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P L Morselli - One of the best experts on this subject based on the ideXlab platform.
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determination of Progabide and its main acid metabolite in biological fluids using high performance liquid chromatography and electrochemical detection application to the measurement of blood plasma partition ratio
Journal of Chromatography A, 1998Co-Authors: P Padovani, C Deves, G Bianchetti, J P Thenot, P L MorselliAbstract:Abstract A method for the measurement in plasma, blood and urine of Progabide, its main acid metabolite, and the corresponding benzophenone is described. This assay allows the determination of Progabide and its acid metabolite for therapeutic drug monitoring, and with a minimum detectable concentration of 1–10 ng/ml for Progabide and its acid metabolite, it is sensitive enough for pharmacokinetic studies. Progabide and its metabolites are extracted from biological samples with toluene at pH 4.5. Following reduction of the imine bond with sodium borohydride, the reduced drugs are back-extracted into an aqueous phase at acid pH and reextracted by diethyl ether at alkaline pH. Progabide, its acid metabolite and the benzophenone are separated by high-performance liquid chromatography using a 3-μm ODS column with a quaternary solvent mixture of methanol-acetonitrile-phosphate buffer (0.033 M , pH 5.5)—sodium chloride (1.5 M ) (30:30:40:9, v/v), and detected electrochemically at a potential of +850 mV vs. an Ag/AgCl electrode. Antiepileptic drugs like carbamazepine, carbamazepine epoxide, phenytoin, valproic acid and ethosuximide do not interfere with the assay. Blood/plasma partition ratios of 0.69 and 0.55 for Progabide and its acid metabolite, respectively, indicate that the former but not the latter is present in red blood cells.
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double blind placebo controlled cross over trial of Progabide as add on therapy in epileptic patients
Epilepsia, 1991Co-Authors: Gerstle E De Pasquet, A Scaramelli, Pineyrua M De Caceres, C Lheritier, S Feldman, R Santana, J Aguilar, B Musch, P L MorselliAbstract:SUMMARY: In a double-blind, cross-over trial, Progabide (PGB) and placebo were compared as add-on therapy in 59 patients with moderate to severe epilepsy. Eight patients did not complete the study, 4 because of adverse drug reactions (elevation of liver transaminases, 2; gastritis, 1; and acute psychosis, 1) and 4 because of administrative reasons. Among the remaining 51 patients, seizure frequency was reduced >50% in 18 patients with PGB treatment and in 8 patients with placebo (p<0.05). The number of days with seizures was significantly (p=0.034) reduced during PGB treatment. Both patients' and physicians' preferences at the end of the trial were in favor (p<0.01) of PGB. Mild clinical side effects were present in 54.7% of the patients treated with PGB and in 37.7% with placebo. Increase in liver transaminases was observed in 2 patients during the double-blind study and in 1 during the follow-up period. Our data show that PGB, as previously reported, is useful in 30–40% of patients who are not responding completely to other antiepileptic drugs (AEDs). The compound is well tolerated, but liver function must be monitored. RESUME Dans une etude croisee en double-aveugle, avec croisement, le Progabide et le placebo ont ete comparees comme medicaments d'appoint chez 59 patients presentant une epilepsie moyenne ou severe. Huit patients n'ont pas termine l'etude, 4 en raison d'effets indesirables (2 pour elevation des enzymes hepatiques, l pour gastrite, 1 pour episode psychotique aigu) et 4 pour des raisons administratives. Parmi les 51 patients restants, une reduction de la frequence des crises de plus de 50% a ete notee chez 18 patients sous Progabide et chez 8 patients sous placebo (p < 0.05). Le nombre de jours avec crises etait significativement reduit pendant le traitement par Progabide (p = 0.034). Les preferences des patients et des medecins etaient en faveur du Progabide a la fin de l'etude (p < 0.01). Des effets cliniques collateraux d'intensite moderee ont ete constates chez 54.7% des patients traites par Progabide et chez 37.7% des patients traites par placebo. Une augmentation des transaminases hepatiques a ete observee chez 2 patients pendant l'etude en double-aveugle, et chez 1 patient pendant la periode de suivi. Les donnees fournies par ces auteurs montrent que le Progabide, comme il a eie rapporte anterieurement, est utile chez 30–40% des patients qui ne sont pas completement controles par les antiepileptiques classiques. Le produit est bien tolere, mais il est necessaire de controler les enzymes hepatiques. RESUMEN En 59 enfermos que padecian una epilepsyia, de moderada a severa se ha realizado un estudio doble ciego y cruzado utilizando Progabide y placebo como terapia anadida. Ocho enfermos no completaron el estudio; cuatro debido a reacciones adversas a la medicacion (elevateon de las transaminasas hepalicas en dos casos, gastritis en uno y psicosis aguda en otro caso) y cuatro debido a razones administrativas. En los 51 enfermos restantes se observo una reduction de la frecuencia de ataques por encima del 50% en 18 enfermos que tomaban Progabide y en ocho que tomaban placebo (p < 0.05). El numero de dias con ataques se redujo de modo significativo (p=0.034) durante el tratamiento con Progabide. Tanto los pacientes como los medicos mostraron preferencias en favor del Progabide al final del ensayo (p < 0.01). Se observaron efectos colaterales clfnicos de escasa importancia en 54.7% de los casos con Progabide y en 37.7% en los tratados con placebo. Se observo una elevacion de las transaminasas hepaticas en dos pacientes durante el estudio doble ciego y en uno durante el periodo de seguimiento. Nuestra informacion muestra que el Progabide, como ya se ha publicado previamente, es util en 30–40% de los enfermos que no re-sponden completamente a otro tipo de medicaciones antiepilepticas. Este compuesto se tolera bien pero es necesaria monitorazion de la funcion hepatica. ZUSAMMENFASSUNG In einem Doppelblind-Cross over-Versuch wurden Progabide und Placebo als Zusatztherapie bei 59 Patienten mit mittelschwerer oder schwerer Epilepsie getestet. 8 Patienten fielen aus der Studie heraus: 4 wegen Arzneimittelnebenwirkung (Erhohung der Transaminasen, Gastritis 2 ×, aktue Psychose 1 ×) und 4 administrativer Griinden wegen. Bei den verbliebenen 51 Patienten wurde eine Anfallsreduktion um 50% erreicht bei 18 Patienten mit Progabide, bei 8 mit Placebo (p < 0.05). Die Zahl der Tage mit Anfallen ging unter Progabide signifikant zuruck (p=0.034). Sowohl Patienten als auch Arzt schatzten Progabide gunstiger ein. Leichte Nebenwirkungen fanden sich bei 54% der Patienten mit Progabide, bei 37.7% unter Placebo. Eine Er-hohung der Lebertransaminasen wurde bei 2 Patienten wahrend der Doppelblind-Studie beobachtet und einmal im spateren Verlauf. Unsere Ergebnisse bestatigen andere Untersuchungsbefunde: Progabide ist bei 30–40% der Patienten mit unvollstandigem Ansprechen auf antiepileptische Medikation nutzlich. Die Substanz wird gut vertragen, wenn-gleich Leberfunktionsuberwachung notwendig ist.
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DOUBLE-BLIND, PLACEBO-CONTROLLED, CROSS-OVER TRIAL OF Progabide AS ADD-ON THERAPY IN EPILEPTIC PATIENTS
Epilepsia, 1991Co-Authors: E. Gerstle De Pasquet, A Scaramelli, S Feldman, R Santana, J Aguilar, B Musch, M. Piñeyrúa De Cáceres, C. L'héritier, P L MorselliAbstract:SUMMARY: In a double-blind, cross-over trial, Progabide (PGB) and placebo were compared as add-on therapy in 59 patients with moderate to severe epilepsy. Eight patients did not complete the study, 4 because of adverse drug reactions (elevation of liver transaminases, 2; gastritis, 1; and acute psychosis, 1) and 4 because of administrative reasons. Among the remaining 51 patients, seizure frequency was reduced >50% in 18 patients with PGB treatment and in 8 patients with placebo (p
Rene H Levy - One of the best experts on this subject based on the ideXlab platform.
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in vivo and in vitro correlation of microsomal epoxide hydrolase inhibition by Progabide
Clinical Pharmacology & Therapeutics, 1993Co-Authors: Deanna L Kroetz, P Loiseau, M Guyot, Rene H LevyAbstract:Progabide was investigated as a potential inhibitor of microsomal epoxide hydrolase as a result of reports of elevated levels of carbamazepine-10,11-epoxide after coadministration of Progabide and carbamazepine to patients with epilepsy. The formation clearance of carbamazepine transdihydrodiol after administration of carbamazepine-10,11-epoxide to healthy volunteers was decreased 26% by Progabide. Therapeutic concentrations of Progabide inhibited S (+)-styrene oxide hydrolysis in human liver microsomes (inhibition constant [Ki] = 1.9 µmol/L) and purified human liver microsomal epoxide hydrolase (Ki = 4.4 µmol/L). A mixed competitive and noncompetitive mechanism of inhibition best described the effect of Progabide on microsomal epoxide hydrolase; the most potent inhibition was competitive. A similar model described the inhibition by the acid metabolite of Progabide, although inhibitory concentrations are higher than concentrations observed after Progabide therapy. An excellent agreement between the in vivo and in vitro inhibitory potencies of Progabide suggests that potential inhibitors of this important detoxification enzyme can be predicted in vitro. Clinical Pharmacology and Therapeutics (1993) 54, 485–497; doi:10.1038/clpt.1993.180
Deanna L Kroetz - One of the best experts on this subject based on the ideXlab platform.
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in vivo and in vitro correlation of microsomal epoxide hydrolase inhibition by Progabide
Clinical Pharmacology & Therapeutics, 1993Co-Authors: Deanna L Kroetz, P Loiseau, M Guyot, Rene H LevyAbstract:Progabide was investigated as a potential inhibitor of microsomal epoxide hydrolase as a result of reports of elevated levels of carbamazepine-10,11-epoxide after coadministration of Progabide and carbamazepine to patients with epilepsy. The formation clearance of carbamazepine transdihydrodiol after administration of carbamazepine-10,11-epoxide to healthy volunteers was decreased 26% by Progabide. Therapeutic concentrations of Progabide inhibited S (+)-styrene oxide hydrolysis in human liver microsomes (inhibition constant [Ki] = 1.9 µmol/L) and purified human liver microsomal epoxide hydrolase (Ki = 4.4 µmol/L). A mixed competitive and noncompetitive mechanism of inhibition best described the effect of Progabide on microsomal epoxide hydrolase; the most potent inhibition was competitive. A similar model described the inhibition by the acid metabolite of Progabide, although inhibitory concentrations are higher than concentrations observed after Progabide therapy. An excellent agreement between the in vivo and in vitro inhibitory potencies of Progabide suggests that potential inhibitors of this important detoxification enzyme can be predicted in vitro. Clinical Pharmacology and Therapeutics (1993) 54, 485–497; doi:10.1038/clpt.1993.180
Irma Garces - One of the best experts on this subject based on the ideXlab platform.
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The inhibitory effects on sexual behavior and ambulatory activity of the mixed GABAA/GABAB agonist Progabide are differentially blocked by GABA receptor antagonists.
Psychopharmacology, 1997Co-Authors: Anders Agmo, Raul G Paredes, Laura Sierra, Irma GarcesAbstract:Progabide inhibited male rat sexual behavior at a dose of 200 mg/kg. This dose had only modest effects on ambulatory activity and no effect at all on motor coordination as evaluated by a rotarod test. The GABAA antagonist bicuculline, at a dose of 1 mg/kg, blocked the effects of Progabide on sex behavior. In contrast, the GABAB antagonist CGP 35348, at doses of 50 and 100 mg/kg, was ineffective. These doses have previously been shown to block the actions of baclofen on sexual behavior. It was concluded that the GABAA but not the GABAB receptor is important for the inhibitory effects of Progabide on that behavior. The actions of Progabide on ambulatory activity were not blocked by bicuculline or CGP 35348 at any of the doses used (up to 2 and 200 mg/kg, respectively). Even the combination of both antagonists was ineffective. This suggests that the motor effects of Progabide are mediated by either a non-GABAergic receptor or by a subtype of the GABAA or the GABAB receptor that is not sensitive to the antagonists. Present results show that the effects of Progabide on motor functions depend on mechanisms different from those involved in its effects on sexual behavior. They further suggest that the GABAA receptor may be important for drug actions on male sexual behavior.
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the inhibitory effects on sexual behavior and ambulatory activity of the mixed gabaa gabab agonist Progabide are differentially blocked by gaba receptor antagonists
Psychopharmacology, 1997Co-Authors: Anders Agmo, Raul G Paredes, Laura Sierra, Irma GarcesAbstract:Progabide inhibited male rat sexual behavior at a dose of 200 mg/kg. This dose had only modest effects on ambulatory activity and no effect at all on motor coordination as evaluated by a rotarod test. The GABAA antagonist bicuculline, at a dose of 1 mg/kg, blocked the effects of Progabide on sex behavior. In contrast, the GABAB antagonist CGP 35348, at doses of 50 and 100 mg/kg, was ineffective. These doses have previously been shown to block the actions of baclofen on sexual behavior. It was concluded that the GABAA but not the GABAB receptor is important for the inhibitory effects of Progabide on that behavior. The actions of Progabide on ambulatory activity were not blocked by bicuculline or CGP 35348 at any of the doses used (up to 2 and 200 mg/kg, respectively). Even the combination of both antagonists was ineffective. This suggests that the motor effects of Progabide are mediated by either a non-GABAergic receptor or by a subtype of the GABAA or the GABAB receptor that is not sensitive to the antagonists. Present results show that the effects of Progabide on motor functions depend on mechanisms different from those involved in its effects on sexual behavior. They further suggest that the GABAA receptor may be important for drug actions on male sexual behavior.
Mitsumoto Sato - One of the best experts on this subject based on the ideXlab platform.
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an analysis of anticonvulsant actions of gaba agonists Progabide and baclofen in the kindling model of epilepsy
Epilepsy Research, 1990Co-Authors: Keiko Sato, Kiyoshi Morimoto, Motoi Okamoto, Yasushi Nakamura, Saburo Otsuki, Mitsumoto SatoAbstract:Abstract The anticonvulsant action of Progabide, an agonist of γ-aminobutyric acid (GABA) A and GABA B receptors, was investigated in the kindling model of epilepsy in rats. Progabide shortened afterdischarge durations and attenuated the severity of the accompanying convulsive responses in previously kindled rats from the amygdala (AM), frontal cortex(FC), ventral and dorsal hippocampus (HIPP), in a dose-dependent manner. Although Progabide was less effective in the dorsal HIPP kindled seizures, the efficacy was potent in AM, FC and ventral HIPP kindled seizures. On the other hand, the anticonvulsant action of baclofen, a selective agonist of GABA B receptors, was relatively weak in terms of the measurement of the afterdischarge duration of AM and HIPP kindled seizures even at toxic doses, compared with Progabide. In addition, the anticonvulsant effects of Progabide were partially reversed by treatment with the antagonist of benzodiazepine receptors, Ro 15-1788, whereas Ro 15-1788 administration alone did not alter AM kindled seizures. We concluded that the action of Progabide may be mediated via the GABA A /benzodiazepine receptor complex. These results support the hypothesis that a failure of GABA A -mediated inhibition is one of the bases of induction and generalization of seizures.