The pharmacokinetics and metabolism of sarafloxacin were studied in two groups of six volunteers given a single oral dose of 100 or 200 mg sarafloxacin and two groups of five volunteers given a single oral dose of 400 or 800 mg. ... The metabolism of sarafloxacin appears to involve mainly oxidative degradation of the piperazinyl substituent, first producing 3'-oxo-sarafloxacin. Subsequent oxidation produces an ethylene diamine-substituted quinolone, which in turn is oxidized to an aminoquinolone. The plasma concentrations of the ethylene diamine-substituted quinolone parallel those of the parent drug, but the average AUC for the quinolone was consistently only about 6% that of sarafloxacin. The concentration of the aminoquinolone in plasma and urine was considerably lower than that of the ethylene diamine-substituted quinolone. Owing to its weak fluorescence, 3'-oxo-sarafloxacin was not detected in plasma. In urine, the major drug-related peak was sarafloxacin, accounting for 75-80% of all urinary metabolites. After sarafloxacin, the predominant metabolite in urine was tentatively identified as 3'-oxo-sarafloxacin, which occurred at concentrations that were typically one-third to one-fourth those of sarafloxacin. The total urinary recovery of parent drug plus metabolites was low and dose-dependent, decreasing from 24 to 10% as the dose increased from 100 to 800 mg. The extent of the decrease was similar to that in the dose-normalized AUC. Collectively, the aminoquinolone, the ethylene diamine-substituted quinolone, and their conjugates accounted for < 7% of the urinary excretion.
... /Dogs (breed, sex, and number not stated) were given an oral or intravenous dose of 10 mg/kg bw dose of (14)C-sarafloxacin base./ ... About 79% of the 10 mg/kg bw dose of (14)C-sarafloxacin base was excreted as unmetabolized parent drug in urine and faeces. In bile, the unchanged parent drug and its glucuronide were found in about equal proportions
To investigate the microbial biotransformation of veterinary fluoroquinolones, Mucor ramannianus was grown in sucrose/peptone broth with sarafloxacin for 18 days. Cultures were extracted with ethyl acetate and extracts were analyzed by liquid chromatography. The two metabolites (26% and 15% of the A280, respectively) were identified by mass and 1H nuclear magnetic resonance spectra as N-acetylsarafloxacin and desethylene-N-acetylsarafloxacin. The biological formation of desethylene-N-acetylsarafloxacin has not been previously observed.
IDENTIFICATION AND USE: Sarafloxacin is a fluoroquinolone antibacterial agent. It is used in veterinary medicine for the treatment and control of bacterial infections in poultry. Sarafloxacin is also used in aquaculture for the treatment in of furunculosis, vibriosis and enteric redmouth in Salmonidae. HUMAN EXPOSURE AND TOXICITY: The safety of single oral doses of sarafloxacin was studied in groups of healthy male volunteers. Six subjects received 100 mg sarafloxacin, six received 200 mg, five received 400 mg, and five received 800 mg. The adverse events reported most frequently were dizziness and asthenia. Emotional lability, somnolence, and hiccoughs were reported by those receiving the lowest dose. The safety of oral sarafloxacin administered for seven consecutive days was also studied in groups of six healthy male volunteers who received 100 mg every 12 hr, 200 mg every 12 hr, or 100 mg every 6 hr. The most frequently reported adverse events were asthenia and dizziness. The most frequently reported adverse events in the group receiving placebo were asthenia and somnolence. ANIMAL STUDIES: In a study of dietary palatability, sarafloxacin was administered to four groups of five rats of each sex, four to five weeks old, as a dietary admixture for two weeks. No overt signs of toxicity or mortality were reported in animals consuming diets containing up to 10,000 mg/kg feed. Alopecia, emaciation, dehydration, decreased feed consumption, and body-weight gain were treatment-related effects observed in rats consuming 50,000 mg/kg feed. Sarafloxacin was also administered to four groups of five mice of each sex, four to five weeks old, as a dietary admixture for 15 consecutive days. No overt signs of toxicity or mortality were reported in animals consuming diets containing up to 10,000 mg/kg feed. Decreased feed consumption and body-weight gain were the only treatment-related effects observed in rats consuming the diets containing 25,000 and 50,000 mg/kg feed. Sarafloxacin was administered to groups of 60 mice of each sex as a dietary admixture (150, 750, and 3000 mg/kg bw per day). An additional 10 animals of each sex were included in each group for hematological evaluations and sacrifice at 52 weeks. The carcinogenicity phase was terminated at 78 weeks because of high mortality. Mortality was increased in mice of each sex at the intermediate and high doses. Nephrotoxic effects were observed in females at the intermediate and high doses. Gall-bladder calculi and urolithiasis were found in males at the high dose. Cecal dilatation was observed in males and females at all doses, and cecal torsion was also observed in males and females at the intermediate and high doses. There was no evidence of carcinogenicity. A three-generation study of reproductive toxicity was conducted in rats, each generation consisting of 30 males and 30 females per group. The animals were treated orally by gavage with sarafloxacin base at 75, 275, or 1000 mg/kg bw per day, beginning a minimum of 70 days before breeding. Gross necropsy of the F0 animals revealed red contents in the gastrointestinal tract and/or red foci in the stomach. In female parental animals of the first generation at the intermediate and high doses, the absolute and relative liver weights were significantly decreased. The relative liver weights were also significantly decreased in male and female parental animals of the second generation and in males of the third generation at the intermediate and high doses. Parental females of the third generation at the high dose had decreased relative liver weights. A study of developmental toxicity was conducted in three groups of 18 artificially inseminated white rabbits given sarafloxacin by gavage once daily on gestation days 6-18 at doses of 15, 35, or 75 mg/kg bw per day. Fourteen females aborted between gestation days 21 and 29. External examination showed that six fetuses from one litter at the high dose had malformations, reported as carpal and/or tarsal flexure. Visceral examination revealed that five fetuses from one litter at the high dose had malformations, reported as hydrocephaly. Six fetuses from one litter at the high dose had skeletal malformations, reported as cartilaginous skeletal anomalies. Three malformations were observed in two litters at the intermediate dose. The only parameters not affected by treatment were the mean numbers of corpora lutea, implantation sites, viable fetuses per litter, and mean post implantation loss at scheduled removal of fetuses. A dose-related decrease in mean fetal weight occurred at doses of 35 and 75 mg/kg bw per day. The teratogenic effects were considered to be secondary to maternal toxicity and not directly attributable to treatment.
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
解毒与急救
/SRP:/ 高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W TKO /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸钠林格氏液（LR）。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒物A和B/
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. 2. Treat coma, seizures, hypotension, anaphylaxis, and hemolysis if they occur. 3. replace fluid losses resulting from gastroenteritis with IV crystalloids. 4. Maintain steady urine flow with fluids to alleviate crystalluria from overdoses of sulfonamides, ampicillin, or amoxicillin. /Antibacterial agents/
(14)C-Sarafloxacin was orally administered to six laying hens for five consecutive days. Eggs were collected for 15 days after the initial drug treatment. Egg yolk and egg albumen were separated and assayed for total radioactive residues (TRR) using a combustion oxidizer and scintillation counting techniques. Radioactivity was detected in egg yolk and egg albumen on the second day of dosing and reached a maximum at 24 hr after drug withdrawal. Thereafter, the sarafloxacin TRR levels in egg albumen declined rapidly and were undetectable 2 days after the last dose, whereas the levels in egg yolk declined at a much slower rate and were undetectable 7 days after drug withdrawal. In both the egg albumen and yolk, HPLC analysis indicated that the parent sarafloxacin was the major component.
Pharmacokinetics of sarafloxacin, a fluoroquinolone antibiotic, was determined in pigs and broilers after intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration at a single dose of 5 (pigs) or 10 mg/kg (broilers). Plasma concentration profiles were analysed by a noncompartmental pharmacokinetic method. Following i.v., i.m. and p.o. doses, the elimination half-lives were 3.37 +/- 0.46, 4.66 +/- 1.34, 7.20 +/- 1.92 (pigs) and 2.53 +/- 0.82, 6.81 +/- 2.04, 3.89 +/- 1.19 hR (broilers), respectively. After i.m. and p.o. doses, bioavailabilities (F) were 81.8 +/- 9.8 and 42.6 +/- 8.2% (pigs) and 72.1 +/- 8.1 and 59.6 +/- 13.8% (broilers), respectively. Steady-state distribution volumes (Vd(ss)) of 1.92 +/- 0.27 and 3.40 +/- 1.26 L/kg and total body clearances (ClB) of 0.51 +/- 0.03 and 1.20 +/- 0.20 L/kg/hr were determined in pigs and broilers, respectively. Areas under the curve (AUC), mean residence times (MRT), and mean absorption times (MAT) were also determined. Sarafloxacin was demonstrated to be more rapidly absorbed, more extensively distributed, and more quickly eliminated in broilers than in pigs. Based on the single-dose pharmacokinetic parameters determined, multiple dosage regimens were recommended as: a dosage of 10 mg/kg given intramuscularly every 12 hr in pigs, or administered orally every 8 hr in broilers, can maintain effective plasma concentrations with bacteria infections, in which MIC90 are <0.25 ug/mL.
The absorption, metabolism, and excretion of (14)C-labelled sarafloxacin was studied in three-month-old female New Zealand white rabbits. Two groups of three animals per group were treated orally by gavage with 10 mg/kg bw of (14)C-sarafloxacin base. A third group of three animals received the same dose by intravenous administration. Blood samples were collected 1, 3, 6, 12, and 24 hr after oral administration from animals in one of the groups, and urine and feces were collected daily for five days from animals in the other groups. ... Within five days of oral administration, about 11% of the dose was eliminated in the urine and about 79% in the feces. Urinary excretion after intravenous administration indicated that about 16% of the oral dose had been systemically absorbed.
Five groups of 18 Sprague-Dawley rats of each sex were treated with sarafloxacin as follows: One group received a single intravenous dose of 20 mg/kg bw; three groups received a single oral dose of 20, 75, or 275 mg/kg bw; and animals in the fifth group received an oral dose of 1000 mg/kg bw daily for 14 consecutive days. Blood samples were collected from four rats in each group just before treatment and 0.5, 1, 2, 4, 6, 8, 12, and 24 hr after treatment on day 1 for the groups receiving the single dose and on days 1 and 14 for the 14-day treatment group. Plasma and urine samples were assayed for sarafloxacin base by high-performance liquid chromatography. ... A comparison of the 0 to infinity area under the concentration time curve (AUC) after a single intravenous or oral dose of 20 mg/kg bw sarafloxacin indicated that its bioavailability was about 12%. A plot of the AUC against dose was linear up to 275 mg/kg bw but deviated from linearity at 1000 mg/kg bw.
Quinolone antibiotic derivatives as new selective Axl kinase inhibitors
摘要：
Axl is a new promising molecular target for antineoplastic therapies. A series of quinolone antibiotic derivatives were designed and synthesized as new selective Axl inhibitors. One of the most promising compound 8i bound tightly to Axl with a K-d value of 1.1 nM, and inhibited its kinase activity with an IC50 value of 26 nM. The compound also significantly inhibited the phosphorylation of Axl and dose dependently inhibited cell invasion and migration in TGF-beta 1 induced MDA-MD-231 breast cancer cells. In addition, 8i demonstrated reasonable pharmacokinetic properties and exhibited extraordinary target selectivity over 468 kinases except for Flt3 (IC50 = 50 nM)), with a S(10) and S(35) value of 0.022 and 0.42 at 1.0 mu M, respectively. Compound 8i may serve as a new valuable lead compound for future anti-cancer drug discovery. (C) 2019 Elsevier Masson SAS. All rights reserved.
Synthesis and structure-activity relationships of novel arylfluoroquinolone antibacterial agents
摘要：
A series of novel arylfluoroquinolones has been prepared. These derivatives are characterized by having a fluorine atom at the 6-position, substituted amino groups at the 7-position, and substituted phenyl groups at the 1-position. Structure-activity relationship (SAR) studies indicate that the in vitro antibacterial potency is greatest when the 1-substituent is either p-fluorophenyl or p-hydroxyphenyl and the 7-substituent is either 1-piperazinyl, 4-methyl-1-piperazinyl, or 3-amino-1-pyrrolidinyl. The electronic and spatial properties of the 1-substituent, as well as the steric bulk, play important roles in the antimicrobial potency in this class of antibacterials. As a result of this study, compounds 45 and 41 were found to possess excellent in vitro potency and in vivo efficacy.
[EN] AGENTS FOR USE IN THE TREATMENT OF CARDIOVASCULAR AND INFLAMMATORY DISEASES STRUCTURALLY BASED ON 4(1 H)-QUINOLONE<br/>[FR] AGENTS DESTINÉS À ÊTRE UTILISÉS DANS LE TRAITEMENT DE MALADIES CARDIOVASCULAIRES ET INFLAMMATOIRES AYANT UNE STRUCTURE BASÉE SUR LA 4(1H)-QUINOLONE
申请人：UCL BUSINESS PLC
公开号：WO2015189560A1
公开（公告）日：2015-12-17
The present invention provides a compound of formula I, a tautomer thereof, or a pharmaceutically acceptable salt or N-oxide thereof for use in the treatment or prevention of a cardiovascular disease or of an inflammatory disease or condition:
Phosphonated Fluoroquinolones, Antibacterial Analogs Thereof, and Methods for the Prevention and Treatment of Bone and Joint Infections
申请人：Delorme Daniel
公开号：US20080287396A1
公开（公告）日：2008-11-20
The present invention relates to phosphonated fluoroquinolones, antibacterial analogs thereof, and methods of using such compounds. These compounds are useful as antibiotics for prevention and/or the treatment of bone and joint infections, especially for the prevention and/or treatment of osteomyelitis.
[EN] ANTIFUNGAL COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS ANTI-FONGIQUES ET UTILISATIONS ASSOCIÉES
申请人：DANA FARBER CANCER INST INC
公开号：WO2017143230A1
公开（公告）日：2017-08-24
Provided herein are compounds (e.g., compounds of Formulae (I), (II), and (III)) which are anti-fungal agents and can be used in the treatment of diseases, including infectious diseases. The invention provides methods of treating diseases in a subject (e.g., infectious diseases such as fungal infections), and methods of killing or inhibiting the growth of fungi in or on a subject or biological sample. The compounds may be used in subjects, in clinical settings, or in agricultural settings.
Beta-O/S/N fatty acid based compounds as antibacterial and antiprotozoal agents
申请人：Ludwig-Maximilians-Universität München
公开号：EP2601941A1
公开（公告）日：2013-06-12
The present invention relates to beta-O/S/N fatty acids and derivatives thereof, in particular the compounds of formula (I) as described and defined herein, and their pharmaceutical use, including their use in the treatment or prevention of bacterial as well as protozoan infections, in particular the treatment or prevention of infections with Gram-positive and/or Gram-negative bacteria and infectious diseases caused by and/or related to Gram-positive and/or Gram-negative bacteria. The invention further relates to the use of these compounds for preventing or eliminating biofilms.
[EN] BETA-O/S/N FATTY ACID BASED COMPOUNDS AS ANTIBACTERIAL AND ANTIPROTOZOAL AGENTS<br/>[FR] COMPOSÉS À BASE DE BÊTA-O/S/N ACIDES GRAS EN TANT QU'AGENTS ANTIBACTÉRIENS ET ANTI-PROTOZOAIRES
申请人：UNIV MUENCHEN L MAXIMILIANS
公开号：WO2013083724A1
公开（公告）日：2013-06-13
The present invention relates to beta-O/S/N fatty acids and derivatives thereof, in particular the compounds of formula (I) as described and defined herein, and their pharmaceutical use, including their use in the treatment or prevention of bacterial as well as protozoan infections, in particular the treatment or prevention of infections with Gram-positive and/or Gram-negative bacteria and infectious diseases caused by and/or related to Gram-positive and/or Gram-negative bacteria. The invention further relates to the use of these compounds for preventing or eliminating biofilms.
