Presence Of Valproic Acid Research Articles

Phenacemide: A New clinical pharmacologic perspective

Phenacemide (Phenurone®) is an older antiepileptic agent about which little modern clinical pharmacologic information has been available. As assay was developed to measure serum phenacemide levels, and kinetic parameters were studied. In the course of therapy of maximally severe epilepsy in 21 patients, clinical and pharmacologic data were gathered. The therapeutic range for phenacemide is 50–100 μg/ml. Mean dose to reach these levels is 56 mg/kg/day. It is not strongly bound to serum proteins (76% unbound in serum). Phenacemide clearance was significantly lower in the presence of valproic acid but was not changed by any other antiepileptic drug. Elimination T/2 in one patient was 15 h. Seizures were consistently better in 10 of 21 patients (4 with complex partial seizures, 5 with atypical absences with minor motor phenomena, and 1 with generalized convulsions). No idiosyncratic side effects were seen to affect marrow, liver, skin, kidney, etc. Mood-altering side effects were seen in seven patients: five showed a withdrawn syndrome and two showed a restless syndrome. This drug is not frequently useful, but the availability of modern pharmacologic information will maximize the success when it is used.

Inhibitory effect of valproic acid on metabolic clearance of carbamazepine epoxide.

In order to clarify the inhibitory effect of valproic acid (VPA) on the metabolic clearance of carbamazepine-10,11-epoxide (EPO), an active metabolite of carbamazepine, in rat, the disposition of EPO from plasma and the in vitro hydration of EPO were measured in the presence of VPA, in addition to estimating the effect of the antiepileptic on uridine 5'-diphosphoglucuronyltransferase (UDPGT) activity. It was found that the elimination of EPO from plasma was hardly affected by the pretreatment of VPA (100 mg/kg/d for 7 d). However, the elimination was significantly delayed by VPA at steady-state concentration, maintained by the repeated oral administration of the drug, with a 38% decrease in total clearance and a 52% increase in the fraction of EPO eliminated unchanged in urine. The in vitro hydration of EPO was inhibited competitively by VPA at the concentrations comparable to the in vivo levels. The UDPGT activity of hepatic microsomes was also partly inhibited by VPA. These results suggest that VPA at steady state interferes with the metabolic clearance of EPO, by inhibiting the hydration of EPO and glucuronidation of carbamazepine-trans-diol, a hydrated metabolite.

Glutathione status and the incidence of neural tube defects elicited by direct acting teratogens in vitro.

Valproic acid (VPA), cytochalasin D (CD) and 7-hydroxy-2-acetylaminofluorene (7-OH-AAF) each caused abnormal closure of the anterior neuropore in rat embryos cultured in vitro in the absence of an exogenous bioactivation system. Morphological comparisons showed that although all three compounds prevented normal neural tube closure, each did so in a distinctive manner. Modulation of GSH in cultured rat conceptuses was evaluated to determine whether common responses occurred relative to the ability of different chemicals to elicit neural tube defects. Malformation incidence in embryos (10-14 somites) varied widely following exposure to CD (44%), 7-OH-AAF (29%) or VPA (17%). The incidence of CD-elicited malformations was increased by 50% following GSH depletion by L-buthionine-S, R-sulfoximine (BSO) and was decreased by nearly 60% when the cysteine pro-drug 2-oxothiazolidine-4-carboxylate (OTC) was added to the culture medium. GSH modulation also exerted significant effects on the incidence of abnormal neurulation caused by VPA or 7-OH-AAF. A relatively low incidence of open neural tubes produced by VPA or 7-OH-AAF alone was shown to be a function of the state of maturation in the embryos. Conceptuses cultured in the presence of VPA or 7-OH-AAF from an earlier gestational age (6-10 somites) showed 2-3 fold increases in the number of embryos with open neural tubes. Differential alterations in protein and DNA content were observed among embryos and yolk sacs after various treatments indicating possible differences in the site of embryotoxicity. These results demonstrate the role of GSH status on the capacity of three chemically diverse compounds to elicit abnormal neurulation in cultured rat embryos and suggest some possible mechanisms by which normal neurulation may be compromised.

INTERACTION BETWEEN THIOPENTONE AND SODIUM VALPROATE: An In Vitro and In Vivo Study

The effect of sodium valproate on the binding of thiopentone to serum protein was studied in vitro. In the absence of valproate the unbound fraction of thiopentone was 15.2 +/- 0.64%, but with concentrations of valproic acid in excess of the therapeutic range, it increased to 22.42 +/- 1.65%. Scatchard plots for thiopentone in the absence and presence of valproate were investigated also. The barbiturate was bound by one group of binding sites with the association constant, Ka = 2.81 X 10(3) litre mol-1 and the number of binding sites (n) = 2.3. There was a marked decrease in this association constant in the presence of valproic acid (Ka = 1.82 X 10(3) litre mol-1), but without significant change in the number of binding sites (n = 2.13). Additionally, the effect of administration of sodium valproate i.v. on thiopentone anaesthesia was examined in rabbits. The recovery time from thiopentone was markedly longer in the presence of the anticonvulsant drug (17.0 min v. 37.1 min).

Modified colorimetry of free fatty acids in plasma in the presence of valproic acid.

Modified colorimetry of free fatty acids in plasma in the presence of valproic acid.

Time-dependent interaction between phenytoin and valproic acid.

The diurnal variation in total and free plasma phenytoin (PHT) concentration at steady state was examined in eight epileptic patients receiving combination therapy with tid valproic acid (VPA) as sodium salt. Eight patients treated with PHT, but not with VPA, were studied for comparison purposes. In the absence of VPA coadministration, total and free PHT concentrations did not change significantly during the day and showed only minor intrapatient fluctuations (14 and 13%, respectively). In patients receiving VPA, the mean total PHT did not change significantly, whereas the free PHT increased during the day (p less than 0.05). The fluctuations in total and free PHT in these patients were 16 and 17% on average. In the presence of VPA, the free PHT fraction was higher than in controls (13.9 +/- 2.3% versus 8.3 +/- 1.9%; p less than 0.01) and fluctuated to a greater extent (29 versus 14% in controls; p less than 0.01), mainly as a result of combined opposite swings in both total and free concentration. The diurnal changes in free PHT concentration and fraction correlated positively with the changes in plasma VPA. An inverse relationship between total PHT concentration and plasma VPA was found in some patients. These data demonstrate that the displacement interaction between PHT and VPA is subject to diurnal variation, probably as a result of the fluctuation in plasma VPA. The implications of these findings are discussed.

Teratogenicity of valproic acid: In vivo and in vitro investigations

AbstractThe in vivo teratogenic potential of valproic acid was evaluated in the CD‐1 mouse. Dose selection was based on the estimated lethality curve and several doses were evaluated. Treatment during early organogenesis (Days 8–10) produced a dose related increase in congenital abnormalities which was accompanied by a decrease in fetal weight, Rib and vertebral abnormalities together with exencephaly were the most common defects. Greater embryo mortality was apparent following teatment during late organogenesis (Days 11–13), but the surviving fetuses were less sensitive to the dysmorphogenic effects and cleft palate was now the most common defect, Early neurula stage mouse (Day 9) and rat (Day 10) embryos were cultured in the presence of valproic acid (0.6–1.8 mM) for 48 hr. There was significant reduction in growth which was accompanied by a variety of dysmorphogenic effects. Irregular segmentation of somites together with incomplete and irregular fusion of brain folds were most evident. These were observed at concentrations of valproic acid where no adverse effects on the yolk sac circulatory system were apparent. These in vitro effects appear to be comparable to the in vivo observations and suggest a direct teratogenic action of valproic acid on the developing rodent embryo.

Modification of phenytoin clearance by valproic acid in normal subjects.

1 The effect of valproic acid on the distribution and elimination kinetics of intravenously administered phenytoin has been investigated in eight normal volunteers. 2 In each of the subjects studied the volume of distribution of phenytoin increased significantly during treatment with sodium valproate (1200 mg daily for 7 days). 3 Phenytoin clearance was markedly increased in presence of valproic acid as compared to control values (0.52 +/- 0.17 v 0.38 +/- 0.11 ml min-1 kg-1 respectively, P less than 0.02). 4 It is suggested that the increase of the volume of distribution and of the serum clearance are secondary to displacement of phenytoin from plasma protein binding sites by valproic acid.