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At least 19 recordsLinked to original sources
PubMed1990

Pancreatic excretion of dimethadione and trimethadione by repeated oral administration of trimethadione in dogs.

To examine pancreatic excretion of dimethadione (DMO), a weak organic acid, as well as of its precursor trimethadione (TMO), TMO was given orally to dogs with pancreatic fistulae at a dose of 10-160 mg/kg/day over a period of 14 days. Blood samples were taken once a day during the administration of TMO and for 7 days after discontinuation of the drug. On the 15th day, pancreatic juice was collected under stimulation by secretin (2 Crick-Haper-Raper units/kg/h). DMO concentration in plasma reached a maximal plateau around the 10th day after starting TMO administration, and depended directly on the dose of TMO. Pancreatic excretion of DMO at a steady state closely depended on both the dose of TMO and the DMO concentration in plasma. The pancreatic juice/plasma concentration ratio for DMO exceeded 1.0 at a steady rate and decreased with the increased flow rate. Pancreatic DMO clearance (DMO output/DMO concentration in plasma) increased, depending on the flow rate, the bicarbonate concentration, and pH of pancreatic juice. Pancreatic excretion of TMO was zero or extremely low.

Administration, Oral↗
PubMed1989

Inhibition of trimethadione and dimethadione teratogenicity by the cyclooxygenase inhibitor acetylsalicylic acid: a unifying hypothesis for the teratologic effects of hydantoin anticonvulsants and structurally related compounds.

Teratogenicity of the anticonvulsant phenytoin may be due in part to its bioactivation by prostaglandin synthetase, forming a reactive free radical intermediate. We examined whether teratogenicity of the structurally similar oxazolidinedione anticonvulsants, trimethadione and its N-demethylated metabolite dimethadione, could be inhibited by the prostaglandin synthetase inhibitor acetylsalicylic acid (ASA). Trimethadione, 700 or 1000 mg/kg intraperitoneally (ip), was given to pregnant CD-1 mice during (Gestational Days 12 and 13) or before (Days 11 and 12) the critical period of susceptibility to phenytoin-induced fetal cleft palates. Dimethadione was given similarly on Days 11 and 12, or 12 and 13, in a dose (900 mg/kg ip) that was equimolar to 1000 mg/kg of trimethadione. ASA, 10 or 1 mg/kg ip, was given 2 hr before trimethadione or dimethadione on Days 11 and 12, and before trimethadione on Day 11 only. Dams were killed on Day 19 and fetuses were examined for anomalies. Either dose of trimethadione given on Days 12 and 13 was negligibly teratogenic, as evidenced by a non-dose-related, 1.1% mean incidence of fetal cleft palates. 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). Similarly, dimethadione caused a 3.9-fold higher incidence of cleft palates when given earlier on Days 11 and 12 (17.3-34.9%) than on Days 12 and 13 (4.4%) (p less than 0.05). At equimolar doses, dimethadione caused a 1.9- to 3.9-fold higher incidence of cleft palates compared to trimethadione (p less than 0.05), suggesting that dimethadione may be the proximate teratogen. Either dose of ASA given on both days before trimethadione totally prevented cleft palates, and ASA 10 mg/kg given only on Day 11 reduced the incidence of trimethadione-induced cleft palates to 1.1% (p less than 0.05). ASA reduced the incidence of cleft palates caused by dimethadione given on Days 11 and 12 from 34.9 to 20.3% (p less than 0.05). These results suggest that the teratogenic potential of trimethadione may depend at least in part upon its prior N-demethylation to dimethadione, which then can be bioactivated by prostaglandin synthetase to a teratogenic reactive intermediate, possibly involving a free radical located in the oxazolidinedione ring. 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.

Abnormalities, Drug-Induced↗
PubMed2005

The antihyperalgesic effects of the T-type calcium channel blockers ethosuximide, trimethadione, and mibefradil.

The purpose of the present study was to explore the analgesic effects of the low voltage-activated T-type Ca2+ channel blockers ethosuximide, trimethadione, and mibefradil in persistent and acute nociceptive tests. The anticonvulsant effects of the compounds were also determined in the intravenous pentylenetetrazol seizure model. Following intraperitoneal administration, ethosuximide and trimethadione dose-dependently reversed capsaicin-induced mechanical hyperalgesia. Similarly, the highest dose of mibefradil tested (30 microg, intracisternal) reversed capsaicin-induced mechanical hyperalgesia. Ethosuximide and mibefradil produced statistically significant analgesic effects in both early and late phase formalin-induced behaviors and trimethadione reduced late phase behaviors. Additionally, ethosuximide and trimethadione produced antinociceptive effects in the rat-tail flick reflex test. In contrast, following intracisternal administration, mibefradil had no effect in the tail flick reflex test. In addition, the anticonvulsants ethosuximide and trimethadione increased the doses of pentylenetetrazol required to produce both first twitch and clonic seizures. In contrast however, mibefradil had no anticonvulsant effect. The present results demonstrate that the clinically used anticonvulsants ethosuximide and trimethadione provide analgesic effects at doses, which are anticonvulsant. Furthermore, the data further supports the idea that T-type Ca2+ channels may be important targets for treating persistent pain syndromes.

Animals↗
PubMedDate not supplied

Dissolution of pancreatic stones by oral trimethadione in patients with chronic calcific pancreatitis.

The effect of oral dissolution therapy for pancreatic stones was evaluated in patients with chronic calcific pancreatitis. The anti-epileptic agent trimethadione was given orally to 30 outpatients at a dose of 0.9-1.5 g daily. On plain X-ray films and CT scans of the abdomen, pancreatic stones began to be dissolved around 8 months of treatment, and diminished in size and number or disappeared in 21 patients (70%) during the mean follow-up period of 32 months. The effect of trimethadione treatment on dissolution of stones was not closely related to the aetiology of the disease, distribution and size of stones, previous history of surgical interventions, or the degree of pancreatic dysfunctions. In three patients who stopped this medication of their own accord, pancreatic stones re-increased or reappeared about 6 months later. During trimethadione treatment, impaired exocrine pancreatic function returned to normal in four of nine patients examined, and diabetes mellitus was well controlled by either diet therapy alone or oral hypoglycaemic agents in eight of 10 patients who did not need insulin before trimethadione treatment. Complete relief of pain was noted in 73% of patients during the treatment. Overall gains and no change in bodyweight were observed in 83% of patients. Mild photophobia was the most common side effect, but could be easily overcome by wearing sunglasses. No severe side effects were observed in the liver, kidney, blood or the eyeground. Pancreatic stones in 30 patients not treated with trimethadione neither disappeared nor diminished spontaneously. Trimethadione treatment may be a useful tool for chemical dissolution of pancreatic stones.

Administration, Oral↗
PubMed1992

Simplified test for determination of drug-oxidizing capacity in rats with chemical-induced liver injury using caffeine and trimethadione as model drugs.

We examined the possibility of predicting the extent of hepatic drug-oxidizing capacity by determination of caffeine, trimethadione and their metabolites in three groups of rats with chemically induced liver injuries. Trimethadione (4 mg/kg) and caffeine (10 mg/kg) were simultaneously administered as two probe drugs. In rats with chemically induced liver injuries pretreated with carbon tetrachloride (CCl4: 0.25 ml/kg), alpha-naphthylisothiocyanate (ANIT: 40 mg/kg), or D-galactosamine (GalN: 400 mg/kg), the half-life (t1/2) of caffeine and trimethadione was significantly (P less than 0.01) prolonged compared to those of control groups total body clearance as dramatically reduced (P less than 0.01), whereas apparent volumes of distribution (Vds) were increased in ANIT and GalN groups. In rats with liver damage the production of three metabolites (theobromine, paraxanthine and theophylline) of caffeine as well as the only metabolite (dimethadione) of trimethadione after oral administration of both drugs were significantly decreased compared to those of controls. In rats with liver injuries, total body clearance of caffeine and trimethadione showed a strong correlations (r = 0.99, P less than 0.01); also total body clearance of caffeine correlated well with the ratio of dimethadione/trimethadione after 1, 2, and 4 hr of trimethadione administration (r = 0.93, P less than 0.01; r = 0.97, P less than 0.01 and r = 0.97, P less than 0.01 respectively). Besides, total body clearance of caffeine also correlated well (coefficients ranging from 0.74 to 0.96; P less than 0.01) with the ratio of theobromine/caffeine, paraxanthine/caffeine and theophylline/caffeine after 1, 2 and 4 hr) of caffeine administration.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Naphthylisothiocyanate↗
PubMed1993

Comparison of hepatic drug-oxidizing activity after simultaneous administration of two probe drugs, caffeine and trimethadione, to human subjects.

Pharmacokinetic interactions between caffeine 2 mg/kg and trimethadione 4 mg/kg were evaluated in 10 healthy volunteers. 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)]. There were also weak correlations between the CL of trimethadione and the area under the serum concentration-time curves (AUC) of theobromine (r = -0.61, P < 0.05), paraxanthine (r = -0.69, P < 0.05) and theophylline (r = -0.60, P < 0.05), when the two drugs were administered alone. After combined administration, the correlation between the CL of trimethadione and the AUCs of the metabolites of caffeine were as follows: theobromine r = -0.63 (P < 0.05); paraxanthine r = -0.68 (P < 0.05); theophylline r = -0.65 (P < 0.05). 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.

Adult↗
PubMed1977

The fetal trimethadione syndrome: report of an additional family and further delineation of this syndrome.

We describe a family in which seven pregnancies resulted in four infants who died and in three abortions. During these pregnancies the mother took trimethadione (Tridione), as well as other anticonvulsants. Two normal children were born after treatment with all medications were stopped. There have now been 53 reported pregnancies in which the fetuses were exposed to trimethadione or paramethadione; 48 (87%) resulted in fetal loss or a child born with congenital malformations. The most common defects include malformed ears, cleft palate, cardiac defects, urogenital malformations, and skeletal abnormalities. Delayed mental and physical development were also seen. These findings constitute a clinical entity termed the fetal trimethadione syndrome. The malformation rate is believed to be due to the teratogenic effects of trimethadione. Physicians need to be aware of the danger of trimethadione and related drugs during pregnancy and should withhold these medications during this period.

Abnormalities, Drug-Induced↗
PubMed1982

Comparison of the actions of trimethadione and chlordiazepoxide in animal models of anxiety and benzodiazepine receptor binding.

Trimethadione was compared with chlordiazepoxide for anti-anxiety activity in two behavioral tests known to predict the anxiolytic action of drugs. In the drug-discrimination test, male hooded rats were trained to discriminate the anxiogenic action of pentylenetetrazol from saline by responding for food reinforcement on one of two levers after treatment with pentylenetetrazol (1450 mumol/kg) and on the other lever after injection of saline. Pretreatment with either chlordiazepoxide (2.8-33 mumol kg) or trimethadione (559-2236 mumol/kg) prior to the injection of pentylenetetrazol, produced a dose-dependent antagonism of the anxiogenic stimulus. In the other test, male Wistar rats were trained to respond for milk reinforcement in a conflict procedure in which some of the reinforced responses resulted in the delivery of footshock. Treatment of these rats with chlordiazepoxide (17-67 mumol/kg) or trimethadione (1118-2236 mumol/kg) antagonized the footshock-induced suppression of responding. In a receptor binding study, trimethadione failed to inhibit flunitrazepam binding. These data suggest that trimethadione is an effective anxiolytic agent whose action does not directly involve benzodiazepine receptors.

Animals↗
PubMed1991

The effect of diltiazem on hepatic drug oxidation assessed by antipyrine and trimethadione.

The effect of pretreatment for 3 days with diltiazem 60 mg three times a day on the pharmacokinetics of 500-mg antipyrine and 250-mg trimethadione was studied in six healthy male subjects. Diltiazem decreased the total body clearance from 34.0 +/- 8.0 to 28.6 +/- 6.1 mL/min (P less than .01), and prolonged the elimination half-life from 12.6 +/- 3.0 to 14.3 +/- 2.5 hours (P less than .01) of antipyrine without any changes in volume of distribution. The cumulative renal excretion (% dose) of antipyrine was significantly increased from 2.23 +/- 0.73 to 2.78 +/- 0.83% (P less than .05). Clearances of production for three major antipyrine metabolites, norantipyrine (4.31 +/- 1.64 to 3.50 +/- 1.28 mL/min, P less than .01), 3-hydroxymethylantipyrine (4.67 +/- 1.63 to 3.82 +/- 1.34 mL/min, P less than .01) and 4-hydroxyantipyrine (10.47 +/- 3.41 to 8.16 +/- 2.82 mL/min, P less than .01) were reduced significantly by diltiazem. On the other hand, diltiazem did not produce any significant changes in pharmacokinetic parameters of trimethadione and plasma concentration ratio, oxidative major metabolite of trimethadione to trimethadione itself. These results suggest that other drugs metabolizing the same hepatic oxidative pathways as antipyrine, may be influenced by diltiazem.

Adult↗
PubMed1992

Tolerance to the anticonvulsant effects of phenobarbital, trimethadione, and clonazepam in kindled rats: cross tolerance to carbamazepine.

The kindled-convulsion model was used to assess the development of tolerance and cross tolerance to the anticonvulsant effects of antiepileptic drugs. In Experiment 1, tolerance developed to the anticonvulsant effects of bidaily (one every 48 h) IP injections of phenobarbital, trimethadione, and clonazepam on convulsions elicited 1 h after each injection in kindled rats by amygdala stimulation. In Experiment 2, kindled rats that were tolerant to the anticonvulsant effects of phenobarbital, trimethadione, or clonazepam received bidaily IP injections of carbamazepine, each followed 1 h later by a convulsive amygdala stimulation. There was a statistically significant transfer of tolerance from phenobarbital to carbamazepine, but not from either trimethadione or clonazepam to carbamazepine. Apparently, tolerance to anticonvulsant drugs is most likely to transfer between drugs that are effective against similar kinds of clinical and experimental seizures and have similar putative mechanisms of action.

Amygdala↗
PubMed1996

Anticonvulsant drug effects on spontaneous thalamocortical rhythms in vitro: ethosuximide, trimethadione, and dimethadione.

Spontaneous generalized epileptiform discharges were elicited in rodent thalamocortical slices by perfusion with a medium containing no added Mg2+. In multiple-channel extracellular field potential recordings in thalamus and cortex, several distinct types of discharges were recorded, with two principal variants bearing marked similarity to spike-wave and generalized tonic-clonic seizure discharges recorded in patients with generalized seizure disorders. These discharges were termed sTBCs and cTBCs, respectively, for simple and complex thalamocortical burst complexes. The sensitivity of these discharges to the generalized absence anticonvulsants ethosuximide, trimethadione and dimethadione (the active metabolite of trimethadione) was studied. sTBCs were reduced or blocked by ethosuximide and dimethadione, when these drugs were applied in clinically relevant concentrations. The order of effectiveness of these agents was dimethadione > or = ethosuximide >> trimethadione. This paralleled the relative efficacy of these drugs in blocking T current in thalamic neurons. cTBCs were unaffected or exacerbated by these drugs. Structural control drugs including succinimide, the behaviorally inactive ring base of ethosuximide, and alpha, alpha-dimethyl-beta-methylsuccinimide, a convulsant succinimide, were inactive or exacerbated either sTBCs or cTBCs, respectively. These spontaneous generalized thalamocortical discharges in rodent thalamocortical slices may represent a potentially valuable in vitro model of generalized seizure discharges, with marked pharmacological and physiological similarities to various forms of clinical epileptic seizure activity.

Animals↗
PubMed1975

The fetal trimethadione syndrome.

Three families are described in which each of the mothers took trimethadione during pregnancy. From a comparison of siblings in each family and of others exposed to trimethadione in utero, a specific phenotype is delineated. Features included in the fetal trimethadione syndrome are developmental delay, speech difficulty, V-shaped eyebrows, epicanthus, low-set ears with anteriorly folded helix, palatal anomaly, and irregular teeth. Additional anomalies in some of the patients include intrauterine growth retardation, short stature, microcephaly, cardiac anomaly, ocular anomaly, hypospadias, inguinal hernia, and simian creases.

Abnormalities, Drug-Induced↗
PubMed1998

Trimethadione metabolism by human liver cytochrome P450: evidence for the involvement of CYP2E1.

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.

Anticonvulsants↗
PubMedDate not supplied

Changes in caffeine, lidocaine and trimethadione metabolism in carbon tetrachloride-intoxicated rats as assessed by a "cocktail" study.

We investigated the possibility of predicting liver damage from changes in the serum concentrations of caffeine (10 mg/kg), lidocaine (4 mg/kg) and trimethadione (4 mg/kg), which are metabolized catalysed by different cytochrome P450 (P450) and/or are dependent on blood flow, in rats with carbon tetrachloride (CCl4: 0.25 ml/kg)-induced liver injury using a strategy referred to as a "cocktail" study. These 3 probe drugs were simultaneously administered intravenously. The half-lives (t1/2) of caffeine, lidocaine and trimethadione were significantly longer in the CCl4-treated group than in oil-treated controls, but no significant differences were observed in mean apparent volumes of distribution (Vd). Serum total body clearance (CL) values of all three drugs were markedly reduced in CCl4-treated animals. In rats with liver damage, the production of 3 metabolites (theobromine, paraxanthine and theophylline) of caffeine in addition to the only metabolite (dimethadione) of trimethadione after intravenous administration of probe drugs were significantly reduced compared to those of controls. These findings suggest that each probe drug, metabolized by different or partially overlapping P450, is useful in evaluating drug-oxidizing capacity in liver disease.

Alanine Transaminase↗
PubMed1984

Simultaneous determination of dimethadione and trimethadione by infrared-spectrometry: application for mean intracellular pH measurement.

A simple infrared-spectrometric method for the simultaneous determination of dimethadione and trimethadione in plasma is described. The method is based on the absorption band of the carbonyl group for trimethadione at the wavenumber of 1740 cm-1 and for dimethadione at the wavenumber of 1770 cm-1. The accuracy and precision of the method are excellent; at a dimethadione and trimethadione concentration of 0.5 mmol X 1(-1) the coefficient of variation for the determination of both compounds is less than 1%, which is better than that for the ultraviolet spectrometric or gas-liquid chromatographic methods. The method can be used for the determination of the ratio trimethadione/dimethadione in the clinical setting as a sensitive check of the patient's adherence to therapy. It can also be used for the determination of dimethadione as an indicator for the mean body intracellular pH.

Dimethadione↗