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At least 19 recordsLinked to original sources
PubMed1982

Comparison of the effects of trimethadione and its primary metabolite dimethadione on neuromuscular function and the effects of altered pH on the actions of dimethadione.

The effects of the anticonvulsant trimethadione (TMO) and its primary metabolite dimethadione (DMO) were investigated at the frog neuromuscular junction using intracellular recording techniques. TMO (1, 2 and 5 mM) caused dose-dependent decreases in miniature end-plate potential (MEPP) and end-plate potential (EPP) amplitudes, decreased quantal content only at the highest dose and did not affect MEPP frequency. DMO (2 and 5 mM) at the normal pH of 7.2 significantly decreased quantal content and decreased EPP amplitude at the higher concentration used. Neither MEPP amplitude nor frequency was significantly affected by DMO at pH 7.2. When 2 mM DMO was added at the same time that pH was lowered to 6.6, considerably larger decreases in EPP( amplitude and quantal content were observed. Under these conditions, DMO still did not alter MEPP amplitude but did cause about a doubling in MEPP frequency. The effects of pH 6.6 alone were also examined, but lowered pH did not account for all of the exaggerated effect of DMO in pH 6.6. Presumably, more DMO accumulates intracellularly in low pH conditions because it is a weak acid and sensitive to alterations in pH. In conclusion, both TMO and DMO cause depression of neuromuscular transmission; however, their mechanisms for depression are different, especially when therapeutically relevant concentrations are considered. TMO acts primarily by suppressing postjunctional sensitivity to acetylcholine, whereas DMO primarily decreases transmitter release from the nerve terminal.

Animals↗
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↗
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↗
PubMed1978

Dimethadione-induced fetotoxicity in rats.

The fetotoxic potential of dimethadione was studied in rats given single daily oral dosages of 0, 54, 433 or 541 mg/kg on days 1--21 or 6--15 of gestation. No maternal toxicity was observed following treatment on days 6--15. When administered from days 1 to 21 only the highest dose (541 mg/kg) produced a significant reduction in maternal body weight gain. Dimethadione caused a dose-related decrease in fetal weight and an increased incidence of umbilical hernia, ecchymoses and subcutaneous edema. There were also increased incidences of non-specific skeleton defects which consisted of unilateral or bilateral wavy ribs, additional ribs (14th rib, uni- and bilateral), retarded ossification of calvaria and a wide variety of sternal defects. Specific defects were bent radius and ulna, and bent tibia and fibula which increased with increasing dosages of dimethadione. Fetal mortality and incidence of skeletal anomalies were higher when the treatment was given on days 1--21 of gestation than on days 6--15 of pregnancy.

Abnormalities, Drug-Induced↗
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↗
PubMed1992

Improved method for the determination of trimethadione and its demethylated metabolite, dimethadione, in human serum by gas chromatography.

An improved gas chromatographic method, involving the use of a wide-bore capillary column, for the determination of trimethadione and its only demethylated metabolite, dimethadione, in human serum is described. The results indicate that both substances and the internal standard (maleinimide) were well separated with no tailing peak. The detection limit was 10 ng/ml for trimethadione and 50 ng/ml for dimethadione. This improved method is reliable in terms of sensitivity, selectivity and reproducibility for the simultaneous determination of both compounds in human serum.

Adult↗
PubMed1992

Abnormalities in ureter and kidney development in mice given acetazolamide-amiloride or dimethadione (DMO) during embryogenesis.

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. When acetazolamide-amiloride was administered in C57BL/6NCrlBR mice on day 9, 9.5, or 10 of gestation (plug = day 0) a second ureter was formed, anterior to the original ureter, inducing a second kidney. The second ureter then fails to make a connection with the developing bladder and remains attached to the mesonephric duct. The mesonephric duct becomes the vas deferens in the male and deteriorates completely in the female leading to either a restricted ureter or a blocked ureter depending on the sex of the fetus. Administration of a single dose of DMO between gestational day 9 and 10.3 produced both renal agenesis and ureters of varying lengths. Some ureters were of normal length with a tuft of one or two nephrons at their tip, while others were one half or one quarter of their normal length. In some instances the ureter was completely absent. The reason for this strong effect on the ureter is unknown.

Abnormalities, Drug-Induced↗
PubMed1983

Clinical evaluation of pancreatic excretion test with dimethadione and oral BT-PABA test in chronic pancreatitis.

Further evaluation of the pancreatic excretion test with 5,5-dimethyl-2,4-oxazolidinedione (dimethadione, DMO) was made in comparison with the pancreozymin-secretin (PS) test on 100 normal subjects, 79 patients with chronic pancreatitis, and 83 patients with nonpancreatic disease. The diagnostic sensitivity of the oral N-benzoyl-L-tyrosyl-PABA (BT-PABA) test was estimated in 42 patients with chronic pancreatitis, on whom both PS and DMO excretion tests were performed as test of reference for exocrine pancreatic function. Pancreatic DMO excretion after secretin injection was significantly diminished in chronic pancreatitis. The DMO excretion test was more sensitive than the PS test to detect chronic pancreatitis and to distinguish between mild to moderate and advanced noncalcific chronic pancreatitis. The specificity of the DMO excretion test was more than adequate to find out pancreatic disease. The 6-hr urinary PABA excretion was significantly reduced in chronic pancreatitis. The BT-PABA test, however, showed the low sensitivity in mild to moderate chronic pancreatitis.

4-Aminobenzoic Acid↗
PubMed1992

Effects of the oxazolidinedione anticonvulsants trimethadione and dimethadione and the barbiturate homolog 5,5-dimethylbarbituric acid on N-nitrosodiethylamine-initiated renal and hepatic carcinogenesis in the F344/NCr rat.

The oxazolidinedione anticonvulsant trimethadione (3,5,5-trimethyl-2,4-oxazolidinedione, TMO) as well as its major metabolite, dimethadione (5,5-dimethyl-2,4-oxazolidinedione, DMO), and a structural analog from the barbiturate series, 5,5-dimethylbarbituric acid (DMB), were fed to F344/NCr male rats previously given a single initiating injection of N-nitrosodiethylamine (NDEA). The known promoter, phenobarbital (5-ethyl-5-phenylbarbituric acid, PB), was employed in this study as a positive control. At dosage levels equimolar to 500 ppm PB, none of the three compounds promoted development of hepatocellular adenomas or carcinomas, in contrast to PB. The two oxazolidinedione analogs and DMB caused minimal or no induction of cytochrome P450 isozyme 2B1 (CYP2B1)-mediated alkoxyresorufin O-dealkylase activities following short-term (2 weeks) feeding to separate groups of 6-week-old male F344/NCr rats, in contrast to the dramatic induction caused by PB. Promotion of neither thyroid nor renal neoplasia was observed following prolonged feeding of any of the tested compounds, although a significantly higher frequency of premalignant renal cortical tubular lesions (dysplasias) was seen in rats exposed to TMO following NDEA initiation than in those treated with NDEA alone. These studies provide important additional data on structure/liver tumor promoting activity relationships, and yield further evidence that within this group of structurally related anticonvulsants, it is possible to separate anticonvulsant activity from tumor promoting activity in the rat liver.

Animals↗
PubMed1986

Comparative pharmacokinetic study of trimethadione and dimethadione for lysis of pancreatic stones.

In order to investigate the biological equivalence of dimethadione (DMO) and its precursor trimethadione (TMO), comparative pharmacokinetic studies were performed in 6 beagle dogs. DMO and TMO power was given orally at the same molar dose of 1.0 g and 1.11 g (7.7 mM), respectively. Plasma concentration of DMO and TMO was determined at an appropriate interval. Four pharmacokinetic parameters were calculated from the plasma concentration-time curves of DMO and TMO; the peak plasma concentration (Cmax), the time to the peak concentration of Cmax (Tmax), the area under the plasma concentration-time curve (AUC), and the biological half-life (t 1/2). In the plasma concentration-time curve of DMO, Tmax after oral administration of TMO was longer than that after administration of DMO. This resulted from the presence of the conversion process of TMO to DMO in the body, because of the very short Tmax observed in the plasma concentration-time curve of TMO. Cmax, AUC and t 1/2 did not differ significantly between the drugs. The results obtained indicate that TMO is biologically equivalent to DMO in regard to plasma concentration of DMO.

Administration, Oral↗
PubMed1990

Effect of dimethadione derived from repeated oral administration of trimethadione on pancreatic secretion in dogs.

The effect of the weak organic acid of dimethadione (DMO) on secretin-stimulated pancreatic secretion was studied with repeated oral administration of trimethadione (TMO), the precursor of DMO, to dogs at a dose of 10 to 160mg/kg/day for a period of 14 days. The bicarbonate concentration in pancreatic juice at a steady state decreased significantly, reflecting a close correlation with the dose of TMO and DMO concentrations in plasma and pancreatic juice. The maximal decrement from the control of cases of no TMO administration was 18.8 mEq/l (12.1% of the control level). The chloride concentration in pancreatic juice showed a reciprocal relation to the bicarbonate concentration. The sum of both anion concentration was constant, irrespective of the dose of TMO. The average carbon dioxide tension of pancreatic juice in all doses of TMO was lower than that of the control, but differences were not statistically significant. The pH, flow rate, sodium and potassium concentrations in pancreatic juice at a steady state did not differ significantly in relation to the dose of TMO. These findings suggest that repeated oral administration of TMO cause a significant decrease in bicarbonate concentration in pancreatic juice, resulting probably from the buffer action of bicarbonate on protons provided from the undissociated form of DMO.

Administration, Oral↗
PubMed1984

The excretion of dimethadione in pure pancreatic juice and bile in postoperative patients.

The excretion of dimethadione (DMO) in pure pancreatic juice and bile was studied in postoperative patients undergoing external drainage of pancreatic juice and in those who had undergone percutaneous transhepatic cholangiodrainage. During and after oral administration of trimethadione, which is the precursor of DMO, pancreatic DMO concentration closely paralleled plasma DMO concentration. Pancreatic juice/plasma concentration ratio for DMO exceeded 1.0. In a patient with a large pancreatic cyst communicating with the main pancreatic duct, pancreatic DMO concentration after single rapid injection of secretin inversely correlated with the flow rate, while its output depended directly on the rate. Biliary DMO output after secretin injection was closely dependent on the flow rate, but was extremely low. The present results are essentially compatible with the findings previously observed in dogs.

Adult↗
PubMed1988

Macroautoradiographic and densitometric studies of [14C]dimethadione in rats: accumulation of the compound in the pancreas.

Whole-body autoradiographic and densitometric distribution studies were performed on rats to investigate the accumulation of [14C]dimethadione (DMO) in the pancreas. [14C]DMO was intravenously administered at a dose of 167 microCi/0.5 mg/kg. Animals were sacrificed 1, 15, 30, 60 and 180 min after administration of the radioactive compound. The compound was found to rapidly distribute in all body tissues. The distribution pattern of the compound in the pancreas was spotty or linear due to the presence of the radioactive compound in blood of intrapancreatic vessels and in pancreatic ducts at higher levels than parenchyma. The radioactivity of pancreatic ducts became more evident with time, indicating the gradual accumulation of the compound in the ducts. These findings provide morphological evidence that DMO is accumulated in the pancreas and possibly eliminated from pancreatic juice. Densitometry revealed that the levels of radioactive compound in the pancreas were virtually as high as those in the liver and kidney.

Animals↗
PubMed1996

Intracellular pH monkey embryos at various stages of organogenesis estimated by dimethadione distribution.

Previous experiments using the transplacental distribution of 14C-DMO (5,5-dimethyloxazolidine-2,4-dione or commonly known as dimethadione) have demonstrated that the pH of rat embryos and fluids progressively decreases during organogenesis. The aim of the present experiments was to similarly evaluate pH changes during organogenesis in the cynomolgus monkey, which is a model for human embryogenesis. Using DMO quantitated by gas chromatography-mass spectrometry as opposed to the counting of radiolabelled compound, cynomolgus monkey embryos were determined to undergo a similar decrease in embryonic pHi over an approximately comparable period of development (Days 24-36 of gestation). The ratio of DMO in chorionic fluid to DMO in maternal plasma in the cynomolgus monkey also displayed a decrease with advancing gestational age indicative of a pH decrease. The DMO transplacental distribution was found to be significantly slower in the cynomolgus monkey than that in rodents. The present investigation indicates that the magnitude of the reduction of pH in embryonic cells and in extra-embryonic fluids over a period of organogenesis in the cynomolgus monkey is similar to the reduction detected in rodent embryos and fluids over a comparable developmental period, but the relative gradient between maternal blood pH and embryonic intracellular pH is different. The difference in the pH gradient between the two species may lead to differential transplacental distribution of exogenous and endogenous substances.

Analysis of Variance↗
PubMedDate not supplied

Effect of dimethadione administered intravenously on pancreatic secretion in dogs.

In order to detect both pancreatic excretion of dimethadione (DMO), a weak organic acid, and the effect of pancreatic DMO on secretin-stimulated pancreatic secretion, DMO was given intravenously to dogs with pancreatic fistulae at a dose of 50, 100 and 200 mg/kg. DMO was promptly excreted into pancreatic juice; the concentration decreased exponentially as it did in plasma at the highest dose of the compound. At equilibrium of DMO between pancreatic juice and plasma, the DMO concentration in the juice depended directly on that in plasma; the juice/plasma concentration ratios for DMO exceeded 1.0, ranging from 1.7 to 2.1. Pancreatic DMO caused a small but significant decrease in the water, bicarbonate and sodium secretion at non-equilibrium, and in the bicarbonate secretion at equilibrium. A decrease in the bicarbonate secretion may result largely from the buffer action of bicarbonate on protons provided by the undissociated form of DMO. The sum of both bicarbonate and chloride concentrations in pancreatic juice decreased with the increased DMO concentration in the juice, implying that DMO may compete with the secretion of bicarbonate and/or chloride across the apical membrane of the duct cell. Pancreatic DMO can act as a non-specific inhibitor of pancreatic water and electrolyte secretions.

Animals↗
PubMed1978

Consecutive gas chromatographic determination of phenytoin, phenobarbital, primidone, phenylethylmalondiamide, carbamazepine, trimethadione, dimethadione, ethosuximide, and valproate from the same serum specimen.

A quantitative gas-liquid chromatographic procedure is described for the consecutive determination of phenytoin, phenobarbital, primidone, phenylethylmalondiamide, carbamazepine, trimethadione, dimethadione, ethosuximide and valproate from a single serum specimen of 1.2 ml. After extraction from serum by two different procedures, the anticonvulsants are chromatographed without further purification on a 3% OV 17 column either with or without derivative formation by means of "on-column" methylation. Multiple internal standards are employed in order to enhance the reproducibility of drug-concentration measurement.

Anticonvulsants↗
PubMed1985

Intracellular pH transients in rainbow trout tissues measured by dimethadione distribution.

Intracellular pH transients in response to PCO2 changes were measured in vitro with the weak acid dimethadione (DMO) in gas-equilibrated red blood cells and a perfused trunk preparation (white muscle) of the rainbow trout. Red cell intracellular pH (pHi) was also measured directly on cell lysates. At an extracellular pH (pHe) of 7.81 +/- 0.04, PCO2 = 2 Torr, red cell pHilysate averaged 7.40 +/- 0.02, and [DMO]i/[DMO]e averaged 0.37 +/- 0.02, corresponding to a mean pHiDMO of 7.39 +/- 0.02. Decreasing pHe to 7.53 +/- 0.04 by increasing PCO2 to 8 Torr caused [DMO]i/[DMO]e to increase to 0.50 +/- 0.03 and resulted in a decline in pHi to a mean of 7.19 +/- 0.03 as measured by both techniques. With both methods red cell pHi responded rapidly (less than 5 min) to the PCO2 change, paralleling the response of pHe. In the isolated perfused trunk preparation at a perfusate pHe of 7.79 +/- 0.04 and PCO2 of 2 Torr, [DMO]i/[DMO]e averaged 0.38 +/- 0.03, yielding an average white muscle pHi of 7.35 +/- 0.04. Decreasing pHe to 7.34 +/- 0.02 by elevating PCO2 to 15 Torr caused pHi to drop to a mean of 7.11 +/- 0.03, as indicated by the significant increase in [DMO]i/[DMO]e to 0.58 +/- 0.03. The response of [DMO]i/[DMO]e was complete within 15 min. In both preparations the pHi changes were fully reversible. The DMO distribution method for measuring intracellular pH transients proved to be rapid and reliable in fish tissues.

Animals↗
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↗