Antiepileptic Drugs, 5th Edition




Thomas R. Browne MD

Professor of Neurology, Department of Neurology, Boston University School of Medicine, Boston, Massachusetts

The three marketed succinimide antiepileptic drugs are ethosuximide (Zarontin), methsuximide (Celontin), and phensuximide (Milontin). These drugs are all derivatives of a five-membered succinimide ring (6) (Table 70.1).

Numerous succinimide derivatives have undergone animal screening tests for antiepileptic activity (11,12,38). The results show that methyl and ethyl substitutions at the 2 and 3 positions produce drugs that are more effective against pentylenetetrazol-induced seizures than against maximal electroshock seizures, methylation at the 5 position results in increased activity against pentylenetetrazol-induced seizures, activity against pentylenetetrazol-induced seizures decreases with increasing length of alkyl chain substitutions at the 2, 3, and 5 positions, and phenyl substitution at the 2 and 3 positions decreases activity against pentylenetetrazol-induced seizures and increases activity against maximal electroshock seizures.

Effectiveness against pentylenetetrazol-induced seizures in animals is thought to correlate with clinical efficacy against absence seizures in humans, and activity against maximal electroshock seizures in animals is thought to correlate with activity against tonic-clonic and complex partial seizures in humans (Chapter 3). The rank order of the therapeutic index of succinimides against pentylenetetrazol-induced seizures in animals is (from most to least effective) ethosuximide, methsuximide, and phensuximide (10). Clinical experience indicates that ethosuximide is the most effective succinimide against absence seizures. The rank order of the therapeutic index of succinimides against maximal electroshock seizures in animals is (from most to least effective) methsuximide, phensuximide, and ethosuximide (12). Clinical experience indicates that methsuximide has some efficacy against complex partial seizures, whereas ethosuximide has almost none.

In more recent work, N-desmethylmethsuximide (active metabolite of methsuximide) has been shown to be effective in the spontaneous generalized low-magnesium ion thalamocortical slice model of epilepsy (56). This work predicts efficacy for absence and primarily generalized tonic-clonic seizures (56).


Methsuximide has the structure shown in Figure 70.1. It has the following physical characteristics: molecular weight of 203.23, melting point of 52°C, and water solubility at pH 7.0 (25°C) of mg/mL (24). Methsuximide is prepared by the action of methylamine on methylphenylsuccinic acid (39). Methsuximide is marketed in the United States as 150-mg and 300-mg capsules.


Methsuximide is rapidly demethylated to form 2-methyl-2-phenylsuccinimide (N-desmethylmethsuximide) (Table 70.1) (18,24,32,48,49). Only N-desmethylmethsuximide accumulates in the plasma in detectable quantities during long-term methsuximide administration in children or adults (8,23,24,37,40,48). Gibbs et al. (23) reported no plasma methsuximide concentrations >1 µg/mL in >100 patients receiving long-term methsuximide therapy.








Generic Name

Trade Name





















a Phenyl ring.

b Active metabolite of methsuximide.

From Browne TR. Ethosuximide and other succinimides. In: Browne TR, Feldman RG, eds. Epilepsy: diagnosis and management. Boston: Little, Brown, 1983:215-224, with permission.




FIGURE 70.1. Structure of methsuximide.

Colorimetric and gas-liquid chromatographic methods have been reported for the determination of methsuximide in biologic fluids (18,24,53). However, the sensitivity of these methods is not sufficient to detect the low concentrations of methsuximide present in plasma after administration of methsuximide at typical dosing rates (Figure 70.2) (40,48). Two gas chromatographic-mass spectrometric methods with sufficient sensitivity (0.1 µg/mL) to detect the usual plasma concentrations of methsuximide and N-desmethylmethsuximide have been reported (40,48).

For routine therapeutic drug monitoring, only the plasma concentration of N-desmethylmethsuximide needs to be followed (8,23,37,30,48,52). High-performance liquid chromatographic (24,25,36,49), capillary gas chromatography (10), enzyme-multiplied immunoassay (36), and fluorescence polarization immunoassay (36) techniques have been reported.


FIGURE 70.2. Serum concentration versus time course for methsuximide and N-desmethylmethsuximide after a single 1,200-mg dose of methsuximide. (From Porter RJ, Penry JK, Lacey JR, et al. Plasma concentrations of phensuximide, methsuximide, and their metabolites in relation to clinical efficacy. Neurology 1979; 29:1509-1513, with permission.)


The absorption, distribution, and excretion of methsuximide in animals were reviewed by Porter and Kupferberg (39). Maximal plasma concentration of N-desmethylmethsuximide occurs 1 to 4 hours after an oral dose in humans of all ages (24,37). The protein binding of N-desmethylmethsuximide is 45% to 60% in human plasma (52). Animal research indicates that methsuximide crosses the blood-brain barrier (24,39). Less than 1% methsuximide is excreted unchanged in humans (24).

Biotransformation and Clinical Pharmacokinetics

Methsuximide is rapidly converted to N-desmethylmethsuximide, with an elimination half-life of 1.0 to 2.6 hours (Table 70.2 and Figure 70.2) (24,40,48). N-desmethylmethsuximide is then slowly metabolized, with an elimination half-life of 34 to 80 hours in adults (Figure 70.2) (8,23,40) and 16 to 45 hours in children (37). N-desmethylmethsuximide accumulates to steady-state plasma concentrations that are, on the average, about 600 to 800 times higher than the concentration of the parent drug methsuximide (39,40,48). Based on the following observations, N-desmethylmethsuximide is probably the major antiepileptic substance in the plasma of patients receiving methsuximide: (a) N-desmethylmethsuximide plasma levels


are much higher than methsuximide serum levels; (b) methsuximide and N-desmethylmethsuximide have similar effectiveness against pentylenetetrazol and maximal electroshock seizures in animals (11); and (c) a small clinical trial has shown that methsuximide and N-desmethylmethsuximide have similar clinical effectiveness against absence seizures (57).


Pharmacokinetic Parameter

Range of Values


MSM time to reach maximal serum concentration (hr)a



MSM elimination half-life (hr)b



NDM accumulation half-life (hr)c



NDM elimination half-life (hr)b



NDM elimination half-life (hr)d



NDM elimination half-life (hr)e



Therapeutic range of NDM plasma concentration (µg/mL)


17,40,46, 48,54

MSM, methsuximide; NDM, N-desmethylmethsuximide.

a Adults and children.

b Values for low plasma concentrations of NDM in adults on MSM monotherapy.

c Values for low plasma concentration of NDM in adults taking other antiepileptic drugs.

d Children.

The major urinary metabolites of methsuximide are hydroxylated at the 3 and 4 positions of the phenyl ring by an epoxide-diol pathway (27). This pathway uses the cytochrome P450 enzyme CYP2C19 (26,56). CYP2C19 is discussed in detail in Chapter 58. The following substances are lesser urinary metabolites of methsuximide: unmetabolized methsuximide; N-desmethyl-2-hydroxy-methyl-2-phenylsuccinimide; N,2-dimethyl-3-hydroxy-2-phenylsuc-cinimide; and a dihydrodiol derivative (24,37,39).

The CYP2C19 pathway exhibits nonlinear (concentration-dependent) pharmacokinetics for phenytoin at therapeutic plasma concentrations in humans (Chapter 58). This raises the possibility that N-desmethylmethsuximide may exhibit nonlinear pharmacokinetics at therapeutic plasma concentrations in humans, and my colleagues and I (8) presented indirect evidence of this possibility. If N-desmethylmethsuximide has nonlinear pharmacokinetics, then the elimination half-life of N-desmethylmethsuximide would be longer at steady-state serum concentrations than in single-dose studies (7, 8, 9).

The package insert states that increases in methsuximide dosing rate may be made at weekly intervals. However, increases in methsuximide dosing rate should only be made at intervals of 14 days or longer in adults because (a) a drug's accumulation half-life should be similar to its elimination half-life, and five half-lives are required to attain a steady-state plasma concentration (8); and (b) the elimination half-life of N-desmethylmethsuximide at low plasma concentrations is 34 to 80 hours in adults and may be longer at steady-state plasma concentrations. If methsuximide dosage is increased at weekly intervals, then the plasma concentration of N-desmethylmethsuximide will rise rapidly because of the combined effects of the continuing rise in plasma concentration from the previous dosing rate (which had not risen to steady-state value) and the new increase in dosing rate. This may lead to toxic plasma concentrations of N-desmethylmethsuximide (8).


The plasma concentration of methsuximide in patients taking the usual doses of the drug is so small that it can be measured accurately only by gas chromatography-mass spectroscopy (8,40,48). There is no apparent correlation between the administered dose of methsuximide and the antiepileptic effect or the plasma concentration of methsuximide, presumably because methsuximide is converted to N-desmethylmethsuximide so rapidly (8).

There is a significant correlation between the administered dose of methsuximide and the plasma concentration of N-desmethylmethsuximide (4,48). On average, the plasma concentration of N-desmethylmethsuximide in micrograms per milliliter is 1.6 to 2.0 times the daily dose of methsuximide in milligrams per kilogram (8,48). Several studies indicate that the range of therapeutic plasma concentration of N-desmethylmethsuximide is 10 to 40 µg/mL (8,16,40,46,48,54) in adults. Children appear to tolerate higher plasma concentrations of N-desmethylmethsuximide, and the upper value for the therapeutic range may be 50 µg/mL in children (37,46).


Patients taking methsuximide in addition to phenytoin or phenobarbital have higher values for N-desmethylmethsuximide plasma concentration than patients taking methsuximide alone (41). The addition of methsuximide to a regimen of phenytoin or phenobarbital results in an appreciable increase in the plasma concentration of the latter two drugs in many patients (8,41,47). These observed interactions among phenytoin, phenobarbital, and N-desmethylmethsuximide probably occur as a result of competition for a common arene oxidase metabolic pathway, probably cytochrome P450 CYP2C isoforms shared by all three drugs.

My colleagues and I (8) reported that the addition of methsuximide to primidone was accompanied by a significant (17%, p < .05) increase in the serum concentration of phenobarbital derived from primidone. The addition of methsuximide to carbamazepine was accompanied by a


23% decrease in carbamazepine plasma concentration in six adult patients (p = .08) (8). Similarly, Tennison et al. (50) reported decreases of 26% to 44% in carbamazepine plasma concentration when methsuximide was added to carbamazepine in five children (p = .01). These observations suggest that methsuximide may induce CYP3A4.

The addition of methsuximide to lamotrigine results in a drop in lamotrigine plasma concentration of 36% to 72% (4,34). The addition of methsuximide to combination therapy of lamotrigine and valproic acid also results in a decrease in lamotrigine plasma concentration, but not as great a decrease as when methsuximide is added to lamotrigine monotherapy (34).


Common Side Effects

Large series report side effects of methsuximide in 11% to 57% (median, 35%) of patients taking the drug. The frequency of common side effects of methsuximide is shown in Table 70.3. Because patients are less apt to develop tolerance to the common side effects of methsuximide than with ethosuximide, methsuximide has to be discontinued because of side effects more often than ethosuximide. Some of the drowsiness, irritability, and ataxia reported in association with methsuximide therapy may result from interference with the elimination of phenobarbital or phenytoin caused by methsuximide drug interactions, rather than from a direct toxic effect of methsuximide or its metabolites.


Four reported patients with methsuximide overdose all recovered without sequelae (4,22,30,45). Methsuximide overdose is characterized by stupor and coma, which may develop slowly or may have a biphasic (coma-more alertcoma) course. The late worsening may be the result of conversion of methsuximide to N-desmethylmethsuximide or interference with metabolism of other antiepileptic drugs caused by methsuximide. Other clinical features reported with methsuximide overdosage include respiratory depression, central neurogenic hyperventilation, increased reflexes, decreased reflexes, myoclonus, and second-degree heart block. Charcoal hemoperfusion was employed in one case and was reported to result in a high rate of N-desmethylmethsuximide clearance and rapid clinical improvement (32). A single case of massive combined overdosage of methsuximide and primidone resulted in flaccid coma, respiratory arrest, hypotension, and death (29).





Side Effect

Range (%)

Median (%)

Range (%)

Median (%)






Gastrointestinal disturbances (anorexia, nausea, vomiting, or abdominal pain)



































Any side effect





a Based on 12 published reports. See Browne (6) for original references.

b Based on 8 published reports. See Browne (6) for original references.

From Browne TR. Ethosuximide and other succinimides. In: Browne TR, Feldman RG, eds. Epilepsy: diagnosis and management. Boston: Little, Brown, 1983:215-224, with permission.


Extensive toxicity testing of methsuximide in animals showed no abnormalities on hematologic and chemical tests of blood (12). Autopsy studies of mice, rats, dogs, and monkeys showed no abnormalities except for “mild centrilobular hepatic necrosis” in rats receiving 600 mg/kg/day of the drug (12). These changes were believed to be reversible and of no functional consequence (12).

No serious hepatic damage has ever been attributed to methsuximide. Dow et al. (19) reported an increase in cephalin flocculation in two of 62 patients taking methsuximide. Both patients were taking other antiepileptic drugs as well.

Trolle and Kiorboe (51) reported one case of transient leukopenia in which blood cell counts returned to normal while the patient was still taking methsuximide. Stenzel et al. (47) reported another case of apparently transient leukopenia. Trolle and Kiorboe (51) reported one patient with multiple small bruises in whom a platelet count was not performed.

The only reported fatal blood dyscrasia associated with methsuximide was a case of pancytopenia occurring in a


middle-aged woman 3 months after beginning methsuximide (25). It is not certain that methsuximide was the cause of the pancytopenia because the woman had breast carcinoma and was taking four other medications.

There is a reported case of neonatal hemorrhage after combined maternal therapy with methsuximide and metharbital (5). Other rare reported complications with methsuximide are behavioral changes, confusion, diplopia, headache, periorbital edema, extrapyramidal reactions, Stevens-Johnson syndrome, restless legs syndrome, and reversible osteomalacia (3,17,20,24,39). Methsuximide may precipitate attacks of hepatic porphyria in susceptible patients (42). Rashes can occur with methsuximide (Table 70.3).


Methsuximide possesses activity against both absence and partial seizures. There is considerable experimental evidence that the antiabsence activity of succinimides in general (14,15,31,56), and of N-desmethylmethsuximide in particular (16) (Figure 70.3), is the result of blockage of low-threshold calcium currents (T-calcium currents) of thalamic neurons (Chapter 66). Blockage of T-calcium channels may also inhibit primarily generalized tonic-clonic seizures (56). Because of the structural and functional similarities of methsuximide and N-desmethylmethsuximide with phenytoin, it has been presumed that the antiepileptic activity of methsuximide against partial seizures results from sodium channel inactivation similar to that induced by phenytoin (Chapter 57).


FIGURE 70.3. Effects of N-desmethylmethsuximide (NDM, 200 µmol/L) on calcium currents in a thalamic neuron. Plot of voltage command potential versus transient and sustained calcium current amplitude under control, NDM-exposed, and wash conditions. Transient current was defined as the portion of current that decayed during the 200-millisecond duration of the step command, and the sustained current was defined as the portion of the current that remained at the end of the 200-millisecond step command. NDM specifically reduced the transient, low-threshold calcium current, and this effect was fully reversible. Solid box, control transient current; open box, transient current in the presence of NDM; solid circle, control sustained current; open circle, sustained current in the presence of NDM; solid triangle, recovery. (From Coulter DA, Huguenard JR, Prince DA. Differential effects of petit-mal anticonvulsants and convulsants on thalamic neurones: calcium current reduction. Br J Pharmacol 1990;100:800-806, with permission.)


Absence Seizures

Treatment of absence seizures is the only indication for methsuximide approved by the United States Food and Drug Administration. In four reported series with 20 or more patients in whom methsuximide was used as an adjunctive drug for absence seizures, the seizures were completely controlled in 0% to 31% of cases, and the frequency of absence seizures was reduced by ≥50% in 13% to 66% of cases (19,21,33,58). In the one reported study in which methsuximide was used as the first drug for previously untreated absence seizures, only 20% of patients had a ≥50% reduction in frequency of seizures, and none had complete seizure control (33).

Ethosuximide offers the following advantages over methsuximide for treatment of absence seizures: (a) ethosuximide controls absence seizures in a higher percentage of cases (Chapter 68); (b) the common side effects of succinimides (drowsiness, gastrointestinal upset) are less severe and less persistent with ethosuximide (Table 70.3); (c) ethosuximide plasma concentration determinations are more generally available; and (d) ethosuximide has fewer drug interactions with other antiepileptic drugs (Chapter 67). Methsuximide is indicated for absence seizures only when less toxic drugs fail to control seizures adequately.

Complex Partial Seizures

In eight reported series with 18 or more patients in whom methsuximide was used as an adjunctive antiepileptic drug for complex partial seizures, complete seizure control was obtained in 4% to 30% of patients, and a ≥50% reduction in seizure frequency was obtained in 25% to 80% of patients (1,8,13,17,21,44,54,59). The four most recent series (1,8,17,54) are most applicable to current-day practice and indicate the following: (a) many patients in whom a trial of phenytoin and phenobarbital has failed will have a ≥50% reduction in seizure frequency immediately after the addition of methsuximide; (b) most patients in whom a trial of phenytoin, phenobarbital, and carbamazepine has failed will not have a ≥50% reduction in seizure frequency after the addition of methsuximide; (c) some patients will develop tolerance to the antiepileptic effect of methsuximide


after 4 to 7 months of maximal therapy; (d) the response rate may be higher in patients with focal spike-wave electroencephalographic patterns (complexes consisting of a spike, often blunt, followed by a slow wave at a frequency of 1 to 2 Hz occurring predominantly in one temporal region). In the one reported study in which methsuximide was used as the first antiepileptic drug in previously untreated patients with complex partial seizures, a ≥50% reduction in seizure frequency occurred in 27% of patients, and 18% of patients experienced complete control of seizures (33).

Other Seizure Types

Stenzel et al. (47) reported some success with methsuximide in patients with “complex atypical absences” and “slow spike-wave, or sharp and slow.” Tennison et al. (50) reported some success with methsuximide in children with tonic, “astatic/myoclonic,” and atypical absence seizures. In a review, Schmidt and Bourgeois (43) recommended methsuximide as a fourth-line drug for Lennox-Gastaut syndrome. An open-label study reported good results with methsuximide in the treatment of juvenile myoclonic epilepsy (28). Trials of methsuximide for tonic-clonic and simple partial seizures generally have been discouraging.

Dosage and Administration

The usual starting dose of methsuximide is 300 mg/day. The daily dosage of methsuximide may be increased in increments of 150 mg or 300 mg/day at intervals of at least 2 weeks. The smaller increment is preferred in small children and persons of any age who are taking other antiepileptic drugs because of the longer elimination half-life and, therefore, reduced clearance of N-desmethylmethsuximide in patients receiving polytherapy. Dosage is increased until seizures are controlled, toxicity develops, or a maximal dosing rate of 1,200 mg/day is reached. Because N-desmethylsuccinimide elimination half-life is shorter in children than in adults, children will require a larger dose (mg/kg/day) of methsuximide to attain a given plasma concentration than adults (37).


Conversion factor:


(µg/mL) × 4.92 = µmol/L

(µmol/L) ÷ 4.92 = µg/mL


  1. Ali A, Harden CL, Milrod L, et al. Antiepileptic drugs of last resort: recent clinical experience. Epilepsia1993;34[Suppl 6]: 103.
  2. Aponte CJ, Petrelli MP. Anticonvulsants and vitamin D metabolism. JAMA1973;225:1248.
  3. Baehler RW, Work J, Smith W, et al. Charcoal hemoperfusion in therapy of methsuximide and phenytoin overdose. Arch Intern Med1980;140:1466-1468.
  4. Besag FM, Berry DJ, Pool F. Methsuximide lowers lamotrigine blood levels: a pharmacokinetic antiepileptic drug interaction. Epilepsia2000;41:624-627.
  5. Bleyer WA, Skinner AL. Fatal neonatal hemorrhage after maternal anticonvulsant therapy. JAMA1976;235:626-627.
  6. Browne TR. Ethosuximide and other succinimides. In: Browne TR, Feldman RG, eds. Epilepsy: diagnosis and management.Boston: Little, Brown, 1983:215-224.
  7. Browne TR, Evans JE, Szabo GK, et al. Studies with stable isotopes. I. Changes in phenytoin pharmacokinetics and biotransformation during monotherapy. J Clin Pharmacol1985; 25:43-50.
  8. Browne TR, Feldman RG, Buchanan RA, et al. Methsuximide for complex partial seizures: efficacy, toxicity, clinical pharmacology, and drug interactions. Neurology1983;33:414-418.
  9. Browne TR, Greenblatt DJ, Evans JE, et al. Estimation of a drug's elimination half-life at any serum concentration when the drug's Kmand Vmax are known: calculations and validation with phenytoin. J Clin Pharmacol 1987;27:318-320.
  10. Cardella DS, Leutzow CB, Rafai N, et al. Measurement of methsuximide and N-desmethylmethsuximide using solid phase extraction and wide-bore capillary gas chromatography. Clin Biochem1988;21:329-331.
  11. Chen G, Portman R, Ensor CR, et al. The anticonvulsant activity of ?[SC]-phenyl succinimides. J Pharmacol Exp Ther1951; 103:54-61.

12 Chen G, Weston JK, Bratton AC Jr. Anticonvulsant activity and toxicity of phensuximide, methsuximide and ethosuximide. Epilepsia 1963;4:66-76.

  1. Cardoba EF, Strobos RRJ. N-methyl-?[SC]-?[SC]methylphenylsuccinimide in psychomotor epilepsy. Dis Nerv Syst 1956;17: 383-385.
  2. Coulter DA, Huguenard JR, Prince DA. Specific petit-mal anticonvulsants reduce calcium currents in thalamic neurones. Neurosci Lett1989;98:74-78.
  3. Coulter DA, Huguenard JR, Prince DA. Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurones. Ann Neurol1989;25:582-593.
  4. Coulter DA, Huguenard JR, Prince DA. Differential effects of petit-mal anticonvulsants and convulsants on thalamic neurones: calcium current reduction. Br J Pharmacol1990;100:800-806.
  5. Dasheiff RM, McNamara D, Dickson LV. Efficacy of second line antiepileptic drugs in the treatment of patients with medically refractive complex partial seizures. Epilepsia1986;27:124-127.
  6. Dobrinska MR, Welling PG. Pharmacokinetics of methsuximide and a major metabolite in dog. J Pharm Sci1977;66:688-692.
  7. Dow RS, Macfarlane JP, Stevens JR. Celontin in patients with refractory epilepsy. Neurology1958;8:201-207.
  8. Drake ME. Restless legs with antiepileptic drug therapy. Clin Neurol Neurosurg1988;90:151-154.
  9. French EG, Rey-Bellet J, Lennox WG. Methsuximide in psychomotor and petit-mal seizures. N Engl J Med1958;258: 892-894.
  10. Gellman V. A case of accidental methsuximide (Celontin) ingestion. Manitoba Med Rev1956;45:141-143.



  1. Gibbs EL, Gibbs TJ, Appell MR. Subtle side effects caused by Dilantin and Celontin: a report of two pilot volunteer studies. Clin Electroencephalogr1974;5:192-198.
  2. Glazko AJ, Dill WA. Other succinimides. Methsuximide and phensuximide. In: Woodbury DM, Penry JK, Schmidt RP, eds. Antiepileptic drugs.New York: Raven Press, 1972:455-464.
  3. Green RA, Gilbert MG. Fatal bone marrow aplasia associated with Celontin therapy. Minn Med1959;42:130.
  4. Hall SD, Guengerich FP, Branch RA, et al. Characterization and inhibition of mephenytoin 4-hydroxylase activity in human liver microsomes. J Pharmacol Exp Ther1987;240:216-222.
  5. Horning MG. Metabolism of N,2-dimethyl-2-phenylsuccinimide (methsuximide) by epoxide-diol pathway in rat, guinea pig, and human. Res Commun Chem Pathol Pharmacol1973;6:565-578.
  6. Hurst DL. Methsuximide therapy of juvenile myoclonic epilepsy. Seizure1996;5:47-50.
  7. Johnson GF, Least CJ Jr, Serum JW, et al. Monitoring drug concentration in a case of combined overdosage with primidone and methsuximide. Clin Chem1976;22:915-921.
  8. Karch SB. Methsuximide overdose: delayed onset of profound coma. JAMA1973;223:1463-1465.
  9. Klunk WE, Convey DF, Ferendelli JF. Structure activity relationships of alky-substituted ?[SC]-butyrolactones and succinimides. Mol Pharmacol1982;27:444-450.
  10. Kupferberg HJ, Yonekawa WD, Lacy JR, et al. Comparison of methsuximide and phensuximide metabolism in epileptic patients. In: Gardner-Thrope C, Janz D, Meinardi H, et al., eds. Antiepileptic drug monitoring.Tunbridge Wells, UK: Pitman Medical, 1977:173-180.
  11. Livingston S, Pauli L. Celonin in the treatment of epilepsy. Pediatrics1957;19:614-617.
  12. May TW, Rambeck B, Jurgens U. Influence of oxcarbazepine and methsuximide on lamotrigine concentrations in epileptic patients with and without valproic acid comedication: results of a retrospective study. Ther Drug Monit1999;21:175-181.
  13. Meatherall R, Ford D. Isocratic liquid chromatographic determination of theophylline, acetaminophen, chloramphenicol, caffeine, anticonvulsants, and barbiturates in serum.Ther Drug Monit1988;10:101-115.
  14. Miles MV, Howlett CM, Tennison MB. Determination of N-desmethylmethsuximide serum concentrations using enzyme-multiplied and fluorescence polarization immunoassays.Ther Drug Monit1989;11:337-342.
  15. Miles MV, Tennison MB, Greenwood RS. Pharmacokinetics of N-desmethylmethsuximide in pediatric patients. J Pediatrics1989;114:647-650.
  16. Miller CA, Long LM. Anticonvulsants: an investigation of N-R-?[SC]-R1-?[SC]-phenylsuccinimides. J Am Chem Soc1951;73: 4895-4898.
  17. Porter RJ, Kupferberg HJ. Other succinimides: methsuximide and phensuximide. In: Woodbury DM, Penry JK, Pippenger CE, eds. Antiepileptic drugs,2nd ed. New York: Raven Press, 1982: 663-671.
  18. Porter RJ, Penry JK, Lacey JR, et al. Plasma concentrations of phensuximide, methsuximide, and their metabolites in relation to clinical efficacy. Neurology1979;29:1509-1513.
  19. Rambeck B. Pharmacological interactions of methsuximide with phenobarbital and phenytoin in hospitalized epileptic patients. Epilepsia1979;20:147-156.
  20. Reynolds NC, Miska RM. Safety of anticonvulsants in hepatic porphyrias. Neurology1981;31:480-484.
  21. Schmidt D, Bourgeois B. A risk-benefit assessment of therapies for Lennox-Gastaut syndrome. Drug Saf2000;22:467-477.
  22. Scholl ML, Abbot JA, Schwab RS. Celontin: a new anticonvulsant. Epilepsia1959;1:105-109.
  23. Schulte CJA, Good TA. Acute intoxication due to methsuximide and diphenylhydantoin. J Pediatr1966;68:635-637.
  24. Sigler M, Strassburg HM, Boenigk HE. Effective and safe but forgotten: methsuximide in intractable epilepsies in childhood. Seizure2001;10:120-124.
  25. Stenzel E, Boenigk HE, Rambeck B. Methsuximide in der Epilepsiebenhandlung. Nervenarzt1977;48:377-384.
  26. Strong JM, Abe T, Gibbs EL, et al. Plasma levels of methsuximide and N-desmethylmethsuximide during methsuximide therapy. Neurology1974;24:250-255.
  27. Szabo GK, Browne TR. Improved isocratic liquid-chromatographic simultaneous measurement of phenytoin, phenobarbital, primidone, carbamazepine, ethosuximide, and N-desmethylsuximide in serum. Clin Chem1982;28:100-104.
  28. Tennison MB, Greenwood RS, Miles MV. Methsuximide for intractable childhood seizures. Pediatrics1991;87:186-189.
  29. Trolle R, Kiorboe E. Treatment of petit-mal epilepsy with new succinimides: PM60 and Celontin (a clinical comparative study). Epilepsia1960;1:587-697.
  30. Wad N, Bourgeois B, Kramer G. Serum protein binding of desmethyl-methsuximide. Clin Neuropharmacol1999;22: 239-240.
  31. Watson JR, Lawrence RC, Lovering EB. Simple GLC analysis of anticonvulsant drugs in commercial dosage forms. J Pharm Sci1978;67:950-953.
  32. Wilder BJ, Buchanan RB. Methsuximide for refractory complex partial seizures. Neurology1981;31:741-744.
  33. Wright JD, Helsby NA, Ward SA. The role of S-mephenytoin hydroxylase (CYP2C19) in the metabolism of the antimalarial biguanides. Br J Clin Pharmacol1995; 39:441-444.
  34. Zhang YF, Gibbs JW, Coulter DA. Anticonvulsant drug effects spontaneous thalamocortical rhythms in vitro:valproic acid, clonazepam, and alpha-methyl-alpha-phenylsuccinimide. Epilepsy Res1996;5:37-53.
  35. Zimmerman FT. New drugs in the treatment of petit-mal epilepsy. Am J Psychiatry1953;109:767-773.
  36. Zimmerman FT. Milontin in the treatment of epilepsy. NY State J Med1955;56:1460-1465.
  37. Zimmerman FT. N-methyl-?[SC]-?[SC]-methylphenylsuccinimide in psychomotor epilepsy therapy. Arch Neurol Psychiatry1956;76:65-71.