In urine, only a minor fraction of radioactivity recovered was parent ractopamine. Swine excreted about 4-16% of the parent compound in the urine after a single oral dose of ractopamine. After repeated doses, the amount of unchanged drug increased to 36-85% of total radioactivity in the urine collected on day 4 of a 4-day dosing regimen. In rats injected with (14)C-ractopamine at 9 mg/kg bw intraperitoneally, parent drug represented 22.6% of total urinary radioactivity while only 1.9% of radioactivity was associated with unchanged ractopamine after an oral dose of 9.9 mg/kg bw. The greater proportion of parent drug in the urine after parenteral administration than after oral administration suggests that liver and intestine play an important role in the biotransformation of ractopamine after oral administration. Therefore, although well absorbed from the gastrointestinal tract, the systemic availability of parent ractopamine is reduced, owing to a significant first-pass metabolism.
In the bile of rats dosed orally with (14)C-ractopamine, at least seven different crude metabolite fractions were partitioned chromatographically. Four of the crude metabolite fractions representing 76% of biliary radioactivity were isolated and identified with a sulfate-ester/glucuronic acid diconjugate of ractopamine as the main metabolite (46% of total biliary radioactivity). A further 6% of radioactivity was identified as a monosulfate conjugate and 25% as monoglucuronides of ractopamine. The site of sulfation was established at the C-10' phenol (aromatic ring attached to carbinol). The sulfate conjugation was not stereospecific. The major site of glucuronidation was the C-10 phenol (phenol attached to the nitrogen substituent).
After a withdrawal of 6 hr (rats, dogs) or 12hr (swine, cattle), unchanged ractopamine represented 40, 14, 52, and 13-16% of the total extractable and identifiable residues in the rat, dog, pig, and cattle livers, respectively, and 21, 29, 28-30, and 14% in the kidneys, respectively. After a withdrawal of 24 hr and 72 hr, parent ractopamine represented 14.1% and 3.6% in liver, and 27.5% and 3% of total residues in kidney, respectively, in swine. The remaining residue was found to comprise conjugates of ractopamine. The chromatographic profiles of the (14)C-labelled residue extracts of rat, dog, pig, and cattle liver were qualitatively similar. The laboratory animals had generally a higher percentage of metabolites as residues. Studies in rats and dogs showed that urine from animals dosed with (14)C-ractopamine contained the same four glucuronide metabolites of ractopamine as in pigs. It is concluded that the dogs and rats used in the toxicological studies were exposed to the same metabolites as those found in the edible tissues of pigs and cattle.
In studies in rats, dogs, pigs, and cattle fed (14)C-ractopamine, a fourth metabolite was identified as a glucuronic acid diconjugate. The conjugation of the hydroxyl groups in both the aromatic ring attached to the carbinol and the phenol attached to the nitrogen substituent was not stereospecific.
An 8-wk study of the effects of CLA, rendered animal fats, and ractopamine, and their interactive effects on growth, fatty acid composition, and carcass quality of genetically lean pigs was conducted. Gilts (n = 228; initial BW of 59.1 kg) were assigned to a 2 x 2 x 3 factorial arrangement consisting of CLA, ractopamine, and fat treatments. The CLA treatment consisted of 1% CLA oil (CLA-60) or 1% soybean oil. Ractopamine levels were either 0 or 10 ppm. Fat treatments consisted of 0% added fat, 5% choice white grease (CWG), or 5% beef tallow (BT). The CLA and fat treatments were initiated at 59.1 kg of BW, 4 wk before the ractopamine treatments. The ractopamine treatments were imposed when the gilts reached a BW of 85.7 kg and lasted for the duration of the final 4 wk until carcass data were collected. Lipids from the belly, outer and inner layers of backfat, and LM were extracted and analyzed for fatty acid composition from 6 pigs per treatment at wk 4 and 8. Feeding CLA increased (P < 0.02) G:F during the final 4 wk. Pigs fed added fat as either CWG or BT exhibited decreased (P < 0.05) ADFI and increased (P < 0.01) G:F. Adding ractopamine to the diet increased (P < 0.01) ADG, G:F, and final BW. The predicted carcass lean percentage was increased (P < 0.05) in pigs fed CLA or ractopamine. Feeding either 5% fat or ractopamine increased (P < 0.05) carcass weight. Adding fat to the diets increased (P < 0.05) the 10th rib backfat depth but did not affect predicted percent lean. Bellies of gilts fed CLA were subjectively and objectively firmer (P < 0.01). Dietary CLA increased (P < 0.01) the concentration of saturated fatty acids and decreased (P < 0.01) the concentration of unsaturated fatty acids of the belly fat, both layers of backfat, and LM. Ractopamine decreased (P < 0.01) the i.m. fat content of the LM but had relatively little effect on the fatty acid profiles of the tissues compared with CLA. These results indicate that CLA, added fat, and ractopamine work mainly in an additive fashion to enhance pig growth and carcass quality. Furthermore, these results indicate that CLA results in more saturated fat throughout the carcass.
/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5%葡萄糖水（D5W）/SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%盐水（NS）或乳酸林格液。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...。使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...。/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 /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's 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/
/HUMAN EXPOSURE STUDIES/ The dose-dependent effects of ractopamine on the human cardiovascular system were studied in a limited number of human volunteers (six persons) given ascending single oral doses equal to 67, 133, 200, 333, and 597 ug/kg bw, with an interval of 48 h between doses. Occasional mild to moderate sensations of increase in heart rate and heart pounding were reported at doses of 200, 333, and 597 ug/kg bw. Dose dependent increases in heart rate and cardiac output, and shortened electromechanical systole, as measured by echocardiography, were observed. The changes appeared within the first hour after the administration of ractopamine and values gradually returned to those before treatment. The systolic blood pressure increased in a dose dependent manner. Unlike in monkeys and dogs, ractopamine had little effect on diastolic blood pressure in humans. Only minor cardiovascular effects were observed at 133 ug/kg bw. The NOELs for the relevant cardiac variables were 67 ug/kg bw for electromechanical systole, ventricular ejection time, and maximum velocity of circumferential fibre shortening, 133 ug/kg bw for heart rate and 200 ug/kg bw for cardiac output.
/SIGNS AND SYMPTOMS/ Adverse effects of prolonged therapeutic use of beta-agonists including tachycardia, vasodilation, skeletal muscle tremor, nervousness, metabolic disturbances, and beta-adrenoceptor desensitization are pharmacologically predictable, dose-related and potency-related. Non-pharmacological effects include airway hyper-responsiveness and increased airway inflammation. The incidence and severity of adverse reactions may vary for any given compound. The impact of the R- and S-enantiomers of beta-agonists on adverse effects remains unclear. /beta-Agonists/
/The authors/ investigated the detection, confirmation, and metabolism of the beta-adrenergic agonist ractopamine administered as Paylean to the horse. ... Based on the quantitation ions for ractopamine standards extracted from urine, standard curves showed a linear response for ractopamine concentrations between 10 and 100 ng/mL with a correlation coefficient r > 0.99, whereas standards in the concentration range of 10-1000 ng/mL were fit to a second-order regression curve with r > 0.99. ... Urine concentration of parent ractopamine 24 h post-dose was measured at 360 ng/mL by GC-MS after oral administration of 300 mg. Urinary metabolites were identified by electrospray ionization (+) tandem quadrupole mass spectrometry and were shown to include glucuronide, methyl, and mixed methyl-glucuronide conjugates
In a bioavailability study that complied with good laboratory practice (GLP), groups of five male and five female rats were given [14C]ractopamine as a single oral dose at 0.5, 2.0, or 20 mg/kg bw by gavage. The amount of radiolabel was quantified in samples of plasma and whole blood collected for 24 hr after dosing. Comparison of the area under the curve (AUC) of concentration-time for plasma and whole blood indicated that the bioavailability of (14)C-ractopamine was proportional to dose for males and females at doses up to 2.0 mg/kg bw. Increasing the dose to 20 mg/kg bw resulted in an increase in AUC versus dose in males and, to a more pronounced degree, in females. The absolute bioavailability of (14)C-ractopamine in rats cannot be determined from the results of this study since (14)C-ractopamine was not administered intravenously for comparison of oral and intravenous AUC values.
Experiments were conducted to determine the total residues remaining in ocular tissues of cattle and turkeys after oral administration of (14)C-ractopamine HCl. Twelve cattle were intraruminally dosed with 0.9 mg /kg/d of (14C-)ractopamine HCl for 7 d. Four cattle each were slaughtered with withdrawal periods of 48, 96, and 144 hr. Radioactive residues were not detectable in whole-eye homogenates from the cattle. Eight male and eight female turkeys per treatment received either 7.5, 22.5, or 30 ppm dietary (14)C-ractopamine HCl (0.33, 1.02, and 1.36 mg/kg/d; treatment groups 1, 2, and 3, respectively) for 7 d, and the birds were slaughtered with a 0-d withdrawal period. Eyes were dissected into retina/choroid/schlera (RCS), cornea/iris (CI), and aqueous humor (AH) fractions. Residues in RCS, CI, and AH of treatment 1 turkeys were not detectable. Residues in AH were < 0.02 ppm in treatment groups 2 and 3. Mean residues in RCS ranged from 0.15 to 0.26 ppm, and mean CI residues ranged from <0.09 to 0.17 ppm for treatment groups 2 and 3, respectively.
Ractopamine HCl is a beta-adrenergic leanness-enhancing agent recently approved for use in swine. Depletion of ractopamine in tissues, and elimination of ractopamine and its metabolites in urine, is of interest for the detection of off-label use. The objectives of this study were to measure the residues of ractopamine in livers and kidneys of cattle (n = 6), sheep (n = 6), and ducks (n = 9) after treatment with dietary ractopamine for seven (sheep, ducks) or eight (cattle) consecutive days and to measure the depletion of ractopamine from urine of cattle and sheep. Two cattle and sheep and three ducks were each slaughtered with withdrawal periods of 0, 3, and 7 day. Urine samples were collected daily from cattle and sheep. Tissue ractopamine concentrations were determined using the regulatory method (FDA approved) for ractopamine in swine tissues. Ractopamine residues in urine samples were measured before and after hydrolysis of conjugates. Analysis was performed with HPLC using fluorescence detection after liquid- (hydrolyzed samples) and(or) solid-phase extraction. No residues were detected in duck tissues. Liver residues in sheep averaged 24.0 and 2.6 ppb after 0- and 3-day withdrawal periods, respectively. Sheep liver residues after a 7-day withdrawal period were less than the limit of quantification (2.5 ppb). Sheep kidney residues were 65.1 and undetectable at 0- and at 3- and 7-day, withdrawal periods, respectively. Cattle liver residues were 9.3, 2.5, and undetectable after 0-, 3-, and 7-day withdrawal periods, respectively; kidney residues were 97.5, 3.4, and undetectable at the same respective withdrawal periods. Concentrations of parent ractopamine in sheep urine were 9.8+ or - 3.3 ppb on withdrawal d 0 and were below the LOQ (5 ppb) beyond the 2-day withdrawal period. After the hydrolysis of conjugates, ractopamine concentrations were 5,272 + or - 1,361 ppb on withdrawal d 0 and 178 + or - 78 ppb on withdrawal d 7. Ractopamine concentrations in cattle urine ranged from 164+ or - 61.7 ng/mL (withdrawal d 0) to below the LOQ (50 ppb) on withdrawal day 4. After the hydrolysis of conjugates in cattle urine, ractopamine concentrations were 4,129+ or - 2,351 ppb (withdrawal day 0) to below the LOQ (withdrawal d 6). These data indicate that after the hydrolysis of conjugates, ractopamine should be detectable in urine of sheep as long as 7 day after the last exposure to ractopamine and as long as 5 day after withdrawal in cattle.
[EN] CARBONATE PRODRUGS AND METHODS OF USING THE SAME<br/>[FR] PROMÉDICAMENTS CARBONATÉS ET LEURS MÉTHODES D'UTILISATION
申请人：NEUROGESX INC
公开号：WO2009143297A1
公开（公告）日：2009-11-26
The present invention provides carbonate prodrugs which comprise a carbonic phosphoric anhydride prodrug moiety attached to the hydroxyl or carboxyl group of a parent drug moiety. The prodrugs may provide improved physicochemical properties over the parent drug. Also provided are methods of treating a disease or condition that is responsive to the parent drug using the carbonate prodrugs, as well as kits and unit dosages.
Compounds according to the formula A-B-Z-W, wherein
A is selected from (C
6
-C
10
)aryl-, or (C
1
-C
9
)heteroaryl-, which groups may be optionally substituted;
B is selected from
(a) O, NH, NR
10
, —(CH
2
)
k
—O—, —(CH
2
)
k
—N—, and —(CH
2
)
k
—NR
10
—, where R
10
is (C
1
-C
6
)alkyl and where k is 1 to 6 in each case, or
1
where said group (i) through (iv) is optionally substituted by 1 to 4, preferably 1 to 2, groups selected from (C
1
-C
6
)alkyl, halo, and (C
1
-C
6
)alkyl optionally substituted by 1 to 3 halo atoms wherein one of carbon atoms C
1
, C
2
, C
3
and C
4
of said piperidine or piperazine group is optionally replaced by a carbonyl group;
Z and W are as herein described; and pharmaceutically acceptable salts, solvates or hydrates thereof; pharmaceutical compositions thereof; and methods useful to facilitate secretion of growth hormone(GH) in mammels.
Compounds of formula (I)
and pharmaceutically acceptable salts thereof are agonists at the beta-2 adrenoceptor. They are useful as feed additives for livestock animals.
Somatostatin antagonists and agonists that act at the SST subtype 2 receptor
申请人：——
公开号：US20020091125A1
公开（公告）日：2002-07-11
Compounds according to the formula A-Z-W as herein described, wherein A is selected from the groups consisting of: A′—(CH
2
)
n
—, A′—(CH
2
)
n
SO
2
—, and A′—(CH
2
)
n
CO—, where n is
0
to
4;
and A′ is selected from
(a) (C
6
-C
10
)aryl-, or
(b) (C
1
-C
9
)heteroaryl-; which groups may be optionally substituted; and pharmaceutically acceptable salts, solvates or hydrates thereof; pharmaceutical compositions thereof; and methods useful to facilitate secretion of growth hormone(GH) in mammals.
The present invention relates to compounds of the formula (I)
and pharmaceutically acceptable salts thereof, compositions containing such compounds and the uses of such compounds as antiparasitic agents.
