Pharmacology of ACC-9653 (Phenytoin Prodrug)

Summary: ACC-9653, the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin, is a prodrug of phenytoin with advantageous physicochemical properties. ACC-9653 is rapidly converted enzymatically to phenytoin in vivo. ACC-9653 and phenytoin sodium have equivalent anticonvulsant activity against seizures induced by maximal electroshock (MES) in mice following i.p., oral, or i.v. administration. The ED₅₀ doses were 16 mg/kg for i.v. ACC-9653 and 8 mg/kg for i.v. phenytoin sodium. ACC-9653 and phenytoin sodium have similar antiarrhythmic activity against ouabain-induced ventricular tachycardia in anesthetized dogs. The total doses of ACC-9653 or phenytoin sodium necessary to convert the arrhythmia to a normal sinus rhythm were 24 ± 6 and 14 ± 3 mg/kg, respectively. Only phenytoin sodium displayed in vitro antiarrhythmic activity against strophanthidin-induced arrhythmias in guinea pig right atria. In anesthetized dogs, a high dose of ACC-9653 (31 mg/kg) was infused over 15, 20, and 30 min and the responses were compared to an equimolar dose of phenytoin sodium (21 mg/kg). The ACC-9653 and phenytoin sodium treatments produced similar marked reductions in diastolic blood pressure and contractile force ( UVdP/dt ). The maximum effects of each treatment occurred at the time of maximum phenytoin sodium levels. Acute toxicity studies of ACC-9653 and phenytoin sodium were carried out in mice, rats, rabbits, and dogs by i.v., i.m., and i.p. routes of administration. The systemic toxic signs of both agents were similar and occurred at approximately equivalent doses. Importantly, the local irritation of ACC-9653 was markedly less than phenytoin sodium following i.m. administration. Thus, ACC-9653 and phenytoin sodium have similar anticonvulsant, antiarrhythmic, hemodynamic, and acute systemic toxicity effects in experimental animals. The enhanced solubility and nonirritating qualities of ACC-9653 support its clinical development.     

Bioavailability of ACC-9653 (Phenytoin Prodrug)

Summary: The bioavailability of phenytoin from ACC-9653 versus intravenously administered sodium phenytoin was determined using a crossover design for intravenous and intramuscular administration of ACC-9653 to healthy volunteers. Absolute bioavailability of phenytoin derived from ACC-9653 in each subject was calculated as the ratio of the phenytoin area under the plasma concentration time curve for time 0 to infinity [AUC(0-inf)] after ACC-9653 divided by the phenytoin AUC(O-inf) after intravenous sodium phenytoin. The mean absolute bioavailability of ACC-9653 was 0.992 after intravenous administration and 1.012 after intramuscular administration. These data establish that the bioavailability of ACC-9653 is complete following intravenous or intramuscular administration in single-dose volunteer studies. The absolute bioavailability of phenytoin derived from ACC-9653 in subjects with therapeutic plasma phenytoin concentrations is being studied in patients given simultaneous infusions of stable isotope-labeled tracer doses of ACC-0653 and sodium phenytoin.     

Cardiac side effects of phenytoin and carbamazepine. A dose-related phenomenon?

Three patients with dystrophia myotonica and echocardiographic signs of subclinical cardiopathy had cardiac side effects during oral treatment with phenytoin sodium or carbamazepine. These side effects were dose related: ventricular tachycardia appeared at a toxic serum phenytoin level in one patient and disappeared as the concentration fell within the therapeutic range, and atrioventricular block grade 1 developed in two patients at low serum carbamazepine levels, its severity increasing with the drug level. Given the risk of dangerous side effects, cardiac status needs to be carefully assessed before administration of phenytoin or carbamazepine in the treatment of dystrophia myotonica.     

Hypocarnitinemia in the handicapped individuals who receive a polypharmacy of antiepileptic drugs

Decrease in the serum concentrations of total and free carnitine were found in patients who had received multiple doses of antiepileptic drugs, either including or excluding sodium valproate. These concentrations were more depressed in a former patient group. In all patients there were no abnormal losses of carnitine in urine. Several factors which may be relevant to the hypocarnitinemia were surveyed statistically. The univariate correlation analyses revealed that in all the patients the total and the free carnitine levels were each correlated with the values of arm muscle circumference, and they were inversely correlated with the dosages of sodium valproate. Double regression analyses again revealed that the value of arm muscle circumference is the most critical positive factor, and dosage of sodium valproate is the most critical negative contributor, to both the total and the free serum carnitine concentrations. There was, however, some additional negative contribution by the dosage of phenytoin to the total carnitine concentration. These results indicate that although sodium valproate itself reduces the carnitine concentrations in serum, a poor muscle volume and co-administration of phenytoin with sodium valproate enhance hypocarnitinemia.     

The bioavailability of phenytoin

Summary The bioavailability of three commercial products of phenytoin (Epanutin, sodium salt; Phenhydan, calcium salt; Zentropil, free acid) was studied relative to a standard solution of sodium phenytoin. Each preparation was given for 14 days in a daily dose of 300 mg according to a cross over design. The three brands tested were equivalent as to their bioavailability with respect to plasma concentrations during one dosing interval, the area under the plasma level time curve, the time of peak plasma concentration, and the urinary excretion of the primary metabolite. Therefore, these phenytoin brands are bioequivalent and exchangeable for antiepileptic treatment. The standard solution of sodium phenytoin had a higher bioavailability as compared to the commercial products.Supported by Bundesministerium für Jugend, Familie und Gesundheit (342-4801-8/3)     

The role or non-role of ATPase activation by phenytoin in the stabilization of excitable membranes.

The role or non-role of NaK ATPase, Mg ATPase, and CaMg ATPase involvement in stabilization of excitable membranes by phenytoin is critically evaluated. There is no substantial evidence to indicate that the membrane-stabilizing effect of phenytoin is due to activation of the NaK ATPase. Previous reports of activation of the NaK ATPase at low potassium and high sodium are probably not due to phenytoin but to a potassium contamination in the phenytoin solution. In vitro experiments do not provide any clear evidence of any alterations of NaK ATPase properties by phenytoin. However, one cannot rule out the possibility that phenytoin alters the efficiency of the sodium-potassium pump. Likewise, the Ca ATPase is not inhibited by phenytoin. However, there is some evidence that the Mg ATPase in synaptic vesicles is substantially inhibited by phenytoin. There is substantial evidence indicating that phenytoin partially blocks passive diffusion of sodium into stimulated nerves. The mechanism by which phenytoin blocks sodium influx and the relationship of this effect to the drug's anticonvulsant action remain to be determined.     

Phenytoin as an antimanic anticonvulsant: a controlled study

OBJECTIVE: Phenytoin, a classical anticonvulsant, shares with antimanic anticonvulsants the property of blockade of voltage-activated sodium channels. The authors therefore planned a trial of phenytoin for mania. METHOD: Patients with either bipolar I disorder, manic type, or schizoaffective disorder, manic type, entered a 5-week, double-blind controlled trial of haloperidol plus phenytoin versus haloperidol plus placebo. Of 39 patients, 30 completed at least 3 weeks and 25 completed 5 weeks. RESULTS: Significantly more improvement was observed in the patients receiving phenytoin. Added improvement with phenytoin in scores on the Brief Psychiatric Rating Scale and Clinical Global Impression was seen in the patients with bipolar mania but not those with schizoaffective mania. CONCLUSIONS: Blockade of voltage-activated sodium channels may be a common therapeutic mechanism of many anticonvulsants given for mania, and phenytoin may be a therapeutic option for some manic patients.     

Salivary free concentrations of anti-epileptic drugs: an evaluation in a routine clinical setting

OBJECTIVE: This study was aimed at correlating the salivary and serum free concentrations of anti-epileptic drugs (carbamazepine, phenytoin and sodium valproate) in a population of neurological patients in a routine clinical setting. METHOD: Twenty-seven paired serum/saliva specimens from 22 patients: 10 for carbamazepine, 8 for phenytoin and 9 for sodium valproate were obtained to study these correlations. Salivary and serum free concentrations of anti-epileptic drugs, anti-epileptic drug dosing history, and associated information were collected prospectively. The salivary and serum free concentrations of the anti-epileptic drugs were simultaneously quantified using fluorescence polarization immunoassay (TDx analyzer). RESULTS: For both carbamazepine and phenytoin there was a strong correlation between the salivary and serum free concentrations, 0.99 and 0.98, respectively. The mean ratio of salivary to serum free carbamazepine concentration was 1.02 +/- 0.11 and 0.82 +/- 0.15 for phenytoin. A poor correlation between salivary and serum free concentration was observed for sodium valproate (0.70) with a mean ratio of salivary to serum free concentration of 0.48 +/- 0.27. CONCLUSION: Monitoring of free salivary concentrations of anti-epileptic drugs, particularly phenytoin and carbamazepine proved to be a realistic alternative in this routine clinical setting.     

Diazepam-potentiated [H]phenytoin binding is associated with peripheral-type benzodiazepine receptors and not with voltage-dependent sodium channels

In the presence of diazepam, [³H]phenytoin binds with high affinity to brain membranes. The present experiments examined whether this high affinity [³H]phenytoin-binding site co-localized with the standard [³H]phenytoin-binding site on the voltage-dependent sodium channel (VDSC). Veratridine, a pharmacological activator of the voltage-dependent sodium channel, that inhibits standard [³H]phenytoin binding, failed to affect the high affinity diazepam-potentiated [³H]phenytoin binding in brain membranes, suggesting that the potentiated binding interaction resides at a site distinct from the voltage-dependent sodium channel. This possibility was confirmed by anion exchange chromatography of digitonin-solubilized rat brain membranes, as diazepam-potentiated high affinity [³H]phenytoin binding eluted in column fractions that were distinct from [³H]saxitoxin-defined voltage-dependent sodium channels. To examine whether diazepam-potentiated [³H]phenytoin binding might be associated with other ‘classic’ benzodiazepine receptor sites, we tested whether specific ligands for benzodiazepine receptors would either produce or block potentiated [³H]phenytoin binding. Neither agonists, nor antagonists, of the high affinity central-type benzodiazepine receptor affected potentiated [³H]phenytoin binding, suggesting that the high affinity potentiated binding site is not likely associated with central benzodiazepine receptors. Peripheral-type benzodiazepine receptor agonists, however, did potentiate [³H]phenytoin binding, and a specific receptor antagonist (PK11195) attenuated the potentiation seen with diazepam. Overall, these data illustrate that [³H]phenytoin interacts with a novel site in brain membranes that is distinct from the voltage-dependent sodium channel and is allosterically revealed by peripheral-type, but not central-type, benzodiazepine receptor agonists.     

Continuous muscle fiber activity: a case with unusual clinical features

A patient with continuous muscle fiber activity is described. From our search of the literature, we believe this is the oldest patient with a reported case of this disorder, and the symptoms and treatment varied from previously reported cases in these respects: symptoms remained confined to the lower extremities after 18 months had elapsed, there was no response to phenytoin sodium or carbamazepine, and the patient required a full dose of tubocurarine chloride to stop the abnormal myoelectric potentials. A site of dysfunction in the unbranched motor axon is suggested as the locus of generation of the stimulus for the abnormal myoelectric activity.     

An epilepsy mutation in the beta1 subunit of the voltage-gated sodium channel results in reduced channel sensitivity to phenytoin

The antiepileptic drug phenytoin inhibits voltage-gated sodium channels. Phenytoin block is enhanced at depolarized membrane potentials and during high frequency channel activation. These properties, which are important for the clinical efficacy of the drug, depend on voltage-dependent channel gating. In this study, we examined the action of phenytoin on sodium channels, comprising a mutant auxiliary beta1 subunit (mutation C121Wbeta1), which causes the inherited epilepsy syndrome, generalized epilepsy with febrile seizures plus (GEFS+). Whole cell sodium currents in Chinese hamster ovary (CHO) cells coexpressing human Na(v)1.3 sodium channels and C121Wbeta1 exhibited altered gating properties, compared to currents in cells coexpressing Na(v)1.3 and wild type beta1. In addition mutant channels were less sensitive to inhibition by phenytoin, showing reduced tonic block at -70mV (EC(50)=26microM for C121Wbeta1 versus 11microM for wild type beta1) and less frequency-dependent inhibition in response to a 20Hz pulse train ( approximately 40% inhibition for C121Wbeta1 versus approximately 70% inhibition for wild type beta1, with 50microM phenytoin). Mutant and wild type channels did not differ in inactivated state affinity for phenytoin, suggesting that their pharmacological differences were secondary to their differences in voltage-dependent gating, rather than being caused by direct effects of the mutation on the drug receptor. Together, these data show that a sodium channel mutation responsible for epilepsy can also alter channel response to antiepileptic drugs.     

Cognitive Impairment in New Cases of Epilepsy Randomly Assigned to Carbamazepine, Phenytoin and Sodium Valproate

Sixty-four new cases of childhood epilepsy were randomly assigned to either carbamazepine, phenytoin or sodium valproate, and were assessed with cognitive tests before medication and three subsequent times over a year. Carbamazepine in moderate dosage adversely affected memory, but sodium valproate and phenytoin did not.     

A prospective study between carbamazepine, phenytoin and sodium valproate as monotherapy in previously untreated and recently diagnosed patients with epilepsy.

One hundred and eighty one patients with previously untreated epilepsy were randomised to sodium valproate, phenytoin or carbamazepine as monotherapy and followed up for a median period which ranged from 14 to 24 months. All three drugs were highly effective in the control of generalised seizures but less effective for partial seizures. Excellent or good control was achieved with therapeutic levels of sodium valproate and carbamazepine, but with subtherapeutic levels of phenytoin.     

Phenytoin: effects on calcium flux and cyclic nucleotides.

Previous studies have demonstrated that phenytoin alters calcium conductance in isolated presynaptic nerve endings (synaptosomes) from rat or rabbit brain. Drug concentrations of 0.08 mM (20 microgram/ml) or higher inhibit stimulated calcium influx into synaptosomes depolarized by high concentrations of potassium (69 mM) by 7-58%. Calcium transport into undepolarized synaptosomes is only inhibited by 0.4 mM or greater concentrations of phenytoin. Recent investigations show that in mouse brain slices, phenytoin inhibited elevations of cyclic GMP and cyclic AMP produced by ouabain or veratridine. In contrast, elevations of the two cyclic nucleotides produced by high concentrations of potassium were not inhibited by phenytoin, suggesting that the anticonvulsant suppresses depolarization-induced elevation of cyclic nucleotide levels in brain slices by inhibiting influx of sodium into cells. These data indicate that phenytoin inhibits both sodium and calcium influx into cells during cellular depolarization and alters regulation of brain cyclic nucleotide levels. Both of these actions may be important for the antiepileptic effect of phenytoin.     

Exacerbation of experimental autoimmune encephalomyelitis after withdrawal of phenytoin and carbamazepine

OBJECTIVE: In vitro observations and studies in murine experimental autoimmune encephalomyelitis (EAE) have shown protective effects of sodium channel blockers on central nervous system axons and improved clinical status when treatment is continued throughout the period of observation. Several clinical studies of sodium channel blockers are under way in patients with multiple sclerosis. Here we asked whether a protective effect would persist after withdrawal of a sodium channel blocker. METHODS: We studied a mouse model of myelin oligodendrocyte glycoprotein-induced EAE treated with phenytoin or carbamazepine. RESULTS: Both phenytoin and carbamazepine significantly improved the clinical course of the disease. Withdrawal of phenytoin resulted in acute exacerbation, accompanied by a significantly increased inflammatory infiltrate within the central nervous system and the death of nearly 60% of EAE mice. There were no clinical worsening or deaths in control mice after withdrawal of phenytoin. Withdrawal of carbamazepine led to acute worsening of EAE symptoms, increased inflammatory infiltrate, and was associated with the death of 8% of mice. INTERPRETATION: These results, together with results showing effects of sodium channel blockers in immune cells, raise questions about the long-term effects of sodium channel blockers in neuroinflammatory disorders, and suggest that clinical studies of sodium channel blockers in these disorders should be planned carefully.     

Safety of Valproate in Porphyria Cutanea Tarda

Treatment of epileptic seizures in patients with hepatic porphyrias is a challenging problem due to enzymatic induction activity of phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), and clonazepam (CZP). We present the case of a patient with partial seizures treated with PHT and showing clinical signs and biochemical abnormalities of porphyria cutanea tarda (PCT). We withdrew PHT and treated the patient with sodium valproate (VPA). We followed the patient for 6 months during VPA therapy. During this period, clinical signs of PCT disappeared and biochemical values normalized. Our study shows that VPA is a safe treatment in epileptic patients with PCT.     

Interdosage fluctuations in plasma carbamazepine concentration determine intermittent side effects

Fluctuations in plasma carbamazepine concentrations were related to side effects in five epileptics. One patient was receiving only carbamazepine; four were receiving carbamazepine plus phenobarbital sodium or phenytoin sodium. The patients were studied during two 12-hour periods: carbamazepine given (1) twice daily or (2) four times daily. Concomitant medication regimens were kept constant; administration was single-blind. Plasma concentrations of carbamazepine, carbamazepine's epoxide metabolite, phenobarbital, and phenytoin were determined hourly; side effects were assessed simultaneously. Fluctuations in carbamazepine concentrations were 79% +/- 29% higher than trough levels on a twice-daily dosage schedule and 40% +/- 13% higher during four-times-a-day administration. The appearance and intensity of side effects followed the fluctuations in carbamazepine levels and were thus substantially reduced during the four-times-daily regimen. The intrapatient reproducibility of the side effects was good, whereas the thresholds of carbamazepine concentrations at which side effects appeared ranged from 17 to 37 mumole/L.     

The novel anticonvulsant AWD 140-190 acts as a highly use-dependent sodium channel blocker in neuronal cell preparations

The effect of the new anticonvulsant drug AWD 140-190 (4-(p-bromophenyl)-3-morpholino-1H-pyrrole-2-carboxylic acid methyl ester) on neuronal sodium channels was evaluated in differentiated NG 108-15 cells using the patch clamp technique. AWD 140-190 blocked neuronal sodium channels more potently than phenytoin in a dose-dependent manner (1-30 microM). As with phenytoin, the blocking effect was voltage and frequency dependent. However, comparing equi-effective doses of AWD 140-190 and phenytoin, the frequency dependence was two to three times stronger. This pronounced use dependent effect of AWD 140-190 may be the reason for the superior tolerability and anticonvulsant activity in experimental models of epilepsy.     

Kinetics of CSF phenytoin in children

The efficacy of intravenous phenytoin for the treatment of status epilepticus is related to the rapid entry of phenytoin into brain parenchyma. There is no information concerning the correlation between phenytoin serum and CSF concentrations in children, and the application of CSF data to clinical use. We report 7 children (2-11 yrs) who were treated or exposed to phenytoin in doses between 10.5-230 mg/kg. Lumbar puncture was performed 9 times in 6 of the patients. In one patient, an intraventricular catheter permitted successive assessment of CSF phenytoin concentrations. The ratio of CSF/serum phenytoin concentrations was 0.16 +/- 0.08, with gradual increase over the first 8 hours as the serum phenytoin concentration decreased. There was good correlation between therapeutic outcome and CSF phenytoin levels higher than 2 mcg/ml. In one patient the coma state secondary to phenytoin intoxication was associated with high CSF concentration (6 mcg/ml).     

Salivary and Plasma IgA of Seizure Subjects Receiving Phenytoin

Immunoglobulin A, phenytoin, and protein were determined in plasma, unstimulated and stimulated whole saliva and stimulated and unstimulated parotid saliva from seizure subjects, aged 18 or more, who had ingested phenytoin for 1 year or more from controls. Patient subgroups with low plasma IgA and with gingival overgrowth were evaluated separately. Plasma and salivary phenytoin and ratios of salivary to plasma phenytoin concentrations corresponded to published reports. Plasma IgA was significantly decreased in the total patient group. However, salivary IgA expressed as the concentration or as the proportion of salivary protein, with one exception, was not significantly decreased in any type of saliva from the total patient group or subgroups. Significant phenytoin induced increases in salivary IgA were noted. IgA secretion rate by the parotid gland was significantly increased in the total patient group. This investigation does not indicate a deficiency of oral IgA from chronic phenytoin ingestion. Thus, it appears unlikely that decreased oral IgA with a consequent enhanced susceptibility to inflammation contributes to phenytoin associated gingival overgrowth.