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PubMed2005

Acute seizures due to a probable interaction between valproic acid and meropenem.

OBJECTIVE: To report a probable interaction between meropenem and valproic acid that resulted in the development of epileptic seizures. CASE SUMMARY: A 21-year-old woman presented to our emergency department because of a new-onset, generalized tonic-clonic seizure and was admitted to the intensive care unit. Treatment with valproic acid 1000 mg as a continuous intravenous infusion over 24 hours was initiated. On day 6, the serum concentration of valproic acid was 52.5 microg/mL. On day 13, treatment with intravenous meropenem 1 g 3 times daily was started. On day 15, when the patient was afebrile, numerous myoclonic episodes occurred involving her arms and face; the serum concentration of valproic acid at that time was 42 mug/mL. The valproic acid dose was increased to 2880 mg. Two days later, a generalized tonic-clonic seizure occurred despite the increased dosage, and the plasma concentration of valproic acid fell to 7 microg/mL. The valproic acid dose was increased the following day to 3600 mg; however, the serum concentrations remained <10 microg/mL. On day 19, based on the results of a blood culture and the suspicion of an interaction between meropenem and valproic acid, meropenem therapy was suspended. The serum concentration of valproic acid was 52.4 microg/mL on day 27. Three days later, the patient was asymptomatic and was discharged. DISCUSSION: Coadministration of valproic acid and other drugs that are metabolized by the hepatic cytochrome P450 isoenzyme system can lead to clinically relevant interactions by induction or inhibition of enzymes in shared metabolic pathways. In view of studies in experimental models, the interaction between carbapenem antibiotics and valproic acid is at least possible. Use of the Naranjo probability scale indicated a probable relationship between acute seizures and a meropenem-valproic acid interaction in this patient. CONCLUSIONS: This case report provides strong evidence for an interaction between valproic acid and meropenem. Clinicians should be aware of this potential interaction that may be associated with a serious adverse effect as the result of the decrease of the valproic acid serum concentrations.

Acute Disease↗

PubMed2001

Valproic acid and thrombocytopenia: cross-sectional study.

OBJECTIVE: To investigate the relationship between platelet count and serum valproic acid level, age, duration of valproic acid therapy, and polytherapy, and to determine the clinical significance of thrombocytopenia associated with high-dosage valproic acid therapy. DESIGN: Cross-sectional study. SETTING: Residential unit for neurologically impaired children and paediatric out-patient clinic, Hong Kong. PATIENTS: Ninety-six neurologically impaired children who were treated with valproic acid between 1 July 1991 to 3 June 1999. The comparison group consisted of 48 children receiving antiepileptic drugs other than valproic acid. INTERVENTION: Low- or high-dosage valproic acid, using the threshold value of 40 mg/kg/d. MAIN OUTCOME MEASURES: Platelet count and liver function, duration of valproic acid treatment, dosage, and trough serum valproic acid concentration. RESULTS: Seventeen (17.7%) patients in the treatment group developed thrombocytopenia, compared with two (4.2%) in the comparison group (P<0.05). The platelet count was negatively correlated to serum valproic acid level and age, and positively correlated to polytherapy. The duration of valproic acid treatment was not a confounding factor in the age-related decrease in platelet count. Children with a trough level of >450 micromol/L or a daily dose of >40 mg/kg were more likely to develop thrombocytopenia. Thrombocytopenia was mild in most cases. CONCLUSIONS: A trough valproic acid level of >450 micromol/L or a daily dose of >40 mg/kg should alert the clinician to the risk of developing thrombocytopenia. The risk is further increased for older children. The platelet count should be monitored for patients receiving a high concentration of valproic acid who are also receiving drugs that would affect homeostasis, or who are undergoing surgical procedures.

Adolescent↗

PubMed1988

Common hierarchies of susceptibility to the induction of neural tube defects in mouse embryos by valproic acid and its 4-propyl-4-pentenoic acid metabolite.

The teratogenic effects of valproic acid and its 4-propyl-4-pentenoic acid (4-en) metabolite were investigated in three inbred mouse strains that were known to possess differing sensitivity to heat-induced neural tube defects. In the heat-resistant DBA/2J strain, administration of either valproic acid or the metabolite during the critical period of neural tube development failed to produce any abnormal offspring. Similar treatment in the moderately heat-sensitive LM/Bc strain resulted in up to 19.8% exencephalic fetuses. The highly heat-sensitive SWV strain was also very susceptible to the induction of neural tube defects by either valproic acid or its 4-en metabolite. When administered on gestational day 8 plus 12 hours, the parent compound produced 35% exencephalic fetuses, while the metabolite had a response frequency of 32.4%. Thus, the hierarchy of susceptibility for the induction of neural tube defects in these inbred mouse strains was exactly the same whether the teratogen was a physical agent such as hyperthermia or a chemical compound such as valproic acid. If such diverse agents as these should interact to produce malformations, then it is possible that a wide variety of other agents might interact in a similar manner to produce neural tube defects.

Animals↗

PubMed2005

Analytical performance evaluation of a new turbidimetric immunoassay for valproic acid on the ADVIA 1650 analyzer: effect of gross hemolysis and high bilirubin.

Valproic acid is an anticonvulsant that requires careful therapeutic drug monitoring. Valproic acid is also used in psychiatric patients. Bayer Diagnostics (Tarrytown, NY) recently marketed a turbidimetric immunoassay for monitoring valproic acid concentrations in serum or plasma using the ADVIA 1650 analyzer. We evaluated the performance of this new assay by comparing it with a widely used fluorescence polarization immunoassay (FPIA) on the AxSYM analyzer (Abbott Laboratories, Abbott Park, IL). The total coefficient of variation (CV) for the low control of this new assay was 6.8% (mean = 30.7, SD = 2.1 microg/mL, n = 44) while the corresponding CVs for the medium and high controls were 3.3% (mean = 81.0, SD = 2.7 microg/mL, n = 44) and 5.9% (mean = 142.9, SD = 8.4 microg/mL, n = 44), respectively. The assay is linear up to a serum valproic acid concentration of 170 microg/mL, and the detection limit is 4.4 microg/mL. We observed an excellent correlation between the FPIA of valproic acid and the turbidimetric assay using specimens from 52 different patients who were receiving valproic acid. Using the valproic acid concentrations obtained by the FPIA as the x-axis, and the corresponding valproic acid concentrations obtained by the turbidimetric assay as the y-axis, we developed the following regression equation: y = 1.03 x+1.55 (r = 0.98). With this new assay, high concentrations of bilirubin (unconjugated 30 mg/dL and conjugated 30 mg/dL) and gross hemolysis (4+, hemoglobin: 1,500 mg/dL) have no effect on measurements of valproic acid concentration. We conclude that the new turbidimetric assay for valproic acid can be used for routine therapeutic drug monitoring of valproic acid in clinical laboratories.

Anticonvulsants↗

PubMed2003

The safety of valproic acid use for patients with hepatitis C infection.

OBJECTIVE: Valproic acid is frequently not recommended for patients with hepatic dysfunction. The authors evaluated the association between hepatitis C and alanine aminotransferase (ALT) values during valproic acid treatment. METHOD: ALT changes in 564 individuals beginning valproic acid treatment were examined. Changes among those with positive hepatitis C status were compared with changes among patients with positive hepatitis C status who were taking other psychotropic agents. RESULTS: ALT elevations with valproic acid were significantly greater among patients with positive hepatitis C status than those with negative or unknown status. Among patients with positive hepatitis C status, ALT increases did not differ significantly between valproic acid and other medications. CONCLUSIONS: Use of valproic acid may be possible for some patients with hepatitis C. ALT increases in seropositive patients may be partially related to chronic hepatitis infection. However, ALT levels should be closely monitored in all hepatitis C patients taking valproic acid.

Adult↗

PubMed2002

Proton gradient-dependent transport of valproic acid in human placental brush-border membrane vesicles.

PURPOSE: To investigate the transport mechanism of valproic acid across the human placenta, we used human placental brush-border membrane vesicles and compared them with that of lactic acid. METHODS: Transport of [3H]valproic acid and [14C]lactic acid was measured by using human placental brush-border membrane vesicles. RESULTS: The uptakes of [3H]valproic acid and [14C]lactic acid into brush-border membrane vesicles were greatly stimulated at acidic extravesicular pH. The uptakes of [3H]valproic acid and [14C]lactic acid were inhibited by various fatty acids, p-chloromercuribenzene sulfonate, alpha-cyano-4-hydroxycinnamate, and FCCP. A kinetic analysis showed that it was saturable, with Michaelis constants (Kt) of 1.04 +/- 0.41 mM and 1.71 +/- 0.33 mM for [3H]valproic acid and [14C]lactic acid, respectively. Furthermore, lactic acid competitively inhibited [3H]valproic acid uptake and vice versa. CONCLUSION: These results suggest that the transport of valproic acid across the microvillous membrane of human placenta is mediated by a proton-linked transport system that also transports lactic acid. However, some inhibitors differentially inhibited the uptakes of [3H]valproic acid and [14C]lactic acid, suggesting that other transport systems may also contribute to the elevated fetal blood concentration of valproic acid in gravida.

Adult↗

PubMed2002

Extracorporeal removal of toxic valproic acid levels in children.

Toxic ingestion of valproic acid is difficult to treat as no antidote exists and hemodialysis has been considered ineffective for clearance due to high protein binding of this drug. Recent reports suggest that protein binding of valproic acid is saturated at toxic levels, thereby allowing for removal of free drug by extracorporeal circuits. We describe our experiences in two children with toxic blood levels of valproic acid, in whom we were able to achieve effective clearances by extracorporeal removal without charcoal hemoperfusion. In an 18-year-old girl with initial valproic acid levels of 663 microg/ml (therapeutic 46-88 microg/ml), the elimination constant (k(el)) increased five- to eightfold from 0.04/h pre dialysis and 0.06/h post dialysis to 0.31/h during high-flux hemodiafiltration. In the same time periods, drug half-life reduced from 15.96 h pre dialysis and 21 h post dialysis to 2.23 h during hemodiafiltration. In a younger 18-month-old child with initial levels of 922 microg/ml, k(el) was fivefold higher at 0.25/h during conventional hemodialysis, compared with 0.05/h after dialysis. Similarly, the drug half-life was 2.9 h during dialysis and 12.9 h after dialysis. Both conventional hemodialysis and high-flux hemodiafiltration are effective treatment modalities that should be offered to all pediatric patients with valproic acid ingestion and neurological compromise.

Adolescent↗

PubMed2003

The effect of valproic acid on drug and steroid glucuronidation by expressed human UDP-glucuronosyltransferases.

Valproic acid glucuronidation kinetics were carried our with three human UGT isoforms: UGT1A6, UGT1A9, and UGT2B7 as well as human liver and kidney microsomes. The glucuronidation of valproic acid was typified by high K(m) values with microsomes and expressed UGTs (2.3-5.2mM). The ability of valproic acid to interact with the glucuronidation of drugs, steroids and xenobiotics in vitro was investigated using the three UGT isoforms known to glucuronidate valproic acid. In addition to this the effect of valproic acid was investigated using two other UGT isoforms: UGT1A1 and UGT2B15 which do not glucuronidate valproic acid. Valproic acid inhibited UGT1A9 catalyzed propofol glucuronidation in an uncompetitive manner and UGT2B7 catalyzed AZT glucuronidation competitively (K(i)=1.6+/-0.06mM). Valproate significantly inhibited UGT2B15 catalyzed steroid and xenobiotic glucuronidation although valproate was not a substrate for this UGT isoform. No significant inhibition of UGT1A1 or UGT1A6 by valproic acid was observed. These data indicate that valproic acid inhibition of glucuronidation reactions is not always due to simple competitive inhibition of substrates.

Animals↗

PubMed1993

Simultaneous "in series" hemodialysis and hemoperfusion in the management of valproic acid overdose.

There is little published experience with the extracorporeal treatment of valproic acid overdose, although the pharmacokinetic properties of valproic acid suggest a potential role for hemodialysis and/or hemoperfusion. At therapeutic concentrations valproic acid is highly protein bound, but at the higher concentrations seen in the overdose setting binding sites become saturated and free valproic acid should be subject to removal by hemodialysis. We report the case of a patient with serious toxicity secondary to valproic acid overdose who was successfully treated with a combination of hemodialysis and hemoperfusion. With this treatment the half-life of valproic acid was reduced from a predialysis level of 13 hours to 1.7 hours, with rapid lowering of valproic acid levels and dramatic clinical improvement. Based on our experience in this patient and a review of previously reported cases, hemodialysis should be considered in the treatment of valproic acid overdose.

Adult↗

PubMed2000

The safety of rapid valproic acid infusion.

PURPOSE: The recommended rate of administration of valproic acid injection is 20 mg/min. Drug delivery at this rate may be inadequate for expeditious control of seizures. The safety of rapid infusion of valproic acid has not been established, and this study was designed to explore the effects of rapid infusion in patients with acute seizures. METHODS: Twenty patients with acute repetitive seizures received 20 mg/kg loading doses of valproic acid. Infusion rates ranged from 33.3 to 555 mg/min (median, 200 mg/min). Sixteen patients had received previous or concomitant antiepileptic drugs, with inadequate seizure control. Heart rate, blood pressure, and respiratory rate were measured before infusion and at frequent intervals for 1 hour after infusion. Patients were also observed for changes in level of alertness and signs of local irritation. RESULTS: No patient exhibited a decline in level of consciousness or respiratory function. Two patients with significant contributing factors exhibited declines in blood pressure requiring vasopressors. No significant local irritation was reported. Although efficacy was not a measured end point, seizures were abolished in all patients. CONCLUSIONS: Infusion of valproic acid at rates between 33 and 555 mg/min is well tolerated. No serious adverse effects attributable to the rapid infusion of valproic acid were encountered, although valproic acid, along with other factors, may have contributed to the hypotension in two patients. Intravenous valproic acid is an option for the control of acute seizures.

Adolescent↗

PubMed1994

Developmental toxicity and structure-activity relationships of aliphatic acids, including dose-response assessment of valproic acid in mice and rats.

The anticonvulsant valproic acid (VPA), or 2-propylpentanoic acid, is a short-chain aliphatic acid that is teratogenic in humans and rodents. VPA and 14 related chemicals were screened for developmental toxicity using the Chernoff/Kavlock assay. Test agents, in corn oil, were administered by gavage to Sprague-Dawley rats once daily during organogenesis. The dams were allowed to deliver and the pups were examined postnatally. Segment II studies were also conducted using VPA and pentanoic acid in rats and with VPA in CD-1 mice. In both mice and rats, VPA caused transient maternal ataxia and developmental defects of the digits and, especially, the axial skeleton. Exencephaly, however, was seen only in mice. The screening protocol was effective in prioritizing agents within this class of compounds for more definitive developmental toxicity testing. All congeners tested induced maternal respiratory effects and six compounds caused motor depression. Only 2-ethylhexanoic (2EH) and 2-propylhexanoic (2PH) acid caused dramatic VPA-like effects on rat development (including mortality, extra presacral vertebrae, fused ribs, and delayed parturition), confirming the strict structural requirements for developmental toxicity previously reported for acute exposure in mice. The incorporation of skeletal examinations in the Chernoff/Kavlock assay enabled the detection of the sole developmental effect (increased incidence of lumbar ribs) of 2-butylhexanoic acid. VPA, 2EH, and 2PH were among the compounds that caused maternal motor depression. These data, consistent with previous reports, indicate a broader specificity for activity in the adult nervous system than that in the developing system and suggest differing mechanisms for the two effects.

Acids↗

PubMed2002

Carbapenem antibiotics inhibit valproic acid transport in Caco-2 cell monolayers.

The concomitant use of carbapenem antibiotics with valproic acid has been prohibited because carbapenems induced a decrease in plasma concentration of valproic acid in epileptic patients during valproic acid therapy. Our previous in vivo study in rats proposed that inhibition by carbapenem of the intestinal absorption of valproic acid might be a possible mechanism for the drug-drug interaction. To demonstrate the hypothesis, we examined the effects of imipenem and panipenem on intestinal transepithelial transport of valproic acid using Caco-2 cell monolayers. Imipenem and panipenem inhibited the transport of [14C]-valproic acid across the Caco-2 cell monolayers from apical-to-basolateral side in a concentration-dependent manner, although they had no effect on the uptake of [14C]-valproic acid by Caco-2 cells. The inhibition by the carbapenems of the valproic acid transport was found even when they were added to only the basolateral side. From these results, the carbapenems may inhibit the absorption of valproic acid at the basolateral membrane of intestinal epithelial cells, which contributes to the decrease in plasma concentration of valproic acid after oral administration.

Anticonvulsants↗

PubMed2000

Developmental toxicity of valproic acid during embryonic chick vertebral chondrogenesis.

STUDY DESIGN: Valproic acid (2-n-propylpentanoic acid, VPA), an anticonvulsant drug, was studied for its effects on cartilage matrix gene expression using dot blot hybridization with cDNA probes during early chondrogenesis in the developing lumbar spine. OBJECTIVES: To determine the noncytotoxic effects of VPA on vertebral chondrocytes at various stages of embryonic chick spine development. SUMMARY OF BACKGROUND DATA: Clinical and epidemiologic studies have indicated that maternal use of valproic acid during early pregnancy causes an increased risk for spina bifida. METHODS: The sequence of chondrogenesis in the chick lumbar region was determined for stages HH23-32 and stage-correlated with matrix gene expression by dot blot hybridization analysis using cDNA probes for type II collagen, type IX collagen, and cartilage-specific aggrecan core protein. RESULTS: The mesenchymal stage of lumbar chondrogenesis in the chick spine occurs from HH23-26, the prechondrogenic stage between HH27-28, and the chondrogenic period from HH29-32. Stabilization of the cartilage phenotype in the lumbar region is evident at HH-29. Type IX collagen and aggrecan core protein mRNA levels were significantly reduced (P < 0.01) after 48 hours of incubation of the lumbar spines from HH29-31 in the presence of 200 microg/mL and 300 microg/mL valproic acid. Lumbar spines cultured for an additional 24 hours after removal of valproic acid showed only an isolated instance of escape from the inhibitory action of 200 microg/mL valproic acid for type IX collagen at HH31. CONCLUSIONS: Valproic acid significantly alters cartilage matrix gene expression during embryonic lumbar vertebral chondrogenesis. The alteration in gene expression for critical matrix proteins during vertebral chondrogenesis may be related to mechanisms underlying the failure of neural arch development in lumbar spina bifida.

Abnormalities, Drug-Induced↗

PubMed1984

Metabolism of valproic acid by hepatic microsomal cytochrome P-450.

Incubation of valproic acid with rat liver microsomes led to the formation of 3-, 4- and 5-hydroxy-valproic acid. The latter two metabolites, which have been characterized previously from in vivo studies, may be regarded as products of fatty acid omega-1 and omega hydroxylation, respectively. 3-Hydroxy-valproic acid, however, had been thought to derive from the beta-oxidation pathway in mitochondria. Conversion of valproic acid to all three metabolites in microsomes required NADPH (NADH was less effective), utilized molecular oxygen, was suppressed by inhibitors of cytochrome P-450 and was stimulated (notably at C-3 and C-4) by phenobarbital pretreatment of the rats. It is concluded that rat liver microsomal cytochrome P-450 catalyzes omega-2 hydroxylation of valproic acid, a reaction not detected previously with fatty acids in mammalian systems, and that the product, 3-hydroxy-valproic acid, should not be used to assess in vivo metabolism of valproate via the beta-oxidation pathway.

Anaerobiosis↗

PubMedDate not supplied

Severe valproic acid intoxication is associated with atrial tachycardia: secondary detoxication by hemoperfusion.

Valproic acid is an anticonvulsant drug which is associated with serious toxicity including fatal outcome in case of severe intoxication. Secondary detoxication by hemodialysis or hemoperfusion has been employed successfully in valproic acid intoxication. Cardiac arrhythmias have only been described rarely in valproic acid intoxication in humans. We report on a 15 year-old boy with severe valproic acid intoxication (valproic acid plasma level on admission: 1 150 mg/l) who presented with coma, hypernatremia and atrial tachycardia. The patient was successfully treated with hemoperfusion and intensive supportive care without implementation of a specific antiarrhythmic therapy. We conclude that patients with severe valproic acid intoxication may benefit from secondary detoxication. In addition to generally known symptoms valproic acid intoxication may also be associated with cardiac arrhythmias.

Adolescent↗

PubMed2006

Disposition of valproic acid in self-poisoned adults.

Acute intoxication with valproic acid is increasingly being observed in clinical practice. In Poland, such intoxication frequently occurs as a result of mixing different drugs or alcohol. We studied the pharmacokinetics of valproic acid in five intoxicated patients. Apart from valproic acid, barbiturates, chlorprotixene, tricyclic antidepressants, tetrahydrocannabinols and alcohol were detected and measured. The absorption of the drug was rapid and the maximum concentration was observed after the period of 3.5-5.6 hr. The lowering of the valproic acid level in plasma was biphasic, with terminal half-life ranging between 8.8-30.9 hr. The calculated apparent volume of distribution was 0.17-0.72 l/kg and could be affected by varied levels of doses as well as time of drug intake (data from interviews of patients) used for calculation and reduction in plasma protein binding at higher concentration of valproic acid. Frequent multiple drug poisonings oblige toxicological laboratories not only to monitor valproic acid concentration in serum, but also to perform the toxicological screenings.

Adolescent↗

PubMed1998

Valnoctamide, valpromide and valnoctic acid are much less teratogenic in mice than valproic acid.

The teratogenic properties of valproic acid (VPA) and its analogues depend to a great extent on their chemical structure. We investigated the structure-teratogenicity relationships of VPA, its structural isomer, valnoctic acid (VCA), and their two amide analogues, valpromide (VPD) and valnoctamide (VCD), respectively. Each substance was injected (3 mmol/kg) in NMRI-mice on the morning of day 8 of gestation. Embryolethality, fetal weight and exencephaly rates were recorded on day 18 of gestation. VPA caused 53% exencephaly, VPD induced 6%, VCA and VCD produced only 1% exencephaly (control values between 0 and 1%). VPA-treated mice also had increased embryolethality rates (52%). There was no significant change of embryolethality in the other treatment groups. Pharmacokinetic studies showed that VCD was eliminated from plasma at a slower rate than VPA. Also, the residual teratogenic activity of VPD was not accounted for by the relatively small amounts of its hydrolysis product VPA. This study indicates that VPD, VCA and VCD were distinctly less teratogenic than VPA. Apparently the amidation of the free carboxylic group and/or methyl-substitution at the beta-position of the carbon chain greatly decreased the teratogenic activity of VPA.

Abnormalities, Drug-Induced↗

PubMed1992

Dose-dependent inhibition in plasma protein binding of valproic acid during continued treatment in guinea-pigs.

Plasma protein binding of valproic acid over a wide range of steady-state plasma concentration (11.3 +/- 2.6-1303.0 +/- 122.9 micrograms mL-1: s.e.m., n = 5) in guinea-pigs has been studied. Valproic acid was given by intravenous constant infusion. At steady-state the plasma protein binding of valproic acid was analysed. Nonlinear binding was observed. Unbound fraction (fu) of valproic acid increased from 25 to 95% with the increase of steady-state plasma concentration (Css). The plasma protein-bound drug concentration (Cb) of valproic acid increased initially with Css but decreased after the Css exceeded 345.0 micrograms mL-1, where the Cb was 152.5 +/- 26.8 micrograms mL-1. At a Css of 1303.3 +/- 122.9 micrograms mL-1 the Cb was significantly (P less than 0.05) decreased to 72.8 +/- 20.2 micrograms mL-1. Binding characteristics of valproic acid in-vitro were studied using drug-free guinea-pig plasma with added valproic acid (10-1000 micrograms mL-1). The binding behaviour was also nonlinear in-vitro. The fu increased from 14 to 79% with the increase of valproate concentrations. No decrease in Cb was observed throughout the range. The study demonstrated that binding characteristics of valproic acid in-vivo and in-vitro are not parallel. The results suggest that valproic acid may produce or induce plasma protein binding competitors; metabolites of valproic acid may be implicated.

Animals↗