Progabide

Uses

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.

Side effects

Side effects of progabide include drowsiness, insomnia, and nausea. Less frequent side effects have been reported to include diaphoresis, malaise, gastralgia, somnolence, pruritus, urticaria, darkening of urine, and elevated liver enzymes. The drug has been associated with liver toxicity.

Pharmacology

Progabide acts as a non-selective GABA receptor agonist, including of both the GABAA and GABAB receptors. It is a GABA receptor agonist itself but also metabolizes into the more potent GABA receptor agonist progabide acid (SL-75.102). In addition, progabide and progabide acid are metabolized into gabamide and γ-aminobutyric acid (GABA), which act as GABA receptor agonists as well. Progabide crosses the blood–brain barrier, whereas gabamide and GABA do not, but progabide form gabamide and GABA within the brain. The drug and its metabolites are selective for GABA receptors and do not interact with various other neurotransmitter receptors, nor do they affect GABA reuptake, GABA release, or GABA transaminase. As such, progabide is a centrally active and pure GABA receptor agonist that acts in part via active metabolites including progabide acid, gabamide, and GABA.

The drug produces anticonvulsant effects in animals, but findings in humans have been more mixed. It is not known to produce some of the undesirable effects observed with other GABAA receptor agonists like muscimol such as myoclonus and psychological disturbances. This might be partly due to the lower potency of progabide compared to muscimol.

Progabide reaches peak levels after 2 to 3hours with oral administration in humans. Steady-state levels are reached after 2 to 4days of repeated administration. Its elimination half-life is 10 to 12hours. The drug is extensively metabolized, with only trace amounts of progabide being recovered in urine.

Chemistry

Progabide is a synthetic compound defined as the Schiff base of γ-aminobutyramide and a substituted benzophenone.

Synthesis

History

Progabide was first described in the literature by at least 1979 and was introduced for medical use in France by 1985. It was developed and marketed by Dausse-Synthelabo in France. The drug was also in clinical trials in the United States and elsewhere in Europe, but ultimately does not appear to have been ever marketed outside of France. Its adoption was limited by poor clinical effectiveness and incidence of liver toxicity.

Society and culture

Names

Progabide is the generic name of the drug and its , , , and . It is also known by its former developmental code name SL-76.002 or SL-76002, by its brand name Gabrene or Gabren, and by its synonym halogabide.

Availability

Progabide was marketed only in France as of 2000.

Research

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

In 1987, Bartolini and colleagues reported progabide's actions on dopamine to be contradictory, decreasing dopamine release, dopamine receptor density and postsynaptic dopamine receptor responsivity while reducing striatal cholinergic activity so as to increase dopaminergic signaling. Bartholini and colleagues concluded that it was this that caused Parkinson's patients in clinical trials to either see an improvement in their Parkinson's with a worsening of levodopa-induced dyskinesia or an improvement in dyskinesia but with sometimes aggravated Parkinson's symptoms. 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. 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."

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. While progabide may have been devoid of antipsychotic effects, it did have the effect in schizoaffective and hebephrenic patients of improving environmental responsiveness and social interactions.

References

References

1. (1985). "Progabide: a new GABA-mimetic agent in clinical use". Clin Neuropharmacol.
2. Shek, Efraim. (1994). "Chemical delivery systems and prodrugs of anticonvulsive drugs". Advanced Drug Delivery Reviews.
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8. (September 2023). "New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development". CNS Drugs.
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12. (1980). "Effect of the new gamma-aminobutyric acid agonist SL 76 002 on striatal acetylcholine: relation to neuroleptic-induced extrapyramidal alterations". Advances in Biochemical Psychopharmacology.
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