Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
Add more filters










Database
Language
Publication year range
1.
Neurochem Res ; 42(7): 1995-2010, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28508174

ABSTRACT

The series of experiments herein evaluated prototype drugs representing different mechanisms of antiseizure, antinociceptive or antidepressant action in a battery of preclinical pain models in adult male CF#1 mice (formalin, writhing, and tail flick) and Sprague Dawley rats partial sciatic nerve ligation (PSNL). In the formalin assay, phenytoin (PHT, 6 mg/kg), sodium valproate (VPA, 300 mg/kg), amitriptyline (AMI, 7.5 and 15 mg/kg), gabapentin (GBP, 30 and 70 mg/kg), tiagabine (TGB, 5 and 15 mg/kg), and acetominophen (APAP, 250 and 500 mg/kg) reduced both phases of the formalin response to ≤ 25% of vehicle-treated mice. In the acetic acid induced writhing assay, VPA (300 mg/kg), ethosuximide (ETX, 300 mg/kg), morphine (MOR, 5 & 10 mg/kg), GBP (10, 30, and 60 mg/kg), TGB (15 mg/kg), levetiracetam (LEV, 300 mg/kg), felbamate (FBM, 80 mg/kg) and APAP (250 mg/kg) reduced writhing to ≤ 25% of vehicle-treated mice. In the tail flick test, MOR (1.25-5 mg/kg), AMI (15 mg/kg) and TGB (5 mg/kg) demonstrated significant antinociceptive effects. Finally, carbamazepine (CBZ, 20 and 50 mg/kg), VPA, MOR (2 and 4 mg/kg), AMI (12 mg/kg), TPM (100 mg/kg), lamotrigine (LTG, 40 mg/kg), GBP (60 mg/kg), TGB (15 mg/kg), FBM (35 mg/kg), and APAP (250 mg/kg) were effective in the PSNL model. Thus, TGB was the only prototype compound with significant analgesic effects in each of the four models, while AMI, GBP, APAP, and MOR each improved three of the four pain phenotypes. This study highlights the importance evaluating novel targets in a variety of pain phenotypes.


Subject(s)
Analgesics/therapeutic use , Anticonvulsants/therapeutic use , Antidepressive Agents/therapeutic use , Disease Models, Animal , Neuralgia/drug therapy , Pain Measurement/drug effects , Analgesics/pharmacology , Animals , Anticonvulsants/pharmacology , Antidepressive Agents/pharmacology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Male , Mice , Neuralgia/pathology , Nipecotic Acids/pharmacology , Nipecotic Acids/therapeutic use , Pain Measurement/methods , Rats , Rats, Sprague-Dawley , Rodentia , Tiagabine
2.
Epilepsy Res ; 58(1): 1-12, 2004 Jan.
Article in English | MEDLINE | ID: mdl-15066669

ABSTRACT

N-methyl-tetramethylcyclopropanecarboxamide (MTMCD) is a new antiepileptic drug (AED) structurally related to valproic acid (VPA) that has a broad spectrum of anticonvulsant activity including models of therapy-resistant epilepsy. The purpose of this study was to identify in vivo metabolites of MTMCD that could contribute to its anticonvulsant efficacy. The metabolism of MTMCD was studied in mice, in human liver microsomes (HLM), and in recombinant human CYP isoforms with focus on formation of the hydroxylation product, N-hydroxymethyl-tetramethylcyclopropanecarboxamide (OH-MTMCD) and the N-demethylation product tetramethylcyclopropanecarboxamide (TMCD). The anticonvulsant activity of MTMCD's metabolites was evaluated in the maximal electroshock (MES), subcutaneous metrazole (s.c. Met), and in the 6Hz model in mice. In mice, OH-MTMCD was identified as a phase I metabolite of MTMCD and detected in plasma and brain after administration of MTMCD. In human liver microsomes MTMCD was biotransformed to OH-MTMCD but not to TMCD. Chemical inhibition studies suggested that MTMCD hydroxylation is mainly mediated by CYP 2A6 and CYP 2C19, which was confirmed using cDNA-expressed P450 isozymes. OH-MTMCD was a broad-spectrum anticonvulsant and possessed significant anticonvulsant activity in mouse models of partial and generalized seizures (ED50 values 75-220mg/kg), but was less potent than MTMCD. As OH-MTMCD was also present at lower concentrations than MTMCD in mouse brain, it is likely that MTMCD itself and not one of its metabolites is responsible for its activity in therapy-resistant epilepsy.


Subject(s)
Amides/metabolism , Anticonvulsants/metabolism , Cyclopropanes/metabolism , Valproic Acid/analogs & derivatives , Amides/chemistry , Amides/therapeutic use , Animals , Anticonvulsants/chemistry , Anticonvulsants/therapeutic use , Aryl Hydrocarbon Hydroxylases , Behavior, Animal/drug effects , Biotransformation , Brain/drug effects , Brain Chemistry/physiology , Chemical Phenomena , Chemistry , Chromatography, High Pressure Liquid/methods , Cyclopropanes/chemistry , Cyclopropanes/therapeutic use , Cytochrome P-450 CYP2A6 , Cytochrome P-450 CYP2C19 , Dose-Response Relationship, Drug , Electroshock/adverse effects , Gas Chromatography-Mass Spectrometry/methods , Humans , Hydroxylation/drug effects , In Vitro Techniques , Male , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Mixed Function Oxygenases , Pentylenetetrazole , Seizures/chemically induced , Seizures/drug therapy , Valproic Acid/therapeutic use
3.
Pharm Res ; 20(8): 1293-301, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12948028

ABSTRACT

PURPOSE: Racemic valnoctamide (VCD) is a central nervous system-active drug commercially available in Europe. VCD possesses two chiral centers and, therefore, it exists as a mixture of four stereoisomers. The purpose of this study was to evaluate the anticonvulsant activity of two VCD stereoisomers in comparison with VCD (racemate), valpromide (VPD), and valproic acid (VPA) and to study their pharmacokinetic-pharmacodynamic relationships. METHODS: The ability of racemic VCD, (2S,3S)-VCD, (2R,3S)-VCD and VPD to block partial seizures was studied in the 6Hz psychomotor seizure model in mice and in the hippocampal kindled rat. The ability of (2S,3S)-VCD and (2R,3S)-VCD to prevent generalized seizures was evaluated in the maximum electroshock (MES) and subcutaneous metrazole (sc Met) seizure tests. The PK of (2S,3S)-VCD, (2R,3S)-VCD, and VPD was studied in the mice utilized in the 6Hz model. RESULTS: All of the tested compounds were effective in the models tested. No significant difference in ED50 values was observed but the plasma and brain EC50 values of (2R,3S)-VCD in the 6Hz model at 32 mA stimulation were 2-fold higher than the EC50 values of (2S,3S)-VCD. An excellent pharmacokinetic-pharmacodynamic correlation was found between the plasma and brain concentrations of the VCD stereoisomers and their anticonvulsant effect in mice. Stereoselectivity was observed in clearance, volume of distribution, and in brain-to-plasma AUC ratio at a dose of 25 mg/kg, but the difference disappeared at higher doses as the clearance of the stereoisomers decreased and their half-life increased. For (2R,3S)-VCD the brain-to-plasma AUC ratio doubled at the tested dose range, while it remained constant for (2S,3S)-VCD. CONCLUSIONS: Racemic VCD, VPD, (2R,3S)-VCD, and (2S,3S)-VCD are effective anticonvulsants in animal models of partial seizures and are more potent than VPA. The more favorable brain penetration of (2S,3S)-VCD and its lower EC50 value in the 6Hz test provides one advantage over (2R,3S)-VCD as a new antiepileptic drug.


Subject(s)
Amides/pharmacology , Amides/pharmacokinetics , Anticonvulsants/pharmacology , Anticonvulsants/pharmacokinetics , Epilepsy/drug therapy , Amides/chemistry , Animals , Anticonvulsants/chemistry , Area Under Curve , Brain/metabolism , Epilepsy/metabolism , Half-Life , Injections, Intraperitoneal , Kindling, Neurologic , Male , Mice , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Time Factors
4.
Br J Pharmacol ; 139(4): 755-64, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12812999

ABSTRACT

1 The purpose of this study was to synthesize novel valproyltaurine (VTA) derivatives including valproyltaurinamide (VTD), N-methyl-valproyltaurinamide (M-VTD), N,N-dimethyl-valproyltaurinamide (DM-VTD) and N-isopropyl-valproyltaurinamide (I-VTD) and evaluate their structure-pharmacokinetic-pharmacodynamic relationships with respect to anticonvulsant activity and teratogenic potential. However, their hepatotoxic potential could not be evaluated. The metabolism and pharmacokinetics of these derivatives in mice were also studied. 2 VTA lacked anticonvulsant activity, but VTD, DM-VTD and I-VTD possessed anticonvulsant activity in the Frings audiogenic seizure susceptible mice (ED(50) values of 52, 134 and 126 mg kg(-1), respectively). 3 VTA did not have any adverse effect on the reproductive outcome in the Swiss Vancouver/Fnn mice following a single i.p. injection of 600 mg kg(-1) on gestational day (GD) 8.5. VTD (600 mg kg(-1) at GD 8.5) produced an increase in embryolethality, but unlike valproic acid, it did not induce congenital malformations. DM-VTD and I-VTD (600 mg kg(-1) at GD 8.5) produced a significant increase in the incidence of gross malformations. The incidence of birth defects increased when the length of the alkyl substituent or the degree of N-alkylation increased. 4 In mice, N-alkylated VTDs underwent metabolic N-dealkylation to VTD. DM-VTD was first biotransformed to M-VTD and subsequently to VTD. I-VTD's fraction metabolized to VTD was 29%. The observed metabolic pathways suggest that active metabolites may contribute to the anticonvulsant activity of the N-alkylated VTDs and reactive intermediates may be formed during their metabolism. In mice, VTD had five to 10 times lower clearance (CL), and three times longer half-life than I-VTD and DM-VTD, making it a more attractive compound than DM-VTD and I-VTD for further development. VTD's extent of brain penetration was only half that observed for the N-alkylated taurinamides suggesting that it has a higher intrinsic activity that DM-VTD and I-VTD. 5 In conclusion, from this series of compounds, although VTD caused embryolethality, this compound emerged as the most promising new antiepileptic drug, having a preclinical spectrum characterized by the highest anticonvulsant potential, lowest potential for teratogenicity and favorable pharmacokinetics.


Subject(s)
Anticonvulsants/adverse effects , Anticonvulsants/pharmacokinetics , Teratogens/toxicity , Valproic Acid/pharmacokinetics , Animals , Anticonvulsants/chemical synthesis , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Embryonic and Fetal Development/drug effects , Injections, Intraperitoneal , Mice , Mice, Mutant Strains , Molecular Structure , Seizures/drug therapy , Teratogens/pharmacokinetics , Valproic Acid/chemical synthesis , Valproic Acid/therapeutic use
5.
Br J Pharmacol ; 138(4): 602-13, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12598414

ABSTRACT

1. Propylisopropyl acetamide (PID) is a new chiral amide derivative of valproic acid. The purpose of this study was to evaluate the anticonvulsant activity of PID in rodent models of partial, secondarily generalized and sound-induced generalized seizures which focus on different methods of seizure induction, both acute stimuli, and following short-term plastic changes as a result of kindling, and to assess enantioselectivity and enantiomer-enantiomer interactions in the pharmacokinetics and pharmacodynamics of racemic PID and its pure enantiomers in rodents. 2. Anticonvulsant activity of (S)-PID, (R)-PID and racemic PID was evaluated in the 6 Hz psychomotor seizure model in mice, in the hippocampal kindled rat, and in the Frings audiogenic seizure susceptible mouse. The pharmacokinetics of (S)-PID and (R)-PID was studied in mice and rats. 3. In mice (S)-PID, (R)-PID and racemic PID were effective in preventing the 6 Hz seizures with (R)-PID being significantly (P < 0.05) more potent (ED(50) values 11 mg kg(-1), 46 mg kg(-1) and 57 mg kg(-1) at stimulation intensities of 22, 32 and 44 mA, respectively) than (S)-PID (ED(50) values 20 mg kg(-1), 73 mg kg(-1) and 81 mg kg(-1) at stimulation intensities of 22, 32 and 44 mA, respectively). (S)-PID, (R)-PID and racemic PID also blocked generalized seizures in the Frings mice (ED(50) values 16 mg kg(-1), 20 mg kg(-1) and 19 mg kg(-1) respectively). 4. In the hippocampal kindled rat a dose of 40 mg kg(-1) of (R)- and (S)-PID prevented the secondarily generalized seizure, whereas racemic PID also blocked the expression of partial seizures following an i.p. dose of 40 mg kg(-1). Racemic PID also significantly increased the seizure threshold in this model. 5. Mechanistic studies showed that PID did not affect voltage-sensitive sodium channels or kainate-, GABA- or NMDA- evoked currents. 6. The pharmacokinetics of PID was enantioselective following i.p. administration of individual enantiomers to mice, with (R)-PID having lower clearance and longer half-life than (S)-PID. In rats and mice, no enantioselectivity in the pharmacokinetics of PID was observed following administration of the racemate, which may be due to enantiomer-enantiomer interaction. 7. This study demonstrated that PID has both enantioselective pharmacokinetics and pharmacodynamics. The better anticonvulsant potency of (R)-PID in comparison to (S)-PID may be due to its more favorable pharmacokinetic profile. The enhanced efficacy of the racemate over the individual enantiomers in the kindled rat may be explained by a pharmacokinetic enantiomer-enantiomer interaction in rats. This study also showed the importance of studying the pharmacokinetics and pharmacodynamics of chiral drugs following administration of the individual enantiomers as well as the racemic mixture.


Subject(s)
Allylisopropylacetamide/analogs & derivatives , Allylisopropylacetamide/pharmacokinetics , Anticonvulsants/pharmacokinetics , Seizures/drug therapy , Valproic Acid/pharmacokinetics , Allylisopropylacetamide/chemistry , Allylisopropylacetamide/therapeutic use , Amides/chemistry , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Anticonvulsants/chemistry , Anticonvulsants/therapeutic use , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Cerebral Cortex/physiology , Dose-Response Relationship, Drug , Male , Mice , Rats , Rats, Sprague-Dawley , Stereoisomerism , Valproic Acid/chemistry , Valproic Acid/therapeutic use
6.
Epilepsia ; 43(2): 115-26, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11903457

ABSTRACT

PURPOSE: The studies presented here represent our efforts to investigate the anticonvulsant activity of N-methyl-tetramethylcyclopropyl carboxamide (M-TMCD) and its metabolite tetramethylcyclopropyl carboxamide (TMCD) in various animal (rodent) models of human epilepsy, and to evaluate their ability to induce neural tube defects (NTDs) and neurotoxicity. METHODS: The anticonvulsant activity of M-TMCD and TMCD was determined after intraperitoneal (i.p.) administration to CF#1 mice, and either oral or i.p. administration to Sprague-Dawley rats. The ability of M-TMCD and TMCD to block electrical-, chemical-, or sensory-induced seizures was examined in eight animal models of epilepsy. The plasma and brain concentrations of M-TMCD and TMCD were determined in the CF#1 mice after i.p. administration. The induction of NTDs by M-TMCD and TMCD was evaluated after a single i.p. administration at day 8.5 of gestation in a highly inbred mouse strain (SWV) that is susceptible to valproic acid-induced neural tube defects. RESULTS: In mice, M-TMCD afforded protection against maximal electroshock (MES)-induced, pentylenetetrazol (Metrazol)-induced, and bicuculline-induced seizures, as well as against 6-Hz "psychomotor" seizures and sound-induced seizures with ED50 values of 99, 39, 81, 51, and 10 mg/kg, respectively. In rats, M-TMCD effectively prevented MES- and Metrazol-induced seizures and secondarily generalized seizures in hippocampal kindled rats (ED50 values of 82, 45, and 39 mg/kg, respectively). Unlike M-TMCD, TMCD was active only against Metrazol-induced seizures in mice and rats (ED50 values of 57 and 52 mg/kg, respectively). Neither M-TMCD nor TMCD was found to induce NTDs in SWV mice. CONCLUSIONS: The results obtained in this study show that M-TMCD is a broad-spectrum anticonvulsant drug that does not induce NTDs and support additional studies to evaluate its full therapeutic potential.


Subject(s)
Amides/therapeutic use , Anticonvulsants/therapeutic use , Cyclopropanes/therapeutic use , Epilepsy/drug therapy , Mutagenicity Tests , Acoustic Stimulation , Administration, Oral , Amides/administration & dosage , Amides/adverse effects , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/adverse effects , Behavior, Animal/drug effects , Bicuculline , Convulsants , Cyclopropanes/administration & dosage , Cyclopropanes/adverse effects , Electrophysiology , Electroshock , Epilepsy/psychology , Injections, Intraperitoneal , Mice , Mice, Inbred Strains , Neural Tube Defects/chemically induced , Pentylenetetrazole , Rats , Rats, Sprague-Dawley , Seizures/chemically induced , Seizures/etiology , Seizures/prevention & control
SELECTION OF CITATIONS
SEARCH DETAIL
...