In dogs, less than 5% of the dose was excreted in the urine as unchanged drug and 13-15% was excreted as an acid-labile urinary conjugate of flumequine (or a material fluorometrically similar to flumequine). In rats, 20-36% was excreted in the urine as unchanged drug and very little as an acid-labile conjugate.
In a 13-week study designed to investigate hepatotoxic lesions and the activities of hepatic drug-metabolizing enzymes, flumequine was administered to male CD-1 mice in the feed at doses equal to 0, 25, 50, 100, 400, or 800 mg/kg bw per day and to females at 0, 100, 400, or 800 mg/kg bw per day. ... Flumequine caused little or no induction of hepatic cytochrome P450-dependent drug-metabolizing enzymes or glucuronyltransferase when given at doses up to 800 mg/kg bw per day. ...
To determine the plasma and urine levels of flumequine and its metabolite, 7-hydroxyflumequine, 28 healthy male subjects were given single and multiple oral doses of 400, 800 and 1200 mg flumequine. Results showed mean concentrations at 2 hr of 13.5, 23.8 and 31.9 mg/L, respectively. These levels were sustained up to 6 hr postdose. Following a single 800 mg dose, peak plasma levels of 14-25 mg/L occurred between 2.5 and 3.5 hr. The mean elimination half-life was 7.1 hr. In plasma only minimal levels of 7-hydroxyflumequine were found. Following 800 mg of flumequine four times a day, mean trough plasma levels of unchanged drug ranged from 21-23 mg/L. Mean peak concentrations were 41 mg/L at steady-state. The half-life following the last dose (8.5 hr) was not significantly different from the 7.1 hr half-life following the first dose. Substantial drug levels were present in the urine for 24 hr following single oral doses of 400, 800 and 1200 mg of flumequine. Urine levels of 7-hydroxyflumequine were generally higher than the parent compound. In the multiple dose study, the overnight concentration of flumequine always exceeded 50 mg/L, and the overnight concentration of 7-hydroxyflumequine always exceeded 80 mg/L.
IDENTIFICATION AND USE: Flumequine is a fluoroquinolone compound with antimicrobial activity against Gram-negative organisms. It is used in the treatment of enteric infections in food animals and in the treatment of bacterial infections in farmed fish. Flumequine also has limited use in humans for the treatment of urinary tract infections. HUMAN EXPOSURE AND TOXICITY: Ocular side effects in 3 patients being treated with flumequine for urinary infections were reported. All 3 patients had chronic renal failure and all exhibited bilateral symmetry. Complete recovery occurred within 2 days of withdrawing the drug. ANIMAL STUDIES: Flumequine was administered by gastric tube to female mice for 14 days. No signs of alopecia or other toxicity were noted. Rats were orally administered flumequine for 14 days. Marked alopecia was observed in both sexes after 3 to 5 days treatment, which persisted for the duration of the study. In other study rats were orally administered flumequine for 14 days. Clinical signs included bloating, cyanosis, dehydration, reduced weight gain, and shedding. Guinea pigs were given oral doses of flumequine for 14 days. Mortality was noted. Beagle dogs were given daily oral doses of flumequine. All dogs survived the one-year treatment period. A decrease in food consumption was noted in all treatment groups throughout the study. A dose-dependent incidence of convulsive episodes was observed in treated dogs. The convulsions were relatively severe, of short duration (15-30 seconds), and almost always followed by ataxia and tremors. Normal behavior returned within about ten minutes after treatment. Other drug-related clinical signs observed included ataxia, hypoactivity, tremors, emesis, decreased food consumption, and body-weight loss. In an 18-month study, flumequine was administered in the feed to mice of each sex. A slight depression in body weight occurred in the high-dose group from the sixth week to termination of the study. Incidences of liver tumors seen grossly at necropsy were dose-related and more prevalent in males than in females. The incidence of hepatic toxic changes paralleled the liver tumor incidence. Chi-square analysis of the number of tumor-bearing animals indicated significant increases for the low- and high-dose males considering all tumors and benign tumors. The number of high-dose males with both benign and malignant liver tumors was also statistically significant. In females, the only significant increases occurred in the high-dose group for numbers of animals with any type or benign only tumors. In a 13-week study designed to investigate hepatotoxic lesions and the activities of hepatic drug-metabolizing enzymes, flumequine was administered to mice. The effects observed were reduced body weight, significantly increased plasma activities of alanine and aspartate aminotransferases, alkaline phosphatase and lactic dehydrogenase, and increased liver weights. Pregnant mice were orally administered flumequine from the second to fifteenth days of gestation. Incomplete ossification, invaginated trachea, dilatation of the renal pelvis, and cleft palate were observed in fetuses. These observations were interpreted as evidence of fetotoxic, not teratogenic, responses to exposure to flumequine. Pregnant rats were dosed orally with flumequine from the sixth through fifteenth days of gestation. There was a dose-related reduction of mean body weight in the treated dams and the difference from controls was significant at 400 mg/kg bw/day. The mean fetal weights of the mid- and high-dose groups were significantly lower as compared to controls. Dose-related incomplete ossification of sternebra, vertebrae, and skull bones were also noted in fetuses. No drug-related visceral or skeletal malformations were found and there was no embryotoxic effect noted in this study. Flumequine was negative in the following genotoxicity tests: Ames test, HGPRT test, Gene Mutation Assay and the Chromosome Aberration Assay.
The combined effects of various carcinogens found in food products are a concern for human health. In the present study, the effects of flumequine (FL) on the in vivo mutagenicity of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in the liver were investigated. Additionally, we attempted to clarify the underlying mechanisms through comprehensive gene analysis using a cDNA microarray. Male gpt delta mice were fed a diet of 0.03 % MeIQx, 0.4 % FL, or 0.03 % MeIQx + 0.4 % FL for 13 weeks. The effects of cotreatment with phenobarbital (PB) were also examined. Treatment with MeIQx alone increased gpt and Spi(-) mutant frequencies, and cotreatment with FL, but not with PB, further exacerbated these effects, despite the lack of in vivo genotoxicity in mice treated with FL alone. FL caused an increase in Cyp1a2 mRNA levels and a decrease in Ugt1b1 mRNA levels, suggesting that the enhancing effects of FL may be due in part to modification of MeIQx metabolism by FL. Moreover, FL induced an increase in hepatocyte proliferation accompanied by hepatocellular injury. Increases in the mRNA levels of genes encoding cytokines derived from Kupffer cells, such as Il1b and Tnf, and cell cycle-related genes, such as Ccnd1 and Ccne1, suggested that FL treatment increases compensatory cell proliferation. Thus, the present study clearly demonstrated the combined effects of 2 different types of carcinogens known as contaminants in foods.
/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/
/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/
Peak plasma levels occurred in male dogs between 2 and 4 hours after dosing. Peak plasma levels were approximately 55-65 ug flumequine equivalents/mL of plasma after an oral dose of 25 mg/kg bw. Approximately one-half the concentration of total radioactivity for the first 12 hours following administration corresponded to unchanged drug. The disappearance of flumequine from the plasma appeared to follow multi-exponential kinetics with an initial half-life of about 75 minutes and a terminal beta-phase half-life of 6.5 hours.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
使用碳-14标记的氟喹诺酮对狗和老鼠的研究表明，氟喹诺酮在口服给药后容易被吸收。
Studies with (14)C-flumequine in dogs and rats indicated that flumequine is readily absorbed following oral administration.
There was a significant difference in the mode of drug excretion between dogs and rats. In dogs, 55-75% of the dose was excreted in the faeces compared to only 10-15% in rats. Less than 5% of the dose was present in the urine of dogs as unchanged drug while another 13-15% was excreted as a conjugate of flumequine. In rats, 20-36% of the dose was excreted in urine as unchanged drug and very little as a conjugate of flumequine. The concentrations of free flumequine in the 24-hour urine sample were about the same for both species.
Total recovery of the orally administered dose was achieved in the urine and feces within 5 days after dosing in both species /rats and dogs/, indicating that very little residual flumequine and/or metabolites were retained in the tissues.
Synthesis, absolute configuration and intermediates of 9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (flumequine)
摘要：
The antibacterial agent 9-fluoro-6,7-dihydro-5-methyl- 1-oxo- 1H,5H-benzo[iJ]quinolizine-2-carboxylic acid (flumequine) was synthesized in optically active form from 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (FTHQ). Racemic FTHQ was resolved with the enantiomers of 3-bromocamphor-8-sulfonic acid. The configurations were established by X-ray structures of the two diastereoisomeric salts. Enantiomeric excesses were determined by H-1 NMR analysis. (C) 1999 Elsevier Science Ltd. All rights reserved.
Kappa agonist compounds and pharmaceutical formulations thereof
申请人：——
公开号：US20030144272A1
公开（公告）日：2003-07-31
Compounds having kappa opioid agonist activity, compositions containing them and method of using them as analgesics are provided.
The compounds of formulae I, II, IIA, III, IIIA, IIIB, IIIB-i, IV and IVA have the structure:
1
2
wherein
R
1
, R
2
, R
3
, R
4
; and
X, X
4
, X
5
, X
7
, X
9
;
Y, Z and n are as described in the specification.
[EN] COMPOUNDS (CYSTEIN BASED LIPOPEPTIDES) AND COMPOSITIONS AS TLR2 AGONISTS USED FOR TREATING INFECTIONS, INFLAMMATIONS, RESPIRATORY DISEASES ETC.<br/>[FR] COMPOSÉS (LIPOPEPTIDES À BASE DE CYSTÉINE) ET COMPOSITIONS EN TANT QU'AGONISTES DES TLR2 UTILISÉS POUR TRAITER DES INFECTIONS, INFLAMMATIONS, MALADIES RESPIRATOIRES ENTRE AUTRES
申请人：IRM LLC
公开号：WO2011119759A1
公开（公告）日：2011-09-29
The invention provides a novel class of compounds viz. generally lipopeptides like Pam3CSK4, immunogenic compositions and pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with Toll-Like Receptors 2. In one aspect, the compounds are useful as adjuvants for enhancing the effectiveness a vaccine.
GLUTATHIONE-CHOLESTEROL DERIVATIVES AS BRAIN TARGETING AGENTS
申请人：South Dakota Board of Regents
公开号：US20200048305A1
公开（公告）日：2020-02-13
The present invention describes compositions containing cholesterol-linker-glutathione conjugates for targeting the brain by overcoming barrier entry to the CNS through the blood brain barrier (BBB), including micelle and liposome forms of such compositions. In addition, methods for treating subjects by administering such compositions are also disclosed.
Compounds that are Analogs of Squalamine, Used as Antibacterial Agents
申请人：VIRBAC
公开号：US20180042942A1
公开（公告）日：2018-02-15
The invention relates to compounds of formula (I), to the pharmaceutical compositions comprising same, and to the use thereof in the treatment of bacterial, fungal, viral and parasitic infections or in the treatment of cancer in humans or animals. In formula (I), R1 and R2 are as defined in claim
1.
Carboxamide and amino derivatives and methods of their use
申请人：Dolle E. Roland
公开号：US20050113294A1
公开（公告）日：2005-05-26
Carboxamide and amino derivatives, pharmaceutical compositions containing these compounds, and methods for their pharmaceutical use are disclosed. In certain embodiments, the carboxamide derivatives are ligands of the δ opioid receptor and are useful, inter alia, for treating and/or preventing pain, anxiety, gastrointestinal disorders, and other δ opioid receptor-mediated conditions.
