Seven-week-old pigs received unlabelled carbadox in feed at the rate of 50 g/ton for several weeks followed by a single oral dose of (14)C-carbadox labelled in the carbonyl position via stomach tube. The following evaluations were made: expired air was evaluated for (14)CO2, labelled material in liver and urine was evaluated to determine if it was methyl carbazate-related, and plasma and urine were evaluated for free hydrazine. Maximum plasma concentrations of radiolabelled material occurred at approximately 3 hours. While early plasma concentrations were similar to those found for ring-labelled carbadox, concentrations at 24 hours remained somewhat higher. Approximately 50% of the radiolabelled material in the plasma at 3 hours was identified as carbadox, while methyl carbazate was estimated to be 30%. The major route of radiolabel excretion was urinary. However, less than half the total amount recovered with ring-labelled carbadox was recovered from carbonyl- labelled carbadox (37% vs 88%). The reason for this is the apparently high conversion of the radiolabel to CO2 (verified in the rat as up to 36%). Radiolabelled material equivalent to 0.1 - 0.34 ppm carbadox was present in liver at 5 days. The authors concluded that some of this material was incorporated CO2 (potentially 25%). The pig receiving 7 mg/kg was found to have eliminated 7% of the dose as free hydrazine in the urine at 24 hours, while pigs receiving lesser doses were not found to have any identifiable hydrazine in their urine.
Seven-week-old swine received feed containing 50 g/ton of unlabelled carbadox for several weeks, then received a single oral dose of either 3.5 mg/kg or 0.8 mg/kg of (14)C-carbadox labelled in the phenyl ring. Peak radioactivity was observed in plasma approximately 3 hours after dosing. The following were identified in plasma at 5-8 hours post dose: carbadox (13%), desoxycarbadox (9-19%), carbadoxaldehyde (13%), and quinoxaline-2-carboxylic acid (19%) (all expressed in terms of total plasma radioactivity). The presence of carbadoxaldehyde in stomach contents was confirmed. Carbadox was rapidly eliminated. Approximately 2/3 of the dose was eliminated in the urine and the remainder in the feces (total of approximately 90%) within 48-72 hours. Radioactivity equivalent to approximately 0.1 ppm carbadox was found to be retained in the liver at 14 days post dose. Attempts to identify this residual radioactivity were not successful. The only metabolite identified in liver after 24 hours was the major urine-eliminated metabolite, quinoxaline-2-carboxylic acid.
IDENTIFICATION AND USE: Carbadox is an antimicrobial antibiotic used for the control of swine dysentery (vibrionic dysentery, bloody scours or hemorrhagic dysentery); control of bacterial swine enteritis (salmonellosis or necrotic enteritis caused by salmonella choleraesuis); increased rate of weight gain and improved feed efficiency in swine. HUMAN EXPOSURE AND TOXICITY: Carbadox tested positive in a chromosomal damage test of in vitro human lymphocytes at 0 - 250 ug/mL. Carbadox was also found to be reactive towards human serum albumin. ANIMAL STUDIES: The short-term toxicity of carbadox was studied by dosing dogs 6 days/week for three weeks. Dogs were initially dosed with 25 or 50 mg/kg bw/day carbadox via oral capsule. These doses were later reduced to 10 and then 15 mg/kg bw/day due to emesis. The dogs lost weight and had elevated SGPT's. Weanling rats were dosed for 30 days at 50 mg/kg bw/day and 100 mg/kg bw/day. Carbadox was administered in the diet. A dose-dependent decrease in weight gain and food- consumption were noted. Male rats and female rats of the same strain received 2.5, 1.0, or 0 mg/kg bw/day of carbadox in the diet. All parameters evaluated, including histopathologic examination, were within normal limits at 54 weeks. Survival at 2 years was as follows: control - 38%, 1.0 mg/kg bw/day - 45%, 2.5 mg/kg bw/day - 43%. At the 2.5 mg/kg bw/day level 7/27 rats displayed hepatic benign nodular hyperplasia and 7/27 showed peliosis hepatis. At the 1.0 mg/kg bw/day level 1/29 rats was found to have hepatic benign nodular hyperplasia and 3/29 displayed peliosis hepatis. In the control group 3/29 rats had benign nodular hyperplasia and 2/29 had peliosis hepatis. Additionally, an increase in total mammary tumors was reported in the 2.5 mg/kg bw/day dose group, while 2/18 rats receiving carbadox showed evidence of hepatocellular carcinoma. A study was performed to assess the long-term toxicity of carbadox in primates. Twenty-eight monkeys were dosed with carbadox in gelatin capsules 5 days/week. The doses were 20 (5 mg/kg QID), 10 (5 mg/kg BID) or 5 mg/kg bw/day and controls. The diet contained 0.2% isoniazid as prophylaxis for tuberculosis. Elevated transaminase levels were detected at the 3 and 6 month evaluations in both treated and control animals. Carbadox was administered by gavage once daily to pregnant rats at doses of 0 (control), 10, 25, 50 or 100 mg/kg on days 8 through 15 of pregnancy. A significant dose-related decrease in maternal body weight gains during treatment (days 8 through 15 of pregnancy) occurred at doses of 10 mg/kg and above. There was a dose-related decrease in fetal body weight at 25 mg/kg and above. This compound showed not only embryolethal but teratogenic effect. Resorption rates were 81.8% at 100 mg/kg, occurring complete resorptions in five dams, compared with 3.4% resorption rate in the control. In fetal examinations, a significant increase in the incidence of external, skeletal and internal malformations occurred at 100 mg/kg, where the surviving fetuses born to dams with 40-93% resorptions had any malformations, short tail; kinky tail; brachygnathia or ectrodactyly. A weaner ration containing carbadox at concentrations of 331 to 363 mg/kg was accidentally fed to suckling and weaned pigs in an 84 sow herd. Discarded ration was fed to 36 sows. One hundred and sixty five weaner pigs died in a 10 week period with clinical signs including refusal to eat, ill thrift, the passing of hard pelleted feces, posterior paresis and death in seven to nine days. The surviving weaners did not thrive and some males showed poor testicular development. Sows and suckling pigs that consumed the ration also failed to thrive as did the progeny of affected sows. The main pathological finding was obliteration of the zona glomerulosa of the adrenal cortex. Increased potassium and decreased sodium concentrations in serum were the most notable and consistent biochemical findings. Carbadox was examined for mutagenicity in the repair tests with Bacillus subtilis (rec assay) and Salmonella typhimurium (uvr assay) and in the reverse mutation test (TA100 and TA98 of S. typhimurium). Carbadox was positive in the rec and uvr assays, and was highly mutagenic for strains TA100 and TA98. The cytogenetic activity of carbadox was examined by the micronucleus test. Over the entire dose range tested, carbadox induced a statistically significant increase in the number of micronucleated polychromatic erythrocytes in the rat bone marrow. Carbadox tested positive for DNA-modifying effects by the repair test named "rec-assay" with Bacillus subtillis H17 (rec+) and M45 (rec-), and for mutagenicity with Escherichia coli WP2 hcr and 5 Salmonella typhimurium tester strains.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
暴露途径
该物质可以通过吸入其气溶胶和通过摄入被身体吸收。
The substance can be absorbed into the body by inhalation of its aerosol and by ingestion.
The concn of quinoxaline-2-carboxylic acid (QCA) determined by HPLC after alkaline hydrolysis of liver & muscle of swine, ranged from < 3 ng/g to 45.3 ng/g in liver, & from < 3 ng/g to 10.8 ng/g in muscle samples. After the 77th day of therapy QCA was found in samples of liver (9.7 ng/g). Recoveries obtained for both liver & muscle were 70% at 5 ng/g, 77% & 75% respectively at 10 ng/g, & 90% for both liver & muscle at 30 ng/g. This experiment was performed within the frame of the National Monitoring Programme of Residues in Animal Tissues in the Republic of Croatia.
Concns of carbadox & a first metabolite, desoxycarbadox, were measured in contents of the porcine GI tract after in-feed admin of carbadox in therapeutic dosages (100-150 ppm). The levels of carbadox in the relevant parts of the GI tract were found to be lower than the minimal inhibitory concentration (MIC)-values reported for enteropathogenic microorganisms at their sites of action. The presented observations do not provide a pharmacological rationale for the therapeutic use of carbadox in the treatment of dysentery & diarrhea in swine. The carbadox levels encountered in the proximal part of the gut (stomach, duodenum) however, seem to indicate that in-feed admin of 50 ppm carbadox can provide an effective prophylaxis against Treponema hyodysenteriae, a causative agent in swine dysentery. The timecourse of the blood levels of carbadox & desoxycarbadox after in-feed admin of carbadox (50 ppm) & the concn profiles in the GI tract are discussed with regard to the disposition of this drug in pigs.
The elimination of carbadox was studied in rats, swine and monkeys. Pigs received 3.5 mg/kg of (14)C-carbadox after several of weeks of receiving feed containing 50 g/ton of unlabelled carbadox, while rats and monkeys received a single dose of 5 mg/kg (14)C-carbadox. Urine and feces were collected and assayed for radioactivity. The urinary metabolites were evaluated qualitatively using TLC. Nearly all (13/15) of the metabolites present in swine urine are found in rat and monkey urine. One of the other two was a glycine conjugate of quinoxaline-2-carboxylic acid. All species excreted more than 50% of the dose in urine (swine: 74%, monkey: 61%, rat: 54%) during the 72 hour collection period. The following activities were reported for feces during the 72 hour period: swine, 17%, monkey, 8-10%, and rat, 29%. Total excretion appeared to be in the 70-90% range over the 72 hour period. The author concluded that the distribution of radioactivity was similar in the three species.
[EN] BORON-CONTAINING SMALL MOLECULES AS ANTI-PROTOZOAL AGENT<br/>[FR] PETITES MOLÉCULES BORÉES EN TANT QU'AGENT ANTI-PROTOZOAIRE
申请人：ANACOR PHARMACEUTICALS INC
公开号：WO2011116348A1
公开（公告）日：2011-09-22
This invention provides, among other things, novel compounds useful for treating protozoal infections, pharmaceutical compositions containing such compounds, as well as combinations of these compounds with at least one additional therapeutically effective agent. The compounds are of the formula, wherein Y' is a halogen, Y is halosubstituted alkyl, or a salt thereof.
[EN] BORON-CONTAINING SMALL MOLECULES AS ANTIPROTOZOAL AGENTS<br/>[FR] PETITES MOLÉCULES CONTENANT DU BORE EN TANT QU'AGENTS ANTI-PROTOZOAIRES
申请人：ANACOR PHARMACEUTICALS INC
公开号：WO2011022337A1
公开（公告）日：2011-02-24
This invention provides novel compounds of the following formula useful for treating protozoal infections, pharmaceutical compositions containing such compounds, as well as combinations of these compounds with at least one additional therapeutically effective agent.
[EN] BORON-CONTAINING SMALL MOLECULES AS ANTIPROTOZOAL AGENTS<br/>[FR] PETITES MOLÉCULES CONTENANT DU BORE EN TANT QU'AGENTS ANTIPROTOZOAIRES
申请人：ANACOR PHARMACEUTICALS INC
公开号：WO2011019612A1
公开（公告）日：2011-02-17
This invention provides, among other things, novel compounds useful for treating protozoal infections, pharmaceutical compositions containing such compounds, as well as combinations of these compounds with at least one additional therapeutically effective agent. The compounds are of formula (I), wherein Z is S or O; and X is selected from the group consisting of substituted phenyl, substituted or unsubstituted heteroaryl, and unsubstituted cycloalkyl, or a salt thereof.
[EN] GOLD COMPOUNDS AND THEIR USE IN THERAPY<br/>[FR] COMPOSÉS D'OR ET LEUR UTILISATION DANS LE CADRE D'UNE THÉRAPIE
申请人：AUSPHERIX LTD
公开号：WO2018220171A1
公开（公告）日：2018-12-06
Compound of formula (I) and pharmaceutically acceptable salts and solvates thereof are described, wherein: Px selected from (P1), (P2) or (P3); The compounds are useful in the prevention or treatment of a bacterial infection.
Defined herein are immunemodulating Formula (1) compounds wherein R1, R2, R3, and W are as defined herein, stereoisomers thereof, and pharmaceutically acceptable salts thereof; and compositions comprising said compounds. The invention also includes methods for treating an inflammatory and/or immunological disease or disorder in an animal by administering a therapeutically effective amount of a Formula (1) compound, stereoisomer thereof, and a pharmaceutically acceptable salt thereof; or use of said compound of Formula (1 ) to prepare a medicament for treating an inflammatory and/or immunological disease or disorder in an animal.
