Progabide

drugbox
IUPAC_name = 4- [(4-chlorophenyl)- (5-fluoro-2-hydroxy-phenyl)- methylidene] aminobutanamide


CAS_number = 62666-20-0
ATC_prefix = N03
ATC_suffix = AG05
ATC_supplemental =
PubChem = 5361323
DrugBank = APRD00072
C = 17 | H = 16 | Cl = 1 | F = 1 | N = 2 | O = 2
molecular_weight = 334.772 g/mol
bioavailability = 60%
protein_bound = 95%
metabolism = Hepatic
elimination_half-life = 4 hours
pregnancy_category =
legal_status = Prescription only
routes_of_administration = Oral
excretion = Renal

Progabide (INN) (trade name Gabrene, Sanofi-Synthelabo) is an analog and prodrug of gamma-aminobutyric acid used in the treatment of epilepsy. It has agonistic activity at both the GABA_A and GABA_B receptors.

Uses

Approved

Progabide is approved in France for either monotherapy or adjunctive use in the treatment of epilepsy—specifically, generalized tonic-clonic, myoclonic, partial, and Lennox-Gastaut syndrome seizures—in both children and adults. [http://www.biam2.org/www/Sub1618.html PROGABIDE] "Biam." 5 March 2001." (French)]

Unapproved/Off-Label/Investigational

Progabide has been investigated for many diseases besides epilepsy, including Parkinson's disease, schizophrenia, clinical depression, anxiety disorder and spasticity with various levels of success.

In 1979, Progabide's actions on dopamine are contradictory, decreasing dopamine release, dopamine receptor density and postsynaptic receptor responsivity to dopamine while reducing striatal cholinergic activity so as to increase dopaminergic effects.Bartholini G, Scatton B, Zivkovic B, Lloyd KG. "GABA receptor agonists and extrapyramidal motor function: therapeutic implications for Parkinson's disease." "Advances in Neurology." 1987;45:79-83. PMID 3030072] Bartholini and colleagues concluded that it was this that caused Parkinson's patients in human clinical trials to either see an improvement in their Parkinson's with a worsening of L-dopa dyskinesia or an improvement in dyskinesia but with sometimes aggravated Parkinson's symptoms.Bartholini G, Scatton B, Zivkovic B, Lloyd KG. "GABA receptor agonists and extrapyramidal motor function: therapeutic implications for Parkinson's disease." "Advances in Neurology." 1987;45:79-83. PMID 3030072] The cholinergic effect takes only a single injection to achieve in rats; when given with haloperidol, the development of tolerance to haloperidol's cataleptic effects did not develop.cite journal | author = Bartholini G. | coauthors = Scatton B, Zivkovic B. | year = 1980 | title = Effect of the new gamma-aminobutyric acid agonist SL 76 002 on striatal acetylcholine: relation to neuroleptic-induced extrapyramidal alterations | journal = Advances in Biochemical Psychopharmacology | volume = 24 | pages = 207–13 | pmid = 6105775] It was hoped that this would be effective for tardive dyskinesia. However, Soares, Rathbone and Deeks wrote in the 2004 issue of "The Cochrane Database of Systematic Reviews" that "Any possible benefits are likely to be outweighed by the adverse effects associated with their [GABAergic agents'] use."cite journal | first = K | last = Soares | coauthors = Rathbone J, Deeks J. | date = 18 October 2004 | title = Gamma-aminobutyric acid agonists for neuroleptic-induced tardive dyskinesia | journal = The Cochrane Database of Systematic Reviews | issue = 4 | doi = 10.1002/14651858.CD000203.pub2 | url = http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD000203/frame.html]

In addition to being tested for antipsychotic-induced tardive dyskinesia, progabide was itself tested as an antipsychotic; as early as 1979, it was obvious that it was ineffective for psychosis.cite journal | first = G. | last = Bartholini | year = 1979 | title = [Potential therapeutic activity of GABA-mimetic drugs in neuropsychiatry] | journal = Schweizer Archiv fur Neurologie, Neurochirurgie und Psychiatrie = Archives suisses de neurologie, neurochirurgie et de psychiatrie | volume = 125 | issue = 2 | pages = 265–9 | pmid = 45343 (French)] While progabide may have devoid of antipsychotic effects, it did have the effect in schizoaffective and hebephrenic patients of improving environmental responsiveness and social interactions.cite journal | author = Lloyd KG | coauthors = Morselli PL, Depoortere H, Fournier V, Zivkovic B, Scatton B, Broekkamp C, Worms P, Bartholini G. | year = 1983 | month = June | title = The potential use of GABA agonists in psychiatric disorders: evidence from studies with progabide in animal models and clinical trials | journal = Pharmacology, Biochemistry, and Behavior | volume = 18 | issue = 6 | pages = 957–66 | pmid = 6351106 | doi = 10.1016/S0091-3057(83)80021-5]

References and notes