroidal antiandrogens. Bicalutamide has an af®nity two to four times higher than 2-hydroxy¯utamide, the active metabolite of ¯utamide, and around two times higher than nilutamide for wild-type rat and human prostate androgen receptors. Animal studies have indicated that bicalutamide also exhi- bits greater potency in reducing seminal vesicle and ventral prostate weights and inhibiting prostate tumour growth than ¯utamide. Although preclinical data can give an indication of the likely clinical activity, clinical studies are required to determine effective, well-tolerated dosing regimens. As components of combined androgen blockade (CAB), controlled studies have shown survival bene®ts of ¯utamide plus a luteinising hormone-releasing hormone analogue (LHRH-A) over LHRH-A alone, and for nilutamide plus orchiectomy over orchiectomy alone. Other studies have failed to show such survival bene®ts, including those comparing ¯utamide plus orchiectomy with orchiectomy alone, and nilutamide plus LHRH-A with LHRH-A alone.
    [Show full text]
  • NIH Public Access Author Manuscript Chem Biol
    NIH Public Access Author Manuscript Chem Biol. Author manuscript; available in PMC 2012 November 23. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Chem Biol. 2011 November 23; 18(11): 1442±1452. doi:10.1016/j.chembiol.2011.08.011. Titration-based screening for evaluation of natural product extracts: identification of an aspulvinone family of luciferase inhibitors Patricia G. Cruz2, Douglas S. Auld1, Pamela J. Schultz2, Scott Lovell3, Kevin P. Battaile4, Ryan MacArthur1, Min Shen1, Giselle Tamayo-Castillo5, James Inglese1,*, and David H. Sherman2,* 1NIH Chemical Genomics Center, National Human Genome Research Institute, NIH, Bethesda, MD 20892-3370, USA 2Center for Chemical Genomics, Life Sciences Institute and Departments of Medicinal Chemistry, Chemistry, Microbiology & Immunology, University of Michigan, Ann Arbor, MI 48109-2216 3Protein Structure Laboratory, University of Kansas, Del Shankel Structural Biology Center, Lawrence, KS 66047 4IMCA-CAT, Hauptman-Woodward Medical Research Institute, Argonne National Laboratory 9700 S. Cass Avenue, Bldg. 435A, Argonne, IL 60439 USA 5Unidad Estrategica de Bioprospeccion, Instituto Nacional de Biodiversidad (INBio), Santo Domingo de Heredia, Costa Rica & Escuela de Química, Universidad de Costa Rica, 2050 San Pedro Abstract The chemical diversity of nature has tremendous potential for discovery of new molecular probes and medicinal agents. However, sensitivity of HTS assays to interfering components of crude extracts derived from plants, macro- and microorganisms has curtailed their use in lead discovery efforts. Here we describe a process for leveraging the concentration-response curves (CRCs) obtained from quantitative HTS to improve the initial selection of “actives” from a library of partially fractionated natural product extracts derived from marine actinomycetes and fungi.
    [Show full text]
  • Today's Topic
    January 30th, 2020 Vol. 6, No. 4 Palliative Care TODAY’S TOPIC: Pharmacy Team: What’s New in Palliative Care Medications Drug #4: Bremelanotide (Vylessi®) Clinical Pharmacy Specialist: Background: Jenn Pruskowski, Bremelanotide (Vylessi®) is a melanocortin receptor (MCR) agonist PharmD, BCPS, that nonselectively activates several receptor subtypes that BCGP, CPE improves hypoactive sexual desire disorder in women [email protected] - Initial US approval: 2019 - Available as: 1.74mg/0.3mL subcutaneous solution If you have a topic you would like the pharmacy Importance: team to answer, please In a US national household survey of adult sexual behavior send your suggestions conducted in 1992, the overall prevalence of sexual dysfunction to: [email protected] among women 18–59 years old was 43%. Palliative care providers should be aware of pharmacological options for hypoactive sexual desire disorder in premenopausal women. Pharmacology: Bremelantoide is a melanocortin receptor (MCR) agonist that nonselectively activates several receptor subtypes with the following order of potency: MC1R, MC4R, MC3R, MC5R, MC2R. At MoA: therapeutic dose levels, binding to MC1R and MC4R is most relevant. Neurons expressing MC4R are present in many areas of the central nervous system (CNS) - A: Tmax: 1 hour - M: Hydrolyses of the amide bond of the cyclic ADME: peptide - E: T ½: 2.7 hours Concomitant use naltrexone may result is DIs: naltrexone treatment failure Key: MoA: Mechanism of Action; ADME: Absorption, Distribution, Metabolism, and Excretion; DI:
    [Show full text]
  • Multidrug-Resistant Gram-Negative Bacteria: How to Treat and for How Long Helen Giamarellou
    Multidrug-resistant Gram-negative bacteria: How to treat and for how long Helen Giamarellou To cite this version: Helen Giamarellou. Multidrug-resistant Gram-negative bacteria: How to treat and for how long. International Journal of Antimicrobial Agents, Elsevier, 2010, 36, 10.1016/j.ijantimicag.2010.11.014. hal-00650375 HAL Id: hal-00650375 https://hal.archives-ouvertes.fr/hal-00650375 Submitted on 10 Dec 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Accepted Manuscript Title: Multidrug-resistant Gram-negative bacteria: How to treat and for how long Author: Helen Giamarellou PII: S0924-8579(10)00475-9 DOI: doi:10.1016/j.ijantimicag.2010.11.014 Reference: ANTAGE 3468 To appear in: International Journal of Antimicrobial Agents Please cite this article as: Giamarellou H, Multidrug-resistant Gram-negative bacteria: How to treat and for how long, International Journal of Antimicrobial Agents (2010), doi:10.1016/j.ijantimicag.2010.11.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form.
    [Show full text]
  • Challenges of Antibacterial Discovery Lynn L
    CLINICAL MICROBIOLOGY REVIEWS, Jan. 2011, p. 71–109 Vol. 24, No. 1 0893-8512/11/$12.00 doi:10.1128/CMR.00030-10 Copyright © 2011, American Society for Microbiology. All Rights Reserved. Challenges of Antibacterial Discovery Lynn L. Silver* LL Silver Consulting, LLC, 955 S. Springfield Ave., Unit C403, Springfield, New Jersey 07081 INTRODUCTION .........................................................................................................................................................72 The Discovery Void...................................................................................................................................................72 Class Modifications versus Novel Classes.............................................................................................................72 BACKGROUND............................................................................................................................................................72 Early Screening—a Brief and Biased Philosophical History .............................................................................72 The Rate-Limiting Steps of Antibacterial Discovery ...........................................................................................74 The Multitarget Hypothesis ....................................................................................................................................74 ANTIBACTERIAL RESISTANCE ..............................................................................................................................75
    [Show full text]
  • DOSE-EFFECT RELATIONSHIP Drug Receptor K1 K2 Drug-Receptor
    DOSE-EFFECT RELATIONSHIP A fundamental principle of pharmacology is that the intensity of effect produced by a drug is a function of the quantity of drug administered (or the concentration of the drug at the target site). The relationship between dose and drug effect can be expressed mathematically by two methods, which are called graded and quantal. • Graded - The graded dose-effect is measured in a single biologic unit (a cell, a tissue or organ, or an entire organism). The effect is measured on a continuous scale and the intensity of effect is proportional to the dose. • Quantal - A quantal effect is an all-or-none effect such as alive or dead, asleep or awake, pain-free or in pain. Quantal dose-effect studies are performed in populations of subjects and they relate dose to the frequency of the all-or-none effect, such as the % of animals that are killed. GRADED DOSE-EFFECT RELATIONSHIP The effects of most drugs result from their interaction with macromolecules, which are called receptors. A receptor can be any cellular macromolecule to which a drug binds to initiate its effect. Proteins form the most important class of drug receptors Drug Drug-Receptor Complex Receptor k1 k2 EFFECT Cellular proteins that are receptors for endogenous regulatory ligands (hormones, growth factors, neurotransmitters) are the most important drug receptors. These proteins have a ligand binding domain where the drug interacts and an effector domain that propagates the message, leading to an effect. Other receptors include enzymes (e.g., acetylcholinesterase), transport proteins (e.g., Na+,K+-ATPase), structural proteins (e.g., tubulin), and nucleic acids.
    [Show full text]