Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new depakene research articles will be listed here shortly after becoming available to us.
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Medical research on depakene
Clin Cancer Res. 2008 Oct 1; 14(19): 6296-6301
Braiteh F, Soriano AO, Garcia-Manero G, Hong D, Johnson MM, Silva LD, Yang H, Alexander S, Wolff J, Kurzrock R
PURPOSE: 5-Azacytidine (5-AZA) is a DNA-hypomethylating agent. Valproic acid is a histone deacetylase inhibitor. Combining hypomethylating agents and histone deacetylase inhibitors produces synergistic anticancer activity in vitro and in vivo. On the basis of this evidence, we conducted a phase I study of the combination of 5-AZA and valproic acid in patients with advanced cancers. EXPERIMENTAL DESIGN: 5-AZA was administered s.c. daily for 10 days. Valproic acid was given orally daily with a goal to titrate to plasma levels of 75 to 100 mug/mL (therapeutic for seizures). Cycles were 28 days long. 5-AZA was started at 20 mg/m(2) and escalated using an adaptive algorithm based on the toxicity profile in the prior cohort (6 + 6 design). Peripheral blood mononuclear cell global DNA methylation and histone H3 acetylation were estimated with the long interspersed nucleotide elements pyrosequencing assay and Western blots, respectively, on days 1 and 10 of each cycle when patients agreed to provide them. RESULTS: Fifty-five patients were enrolled. Median age was 60 years (range, 12-77 years). The maximum tolerated dose was 75 mg/m(2) of 5-AZA in combination with valproic acid. Dose-limiting toxicities were neutropenic fever and thrombocytopenia, which occurred at a dose of 94 mg/m(2) of 5-AZA. Stable disease lasting 4 to 12 months (median, 6 months) was observed in 14 patients (25%). A significant decrease in global DNA methylation and induction of histone acetylation were observed. CONCLUSION: The combination of 5-AZA and valproic acid is safe at doses up to 75 mg/m(2) for 5-AZA in patients with advanced malignancies.
[Antiepileptic drugs in pediatric migraine.]
Arch Pediatr. 2008 Sep 29;
Cuvellier JC, Riquet A, Vallée L
According to the criteria of the International Headache Society, migraine occurs in approximately 5 to 10% of children. As many as 30% of young patients with migraine experience such frequent and disabling attacks, or have unsatisfactory results and/or experience adverse effects with pharmacologic treatment of acute migraine attack, that daily preventive medications are required. Many studies have investigated the use of antiepileptic drugs in this indication but there is a paucity of placebo-controlled studies. So far, in the setting of migraine with and without aura, only flunarizine and topiramate have proved their efficacy in more than one placebo-controlled study. Uncontrolled studies suggest the possible efficacy of valproic acid, gabapentin, levetiracetam, zonisamide, and magnesium in preventive therapy of childhood periodic syndromes. Most of antiepileptic drugs used in pediatric preventive therapy are well tolerated. The most common adverse events are asthenia and somnolence.
Valproate-associated reversible encephalopathy in a 3-year-old girl with Pallister-Killian syndrome.
Ther Clin Risk Manag. 2008 Jun; 4(3): 645-7
Gerstner T, Bell N, Koenig SA
Valproic acid (VPA) is considered to be a drug of first choice for the therapy of generalized and focal epilepsies, including special epileptic syndromes. The drug is usually well tolerated, rare serious complications may occur in some patients, including hemorrhagic pancreatitis, coagulapathies, bone marrow suppression, VPA-induced hepatotoxicity and encephalopathy. We report a case of VPA-associated encephalopathy without hyperammonemia in a 3-year-old girl with Pallister-Killian-Syndrom, combined with a mild hepatopathy and thrombopathy. After withdrawal of VPA, the clinical symptoms and the electroencephalography-alterations vanished rapidly.
Pisa syndrome and Parkinsonism secondary to valproic acid in Huntington's disease.
Mov Disord. 2008 Sep 29;
Salazar Z, Tschopp L, Calandra C, Micheli F
No longer room for valproic acid as anti-HIV therapy (Hot News).
AIDS Rev. 2008 Jul-Sep; 10(3): 190-1
Poveda E
Highly active antiretroviral therapy (HAART) can reduce and maintain plasma HIV RNA levels below the limit of detection (< 50 copies/ml) in most adherent patients. Despite its benefits, antiretroviral therapy cannot eliminate HIV infection since there is an early establishment of a latent HIV reservoir, mainly constituted by a pool of "resting" CD4+ T-cells, following acute infection. Hypothetically, the use of compounds that selectively induce the expression of quiescent proviral genomes might allow reducing the size or even eliminating the latent HIV reservoir in patients with long-term suppression of viremia. The histone deacetylase (HDAC) is a critical enzyme involved in the regulation of HIV latency. It in nottroduces an acetyl group in the N-terminal domain of histones, increasing their affinity for the DNA, which then is no longer substrate for transcription. Therefore, HDAC inhibits DNA replication and transcription, favoring HIV latency. Valproic acid is an anticonvulsant and mood-stabilizing drug, extensively used in the treatment of epilepsy, bipolar disorders, or migraine prophylaxis. Valproic acid acts as a non-selective HDAC inhibitor and may induce viral and cellular gene expression from resting CD4+ T-cells. In 2005, Lehrman, et al. (Lancet. 2005;366:549-55) tested the ability of valproic acid to deplete HIV infection of resting CD4+ T-cells. These authors selected four HIV-infected patients on HAART with long-term suppression of viremia (< 50 HIV RNA copies/ml) for > 2 years. After intensifying the effect of HAART with enfuvirtide during 4-6 weeks, patients received valproic acid (500-750 mg twice daily) for three months. A significant decline in the number of resting CD4+ T-cells was noticed. However, this observation could not be confirmed by Siliciano, et al. (J Infect Dis. 2007;195:833-6) who did not observe any ancillary effect on the decay of the latent HIV reservoir. The apparent discordance between these results was attributed to differences in study design: (i) the prior use of enfuvirtide by Lehrman, et al., which could have driven a more intensive suppressive effect on viral replication and new cellular infections, (ii) the different valproic acid doses used in the two studies, or (iii) differences in the methodologies used to measure the number of resting CD4+ T-cells. Two recent reports (Sagot-Lerolle, et al. AIDS. 2008;22:1125-9; and Archin, et al. AIDS. 2008;22:1131-5) had ended the controversy about the potential role of valproic acid for accelerating the decay of the HIV reservoir on HAART. Both studies agreed that the effect of adding valproic acid to conventional HAART seems to be negligible and does not impact significantly on the size of the HIV reservoir. Alternative approaches using drugs such as enfuvirtide, maraviroc, or raltegravir, which by themselves reduce new HIV infections and potentially the size of the HIV reservoir, along with more potent HDAC inhibitors are currently under evaluation. Therefore, the opportunity to find a way to eradicate HIV infection, although extremely difficult, is still open.
Brain Dev. 2008 Sep 22;
Arslan M, Vurucu S, Balamtekin N, Unay B, Akin R, Ozcan O
Valproic acid (VPA) is a widely used and well-tolerable antiepileptic drug in epileptic patients. However, VPA has many side effects dose-dependent or non-dose-dependent. It is reported that VPA treatment may lead to biotin deficiency and low serum and liver tissue biotinidase enzyme activity (BEA). Major clinical manifestations in biotin deficiency are seborrheic dermatitis, dry skin, fine and brittle hair, and alopecia. We aimed to investigate the effects of biotin supplementation on serum and liver tissue BEA and alopecia during VPA therapy. Rats were randomly divided into 4 groups, each consisted of 15 rats (VPA-B1, VPA-B2, VPA, and control). Except the control group, all groups were administrated VPA dose of 600mg/kg/d per oral (PO) for 60 days with 12h intervals two divided doses. VPA-B1 was administrated biotin dose of 6mg/kg/d and VPA-B2 was administrated biotin dose of 0.6mg/kg/d. In the third week of the study, we determined alopecia in the study groups. Alopecia was seen in the subjects of 13.3% of VPA-B1 (n=2), 13.3% of VPA-B2 (n=2), and 40% of VPA (n=6). But statistical significant effect on alopecia by biotin supplementation was not able to be determined between the study groups. In the control group, alopecia was not observed. The ratios of alopecia in the study groups were statistically higher than the control group (p=0.028). Itchiness was more obvious in the study groups compared with the control group. Serum biotin levels of the biotin supplemented groups (VPA-B1 and VPA-B2) were higher than the other groups (VPA and control group). Serum biotin levels of the VPA group were lower than the control group. There were significant decreaeses in the levels of serum and liver tissue BEA of the study groups compared with the control group. In conclusion we showed that VPA usage reduced the serum and liver tissue BEA and impaired the biotin utilization by affecting the liver. Partial biotinidase deficiency may lead to alopecia. It might be prevented by biotin supplementation in the patients receiving VPA therapy. We considered that further studies are necessary to find out the effective and safe biotin dose.
[Alternatives to beta blockers in preventive migraine treatment.]
Nervenarzt. 2008 Sep 19;
Evers S
Drug prevention of migraine is recommended if more than three attacks occur per month, acute drug treatment is insufficient, or very severe attacks with aura are the main problem. Besides beta blockers, a variety of substances have proved efficacious in migraine prevention. Thus individualised treatment of migraine patients is possible. When choosing the appropriate preventive drug, the potential side effects are considered. Drugs of first choice, besides beta blockers, are flunarizine, valproic acid, and topiramate. Second-choice drugs with lower efficacy or less well published evidence include amitriptyline, venlafaxine, gabapentin, naproxen, acetylsalicylic acid, butterbur root, vitamin B(2), and magnesium. Flunarizine or propranolol are recommended for children.
Drug interactions between chemotherapeutic regimens and antiepileptics.
Clin Ther. 2008 Aug; 30(8): 1385-407
Yap KY, Chui WK, Chan A
BACKGROUND: Drug-drug interactions (DDIs) are commonly seen in daily clinical practice, particularly in the treatment of patients with cancer. Seizures are often seen in patients with brain tumors and brain metastases, in whom antiepileptic drugs (AEDs) are often indicated. The risk for DDIs between anticancer drugs and AEDs is high. OBJECTIVE: This review aimed to investigate the types of interactions that are observed between the AEDs and the most commonly prescribed chemotherapeutic regimens. The risk for DDIs is discussed with regard to tumor type. METHODS: Data on DDIs between anticancer drugs and AEDs were compiled from the British National Formulary, Drug Information Handbook, and Micromedex Healthcare Series version 5.1. Product information of the individual drugs, as well as literature on anticancer drug-AED interactions, was searched using PubMed (years: December 1970 to January 2008; search terms: anticancer, antiepileptic, chemotherapy regimen, drug interactions, and the generic names of the individual anticancer drugs and AEDs [acetazolamide, carbamazepine, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic acid, vigabatrin, and zonisamide]). RESULTS: Our search identified clinically important DDIs observed with single-agent and combination regimens used for the treatment of breast cancers, colorectal cancers, lung cancers, lymphomas, and renal cell carcinomas. Carbamazepine, phenytoin, phenobarbital, and primidone were found to have prominent cytochrome P450 (CYP) enzyme-induction effects, while valproic acid had an inhibitory effect. The isozymes of major relevance to anticancer drug-AED interactions included CYP3A4, CYP2C9, and CYP2C19. Induction or inhibition of these isozymes by AEDs can cause a decrease or increase in anticancer drug concentrations. Similarly, enzyme inhibition or induction by anticancer drugs can lead to toxicity or loss of seizure control. CONCLUSIONS: In this review of anticancer drug-AED DDIs, carbamazepine, phenytoin, phenobarbital, primidone, and valproic acid were found to interact the most frequently with anticancer drugs. Based on the results of this review, clinicians should be vigilant when AEDs are prescribed concurrently with anticancer drugs. DDIs can be avoided or minimized by selecting alternative AEDs that are less likely to interact. However, if potentially interacting drug combinations must be used for treatment, serum drug concentrations should be closely monitored to avoid toxicity in the patient, as well as to ensure adequate chemotherapeutic and antiepileptic coverage.
Treatment of migraine with prophylactic drugs.
Expert Opin Pharmacother. 2008 Oct; 9(15): 2565-73
Evers S
BACKGROUND: Migraine is among the 10 most disabling disorders worldwide. Besides acute attack treatment, drug prophylaxis of migraine is important in order to improve the quality of life. OBJECTIVE: The aim of this paper is to describe the indications, principles and appropriate drugs with published evidence for the prophylaxis of migraine in general and in specific situations. METHODS: Based on the American and European guidelines for the treatment of migraine, the evidence for different drugs in the prophylaxis of migraine was evaluated. In addition, all trials on migraine drug prophylaxis published since the publication of the guidelines were included in the evaluation. These trials were identified by a literature search in MedLine, Embase and the Cochrane library. RESULTS: The drugs of first choice are beta-blockers, flunarizine, valproic acid and topiramate and, in the US, amitriptyline is also grouped among the first-choice drugs. Drugs of second choice, with less efficacy or poorer evidence, are venlafaxine, gabapentin, naproxen, butterbur root, vitamin B(2) and magnesium. The potential side effects are considered when choosing the appropriate prophylactic drug. All drugs used in migraine prophylaxis have been detected by chance and not by pathophysiological considerations. In the future, drugs developed on the basis of the current knowledge of migraine pathophysiology will hopefully be more effective.
Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin.
Acta Neurol Scand. 2008 Sep 15;
Gilad R, Izkovitz N, Dabby R, Rapoport A, Sadeh M, Weller B, Lampl Y
Objective - To evaluate the efficacy and tolerability of the treatment with valproic acid (VPA) in patients with status epilepticus (SE) or acute repetitive seizures (ARS) comparing it with phenytoin (PHT) treatment. Materials and methods - Patients with SE or ARS were treated in a consecutive manner with either VPA or PHT intravenously. The primary endpoint was defined as clinical seizure cessation; the secondary endpoint was evaluation of drug tolerability. Results - Seventy-four adult patients with SE or ARS participated in the study, 49 with VPA i.v. and 25 PHT i.v. In 43 (87.8%) of the VPA patients, the seizures discontinued, and no rescue medication was needed. Similar results were found in the PHT group in which seizures of 22 (88%) patients were well controlled. Side effects were found in 12% of the PHT group, and in none of the VPA group. Conclusions - VPA i.v. seems to be effective and well tolerated in adult patients with SE or ARS.