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American Journal of Hematology May 2006Pharmacological induction of hemoglobin F expression may be a promising approach for the treatment of beta-thalassemia and sickle cell disease. Valproic acid, a drug...
Pharmacological induction of hemoglobin F expression may be a promising approach for the treatment of beta-thalassemia and sickle cell disease. Valproic acid, a drug frequently used for the treatment of seizure disorders, has been shown to enhance fetal hemoglobin synthesis in erythroid cells. However, this effect is only modest and requires relative high concentrations. Therefore, the drug appears not to be applicable for the treatment of beta-globin chain disorders. Here, we describe the identification of novel valproic acid derivatives with potent hemoglobin F inducing activities at concentrations that presumably can be obtained in vivo.
Topics: Cell Survival; Dose-Response Relationship, Drug; Fetal Hemoglobin; Humans; K562 Cells; Structure-Activity Relationship; Valproic Acid
PubMed: 16628726
DOI: 10.1002/ajh.20575 -
Therapeutic Drug Monitoring 1985Free valproic acid concentrations were determined using the MPS-1 ultrafiltration device marketed by Amicon with one YMB membrane per device. Valproic acid binding to...
Free valproic acid concentrations were determined using the MPS-1 ultrafiltration device marketed by Amicon with one YMB membrane per device. Valproic acid binding to the membrane was 5.6% of the free valproic acid concentration. The free valproic acid concentration increased as serial ultrafiltrate volumes were collected, suggesting that only small ultrafiltrate volumes should be collected from a large initial sample. The protein content of the ultrafiltrate was acceptable and was within the tolerances stated by Amicon. There was no significant difference between free valproic acid concentrations determined within 3 h of sample collection and those determined after storage at 4 degrees C or -20 degrees C for 1 week. There was no significant difference between free valproic acid concentrations in serum and heparinized plasma samples collected simultaneously.
Topics: Humans; Membranes, Artificial; Plasma; Serum Albumin; Ultrafiltration; Valproic Acid
PubMed: 3922094
DOI: 10.1097/00007691-198503000-00020 -
Clinical Pharmacology and Therapeutics Sep 1978Pharmacokinetic evaluation and prediction were carried out in 20 epileptic patients. Using conventional pharmacokinetic techniques and a one-compartment model, predicted...
Pharmacokinetic evaluation and prediction were carried out in 20 epileptic patients. Using conventional pharmacokinetic techniques and a one-compartment model, predicted and observed valproic acid plasma concentrations were compared. Valproic acid assay was performed by gas-liquid chromatography. There was good agreement between predicted and observed plasma concentrations. Most patients had predicted half-lives (t1/2s) of 6 to 8 hr, independent of the plasma concentration of valproic acid. Five patients had predicted t1/2s of 12 hr. The correlation between dose and plasma level was poor. Most patients had valproic acid plasma levels between 55 and 100 microgram/ml. Administration of valproic acid three times a day with determination of individual plasma concentrations offers a reliable method of monitoring. Constant levels are maintained in individual patients, but there is substantial intersubject variation.
Topics: Adolescent; Adult; Epilepsy; Female; Half-Life; Humans; Kinetics; Male; Models, Biological; Valproic Acid
PubMed: 357068
DOI: 10.1002/cpt1978243324 -
Archives of Neurology Aug 1989The absorption of valproic acid administered by rectal suppository was studied in six male volunteers. Valproic acid was incorporated into a synthetic lipid base in our... (Clinical Trial)
Clinical Trial Comparative Study
The absorption of valproic acid administered by rectal suppository was studied in six male volunteers. Valproic acid was incorporated into a synthetic lipid base in our pharmacy. Each subject received 500 mg of valproic acid by rectal suppository and 500 mg of oral valproate sodium syrup one week apart; 13 blood samples were drawn to determine serum concentrations over 48 hours after administration of each formulation. Significant differences were evident in the amount absorbed, maximum serum concentration, and time to achieve maximum serum concentration between the oral and rectal formulations. Mean absorption after rectal suppository was 80%. Maximum serum concentration was 43.4 mg/L after oral administration and 29.2 mg/L after rectal suppository. The time to achieve maximum serum concentration was 1.0 hour after oral syrup and 3.1 hours after rectal suppository. Absorption of the rectal suppository was consistent and complete within 3 hours. The use of valproate sodium in rectal suppository form can be a more convenient and satisfactory method of administering valproic acid when the oral route is impossible. Dosage increases may be necessary, and serum concentrations should be monitored.
Topics: Administration, Oral; Adult; Chromatography, Gas; Humans; Intestinal Absorption; Male; Random Allocation; Suppositories; Valproic Acid
PubMed: 2502974
DOI: 10.1001/archneur.1989.00520440100026 -
Neuropharmacology May 1985Thirty-two metabolites and analogues of the antiepileptic drug valproic acid (2-propylpentanoic acid; VPA) were tested for anticonvulsant and toxic effects in mice, in... (Comparative Study)
Comparative Study
Thirty-two metabolites and analogues of the antiepileptic drug valproic acid (2-propylpentanoic acid; VPA) were tested for anticonvulsant and toxic effects in mice, in an attempt to find out if any of these compounds were superior to valproic acid. Valproic acid and ethosuximide, another clinically established antiepileptic drug, were included in these studies for comparison. After intraperitoneal administration, the anticonvulsant potency of the various drugs was determined in three seizure tests: the threshold for maximal electroconvulsions, the maximal electroshock seizure test and seizures induced by subcutaneous injection of pentylenetetrazol. For the most potent compounds, median minimal neurotoxic doses (TD50S) and LD50S (after i.p. and i.v. injection) were determined. Valpramide, the primary amide of valproic acid, proved to be the most potent compound in the three seizure tests, used, being 2-5 times as potent as valproic acid, but valpramide was also considerably more sedative and toxic than valproic acid or ethosuximide. Of the metabolites of valproic acid tested, the unsaturated compounds 4-en-valproic acid (4-en-VPA) and the trans-isomer of 2-en-valproic acid (2-en-VPA) were most potent and, depending on the seizure test used, reached 60-100% of the efficacy of the parent drug. Both metabolites had LD50 values which were similar or greater than those of valproic acid but they were more sedative than the parent compound.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Anticonvulsants; Chemical Phenomena; Chemistry; Disease Models, Animal; Epilepsy; Ethosuximide; Male; Mice; Structure-Activity Relationship; Valproic Acid
PubMed: 3927183
DOI: 10.1016/0028-3908(85)90028-0 -
In Vivo (Athens, Greece) 2013The mechanism of valproic acid (VPA)-induced teratogenicity is poorly known. This study was carried out to probe into the potential consequences of nitric oxide (NO)...
BACKGROUND/AIM
The mechanism of valproic acid (VPA)-induced teratogenicity is poorly known. This study was carried out to probe into the potential consequences of nitric oxide (NO) deprivation on VPA teratogenicity.
MATERIALS AND METHODS
On gestation day 8, mice were injected with a non-teratogenic dose (20 mg/kg) of the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl esther (L-NAME). Thirty minutes later, animals received a teratogenic dose of VPA (400 or 500 mg/kg). Developmental end-points were evaluated near the end of gestation.
RESULTS
After treatment with VPA at 400 mg/kg, 35.2% of fetuses exhibited skeletal teratogenesis. The rate of skeletally affected fetuses significantly increased to 53.7% after L-NAME co-administration. In the group treated with VPA at 500 mg/kg group, L-NAME pre-treatment increased the incidence of exencephaly from 5.4% to 22.2%.
CONCLUSION
Inhibition of NO synthesis can result in an enhancement of VPA-induced teratogenesis.
Topics: Animals; Biosynthetic Pathways; Congenital Abnormalities; Mice; Nitric Oxide; Teratogenesis; Teratogens; Valproic Acid
PubMed: 23812222
DOI: No ID Found -
Journal of Chromatography Jul 1987A modified method for the determination of valproic acid, its eleven metabolites and their conjugates in small samples of serum and urine by gas chromatography-mass...
A modified method for the determination of valproic acid, its eleven metabolites and their conjugates in small samples of serum and urine by gas chromatography-mass spectrometry with selected-ion monitoring was developed. Valproic acid and its eleven metabolites were determined in serum and urine of epileptic patients treated with valproic acid. 2-Hydroxy-2-propylpentanoic acid was identified as a new metabolite of valproic acid in the urine of 11 of the 12 patients. The unsaturated metabolites, such as (Z)- and (E)-2-propyl-2-pentenoic acid, were found to be predominantly excreted as glucuronides. 3-Hydroxy-2-propylpentanoic acid and 2-propylglutaric acid were also excreted as glucuronides.
Topics: Adolescent; Adult; Biotransformation; Child; Child, Preschool; Drug Stability; Epilepsy; Female; Gas Chromatography-Mass Spectrometry; Humans; Male; Valproic Acid
PubMed: 3116023
DOI: No ID Found -
Circulation Apr 2013
Response to letter regarding article, “histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid”.
Topics: Animals; Histone Deacetylases; Humans; Hydroxamic Acids; Hypertension, Pulmonary; Male; Valproic Acid
PubMed: 23691553
DOI: 10.1161/circulationaha.112.154757 -
Circulation Apr 2013
Letter by Bogaard et al regarding article, "histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid".
Topics: Animals; Histone Deacetylases; Humans; Hydroxamic Acids; Hypertension, Pulmonary; Male; Valproic Acid
PubMed: 23569123
DOI: 10.1161/CIRCULATIONAHA.112.127092 -
Seizure May 2017Valproic acid (VPA) is a broad-spectrum antiepileptic drug, which is widely used as a first line treatment for idiopathic and symptomatic generalized epilepsy, as well... (Review)
Review
PURPOSE
Valproic acid (VPA) is a broad-spectrum antiepileptic drug, which is widely used as a first line treatment for idiopathic and symptomatic generalized epilepsy, as well as in non-epileptic psychiatric disorders in adult and pediatric patients. Although valproic acid is considered to be a generally well-tolerated drug, numerous studies have shown an increased bone loss and fracture risk in patients treated with VPA. The purpose of this review is to outline recent findings on VPA molecular mechanisms and their action on bone metabolism.
METHODS
Unrestricted electronic search of medical databases, complemented by additional manual searches, was performed by August 2016.
RESULTS/CONCLUSION
The main effects of VPA on bone metabolism involve a decrease in osteoblast proliferation, changes in collagen synthesis as well as an induction of vitamin D catabolism. Apart from these direct actions of VPA in bone, indirect effects affecting other endocrine organs also contribute to VPA-induced bone loss.
Topics: Animals; Anticonvulsants; Bone Diseases, Metabolic; Bone and Bones; Cells, Cultured; Humans; Valproic Acid; Vitamin D
PubMed: 28391043
DOI: 10.1016/j.seizure.2017.03.013