- Trimethadione metabolism by human liver cytochrome P450: Evidence for the involvement of CYP2E1
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1. Caucasian liver samples were used in this study. N-demethylation of trimethadione (TMO) to dimethadione (DMO) was monitored in the presence of chemical inhibitors of CYPs, such as fluconazole, quinidine, dimethyl-nitrosamine, acetaminophen, phenacetin, chlorzoxazone and mephenytoin. Trimethadione N-demethylation was selectively inhibited by dimethylnitrosamine and chlorzoxazone (> 50%) and weakly inhibited by tolbutamide (12%) and fluconazole (22%), whereas other inhibitors showed no effect. This result suggested that TMO metabolism to DMO is mainly mediated by CYP2E1 and marginally by CYP2C and CYP3A4. 2. Fifteen human livers were screened and interindividual variability of TMO N-demethylation activity was 3-fold. Chlorzoxazone 6-hydroxylation activity was also measured and both activities were significantly correlated (r = 0.735, p 0.01). 3. DMO production by human cDNA expressed CYP enzymes was observed mainly for CYP2E1 (10.8 nmol/tube), marginally for CYP2C8 (0.22 nmol/tube) and not detectable for other CYP enzymes. 4. These results indicate that TMO metabolism is primarily catalysed by CYP2E1 and that trimethadione would be a suitable selective probe drug for the estimation of human CYP2E1 activity in vivo.
- Kurata,Nishimura,Iwase,Fischer,Tang,Inaba,Yasuhara
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- N-Acyl and N-sulfonyloxazolidine-2,4-diones are pseudo-irreversible inhibitors of serine proteases
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The synthesis, inhibitory activity and mode of action of oxazolidine-2,4-diones against porcine pancreatic elastase, here used as a model for human neutrophil elastase, are reported. The nature of N-substitution at the oxazolidine-2,4-dione scaffold has large effect on the inhibitory potency against elastase. N-Acyl and N-sulfonyloxazolidine-2,4-diones emerged as potent pseudo-irreversible inhibitors, displaying high second-order rate constants for PPE inactivation. The title compounds were also shown to be potent inhibitors of human neutrophil elastase (HNE) and proteinase-3, and weak inhibitors of human cathepsin G. The results herein presented show that the oxazolidine-2,4-diones represent a new promising class of serine protease inhibitors.
- Santana, Ana Bela,Lucas, Susana D.,Goncalves, Lidia M.,Correia, Henrique F.,Cardote, Teresa A.F.,Guedes, Rita C.,Iley, Jim,Moreira, Rui
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scheme or table
p. 3993 - 3997
(2012/07/03)
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- A facile one-pot synthesis of 3-unsubstituted-2,4-oxazolidinediones via in situ generation of carbamates from α-hydroxyesters using trichloroacetyl isocyanate
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A convenient, high yield one-pot methodology for the synthesis of pharmaceutically interesting 3-unsubstituted-2,4-oxazolidinediones from α-hydroxyesters is described. A primary carbamate was generated in situ from the corresponding α-hydroxyester and tri
- Li, Yue H.,Zhang, Li,Tseng, Pei-San,Zhang, Yongliang,Jin, Yu,Shen, Jingkang,Jin, Jian
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scheme or table
p. 790 - 792
(2009/05/07)
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- Process for producing 2,4-oxazolidinedione
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Provided is a process which comprises reacting a 2-hydroxycarboxylic acid ester with urea to form a 2,4-oxazolidinedione , separating an unreacted 2-hydroxycarboxylic acid ester and a catalyst from the resulting reaction solution through distillation, and purifying the fraction composed mainly of the 2,4-oxazolidinedione through crystallization and/or extraction. In accordance with the present invention, the purified 2,4-oxazolidinedione is easily produced in a high yield by a simple purification method without using a costly alkali metal compound.
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- Method for stimulating hair growth with cationic derivative of minoxidil using therapeutic iontophoresis
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This invention relates to a method of applying a cationic derivative of Minoxidil which is transported by means of iontophoresis to hair follicles where the cationic derivatives promote hair growth. Each of the cationic derivatives of Minoxidil are synthesized by reacting the Minoxidil parent compound with an organic or an inorganic acid to form the cationic derivative.
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- Study of the reaction between cyanohydrins and chlorosulfonyl isocyanate. A new, efficient method for the one-pot synthesis of 2,4-oxazolidinediones
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The reaction between cyanohydrins and chlorosulfonyl isocyanate, followed by acid hydrolysis, provides and efficient route for the one-pot preparation of 5,5-disubstituted 2,4-oxazolidinediones.
- Garcia,Menendez,Villacampa,Sollhuber
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p. 697 - 698
(2007/10/02)
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- Soil disease-controlling imides
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A soil disease controlling agent for preventing and controlling diseases caused by pathogenic fungi living in soil, which comprises an effective amount of at least one of a 2-cycloalkenylamine derivative and its salts as an active ingredient, and at least one inert carrier or diluent.
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- Anticonvulsants in epileptic fowl
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The high seizure susceptibility in epileptic fowl is an autosomal recessive trait characterized in homozygotes by seizures that occur spontaneously and in response to photic stimulation or hyperthermia. Both of the latter stimuli can be used to evoke seizures in drug studies. Epileptic fowl have abnormal inter-ictal EEG activity. When exposed to photic stimulation spiking is apparent on the EEG at seizure onset. Phenobarbital, primidone, phenytoin, and valproic acid reduce seizure susceptibility at plasma concentrations approximating those used to control generalized and focal cortical tonic-clonic seizures in humans. Carbamazepine and the benzodiazepines also reduce seizure susceptibility. These data include that epileptic fowl provide a useful model for generalized and focal cortical tonic-clonic epilepsies. Ethosuximide was inactive in epileptic fowl. However, trimethadione had anticonvulsant activity indicating that this model is only relatively specific for the above seizure types. When seizures were evoked by hyperthermia phenobarbital but not phenytoin or valproate reduced seizure susceptibility. GABA (γ-aminobutyric acid), AOAA (amino-oxyacetic acid) and THPO (4,5,6,7-tetrahydroisoxazolo[4,5-c] pyridin-3-ole, a glial specific inhibitor of GABA uptake) all have anticonvulsant activity against seizures evoked by photic stimulation in young chicks. These data indicate that this model may be particularly useful for studies of the anticonvulsant activity of compounds designed to enhance GABAergic transmission.
- Johnson,Davis
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p. 1753 - 1757
(2007/10/02)
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