Lacosamide: a review of preclinical properties.
Lacosamide (LCM), (SPM 927, (R)-2-acetamido-N-benzyl-3-methoxypropionamide, previously referred to as harkoseride or ADD 234037) is a member of a series of functionalized amino acids that were specifically synthesized as anticonvulsive drug candidates. LCM has demonstrated antiepileptic effectiveness in different rodent seizure models and antinociceptive potential in experimental animal models that reflect distinct types and symptoms of neuropathic as well as chronic inflammatory pain. Recent results suggest that LCM has a dual mode of action underlying its anticonvulsant and analgesic activity. It was found that LCM selectively enhances slow inactivation of voltage-gated sodium channels without affecting fast inactivation. Furthermore, employing proteomic affinity-labeling techniques, collapsin-response mediator protein 2 (CRMP-2 alias DRP-2) was identified as a binding partner. Follow-up experiments confirmed a functional interaction of LCM with CRMP-2 in vitro. LCM did not inhibit or induce a wide variety of cytochrome P450 enzymes at therapeutic concentrations. In safety pharmacology and toxicology studies conducted in mice, rats, rabbits, and dogs, LCM was well tolerated. Either none or only minor side effects were observed in safety studies involving the central nervous, respiratory, gastrointestinal, and renal systems and there is no indication of abuse liability. Repeated dose toxicity studies demonstrated that after either intravenous or oral administration of LCM the adverse events were reversible and consisted mostly of exaggerated pharmacodynamic effects on the CNS. No genotoxic or carcinogenic effects were observed in vivo, and LCM showed a favorable profile in reproductive and developmental animal studies. Currently, LCM is in a late stage of clinical development as an adjunctive treatment for patients with uncontrolled partial-onset seizures, and it is being assessed as monotherapy in patients with painful diabetic neuropathy. Further trials to identify LCM's potential in pain and for other indications have been initiated.
Beyreuther
Bettina K
BK
SCHWARZ BIOSCIENCES, Department of Pharmacology/Toxicology, GmbH, Monheim, Germany. bettina.beyreuther@schwarzpharma.com
Freitag
Joachim
J
Heers
Cara
C
Krebsfänger
Niels
N
Scharfenecker
Ute
U
Stöhr
Thomas
T
D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004827:Epilepsy / Q000188:drug therapy; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000078334:Lacosamide; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010146:Pain / Q000188:drug therapy
D000081:Acetamides; D000927:Anticonvulsants; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C095114:collapsin response mediator protein-2; D000078334:Lacosamide