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Journal of Chromatography. B,... Mar 2021Valproic acid (VA) is a drug widely used on the treatment of epilepsy and bipolar affective disorders, with stablished therapeutic concentration ranges in serum. The...
Valproic acid (VA) is a drug widely used on the treatment of epilepsy and bipolar affective disorders, with stablished therapeutic concentration ranges in serum. The measurement of VA serum concentrations using chromatographic methods requires a sample preparation step. In this context, this study aims to describe the development and validation of an assay for VA measurement in serum using a new microextraction strategy, known as BioSPME, followed by GC-MS analysis. The extraction procedure was very simple based on direct immersion of the BioSPME tips on acidified serum, followed by agitation and desorption in methanol. The methanolic extracts were directly injected into the chromatograph. Extraction yield was 95.6 to 101.3%. The assay was linear from 10 to 150 mg L. Precision, accuracy and stability assays were acceptable according to bioanalytical validation guidelines. The method was applied to 41 clinical serum samples also tested with a previously GC-MS validated assay, which used liquid-liquid extraction as sample preparation. Measurements obtained with both methods were comparable. This study is the first description of the use of BioSPME tips for a therapeutic drug. BioSPME is a promising alternative for the preparation of biological specimens prior to the determination of therapeutic drugs by GC-MS.
Topics: Gas Chromatography-Mass Spectrometry; Humans; Linear Models; Reproducibility of Results; Sensitivity and Specificity; Solid Phase Microextraction; Valproic Acid
PubMed: 33621796
DOI: 10.1016/j.jchromb.2021.122574 -
Pediatric Emergency Care Aug 2000Valproic acid (VA) has been reported to be effective in status epilepticus (SE) when given rectally. More recently, intravenous (IV) VA has been demonstrated to be... (Review)
Review
Valproic acid (VA) has been reported to be effective in status epilepticus (SE) when given rectally. More recently, intravenous (IV) VA has been demonstrated to be effective and safe. Pharmacokinetic studies and initial clinical experience with IV valproic acid suggest that it may have a useful role in the management of refractory status epilepticus, but the magnitude of its utility is not possible to quantify or compare with phenytoin and phenobarbital. In simple SE, IV VA provides less additional benefit, since standard therapy usually works well. IV VA may be useful as a substitute for standard simple SE therapy, but this is difficult to justify unless adverse reactions to standard therapy are anticipated. The published pediatric experience with IV VA for SE is scant.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Anticonvulsants; Child; Humans; Infusions, Intravenous; Middle Aged; Status Epilepticus; Valproic Acid
PubMed: 10966355
DOI: 10.1097/00006565-200008000-00022 -
Annals of Neurology Jan 1978The antiepileptic drug valproic acid was studied in an open clinical trial as adjunct medication for 23 patients with uncontrolled seizures of a generalized or partial... (Clinical Trial)
Clinical Trial
The antiepileptic drug valproic acid was studied in an open clinical trial as adjunct medication for 23 patients with uncontrolled seizures of a generalized or partial type. Two-thirds of the patients experienced reduction in seizure frequency ranging from 25 to 100%. Extensive testing revealed no evidence of serious systemic toxicity due to the drug. Minor side effects (e.g., nausea, vomiting, or sedation) were usually transient. Sodium valproate syrup and valproic acid in capsules gave equivalent mean low (23.3 microgram/ml) and maximum (42.5 microgram/ml) serum concentrations. The drug had a relatively short half-life of 8.7 hours, necessitating administration in divided daily doses. During initiation of valproate therapy there was evidence of a decline in total serum phenytoin concentration (16.5 to 10.2 microgram/ml; p less than 0.001) while the percentage of free phenytoin increased (10.9 to 20%). The quantity of unbound phenytoin was relatively stable throughout. This observation was interpreted as a drug interaction: valproic acid competed with phenytoin for access to plasma protein binding sites.
Topics: Adult; Binding, Competitive; Biological Availability; Blood Proteins; Clinical Trials as Topic; Drug Interactions; Epilepsy; Female; Humans; Male; Phenytoin; Protein Binding; Valerates; Valproic Acid
PubMed: 350128
DOI: 10.1002/ana.410030105 -
The American Journal of the Medical... May 2007To report a case of valproic acid-induced eosinophilic pleural effusion and to review the existing literature.
OBJECTIVE
To report a case of valproic acid-induced eosinophilic pleural effusion and to review the existing literature.
CASE SUMMARY
A 25-year-old African-American man receiving valproic acid, 250 mg/d, had a moderate-sized right pleural effusion. Pleural fluid analysis revealed 75% eosinophils. The patient had no evidence of parasitic infection, hemothorax, or pneumothorax. One month after valproic acid was discontinued, there was no evidence of a pleural effusion by both chest radiography and thoracic ultrasonography.
DISCUSSION
Valproic acid-induced pleural effusions have been reported in the medical literature in 5 case reports. Pleural fluid eosinophilia is almost always related to pneumothorax, hemothorax, parasitic infection, or drug toxicity; therefore, when the first 3 causes have been eliminated, a drug should be suspected. Only a few medications are known to cause pleural fluid eosinophilia, one being valproic acid. The Naranjo probability scale rated this adverse reaction as probably drug-related.
CONCLUSIONS
In all 6 patients discussed in this review, the pleural effusions resolved after discontinuation of the valproic acid. None of these patients had associated pulmonary infiltrates. Valproic acid eosinophilia may be associated with peripheral blood eosinophilia. Valproic acid should be added to the list of medications that can cause an eosinophilic pleural effusion.
Topics: Adult; Eosinophilia; Humans; Male; Pleural Effusion; Valproic Acid
PubMed: 17505171
DOI: 10.1097/MAJ.0b013e31805339ae -
Headache Sep 2001We evaluated the efficacy of prophylactic valproic acid treatment (6 months) on the frequency of migraine attacks and the number of migraine headache days with respect... (Clinical Trial)
Clinical Trial Comparative Study
OBJECTIVE
We evaluated the efficacy of prophylactic valproic acid treatment (6 months) on the frequency of migraine attacks and the number of migraine headache days with respect to serum levels.
BACKGROUND
Valproic acid, a GABAergic drug, has been shown to be effective for migraine prophylaxis. Results from several dose- and serum level-adjusted studies have recommended valproic acid doses within a range of 500 to 1500 mg per day for migraine prophylaxis.
DESIGN AND METHODS
In this prospective open-label study, 52 patients received valproic acid doses of 300 to 1200 mg per day; 45 patients were treated per protocol. Valproic acid serum levels increased linearly in relation to the valproic acid dose and were between 21 and 107 microg/mL at the end of the treatment period. Patients were divided into two groups: those with valproic acid serum levels less than 50 microg/mL (group 1) and those with serum levels greater than 50 microg/mL (group 2).
RESULTS
The frequency of migraine attacks was significantly reduced in group 1 from 3.5 +/- 0.9 to 2.0 +/- 0.9 attacks per month. Migraine headache days also decreased (6.4 +/- 3.5 to 4.6 +/- 2.9 days per month). In the high serum level group, a reduction of migraine attacks from 3.5 +/- 0.9 to 2.8 +/- 1.0 attacks per month and only a slight decrease in headache days (6.4 +/- 3.5 to 6.1 +/- 2.4 days per month) was observed. The outcome of group 1 (low serum level) was significantly better than that of group 2 with respect to both parameters (P<.05). Side effects were generally mild and temporary.
CONCLUSIONS
Due to the lack of additional benefit from higher valproic acid doses (more than 600 mg per day), we recommend daily valproic acid doses of 500 to 600 mg with a target serum level less than 50 microg/mL for the prophylactic treatment of migraine.
Topics: Anticonvulsants; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Migraine Disorders; Prospective Studies; Valproic Acid
PubMed: 11576201
DOI: 10.1046/j.1526-4610.2001.01142.x -
The Journal of Pharmacy and Pharmacology Jul 1991To explore whether biliary cannulation, biliary obstruction or gall bladder obstruction could alter the disposition of valproic acid, guinea-pigs were subjected to...
To explore whether biliary cannulation, biliary obstruction or gall bladder obstruction could alter the disposition of valproic acid, guinea-pigs were subjected to common bile duct cannulation or ligation, gall bladder-neck ligation or sham surgery as a control. They were then given an intravenous (i.v.) dose of sodium valproate (50 mg kg-1) and the pharmacokinetics of valproic acid in each group were compared. In the cannulated group, significant decreases (P less than 0.05) in the area under the elimination curve (AUC), the volume of distribution at steady-state (Vdss) and the mean residence time (MRT) were observed. Significant increases (P less than 0.05) in the elimination rate constant (kz) and total clearance (CLtot) of valproic acid were noted. In the biliary obstructed guinea-pigs, the Vdss was significantly decreased (P less than 0.05). In the gall bladder obstructed guinea-pigs, there was a secondary peak of valproate plasma concentration, and the kz was significantly decreased. The biliary excretion of unchanged and conjugated valproic acid was 2.0 +/- 0.7 (s.e.m.) and 19.7 +/- 3.6 (s.e.m.)% of dose, respectively, and was almost completely reabsorbed in the enterohepatic recycling. Urinary excretion of unchanged and conjugated valproic acid, as well as non-conjugate metabolic clearance of valproic acid, were not significantly different among the four groups. The results suggest that the pharmacokinetics of valproic acid in guinea-pigs are particularly sensitive to interruption of the enterohepatic cycle. Biliary obstruction may elevate plasma concentrations owing to the decreased Vdss of valproic acid. Gall bladder obstruction may cause fluctuation of valproate plasma concentrations. The data indicate that the apparent total clearance of valproic acid is significantly less than the intrinsic clearance owing to enterohepatic recycling.
Topics: Animals; Bile Ducts; Chromatography, Gas; Guinea Pigs; Half-Life; Injections, Intravenous; Male; Metabolic Clearance Rate; Valproic Acid
PubMed: 1682459
DOI: 10.1111/j.2042-7158.1991.tb03516.x -
The Medical Letter on Drugs and... Apr 2009
Topics: Anticonvulsants; Capsules; Chemistry, Pharmaceutical; Delayed-Action Preparations; Epilepsy; Humans; Migraine Disorders; Therapeutic Equivalency; Valproic Acid
PubMed: 19343008
DOI: No ID Found -
ALTEX 2022Chemical read-across is commonly evaluated without specific knowledge of the biological mechanisms leading to observed adverse outcomes in vivo. Integrating data that...
Chemical read-across is commonly evaluated without specific knowledge of the biological mechanisms leading to observed adverse outcomes in vivo. Integrating data that indicate shared modes of action in humans will strengthen read-across cases. Here we studied transcriptomic responses of primary human hepatocytes (PHH) to a large panel of carboxylic acids to include detailed mode-of-action data as a proof-of-concept for read-across in risk assessment. In rodents, some carboxylic acids, including valproic acid (VPA), are known to cause hepatic steatosis, whereas others do not. We investigated transcriptomics responses of PHHs exposed for 24 h to 18 structurally different VPA analogues in a concentration range to determine biological similarity in relation to in vivo steatotic potential. Using a targeted high-throughput screening assay, we assessed the differential expression of ~3,000 genes covering relevant biological pathways. Differentially expressed gene analysis revealed differences in potency of carboxylic acids, and expression patterns were highly similar for structurally similar compounds. Strong clustering occurred for steatosis-positive versus steatosis-negative carboxylic acids. To quantitatively define biological read-across, we combined pathway analysis and weighted gene co-expression network analysis. Active carboxylic acids displayed high similarity in gene network modulation. Importantly, free fatty acid synthesis modulation and stress pathway responses are affected by active carboxylic acids, providing coherent mechanistic underpinning for our findings. Our work shows that transcriptomic analysis of cultured human hepatocytes can reinforce the prediction of liver injury outcome based on quantitative and mechanistic biological data and support its application in read-across.
Topics: Carboxylic Acids; Hepatocytes; Liver; Transcriptome; Valproic Acid
PubMed: 35040482
DOI: 10.14573/altex.2107261 -
Therapeutic Drug Monitoring 1984Valproic acid (VPA) concentrations were measured by a sensitive and highly specific gas chromatographic/mass spectrometric assay in breast milk from 16 patients treated...
Valproic acid (VPA) concentrations were measured by a sensitive and highly specific gas chromatographic/mass spectrometric assay in breast milk from 16 patients treated with VPA during 17 lactation periods. The range of VPA levels in 36 breast milk samples was 0.4-3.9 micrograms/ml (mean 1.9 +/- 1.2 microgram/ml). During the investigations of breast milk it was found that the concentration of total VPA in breast milk was not much higher than that of unbound VPA. These findings agree with clinical observations of infants fed with milk from VPA-treated mothers.
Topics: Adult; Female; Gas Chromatography-Mass Spectrometry; Humans; Infant; Milk, Human; Valproic Acid
PubMed: 6438834
DOI: 10.1097/00007691-198409000-00003 -
Epilepsia Dec 1976Valproic acid [dipropylacetic acid (DPA)] was evaluated in an alumina-gel monkey model (N = 12) by constant-rate intravenous infusion. The data indicated: (a) a...
Valproic acid [dipropylacetic acid (DPA)] was evaluated in an alumina-gel monkey model (N = 12) by constant-rate intravenous infusion. The data indicated: (a) a statistically significant decrease in seizure frequency the first 2 days of drug Step I (45-55 mug/ml) and drug Step II (90-110 mug/ml) which was temporary, lasting 2 days only; (b) a later, more permanent decrease in siezure frequency which was not apparent until drug Setp III (130-170 mug/ml); and a delayed return of the seizure frequency to predrug levels for 2 weeks after drug administration was discontinued, with no DPA detectable in plasma after the initial postdrug day. Whether DPA will behave as a reversibly acting drug was discussed.
Topics: Animals; Anticonvulsants; Half-Life; Haplorhini; Injections, Intravenous; Macaca mulatta; Male; Time Factors; Valerates; Valproic Acid
PubMed: 826396
DOI: 10.1111/j.1528-1157.1976.tb04459.x