Fipexide

Fipexide improvement of cognitive functions in rat: behavioural and neurochemical studies

Dopamine neurotransmission plays a role in learning, memory and related cognitive processes. We evaluated the effect of a nootropic drug, fipexide, a parachloro-phenossiacetic acid derivative, both on behavioural and biochemical parameters. The compound was able to cause an improved performance on active avoidance test, when administered just before the trial, being also effective on memory retention and recall experiments. Fipexide was also able to revert the impairment of the acquired behaviour caused by sulpiride in pretrained rats, while it failed to be effective on the haloperidol deconditioning effect. Striatal adenylate cyclase activity, from fipexide pretreated rats, was significantly reduced both in basal and dopamine stimulated conditions. Furthermore, fipexide, directly added to membrane preparations, was able to inhibit striatal adenylate cyclase activity. These results, along with our previous reports on fipexide effect on locomotor activity, allow us to hypothesize that the positive effect of this drug on cognitive performance seems to be mediated, at least partially, by dopaminergic neurotransmission.

Fipexide, an effective cognition activator in the elderly: a placebo-controlled, double-blind clinical trial

Forty geriatric in-patients with severe cognition disorders were randomly allocated to treatment with either 600 mg fipexide daily or placebo over a period of 3 weeks. Before and after treatment, the symptoms of cognitive performance (disorders of memory and attention, asthenia, apathy and disorders of coenaesthesia) were monitored and scored. Similarly, the Thurstone test (symbol matching test) was performed and time to completion, number of errors and exactitude index were recorded. Haemodynamics, haematology and haematochemistry investigations were made before and after treatment, and accessory symptoms of potential side-reactions were monitored by positive questioning. Treatment with fipexide was associated with a significant improvement in each and all monitored symptoms and signs to an average extent of 60%, whereas placebo was not. Similarly, the patients given fipexide experienced a significant improvement in the Thurstone test, in terms of time to completion (-22%), number of errors (-46%) and exactitude index (+60%); again, placebo was not associated with any significant improvement (variations, respectively, of -5%, -14%, and +24%). Overall, 85% of the patients given fipexide experienced clinical improvement to a greater or lesser degree, a significantly greater proportion than that associated with placebo (25%; p less than 0.001). Tolerance, both subjective and objective, was good in both treatment groups.

Investigating the in vitro metabolism of fipexide: characterization of reactive metabolites using liquid chromatography/mass spectrometry

The in vitro metabolism of the nootropic drug fipexide was studied using different liquid chromatography/mass spectrometry (LC/MS) techniques. This drug has been withdrawn from the market due to toxic effects. No previous reports have investigated the possible involvement of reactive metabolites in the toxicity of fipexide. The hydrolysis of this drug leads to the formation of two potentially toxic species, 3,4-methylenedioxybenzylpiperazine (MDBP) and 4-chlorophenoxyacetic acid (4-CPA). Here, we investigate the in vitro metabolism of fipexide in human, rat, mouse and dog, as well as of MDBP and 4-CPA in human and rat, while focusing on the formation of reactive metabolites. A combination of LC/MS analyses on a hybrid quadrupole-linear ion trap instrument and accurate mass data from QqTOF measurements was employed for the characterization of these metabolites. Microsomal metabolites of fipexide were MDBP, 4-CPA, fipexide N-oxide or hydroxyl, demethylenated fipexide and other minor ones, all of which were investigated by tandem mass spectrometry. Reactive metabolites were detected using several trapping procedures with small molecules such as glutathione, its ethyl ester derivative and N-acetylcysteine. The demethylenated metabolite, a catechol, formed its corresponding ortho-quinone, which readily reacts with these nucleophiles. MDBP was studied in a similar manner, due to its ability to form an analogous catechol. Because of its acidic nature, 4-CPA was assessed for possible acylglucuronide and acyl-CoA thioester metabolites, which could also be involved in bioactivation pathways. Several important metabolites were identified as potential mediators of toxicity via protein binding.

Fipexide-induced fulminant hepatitis. Report of three cases with emergency liver transplantation

Fipexide belongs to a new class of cognition activators and is noted for its lack of amphetamin-like side effects. We describe three patients who developed fulminant hepatic failure less than 2 months after beginning fipexide administration. The mean interval from the onset of jaundice to the onset of encephalopathy was 8 days. Emergency liver transplantation was undertaken when factor V was 20% of normal or less and coma developed. All patients were transplanted less than 1 week after the onset of encephalopathy. Two survived and one died immediately after transplantation. Histologic examination of the livers revealed massive liver cell necrosis, predominantly centrilobular, and a moderate inflammatory infiltrate within the portal spaces. We conclude that fipexide can induce massive liver cell necrosis and fulminant liver failure. As a result of this life-threatening complication, reconsideration of the indications for this drug is warranted.

Determining protein adducts of fipexide: mass spectrometry based assay for confirming the involvement of its reactive metabolite in covalent binding

Fipexide is a nootropic drug, withdrawn from the market due to its idiosyncratic drug reactions causing adverse effects in man. Previous work on its metabolites has identified several potential reactive metabolites which could be implicated in protein binding. Here, we investigated the formation of these metabolites in rat and human hepatocytes. Based on these results, the o-quinone of fipexide (FIP), formed via the demethylenation reaction through a catechol intermediate, was chosen for further investigation. Studies were then pursued in order to relate this metabolite to protein binding, and thus better understand potential mechanisms for the toxicity of the parent compound. An assay was developed for determining the fipexide catechol-cysteine adduct in the microsomal protein fractions following in vitro incubations. This method digests the entire protein fraction into amino acids, followed by the detection of the Cys-metabolite adduct by liquid chromatography/mass spectrometry (LC/MS). We have designed a strategy where drug metabolism taking place in microsomal incubations and involved in protein binding can be assessed after the proteins have been digested, with the detection of the specific amino acid adduct. In this study, the structure of the fipexide adduct was hypothesized using knowledge previously gained in glutathione and N-acetylcysteine trapping experiments. Acetaminophen was used as a positive control for detecting a drug metabolite-cysteine adduct by LC/MS. This approach has the potential to be applicable as a protein-binding assay in early drug discovery without the need for radioactive compounds.