Thirty-five years since its introduction into clinical use, valproate (valproic acid) has become the most widely prescribed antiepileptic drug (AED) worldwide. Its pharmacological effects involve a variety of mechanisms, including increased γ-aminobutyric acid (GABA)-ergic transmission, reduced release and/or effects of excitatory amino acids, blockade of voltage-gated sodium channels and modulation of dopaminergic and serotoninergic transmission.

Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience.

To the Editor:

The article by Farhat et al.1 poses the following question: Do antiepileptic drugs (AED) and in particular chronicity of use give rise to an altered bone mineral density (BMD)? The use of the American database as a control group may flaw this study and invalidate the implication set out in the conclusion: that the differences found are due to antiepileptic medication. The population in Beirut is very different from the database and without first validating the database in Beirut we should be very cautious in suggesting that differences found relate to epilepsy or AED. Also, the authors found a significant correlation between duration of AED use and BMD. Was …

https://www.osteos.org.lb/admin/uploads/3.pdf

Effect of antiepileptic drugs on bone density in ambulatory patients

Preclinical studies have been carried out during the past four decades to investigate the different mechanisms of action of valproate (VPA). The mechanisms of VPA which seem to be of clinical importance include increased GABAergic activity, reduction in excitatory neurotransmission, and modification of monoamines. These mechanisms are discussed in relation to the various clinical uses of the drug. VPA is widely used as an antiepileptic drug with a broad spectrum of activity. In patients, VPA possesses efficacy in the treatment of various epileptic seizures such as absence, myoclonic, and generalized tonic-clonic seizures. It is also effective in the treatment of partial seizures with or without secondary generalization and acutely in status epilepticus. The pharmacokinetic aspects of VPA and the frequent drug interactions between VPA and other drugs are discussed. The available methods for the determination of VPA in body fluids are briefly evaluated. At present, investigations and clinical trials are carried out and evaluated to explore the new indications for VPA in other conditions such as in psychiatric disorders, migraine and neuropathic pain. Furthermore, the toxicity of VPA, both regarding commonly occurring side effects and potential idiosyncratic reactions are described. Derivatives of VPA with improved efficacy and tolerability are in development.

/pdf/valproate-past-present-and-future-3yt4kms372.pdf

Valproate: Past, Present, and Future

Epilepsy and migraine are chronic neurological disorders with episodic manifestations that are commonly treated in neurological practice and frequently occur together. In this review we examine similarities and contrasts between these disorders, with focus on epidemiology and classification, temporal coincidence, triggers, and mechanistically based therapeutic overlap. This investigation draws attention to unique aspects of both epilepsy and migraine, while identifying areas of crossover in which each specialty could benefit from the experience of the other.

Chronic disorders with episodic manifestations: focus on epilepsy and migraine

HDIs are potential therapeutic agents for cancer and neurological diseases because of their abilities to alter gene expression, induce growth arrest or apoptosis of tumors cells, and stimulate differentiation. In this report, we show that several HDIs promote osteoblast maturation in vitro and in calvarial organ cultures.



Introduction: Histone deacetylase inhibitors (HDIs) are currently in phase I and II clinical trials as anticancer agents. Some HDIs are also commonly prescribed treatments for epilepsy and bipolar disorders. Although administered systemically, the effects of HDIs on osteoblasts and bone formation have not been extensively examined. In this study, we investigated the effect of histone deacetylase inhibition on osteoblast proliferation and differentiation.



Materials and Methods: MC3T3-E1 cells, calvarial-derived primary osteoblasts, and calvarial organ cultures were treated with various commercially available HDIs (trichostatin A [TSA], sodium butyrate [NaB], valproic acid [VPA], or MS-275). The effects of these inhibitors on cell proliferation, viability, cell cycle progression, Runx2 transcriptional activity, alkaline phosphatase production, and matrix mineralization were determined. Expression levels of osteoblast maturation genes, type I collagen, osteopontin, bone sialoprotein, and osteocalcin in response to TSA were measured by quantitative PCR.



Results: Concentrations of HDIs that caused hyperacetylation of histone H3 induced transient increases in osteoblast proliferation and viability but did not alter cell cycle profiles. These concentrations of HDIs also increased the transcriptional activity of Runx2. TSA accelerated alkaline phosphatase production in MC3T3-E1 cells and calvarial organ cultures. In addition, TSA accelerated matrix mineralization and the expression of osteoblast genes, type I collagen, osteopontin, bone sialoprotein, and osteocalcin in MC3T3-E1 cells.



Conclusions: These studies show that histone deacetylase activity regulates osteoblast differentiation and bone formation at least in part by enhancing Runx2-dependent transcriptional activation. Therefore, HDIs are a potentially new class of bone anabolic agents that may be useful in the treatment of diseases that are associated with bone loss such as osteoporosis and cancer.

Histone Deacetylase Inhibitors Promote Osteoblast Maturation

Background: Bone loss and hypovitaminosis D are reported in patients taking antiepileptic drugs, but little is known about changes in bone and calcium metabolism from valproic acid (VPA). Objective: To assess the relationship of VPA to bone mass and calcium metabolism in 40 adults with epilepsy on long-term VPA monotherapy, 40 age- and sex-matched epileptic patients taking phenytoin (PHT), and 40 healthy control subjects. Bone mineral density (BMD) of the second metacarpal was determined as T- and Z-scores. Results: BMD reduction from control values was 14% (12% in men, 16% in women) with VPA and 13% (12% in men, 15% in women) with PHT. Among patients on VPA, nine (23%) had T-scores below −2.5 SD, suggesting osteoporosis; 15 (37%) had T-scores between −1 and −2.5 SD, suggesting osteopenia. Serum concentrations of calcium were significantly higher with VPA than in PHT or control groups. Serum concentrations of bone Gla protein (a bone formation marker) and pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP; a bone resorption marker) associated with either drug significantly exceeded control values. Z-scores for BMD in the VPA group correlated negatively with calcium and ICTP. High ICTP correlated positively with ionized calcium, implying that increased bone resorption caused the latter. Conclusion: Long-term VPA monotherapy can increase bone resorption, leading to decreased BMD.

K. Takayama

Papers

Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy