- 1 -
(1) 4710 (6) 1L50100mg11kg 510mg()35 7 () (2) EMEAFDAJECFA ADIMRL (2) Medline (2) 1,629,946 MRL ADI ADI 0.005mg/kg/ - 2 -
- 3 -
() (1) (1),(2) (Ofloxacin) C 18 H 20 FN 3 O 4 361.37 260270 () 2 g/l (20) nonvolatile (2) a b DNA DNA (3) 2 (S)-(-)-(R)-(+)- (S)-(-)- (Levofloxacin) (3) a 6 b DNADNA
2-1. (4), (5) ICR( 5 )(5mg/kg)T max 0.5 C max 1.3µg/mlT 1/2 () 1.0 (4) ICR( 8 /) 40mg/kg 180 C max 14.5µg/mL 16.8µg/mLT 1/2 () 46 45 AUC15.1 23.5µh/mL 64%24 39.5% 35.1% (5) (4) Wistar(5)(5mg/kg)T max 0.5 C max 1.7µg/mlT 1/2 () 1.8 Wistar (3 )(10mg/kg ) 0.512 (6) (3 /)(51020mg/kg) 7 7 T max C max T 1/2 () T max 1.71.01.7 C max 3.46.812.1µg/mLT 1/2 () 5.2 4.34.8 7 T max 2.01.02.0 C max 3.36.0 11.5µg/mLT 1/2 () 5.24.74.5 (7) ( 5 /) (12.52550mg/kg)0.250.512 4681224 T max 11.62.4 C max 5.88.512.9µg/mLT 1/2 () 1.732.472.58 24 (0.8ppm) 25mg/kg124681224 5 T max 2 1 C max 9.444.737.610.78.86.9µg/gT 1/2 () 1.352.111.821.85 1.281.75 24 SPFS(3) 100mg/kg24 c TLCN- 2HPLCN- c
10.0044 (8), (9), (10), (11) 6 ( 5 1) 200mg 12 1 2 3.5 ( 7 ) 0.250.511.5236122736 T max 1.9 (0.5-3.0 )C max 2.96µg/mL(2.17-4.01µg/mL) T 1/2 ()6.6 (6.5-7.0 ) (8) 14 400mg 12 1 2 3.5 ( 7 )1 7 0.250.511.523612 7 16202428 32 T max 1.5 C max 4.5µg/mLT 1/2 () 4.6 7 T max 1.8 C max 6.5µg/mLT 1/2 () 6.5 (9) 6 600mgT max 1.2 C max 10.7µg/mLT 1/2 () 7 48 80.3% (10) 10 ( 5 ) 100 200mg T 1/2 () 4.54.2 AUC 7.314.4mgh/L24 73.1 77.0% 200 400mg T max 1.31.9 C max 2.193.51µg/mLT 1/2 () 5.64.9 AUC 14.628.0 mgh/l24 73.673.3% AUC 200mg 73.677.0% 3.03.2%N- 1.01.1% 3.9% (11) 7 200ppm135710 12.9ppm 10.6ppm 5.3ppm 2.4ppm 2.0ppm 0.6ppm 5 (0.02ppm) (12) 100 200ppm13579 100ppm 3.3ppm 3.2ppm 0.88ppm 0.62ppm 0.29ppm 0.21ppm 3 (0.05ppm)200ppm 6.5ppm 5.5ppm 4.8ppm 0.95ppm 0.54ppm 0.40ppm 3 (0.05ppm) (13) 2-2. (1) (14), (15), (16) LD 50 (Std:ddY) 5290mg/kg 5450mg/kg
(Wistar) 3750mg/kg 3590mg/kg()200mg d 500-1000mg/kg e (Std:ddy) 233mg/kg 208mg/kg(Wistar) 276mg/kg 273mg/kg() 70mg f (Std:ddy)10000mg/kg(Wistar) 9000mg/kg 7070mg/kg g (14) N-(Slc:ddY)LD 50 40.2mg/kg 38.5mg/kg (15) LD 50 (Std:ddY) 1803mg/kg 1881mg/kg (SD) 1507mg/kg 1478mg/kg250mg/kg (16) (2) 4 (17) 6 SlcSprague-Dawley ( 5 /) (03090270810 mg/kg /) 4 810mg 1 270mg 270mg 90mg 270mg 270mg 270mg () h 810mg Hb / 90mg 810mg 810mgAPCl - BUNTcho 4 270mgNa + d 200, 400mg2 (1/22/2) e 500mg(0/3)1000mg(4/4) f 50, 70mg(0/2)100mg1 (1/2) g h Preyer s
90mg 810mg 270mg 270mg 810mg 810mg 270mg 810mg NOAEL 90mg/kg 26 (18) 5 SlcSprague-Dawley ( 15 / 25 /) (0103090270 mg/kg /) 26 5 13 55 13 90mg 270mg 1 270mg 270mg 1 270mg () i QRS 13 26 13 270mg 26 30mg 270mg WBC 4 13 270mg AP 26 270mg ASTTcho 30mg / i Preyer s
13 26 13 270mgNa + 10mg13 26 26 90mg26 90mgpHCl - 13 30mg 30mg 270mg 26 30mg 90mg 90mg 270mg 5 13 13 30mg 90mg 26 30mg 30mg 90mg 26 270mg NOAEL 10mg/kg 26 (19) 5 CD(SD)(20 /) (02080320 mg/kg/) 26 80mg 320mg 1 80mg 26 WBC LDHCa + 80mgA/G 320mg AP 26 80mg ph ()80mg 80mg 320mg
(elongated) 80mg 320mg (glandular mucosa) 20 320mg 320mg 4 NOAEL 20mg/kg 26 (19) 2-4 ( 4 /) (0102562.5mg/kg /) 26 () 1 26 25 25 26 (3) 3 (DENdiethylnitrosamineMNUN-methylnitrosoureaDHPN dihydroxy-di-n-propylnitrosamine)(dmd)(f344/du Crj1 15 j )( (LV0.9%) 16 (20) (4) 2 (21) SlcSD ( 24 /) (01060360mg/kg /) 9 2 2 7 21 j LVLV 16
360mg 10 mg 60 mg 360mg NOAEL 10mg/kg / 360 mg/kg / () (22) SlcSD( 36 /) (01090810mg/kg/) F 0 7 17 24 21 12 F 0 F 1 11-15 F 1 21 F 2 F 0 810mg 810mg F 0 810mg 90 mgf 1 90mg 810mg 13 F 1 810mgF 1 4 0-11 0-7 F 1 k 810 mg F 1 / F 1 /F 2 NOAEL 90mg/kg / 10mg/kg / 810mg/kg / (23) SD( 20-24 /) (01060360mg/kg/) F 0 17 20 F 0 F 1 F 1 F 1 F 2 60mgF 0 360mg
F 0 / F 1 F 1 / F 2 NOAEL 10mg/kg/ 360 mg/kg/ (23) SD ( 5-10 /) 810mg/kg / 7-89-1011-1213-1415-17 7-17 9-10 7-17 13 (23) SD ( 23-24 /)(081011001600mg/kg /) 9-10 13 13 (23) SD 0810 mg/kg / 9-10 13 21 21 13 21 13 () (23) (10-15/)(01040160 mg/kg/) 6 18 160mg 160mg / NOAEL 40 mg/kg / 160mg/kg /
(5) in vitro in vivo in vitro DNA WI-38 0.1300 µg/ml (24) (UDS ) Ames S. typhimurium TA1535, TA1537,TA1538, TA98, TA100, E. coli WP2 uvra 0.0010.5 µg/plate(s9) 1 (24) Rec-assay Bacillus subtilis M45(Rec - ) 3.125µg/mL (24) Bacillus subtilis H17(Rec + ) 0.10.3131030100 2 300 µg/ml(-s922h) (24) CHL 0.11000 µg/ml 3 1 0.5µg/plate 2 100µg/mL 3 1000µg/mL 4 100µg/mL 0.1300 µg/ml 4 (24) (24) in vivo 600 mg/kg (24) (in vivo / in vitro) 10908102500mg/kg 1040160500 mg/kg/, (24) 1 /5 SLC-BDF 1 2502500mg/kg (25) 1251250mg/kg/ (25) 1 /5 (24) in vitro Rec-assay UDS in vitro/in vivo in vivo Rec-assay in vivo / in vitro in vitro in vivo
R- () R- in vitro Ames S. typhimurium TA1535, TA1537, TA98, 0.00160.1µg/plate 1 TA100, E. coli WP2 uvra (S9) (26) CHO(K-1/Hprt) 0.3750.7501.50 mg/ml (26) (S9) CHL 2505001000 µg/ml (S96h) 2 (26) 50100200300400 500 µg/ml(-s924h) (26) 50100200300µg/mL (26) (-S948h) CHL 50100200300µg/mL(-S9) (26) 1252505001000µg/mL (+S9) 250 (26) 1 0.025µg/plate (+S9 TA1537TA98 0.05µg/plate ) 2 1000 µg/ml in vivo UDS (in vivo/in vitro) F344/N 300600 mg/kg 150300600mg/kg 150300600mg/kg 100200400mg/kg/ 1 /5 SLC-BDF 1 3090270mg/kg/ 1 /5 312 2 200mg 1 (26) (26) (26) 2 (26) (26) CHL CHL in vivo
R- in vitro Ames S. typhimurium TA1535, TA1537, TA98, TA100, E. coli WP2 uvra CHL 1 12.5µg/plate 2 2000µg/mL 0.3925µg/plate (S9) 25050010002000µg/mL (S96h) 50100200300400 500 µg/ml(-s924h) 50100200300µg/mL (-S948h) 1 (26) 2 (26) (26) (26) in vivo 150300600mg/kg 1 400mg 100200400mg/kg/ 1 /5 (26) 1 (26) R- CHL in vivo (7) (27), (28) 7 3 5 CDSD( 10 /) 7 (OFLX) (NA)(OFLX030100300900mg/kg /NA100300mg/kg /) OFLX 900mg NA OFLX 300mg 6/10OFLX 900mg NA 10/10 (27) NOAEL 30 mg/kg / 68 10 CRCD (7 / 3 /) OFLX 900mg/kg / 7 6 1/7 2/7
8 (28) 8 (6) 3 ( 3 /20mg 6 /)(051020mg/kg /) 8 20mg 32 20mg 2 (2/3) 7-8 (humerus)(femur) 10mg 10mg 20mg 2 8 2 2 8 NOAEL 5 mg/kg / (7) (1836108180µg/mL) 15 ERG l 180µgB108µg36µg 5 3 50 100µg/mL 124 ERG4 VEP m VEP 100µgABC4 VEP50µg (29) (8) (30) Irwin () 300mg/kg 1000mg/kg 20 2 100mg/kg l Electroretinogram m Visual evoked potential
(EEGECG n ) 10mg/kg (3mg/kg)(wheel cage) 300mg/kg (100mg/kg)() 1000mg/kg(300mg/kg)( writhing) 100mg/kg writhing300mg/kg ( 30100mg/kg)() 1000mg/kg(300mg/kg) ()( )(shuttle box) () ((NE)(Ach))NE 30mg/kgAch 10mg/kg ( 103mg/kg ) ()() ()10-3 g/ml NE (10-4 g/ml) 10-4 g/ml o () 10-3 g/ml 10-4 g/ml p ( ) 300mg/kg(100mg/kg) (ph) 300mg/kg ph(100mg/kg) ()3mg/kg(1mg/kg ) ()() 3mg/kg () n ElectroencephalogramElectrocardiogram o 10-3 g/ml 10-4 g/ml p 10-3 g/ml 10-4 g/ml
10mg/kg 30mg/kg () 1g/kg () 30mg/kg (10mg/kg )( Na + K + Cl ) 300mg/kg Na + Cl () 0.11% (9) in vitro MIC (MIC) MIC ADIMIC 50 (µg/ml) MIC 50 MIC 90 Bacteroides bivius 46 4 8 31 Bacteroides caccae 10 8 8 1->128 32 Bacteroides distasonis 10 2 8 2-64 33 12 2 16 2-64 32 Bacteroides fragilis 42 1.56 6.25 0.78-12.5 34 13 2 4 2-16 35 51 4 4 2->64 36 29 4 8 1-16 37 27 2 2 0.5-8 38 50 2 4 2-4 39 20 4 8 2-16 40 41 3.13 12.5 0.78->25 41 32 1.0 4.0 1-16 5 4 2 4 31 23 1 4 1-128 42 11 2 4 1-8 33 23 2 8 2-64 32
25 1.56 3.13 0.78-3.13 43 Bacteroides fragilis group 52 4 32 1-128 42 Bacteroides melaninogenicuss 20 1 2 0.5-2 39 Bacteroides ovatus Bacteroides thetaiotaomicrom Bacteroides uniformis 12 16 32 16-32 33 10 16 16 8-16 32 14 16 16 8-256 33 17 8 128 4-128 32 10 8 16 2-64 33 12 4 8 2-8 32 Bacteroides ureolyticus group 11 0.125 0.5 <0.06-1 32 Bacteroides vulgatus Bacteroides spp.(fragilis ) 12 4 8 1-16 33 12 2 16 1-16 32 29 8 32 <0.03-64 36 29 8 32 2-128 42 17 2 4 0.25-8 33 Bifidobacterium spp. 10 4 4 1-8 42 Clostridium perfringens Clostridium ramosum / innocuum / clostridiiforme Clostridium spp. Eubacterium spp. 17 0.39 0.78 0.39-12.5 34 50 0.5 1 0.5-1 39 20 1.0 1.0 0.5-1 5 6 0.5 1 0.5-1 42 10 1 1 0.5-1 33 12 0.5 0.5 0.5-1 32 15 16 128 1->128 32 13 2 >64 0.5-16 36 20 1 8 0.25-16 40 17 2 8 0.5-256 33 23 4 16 0.5-32 32 12 0.5 2 0.5-8 42 10 1 2 0.25-4 33 Fusobacterium nucleatum 5 1 2 31 Fusobacterium nucleatum / necrophorum 15 2 2 1-4 33 Fusobacterium mortiferum / varium 19 4 16 2-64 33 Fusobacterium varium / ulcerans / gonidiaformans Fusobacterium spp. Peptococcus spp. Peptostreptococcus spp. 14 8 16 2-128 32 10 4 4 0.25-64 42 20 2 16 0.5-64 32 11 8 16 0.25-16 36 25 1.56 6.25 0.39-12.5 41 8 0.5 4 0.25-4 36 50 2 4 1-4 39 18 0.5 2 0.12-8 42
20 0.5 8 0.125-16 33 22 0.5 8 0.125-16 32 25 6.25 25 0.20-25 44 Peptococcus / Peptostreptococcus 10 1 2 0.25-2 40 Prevotella bivia 12 8 8 2-8 32 Prevotella spp. (pigmented) 17 1 16 0.25-64 32 Prevotella spp. (nonpigmented) 14 2 2 1-2 32 Prevotella spp 6 2 8 0.5-32 42 Enterococcus faecalis 25 2 2 1-4 40 50 3.13 6.25 0.78-25 41 16 4 4 2-4 5 25 1.56 3.13 0.78-3.13 43 Enterococcus faecium 16 2.0 16.0 1-16 5 Enterococci 10 2 32 1-32 42 29 2 4 1-4 38 100 2 4 1-8 39 Escherichia coli 100 0.05 0.19 0.025-1.56 34 54 0.063 0.125 0.031-1 35 23 0.06 0.125 0.06-0.125 37 49 0.06 0.06 0.03-0.5 38 100 0.06 0.12 0.06-0.12 39 35 0.06 0.125 0.03-1 40 50 0.05 0.10 0.025-3.13 41 32 0.06 0.13 0.03-0.25 5 39 0.5 1 31 10 0.06 32 0.03-64 42 25 0.05 0.05 0.013-0.10 43 Lactobacillus spp. 50 4 32 31 13 4 32 1-32 42 Propionibacterium acnes 14 1 4 1-8 36 Propionibacterium granulosum 6 1 4 1-4 36 Propionibacterium spp. 11 0.5 0.5 0.25-0.5 32 10 3 10 7 CFU/spot q 10 4 10 6 CFU/spot (34) (S)-(-)-10 3 10 7 CFU/spot MIC (41) MIC 50 Escherichia coli 0.05µ/mL Bacteroides ureolyticus group 0.125µg/mL Clostridium perfringens 0.39µg/mL Eubacterium spp.peptostreptococcus spp.propionibacterium spp. 0.5µg/mLMIC 50 q
ATCCMIC 50 ATCC Bacteroides fragilis ATCC25285 Bacteroides thetaiotaomicron ATCC29741 Eubacterium lentum ATCC43055MIC1-2(2)8-8(8)1-1(1) r (32) ph MIC ph (6.67.38.1) MIC Bacteroides fragilis(6 ) ph MIC()Bacteroides spp.(7 ) Fusobacterium spp.(2 )Clostridium spp.(4 )PeptococcusPeptostreptococcus spp.(5 ) ph7.3 MIC ph (36) 5 200mg 1 2 5 2345 6 Staphylococci D Staphylococci 4 4 MIC 50 MIC 90 D Staphylococci 2/5 4 Candida sp. Candida sp. µg/gin vitro MIC 50 1µg/mLin vitro (44) MIC 8 7 (Enterobacter aerogenesescherichia coliklebsiella pneumoniaepseudomonas aeruginosastaphylococcus aureusprovidencia stuartiiserratia marcescens) 8.5 10-9 (S. marcescens)1.6 10-9 (P. stuartii) (37) 24 ( 12 )400mg 1 2 10 r
/(5/5 s )(2/3)(2/3)3 (3/9) 1 1 3 (3/9) (45) 13,717 577 577 361 124 84 45 8 (1 )(1 )(1 )(2 ) (46) (S)-(-)- 14 C 20 (47) 100µg/mL ERG 50µg/mL ERGVEP 26 (62.5mg/kg /) 8 NOAEL s /
F 1 F 2 / UDS Rec-assay in vivo / in vitro R- () DENMNUDHPN 6 ADI 1990 DNA 6 8 8 (48) 8 1 in vivo in vitro CHLV79 UV (49) (50) UV UV (48) UV 1 100mg1 3 (51) 1/1,800,000 (52) 5
10mg/kg / NOAEL 8 NOAEL 5.0mg/kg / 90 8 ADI in vitro MIC 50 in vivo 5 10 5 5 (200mg/1 2 ) 2/5 Candida spp. 4 400mg// NOEL in vitro Bacteroides BifidobacteriumClostridiumEubacteriumFusobacteriumPeptococcus / Peptostreptococcus R-plasmidEnterococcusE. coli LactobacillusADIMIC 50 37 2164 MIC 50 0.5 g/mleubacteriumpeptostreptococcuspropionibacterium MIC 50 E. coli E. coli (0.1%)
ADI MIC 50 (53),(54) Bacteroides ureolyticus group 0.125 g/ml Clostridium perfringens () 0.39 g/mlmic 50 12 Bacteroides 1µg/mL Bacteroides ADI ADI EubacteriumPeptostreptococcusPropionibacteriumMIC 50 0.5µg/mL (ADI) ADI 8 NOAEL 5mg/kg / ADI 10 10 100 / 10 ADI 0.005mg/kg / in vitro MIC 50 220g 30%() 1 60kg ADI (mg/kg /) 0.0005 (mg/ml) 220 (g) 0.3 1 60 (kg) 0.006 mg/kg / ADI ADI ADI 0.005 mg/kg / ADI 0.005 mg/kg /
1. ()() 2. () 3. William 2001 () 10 4. T-3761 (1995) Jap J Antibiotics1995(48), 626-641 5. J. Fung-Tomc, et al. (1989)In vitro and in vivo antibacterial activities of BMY 40062, a new fluoronaphtyridone Antimicrob Agents Chemother.1989 (33), No.6, 906-914 6. Yabe K, et al. (2001)A non-arthropathic dose and its disposition following repeated oral administration of ofloxacin, a new quinolone antimicrobial agent, to juvenile dogs J Vet Med Sci2001 (63), No.8, 867-72 7. DP-1764(Ofloxacin)() 8. R. Warlich, et al. (1990)Multiple-dose pharmacokinetics of ofloxacin in serum, saliva, and skin blister fluid of healthy volunteers Antimicrob Agents Chemother.1990 (34), No.1, 78-81 9. D. Israel, et al. (1993)Pharmacokinetics and serum bactericidal titers of ciprofloxacin and ofloxacin following multiple oral doses in healthy volunteers Antimicrob Agents Chemother.1993 (37), No.10, 2193-2199 10. Lockley MR, et al. (1984)The pharmacokinetics and tissue penetration of ofloxacin J Antimicrob Chemother.1984 (14), No.6, 647-52 11. H. Lode, et al. (1987)Pharmacokinetics of ofloxacin after parenteral and oral administration Antimicrob Agents Chemother.1987 (31), No.9, 1338-1342 12. DP-1764()( 1)() 13. DP-1764()( 2)() 14. DL-8280 (1984) Chemotherapy1984(32), S-1, 1084-1090 15. DL-8280 () 16. M. Kato, et. al. (1992)Acute oral toxicity of the new quinolone antibacterial agent levofloxacin in mice, rats and monkeys Arzneim-Forsch1992 (42), 3a, 365-366 17. DL-8280 4 (1984) Chemotherapy1984(32), S-1, 1091-1104 18. DL-8280 26 (1984) Chemotherapy1984(32), S-1, 1122-1141 19. M. Kato, et. al. (1992)Twenty-six-week oral toxicity of the new quinolone antibacterial agent levofloxacin in rats and cynomolgus monkeys Arzneim-Forsch1992 (42), 3a, 367-373 20. T. Kajimura, et. al. (1992)Effect of the new quinolone antibacterial agent levofloxacin on multiple organ carcinogenesis initiated with wide-spectrum carcinogens in rats Arzneim-Forsch1992 (42), 3a, 390-395 21. DL-8280 () 22. DL-8280 () 23. S. Takayama, et. al. (1986)Reproductive toxicity of Ofloxacin
Arzneim-Forsch1986 (36(II)), Nr. 8, 1244-1248 24. DL-8280 (1984) Chemotherapy1984(32), S-1, 1162-1170 25. DL-8280 () 26. H. Shimada, et. al. (1992)Mutagenicity of the new quinolone antibacterial agent levofloxacin Arzneim-Forsch1992 (42), 3a, 378-385 27. DL-8280 7 () 28. DL-8280 3 () 29. H. Sakai, et. al. (1994)Nontoxic intravitreal dose of ofloxacin for rabbit retina Ophthalmic res1994 (26), 344-351 30. DL-8280 (1984) Chemotherapy1984(32), S-1, 1148-1161 31. MG Martens, et al (1991)Susceptibility of female pelvic pathogens to oral antibiotic agents in patients who develop postpartum endometritis Am J Obset Gynecol1991 (164), 1383-1386 32. EJ C Goldstein and DM Citron (1991)Comparative activity of ciprofloxacin, ofloxacin, sparfloxacin, Temafloxacin, CI-960, CI-990, and WIN 57273 against anaerobic bacteria Antimicrob Agents Chemother.1992 (36), No.5, 1158-1162 33. EJ C Goldstein and DM Citron (1991)Susceptibility of anaerobic bacteria isolated from intra-abdominal infections to ofloxacin and interaction of ofloxacin with metronidazole Antimicrob Agents Chemother.1991 (35), No.11, 2447-2449 34. K. Sato, et al. (1982)In vitro and in vivo activity of DL-8280, a new oxazine derivative Antimicrob Agents Chemother.1982 (22), No.4, 548-553 35. Dirk L VC and Stefan RP (1984)In vitro activity of ciprofloxacin compared with those of other new fluorinated piperazinyl-substituted quinolone derivatives Antimicrob Agents Chemother.1984 (25), No.4, 518-521 36. Prabhavathi BF, et al. (1986)In-vitro and in-vivo potency of five new fluoroquinolones against anaerobic bacteria J Antimicrobial Chemother.1986 (18), 693-701 37. Lisa H and Harold CN (1987)In vitro activity of two new aryl-fluoroquinolone antimicrobial agents, difloxacin (A-56619) and A-56620 compared to that of other antimicrobial agents Chemotherapy1987 (33), 28-39 38. Asbjrn D and William LD (1988)In vitro activity of A-56619 (difloxacin) and A-56620, two aryl fluoroquinolones Chemotherapy1988 (34), 298-307 39. RN Gruneberg, et al. (1988)The comparative in-vitro activity of ofloxacin J Antimicrobial Chemotherapy1988 (22), Suppl. C, 9-19 40. AM Espinoza, et al (1988)Comparative in vitro activity of a new fluorinated 4-quinolone, T-3262 (A-60969) Antimicrob Agents Chemother.1988 (32), No.5, 663-670 41. T Une, et al (1988)In vitro activity of DR-3355, an optically active ofloxacin Antimicrob Agents Chemother.1988 (32), No.9, 1336-1340 42. L. Dubreuil, et al (1996)Activé in vitro D une nouvelle fluoroquinolone, la marbofloxacine (RO 09-1168) sur les anaérobies strcts et quelques bactéries de la flore fécale humaine
Path Biol1996 (44), 333-336 43. Y Fukuoka, et al (1993)In vitro and in vivo antibacterial activities of T-3761, an new quinolone derivative Antimicrob Agents Chemother.1993 (37), No.3, 384-392 44. S Pecquet, et al (1987)Effect of oral ofloxacin on fecal bacteria in human volunteers Antimicrob Agents Chemother.1987 (31), No.1, 124-125 45. Stein GE, et al (1991)Safety of multiple doses of ofloxacin in healthy volunteers Drugs Exptl Clin Res1991 (XVII), 10/11, 525-529 46. RBlomer,et al (1986)Safety of ofloxacin adverse drug reactions reported during phase-ii studies in Europe and in Japan Infection1986 (14), Suppl. 4, S332-S334 47. M Tanaka, et al. (2004)Absorption, distribution and excretion of 14 C-levofloxacin after single oral administration in albino and pigmented rats: binding characteristics of levofloxacin-related radioactivity to melanin in vivo. J Pharm Pharmacol.2004 Apr; 56(4), 463-9. 48. K Marutani, et al. (1993)Reduced phototoxicity of a fluoroquinolone antibacterial agent with a methoxy group at the 8 position in mice irradiated with long-wavelength UV light Antimicrob Agents Chemother.1993 (37), No.10, 2217-2223 49. Zhang T, et al. (2004) Compare two methods of measuring DNA damage induced by photogenotoxicity of fluoroquinolones. Acta Pharmacol Sin.2004 Feb, 25(2), 171-5. 50. Ronald et, al. (1999) Photogenotoxicity of fluoroquinolones in Chinese hamster V79 cells: dependency on active topoisomerase II. Photochem Photobiol.1999 Mar; 69(3), 288-93. 51. Scheife RT et, al.photosensitizing potential of ofloxacin Int J Dermatol. 1993 Jun, 32(6)413-6 52. Yagawa K.Latest industry information on the safety profile of levofloxacin in Japan. Chemotherapy.2001 (47) Suppl 3, 38-43, discussion 44-8. 53. WHO TRS 893 (2000) 54. EMEA (2002)REVISED GUIDELINE ON SAFETY EVALUATION OF ANTIMICROBIAL SUBSTANCES REGARDING THE EFFECTS ON HUMAN GUT FLORA