7/19/2012                                    By- Jitendra Bhangale                                  Assistant Professor & ...
7/19/2012All   sulfonamides         may     be    considered       to   be    derivatives         of       sulfanilamide ...
7/19/2012                                                           Para-amino-benzoic acid                               ...
7/19/2012Bacteria resistant to sulfonamides is presumed to originate by          random mutation and selection or by tran...
7/19/2012DistributionSulfonamides are distributed throughout all tissues of the body.Sulfonamides pass readily through t...
7/19/2012Sulfisoxazole is a rapidly absorbed and excreted sulfonamide with         excellent antibacterial activity.Sulf...
7/19/2012Sulfadiazine given orally is absorbed rapidly from the GI tract.Sulfadiazine is excreted quite readily by the k...
7/19/2012Sulfasalazine       is    broken       down      by     intestinal     bacteria      to        sulfapyridine, an...
7/19/2012Silver sulfadiazine inhibits the growth in vitro of nearly all        pathogenic bacteria and fungi, including s...
7/19/2012Therapy is continued until skin grafting is possible.Mafenide is rapidly absorbed systemically and converted to...
7/19/2012Disturbances of the Urinary TractAcute Hemolytic AnemiaAgranulocytosisAplastic AnemiaHypersensitivity Reacti...
7/19/2012Chlamydia diphtheriae                         Enterobacter spp.,N. Meningitidis                               ...
7/19/2012After a single oral dose of the combined preparation,        trimethoprim           is     absorbed          mor...
7/19/2012Megaloblastosis, leukopenia, or thrombocytopeniaDermatitis, toxic epidermal necrolysisStomatitisPatients with...
7/19/2012These are synthetic antimicrobials having a quinolone structure        that are active primarily against gram-ne...
7/19/2012Mechanism of actionThe quinolone antibiotics target bacterial DNA gyrase and         topoisomerase IV.For     m...
7/19/2012Adverse effectsG.I. upset and rashes, neurological-headache, drowsiness, vertigo,        visual disturbances, oc...
7/19/2012Mechanism of actionThe FQs inhibit the enzyme bacterial DNA topoisomerase IV,which nicks        double-stranded ...
7/19/2012              CLASSIFICATION OF FLUOROQUINOLONES1st generation fluoroquinolone                 2nd generation flu...
7/19/2012Notable resistant bacteria are: Bacteroides fragilis, Clostridia,         anaerobic cocci.Adverse effectsGastro...
7/19/2012Examples: -                  Lomefloxacin,                 Sparfloxacin,           Levofloxacin ,              Ga...
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Sulfonamides, quinolones and fluoroquinolones BY JITENDRA BHANGALE

  1. 1. 7/19/2012 By- Jitendra Bhangale Assistant Professor & Head, Department of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad 1 © 2010 Delmar, Cengage LearningSulphonamide derived from prontosil (prodrug)1932 Gerhard DomagkDiscovered protective aspects of Prontosil (azo dye).1933 Prontosil given to 10 month old girl who survived1935 Sulfa first used in US unsuccessfullyLate 1930’s sulfanilamide derivatives synthesizedIncrease efficacy and decrease side effects1968 Sulfa combined with TrimethoprimSulfonamides also called sulfanilamides or sulfa drugs. By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad2 © 2010 Smt N. M. Padalia 1
  2. 2. 7/19/2012All sulfonamides may be considered to be derivatives of sulfanilamide (p-aminobenzene sulfonamides).All the drugs individually differ in their nature of N1 substitution, which governs pharmacokinetic property.A free amino group in the para position N4 is required for antibacterial activity. By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad3 © 2010 Smt N. M. Padalia Sulfonamides are primarily bacteriostatic against many gram +ve and –ve bacteria. Microorganisms that may be susceptible in vitro to sulfonamides include Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus ducreyi, Nocardia, Actinomyces, Calymmatobacterium granulomatis, Vibrio cholerae , Staphylococcus aureus, and Chlamydia trachomatis. Sulfonamides were used successfully for the management of meningococcal infections for many years, the majority of isolates of Neisseria meningitidis By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad4 © 2010 Smt N. M. Padalia 2
  3. 3. 7/19/2012 Para-amino-benzoic acid Dihydopteroate -Sulfonamides, structural synthetase Sulfonamideanalogs and competitive Folateantagonists of para- Dihydofolate - reductase Trimethoprimaminobenzoic acid (PABA), Tetrahydrofolateprevent normal bacterialutilization of PABA for thesynthesis of folic acid Synthesis of DNA(pteroylglutamic acid). Growth of bacteria By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad5 © 2010 Smt N. M. Padalia Para-amino-benzoic acidMore specifically, Dihydopteroate - synthetasesulfonamides are competitive Sulfonamide Folateinhibitors of dihydropteroate Dihydofolate -synthase, the bacterial enzyme reductase Trimethoprimresponsible for the Tetrahydrofolateincorporation of PABA intodihydropteroic acid, the Synthesis of DNAimmediate precursor of folicacid Growth of bacteria By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad6 © 2010 Smt N. M. Padalia 3
  4. 4. 7/19/2012Bacteria resistant to sulfonamides is presumed to originate by random mutation and selection or by transfer of resistance by plasmids.Resistance to sulfonamide probably is the consequence of an altered enzymatic constitution of the bacterial cell; and may be characterized bylower affinity for sulfonamides by dihydropteroate synthase,decreased bacterial permeability or active efflux of the drug,an alternative metabolic pathway for synthesis of an essentialmetabolite,increased production of an essential metabolite or drugantagonist. By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad7 © 2010 Smt N. M. Padalia Absorption This class of drugs is absorbed rapidly from the gastrointestinal tract. The small intestine is the major site of absorption, but some of the drug is absorbed from the stomach. Absorption from other sites, such as the vagina, respiratory tract, or abraded skin, is variable and unreliable. By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad8 © 2010 Smt N. M. Padalia 4
  5. 5. 7/19/2012DistributionSulfonamides are distributed throughout all tissues of the body.Sulfonamides pass readily through the placenta and reach the fetal circulation.EliminationSulfonamides are eliminated from the body partly as the unchanged drug and partly as metabolic products. The largest fraction is excreted in the urine.Small amounts are eliminated in the feces, bile, milk, and other secretions. By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad9 © 2010 Smt N. M. PadaliaThe sulfonamides may be classified on the basis of the rapidity with which they are absorbed and excreted:1. Agents that are absorbed and excreted rapidly, such as sulfisoxazole and sulfadiazine;2. Agents that are absorbed very poorly when administered orally and hence are active in the bowel lumen, such as sulfasalazine;3. Agents that are used mainly topically, such as sulfacetamide, mafenide, & silver sulfadiazine;4. Long-acting sulfonamides, that are absorbed rapidly but excreted slowly such as sulfadoxine & sulfamethopyrazine By Jitendra Bhangale 10 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 5
  6. 6. 7/19/2012Sulfisoxazole is a rapidly absorbed and excreted sulfonamide with excellent antibacterial activity.Sulfisoxazole is bound extensively to plasma proteins.Sulfisoxazole acetyl is tasteless and hence preferred for oral use in children. Sulfisoxazole acetyl is marketed in combination with erythromycin ethylsuccinate for use in children with otitis media.The urine becomes orange-red soon after ingestion of this mixture because of the presence of phenazopyridine, an orange-red dye.Unwanted effetct:Hematuria or crystalluria (0.2% to 0.3%), hypersensitivity reactions By Jitendra Bhangale 11 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. PadaliaSulfamethoxazole is a close congener of sulfisoxazole, but its rates of enteric absorption and urinary excretion are slower.It is administered orally and employed for both systemic and urinary tract infections.Precautions must be observed to avoid sulfamethoxazole crystalluriaThe clinical uses of sulfamethoxazole are the same as those for sulfisoxazole.It also is marketed in fixed-dose combinations with trimethoprim. By Jitendra Bhangale 12 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 6
  7. 7. 7/19/2012Sulfadiazine given orally is absorbed rapidly from the GI tract.Sulfadiazine is excreted quite readily by the kidney in both thefree and acetylated forms, rapidly at first and then more slowly overa period of 2 to 3 days. In adults and children who are being treated with sulfadiazine,every precaution must be taken to ensure fluid intake adequate toproduce a urine output of at least 1200 ml in adults.If this cannot be accomplished, sodium bicarbonate may be givento reduce the risk of crystalluria. By Jitendra Bhangale 13 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. PadaliaSulfasalazine is very poorly absorbed from the GI tract.It is used in the therapy of ulcerative colitis and regional enteritis. Corticosteroids are more effective in treating acute attacks, but sulfasalazine is preferred to corticosteroids for the treatment of patients who are mildly or moderately ill with ulcerative colitis. By Jitendra Bhangale 14 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 7
  8. 8. 7/19/2012Sulfasalazine is broken down by intestinal bacteria to sulfapyridine, an active sulfonamide that is absorbed and eventually excreted in the urine, and 5-aminosalicylate, which reaches high levels in the feces. 5-Aminosalicylate is the effective agent in inflammatory bowel disease, whereas sulfapyridine is responsible for most of the toxicity.Toxic reactions include Heinz-body anemia, acute hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, and agranulocytosis. Nausea, fever, arthralgiasSulfasalazine can cause a reversible infertility in males. By Jitendra Bhangale 15 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. PadaliaIts aqueous solubility (1:140) is approximately 90 times that of sulfadiazine.Solutions of the sodium salt are employed extensively in the management of ophthalmic infections.Although topical sulfonamide for most purposes is discouraged because of lack of efficacy and a high risk of sensitization, sulfacetamide has certain advantages. Very high aqueous concentrations are not irritating to the eye and are effective against susceptible microorganisms.The drug should not be used in patients with known hypersensitivity to sulfonamides. By Jitendra Bhangale 16 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 8
  9. 9. 7/19/2012Silver sulfadiazine inhibits the growth in vitro of nearly all pathogenic bacteria and fungi, including some species resistant to sulfonamides.The compound is used topically to reduce microbial colonization and the incidence of infections of wounds from burns.Silver is released slowly from the preparation in concentrations that are selectively toxic to the microorganisms.Adverse reactions burning, rash, and itching are infrequent.Silver sulfadiazine is considered by most authorities to be one of the agents of choice for the prevention of burn infection. By Jitendra Bhangale 17 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. PadaliaWhen applied topically, it is effective for the prevention of colonization of burns by a large variety of gram-negative and gram-positive bacteria.It should not be used in treatment of an established deep infection.The cream is applied once or twice daily to a thickness of 1 to 2 mm over the burned skin.Cleansing of the wound and removal of debris should be carried out before each application of the drug. By Jitendra Bhangale 18 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 9
  10. 10. 7/19/2012Therapy is continued until skin grafting is possible.Mafenide is rapidly absorbed systemically and converted to para- carboxybenzenesulfonamide.Adverse effects include intense pain at sites of application, allergic reactions.The drug and its primary metabolite inhibit carbonic anhydrase, and the urine becomes alkaline. By Jitendra Bhangale 19 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. PadaliaSulfadoxine has a particularly long half-life (7 to 9 days).It is used in combination with pyrimethamine for the prophylaxis and treatment of malaria caused by mefloquine - resistant strains of Plasmodium falciparumBecause of severe and sometimes fatal reactions, including the Stevens-Johnson syndrome, the drug should be used for prophylaxis only where the risk of resistant malaria is high. By Jitendra Bhangale 20 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 10
  11. 11. 7/19/2012Disturbances of the Urinary TractAcute Hemolytic AnemiaAgranulocytosisAplastic AnemiaHypersensitivity ReactionsMiscellaneous Reactions- Anorexia, nausea, and vomiting By Jitendra Bhangale 21 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia By Jitendra Bhangale 22 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 11
  12. 12. 7/19/2012Chlamydia diphtheriae Enterobacter spp.,N. Meningitidis Salmonella, Shigella,S. Pneumoniae, Pseudomonas pseudomallei,Staphylococcus aureus,  Klebsiella spp.,Staphylococcus epidermidis, Brucella abortus,S. pyogenes, Pasteurella haemolytica,E. coli,  Yersinia pseudotuberculosis,Proteus mirabilis,  Yersinia enterocolitica,Proteus morganii, Nocardia asteroides. By Jitendra Bhangale 23 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. PadaliaSulfonamide inhibits the Para-amino-benzoic acidincorporation of para- Dihydopteroate -aminobenzoic acid (PABA) into synthetasefolic acid Sulfonamide FolateTrimethoprim prevents the Dihydofolate -reduction of dihydrofolate to reductase Trimethoprimtetrahydrofolate. TetrahydrofolateTetrahydrofolate is essentialfor one-carbon transferreactions Synthesis of DNATrimethoprim is a highlyselective inhibitor ofdihydrofolate reductase Growth of bacteria By Jitendra Bhangale 24 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 12
  13. 13. 7/19/2012After a single oral dose of the combined preparation, trimethoprim is absorbed more rapidly than sulfamethoxazole.When 800 mg sulfamethoxazole is given with 160 mg trimethoprim (the conventional 5:1 ratio) twice daily.Trimethoprim is distributed and concentrated rapidly in tissues, and about 40% is bound to plasma protein in the presence of sulfamethoxazole. The volume of distribution of trimethoprim is almost nine times that of sulfamethoxazole. By Jitendra Bhangale 25 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia Urinary Tract Infections Bacterial Respiratory Tract Infections Gastrointestinal Infections Infection by Pneumocystis jiroveci Miscellaneous Infections By Jitendra Bhangale 26 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 13
  14. 14. 7/19/2012Megaloblastosis, leukopenia, or thrombocytopeniaDermatitis, toxic epidermal necrolysisStomatitisPatients with AIDS frequently have hypersensitivity reactionsRash, neutropenia, pulmonary infiltrates By Jitendra Bhangale 27 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia By Jitendra Bhangale 28 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 14
  15. 15. 7/19/2012These are synthetic antimicrobials having a quinolone structure that are active primarily against gram-negative bacteria, though newer fluorinated compounds also inhibit gram- positive ones.The first member Nalidixic acld introduced in mid-1960s By Jitendra Bhangale 29 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. PadaliaNalidixic acidAntibacterial spectrumIt is active against gram-negative bacteria, especially coliforms: E. coli, Proteus, Klebsiella, Enterobacter, Shigella but not Pseudomonas.PharmacokineticsNalidixic acid is absorbed orally, highly plasma protein bound and partly metabolized in liver. It is excreted in urine. By Jitendra Bhangale 30 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 15
  16. 16. 7/19/2012Mechanism of actionThe quinolone antibiotics target bacterial DNA gyrase and topoisomerase IV.For many gram-positive bacteria (such as S. aureus), topoisomerase IV is the primary activity inhibited by the quinolones.In contrast, for many gram-negative bacteria (such as E. coli), DNA gyrase is the primary quinolone target. By Jitendra Bhangale 31 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. PadaliaThe enzyme binds to two segments of DNA (1), creating a node of positive (+) superhelix. The enzyme then introduces a double-strand break in the DNA and passes the front segment through the break (2). The break is then resealed (3), creating a negative (-) supercoil.Quinolones inhibit the nicking and closing activity of the gyrase and also block the decatenating activity of topoisomerase IV. By Jitendra Bhangale 32 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 16
  17. 17. 7/19/2012Adverse effectsG.I. upset and rashes, neurological-headache, drowsiness, vertigo, visual disturbances, occasionally seizures (especially in children).Individuals with G-6-PD deficiency may develop haemolysis. Nalidixic acid is contraindicated in infants.Therapeutic usesNalidixic acid is primarily used as a urinary antisepticIt has also been employed in diarrhoea caused by Proteus, E . coli, Shigella or Salmonella, and has a special place in ampicillin resistant Shigella enteritis. By Jitendra Bhangale 33 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia By Jitendra Bhangale 34 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 17
  18. 18. 7/19/2012Mechanism of actionThe FQs inhibit the enzyme bacterial DNA topoisomerase IV,which nicks double-stranded DNA, introduces negative supercoilsand then reseals the nicked ends.This is necessary to prevent excessive positive supercoiling of the strands when they separate to permit replication or transcription.The DNA gyrase consists of two A and two B subunits: The A subunit carries out nicking of DNA, B subunit introduces negative supercoils and then A subunit reseals the strands. By Jitendra Bhangale 35 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. PadaliaFQs bind to A subunit with high affinity and interfere with its strand cutting and resealing function.Recent evidence indicates that in gram-positive bacteria the major target of FQ action is a similar enzyme topoisomerase IV which nicks and separates daughter DNA strands after DNA replication.Mechanism of resistanceResistance noted so far is due to chromosomal mutation producing a DNA gyrase or topoisomerase IV with reduced affinity for FQsResistance has been reported among Salmonella, Pseudomonas, staphylococci and pneumococci. By Jitendra Bhangale 36 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 18
  19. 19. 7/19/2012 CLASSIFICATION OF FLUOROQUINOLONES1st generation fluoroquinolone 2nd generation fluoroquinolones LomefloxacinNorfloxacin SparfloxacinOfloxacin LevofloxacinCiprofloxacin GatifloxacinPefloxacin Moxifloxacin By Jitendra Bhangale 37 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. PadaliaIt is the most potent first generation FQ active against a broad rangeof bacteria, the most susceptible ones are the aerobic gram negativebacilli, especially the Enterobacteriaceae and Neisseria.Highly susceptible Neisseria gonorrhoeaeE. Coli N. meningitdisS. pneumoniae H. InfluenzaeEnterobacter Campylobacter jejuniSalmonella typhi Yersinia enterocoliticaShigella Vibrio choleraeProteus By Jitendra Bhangale 38 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 19
  20. 20. 7/19/2012Notable resistant bacteria are: Bacteroides fragilis, Clostridia, anaerobic cocci.Adverse effectsGastrointestinal: nausea, vomiting, bad taste, anorexia.CNS: dizziness, headache, restlessness, anxiety, insomnia.Skin/hypersensitivity: rash, pruritus, photosensitivity, urticaria,swelling of lips, etc.Ciprofloxacin and other FQs are contraindicated during pregnancy. By Jitendra Bhangale 39 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia Therapeutic Uses Bone, soft tissue and woundUrinary tract infection infectionsGonorrhoe Respiratory infectionsChancroid TuberurlosisBacterial gastroenteritis MeningitisTyphoid Conjunctivitis By Jitendra Bhangale 40 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 20
  21. 21. 7/19/2012Examples: - Lomefloxacin, Sparfloxacin, Levofloxacin , Gatifloxacin, MoxifloxacinThis second generation difluorinated quinolone has enhancedactivity against gram-positive bacteria (especially Strep.Pneumoniae, Staphylococcus Enterococcus), Bacteroides fragilis,other anaerobes and mycobacteria. By Jitendra Bhangale 41 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia By Jitendra Bhangale 42 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 21

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