Clavulanic acid: a competitive inhibitor of beta-lactamases with novel anxiolytic-like activity and minimal side effects.
Clavulanic acid is a member of the beta lactam family of antibiotics with little or no intrinsic antibacterial activity of its own; instead, it is used to enhance the activity of antibiotics by blocking bacterial beta-lactamases. Because clavulanic acid by itself is very safe, orally active and shows good brain penetrance, we sought to determine if it had any potential as a psychotherapeutic. Clavulanic acid was a tested across three mammalian species, hamsters, rats and cotton-top tamarin monkeys in a series of behavioral assays designed to screen for anxiolytic activity. In addition, several studies were done in rodents to compare the behavioral profile of clavulanic acid to the commonly prescribed benzodiazepines, particularly with respect to their unwanted side effects of motor depression, amnesia and neuroendocrine dysregulation. Our findings show that clavulanic acid is a highly potent anxiolytic in rodents without altering motor activity in the open field test, normal learning and memory in the Morris water maze, or normal stress hormone release. Orally administered clavulanic acid significantly reduces measures of anxiety in male/female pairs of cotton-top tamarins. In addition, male tamarins showed a highly significant increase in sexual arousal as measured by the number of penile erections. The fact clavulanic acid has anxiolytic activity in the tamarin holds the promise that this drug may be an effective therapeutic for the treatment of anxiety disorders in humans.
Kim
Deog J
DJ
Rexahn Pharmaceuticals Inc., Rockville, Maryland 20850, USA. kimdj@rexahn.com
King
Jean A
JA
Zuccarelli
Lisa
L
Ferris
Craig F
CF
Koppel
Gary A
GA
Snowdon
Charles T
CT
Ahn
Chang H
CH
D000818:Animals; D014151:Anti-Anxiety Agents; D002707:Chlordiazepoxide / Q000494:pharmacology; D019818:Clavulanic Acid / Q000009:adverse effects / Q000494:pharmacology*; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D007858:Learning / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008647:Mesocricetus; D009043:Motor Activity / Q000187:drug effects; D009490:Neurosecretory Systems / Q000187:drug effects; D010410:Penile Erection / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012452:Saguinus; D013315:Stress, Psychological / Q000503:physiopathology / Q000517:prevention & control; D065093:beta-Lactamase Inhibitors
D014151:Anti-Anxiety Agents; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D019818:Clavulanic Acid; D002707:Chlordiazepoxide