DOCSLIB.ORG

Effects of Magnesium, Calcium, and Aluminum Chelation on Fluoroquinolone Absorption Rate and Bioavailability: a Computational Study

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Effects of Magnesium, Calcium, and Aluminum Chelation on Fluoroquinolone Absorption Rate and Bioavailability: a Computational Study pharmaceutics Article Effects of Magnesium, Calcium, and Aluminum Chelation on Fluoroquinolone Absorption Rate and Bioavailability: A Computational Study Daniel M. Walden, Maksim Khotimchenko , Hypatia Hou, Kaushik Chakravarty and Jyotika Varshney * VeriSIM Life, San Francisco, CA 94104, USA; [email protected] (D.M.W.); [email protected] (M.K.); [email protected] (H.H.); [email protected] (K.C.) * Correspondence: [email protected] Abstract: Fluoroquinolones (FQs) are a widespread class of broad-spectrum antibiotics prescribed as a first line of defense, and, in some cases, as the only treatment against bacterial infection. However, when administered orally, reduced absorption and bioavailability can occur due to chelation in the gastrointestinal tract (GIT) with multivalent metal cations acquired from diet, coadministered com- pounds (sucralfate, didanosine), or drug formulation. Predicting the extent to which this interaction reduces in vivo antibiotic absorption and systemic exposure remains desirable yet challenging. In this study, we focus on quinolone interactions with magnesium, calcium and aluminum as found in Citation: Walden, D.M.; dietary supplements, antacids (Maalox) orally administered therapies (sucralfate, didanosine). The Khotimchenko, M.; Hou, H.; effect of FQ–metal complexation on absorption rate was investigated through a combined molecular Chakravarty, K.; Varshney, J. Effects and pharmacokinetic (PK) modeling study. Quantum mechanical calculations elucidated FQ–metal of Magnesium, Calcium, and binding energies, which were leveraged to predict the magnitude of reduced bioavailability via a Aluminum Chelation on quantitative structure–property relationship (QSPR). This work will help inform clinical FQ formula- Fluoroquinolone Absorption Rate tion design, alert to possible dietary effects, and shed light on drug–drug interactions resulting from and Bioavailability: A Computational Study. Pharmaceutics 2021, 13, 594. coadministration at an earlier stage in the drug development pipeline. https://doi.org/10.3390/ pharmaceutics13050594 Keywords: fluoroquinolones; antibiotics; antacids; multivalent metals; pharmacokinetics; bioavail- ability; oral absorption; molecular modeling Academic Editors: Isabel Gonzalez-Alvarez and Peter Langguth 1. Introduction Received: 31 March 2021 Quinolones comprise a widely prescribed class of antibiotics against both Gram- Accepted: 16 April 2021 negative and Gram-positive bacterial infections. In 2018, ciprofloxacin alone was pre- Published: 21 April 2021 scribed over 6.7 million times in the United States, representing the 109th most prescribed medication in the country [1]. Significant attention to quinolone development followed the Publisher’s Note: MDPI stays neutral discovery of the antibacterial properties of nalidixic acid, itself a by-product of chloroquine with regard to jurisdictional claims in synthesis. As the spearheading member of the first-generation quinolones, nalidixic acid published maps and institutional affil- was approved to treat Gram-negative (primarily Escherichia coli) urinary tract infections iations. (UTIs) and began clinical applications in 1967, yet ultimately saw limited use due to its narrow spectrum and high dosage requirements for efficacy [2]. Over the last five decades, quinolone development and structure–activity relationships have focused on expanding the antimicrobial spectrum and overall activity while also improving compound pharma- Copyright: © 2021 by the authors. cokinetics (PK) and reducing both toxicity and drug interactions [3,4]. Nalidixic acid, while Licensee MDPI, Basel, Switzerland. technically a 1,8-naphthyridine derivative, exhibits the defining core 4-quinolone bicyclic This article is an open access article ring system shared by quinolone therapeutic compounds (Figure1). Critical substituents distributed under the terms and for high potency are hydrogen substitution at position-2, a carboxylic acid at position-3, conditions of the Creative Commons Attribution (CC BY) license (https:// and a ketone at position-4 [5,6]. Fluorine substitution at C6 was identified as key to in- creativecommons.org/licenses/by/ creased antibacterial potency and tissue penetration [7]. The C6 fluorine substitution to the 4.0/). initial quinolone scaffold is now recognized as a critical pharmacophoric component, and Pharmaceutics 2021, 13, 594. https://doi.org/10.3390/pharmaceutics13050594 https://www.mdpi.com/journal/pharmaceutics PharmaceuticsPharmaceutics 20212021,, 1313,, 594x 22 of of 1416 key to increased antibacterial potency and tissue penetration [7]. The C6 fluorine substi- tution to the initial quinolone scaffold is now recognized as a critical pharmacophoric thiscomponent, subclass, and termed this subclass, fluoroquinolones termed fluoro (FQs),quinolones comprise most (FQs), contemporary comprise most quinolones contempo- in developmentrary quinolones and in with development clinical applications. and with clinical applications. Figure 1. 1. SharedShared core core scaffold scaffold of quinolone of quinolone antibact antibacterialerial compounds. compounds. X = N indicates X = N indicates1,8-naphthy- 1,8- naphthyridine,ridine, X = C defines X = C quinolones. defines quinolones. R6 = F defines R6 = Ffluoroquinolones. defines fluoroquinolones. Reduction inin oraloral bioavailabilitybioavailability due due to to chelation chelation between between FQs FQs and and multivalent multivalent metals met- isals a is well-established a well-established phenomenon phenomenon with with numerous numerous studies studies disclosing disclosing disruptive disruptive interactions inter- betweenactions between quinolones quinolones and metal and cationsmetal cations [8]. Nix [8]. et Nix al. studiedet al. studied the effect the effect of aluminum of aluminum and magnesiumand magnesium from from Maalox Maalox antacid antacid on ciprofloxacin on ciprofloxacin PK. The PK. maximum The maximum plasma plasma concentration concen- (trationCmax) and(Cmax area) and under area theunder plasma the plasma concentration-versus-time concentration-versus-time curve (AUC) curve of(AUC) single of 750 single mg ciprofloxacin750 mg ciprofloxacin dose were dose each were reduced each reduced by 85% relative by 85% to relative ciprofloxacin to ciprofloxacin alone (control) alone when(con- administeredtrol) when administered 5–10 min after 5–10 Maalox min after ingestion Maalox [ingestion9]. Nix et [9]. al. Nix investigated et al. investigated the effect the of sucralfateeffect of sucralfate pretreatment pretreatment at time intervalsat time interv of 6als and of 2 6 h and prior 2 h to prior a single to a single ciprofloxacin ciprofloxacin dose withdose reductionswith reductions in Cmax inand Cmax AUC and ofAUC 30% of relative 30% relative to ciprofloxacin to ciprofloxacin alone [9 alone]. Coadministra- [9]. Coad- tionministration of ciprofloxacin of ciprofloxacin and sucralfate and sucralfate was subsequently was subsequently studied studied by Garrelts by Garrelts et al., finding et al., reductionsfinding reductions in Cmax andin Cmax AUC and of AUC 90% of and 90% 87%, and respectively, 87%, respectively, versus controlversus control [10]. Sahai [10]. et Sa- al. probedhai et al. the probed effects the of magnesiumeffects of magnesium and aluminum and aluminum found in didanosinefound in didanosine on ciprofloxacin on ciprof- PK highlighting significant reductions in both mean C (94%) and AUC (98%) seen versus loxacin PK highlighting significant reductions in bothmax mean Cmax (94%) and AUC (98%) controlseen versus [11]. control Aluminum [11]. has Aluminum emerged has as particularly emerged as important particularly among important product among component prod- saltsuct component as aluminum salts has as been aluminum observed has to been modulate observed quinolone to modulate PK to a higherquinolone degree PK thanto a otherhigher metals. degree For than example, other metals. Sahai etFor al. example, investigated Sahai the et effectsal. investigated of calcium the carbonate effects of from cal- supplements on ciprofloxacin bioavailability [12]. While both Cmax and AUC were reduced cium carbonate from supplements on ciprofloxacin bioavailability [12]. While both Cmax byand about AUC 40%, were the reduced comparatively by about smaller40%, the influence comparatively on bioavailability smaller influence is apparent. on bioavaila- A num- ber of studies disclose the effects of magnesium, aluminum, and calcium on the PK of bility is apparent. A number of studies disclose the effects of magnesium, aluminum, and other fluoroquinolones, including levofloxacin [13,14], enoxacin [15], lomefloxacin [16], calcium on the PK of other fluoroquinolones, including levofloxacin [13,14], enoxacin [15], pefloxacin [17], rufloxacin [18], norfloxacin [19–22], ofloxacin [20,23], and fleroxacin [24]. lomefloxacin [16], pefloxacin [17], rufloxacin [18], norfloxacin [19–22], ofloxacin [20,23], Sources of these multivalent metals are diverse and quite abundant and can origi- and fleroxacin [24]. nate from diet or from drug products. The case of significant reduction in drug systemic Sources of these multivalent metals are diverse and quite abundant and can originate concentration in going from the fasted to fed state represents a negative food effect [25]. from diet or from drug products. The case of significant reduction in drug systemic con- Multivalent metals are found in antacids containing calcium, magnesium, and aluminum centration in going from the fasted to
Load more

Recommended publications
  • (12) United States Patent (10) Patent No.: US 9,662.400 B2 Smith Et Al
    USOO9662400B2 (12) United States Patent (10) Patent No.: US 9,662.400 B2 Smith et al. (45) Date of Patent: *May 30, 2017 (54) METHODS FOR PRODUCING A (2013.01); C08B 37/003 (2013.01); C08L 5/08 BODEGRADABLE CHITOSAN (2013.01); A6 IK 38/00 (2013.01); A61 L COMPOSITION AND USES THEREOF 2300/404 (2013.01) (58) Field of Classification Search (71) Applicant: University of Memphis Research CPC ...... A61K 47/36; A61K 31/00; A61K 9/7007; Foundation, Memphis, TN (US) A61K 9/0024; A61 L 15/28: A61L 27/20; A61L 27/58: A61L 31/042; C08B 37/003 (72) Inventors: James Keaton Smith, Memphis, TN USPC ................................ 514/23, 40, 777; 536/20 (US); Ashley C. Parker, Memphis, TN See application file for complete search history. (US); Jessica A. Jennings, Memphis, (56) References Cited TN (US); Benjamin T. Reves, Memphis, TN (US); Warren O. U.S. PATENT DOCUMENTS Haggard, Bartlett, TN (US) 4,895,724. A * 1/1990 Cardinal .............. A61K9/0024 424,278.1 (73) Assignee: The University of Memphis Research 5,541,233 A 7/1996 Roenigk Foundation, Memphis, TN (US) 5,958,443 A 9/1999 Viegas et al. 6,699,287 B2 3/2004 Son et al. (*) Notice: Subject to any disclaimer, the term of this 6,989,157 B2 1/2006 Gillis et al. patent is extended or adjusted under 35 7,371.403 B2 5/2008 McCarthy et al. 2003, OO15825 A1 1/2003 Sugie et al. U.S.C. 154(b) by 0 days. 2003/0206958 A1 11/2003 Cattaneo et al.
    [Show full text]
  • Repurposing Drug Scaffolds: a Tool for Developing Novel Therapeutics with Applications in Malaria and Lung Cancer
    Repurposing Drug Scaffolds: A Tool for Developing Novel Therapeutics with Applications in Malaria and Lung Cancer A Thesis Submitted by: Hannah Elizabeth Cook In partial fulfilment of the requirements for the degree of: Doctor of Philosophy September 2018 Supervisors: Professor Matthew J. Fuchter & Professor Anthony G. M. Barrett Department of Chemistry Imperial College London 2 Declaration of Originality I, Hannah Cook, hereby confirm that the work presented within this thesis is entirely my own, conducted under the supervision of Professor Matthew J. Fuchter and Professor Anthony G. M. Barrett, at the Department of Chemistry, Imperial College London, unless otherwise stated. All work performed by others has been acknowledged within the text and referenced where appropriate. Hannah E. Cook September 2018 Copyright Declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work. 3 Abstract The definition of repurposing in the context of drug discovery encompasses a variety of strategies designed to redirect current therapeutic knowledge towards new disease indications. This approach can be successful for the design of new drugs to treat diseases of the developing world such as Malaria, where there are limited resources to fund new drug discovery campaigns. Moreover, it can be used to decrease the drug development time for diseases in which there is high drug attrition rates coupled with high mortality rates, which is the case for some cancers.
    [Show full text]
  • A TWO-YEAR RETROSPECTIVE ANALYSIS of ADVERSE DRUG REACTIONS with 5PSQ-031 FLUOROQUINOLONE and QUINOLONE ANTIBIOTICS 24Th Congress Of
    A TWO-YEAR RETROSPECTIVE ANALYSIS OF ADVERSE DRUG REACTIONS WITH 5PSQ-031 FLUOROQUINOLONE AND QUINOLONE ANTIBIOTICS 24th Congress of V. Borsi1, M. Del Lungo2, L. Giovannetti1, M.G. Lai1, M. Parrilli1 1 Azienda USL Toscana Centro, Pharmacovigilance Centre, Florence, Italy 2 Dept. of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), 27-29 March 2019 Section of Pharmacology and Toxicology , University of Florence, Italy BACKGROUND PURPOSE On 9 February 2017, the Pharmacovigilance Risk Assessment Committee (PRAC) initiated a review1 of disabling To review the adverse drugs and potentially long-lasting side effects reported with systemic and inhaled quinolone and fluoroquinolone reactions (ADRs) of antibiotics at the request of the German medicines authority (BfArM) following reports of long-lasting side effects systemic and inhaled in the national safety database and the published literature. fluoroquinolone and quinolone antibiotics that MATERIAL AND METHODS involved peripheral and central nervous system, Retrospective analysis of ADRs reported in our APVD involving ciprofloxacin, flumequine, levofloxacin, tendons, muscles and joints lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, prulifloxacin, rufloxacin, cinoxacin, nalidixic acid, reported from our pipemidic given systemically (by mouth or injection). The period considered is September 2016 to September Pharmacovigilance 2018. Department (PVD). RESULTS 22 ADRs were reported in our PVD involving fluoroquinolone and quinolone antibiotics in the period considered and that affected peripheral or central nervous system, tendons, muscles and joints. The mean patient age was 67,3 years (range: 17-92 years). 63,7% of the ADRs reported were serious, of which 22,7% caused hospitalization and 4,5% caused persistent/severe disability. 81,8% of the ADRs were reported by a healthcare professional (physician, pharmacist or other) and 18,2% by patient or a non-healthcare professional.
    [Show full text]
  • Preclinical Evaluation of Protein Disulfide Isomerase Inhibitors for the Treatment of Glioblastoma by Andrea Shergalis
    Preclinical Evaluation of Protein Disulfide Isomerase Inhibitors for the Treatment of Glioblastoma By Andrea Shergalis A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Medicinal Chemistry) in the University of Michigan 2020 Doctoral Committee: Professor Nouri Neamati, Chair Professor George A. Garcia Professor Peter J. H. Scott Professor Shaomeng Wang Andrea G. Shergalis [email protected] ORCID 0000-0002-1155-1583 © Andrea Shergalis 2020 All Rights Reserved ACKNOWLEDGEMENTS So many people have been involved in bringing this project to life and making this dissertation possible. First, I want to thank my advisor, Prof. Nouri Neamati, for his guidance, encouragement, and patience. Prof. Neamati instilled an enthusiasm in me for science and drug discovery, while allowing me the space to independently explore complex biochemical problems, and I am grateful for his kind and patient mentorship. I also thank my committee members, Profs. George Garcia, Peter Scott, and Shaomeng Wang, for their patience, guidance, and support throughout my graduate career. I am thankful to them for taking time to meet with me and have thoughtful conversations about medicinal chemistry and science in general. From the Neamati lab, I would like to thank so many. First and foremost, I have to thank Shuzo Tamara for being an incredible, kind, and patient teacher and mentor. Shuzo is one of the hardest workers I know. In addition to a strong work ethic, he taught me pretty much everything I know and laid the foundation for the article published as Chapter 3 of this dissertation. The work published in this dissertation really began with the initial identification of PDI as a target by Shili Xu, and I am grateful for his advice and guidance (from afar!).
    [Show full text]
  • Guidelines on Urinary and Male Genital Tract Infections
    European Association of Urology GUIDELINES ON URINARY AND MALE GENITAL TRACT INFECTIONS K.G. Naber, B. Bergman, M.C. Bishop, T.E. Bjerklund Johansen, H. Botto, B. Lobel, F. Jimenez Cruz, F.P. Selvaggi TABLE OF CONTENTS PAGE 1. INTRODUCTION 5 1.1 Classification 5 1.2 References 6 2. UNCOMPLICATED UTIS IN ADULTS 7 2.1 Summary 7 2.2 Background 8 2.3 Definition 8 2.4 Aetiological spectrum 9 2.5 Acute uncomplicated cystitis in pre-menopausal, non-pregnant women 9 2.5.1 Diagnosis 9 2.5.2 Treatment 10 2.5.3 Post-treatment follow-up 11 2.6 Acute uncomplicated pyelonephritis in pre-menopausal, non-pregnant women 11 2.6.1 Diagnosis 11 2.6.2 Treatment 12 2.6.3 Post-treatment follow-up 12 2.7 Recurrent (uncomplicated) UTIs in women 13 2.7.1 Background 13 2.7.2 Prophylactic antimicrobial regimens 13 2.7.3 Alternative prophylactic methods 14 2.8 UTIs in pregnancy 14 2.8.1 Epidemiology 14 2.8.2 Asymptomatic bacteriuria 15 2.8.3 Acute cystitis during pregnancy 15 2.8.4 Acute pyelonephritis during pregnancy 15 2.9 UTIs in post-menopausal women 15 2.10 Acute uncomplicated UTIs in young men 16 2.10.1 Pathogenesis and risk factors 16 2.10.2 Diagnosis 16 2.10.3 Treatment 16 2.11 References 16 3. UTIs IN CHILDREN 20 3.1 Summary 20 3.2 Background 20 3.3 Aetiology 20 3.4 Pathogenesis 20 3.5 Signs and symptoms 21 3.5.1 New-borns 21 3.5.2 Children < 6 months of age 21 3.5.3 Pre-school children (2-6 years of age) 21 3.5.4 School-children and adolescents 21 3.5.5 Severity of a UTI 21 3.5.6 Severe UTIs 21 3.5.7 Simple UTIs 21 3.5.8 Epididymo orchitis 22 3.6 Diagnosis 22 3.6.1 Physical examination 22 3.6.2 Laboratory tests 22 3.6.3 Imaging of the urinary tract 23 3.7 Schedule of investigation 24 3.8 Treatment 24 3.8.1 Severe UTIs 25 3.8.2 Simple UTIs 25 3.9 References 26 4.
    [Show full text]
  • Consideration of Antibacterial Medicines As Part Of
    Consideration of antibacterial medicines as part of the revisions to 2019 WHO Model List of Essential Medicines for adults (EML) and Model List of Essential Medicines for children (EMLc) Section 6.2 Antibacterials including Access, Watch and Reserve Lists of antibiotics This summary has been prepared by the Health Technologies and Pharmaceuticals (HTP) programme at the WHO Regional Office for Europe. It is intended to communicate changes to the 2019 WHO Model List of Essential Medicines for adults (EML) and Model List of Essential Medicines for children (EMLc) to national counterparts involved in the evidence-based selection of medicines for inclusion in national essential medicines lists (NEMLs), lists of medicines for inclusion in reimbursement programs, and medicine formularies for use in primary, secondary and tertiary care. This document does not replace the full report of the WHO Expert Committee on Selection and Use of Essential Medicines (see The selection and use of essential medicines: report of the WHO Expert Committee on Selection and Use of Essential Medicines, 2019 (including the 21st WHO Model List of Essential Medicines and the 7th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization; 2019 (WHO Technical Report Series, No. 1021). Licence: CC BY-NC-SA 3.0 IGO: https://apps.who.int/iris/bitstream/handle/10665/330668/9789241210300-eng.pdf?ua=1) and Corrigenda (March 2020) – TRS1021 (https://www.who.int/medicines/publications/essentialmedicines/TRS1021_corrigenda_March2020. pdf?ua=1). Executive summary of the report: https://apps.who.int/iris/bitstream/handle/10665/325773/WHO- MVP-EMP-IAU-2019.05-eng.pdf?ua=1.
    [Show full text]
  • EMA/CVMP/158366/2019 Committee for Medicinal Products for Veterinary Use
    Ref. Ares(2019)6843167 - 05/11/2019 31 October 2019 EMA/CVMP/158366/2019 Committee for Medicinal Products for Veterinary Use Advice on implementing measures under Article 37(4) of Regulation (EU) 2019/6 on veterinary medicinal products – Criteria for the designation of antimicrobials to be reserved for treatment of certain infections in humans Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2019. Reproduction is authorised provided the source is acknowledged. Introduction On 6 February 2019, the European Commission sent a request to the European Medicines Agency (EMA) for a report on the criteria for the designation of antimicrobials to be reserved for the treatment of certain infections in humans in order to preserve the efficacy of those antimicrobials. The Agency was requested to provide a report by 31 October 2019 containing recommendations to the Commission as to which criteria should be used to determine those antimicrobials to be reserved for treatment of certain infections in humans (this is also referred to as ‘criteria for designating antimicrobials for human use’, ‘restricting antimicrobials to human use’, or ‘reserved for human use only’). The Committee for Medicinal Products for Veterinary Use (CVMP) formed an expert group to prepare the scientific report. The group was composed of seven experts selected from the European network of experts, on the basis of recommendations from the national competent authorities, one expert nominated from European Food Safety Authority (EFSA), one expert nominated by European Centre for Disease Prevention and Control (ECDC), one expert with expertise on human infectious diseases, and two Agency staff members with expertise on development of antimicrobial resistance .
    [Show full text]
  • A Review on Anticancer and Antimicrobial Activity of Tetrafluoroquinolone Compounds
    Central Annals of Medicinal Chemistry and Research Review Article *Corresponding author Mohammad Asif, Department of Pharmacy, GRD (PG) Institute of Management and Technology, Dehradun, A Review on Anticancer (Uttarakhand), 248009, India. Email: and Antimicrobial Activity Submitted: 10 August 2014 Accepted: 07 October 2014 Published: 25 November 2014 of Tetrafluoroquinolone Copyright © 2014 Asif Compounds OPEN ACCESS Mohammad Asif* Keywords Department of Pharmacy, GRD (PG) Institute of Management and Technology, India • Antibacterial activity • Anti cancer activity Abstract • Tetracyclic • Fluoroquinolone. The prokaryotic type II topoisomerases (DNA gyrase and topoisomerase IV) and the eukaryotic type II topoisomerases represent the cellular targets for quinolone antibacterial agents and a wide variety of anticancer drugs, respectively. In view of the mechanistic similarities and sequence homologies exhibited by the two enzymes, tentative efforts to selectively shift from an antibacterial to an antitumoral activity was made by a series of functionalized teracyclic fluoroquinolones. Thus, as part of a continuing search for potential anticancer drug candidates in the quinolones series, the interest in cytotoxicity of functionalized tetracyclic fluoroquinolones. The growth inhibitory activities of tetracyclic fluoroquinolones were against cancer cell lines using an in vitro cell culture system. Some of tetracyclic fluoroquinolones showed in vitro cytotoxic activity. The tetracyclic group of fluoroquinolones series changes the biological profile of quinolones from antibacterial to cytotoxic activity. The tetracyclic fluoroquinolones have excellent potential as a new class of cytotoxic agents. INTRODUCTION ring with a bridge between C-8 and N-1 is found in levofloxacin and Rufloxacin. Last generation FQLs demonstrated the favorable Fluoroquinolone (FQL), NorfloxacinFigure 1 is an antibacterial influence of an OCH3 substituent at position 8 on Gram positive agent with potent and broad spectrum activity and several and on anaerobic bacteria.
    [Show full text]
  • Disabling and Potentially Permanent Side Effects Lead to Suspension Or Restrictions of Quinolone and Fluoroquinolone Antibiotics
    16 November 2018 EMA/795349/2018 Disabling and potentially permanent side effects lead to suspension or restrictions of quinolone and fluoroquinolone antibiotics EMA has reviewed serious, disabling and potentially permanent side effects with quinolone and fluoroquinolone antibiotics given by mouth, injection or inhalation. The review incorporated the views of patients, healthcare professionals and academics presented at EMA’s public hearing on fluoroquinolone and quinolone antibiotics in June 2018. EMA’s human medicines committee (CHMP) has endorsed the recommendations of EMA’s safety committee (PRAC) and concluded that the marketing authorisation of medicines containing cinoxacin, flumequine, nalidixic acid, and pipemidic acid should be suspended. The CHMP confirmed that the use of the remaining fluoroquinolone antibiotics should be restricted. In addition, the prescribing information for healthcare professionals and information for patients will describe the disabling and potentially permanent side effects and advise patients to stop treatment with a fluoroquinolone antibiotic at the first sign of a side effect involving muscles, tendons or joints and the nervous system. Restrictions on the use of fluoroquinolone antibiotics will mean that they should not be used: • to treat infections that might get better without treatment or are not severe (such as throat infections); • to treat non-bacterial infections, e.g. non-bacterial (chronic) prostatitis; • for preventing traveller’s diarrhoea or recurring lower urinary tract infections (urine infections that do not extend beyond the bladder); • to treat mild or moderate bacterial infections unless other antibacterial medicines commonly recommended for these infections cannot be used. Importantly, fluoroquinolones should generally be avoided in patients who have previously had serious side effects with a fluoroquinolone or quinolone antibiotic.
    [Show full text]
  • The Role of the Immune Response in the Effectiveness of Antibiotic Treatment for Antibiotic Susceptible and Antibiotic Resistant Bacteria
    The role of the immune response in the effectiveness of antibiotic treatment for antibiotic susceptible and antibiotic resistant bacteria. by Olachi Nnediogo Anuforom A thesis submitted to the University of Birmingham for the degree of Doctor of Philosophy. Institute of Microbiology and Infection, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham. May, 2015. University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Abstract The increasing spread of antimicrobial resistant bacteria and the decline in the development of novel antibiotics have incited exploration of other avenues for antimicrobial therapy. One option is the use of antibiotics that enhance beneficial aspects of the host’s defences to infection. This study explores the influence of antibiotics on the innate immune response to bacteria. The aims were to investigate antibiotic effects on bacterial viability, innate immune cells (neutrophils and macrophages) in response to bacteria and interactions between bacteria and the host. Five exemplar antibiotics; ciprofloxacin, tetracycline, ceftriaxone, azithromycin and streptomycin at maximum serum concentration (Cmax) and minimum inhibitory concentrations (MIC) were tested. These five antibiotics were chosen as they are commonly used to treat infections and represent different classes of drug.
    [Show full text]
  • Fluoroquinolone Antibacterials: a Review on Chemistry, Microbiology and Therapeutic Prospects
    Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 66 No. 6 pp. 587ñ604, 2009 ISSN 0001-6837 Polish Pharmaceutical Society REVIEV FLUOROQUINOLONE ANTIBACTERIALS: A REVIEW ON CHEMISTRY, MICROBIOLOGY AND THERAPEUTIC PROSPECTS PRABODH CHANDER SHARMA1*, ANKIT JAIN1 and SANDEEP JAIN2 1 Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra-136119, India 2 Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar-125001, India Abstract: Fluoroquinolones are one of the most promising and vigorously pursued areas of contemporary anti- infective chemotherapy depicting broad spectrum and potent activity. They have a relatively simple molecular nucleus, which is amenable to many structural modifications. These agents have several favorable properties such as excellent bioavailability, good tissue penetrability and a relatively low incidence of adverse and toxic effects. They have been found effective in treatment of various infectious diseases. This paper is an attempt to review the therapeutic prospects of fluoroquinolone antibacterials with an updated account on their develop- ment and usage. Keywords: fluoroquinolone, antibacterial, ciprofloxacin, therapeutic Antiinfective chemotherapy is the science of piratory tract infections (RTI), sexually transmitted administering chemical agents to treat infectious diseases (STD) and skin infections (5, 6). They are diseases. This practice has proven to be one of the primarily used against urinary tract infections and most successful of all pharmaceutical studies (1). are also clinically useful against prostatitis, infec- Historically, the use of anti-infective agents can be tions of skin and bones and penicillin resistant sex- credited with saving more human lives than any ually transmitted diseases (4). These agents are also other area of medicinal therapy discovered to date.
    [Show full text]
  • PRAC Recommendations on Signals Adopted at the 31 Aug-3 Sep 2020
    28 September 20201 EMA/PRAC/458924/2020 Pharmacovigilance Risk Assessment Committee (PRAC) PRAC recommendations on signals Adopted at the 31 August-3 September 2020 PRAC meeting This document provides an overview of the recommendations adopted by the Pharmacovigilance Risk Assessment Committee (PRAC) on the signals discussed during the meeting of 31 August-3 September 2020 (including the signal European Pharmacovigilance Issues Tracking Tool [EPITT]2 reference numbers). PRAC recommendations to provide supplementary information are directly actionable by the concerned marketing authorisation holders (MAHs). PRAC recommendations for regulatory action (e.g. amendment of the product information) are submitted to the Committee for Medicinal Products for Human Use (CHMP) for endorsement when the signal concerns Centrally Authorised Products (CAPs), and to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) for information in the case of Nationally Authorised Products (NAPs). Thereafter, MAHs are expected to take action according to the PRAC recommendations. When appropriate, the PRAC may also recommend the conduct of additional analyses by the Agency or Member States. MAHs are reminded that in line with Article 16(3) of Regulation No (EU) 726/2004 and Article 23(3) of Directive 2001/83/EC, they shall ensure that their product information is kept up to date with the current scientific knowledge including the conclusions of the assessment and recommendations published on the European Medicines Agency (EMA) website (currently acting as the EU medicines webportal). For CAPs, at the time of publication, PRAC recommendations for update of product information have been agreed by the CHMP at their plenary meeting (14-17 September 2020) and corresponding variations will be assessed by the CHMP.
    [Show full text]