Disease relevance of Troxidone

• The pattern is tentatively associated with alterations in maternal physiology resulting from phenylketonuria and diabetes; maternal toxicity of aminopterin, alcohol, and diverse factors co-occurring with warfarin use; and therapeutic doses (generally toxic in adults) of phenytoin, phenobarbital, trimethadione, and valproic acid [1].
• Intrauterine death was found to occur in association with maternal homeostatic alterations resulting from phenylketonuria and diabetes, and with maternal toxicity from toxemia of pregnancy, leukemia, burns, alcohol, aminopterin, isotretinoin, and possibly trimethadione [1].
• All 3 compounds are anticonvulsants that modulate neural activity in vertebrates, and ethosuximide and trimethadione are used to treat absence seizures in humans [2].
• Effects of diphenylhydantoin and trimethadione on seizure activity during cobalt experimental epilepsy in the rat [3].
• However, when given earlier on Days 11 and 12, trimethadione 1000 mg/kg caused an 8.9% incidence of cleft palates (p less than 0.05) [4].

Psychiatry related information on Troxidone

• Influence of short-term water deprivation on kinetics of trimethadione and its metabolite in rats [5].
• The first experiment examined prenatal phenytoin (200 mg/kg), trimethadione (250 mg/kg), and phenobarbital (80 mg/kg) for critical period effects by exposing separate groups of rats to the drugs or to vehicle on embryonic (E) days 7-10, 11-14, or 15-18 [6].

High impact information on Troxidone

• The effects of the anticonvulsant trimethadione (TMO) and its primary metabolite dimethadione (DMO) were investigated at the frog neuromuscular junction using intracellular recording techniques [7].
• Dimethadione was less effective than the parent compound, trimethadione, in reversing withdrawal but caused greater acute toxicity [8].
• The effect of trimethadione on brain energy metabolism and EEG activity of the conscious rat exposed to HPO [9].
• From a comparison of siblings in each family and of others exposed to trimethadione in utero, a specific phenotype is delineated [10].
• (4) Studies based on screening compound libraries using C. elegans aging as a bioassay, which led to the identification of the anticonvulsant medicines ethosuximide and trimethadione [11].

Chemical compound and disease context of Troxidone

• Using this method (which we refer to as the "case-cumulative method") we found that two agents (parvovirus B19 and isotretinoin) demonstrated a logarithmic decrease in the estimated risk over time, as intuitively expected, while trimethadione and the coumarin derivatives showed a more complex pattern over time [12].
• Comparison of the therapeutic effects of trimethadione and phensuximide in acute organophosphate intoxications [13].
• An immunological basis for the penicillamine-induced myasthenia gravis is generally approved, but there may be other examples such as trimethadione and phenytoin [14].
• Human teratogenic conditions are summarized with special emphasis on the fetal alcohol syndrome, fetal hydantoin syndrome, fetal trimethadione syndrome, fetal valproate syndrome, warfarin embryopathy, retinoic acid embryopathy, congenital rubella syndrome, radiation effects, and diabetic embryopathy [15].

Biological context of Troxidone

• Dose-independent pharmacokinetics of trimethadione and its metabolite in rats [16].
• The aim of the present study was to examine the dose-independent kinetics of trimethadione (1) and its only metabolite dimethadione, 5,5-dimethyl-2,4-oxazolidinedione (2), after oral administration of 1-, 2-, and 4-mg/kg doses of 1 to rats [16].
• This would provide a unifying hypothesis for the teratogenicity of hydantoins, as well as structurally related teratogens like trimethadione, which lack the molecular configuration necessary for the formation of a teratogenic arene oxide intermediate [4].
• In this study trimethadione is considered a good indicator for estimating the state of hepatic enzyme induction [17].
• The malformation rates among live births of the first and the second groups were 11.5% and 2.3%, respectively; however, it was estimated that the rate would have been 6.75% among the treated group if trimethadione-treatment had been avoided [18].

Anatomical context of Troxidone

• The cardiovascular teratogens, trimethadione and trypan blue, produced in fetuses nonpatent depressions and VSDs morphologically similar to untreated fetuses [19].
• These experiments more accurately define the effects of the combination acetazolamide-amiloride or a single dose of dimethadione (DMO), the active metabolite of trimethadione, on the development of the ureter [20].
• Involvement of cytochrome P450 2C9, 2E1 and 3A4 in trimethadione N-demethylation in human microsomes [21].
• This showed a hypoplastic aortic arch with an anomolous origin of the left subclavian artery and patent ductus arteriosus, findings similar to those previously reported in neonates following maternal use of troxidone [22].
• Effects of four antiepileptic drugs, viz., diphenylhydantoin, trimethadione, phenobarbitone and ethosuximide, were studied on different in vitro and in vivo skeletal muscle preparations which consisted of frog rectus, rat phrenic nerve diaphragm and cat gastrocnemius sciatic nerve preparations [23].

Associations of Troxidone with other chemical compounds

• Comparison of EEG changes induced by anticonvulsants and urethane during control and convulsant activity showed that only trimethadione produces anticonvulsant activity unaccompanied by general CNS depression [24].
• Ten healthy male volunteers were given trimethadione (TMO) 4 mg/kg and antipyrine (AP) 500 mg alone or concomitantly to determine whether the metabolism of the drugs was mediated by the same or closely related forms of cytochrome P-450 [25].
• Comparative studies with diphenylhydantoin, phenobarbital and trimethadione have shown the profile of activity, potency and duration of action of the dicarboximide to closely resemble diphenylhydantoin [26].
• The contribution of induced cytochrome P450 (P450) isozymes (CMLa; CYP2B, CMLb; CYP2A and CMLc; CYP3A) and related enzymes to trimethadione (TMO) metabolism in phenobarbital-treated rhesus monkey were investigated [27].
• Whether administered alone or together, the total body clearance (CL), the apparent volume of distribution (Vd) and half-life (t1/2) of caffeine and trimethadione were the same, however, there was a weak correlation between the CL of caffeine and trimethadione [alone: r = 0.51 (P < 0.05); coadministered: r = 0.56 (P < 0.05)] [28].

Gene context of Troxidone

• 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 [29].
• Trimethadione metabolism by human liver cytochrome P450: evidence for the involvement of CYP2E1 [29].
• Trimethadione tolerance tests for the assessment of feasible size of hepatic resection in patients with hepatocellular carcinoma [30].
• These findings suggest that caffeine and trimethadione metabolism in healthy subjects is mediated by only in part by a form(s) of P450 enzymes involved [28].
• A slight inhibition of GABA-T (8 to 28%) was seen only with high concentrations of trimethadione, valproate and ethosuximide [31].

Analytical, diagnostic and therapeutic context of Troxidone

• The metabolism of trimethadione (TMO) following oral administration (4 mg kg-1) has been studied in 11 young male and 11 elderly male patients [32].
• Simultaneous determination of serum trimethadione and its metabolite by gas chromatography [33].
• Simultaneous determination of trimethadione and its metabolite in rat and human serum by high-performance liquid chromatography [34].
• Influence of partial hepatectomy in dogs on trimethadione metabolism and microsomal monooxygenases [35].
• After confirming the CRF states, trimethadione (TMO, 100 mg/kg, i.p.) was administered for evaluation of the hepatic drug metabolizing capacity; the ratio of dimethadione (DMO: the only metabolite of TMO) to TMO (DMO/TMO) in the serum and the dialysate from the blood microdialysis method were ascertained [36].

References