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PubMed1988

High-performance liquid chromatographic determination of valproic acid in plasma using a micelle-mediated pre-column derivatization.

A method for the determination of valproic acid (2-propylpentanoic acid) in plasma by high-performance liquid chromatography (HPLC) after pre-column derivatization is described. The derivatization of valproic acid with a fluorophore and UV label, 4-bromomethyl-7-methoxycoumarin, is performed in plasma diluted with an aqueous micellar system. No extraction or solvent evaporation steps are required. The mechanism of the derivatization of the carboxylic acid is based on phase-transfer catalysis. The sample preparation, including the derivatization step, is rapid and very simple. The proposed HPLC-method was evaluated and compared with a standard immunological assay used for the determination of valproic acid in plasma.

Chromatography, High Pressure Liquid↗
PubMed2007

Valproic acid aggravates epilepsy due to MELAS in a patient with an A3243G mutation of mitochondrial DNA.

Epilepsy is one of the most common presentations of patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). MELAS is typically caused by an A-to-G substitution at nucleotide position 3243 of mitochondrial DNA. Valproic acid, a common anticonvulsant, can actually increase the frequency of seizures in individuals with MELAS. Here, we report a single case-study of a 38-year-old man who presented with focal seizures and had MELAS Syndrome due to the A3243G mitochondrial DNA mutation. Manifestation of epilepsia partialis continua was aggravated by use of valproic acid. Convulsions abated after discontinuation of valproic acid. Our experience suggests that valproic acid should be avoided for the treatment of epilepsy in individuals with mitochondrial disease.

Adult↗
PubMed2000

Assessment of drug concentrations in tears in therapeutic drug monitoring: I. Determination of valproic acid in tears by gas chromatography/mass spectrometry with EC/NCI mode.

A rapid and sensitive method for the quantitation of valproic acid in tears has been developed using gas chromatography/electron capture negative chemical ionization/mass spectrometry. Valproic acid was converted directly into its pentafluorobenzyl ester derivative without the need to perform any extraction from the biologic fluid. The concentrations in tears [C]t correlated very well with those of the free form in the plasma [Cf]p and those of the total form in the plasma [Cb+f]p. The ratios between valproic acid concentrations in tears and plasma were as follows: [C]t/[Cb+f]p = 0.10 +/- 0.02; [C]t/[Cf]p = 0.57 +/- 0.11. Ratios of [C]t/[Cb+f]p were in good agreement with previously published data.

Anticonvulsants↗
PubMed2006

Medroxyprogesterone - valproic acid - aspirin. MVA regime to reduce transfusion associated mortality in late-term hemoglobinopathies. Hypothesis and rationale.

Medroxyprogesterone acetate (MPA) - a safe depot contraceptive - is shown previously to reduce painful crises of sickle cell anemia, which is parallel with the recent findings showing progesterone induction of fetal hemoglobin genes. This would be a way to reduce transfusions for late term thalassemia major and sickle cell-disease cases with no chances left for a stem cell transplantation. In these patients, transfusional hemosiderosis causes irreversible damage to many organs despite the available iron-chelating agents. Pharmacological strategies either target the conformal structure of the defective adult hemoglobin or aim to activate fetal hemoglobin concentrations. The only concern on MPA may be its thromboembolic risks, which may be uncoupled with agents acting both anti-coagulant and inductive on the blood oxygen-carrying affinity. Such agents could be valproic acid and aspirin. Valproic acid is being safely used to treat epilepsy and its histone acetylating function may lead its induction of fetal hemoglobin. Aspirin was shown to increase oxygen affinity of hemoglobin via acetylating lysine residues and its general acetylating activity on proteins such as histones makes it also an interesting candidate to activate fetal hemoglobin. We propose that combining MPA with clinically available doses of valproic acid and aspirin would be beneficial in terms of both reduced coagulation risks and increased oxygen affinity to decrease the transfusions and to improve the prognosis in late-phase hemoglobin disorders.

Aspirin↗
PubMed2002

Valproic acid in migraine prophylaxis of young patients. Three new reports.

Several clinical studies report the efficacy of valproic acid in migraine prophylaxis of adult patients and its well tolerability. In childhood and adolescent patients its use is usually restricted to epilepsy and very few cases have been reported in literature on the use of valproic acid for "juvenile migraine". We describe three pediatric patients fulfilling the International Headache Society (IHS) criteria for migraine with and without aura treated with low dose of sodium valproate (10 mg/Kg/die) for six months. They had previously undergone other migraine preventive treatment unsuccessfully. We obtained a good response in all cases: in only one subject, prophylactic treatment was stopped because of weight gain, as adverse effect. In conclusion, in accord with other authors, we suggest that valproic acid may be helpful in the prophylaxis migraine in pediatric age.

Adolescent↗
PubMed1985

Effects of phenobarbital, clonazepam, valproic acid, ethosuximide, and phenytoin on the delayed matching-to-sample performance of pigeons.

The effects of phenobarbital, clonazepam, valproic acid, ethosuximide, and phenytoin were examined in pigeons performing under a delayed matching-to-sample procedure. Clonazepam, valproic acid, ethosuximide, and phenytoin typically reduced the rate of responding to the sample stimulus, whereas phenobarbital usually increased response rates at high doses. Phenobarbital, clonazepam, and valproic acid produced generally dose-dependent decreases in accuracy; ethosuximide and phenytoin failed to do so. These results suggest that there are qualitative as well as quantitative differences in the effects of anticonvulsant drugs under the delayed matching-to-sample procedure.

Animals↗
PubMed1993

Effect of unbound clearance on binding parameters of valproic acid to serum proteins.

Nine healthy subjects received 400 mg sodium valproate orally in the fasting state. Binding parameters of valproic acid to serum proteins were determined by Scatchard analysis for individual series of valproic acid data. Total and unbound (intrinsic) clearances (CLt and CLu) were calculated by dividing the dose by the appropriate area under the serum drug concentration-time curve. Unbound clearance correlated positively with the product of association constant (Ka) and concentration of free protein ((P)) (P < .05). Conversely, no significant correlation was found between CLt and binding parameters. The average unbound concentration correlated negatively with both CLu and ka(P) values. The result indicates an effect of CLu on Ka(P) value of valproic acid.

Administration, Oral↗
PubMedDate not supplied

Pharmacokinetics of valproic acid in volunteers after a single dose study.

The pharmacokinetics of valproic acid (VPA) was investigated in six healthy volunteers. This was done by monitoring total and free (unbound) valproic acid levels in the serum, and the amount of one of its metabolites, VPA glucuronide, in the urine as a function of time, after a single dose administration of the parent drug. VPA half-life calculated from the urine data of the metabolite was shorter than the half-life calculated from the blood data. About 15 to 20 per cent of the administered oral dose of VPA was excreted in the urine as VPA glucuronide. The average free fraction of VPA obtained in this study, by using the EMIT technique, ranged from 1.5 to 11.5 per cent with a mean value of 4.9 per cent.

Adult↗
PubMedDate not supplied

Evaluation of bone mineral metabolism in children receiving carbamazepine and valproic acid.

Dual energy X-ray absorptiometry (DXA) was used to assess lumbar spine (L2-4) and femoral neck bone mineral density (BMD) in 36 children taking either carbamazepine or valproic acid for longer than one year, for generalized idiopathic epilepsy. Patients were matched with controls. Biochemical parameters of bone mineral metabolism were also measured. BMD values at both the femur neck and lumbar spine in both the carbamazepine and valproic acid groups were not significantly different from that of the control group. Serum levels of calcium were subnormal and alkaline phosphatase levels were high in the carbamazepine group. Urinary calcium levels were significantly lower in both groups than in the control group (p< or =0.05) and also significantly lower in the valproic acid group than in the carbamazepine group (p< or = 0.05). There were no other significant biochemical changes in either group. In conclusion, the results suggest that valproic acid and carbamazepine monotherapies have minimal effects on bone mineral metabolism, but routine monitoring of risk and consideration of prophylactic vitamin D supplementation is important.

Absorptiometry, Photon↗
PubMed1992

Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis.

The antiepileptic drug valproic acid (2-propylpentanoic acid; [VPA]) is teratogenic in humans and a number of animal species. Using a murine model, we studied the mechanism of VPA-induced teratogenesis during a period of organogenesis sensitive to interference with closure of the neural tube (days 8 to 9). Teratogenic doses of valproic acid altered the pattern of folate metabolites in the embryo: Levels of 5-formyl- and 10-formyl-tetrahydrofolates decreased, and the level of tetrahydrofolate increased. These changes could be explained by VPA-mediated inhibition of transfer of the formyl group via glutamate formyltransferase. Neural-tube defects, alteration of embryonic folate metabolism, and inhibition of the specific enzyme are all produced by comparable doses and levels of the drug. A closely related structural analog of VPA (2-en-VPA, 2-propyl-2-pentenoic acid), which exhibits antiepileptic activity but not teratogenicity, did not influence the embryonic folate metabolism. Our results suggest that interference with embryonic folate metabolism might be an important aspect of the induction of neural-tube defects by VPA. The novel techniques described also should prove useful in studying the teratogenic mechanisms of other drugs.

Animals↗
PubMed1999

Serum leptin changes in epileptic patients who gain weight after therapy with valproic acid.

Weight gain has been recognized as an adverse effect of valproic acid therapy, but there are are no data about serum leptin levels in patients receiving this drug. To evaluate if valproic acid treatment in epileptic patients in whom obesity develops modifies serum levels of insulin and leptin, 40 female patients with epilepsy were evaluated before therapy and after 1 year of therapy. At the end of follow-up, 15 patients were obese and showed higher serum leptin and insulin levels than patients who did not gain weight. As in other types of obesity, elevation of serum leptin concentrations is related to the increase in body mass index.

Adolescent↗
PubMed2006

CACNA1A mutation in a EA-2 patient responsive to acetazolamide and valproic acid.

BACKGROUND: Episodic ataxia type-2 (EA-2) is an autosomal dominant neurological disorder that has been shown to result from mutations in the CACNA1A gene encoding the P/Q-type calcium channel. Affected individuals experience episodes of cerebellar ataxia usually associated with migraine symptoms, interictal nystagmus, mild residual and in some cases a progressive cerebellar incoordination and respond to acetazolamide treatment. We identified a patient with a positive family history for episodic ataxia, who was originally diagnosed with epilepsy and treated with valproic acid. Subsequent examination revealed that the symptoms were consistent with a diagnosis of EA-2. The patient responded positively to a combination of acetazolamide and valproic acid. Molecular genetic analysis of the CACNA1A gene was performed in order to confirm a diagnosis of EA-2. METHODS: The CACNA1A gene was evaluated for mutations using single strand conformational polymorphism analysis and direct DNA sequencing. Allele specific oligo hybridization was used to confirm that the mutation was segregating with only affected family members and was not present in the control group. RESULTS: In this study we identified a new missense mutation in exon 12 of the CACNA1A gene from a patient with EA-2 whose symptoms could be controlled with a combination of acetazolamide and valproic acid. This G to A transition changes a highly conserved glutamic acid residue to a lysine residue in domain II S2 of the P/Q-type calcium channel alpha1A subunit. CONCLUSIONS: The use of valproic acid in treating patients with EA-2 is not well documented. Here we describe a patient with a novel mutation in the CACNA1A gene who responded positively to a combination of acetazolamide and valproic acid.

Acetazolamide↗
PubMed2002

Comparison of the efficacy of carbamazepine, haloperidol and valproic acid in the treatment of children with Sydenham's chorea: clinical follow-up of 18 patients.

In order to compare and contrast the efficacy of haloperidol, carbamazepine, and valproic acid in the treatment of Sydenham's chorea a prospective study including 18 cases of this disorder was undertaken. Age of patients ranged from 7 to 15 years. Ten children were female and 8 were male. All but one had generalized, either symmetric or asymmetric chorea. The patients were divided in three equal groups, and were given a standardized dose of each of the drugs built-up over a week. Following therapy, the six children receiving valproic acid showed remarkable improvement, without side effects. Five patients receiving carbamazepine showed improvement without side effects. Only three of the patients that received haloperidol improved. In the 4 cases that did not show clinical improvement after one week of treatment, therapy with valproic acid led to disappearance of the symptoms in a lapse that ranged from 4 to 7 days. Recurrence related to discontinuation of treatment was observed in two patients. In view of the present results we recommend valproic acid as the first choice drug to treat Sydenham chorea.

Adolescent↗
PubMed1993

Hyperammonemia secondary to valproic acid as a cause of lethargy in a postictal patient.

Hyperammonemia has been described as a complication of valproic acid therapy but may often be overlooked as a cause of lethargy in the postictal patient who presents to the emergency department. We present the case of a postictal patient with lethargy, hyperammonemia, otherwise normal liver function tests, and a therapeutic valproic acid level. Based on our experience and on previously published data, serum ammonia levels appear to be indicated in all ED patients on valproic acid therapy who present with altered mental status. To the best of our knowledge, this has not been reported previously in the emergency medicine literature.

Adult↗
PubMed1986

Pharmacologic evaluation of various metabolites and analogs of valproic acid: teratogenic potencies in mice.

A number of metabolites of the anticonvulsant drug valproic acid (VPA) as well as related substances were tested in regard to their teratogenicity in the mouse following single sc injections of 600 mg/kg on Day 8 of gestation. VPA was highly teratogenic at this dose level and over 60% of live fetuses had neural tube defects (exencephaly). Homologous compounds with shorter or longer alkyl chains were less teratogenic. Substitution of the alpha-H atoms in related branched carboxylic acids by methyl or ethyl groups abolished the teratogenic response. Introduction of a double bond in the omega-position of VPA (4-en-VPA) did not change the teratogenicity of VPA, while omega-2 double bond (2-en-VPA) abolished teratogenicity. The other VPA metabolites tested as well as two straight-chain acids (n-octanoic acid and 4-pentenoic acid) and the two clinically used substances valpromide (valproic acid amide) and ethosuximide did not induce neural tube defects, although some of them induced slightly increased resorption rates and fetal weight retardation. The serum protein binding capacities of the various compounds did not correlate with the teratogenic response. Also the concentrations reached in the gestational material did not predict the teratogenicity of the substances tested. Our results indicate that the teratogenicity of the class of compounds studied represents a more specific effect than the anticonvulsant activity which could lead to the development of alternative antiepileptic drugs with low embryotoxic potential.

Animals↗
PubMed2000

Effects of valproic acid on fertility and reproductive organs in male rats.

Crj:CD(SD)IGS rats were orally administered valproic acid at doses of 250, 500 or 1000 mg/kg/day for 4, 7 or 10 weeks. At each dose, one group of male rats was euthanized after 4-week dosage (4-week dose group) and the other two were mated with untreated females after 4 (7-week dose group) or 7 (10-week dose group) weeks of treatment with valproic acid and their fertility was evaluated. Females were euthanized on day 14-17 of gestation, and numbers of corpora lutea, implantations and live and dead fetuses were recorded. After 4, 7 or 10 weeks of treatment, males were euthanized, genital organs were weighed, the number of sperm in the cauda epididymis was counted, sperm motion analyzed, and histopathological examination of testes performed. The male rats of the 1000 mg/kg dose group died or were moribund 3 or 4 days after the start of treatment. No effects on fertility of male rats were observed up to the 500 mg/kg 10-week dose group. Treatment for 4 weeks at 500 mg/kg/day decreased epididymis weight. After 7 weeks at 500 mg/kg/day, the weights of epididymis, seminal vesicles and prostate were decreased, and the number of sperm heads per cauda epididymis and percentage of motile sperm were reduced. In the 500 mg/kg 10-week dose group, the weight of testis was decreased. On histopathological examination of the testis, degeneration of seminiferous tubules and loss or exfoliation of spermatids were observed, and the ratio of retention of step 19 spermatids in stage IX-XI was increased in the 500 mg/kg 4-, 7- and 10-week dose groups. These results suggest that analysis of sperm motion and histopathological evaluation of testes are sensitive methods for assessing toxicity of valproic acid on male reproductive organs.

Animals↗
PubMed1985

Effects of phenytoin, phenobarbital, and valproic acid, alone and in selected combinations, on schedule-controlled behavior of rats.

The present study examined the effects of phenytoin (20, 30, 40, and 50 mg/kg), phenobarbital (10, 20, 30, and 40 mg/kg), and valproic acid (80, 120, 160, and 240 mg/kg), and those of phenobarbital (10 and 30 mg/kg) combined with phenytoin (20, 30, and 40 mg/kg) or valproic acid (80, 120, and 160 mg/kg), on the lever pressing of rats maintained under fixed-ratio and interresponse-time-greater-than-t schedules of food delivery. High doses of each individual drug significantly decreased mean group response (and reinforcement) rate under the fixed-ratio schedule. No dose of an individual agent significantly affected mean group response rate under the interresponse-time-greater-than-t schedule, although high doses of phenobarbital and valproic acid significantly reduced the mean group reinforcement rate under this schedule. When given in combination, phenobarbital and phenytoin and phenobarbital and valproic acid significantly reduced response (and reinforcement) rate under the fixed-ratio schedule and reinforcement rate under the interresponse-time-greater-than-t schedule. These reductions did not significantly differ in magnitude from those predicted by an additive model of drug interaction.

Animals↗
PubMed2006

Determination of valproic acid in human serum and pharmaceutical preparations by headspace liquid-phase microextraction gas chromatography-flame ionization detection without prior derivatization.

An efficient and fast extraction technique for the enrichment of valproic acid from human blood serum samples using the headspace liquid phase microextraction (HS-LPME) combined with gas chromatography (GC) analysis has been developed. The extraction was conducted by suspending a 2 microL drop of organic solvent in a 1 mL serum sample; following 20 min of extraction, withdrawing organic solvent into a syringe and injection into a GC with a flame ionization detector (FID), without any further pre-treatment. Four organic solvents, 1-decanole, benzyl alcohol, 1-octanol and n-dodecane, were studied as extractants, and n-dodecane was found to be the most sensitive solvent for valproic acid. The results revealed that HS-LPME is suitable for the successful extraction of valproic acid from human blood serum samples. Parameters like extraction time, ionic strength, pH, organic solvent volume, and temperature of the sample were studied and optimized to obtain the best extraction results. An enrichment factor of 27-fold was achieved in 20 min. The procedure resulted in a relative standard deviation of <13.2% (n=7) and a linear calibration range from 2 to 20 microg mL(-1) (r>0.98), and the limit of detection was 0.8 microg mL(-1) in serum blank samples. Overall, LPME proved to be a fast, sensitive and simple tool for the preconcentration of valproic acid from real samples. The proposed method was also applied to the analysis of valproate in pharmaceutical preparations.

Anticonvulsants↗