The metabolism of PT807-HCl in male and female rats was qualitatively similar. Only minor amounts of parent, PT807 (0.400.8% dose), were identified in urine and feces. The primary metabolite identified in excreta was the carboxylic acid metabolite (M-7) which then undergoes conjugation to glucuronic acid (m-3) or hydroxylation on the alkyl portion of the molecule (RU-10b). Other secondary reactions involved in the metabolism of PT807 included deamination, N-de-ethylation, hydroxylation of the N-ethyl group, and oxidation of the benzyl carbon.
Four rats/sex were administered a single oral dose of [14C-]-PT807-HCl (specific activity 20.9 mCi/mmol; radiochemical purity, 99.68%) at the rate of 200 mg/kg body weight. After 168 hours (7-days) post dose, the rats were sacrificed, and the total radiolabelled residues excreted and retained in the blood and tissues were determined. The majority of the radioactivity was eliminated in urine (ca. 74-79%) with a small amount excreted in feces (ca. 14-18%). No apparent sex difference is observed in metabolism of the test material. No 14C-volatiles were found in the expired air (< 0.01%), and no significant levels of residues were retained in the tissues (ca. 0.21-0.34%). The excretion of 14C was rapid and majority of the radioactivity was excreted within 24-48 hours. The average recovery of the administered dose was > 92%. Twenty eight metabolites including a.i. were found in the excreta, of which 12 (accounting for ca. 95% of the total metabolites) were identified.
The metabolism of PT807-HCl in male and female rats was qualitatively similar. Only minor amounts of parent, PT807 (0.400.8% dose), were identified in urine and feces. The primary metabolite identified in excreta was the carboxylic acid metabolite (M-7) which then undergoes conjugation to glucuronic acid (m-3) or hydroxylation on the alkyl portion of the molecule (RU-10b). Other secondary reactions involved in the metabolism of PT807 included deamination, N-de-ethylation, hydroxylation of the N-ethyl group, and oxidation of the benzyl carbon.
Four rats/sex were administered a single oral dose of [14C-]-PT807-HCl (specific activity 20.9 mCi/mmol; radiochemical purity, 99.68%) at the rate of 200 mg/kg body weight. After 168 hours (7-days) post dose, the rats were sacrificed, and the total radiolabelled residues excreted and retained in the blood and tissues were determined. The majority of the radioactivity was eliminated in urine (ca. 74-79%) with a small amount excreted in feces (ca. 14-18%). No apparent sex difference is observed in metabolism of the test material. No 14C-volatiles were found in the expired air (< 0.01%), and no significant levels of residues were retained in the tissues (ca. 0.21-0.34%). The excretion of 14C was rapid and majority of the radioactivity was excreted within 24-48 hours. The average recovery of the administered dose was > 92%. Twenty eight metabolites including a.i. were found in the excreta, of which 12 (accounting for ca. 95% of the total metabolites) were identified.
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
Basic treatment: Establish a patent airway. 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 normal saline 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 ... . /Poison A and B/
Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Technical PT807-HCl (50% a.i. at 99% purity) was admixed to the feed at dose levels of 0 (basal diet only), 750, 2500, or 7500 ppm (0, 25, 71, and 211 mg/kg/day, respectively, for males and 0, 26, 78, and 233 mg/kg/day, respectively, for females) and fed to 4 beagle dogs per sex per dose level for 91 days. One male at 7500 ppm was sacrificed on day 70 after being found in a moribund condition. No treatment-related clinical signs were observed except for thinness, slow breathing, lethargy, irregular gait, hunched appearance, and abnormal (pale) gums, paleness (entire body), emaciation, poor condition, hypothermia (entire body), and dehydration (entire body) in one high dose male and irregular gait, thinness, and poor condition in one high dose female. A treatment-related decrease in mean body weight gain was observed in both sexes at 7500 ppm. Treatment-related decreases in mean relative testis/epididymis and ovary weights were observed at 7500 ppm. Microscopic examination revealed treatment-related effects in the testes/epididymides (including degenerated seminal product in the seminiferous tubules, arrested maturation of the germinal epithelium, and severe oligospermia) and the ovaries (lack of signs of estrus) at 7500 ppm (possible adverse effect). NOEL (M)= 71 mg/kg/day (2500 ppm) and (F)=78 mg/kg/day (2500 ppm) both based on decreased mean relative reproductive organ weight and microscopic findings.
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Technical PT807-HCl (55.3% a.i. at 100% purity), diluted in acidified deionized water, was administered orally by gavage to 10 Sprague-Dawley Crl:CD (SD)BR rats per sex per dose at dose levels of 0 (vehicle), 30, 300, or 600 mg/kg/day once per day for 13 weeks. 1/10 females at 300 mg/kg/day, and 6/10 males and 7/10 females at 600 mg/kg/day died during the study interval. Treatment-related signs of toxicity including tremors, convulsions, incoordination, abnormal gait, and salivation were observed in both sexes at 300 and 600 mg/kg/day throughout the duration of the study. In addition, incidences of salivation were observed in 10% to 40% of the female animals at 30 mg/kg/day from week 2 through week 13. A treatment-related increase in mean relative liver weight in both sexes at 300 and 600 mg/kg/day was observed. Macroscopic and microscopic examinations revealed no treatment-related abnormalities. Possible adverse effect: Treatment-related incidences of tremors, convulsions, abnormal gait, and incoordination throughout the duration of the study at 300 and 600 mg/kg/day.
(14C)-PT807-HCl was readily absorbed from the GI tract of male and female rats. Within 24 hours of dosing, 75.2 and 66.5% of the administered dose was recovered in urine (plus cage wash) from males and females, respectively. Within 168 hours, 79.3% of the dose was recovered in urine (plus cage wash) and 13.8% was recovered in feces from males, and 73.8% was recovered in urine (plus cage wash) and 18.3% was recovered in feces from females. Only <0.34% of the dose was associated with tissues, and no radioactivity was found in expired air. Radioactivity was generally 2-3x higher in tissues and blood of females than males, except in kidney and spleen. However, the pattern of distribution among tissues was similar between the sexes. With the exception of the uterus, radioactivity was highest in liver, spleen, and carcass and lowest in fat and gonads. In females, radioactivity was highest in the uterus and was >2.3x higher than the liver and carcass.
(14C)-PT807-HCl was readily absorbed from the GI tract of male and female rats. Within 24 hours of dosing, 75.2 and 66.5% of the administered dose was recovered in urine (plus cage wash) from males and females, respectively. Within 168 hours, 79.3% of the dose was recovered in urine (plus cage wash) and 13.8% was recovered in feces from males, and 73.8% was recovered in urine (plus cage wash) and 18.3% was recovered in feces from females. Only <0.34% of the dose was associated with tissues, and no radioactivity was found in expired air. Radioactivity was generally 2-3x higher in tissues and blood of females than males, except in kidney and spleen. However, the pattern of distribution among tissues was similar between the sexes. With the exception of the uterus, radioactivity was highest in liver, spleen, and carcass and lowest in fat and gonads. In females, radioactivity was highest in the uterus and was >2.3x higher than the liver and carcass.
来源:Hazardous Substances Data Bank (HSDB)
文献信息
SYSTEMIC PLANT CONDITIONING COMPOSITION
申请人：REGENTS OF THE UNIVERSITY OF MINNESOTA
公开号：EP1991054A2
公开（公告）日：2008-11-19
Systemic plant conditioning composition
申请人：Levar E. Thomas
公开号：US20070104751A1
公开（公告）日：2007-05-10
This invention relates to compositions and methods facilitating availability, uptake and translocation of active ingredients in plants. More specifically, this invention relates to the surprising discovery that the application to the roots, such as administration to the soil surrounding plants, of two or more osmolytes in combination with an active ingredient, either simultaneously or within a short time of each other, results in an induction of translocation of active ingredient from the roots systemically into the plant.
US8492312B2
申请人：——
公开号：US8492312B2
公开（公告）日：2013-07-23
[EN] SYSTEMIC PLANT CONDITIONING COMPOSITION<br/>[FR] COMPOSITION DE CONDITIONNEMENT DE PLANTE SYSTEMIQUE
申请人：UNIV MINNESOTA
公开号：WO2007058874A2
公开（公告）日：2007-05-24
[EN] This invention relates to compositions and methods facilitating availability, uptake and translocation of active ingredients in plants. More specifically, this invention relates to the surprising discovery that the application to the roots, such as administration to the soil surrounding plants, of two or more osmolytes in combination with an active ingredient, either simultaneously or within a short time of each other, results in an induction of translocation of active ingredient from the roots systemically into the plant. [FR] La présente invention concerne des compositions et des procédés facilitant la disponibilité, la prise et la translocation des substances actives dans les plantes. Plus spécifiquement, la présente invention concerne la découverte surprenante consistant en ce que l'application aux racines, telle que l'administration au sol environnant des plantes, de deux ou plusieurs osmolytes en combinaison avec une substance active, de manière simultanée ou rapidement les uns à la suite des autres, entraîne une induction de la translocation de la substance active des racines systémiquement dans la plante.
