VCD & DID potential to become new drugs for treatment of neuropathic pain

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British Journal of Pharmacology advance online publication, 4 July

2005

Efficacy of antiepileptic isomers of valproic acid and valpromide in

a rat model of neuropathic pain.

Winkler I, Blotnik S, Shimshoni J, Yagen B, Devor M, Bialer M.

1Department of Pharmaceutics, The Hebrew University of Jerusalem,

Jerusalem, Israel.

Antiepileptic drugs (AEDs) are often utilized in the treatment of

neuropathic pain. The major AED valproic acid (VPA) is of particular

interest as it is thought to engage a variety of different neural

mechanisms simultaneously. However, the clinical use of VPA is

limited by two rare but life-threatening side effects: teratogenicity

and hepatotoxicity.

We synthesized VPA's corresponding amide: valpromide (VPD), two of

VPAs isomers and their corresponding amides; valnoctic acid (VCA),

valnoctamide (VCD), diisopropyl acetic acid (DIA),

diisopropylacetamide (DID), and VPD's congener: N-methyl-VPD (MVPD).

VCD, DID and VPD are nonteratogenic, potentially nonhepatotoxic, and

exhibit better anticonvuslant potency than VPA.

In this study, we assessed the antiallodynic activity of these

compounds in comparison to VPA and gabapentin (GBP) using the rat

spinal nerve ligation model of neuropathic pain (SNL, Chung

model).VCA and MVPD were inactive.

However, VPD (20-100 mg kg(- 1)), VCD (20-100 mg kg(- 1)) and DID (20-

90 mg kg(- 1)) produced dose-related reversal of tactile allodynia

with ED(50) values of 61, 52 and 58 mgkg(- 1), respectively. All the

amides were more potent than VPA (ED(50)=269 mgkg(- 1)). The

antiallodynic effect of VPA, VPD, VCD and DID was obtained at plasma

concentrations of 125, 24, 18 and 7 mg l(- 1), respectively, with a

good pharmacokinetic-pharmacodynamic correlation and a minimal lag

response.

VCD and DID were found to have minimal motor and sedative side

effects at analgesic doses, and were equipotent to GBP, currently the

leading drug in neuropathic pain treatment. Consequently, VCD and DID

have potential to become new drugs for the treatment of neuropathic

pain.