Drug Loading- Anticonvulsants
                        =============================

Van Der Meyden CH, Kruger AJ, Muller FO, Rabie W, Schall R
Acute oral loading of carbamazepine-CR and phenytoin in a double-blind
randomized study of patients at risk of seizures.
Epilepsia 1994 Jan-Feb;35(1):189-94

The serum levels and side effects of an acute oral loading dose-schedule of
carbamazepine (CBZ) divitabs [CBZ controlled release (CR)] and phenytoin
(PHT) were assessed in patients at risk of seizures. CBZ-CR and PHT were
administered to 42 adult patients (21 each) at a dosage of 20 mg/kg with a
minimum and maximum dosage of 1,200 and 1,600 mg in patients weighting < 60
and > 80 kg, respectively. CBZ-CR was given as single loading dose; PHT was
split, with two thirds of the dose administered at 0 h and one third
administered 2 h later. The 24- and 36-h doses were assessed according to
the nystagmus status at 24 h. Mean CBZ serum levels (percentage of subjects
with level > 4 micrograms/ml shown in parentheses) were 0.0 (0%), 5.2 (62%),
6.7 (81%), 6.8 (95%), and 6.1 micrograms/ml (95%) at 0, 4, 8, 24, and 48 h
after loading, respectively, and mean PHT levels (percentage of subjects
with PHT level > 10 micrograms/ml in parentheses) were 0.1 (0%), 13.2 (86%),
16.3 (100%), 16.3 (100%), and 15.4 micrograms/ml (82%). One subject in the
CBZ group and 3 in the PHT group vomited. Clinical effects did not differ
significantly between treatment groups and are reported. Acute doses of
CBZ-CR 20 mg/kg and PHT 20 mg/kg (two-thirds at 0 h and one-third at 2 h)
provided therapeutic levels in most patients in < or = 4 h and were well
tolerated.


(2)


Osborn HH, Zisfein J, Sparano R
Single-dose oral phenytoin loading.
Ann Emerg Med 1987 Apr;16(4):407-12

A single 18 mg/kg dose of oral phenytoin capsules or suspension (mean dose,
1.3 g) was given to 44 patients with recent seizures and no detectable serum
phenytoin level. Mean serum phenytoin levels after loading for patients
receiving capsules were 6.8 micrograms/mL at two hours, 9.7 micrograms/mL at
three to five hours, 12.3 micrograms/mL at six to ten hours, and 15.1
micrograms/mL at 16 to 24 hours. Mean levels for patients receiving
suspension were slightly, but not significantly, lower than for patients
receiving capsules. No seizures occurred during an eight-hour observation
period after loading. Drug toxicity was minimal. Single-dose, 18 mg/kg oral
phenytoin loading provides rapid therapeutic levels and is well tolerated.


(3)


Leite PJ, Tsanaclis LM, Markourakis T, Bittencourt PR
[Loading-doses of carbamazepine and diphenylhydantoin: use in high-risk
patients]
Arq Neuropsiquiatr 1987 Sep;45(3):281-7

Loading-doses of phenytoin (1000 mg) and carbamazepine (600 mg) were given
orally respectively to 10 and 6 patients with uncontrolled epileptic
seizures secondary to acute neurological disorders or alcohol withdrawal. In
the phenytoin group age varied between 12-73 years and serum concentrations
at 2, 4, 6, 8, 12 and 18 hours after drug administration were 7.6, 8.8, 8.7,
8.7, 7.2 and 6.5 micrograms/ml (means). A quantitative method did not detect
important side-effects. In the carbamazepine group age varied between 25-56
years and serum concentrations at the same times were 3.9, 5.3, 6.5, 7.5,
7.4 and 8.2 micrograms/ml. Side-effects were discrete. Further medication
was not necessary in the 24 hours after drug administration. Although both
regimens controlled the clinical situation without relevant side-effects
serum concentrations were sub-therapeutic in the case of phenytoin. We
suggest the ideal phenytoin oral loading-dose is 1500 mg. The carbamazepine
load produced therapeutic concentrations. The stability of serum
concentrations for the period of the study shows that those regimens are
useful in the subacute control of epileptic seizures in the maintenance
treatment of status epilepticus and in alcohol withdrawal.


(4)

Goff DA; Spunt AL; Jung D; Bellur SN; Fischer JH
Absorption characteristics of three phenytoin sodium products after
administration of oral loading doses.
Clin Pharm, 3: 6, 1984 Nov-Dec, 634-8

The absorption characteristics of three phenytoin sodium products
given orally as loading doses in five healthy men were studied. Extended
phenytoin sodium capsules, prompt phenytoin sodium capsules, and phenytoin
sodium injection were administered in a randomized, crossover trial as
single 18-mg/kg doses and as divided doses of 6 mg/kg every three hours
for three doses. Each dose was given with 200 ml of water, and a two-week
washout period followed each treatment. The maximum plasma concentration
(Cmax), time to reach maximum plasma concentration, time to reach the
lower end (10 mg/liter) of the therapeutic range, time to reach a plasma
concentration greater than 15 mg/liter, and time within the therapeutic
range were determined for each loading-dose regimen. Prompt phenytoin
sodium capsules (prompt PHT) given in divided doses produced a mean Cmax
of 22.0 mg/liter, which was significantly higher than that observed with
any of the other loading-dose regimens. In addition, all subjects
receiving prompt PHT in divided doses had plasma phenytoin concentrations
of 10 mg/liter within six hours; only this treatment produced plasma
concentrations greater than 15 mg/liter at nine hours in all subjects.
Plasma concentrations remained within the therapeutic range (10-20
mg/liter) for 81 and 78% of the first 24-hour period for prompt PHT in
divided and single doses, respectively. Adverse effects were minimal in
all regimens. The prompt-release phenytoin sodium capsules used in this
study may provide an alternative means for rapidly achieving therapeutic
phenytoin concentrations in situations where i.v. administration is not
indicated or practical.(ABSTRACT TRUNCATED AT 250 WORDS)