μ Key words Streptococcus pneumoniae β Haemophilus influenzae β Moraxella Branhamella catarrhalis I
F F H C SO H H O H N N N N F CO H O Fig.1. Chemicalstructureoftosufloxacintosilatehydrate. α
Body weight (g) 1 Male Control mg/kg 1, mg/kg, mg/kg 7 1 1 8 7 1 1 8 Female Body weight (g) 1 7 1 1 8 Administration (day) 7 1 1 8 Recovery (day) Fig.. ChangesinmeanbodyweightinjuvenileratsadministeredTFLXoralyfor1 month. :Thediferencefrom controlsissignificantatp<.inthe,mg/kggroup. Organ/Tissue andfindings Dose(mg/kg) Numberofanimals Kidney Crystal,renaltubularlumen Dilatation,renaltubule Foreignbodyreaction Table1. HistopathologyinjuvenileratsadministeredTFLXoralyfor1month 8M Control 8F 7M F 1M [+] [±] 1, 1F [±],1[+] [+] 1M, 1F [±],1[+] [±],[+] [±],1[+] [±],[+] [±] [±] Numberofanimalswithfindingsanddegreein[](±,veryslight;+,slight). M:male. F:female. Therewerenohistopathologicalfindingsrelatedtotestarticleadministrationinotherorgans/tissues,includingthebrain,pituitary,salivary gland,thymus,heart,lung,liver,spleen,adrenal,cecum,thyroid,testis,seminalvesicle,prostate,epididymis,ovary,uterus,trachea,pancreas, tongue,esophagus,stomach,smalintestine,largeintestine,submandibularlymphnode,mesentericlymphnode,eye,harderiangland,skele talmuscle,spinalcord,bone,bonemarow,vagina,mammarygland,urinarybladder,skin,andaorta. Therewerenohistopathologicalfindingsrelatedtotestarticleadministrationattheendofrecoveryinthe,mg/kggroup.
Day 7, Male Body weight (kg) 1 C 1 6 1 1 9 119 TFLX NFLX CPFX (mg/kg) Day 7, Female Body weight (kg) 1 C 1 6 TFLX (mg/kg) Fig.. BodyweightinjuveniledogsadministeredTFLX,NFLX,andCPFXfor1 month. Individual( )andgroupmean( )bodyweightsontheendofadministra tion(day7)areindicated. Erorbarsarestandarddeviation. μ μ μ Ω
Table. HistopathologyinjuveniledogsadministeredTFLXoralyfor1month Organ/Tissue Testsubstance TFLX NFLX CPFX Control andfindings Dose(mg/kg) 1 6 1 1 9 119 Numberofanimals Bonemarow,sternal Decrease,hematopoieticcel Bonemarow,femoral Decrease,hematopoieticcel Spleen Decrease,lymphocyte,whitepulp Thymus Decrease,lymphocyte Liver Atrophy/decreasedglycogen area,hepatocyte Bone,sternum Retardedossification, trabecula,spongybone Bone,femur Retardedossification, trabecula,spongybone F F F [±] F [±,++] [±,++] [±,+] Numberofanimalswithfindingsanddegreein[](±,veryslight;+,slight;++,moderate). M:male. F:female. Therewerenochangesrelatedtotestarticleadministrationinanygroupsinotherorgans/tissues,includingthebrain,pituitary,submandibu largland,heart,lung,galbladder,pancreas,kidney,adrenal,thyroid,testis,prostate,epididymis,ovary,uterus,trachea,tongue,stomach, smalintestine,largeintestine,submandibularlymphnode,mesentericlymphnode,eye,lacrimalgland,skeletalmuscle,spinalcord,sciatic nerve,vagina,mammarygland,urinarybladder,skin,aorta,andarticularcartilageofshoulder,elbow,carpal,hip,knee,andtarsaljoint. Therewerenohistopathologicalfindingsrelatedtotestarticleadministrationattheendofrecoveryinthe6mg/kggroup. [±] [±] 1[+] 1[+] II
1 Male Female Plasma level of tosufloxacin ( µ g/ml) 1.1.1 6 1 18 6 1 18 Time after administration (h) Time after administration (h) Fig.. PlasmalevelofTFLXafteroraladministrationinjuveniledogs. Onthefinalday(Day8)ofdosingat1( ),( ),and6mg/kg( ). Erorbarsarestandarddeviation. μ μ μ μ μ μ
Table. Grosspathologyofarticularcartilageandtoxicokineticparametersinjuvenile dogs(-month-old)administeredtflxforweeks Dose(mg/kg) Numberofanimals Control Grosspathology(numberofanimalswithfindings) Shoulderjoint Humerus,proximal Blister Erosion Elbowjoint Humerus,distal Ulna/Radius,proximal Carpaljoint Ulna/Radius,distal Hipjoint Femur,proximal Kneejoint Femur,distal Tibia,proximal Tarsaljoint Tibia/Fibula,distal 1[+] 1[+] [+] Toxicokineticparameters 1stadministration Cmax(μg/mL) AUC-t(μg h/ml) 1thadministration Cmax(μg/mL) AUC-t(μg h/ml).6 6.1.8..9.9 7...8.8 9. 66..6.88 7..1 []:Degreeoffindings(+,slight). Table. Histopathologyofarticularcartilageinjuveniledogs(-month-old)administeredTFLX forweeks Siteandfindings Dose(mg/kg) Numberofanimals Shoulderjoint Humerus,proximal Cavitation Detachment,cartilagesurfacelayer Necrosis,chondrocyte Clusterformation,chondrocyte Fibrosis Hipjoint Femur,proximal Kneejoint Femur,distal Control 1[++] 1[++] 1[++] 1[+] Numberofanimalswithfindingsanddegreein[](+,slight;++,moderate). NE:notexamined. NE NE 1[+] 1[+],1[++] [+],1[++] [+],1[++] III
Table. IncidenceofarthropathyandtoxicokineticparametersinjuveniledogsadministeredNFLXandCPFXfor1 week Drug Animal Dose(mg/kg) Numberofanimals NFLX Beagle,--month-old NFLX CPFX Beagle,--month-old F F Numberofanimalswitharthropathy Total Shoulderjoint Elbowjoint Carpaljoint Hipjoint Kneejoint Tarsaljoint 1 6 6 6 6 Toxicokineticsparameters 1stadministration Cmax(μg/mL) AUC-inf(μg h/ml) 6thadministration Cmax(μg/mL) AUC-inf(μg h/ml) Reference M:male. F:female..±.78.11±1.66 1.±7.1 1.±1.1 6.±. 9.6±9.7 Machida,etal(199) 16) M.±. M.6±.6 F.19±.9 F.9±1.1 M.±1.8 M.8±11.8 F.±16.1 F.9±9.9 M.±1. M.±.79 F1.7±1.1 F6.±1. M 11.9±.7 M.9±9. F1.1±8.8 F.±1.9 Nagai,etal() 17) μ μ
1 11 Mean blood pressure 1 1 Heart rate 7 QTc (mmhg) 1 9 8 7 (beat/min) 8 6 (msec) 6 17 1 1 Time after administration (h) 1 1 Fig.. EfectofTFLXonthecardiovascularparameterindogs. Bloodpressure,heartrate,andECGweremonitoredbytelemetryafterasingleoraldoseofTFLXat ( ),( ),and1( )mg/kg. Table6. TFLXandMFLXefectsonhERGcurentstablyexpressedHEK9cels Testsubstance Concentration (μmol/l) Numberof preparations %before a %inhibition Vehicle b 9.9± 1.9 TFLX 1 1 9.± 1. 9.9± 1.1 9.1±.6 9.6± 1..8.1.1. MFLX 1 1 a :percentageofvaluejustbeforeapplication. b :.vol%dimethylsulfoxide. Eachvaluerepresentsmean±S.E. :Significantdiferencefrom controlatp<.. 87.± 1. 77.9±. 6.±.6 7.8 17.9 6. μ μ μ μ
1 Glucose, Insulin 1, 1 (mg/dl) (pg/ml) 1, 6 8 1 1 Time after administration (h) 6 8 1 1 Time after administration (h) Fig.6. EfectofTFLXonglucoseandinsulinlevelsinserum indogsafterasingleoraldoseof TFLXat( ),1( ),6( )mg/kg,andtolbutamide1,mg/body( ). :Significantdiferencefrom controlatp<.. μ μ μ μ μ β β in vitro μ μ μ β in vitro
In vitro in vivo Chlamydia Streptococcus pneumoniae in vitro β Haemophilus influenzae Haemophilus influenzae In
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