Efficacy of antiepileptic isomers of valproic acid and valpromide in a rat model of neuropathic pain.
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 ED50 values of 61, 52 and 58 mgkg(- 1), respectively. All the amides were more potent than VPA (ED50=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.
Department of Pharmaceutics, The Hebrew University of Jerusalem, Jerusalem, Israel.
Ilan
I
Winkler
Simcha
S
Blotnik
Jakob
J
Shimshoni
Boris
B
Yagen
Marshall
M
Devor
Meir
M
Bialer
D000700:Analgesics; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology*; D006930:Hyperalgesia / Q000188:drug therapy; D007536:Isomerism; D008026:Ligation; D008297:Male; D010146:Pain / Q000188:drug therapy* / Q000209:etiology*; D010147:Pain Measurement / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000150:complications*; D010812:Physical Stimulation; D004856:Postural Balance / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012684:Sensory Thresholds / Q000187:drug effects; D013127:Spinal Nerves / Q000293:injuries / Q000473:pathology; D013329:Structure-Activity Relationship; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D000700:Analgesics; D000927:Anticonvulsants; D014635:Valproic Acid; C004651:dipropylacetamide