TY - JOUR
T1 - Efficacy of antiepileptic isomers of valproic acid and valpromide in a rat model of neuropathic pain
AU - Winkler, Ilan
AU - Blotnik, Simcha
AU - Shimshoni, Jakob
AU - Yagen, Boris
AU - Devor, Marshall
AU - Bialer, Meir
PY - 2005
Y1 - 2005
N2 - 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 anticonvulsant 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.
AB - 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 anticonvulsant 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.
KW - Diisopropyl acetamide
KW - Neuropathic pain
KW - Pharmacodynamics
KW - Pharmacokinetics
KW - Spinal nerve ligation
KW - Valnoctamide
KW - Valproic acid
KW - Valproic acid isomers
KW - Valpromide
UR - http://www.scopus.com/inward/record.url?scp=30544438144&partnerID=8YFLogxK
U2 - 10.1038/sj.bjp.0706310
DO - 10.1038/sj.bjp.0706310
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C2 - 15997234
AN - SCOPUS:30544438144
SN - 0007-1188
VL - 146
SP - 198
EP - 208
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 2
ER -