The oxidative metabolism of monensin, an ionophore antibiotic extensively used in veterinary practice as a coccidiostat and a growth promoter, was studied in hepatic microsomal preparations from horses, pigs, broiler chicks, cattle and rats. As assayed by the measurement of the amount of the released formaldehyde, the rate of monensin O-demethylation was nearly of the same order of magnitude in all species, but total monensin metabolism, which was estimated by measuring the rate of substrate disappearance by a high-performance liquid chromatography (HPLC) method, was highest in cattle, intermediate in rats, chicks and pigs, and lowest in horses. When expressed as turnover number (nmol of metabolized monensin/min nmol cytochrome P450-1), the catalytic efficiency (chick >> cattle >> pig approximately rat > horse) was found to correlate inversely with the well known interspecies differences in the susceptibility to the toxic effects of the ionophore, which is characterized by an oral LD50 of 2-3 mg/kg bodyweight (bw) in horses, 50-80 mg/kg bw in cattle and 200 mg/kg bw in chicks. Chick and cattle microsomes also displayed both the highest catalytic efficiency toward two P450 3A dependent substrates (erythromycin and triacetyloleandomycin) and the highest immunodetectable levels of proteins cross-reacting with anti rat P450 3A1/2. ...
The O-demethylation of monensin is greater in microsomes from phenobarbital-treated rats than in untreated rats and is dependent on reduced nicotinamide adenine dinucleotide phosphate (NADPH), suggesting that monensin is a cytochrome P450 (CYP) enzyme substrate. The oxidative metabolism of monensin appears to occur at least in part by CYP3A, since treatment of rat hepatic microsomes with chemical inducers of CYP3A significantly increased monensin O-demethylation. It has been speculated that competition between monensin and other CYP3A substrates may explain accidental poisonings that have occurred in several domestic species following coadministration of monensin and other chemotherapeutic agents, since monensin metabolism is significantly decreased in the presence of other CYP3A substrates in rats.
Monensin metabolites result mainly from O-demethylation at the methoxylic group and/or hydroxylation at several places on the ionophore backbone. ... Although it is difficult to obtain sufficient monensin metabolites to test activity, four metabolites generated by rat liver microsomes, including a by-product of monensin production (O-desmethylmonensin), have been tested and have at least 10- to 20-fold less antibacterial, anticoccidial, cytotoxic, cardiotonic and ionophoric activity than the parent compound, indicating that metabolism eliminates most of the biological activity of monensin.
Monensin is extensively metabolized in the liver, producing more than 50 different metabolites that have been detected in the liver, bile and faeces of chickens, cattle, rats, pigs, dogs, turkeys, sheep and horses. In most species (chickens, rats, dogs, turkeys and pigs), less than 10% of monensin is excreted as the parent compound, whereas a study in calves indicated that 50-68% of the (14)C identified in the feces was unmetabolized monensin. This difference in amount of metabolized monensin may have been a result of differences in absorption of the molecule in different species. Total microsomal monensin metabolism, estimated by measuring the rate of substrate disappearance by a high-performance liquid chromatographic (HPLC) analytical method, is highest in cattle, intermediate in rats, chickens and pigs, and lowest in horses. The pattern of metabolites is qualitatively similar between laboratory and non-laboratory animal species, although quantitative differences exist. No single metabolite dominates the metabolic profile.
The metabolism of monensin sodium in human liver microsomes has been compared with metabolism in the microsomes of horses and dogs. A pooled human microsomal sample from multiple donors (male and female, Caucasian, Hispanic and African American, 15-66 years old), pooled dog microsome sample and equine microsomes from a single donor were incubated with 0.5, 1 and 10 ug monensin/mL in the presence or absence of NADPH. The metabolite profiles were examined at 0, 5, 10, 20, 40 and 60 min by liquid chromatography/mass spectrometry (LC-MS) analysis. Monensin was metabolized by first-order kinetics in all species, and metabolism was extensive (93-99% by 60 min). The turnover of monensin in humans was similar to that in dogs, whereas the turnover in horses was only 10% of that in dogs and humans.
IDENTIFICATION AND USE: Monensin is a polyether carboxylic ionophore antibiotic. Monensin is a mixture of four analogues, A, B, C and D, with monensin A being the major component (98%). Depending on the method of purification, monensin can exist in mycelial, crystalline and recrystallized forms. It is used for the treatment of coccidiosis in poultry (chickens, turkeys and quail) and ruminants (cattle, sheep and goats). Monensin is also used to control ketosis and bloat in cattle and as a growth promoter feed additive in cattle and sheep. Monensin is mainly effective against Gram-positive bacteria. HUMAN EXPOSURE AND TOXICITY: 17 year-old boy who developed myoglobinuria, renal failure and death 11 days after ingesting sodium monensin. In another case, a patient took a dose of monensin three times higher than a dose considered lethal for cattle and developed a clinical picture similar to that reported in veterinary medicine. There was an early and extremely severe rhabdomyolysis followed by acute renal failure, heart failure, and death. The main changes observed at autopsy were extensive skeletal muscle necrosis, complement deposition at the myocardial level, pulmonary edema, & acute tubular damage. ANIMAL STUDIES: Acute toxicity was examined in mature rhesus monkeys. Pairs of monkeys were exposed to a single dose of 20, 40 or 60 mg monensin/kg bw by gavage and were monitored for 7 days. All animals survived and developed diarrhea within 24 hr after dosing. Adult goats were administered sodium monensin, 13.5 mg kg (-1), daily for five consecutive days via gastric gavage. Monensin exposure caused diarrhea, tachycardia and reduction in ruminal movements and body temperature. In an inhalational exposure study, rats were exposed to either normal air or air containing particulate mycelial monensin sodium at a mean concentration of 79 mg/cu m for 2 weeks (1 hr/day, 5 days/week). Nine of 10 treated females became anorexic and lost weight during the 2nd week of the study. Slight focal myositis of the skeletal muscle was seen in two males and two females but none of the controls. Multifocal myocardial changes were observed in male rats treated with monensin. In a subchronic study, male and female mice were fed diets containing 0, 37.5, 75, 150 or 300 mg mycelial monensin sodium/kg for 3 months. A dose-dependent decrease in body weight gain occurred in all dose groups. At the end of the study, the decrease ranged from 27% and 21% in the lowest dose group in females and males, respectively, to 99% in the highest dose group in both sexes. In a chronic toxicity study, male and female rats were maintained on a diet containing 25, 56 or 125 mg crystalline monensin sodium/kg, whereas control rats received a normal diet for 2 years. Body weight and weight gain were significantly decreased in animals receiving 125 mg monensin/kg in their diet and were transiently decreased during the first 4 months in rats in the middle dose group. Benign and malignant neoplasms were observed in treated and untreated animals, with no association between monensin administration and neoplasm type or severity. Monensin is toxic in horses. Clinical signs were tachycardia and cardiac arrythmia, groaning, incoordination, sudoresis, recumbency, and paddling movements with the limbs before death. Main necropsy findings were in the skeletal muscles and myocardium. The effects of exposure to monensin during development were studied in rats. Groups of female rats received monensin at concentrations of 0, 100 or 300 mg/kg until premating weights achieved 185 g and during pregnancy and lactation. Female body weight was significantly decreased in the highest dose group after 8 days of treatment. The body weights of male and female pups in the highest dose group were reduced from postnatal day 10 until postnatal day 21. Male offspring in the low dose group showed body weight reduction only on postnatal day 21. No external signs of malformation were detected in the pups. A study was also undertaken to explore the effects of monensin, a potent Golgi disturbing agent on male fertility. Male rats were administered monensin at the dose levels of 2.5, 5, and 10 mg/kg b wt. Animals were sacrificed after 67 days of the treatment. The findings from electron microscopy such as membrane disruption, swelling and disintegration of Golgi apparatus strongly suggest the interference of monensin with the functioning of Golgi apparatus in the spermatogenic cells. Data from the sperm number and motility as well as the fertility studies and the resulted litter size further points towards the antifertility effects of monensin in male rats. Genotoxicity tests were negative.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
副作用
神经毒素 - 其他中枢神经系统神经毒素
Neurotoxin - Other CNS neurotoxin
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
An experiment was carried out with male broiler chicks to evaluate the combined effect of monensin (150 mg/kg) & the growth promoters (GPs) Zn bacitracin (BAC, 50 mg/kg), virginiamycin (VIR, 25 mg/kg) & avoparcin (AVO, 20 mg/kg) fed from 7 to 28 days of age on performance, utilization of dietary nutrients, yield of defeathered eviscerated carcases (DEC) & size of various organs. The effect of the GPs in the monensin-unsupplemented diets fed up to 49 d of age on performance & carcase was also determined. Monensin significantly (P < 0.05) depressed food intake, weight gain & food efficiency from 7 to 28 d of age. None of the GPs was able to counteract these effects. However, AVO slightly ameliorated them. AVO also significantly increased food intake & improved gain & food efficiency during 7 to 28, but not 28 to 49 or 7 to 49 d of age. VIR & BAC did not affect performance in either age period. Monensin did not affect the utilisation of dietary dry matter, fat or energy, but it significantly decreased nitrogen utilisation. AVO improved nitrogen & fat utilisation & increased dietary AME(n) content. AME(n) was also increased by VIR. The utilisation of these nutrients was not affected by the interactions between monensin & the GPs. Monensin did not affect yield of the DEC or the relative liver size at 31 d of age. It significantly increased the relative length of the small intestine (SI) & decreased its specific weight. AVO significantly increased yield at 31, but not at 53 d of age. BAC & VIR did not affect this variable. AVO & VIR, but not BAC, at both age periods reduced, at times significantly, the size, length & specific weight of the SI. Our conclusions: BAC, VIR & AVO do not counteract the toxic effect of monensin. The effect of GPs in improving performance decreases & even disappears with age, while their effect in reducing the size of the SI is still evident in 49 day old birds.
The characteristics of the toxic interaction between monensin & tiamulin were investigated in rats. A three-day comparative oral repeated-dose toxicity study was performed in Phase I, when the effects of monensin & tiamulin were studied separately (monensin 10, 30, & 50 mg/kg or tiamulin 40, 120, & 200 mg/kg body weight, respectively). In Phase II, the two compounds were administered simultaneously to study the toxic interaction (monensin 10 mg/kg & tiamulin 40 mg/kg bw, respectively). Monensin proved to be toxic to rats at doses of 30 & 50 mg/kg. Tiamulin was well tolerated up to the dose of 200 mg/kg. After combined administration, signs of toxicity were seen (including lethality in females). Monensin caused a dose-dependent cardiotoxic effect & vacuolar degeneration of the skeletal muscles in the animals given 50 mg/kg. Both compounds exerted a toxic effect on the liver in high doses. After simultaneous administration of the two compounds, there was a mild effect on the liver (females only), hydropic degeneration of the myocardium & vacuolar degeneration of the skeletal muscles. The alteration seen in the skeletal muscles was more marked than that seen after the administration of 50 mg/kg monensin alone.
The pharmacokinetics of monensin, including half-life, apparent volume of distribution, total body clearance, systemic bioavailability and tissue residues were determined in broiler chickens. The drug was given by intracrop and intravenous routes in a single dose of 40 mg/kg body weight. Following intravenous injection the kinetic disposition of monensin followed a two compartments open model with absorption half life of 0.59 hr, volume of distribution of 4.11 l/kg and total body clearance of 28.36 ml/kg/min. The highest serum concentrations of monensin were reached 0.5 hr after intracrop dosage with an absorption half-life of 0.27 hr and an elimination half life of 2.11 hr. The systemic bioavailability was 65.1% after intracrop administration. Serum protein-binding tendency of monensin calculated in vitro was 22.8%. Monensin concentrations in the serum and tissues of chickens after a single intracrop dose of pure monensin (40 mg/kg body weight) were higher than those after feeding a supplemented monensin premix (120 mg/kg) for 2 weeks. Monensin residues were detected in tested body tissues, collected 2, 4, 6 and 8 hr after oral administration. The highest concentration was found in the liver. In addition, monensin residues were detected only in liver, kidney and fat 24 hr after the last oral dose. No monensin residues could be detected in tissues after 48 hr, except in liver which cleared completely by 72 hr.
Six chickens were exposed to (3)H-monensin sodium at 121 mg/kg in the diet for 2 days. Only 52-73% of the radioactivity was recovered; of this, 97% was found in the faeces. The reason for poor radioactivity balance was unknown. /Monensin sodium/
Broiler chickens were administered (14)C-monensin sodium at a concentration of 120 mg/kg in the diet for 4 days (two males, three females) or 6 days (three males, three females). Six hours after withdrawal from the treated feed, radioactivity was detected in the liver, kidney, fat and skin, with the highest level detected in the liver (0.5 mg/kg liver). No radioactivity was detected in the muscle tissue. /Monensin sodium/
Ten White Leghorn roosters and two White Leghorn hens were exposed orally to a single dose of (14)C-monensin in a gelatine capsule (dose range: 2.6-100 mg). Some birds were colostomized, whereas others had bile cannulae inserted. Absorption in the chickens ranged from 11% to 31% of the ingested (14)C-monensin. The primary route of excretion was in the faeces, with a small proportion excreted in the urine and by respiration.
Metal Ion‐Induced Large Fragment Deactivation: A Different Strategy for Site‐Selectivity in a Complex Molecule
摘要：
Complex natural product functionalizations generally involve the use of highly engineered reagents, catalysts, or enzymes to react exclusively at a desired site through lowering of a select transition state energy. In this communication, we report a new, complementary strategy in which all transition states representing undesirable sites in a complex ionophore substrate are simultaneously energetically increased through the chelation of a metal ion to the large fragment we wish to neutralize. In the case of an electrophilic, radical based fluorination reaction, charge repulsion (electric field effects), induced steric effects, and electron withdrawal provide the necessary deactivation and proof of principle to afford a highly desirable natural product derivative. We envisage that many other electrophilic or charge based synthetic methods may be amenable to this approach as well.
Imaging compounds, methods of making imaging compounds, methods of imaging, therapeutic compounds, methods of making therapeutic compounds, and methods of therapy
申请人：Chen Xiaoyuan
公开号：US20080267882A1
公开（公告）日：2008-10-30
Embodiments of the present disclosure provide for RGD compounds that include a multimeric RGD (arginine-glycine-aspartic acid (Arg-Gly-Asp)) peptide, methods of making the RGD compound, pharmaceutical compositions including RGD compound, methods of using the RGD compositions or the pharmaceutical compositions including RGD compositions, methods of diagnosing and/or targeting angiogenesis related disease and related biological events, kits for diagnosing and/or targeting angiogenesis related disease and related biological events, and the like. In addition, the present disclosure includes compositions used in and methods relating to non-invasive imaging (e.g., positron emission tomography (PET) imaging) of the RGD compounds in vivo.
[EN] ISOTOPE ENHANCED AMBROXOL FOR LONG LASTING AUTOPHAGY INDUCTION<br/>[FR] AMBROXOL À ISOTOPE AMÉLIORÉ POUR INDUCTION D'AUTOPHAGIE DURABLE
申请人：STC UNM
公开号：WO2018148113A1
公开（公告）日：2018-08-16
The present invention is directed to 13C and/or 2H isotope enhanced ambroxol ("isotope enhanced ambroxol") and its use in the treatment of autophagy infections, especially mycobacterial and other infections, disease states and/or conditions of the lung, such as tuberculosis, especially including drug resistant and multiple drag resistant tuberculosis. Pharmaceutical compositions comprising isotope enhanced amhroxol, alone or in combination with an additional bioactive agent, especially rifamycin antibiotics, including an additional autophagy modulator (an agent which is active to promote or inhibit autophagy), thus being useful against, an autophagy mediated disease state and/or condition), especially an antophagy mediated disease state and/or condition which occurs in the lungs, for example, a Mycobacterium infection. Chronic Obstructive Pulmonary Disease (COPD), asthma, pulmonary fibrosis, cystic fibrosis, Sjogren's disease and lung cancer (small cell and non-small cell lung cancer, among other disease states and/or conditions, especially of the lung. Methods of treating autophagy disease states and/or conditions, especially including autophagy disease states or conditions which occur principally in the lungs of a patient represent a further embodiment of the present invention. An additional embodiment includes methods of synthesizing compounds according to the present invention as otherwise disclosed herein.
USE OF NITROOXY ORGANIC MOLECULES IN FEED FOR REDUCING METHANE EMISSION IN RUMINANTS, AND/OR TO IMPROVE RUMINANT PERFORMANCE
申请人：Duval Stephane
公开号：US20140147529A1
公开（公告）日：2014-05-29
The present invention relates to a method for reducing the production of methane emanating from the digestive activities of a ruminant and/or for improving ruminant animal performance by using, as active compound at least one organic molecule substituted at any position with at least one nitrooxy group, or a salt thereof, which is administrated to the animal together with the feed. The invention also relates to the use of these compounds in feed and feed additives such as premix, concentrates and total mixed ration (TMR) or in the form of a bolus.
FUSED BICYCLIC HETEROCYCLE DERIVATIVES AS PESTICIDES
申请人：Bayer Aktiengesellschaft
公开号：US20200383334A1
公开（公告）日：2020-12-10
The invention relates to novel compounds of the formula (I)
in which Aa, Ab, Ac, Ad, Q, R
1
and n have the definitions given above,
to their use as acaricides and/or insecticides for controlling animal pests and to processes and intermediates for their preparation.
[EN] INSECTICIDAL METHODS USING NITROGEN-CONTAINING HETEROAROMATIC COMPOUNDS<br/>[FR] PROCÉDÉS INSECTICIDES UTILISANT DES COMPOSÉS HÉTÉROAROMATIQUES CONTENANT DE L'AZOTE
申请人：BASF SE
公开号：WO2011064188A1
公开（公告）日：2011-06-03
Insectical methods using nitrogen containing heteroaromatic compounds The present invention relates to new insecticidal methods of using nitrogen-containing heteroaromatic compounds of the formula (I), wherein A, E, G, M, W, Y, X, R1 and R2 are defined as in the description, and to their enantiomers, diastereomers and agriculturally and veterinary acceptable salts. The present invention relates to methods of administering and applying such Pyridine compounds of formula I for insecticidal use and purposes in agriculture and in the veterinary field. The invention relates also to new derivatives of Pyridine compounds of formula I.
