Oral Litholysis in Patients with Chronic Calcific Pancreatitis Unresponsive to or Ineligible for Extracorporeal Shock Wave Lithotripsy and Endoscopic Therapy.

BACKGROUND/AIMS: Our study aimed to evaluate the effect of oral litholysis in patients with chronic calcific pancreatitis (CCP) unresponsive to or ineligible for extracorporeal shock wave lithotripsy (ESWL) and endoscopic therapy. METHODS: Trimethadione, an antiepileptic agent, was administered orally at a dose of 0.6-0.9 g/day to 15 patients with this condition. Treatment outcome was evaluated by assessment of dissolution of the pancreatic stones on plain X-ray films and computed tomography scans of the upper abdomen. Plasma glucose, hemoglobin A1c, and body mass index (BMI) were also monitored throughout the therapy. RESULTS: Litholysis was observed in 13 out of 15 patients (86.7%) and was definite in 10 and partial in 3. Six patients had pancreatitis attacks during the therapy; 5 of whom showed definite litholysis and had only 1 mild attack. Of the 11 patients with normal or impaired glucose tolerance at baseline, none developed diabetes mellitus and all showed litholysis. BMI significantly increased in patients whose pancreatic stones dissolved. There was no vital organ impairment by trimethadione. CONCLUSION: Oral litholysis using trimethadione may represent a noninvasive and effective complementary treatment in patients with CCP unresponsive to or ineligible for ESWL and endoscopic therapy.

Co-variation in frequency and severity of cardiovascular and skeletal defects in Sprague-Dawley rats after maternal administration of dimethadione, the N-demethylated metabolite of trimethadione.

BACKGROUND: The anticonvulsant trimethadione is a potent inducer of ventricular septation defects, both clinically and in rodents. Teratogenicity requires its N-demethylation to dimethadione, the proximate teratogen. It was previously demonstrated trimethadione only induced membranous ventricular septation defects in rat (Fleeman et al., 2004), and our present goal is to determine whether direct administration of dimethadione increases the incidence and severity of septation defects. METHODS: Pregnant Sprague-Dawley rats were divided into five groups and administered either distilled water (control) or four different regimens of dimethadione. The core treatment was 300 mg/kg dimethadione b.i.d. on gestation day 9, 10 with additional groups given one additional dose of dimethadione 12 hr earlier, 12 hr later or two additional doses 12 hr earlier and later. Caesarian sections occurred on gestation day 21 and fetuses were examined for standard developmental toxicity endpoints. RESULTS: The broadest dosing regimen yielded the highest incidence and the most severe heart and axioskeletal findings with a decrease in mean fetal body weight. The overall incidence of ventricular septation defects was 74%, of which 68% were membranous and 9% muscular. Outflow tract anomalies (17%) were also observed, as were malformations of the axioskeleton (97%), but not of the long bones, and of particular interest was the high incidence of sternoschesis. CONCLUSIONS: Unlike trimethadione, dimethadione induces more serious muscular septation defects that are believed to be more clinically relevant. This, when taken together with the high incidence of total septation anomalies suggests dimethadione is useful for the study of chemically induced ventricular septation defects.

The clinical importance of the trimethadione tolerance test as a method for quantitative assessment of hepatic functional reserve in patients with biliary atresia.

BACKGROUND: The trimethadione (TMO) tolerance test was performed to evaluate its usefulness in the assessment of hepatic functional reserve in patients with biliary atresia. METHOD: Nineteen patients with biliary atresia after hepatic portoenterostomy (age range: 2 months to 25 years; sex: 6 males and 13 females) were studied. The study was performed in the morning after a 12-h fast. TMO was given orally, at a dose of 4 mg/kg, with 5 mL of 5% glucose 2 h before breakfast. Blood samples (0.5 mL) were collected to determine serum TMO and dimethadione (DMO), a metabolite of TMO, levels 4 h after the administration of TMO. TMO and DMO were measured by a gas-liquid chromatographic method. RESULTS: A higher total bilirubin level (over 1 mg/dL) in patients with jaundice was reflected in the smaller serum DMO/TMO ratio 4 h after the oral administration of TMO. In addition, these patients with total bilirubin levels of 1 mg/dL or less had a significantly lower DMO/TMO ratio than the control group (healthy subjects). The serum DMO/TMO ratio showed a close correlation with the Child-Pugh score, which is used for overall evaluation of severity of cirrhosis and Mayo risk scores for primary biliary cirrhosis in adults (0.856, P < 0.01 and 0.788, P < 0.01, respectively). The TMO tolerance test shows the benefit of performing a relatively early test of dynamic liver function to evaluate hepatic functional reserve in pre- and post-operative biliary atresia patients.

Trimethadione as a probe drug to estimate hepatic oxidizing capacity in humans.

Trimethadione (TMO) has the properties required of probe drugs for the evaluation of hepatic drug-oxidizing capacity in humans in vivo. TMO is demethylated to dimethadione (DMO), its only metabolite, in the liver after oral administration. Involvement of two cytochrome P450's--CYP2C9 and 3A4--in TMO metabolism has been seen in humans, but involvement of 1A2 is not clearly established. In humans with various types of liver disease and hepatectomy, the serum DMO/TMO ratios, which were measured on blood samples obtained by a single collection 4 hr after oral administration of TMO, correlated well with the degree of hepatic damage. This finding suggests that TMO may be used as a probe drug in the rapid determination of the functional reserve mass of the liver as well as hepatic drug-oxidizing capacity in humans in vivo.

Effect of antiepileptic drugs on absence-like seizures in the tremor rat.

We examined the effects of conventional antiepileptic drugs (AEDs) on absence-like seizures in homozygous tremor rats (tm/tm) to determine if they corresponded pharmacologically to human absence seizures and absence-like seizures in spontaneously epileptic rats (SER: zi/zi, tm/tm) with both tonic convulsive and absence-like seizures. Cortical and hippocampal EEG activity was recorded with chronically implanted electrodes. The effects of AEDS on seizures of the tremor rat showed profiles similar to those observed in human absence seizures and also in absence-like seizures of SER. The absence-like seizures, associated with paroxysmal bursts of 5-7-Hz spike-wave complexes, were inhibited by trimethadione (TMO 200 mg/kg intraperitoneally, i.p.), ethosuximide (ESM 100 and 200 mg/kg, i.p.), valproate (VPA 100 mg/kg, i.p.), and phenobarbital (PB 10 and 20 mg/kg, i.p.). Phenytoin (PHT 20 mg/kg, i.p.) was ineffective. These results are consistent with the conclusion that the tremor rat is a useful model for evaluating new AEDS for human absence seizures.

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.

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.

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.

Dissolution of pancreatic stones.

Chronic calcific pancreatitis (CCP) is the most clear-cut form of chronic pancreatitis. Till date, the common treatment of CCP has been directed toward discontinuation of alcohol consumption if the disease is associated closely with alcohol abuse, relief of pain, enzyme replacement, and the management of some complications like diabetes mellitus, cyst or abscess of the pancreas, malnutrition etc. In 1979, the research group for chronic pancreatitis in Japan proposed the therapeutic policy for this disease as illustrated in Fig. 1. A plausible new treatment is the dissolution of protein precipitates or calcified stones in pancreatic ducts by oral or intravenous administration of drugs.

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.

Comparison of trimethadione and antipyrine as indicators of oxidative drug metabolizing capacity in man.

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. Whether administered alone or together the clearance (CL) and half-life (t 1/2) of TMO and AP were the same, and there was a good correlation between the CL and t 1/2 of TMO and AP (alone r = 0.755 and 0.623, respectively; coadministered r = 0.771 and 0.503, respectively). Excretion of AP and its main metabolite and the clearance for production of AP metabolites after AP was administered alone were not significantly different when TMO and AP were taken together. When the two drugs were administered alone or coadministered, the correlation between the CL of TMO and the excretion of 3-hydroxymethyl-3-norantipyrine (NORA) was close (alone r = 0.734, coadministered r = 0.749). The correlation between the CL of TMO and CLm of NORA when TMO and AP were given alone or concomitantly was 0.762 and 0.772, respectively. The findings suggest that TMO metabolism and the formation of NORA in healthy subjects are mediated by a closely related form(s) of the cytochrome P-450 system.

Dissolution of pancreatic stones by oral trimethadione in a dog experimental model.

Experiments were conducted to develop a dissolution therapy for human pancreatic calculi in a dog experimental model of pancreatic calculi surgically prepared. On plain x-ray films of the abdomen, pancreatic calculi appeared in 19 of 39 dogs within 12 mo after operation. The antiepileptic agent trimethadione was given orally to 13 dogs at a dose of 1.0-1.5 g daily. Pancreatic calculi disappeared in 13 of 15 observations. The scanning electron microscopy, the elemental analysis, and the powder x-ray diffractometry of pancreatic calculi in this model revealed that the calculi closely resembled human pancreatic calculi, consisting mainly of a calcite of calcium carbonate. There was no histologic finding suggesting drug toxicity in the liver, the kidney, and the blood. Pancreatic calculi in 6 control dogs without the treatment neither disappeared nor diminished spontaneously. The oral treatment with trimethadione may have potential for dissolving human pancreatic calculi.

Protection from oxygen-induced seizures by clonazepam and propylene glycol.

General anesthetics, ganglionic blocking agents, anticonvulsants, and antioxidants have been shown to afford protection from seizures caused by exposure to hyperbaric oxygen. In the present study cats were exposed to 5 ATA oxygen in pairs in a hyperbaric chamber until both the control and pretreated cat convulsed or for a maximum 120 min exposure. Small amounts of four common antiepileptic agents and propylene glycol in amounts far less than previously reported (0.1 to 0.2 ml/kg) were initially tested for potential anticonvulsant activity. Two agents, clonazepam and propylene glycol, offered significant protection in delaying the onset of seizures whereas carbamazepine, valproic acid, and trimethadione appeared to hasten the onset of seizure activity. The time to seizures was increased nearly five times by clonazepam and over three times by very small amounts of propylene glycol.

Pharmacokinetic studies of trimethadione and its metabolite in rats with chemical-induced liver injury.

A rapid and sensitive gas-liquid chromatographic procedure was developed for the measurements of trimethadione (TMO) and its metabolite, 5, 5-dimethyl-2, 4-oxazolidine-dione (DMO) in plasma. TMO and DMO were extracted from plasma by a micro-extraction method and chromatographed on a 10% Carbowax 6000 column using paramethadione as an internal standard. Recoveries of TMO and DMO ranged from 96 to 104% using a 0.1 ml of plasma. The method is capable of measuring at least 5 microgram of TMO and DMO per milliliter. After an oral administration of TMO at a dose of 100 mg/kg, mean plasma levels of TMO and DMO in 6 rats reached a peak of 98 microgram/ml at 0.6 h and 163 microgram/ml at 8 h and declined with a half-life of 2.2 h and 39.4 h, respectively. After the intravenous administration of TMO at a dose of 100 microgram/kg, half-lives of TMO and DMO were 2.5 h and 39.1 h, respectively. Pretreatment of rats with carbon tetrachloride, d-galactosamine amd alpha-naphthyl isothiocyanate, prolonged T 1/2 and Tmax of TMO, reduced the Km value and increased the AUC. These results suggest that plasma levels of TMO and DMO might be useful as an index of drug metabolizing capacity in animal and man.

[Quantitative analysis of conditional-optimal doses of succilep and trimetin in the treatment of children and adolescents with minor forms of epilepsy]. / Kolichestvennyi analiz uslovno-optimal'nykh doz suksilepa i trimetina pri lechenii malykh form épilepsii u detei i podrostkov.

On the basis of a study of 156 patients the authors with the aid of a computer convened a dispersion analysis of interaction found in the process of treatment by conditional optimal doses of trimetin and succilep with 23 clinical parameters of the disease. It was established that on a statistically significant level the largest dose of trimetin (per 1 kg of body weight) was required in the treatment of myoclonic forms of seizures, with duration less that one year, pathological changes in the craniogram, signs of hypertension and the absence of prenatal noxious factors and pathology in the neurological state. The interaction of optimal doses of succilep with the cliniel characteristics is less expressed than for Trimetin and on a significant level is detected only for two of them: a larger dosage in longer duration of the disease and in the existence of prenatal noxious factors in the past history. It was established that with years the used amount of trimetin adn saccilep (per 1 kg of body weight) declines, while the therapeutical effectiveness does not drop.

The photically evoked afterdischarge: a model for the study of drugs useful in the treatment of petit mal epilepsy.

Lightly restrained albino rats were administered dipropylacetic acid, trimethadione, diphenylhydantoin, saline, and a pentylenetetrazol challenge. The results were attributed to the locus of action of the anticonvulsants and strongly support the usefulness of the photically evoked after discharge as a model for the evaluation of thalamically active drugs, with particular reference to those useful in the control of petit mal epilepsy.