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The Quinolones: Past, Present and FutureThe Quinolones: Past, Present and Future
The Past….The Past….
 The Quinolone are class of antimicrobial agents thatThe Quinolone are class of antimicrobial agents...
The Past….The Past….
 Nalidixic acid became the lead compound forNalidixic acid became the lead compound for
medicinal ch...
The Past….The Past….
 This discovery led to the development of a library ofThis discovery led to the development of a lib...
The Past….The Past….
 The various derivatives of fluoroquinoloneThe various derivatives of fluoroquinolone
have varying l...
The PresentThe Present
 Two main classifications for fluoroquinolones based onTwo main classifications for fluoroquinolon...
Table one ….Table one ….
GenerationGeneration DrugsDrugs AntibacterialAntibacterial
spectrumspectrum
FirstFirst Nalidixic ...
Table one…Table one…
GenerationGeneration DrugsDrugs Antibacterial spectrumAntibacterial spectrum
ThirdThird TosufloxacinT...
StructureStructure
 All fluoroquinolones have a basicAll fluoroquinolones have a basic
4-quinolone structure, with a4-qui...
…….Structure.Structure
Some of the key structural modifications are :Some of the key structural modifications are :
 addi...
…….Structure.Structure
 The most recent key modification was theThe most recent key modification was the
observation that...
Mechanism of actionMechanism of action
 Fluoroquinolones enter the cellsFluoroquinolones enter the cells
by porins and ta...
……..Mechanism of action…....Mechanism of action…..
 The fluoroquinolones bind to the enzyme-DNA complex andThe fluoroquin...
Pharmacokinetics andPharmacokinetics and
pharmacodynamicspharmacodynamics
 Most of the fluoroquinolones are available in ...
Development of ResistanceDevelopment of Resistance
In the recent, past there have been increasing number ofIn the recent, ...
Mechanism of developingMechanism of developing
resistanceresistance
Progress in our understanding of the role of
SARs, alo...
Adverse reactions….Adverse reactions….
The rate of adverse events associated with both oral and intravenous fluoroquinolon...
…….Adverse reactions.Adverse reactions
 Three adverse events associated with
quinolones—cardiotoxicity (e.g., prolongatio...
The PresentThe Present
 A number of infectious diseases are
successfully treated with quinolones
administered orally or i...
Approved clinical uses for selected fluoroquinolones.
Ciprofloxacin
 Acute uncomplicated cystitis in females (oral use on...
Levofloxacin
 Uncomplicated urinary tract infections (mild to moderate)
 Complicated urinary tract infections (mild to m...
Moxifloxacin
 Acute bacterial sinusitis
 Acute bacterial exacerbation of chronic
bronchitis
 Community-acquired pneumon...
Gatifloxacin
 Uncomplicated urinary tract infections
 Complicated urinary tract infections
 Pyelonephritis
 Uncomplica...
Gemifloxacin
 Acute bacterial exacerbation of chronic
bronchitis
 Community-acquired pneumonia (mild to
moderate).
The FutureThe Future
 The future prospects of newer Quinolones depends on:
(1) greater potency, particularly against stap...
The Future….The Future….
 In addition, newer quinolones may be developed with greater
activity against targets in infecti...
……..The Future..The Future
 If the use of quinolones in clinical medicine is
to continue,the emergence of bacterial
resis...
GarenoxacinGarenoxacin
 Garenoxacin is a synthetic, des-F(6)-quinolone antibacterialGarenoxacin is a synthetic, des-F(6)-...
GarenoxacinGarenoxacin
 Garenoxacin demonstrates wide spectrum ofGarenoxacin demonstrates wide spectrum of
antibacterial ...
Garenoxacin—Clinical use andGarenoxacin—Clinical use and
Indications.Indications.
 Garenoxacin is a novel des-fluoro 6-qu...
Garenoxacin- ContraindicationsGarenoxacin- Contraindications
Garenoxacin should be administered withGarenoxacin should be ...
Garenoxacin- Adverse reactionsGarenoxacin- Adverse reactions
 The most frequent adverse effects reported in clinicalThe m...
Garenoxacin –Place in therapyGarenoxacin –Place in therapy
 Garenoxacin with its Pharmacodynamic andGarenoxacin with its ...
ReferencesReferences
 http://www.japi.org/jan_2014/pdf/05_dc.pdf#page=1&zoom=auto,-22,777 accessedhttp://www.japi.org/jan...
References…..References…..
 Michael A. Kohanski, Daniel J. Dwyer, James J. Collins. How antibiotics kill bacteria: from
t...
References……References……
 Crumplin GC, Smith JT. Nalidixic acid and bacterial chromosome
replication. Nature 1976; 260:64...
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The wonder drug --Quinolones.

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Quinolones , The Quinolone are class of antimicrobial agents that was not isolated from living organisms but, rather, was synthesized by chemists.
They are a group of synthetic broad spectrum antibacterial drugs that target DNA Synthesis. The prolific development of the Quinolones began in 1962, when Lesher et al. made the accidental discovery of nalidixic acid as a by-product of the synthesis of the antimalarial compound chloroquine.

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Transcript of "The wonder drug --Quinolones."

  1. 1. The Quinolones: Past, Present and FutureThe Quinolones: Past, Present and Future
  2. 2. The Past….The Past….  The Quinolone are class of antimicrobial agents thatThe Quinolone are class of antimicrobial agents that was not isolated from living organisms but, rather,was not isolated from living organisms but, rather, was synthesized by chemists.was synthesized by chemists.  They are a group of synthetic broad spectrumThey are a group of synthetic broad spectrum antibacterial drugs that target DNA Synthesis.antibacterial drugs that target DNA Synthesis.  The prolific development of the Quinolones began inThe prolific development of the Quinolones began in 1962, when Lesher et al. made the accidental1962, when Lesher et al. made the accidental discovery of nalidixic acid as a by-product of thediscovery of nalidixic acid as a by-product of the synthesis of the antimalarial compound chloroquine.synthesis of the antimalarial compound chloroquine.
  3. 3. The Past….The Past….  Nalidixic acid became the lead compound forNalidixic acid became the lead compound for medicinal chemists for structural modificationsmedicinal chemists for structural modifications to get many newer fluoroquinolones in orderto get many newer fluoroquinolones in order to get rid of its three major shortcomings….to get rid of its three major shortcomings….  Narrow spectrum covering Gr (-ve) organismsNarrow spectrum covering Gr (-ve) organisms onlyonly  Achieves inadequate tissue levels forAchieves inadequate tissue levels for systematic infections andsystematic infections and  Bacterial resistance development.Bacterial resistance development.
  4. 4. The Past….The Past….  This discovery led to the development of a library ofThis discovery led to the development of a library of quinolone compounds, especially the newerquinolone compounds, especially the newer quinolones in clinical use at the present time.quinolones in clinical use at the present time.  Fluoroquinolones are the derivatives of quinolonesFluoroquinolones are the derivatives of quinolones which are fluorinated at C-6 position of the quinolonewhich are fluorinated at C-6 position of the quinolone ring. They are broad-spectrum bactericidal agentsring. They are broad-spectrum bactericidal agents inhibiting DNA synthesisinhibiting DNA synthesis  They act on two enzymes involved in DNA synthesis:They act on two enzymes involved in DNA synthesis: DNA gyrase and topoisomerase IV and therebyDNA gyrase and topoisomerase IV and thereby block DNA replication and transcription, leading toblock DNA replication and transcription, leading to cell deathcell death
  5. 5. The Past….The Past….  The various derivatives of fluoroquinoloneThe various derivatives of fluoroquinolone have varying levels of activity depending onhave varying levels of activity depending on the various groups attached at differentthe various groups attached at different positions.positions.  Generating a derivative with increased activityGenerating a derivative with increased activity helps to reduce the Minimum Inhibitoryhelps to reduce the Minimum Inhibitory Concentration (MIC), thereby reducing theConcentration (MIC), thereby reducing the possibility of developing resistance to it.possibility of developing resistance to it.
  6. 6. The PresentThe Present  Two main classifications for fluoroquinolones based onTwo main classifications for fluoroquinolones based on chemical structure and biological properties respectively haschemical structure and biological properties respectively has been described by Bryskier & Chantot , which logicallybeen described by Bryskier & Chantot , which logically embraces the majority of active compounds known till date.embraces the majority of active compounds known till date.  Differences in the in-vitro activity of the fluoroquinolonesDifferences in the in-vitro activity of the fluoroquinolones against gram positive and gram negative organisms primarilyagainst gram positive and gram negative organisms primarily form the basis of their biological classification, as shown inform the basis of their biological classification, as shown in table 1.table 1.  The first generation being the most narrow and the subsequentThe first generation being the most narrow and the subsequent ones having an increase in spectrum of activity and on theones having an increase in spectrum of activity and on the novelty and complexity of the structures of quinolones.novelty and complexity of the structures of quinolones.
  7. 7. Table one ….Table one …. GenerationGeneration DrugsDrugs AntibacterialAntibacterial spectrumspectrum FirstFirst Nalidixic acidNalidixic acid aerobic, gram-aerobic, gram- negativebacteria.negativebacteria. SecondSecond NorfloxacinNorfloxacin CiprofloxacinCiprofloxacin EnoxacinEnoxacin FleroxacinFleroxacin LomefloxacinLomefloxacin OfloxacinOfloxacin LevofloxacinLevofloxacin RufloxacinRufloxacin antimicrobial activityantimicrobial activity against aerobic gram-against aerobic gram- positive bacteria andpositive bacteria and improved activity againstimproved activity against gram-negative bacteriagram-negative bacteria
  8. 8. Table one…Table one… GenerationGeneration DrugsDrugs Antibacterial spectrumAntibacterial spectrum ThirdThird TosufloxacinTosufloxacin GatifloxacinGatifloxacin GemifloxacinGemifloxacin TemafloxacinTemafloxacin GrepafloxacinGrepafloxacin gram-positive bacteria,gram-positive bacteria, particularly pneumococci; theyparticularly pneumococci; they also had good activity againstalso had good activity against anaerobicanaerobic FourthFourth Besifloxacin,ClinafloxacinBesifloxacin,Clinafloxacin Garenoxacin, GGarenoxacin, Gemifloxacinemifloxacin MoxifloxacinMoxifloxacin Gatifloxacin‡Gatifloxacin‡ SitafloxacinSitafloxacin Trovafloxacin‡/Alatrofloxacin‡Trovafloxacin‡/Alatrofloxacin‡ PrulifloxacinPrulifloxacin anaerobes and increased activityanaerobes and increased activity against pneumococciagainst pneumococci FifthFifth DelafloxacinDelafloxacin
  9. 9. StructureStructure  All fluoroquinolones have a basicAll fluoroquinolones have a basic 4-quinolone structure, with a4-quinolone structure, with a fluorine atom at C-6 position.fluorine atom at C-6 position.  Differences between the variousDifferences between the various fluoroquinolones are usually duefluoroquinolones are usually due to various groups that are attachedto various groups that are attached at positions 1, 5, 7 and 8.at positions 1, 5, 7 and 8.  The addition of specificallyThe addition of specifically selected substituents at these keyselected substituents at these key positions on the quinolonepositions on the quinolone nucleus made it possible to targetnucleus made it possible to target specific groups of bacteria and tospecific groups of bacteria and to improve theimprove the pharmacokinetics ofpharmacokinetics of the earlier quinolone compoundsthe earlier quinolone compounds
  10. 10. …….Structure.Structure Some of the key structural modifications are :Some of the key structural modifications are :  addition of a fluorine atom at position C-6, which increased DNA gyraseaddition of a fluorine atom at position C-6, which increased DNA gyrase inhibitory activity, facilitated penetration into the bacterial cell, andinhibitory activity, facilitated penetration into the bacterial cell, and provided activity against staphylococci.provided activity against staphylococci.  The addition of a piperazine group at position C-7 provided the greatestThe addition of a piperazine group at position C-7 provided the greatest activity against aerobic gram-negative bacteria and increased the activityactivity against aerobic gram-negative bacteria and increased the activity against both staphylococci andagainst both staphylococci and PseudomonasPseudomonas species and also increasedspecies and also increased the elimination half-life and improved bioavailability.the elimination half-life and improved bioavailability.  The addition of a second fluorine group at position C- 8 resulted inThe addition of a second fluorine group at position C- 8 resulted in increased absorption and a longer elimination half-life but also increasedincreased absorption and a longer elimination half-life but also increased phototoxicity.phototoxicity.  In addition, increased activity againstIn addition, increased activity against MycoplasmaMycoplasma andand ChlamydiaChlamydia speciesspecies was achieved by adding an amino group at C-5 and a fluorine group at C-8was achieved by adding an amino group at C-5 and a fluorine group at C-8 to quinolone compounds that possessed a cyclopropyl group at N-1 asto quinolone compounds that possessed a cyclopropyl group at N-1 as seen in ciprofloxaxin, sparfloxacin and gatifloxacin.seen in ciprofloxaxin, sparfloxacin and gatifloxacin.
  11. 11. …….Structure.Structure  The most recent key modification was theThe most recent key modification was the observation that the addition of a methoxyobservation that the addition of a methoxy group, instead of a halide, at the C-8 positiongroup, instead of a halide, at the C-8 position specifically targets both topoisomerase II andspecifically targets both topoisomerase II and IV, which also may decrease the possibility ofIV, which also may decrease the possibility of the development of resistance to quinolones .the development of resistance to quinolones .  Of the currently available agents, onlyOf the currently available agents, only gatifloxacin and moxifloxacin have a C-8gatifloxacin and moxifloxacin have a C-8 methoxy group in their chemical structure.methoxy group in their chemical structure.
  12. 12. Mechanism of actionMechanism of action  Fluoroquinolones enter the cellsFluoroquinolones enter the cells by porins and target two enzymes:by porins and target two enzymes: DNA gyrase and topoisomeraseDNA gyrase and topoisomerase IV. DNA gyrase or topoisomeraseIV. DNA gyrase or topoisomerase II helps in producing negativeII helps in producing negative superhelical twists.superhelical twists.  When fluoroquinolones bind toWhen fluoroquinolones bind to these enzymes, it blocks thethese enzymes, it blocks the activity of these enzymes andactivity of these enzymes and hence stops replication,hence stops replication, transcription, repair as well astranscription, repair as well as recombination.recombination.
  13. 13. ……..Mechanism of action…....Mechanism of action…..  The fluoroquinolones bind to the enzyme-DNA complex andThe fluoroquinolones bind to the enzyme-DNA complex and forms a stable ternary complex. The complex of drug,forms a stable ternary complex. The complex of drug, topoisomerase IV and DNA collides with the DNA replicationtopoisomerase IV and DNA collides with the DNA replication complex and forms a physical barrier that blocks the furthercomplex and forms a physical barrier that blocks the further progression of the replication fork.progression of the replication fork.  On the other hand, the complex of drug, DNA gyrase andOn the other hand, the complex of drug, DNA gyrase and DNA blocks the passage of RNA polymerase and leads to theDNA blocks the passage of RNA polymerase and leads to the premature termination of transcription.premature termination of transcription.  In gram negative organisms likeIn gram negative organisms like Escherichia coliEscherichia coli,, fluoroquinolones bind to DNA gyrase as a primary target andfluoroquinolones bind to DNA gyrase as a primary target and topoisomerase IV as the secondary target.topoisomerase IV as the secondary target.  In contrast,in gram positive organisms likeIn contrast,in gram positive organisms like StaphylococcusStaphylococcus aureusaureus, fluoroquinolones bind to topoisomerase IV as the, fluoroquinolones bind to topoisomerase IV as the primary target and DNA gyrase as the secondary target.primary target and DNA gyrase as the secondary target.
  14. 14. Pharmacokinetics andPharmacokinetics and pharmacodynamicspharmacodynamics  Most of the fluoroquinolones are available in the intravenous or oral form. SuchMost of the fluoroquinolones are available in the intravenous or oral form. Such fluoroquinolones include ciprofloxacin, ofloxacin, levofloxacin and alatrofloxacinfluoroquinolones include ciprofloxacin, ofloxacin, levofloxacin and alatrofloxacin (alatrofloxacin is metabolized in the body into trovafloxacin).(alatrofloxacin is metabolized in the body into trovafloxacin).  The bioavailability of the fluoroquinolones from an oral administration is the sameThe bioavailability of the fluoroquinolones from an oral administration is the same as the intravenous administration, and hence gives the same effect as oneas the intravenous administration, and hence gives the same effect as one administered intravenously.administered intravenously.  The bioavailability of fluoroquinolones ranges from 70% to greater than 90%.The bioavailability of fluoroquinolones ranges from 70% to greater than 90%.  Comparison of different fluoroquinolones show that the fourth and higherComparison of different fluoroquinolones show that the fourth and higher generations, like trovafloxacin and moxifloxacin have better bioavailability, highergenerations, like trovafloxacin and moxifloxacin have better bioavailability, higher plasma concentrations, greater tissue penetration, longer elimination half life andplasma concentrations, greater tissue penetration, longer elimination half life and higher volume of distribution .higher volume of distribution .  The fourth generation fluoroquinolones have been shown to have higher proteinThe fourth generation fluoroquinolones have been shown to have higher protein binding than the third generation.binding than the third generation.  This results in higher concentration of the drugs in the tissues and fluids.This results in higher concentration of the drugs in the tissues and fluids. Penetration of the fluoroquinolones into various tissues like kidney, lung, bronchialPenetration of the fluoroquinolones into various tissues like kidney, lung, bronchial mucosa, gallbladder, genital tract and prostate are found to be very high.mucosa, gallbladder, genital tract and prostate are found to be very high.  All the fluoroquinolones undergo either renal or hepatic eliminationAll the fluoroquinolones undergo either renal or hepatic elimination
  15. 15. Development of ResistanceDevelopment of Resistance In the recent, past there have been increasing number ofIn the recent, past there have been increasing number of cases of resistance against fluoroquinolones due tocases of resistance against fluoroquinolones due to many reasons such asmany reasons such as  Incomplete treatment with required doses andIncomplete treatment with required doses and durationduration  OverdosageOverdosage  Excessive and improper use of fluoroquinolonesExcessive and improper use of fluoroquinolones when not requiredwhen not required  Development of mutant strains of causative bacteriaDevelopment of mutant strains of causative bacteria
  16. 16. Mechanism of developingMechanism of developing resistanceresistance Progress in our understanding of the role of SARs, along with the application of current research techniques, has indicated that bacterial resistance to quinolones occurs due to many reasons :  Alteration in DNA gyrase andAlteration in DNA gyrase and topoisomerase IV and decreasedtopoisomerase IV and decreased intracellular accumulation of the drug dueintracellular accumulation of the drug due to modifications of membrane proteins .to modifications of membrane proteins .  Single point mutation in gyr A that codesSingle point mutation in gyr A that codes for a type II topoisomerase subunit A isfor a type II topoisomerase subunit A is most common37.most common37.  Reduction of gyrase affinity for drugReduction of gyrase affinity for drug  Decreased penetration due to loss of keyDecreased penetration due to loss of key membrane proteinsmembrane proteins  Cross resistance among fluoroquinolonesCross resistance among fluoroquinolones -- resistance to one quinolone usually-- resistance to one quinolone usually confers resistance to entire class.confers resistance to entire class.
  17. 17. Adverse reactions….Adverse reactions…. The rate of adverse events associated with both oral and intravenous fluoroquinolones appears to be dose related, with an increasing incidence of adverse events associated with increasing doses and duration of therapy:  Achilles Tendonitis :-Achilles Tendonitis :- Both older and newer fluoroquinolones have been shown to be associated withBoth older and newer fluoroquinolones have been shown to be associated with arthropathy in weight bearing joints . Studies have shown erosion and permanent lesions of cartilage due toarthropathy in weight bearing joints . Studies have shown erosion and permanent lesions of cartilage due to quinolone use in animals .quinolone use in animals .  Cardiac :-Cardiac :- QT prolongation is thought to be due to halogen substitution at the number 8 position ( e.gQT prolongation is thought to be due to halogen substitution at the number 8 position ( e.g Moxifloxacin )Moxifloxacin )  Gastrointestinal :-Gastrointestinal :- Most common side-effects are nausea , vomitting and diarrhoea , with an occurrenceMost common side-effects are nausea , vomitting and diarrhoea , with an occurrence rate ranging from 3 to 17 percent .rate ranging from 3 to 17 percent .  CNS :-CNS :- Effects such as insomnia , dizziness and anxiety have been reported in 0.9 to 11 percent patientsEffects such as insomnia , dizziness and anxiety have been reported in 0.9 to 11 percent patients .Seizures are a rare occurrence but have been increasingly reported when used with Theophylline or with.Seizures are a rare occurrence but have been increasingly reported when used with Theophylline or with NSAID's .NSAID's .  Crystaluria :-Crystaluria :- Associated with fluoroquinolones except Levofloxacin , Gatifloxacin34,Moxifloxacin , andAssociated with fluoroquinolones except Levofloxacin , Gatifloxacin34,Moxifloxacin , and Trovafloxacin . Patients are instructed to drink plenty of water.Trovafloxacin . Patients are instructed to drink plenty of water.  Liver Toxicity :Liver Toxicity :- In 18 months post-approval follow up by US Food and Drug Administration (FDA) for- In 18 months post-approval follow up by US Food and Drug Administration (FDA) for Trovafloxacin 140 cases of liver toxicity were found .Trovafloxacin 140 cases of liver toxicity were found .  Phototoxicity :Phototoxicity :- Most likely to occur with the use of Ciprofloxacin , Lomefloxacin , Norfloxacin- Most likely to occur with the use of Ciprofloxacin , Lomefloxacin , Norfloxacin, fleroxacin, and sparfloxacin..
  18. 18. …….Adverse reactions.Adverse reactions  Three adverse events associated with quinolones—cardiotoxicity (e.g., prolongation of the corrected QT interval), hepatotoxicity, and hypoglycemia—currently command the most attention.
  19. 19. The PresentThe Present  A number of infectious diseases are successfully treated with quinolones administered orally or intravenously.  Clinical efficacy has been demonstrated for respiratory tract infections,including acute bacterial exacerbations of chronic bronchitis, community-acquired pneumonia, nosocomial pneumonia, and bacterial sinusitis.
  20. 20. Approved clinical uses for selected fluoroquinolones. Ciprofloxacin  Acute uncomplicated cystitis in females (oral use only)  Urinary tract infections  Chronic bacterial prostatitis  Uncomplicated cervical and urethral gonorrhea  Skin and skin-structure infections  Bone and joint infections  Infectious diarrhea (oral use only)  Typhoid fever (oral use only)  Complicated intra-abdominal infections, in combination with metronidazole  Acute sinusitis  Lower respiratory tract infections  Nosocomial pneumonia (iv use only)  Empirical therapy for patients with febrile neutropenia, in combination with piperacillin  sodium (iv use only)  Inhalational anthrax (after exposure)  Complicated urinary tract infections and pyelonephritis in pediatric patients (1–17 years old)
  21. 21. Levofloxacin  Uncomplicated urinary tract infections (mild to moderate)  Complicated urinary tract infections (mild to moderate)  Acute pyelonephritis (mild to moderate)  Chronic bacterial prostatitis  Uncomplicated skin and skin-structure infections (mild to moderate)  Complicated skin and skin-structure infections  Acute maxillary sinusitis  Acute bacterial exacerbation of chronic bronchitis  Community-acquired pneumoniaa  Nosocomial pneumonia
  22. 22. Moxifloxacin  Acute bacterial sinusitis  Acute bacterial exacerbation of chronic bronchitis  Community-acquired pneumoniaa  Uncomplicated skin and skin-structure infections
  23. 23. Gatifloxacin  Uncomplicated urinary tract infections  Complicated urinary tract infections  Pyelonephritis  Uncomplicated urethral and cervical gonorrhea  Acute uncomplicated gonococcal rectal infections in women  Uncomplicated skin and skin-structure infections  Acute sinusitis  Acute bacterial exacerbation of chronic bronchitis  Community-acquired pneumoniaa
  24. 24. Gemifloxacin  Acute bacterial exacerbation of chronic bronchitis  Community-acquired pneumonia (mild to moderate).
  25. 25. The FutureThe Future  The future prospects of newer Quinolones depends on: (1) greater potency, particularly against staphylococci and enterococci; (2) better penetration into the CNS and cerebrospinal fluid; (3) broader and more potent activity against anaerobic bacteria; (4) greater activity against infections caused by mycobacteria and Stenotrophomonas, Pseudomonas, and Alcaligenes species, which currently are difficult to treat; (5) decreased drug-drug interactions; and (6) better patient tolerability, with lower incidences of adverse reactions and serious toxicity
  26. 26. The Future….The Future….  In addition, newer quinolones may be developed with greater activity against targets in infectious agents responsible for Lyme disease, malaria, nocardiosis, toxoplasmosis, pneumocystosis, leishmaniasis, fungi, and DNA viruses.  Other poorly poorly explored, area is the development of new compounds with a high and specific affinity for the DNA (eukaryotic topoisomerases) in human malignant cells, which could be used alone or in combination with other chemotherapeutic agents. This potential would provide sufficient economic and humane rewards to justify the investment in such an effort
  27. 27. ……..The Future..The Future  If the use of quinolones in clinical medicine is to continue,the emergence of bacterial resistance to the quinolones should remain of primary importance as an area of current and future research.
  28. 28. GarenoxacinGarenoxacin  Garenoxacin is a synthetic, des-F(6)-quinolone antibacterialGarenoxacin is a synthetic, des-F(6)-quinolone antibacterial agent. The molecule does not contain fluorine at the C-6agent. The molecule does not contain fluorine at the C-6 position, which is present in all the fluoroquinoloneposition, which is present in all the fluoroquinolone antibacterial agents.antibacterial agents.  Garenoxacin is presented for clinical use as 400 mg and 600Garenoxacin is presented for clinical use as 400 mg and 600 mg film-coated tablets and for infusionmg film-coated tablets and for infusion  Garenoxacin demonstrates unique Structure-ActivityGarenoxacin demonstrates unique Structure-Activity Relationship to offer one of the lowest MICs againstRelationship to offer one of the lowest MICs against respiratory pathogens with low potential for resistancerespiratory pathogens with low potential for resistance development.development.  It was developed in Japan that was further researched andIt was developed in Japan that was further researched and developed by Toyoma Ltd in collaboration with Bristoldeveloped by Toyoma Ltd in collaboration with Bristol Meyers Squibb, USAMeyers Squibb, USA
  29. 29. GarenoxacinGarenoxacin  Garenoxacin demonstrates wide spectrum ofGarenoxacin demonstrates wide spectrum of antibacterial activity against Gm positive, Gmantibacterial activity against Gm positive, Gm negative, Atypical and Anaerobic pathogens.negative, Atypical and Anaerobic pathogens.  The novel structure resulted in completeThe novel structure resulted in complete bacteriological eradication rates againstbacteriological eradication rates against Quinolone-resistant (100%), β-lactam resistantQuinolone-resistant (100%), β-lactam resistant (97.7%) and Macrolide resistant (98.7%)(97.7%) and Macrolide resistant (98.7%) strains of Strep. pneumoniaestrains of Strep. pneumoniae
  30. 30. Garenoxacin—Clinical use andGarenoxacin—Clinical use and Indications.Indications.  Garenoxacin is a novel des-fluoro 6-quinolone with uniqueGarenoxacin is a novel des-fluoro 6-quinolone with unique Pharmacokinetic profile that promises to cover a widePharmacokinetic profile that promises to cover a wide spectrum of organisms commonly encountered in communityspectrum of organisms commonly encountered in community acquired infections including Gm positive, Gm negative,acquired infections including Gm positive, Gm negative, Atypical & Anaerobic organisms with negligible potential forAtypical & Anaerobic organisms with negligible potential for resistance development.resistance development.  Garenoxacin has been associated with high clinical successGarenoxacin has been associated with high clinical success rates in patients with Bronchitis, Pneumonia andrates in patients with Bronchitis, Pneumonia and otorhinolaryngological infections when used as initial- orotorhinolaryngological infections when used as initial- or second line settings.second line settings.  Garenoxacin is indicated for the following bacterial infectionsGarenoxacin is indicated for the following bacterial infections caused by susceptible microorganisms including Pharyngitis,caused by susceptible microorganisms including Pharyngitis, Sinusitis Laryngitis, Tonsillitis, Otitis media, Acute bronchitis,Sinusitis Laryngitis, Tonsillitis, Otitis media, Acute bronchitis, Pneumonia and Secondary infection in chronic respiratoryPneumonia and Secondary infection in chronic respiratory lesion.lesion.
  31. 31. Garenoxacin- ContraindicationsGarenoxacin- Contraindications Garenoxacin should be administered withGarenoxacin should be administered with caution in:caution in:  High-risk patients who have convulsiveHigh-risk patients who have convulsive disorders such as epilepsy, and elderlydisorders such as epilepsy, and elderly patients.patients.  Patients who have a history of hypersensitivityPatients who have a history of hypersensitivity to any component of the formulationto any component of the formulation
  32. 32. Garenoxacin- Adverse reactionsGarenoxacin- Adverse reactions  The most frequent adverse effects reported in clinicalThe most frequent adverse effects reported in clinical trials were diarrhea, nausea, and headache.trials were diarrhea, nausea, and headache.  Garenoxacin is a well tolerated drug with itsGarenoxacin is a well tolerated drug with its safety profile well differentiated due to lack of anysafety profile well differentiated due to lack of any significant concerns on Photosensitivity, Abnormalsignificant concerns on Photosensitivity, Abnormal hepatic functioning, Seizures, Arthropathy and QTchepatic functioning, Seizures, Arthropathy and QTc prolongation.prolongation. ..
  33. 33. Garenoxacin –Place in therapyGarenoxacin –Place in therapy  Garenoxacin with its Pharmacodynamic andGarenoxacin with its Pharmacodynamic and pharmacokinetic correlates promises to have thepharmacokinetic correlates promises to have the therapeutic efficacy while treating Skin and Skintherapeutic efficacy while treating Skin and Skin Structure infections, Urinary tract infections,Structure infections, Urinary tract infections, Intraabdominal infections and GastrointestinalIntraabdominal infections and Gastrointestinal infections including Enteric fever though the clinicalinfections including Enteric fever though the clinical data is sparse.data is sparse.  Garenoxacin has been associated with high clinicalGarenoxacin has been associated with high clinical success rates in patients with Bronchitis, Pneumoniasuccess rates in patients with Bronchitis, Pneumonia and Otorhinolaryngological infections when used asand Otorhinolaryngological infections when used as initial- or secondline settings,initial- or secondline settings,
  34. 34. ReferencesReferences  http://www.japi.org/jan_2014/pdf/05_dc.pdf#page=1&zoom=auto,-22,777 accessedhttp://www.japi.org/jan_2014/pdf/05_dc.pdf#page=1&zoom=auto,-22,777 accessed on 4 August 2014 at 10 PM.on 4 August 2014 at 10 PM.  Lesher GY, Froelich EJ, Gruett MD, et al. 1,8-Naphthyridine derivatives.a new class of chemotherapeutic agents. J Med Pharm Chem 1962; 5:1063–8.  Andriole VT. Future role and uses of the quinolones. Infect Dis Clin Pract 1994; 3:S211–5.  Andriole VT. The future of the quinolones. Drugs 1999; 58(Suppl 2): 1–5.  Andriole VT. The quinolones: prospects. In: Andriole VT, ed. The quinolones. 3rd ed. San Diego: Academic Press, 2000:477–95.  Worcel A. Studies on the folded chromosome of E. coli. In: Kolber AR, Kohiyama M, eds. Mechanisms and regulation of DNA replication.New York and London: Plenum, 1974:201–24.  Wang JC. Interactions between DNAs and enzymes: the effect of superhelical turns. J Mol Biol 1974; 87:797–816.  Smith JT, Lewin CS. Chemistry and mechanism of action of the quinolone antibacterials. In: Andriole VT, ed. The quinolones. 1st ed. London: Academic Press, 1988:23–81.
  35. 35. References…..References…..  Michael A. Kohanski, Daniel J. Dwyer, James J. Collins. How antibiotics kill bacteria: from targets to networks. Nat Rev Microbiol. 2010;8:423-35.  Bennett PM. Plasmid encoded antibiotic resistance: acquisition and transfer of antibiotic resistance genes in bacteria. Brit J Pharmacol. 2008;153(Suppl. 1):S347– S357.  Emami S, Shafiee A, Foroumadi A. Quinolones: recent structural and clinical developments. Iran J Pharm Res. 2010;4(3):123-136.  Peter Ball. Quinolone generations: natural history or natural selection? J Antimicrob Chemoth. 2000;46:17-24.  Jason A Wiles, Barton J Bradbury, Michael J Pucci. New quinolone antibiotics: a survey of the literature from 2005 to 2010. Expert Opinion on Therapeutic Patents. 2010;20(10):1295- 1319. (doi: 10.1517/13543776.2010.505922).  Catherine M Oliphant, Gary M Green. Quinolones: a comprehensive review. Am Fam Physician. 2002;65(3):455-65.  Randall C Walker. The fluoroquinolones. Symposium of Antimicrobial Agents-part XIII. Mayo Clin Proc. 1999;74:1030-7.  Wolfson JS, Hooper DC. The fluoroquinolones: structures, mechanisms of action and resistance, and spectra of activity in vitro. Antimicrob Agents Chemother. 1985;28(4):581.  Ebrahim Babaahmady, Afra Khosravi. Toxicology of baytril (enrofloxacin). African Journal of Pharmacy and Pharmacology. 2011;5(18):2042-2045.
  36. 36. References……References……  Crumplin GC, Smith JT. Nalidixic acid and bacterial chromosome replication. Nature 1976; 260:643–5.  Smith JT. Awakening the slumbering potential of the 4-quinolone antibacterials.Pharma 1984; 233:299–305.  Gellert M, Mizuuchi K, O’Dea MH, Nash HA. DNA gyrase. Proc Natl Acad Sci USA 1976; 73:3872–6.  Gellert M, Mizuuchi K, O’Dea MH, Itoh T, Tomizawa JJ. Nalidixic acid resistance: a second genetic character involved in DNA gyrase activity. Proc Natl Acad Sci USA 1977; 74:4772–6.  Sugino A, Peebles CL, Krenzer KN, Cozzarelli NR. Mechanism of action of nalidixic acid: purification of Escherichia coli nalA gene production and its relationship to DNA gyrase and a novel nicking-closing enzyme. Proc Natl Acad Sci USA 1977; 74:4767–71.  Brighty KE, Gootz TD. Chemistry and mechanism of action of the quinolone antibacterials. In: Andriole VT, ed. The quinolones. 3rd ed.San Diego: Academic Press, 2000:33–97.  Higgens NP, Peebles CL, Sugino A, Cozzarelli NR. Purification of subunitsof Escherichia coli DNA gyrase and reconstitution of enzymic activity. Proc Natl Acad Sci USA 1978; 75:1773–7.
  37. 37. Thank youThank you
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