Preclinical profile of the anticonvulsant remacemide and its enantiomers in the rat.

Studies conducted by Fisons Pharmaceuticals and the Antiepileptic Drug Development Program (ADD Program) of the Epilepsy Branch (NINDS, NIH) revealed that 'remacemide' (FPL 12924, formerly PR 934-423) was effective orally in the prevention of maximal electroshock seizures (MES) in rats. In this context (-)stereoisomer (FPL 14145) was of equal potency to the racemate (remacemide), while the (+)stereoisomer (FPL 14144) was 54% less potent. With respect to neurotoxicity, remacemide and its enantiomers possessed more favorable therapeutic indices than phenobarbital and valproate and less favorable indices than phenytoin and carbamazepine. The duration of protection of rats in the MES test at the ED50 or 3 x ED50 of remacemide and the (+)isomer was better or on par with the best reference compounds, phenytoin and phenobarbital. After subchronic administration of either the ED50 or the ED97 of remacemide, no tolerance developed in the hexobarbital sleep test, however, the activities of 3 hepatic microsomal enzymes were elevated. In naive rats high doses of remacemide or its (-)isomer and low doses of phenobarbital caused an increase in spontaneous motor activity. Alternatively, motor activity was depressed subsequent to high doses of phenobarbital and phenytoin. Remacemide was inactive against pentylenetetrazol and 'kindling' seizures. It was without effect in 5 electrophysiological tests (evoked responses, recurrent inhibition, long-term potentiation, penicillin-induced discharge rate and veratridine-induced depolarization) employing the in vitro hippocampal slice technique. Moreover, remacemide failed to demonstrate potent binding in vitro to neuronal L-glutamate, gamma-amino-butyrate A, adenosine A1, benzodiazepine, N-methyl-D-aspartate (strychnine-insensitive glycine and ion channel subsites) or muscarinic receptors. In conclusion, remacemide specifically prevents seizures elicited by MES, an action predicting utility in patients with generalized tonic/clonic convulsions.     

Preclinical profile of remacemide: a novel anticonvulsant effective against maximal electroshock seizures in mice

Anticonvulsant tests in mice revealed specific, potent actions of remacemide for protection of mice against maximal electroshock seizures (MES). Comparisons of oral efficacy to reference compounds yielded the following ED50 values (expressed as mg/kg): remacemide = 33, phenytoin = 11, phenobarbital = 20, carbamazepine = 13 and valproate = 631. The duration for protection by remacemide was longer than carbamazepine or valproate, but shorter than phenytoin or phenobarbital. In neural impairment tests (inverted screen or rotorod) to determine the oral toxic dose 50 (TD50) the following therapeutic indices (TD50/ED50) were obtained: (1) inverted screen--remacemide = 17.6, phenytoin = 57.4, phenobarbital = 5.1, carbamazepine = 10.2, and valproate = greater than 3; and (2) rotorod--remacemide = 5.6, phenytoin = 9.6, phenobarbital 4.8, and valproate = 1.9. Remacemide was devoid of sedative actions and possessed a favorable 28.1 margin of safety value (median estimated lethal dose/ED50 for MES). An intermediate potency against either audiogenic- or N-methyl-D-aspartate-induced seizures was exhibited by remacemide. Tolerance to MES was not apparent after 5 days of oral daily dosing of remacemide. Remacemide was inactive in vitro against gamma-aminobutyrate or benzodiazepine receptors and adenosine uptake mechanisms. Therapeutic utility for generalized tonic/clonic seizures is predicted for remacemide.     

Lippincott-Raven Publishers, Philadelphia © International League Against Epilepsy Remacemide Hydrochloride and ARL 15896AR Lack Abuse Potential: Additional Differences from Other Uncompetitive NMDA Antagonists

Summary: This study was designed to determine the possible abuse liability and phencyclidine-like effects of the low-affinity uncompetitive N-methyla-aspartate (NMDA) antagonists remacemide hydrochloride [(+min)-2–amino-N-(1 -methyl-1,2–diphenylethyl)-acetamine hydrochloride] and ARL 15896AR [(+)-a-phenyl-2–pyridine-ethanamine dihydrochloride]. For the abuse-liability studies, in rats trained to self-administer cocaine intravenously (0.1 mg/kg/injection), doses of remacemide HCI, ARL 15896AR, phencyclidine, and saline were made available, and the number of injections self-administered was recorded. In different sets of rats, we assessed the ability of these drugs to induce phencyclidine-like stereotyped behavior. Doses of the compounds were expressed as multiples of the 50% effective dose (ED,), as determined from the maximal electroshock (MES) test by using either oral or intravenous administration. None of the remacemide hydrochloride or ARL 15896AR doses was self-administered at a level higher than that of the saline vehicle, unlike cocaine and phencyclidine, which were self-administered at high and moderate levels, respectively. Unlike that with remacemide hydrochloride and ARL 15896AR, oral administration of the high-affinity uncompetitive NMDA receptor-antagonists phencyclidine, ARL 16247 [N-(3–ethylphenyl)-N-methyl-N'-naph-thylguanidine] and MK-801 engendered phencyclidine-like stereotypy at doses near their MES ED₅₀, values. These data confirm the unusual safety of remacemide hydrochloride and ARL 15896AR and demonstrate that they do not possess reinforcing properties. As such, they are unlikely to present a drug-abuse problem in human beings.     

Biological profile of the metabolites and potential metabolites of the anticonvulsant remacemide.

Remacemide hydrochloride ((+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)- acetamide hydrochloride or FPL 1292AA) is a novel compound undergoing clinical trials for patients with generalized tonic/clonic and complex partial epilepsy. Remacemide exhibits efficacy against maximal electroconvulsive shock (MES) in rodents and seizures elicited by N-methyl-D,L-aspartate (NMDLA) in mice. Using rat synaptic membrane fractions, remacemide was shown to possess relatively weak noncompetitive binding to the ionic channel site of the NMDA (N-methyl-D-aspartic acid) receptor complex. With the hypothesis that activity against NMDLA-elicited seizures might be reflected by transformation to a more active metabolic species, the aim of the present study was to evaluate potential pharmacological effects of the 9 identified metabolites of remacemide which were all found in human and dog urine. Moreover, specific entities were recognized in plasma (including the rat's), as well as dog and rat cerebrospinal fluid. Five putative metabolites were also examined. A major route of metabolic transformation of remacemide in rats yields the formation of a pharmacologically active more potent desglycine derivative, namely FPL 12495 (+/-). Potency over the parent compound is revealed in the MES test in mice and rats, the NMDA-induced convulsions/mortality test in mice, and especially involving in vitro displacement of MK801 binding to the channel subsite of the NMDA receptor. The S isomer (FPL 12859) of this desglycinate is even more potent, while the R isomer is less potent than the corresponding racemate. Unlike the non-competitive NMDA antagonist, MK801, these desglycinates did not prevent kindled seizures. Three other identified metabolites show efficacy in the mouse and rat in vivo tests, namely the N-hydroxy-desglycinate (FPL 15053) and the p-hydroxy-desglycinates (FPL 14331 and FPL 14465). FPL 15053 exhibited modest activity in all tests. The only in vivo activity exhibited by the 2 p-hydroxy-desglycinates was evidenced in the MES test following i.p. and i.v. dosing. However, FPL 14331 was active in the MK801 binding assay. An oxoacetate metabolite, PFL 15455, failed to demonstrate any biological activity. Of potential metabolites tested 2 beta-hydroxy-desglycinates (FPL 14991 and FPL 14981) displayed modest activity in the MES test, however, only FPL 14981 prevented NMDLA-induced convulsions/mortality in mice and was 2-fold more active regarding MK801 binding. The hydroxy-methyl derivative of remacemide (FPL 13592) and its desglycinate (FPL 15112) prevented MES-induced convulsions only after i.v. administration; only the desglycine derivative displaced MK801 binding.(ABSTRACT TRUNCATED AT 400 WORDS)     

Anticonvulsant profile of valrocemide (TV1901): a new antiepileptic drug

PURPOSE: We sought to investigate the anticonvulsant activity of the new antiepileptic drug (AED), valrocemide or TV1901 (VGD) in various animal (rodent) models of human epilepsy to determine its anticonvulsant profile and safety margin. METHODS: VGD was administered intraperitoneally to CF no. 1 mice and orally or intraperitoneally to Sprague-Dawley rats. The anticonvulsant activity of VGD was examined in nine different animal models of epilepsy for its ability to block electrically, chemically, or sensorily induced seizures. RESULTS: In mice VGD afforded complete protection against maximal electroshock (MES)-, pentylenetetrazole-, picrotoxin-, and bicuculline-induced seizures and 6-Hz "psychomotor" seizures with median effective dose (ED50) values of 151, 132, 275, 248, and 237 mg/kg, respectively. VGD was also effective in preventing sound-induced seizures in Frings audiogenic-seizure susceptible mice (ED50, 52 mg/kg). The median neurotoxic dose in mice was 332 mg/kg. After oral administration to rats, VGD was active in the MES test, with an ED50 of 73 mg/kg, and the median neurotoxic dose was 1,000 mg/kg. Intraperitoneal administration of 300 mg/kg of VGD to hippocampal kindled Sprague-Dawley rats blocked generalized seizures and shortened the afterdischarge duration significantly. VGD also provided complete protection from focal seizures in the corneally kindled rats (ED50,161 mg/kg). CONCLUSIONS: The results obtained in this study suggest that VGD has a broad spectrum of anticonvulsant activity and promising potential as a new AED.     

Anticonvulsant 1-phenylcycloalkylamines: two analogues with low motor toxicity when orally administered.

1-Phenylcyclohexylamine (PCA) and its analogues 1-phenylcyclopentylamine (PPA) and 1-(3-fluorophenyl)cyclohexylamine (3-F-PCA) are potent anticonvulsants in the mouse maximal electroshock (MES) seizure test. Unlike the structurally related dissociative anesthetic phencyclidine (PCP), however, which produces motor toxicity at anticonvulsant doses, PCA, PPA, and 3-F-PCA protect against MES seizures at 2.2- to 3.5-fold lower doses than those that cause motor toxicity when administered intraperitoneally (i.p.). In the present study, we evaluated the oral anticonvulsant activity of PCA, PPA, and 3-F-PCA in mice; we also examined 3-F-PCA in rats. All the compounds were orally active in the mouse MES seizure test (ED50 values 14.5, 53.4, and 26.7 mg/kg, respectively). Moreover, 3-F-PCA was especially potent in rats, either when administered i.p. (ED50 0.4 mg/kg vs. 9.4 mg/kg in mice) or orally (ED50 0.8 mg/kg). Surprisingly, however, oral PPA failed to cause motor toxicity in mice even at doses that were many times higher than those that were protective in the MES test (TD50 greater than 300 mg/kg). In rats, 3-F-PCA also showed a strikingly low oral toxicity (TD50 greater than 50 mg/kg) in relation to its potency as an anticonvulsant. Like PCP, PCA analogues block N-methyl-D-aspartate (NMDA)-induced behavioral effects and lethality in mice. Moreover, in vitro studies indicate that the compounds act as uncompetitive antagonists of the NMDA receptor-channel complex. Therefore, their anticonvulsant activity may, at least in part, relate to an interaction with NMDA receptors.     

Correlation analysis between anticonvulsant ED50 values of antiepileptic drugs in mice and rats and their therapeutic doses and plasma levels

OBJECTIVE: Although there are several animal models of epilepsy, the extrapolation of antiepileptic drug (AEDs) performance to epileptic patients from anticonvulsant activity results in animals is not straightforward. Consequently, the aim of this work was to perform a correlation analysis between therapeutic daily doses (D) and average steady-state plasma concentrations (Css,av) of AEDs and their activity in common anticonvulsant animal models. METHODS: AED activity in anticonvulsant animal models was expressed as maximal electroshock seizure (MES) test ED50 values in mice and rats and ED50 values in audiogenic seizure-susceptible mice (AGS ED50). Data were examined, by use of linear and logarithmic approaches, for an association between Css,av (mg/L or micromol/L) and D (mg or mmol) for each AED in epileptic patients as the dependent variable (Y) and its MES ED50 in mice and rats and AGS ED50 in mice (mg/kg or micromol/kg) as the independent variable (X). RESULTS: Linear correlation analyses between Css,av (mg/L) and ED50 (mg/kg) for 11 AEDs gave the following correlation coefficients (R2): 0.68 (mice, MES); 0.73 (rat, MES); 0.64 (AGS). Switching the units from milligrams to micromoles improved the correlation significantly and gave the following R2 values: 0.88 (mice, MES); 0.90 (rat, MES); 0.76 (AGS). The linear correlation between Css,av and ED50 was better than that between D and ED50. CONCLUSIONS: The results of this analysis suggest that the relationship between Css,av and ED50 is useful in predicting target concentration ranges in humans. The Y intercepts of the Css,av-versus-ED50 and D-versus- ED50 plots were similar in all three animal models and ranged between 12 and 17 mg/L and between 570 and 890 mg, respectively, indicating that for all AEDs analyzed except valproic acid and ethosuximide, the therapeutic plasma concentration is in the range 10-20 mg/L.     

Effects of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate, on thrombus formation and bleeding time in rats

Dabigatran is a reversible direct, selective thrombin inhibitor, undergoing clinical development as its orally active prodrug, dabigatran etexilate. The objective of this trial was to assess the antithrombotic and anticoagulant effects of dabigatran and dabigatran etexilate in a rat model of venous thrombosis. In order to do this a modified Wessler model was used to assess the antithrombotic and anticoagulant effects of intravenous (i.v.) dabigatran and oral dabigatran etexilate administration. In addition, a rat tail bleeding time model was used to investigate the antihemostatic effect of dabigatran. The study demonstrated that bolus administration of dabigatran (0.01-0.1 mg/kg) reduced thrombus formation dose-dependently, with an ED50 (50% of the effective dose) of 0.033 mg/kg and complete inhibition at 0.1 mg/kg. By comparison, ED50 values for heparin (0.03-0.3 mg/kg), hirudin (0.01-0.5 mg/kg) and melagatran (0.1-0.5 mg/kg) were 0.07, 0.15 and 0.12 mg/kg, respectively. Oral administration of dabigatran etexilate (5-30 mg/kg) inhibited thrombus formation in a dose- and time-dependent manner, with maximum inhibition within 30 min of pretreatment, suggesting a rapid onset of action. Following i.v. administration of dabigatran (0.1-1.0 mg/kg), a statistically significant prolongation of bleeding time was observed at doses at least 15- and 5-fold greater than ED50 and ED100 (100% of the effective dose) doses, respectively; there was no significant increase in bleeding tendency at the maximum therapeutically effective dose (0.1 mg/kg). It can be concluded that dabigatran and its oral prodrug, dabigatran etexilate, show promise in the management of thromboembolic disease.     

Evaluation of stereoselective anticonvulsant,teratogenic, and pharmacokinetic profile of valnoctylurea (capuride): A chiral stereoisomer of valproic acid urea derivative

Purpose: The purpose of this study was to evaluate the stereoselective anticonvulsant activity, neurotoxicity, pharmacokinetics, and teratogenic potential of two stereoisomers of valnoctylurea (VCU), a central nervous system (CNS)–active urea derivative of valnoctic acid, which is a constitutional isomer of valproic acid (VPA). Methods: VCU stereoisomers (2S,3S)‐VCU and (2R,3S)‐VCU were synthesized. Their anticonvulsant activity was determined and compared to VPA and racemic‐VCU in rats utilizing the maximal electroshock seizure (MES) and the subcutaneous pentylenetetrazole (scMet) tests. Neurotoxicity was determined in rats using the positional sense test, muscle tone test, and gait and stance test. The induction of neural tube defects (NTDs) by VCU stereoisomers was evaluated in a mouse strain highly susceptible to VPA‐induced teratogenicity. The pharmacokinetics of VCU was studied in a stereoselective manner following intraperitoneal (i.p.) administration to rats. Results: (2S,3S)‐VCU and (2R,3S)‐VCU median effective dose ED₅₀ values were 29 mg/kg [95% confidence interval (CI) = 8–60 mg/kg] and 42 mg/kg (95% CI = 36–51 mg/kg) (MES) and 22 mg/kg (95% CI = 13–51 mg/kg) and 12 mg/kg (95%CI = 7–21 mg/kg) (scMet), respectively. (2S,3S)‐VCU was more potent and had a wider safety margin (p < 0.05), defined as the protective index (PI = TD₅₀/ED₅₀), at both the MES (PI > 17) and scMet (PI > 23) tests than racemic‐VCU or (R,S)‐VCU (PI = 2.8 and 9.9, respectively). VCU stereoisomers caused NTDs at doses >4 times that of their anticonvulsant ED₅₀ values. At a dose of 112 mg/kg, (2R,3S)‐VCU was nonteratogenic and less embryotoxic than its stereoisomer (2S,3S)‐VCU. No stereoselective pharmacokinetics was observed following intraperitoneal dosing of racemic‐VCU to rats. VCU was mainly eliminated by metabolism with a half‐life of 2 h. Conclusions: VCU anticonvulsant activity and wide PI values make it a potential candidate for development as a new, potent antiepileptic drug (AED).     

XAMI and DCDM, agonists at cAMP-associated octopamine receptors in cockroach nerve cord, produce centrally mediated antinociception in mice.

The ability of XAMI (2,3-xylylaminomethyl-2'-imidazoline), the most potent agonist of cAMP-associated octopamine-sensitive adenylate cyclase in cockroach (Periplaneta americana) nerve cord yet reported, and DCDM (N-demethylchlordimeform), a partial octopamine agonist in this preparation, to produce centrally mediated antinociception in mice was evaluated. The antinociception produced by these compounds was compared to that previously reported for p-octopamine, a phenylethylamine and endogenous mammalian hydroxyphenolic analog of norepinephrine. Consonant with the reported greater agonistic activity of XAMI on octopamine-sensitive adenylate cyclase, XAMI was more potent than p-octopamine by spinal or supraspinal administration in the abdominal constriction test (E50 = 0.013 micrograms i.t., 1.45 micrograms i.c.v.) and in the 48 degrees C hot-plate test (ED50 = 0.06 micrograms i.t., 0.4 micrograms i.c.v.), but was inactive in the tail-flick test (up to 4.0 micrograms i.c.v. or i.t.). Unlike p-octopamine, both XAMI and DCDM were active by peripheral routes of administration. DCDM was orally active in the mouse acetylcholine-induced abdominal constriction test (ED50 = 9.98 mg/kg p.o.) and was active via the s.c. route in this test (ED50 = 2.36 mg/kg), the 48 degrees C hot-plate test (ED50 = 5.40 mg/kg) and the tail-flick test (ED50 between 15 and 30 mg/kg). It appeared to be a full agonist against these endpoints. XAMI produced dose-related antinociception in the abdominal constriction test (ED50 = 0.10 mg/kg s.c.) and in the 48 degrees C hot-plate test (ED50 = 3.71 mg/kg p.o. and 0.46 mg/kg s.c.), where the antinociceptive response persisted for at least 60 min following subcutaneous or oral administration. Both compounds were less potent via peripheral routes than clonidine (as reference) in these tests. Mechanistically, XAMI-induced antinociception was antagonized by yohimbine and idazoxan, but not the opiate antagonist naloxone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative Anticonvulsant Activity and Neurotoxicity of 4-Amino-N-(2,6-dimethylphenyl) benzamide and Prototype Antiepileptic Drugs in Mice and Rats

The anticonvulsant and toxic properties of 4-amino-N-(2,6-dimethylphenyl)benzamide, (ADD 75073), were compared with phenytoin (PHT), phenobarbital (PB), ethosuximide (ESM), and valproate (VPA). These compounds were evaluated in mice and rats using well-standardized anticonvulsant test procedures. The results indicate that ADD 75073 is a very potent anticonvulsant in the maximal electroshock seizure (MES) model. The compound was effective in nontoxic doses following intraperitoneal (i.p.) administration in mice and oral administration in both mice and rats. In mice, the i.p. administration of ADD 75073 resulted in an ED50 value of 2.6 mg/kg as compared with a value of 9.5 mg/kg for phenytoin (PHT) in the same assay. Compound ADD 75073 was ineffective in nontoxic doses against all other seizure models examined in this study, and thus has a pharmacologic profile similar to that of PHT.     

Anticonvulsant Activity of N-Palmitoylethanolamide, a Putative Endocannabinoid, in Mice

PURPOSE: The purpose of this study was to evaluate in mice the anticonvulsant potential of N-palmitoylethanolamide, a putative endocannabinoid that accumulates in the body during inflammatory processes. METHODS: N-palmitoylethanolamide was injected intraperitoneally (i.p.) in mice and evaluated for anticonvulsant activity [in maximal electroshock seizure (MES) and chemical-induced convulsions] and for neurologic impairment (rotorod). It was compared with anandamide and with different palmitic acid analogues as well as with reference anticonvulsants (AEDs) injected under the same conditions. RESULTS: The MES test showed, after i.p. administration to mice, that N-palmitoy]ethanolamide had an median effective dose (ED50) value comparable to that of phenytoin (PHT; 8.9 and 9.2 mg/kg, respectively). In the subcutaneous pentylenetetrazol test and in the 3-mercaptropropionic acid test, it was effective only against tonic convulsions. N-palmitoylethanolamide was devoid of neurologic impairment < or = 250 mg/kg, yielding a high protective index. CONCLUSIONS: N-palmitoylethanolamide, an endogenous compound with antiinflammatory and analgesic activities, is a potent AED in mice. Its precise mechanism of action remains to be elucidated.     

Structure-Pharmacokinetic-Pharmacodynamic Relationships of yV-Alkyl Derivatives of the New Antiepileptic Drug Valproyl Glycinamide

PURPOSE: The purpose of this study was to evaluate the structure-pharmacokinetic-pharmacodynamic relationships of a series of N-alkyl and N,N-dialkyl derivatives of the new antiepileptic drug (AED), valproyl glycinamide (VGD). METHODS: The following compounds were synthesized: N-methyl VGD (M-VGD), N,N-dimethyl VGD, N-ethyl VGD, N,N-diethyl VGD (DE-VGD), and N,N-diisopropyl VGD. These compounds were evaluated for anticonvulsant activity, neurotoxicity, and pharmacokinetics. RESULTS: After i.p. administration to mice in the maximal electroshock seizure test (MES), DE-VGD had an ED50 value comparable to that of VGD (145 and 152 mg/kg, respectively), whereas in the subcutaneous metrazol test (sc Met) model, M-VGD had a slightly lower ED50 than VGD (108 and 127 mg/kg, respectively). After oral administration to rats, M-VGD had an MES-ED50 similar to that of VGD (75 and 73 mg/kg, respectively). Of the N-alkyl VGD derivatives studied, M-VGD had the best pharmacokinetic profile: the lowest clearance (5.4 L/h), the longest half-life (1.8 h), and the lowest liver-extraction ratio (14%). N,N-dialkylated VGD derivatives underwent two consecutive N-dealkylations, whereas N-alkylated derivatives underwent a single N-dealkylation process, yielding VGD as a major active metabolite. CONCLUSIONS: M-VGD had the most favorable pharmacodynamic and pharmacokinetic profile of the investigated N-alkyl VGD derivatives. VGD was found to be a major active metabolite of M-VGD and to be less neurotoxic than M-VGD. Therefore VGD rather than one of the investigated N-alkyl VGD derivatives should be considered for development as a new AED.     

Anticonvulsant profile of MDL 27,266: an orally active, broad-spectrum anticonvulsant agent.

The novel anticonvulsant substance MDL 27,266 was tested in a variety of anticonvulsant models to assess its anticonvulsant profile, behavioral toxicity and oral bioavailability. Intraperitoneally (i.p.) administered MDL 27,266 afforded complete protection against sound-induced seizures in DBA/2J and Frings audiogenic-seizure (AGS)-susceptible mice (ED50s: 5.0 and 5.1 mg/kg, respectively). It was also effective following i.p. administration to CF#1 mice against maximal electroshock (MES)-, pentetrazole-, picrotoxin-, quisqualic acid-, and strychnine-induced seizures (ED50s: 24.9, 13.8, 43.3, 8.05, and 60.5 mg/kg, respectively). MDL 27,266, in well tolerated oral doses, prevented the expression of stage 5 behavioral seizures in the corneal-kindled rat and myoclonic seizures in the photosensitive baboon, Papio papio. Chronic administration of MDL 27,266 to AGS-susceptible mice did not markedly affect its anticonvulsant potency or efficacy against sound-induced seizures. These results suggest that MDL 27,266 possesses a broad anticonvulsant profile which most closely approximates that of the broad-spectrum prototype antiepileptic drug valproate.     

Antiparkinsonian effects of remacemide hydrochloride,a glutamate antagonist,in rodent and primate models of Parkinson's disease

Loss of dopaminergic innervation of the striatum results in overactivity of the glutamatergic pathways from the subthalamic nucleus to the internal segment of the globus pallidus and the substantia nigra pars reticulata, the output nuclei of the basal ganglia. Previous work has shown that local blockade of glutamate receptors in the internal segment of the globus pallidus or substantia nigra pars reticulata leads to marked suppression of parkinsonian signs. We have now examined whether systemic administration of a glutamate receptor antagonist has antiparkinsonian effects in rodent and primate models of Parkinson's disease. Remacemide hydrochloride is an anticonvulsant, neuroprotective compound with antagonist activity at the N-methyl-D -aspartate receptor ion channel. In normal rats and monoaminedepleted rats, remacemide hydrochloride did not cause locomotor hyperactivity, unlike MK-801. When monoaminedepleted rats were treated with a subthreshold dose of levodopa methylester, remacemide hydrochloride (5–40mg/kg, orally) caused a dose-dependent increase in locomotor activity. Moreover, remacemide hydrochloride (10 mg/kg, orally) potentiated the effects of each suprathreshold dose of levodopa methylester tested (100–200 mg/kg, intraperitoneally). Parkinsonian rhesus monkeys were tested with oral doses of vehicle plus vehicle, vehicle plus levodopa-carbidopa, and remacemide hydrochloride (5 mg/kg) plus levodopa-carbidopa. Blinded clinical scoring of videotapes revealed that treatment with remacemide hydrochloride plus levodopa-carbidopa was substantially better than levodopa-carbidopa plus vehicle or vehicle plus vehicle. The effects of remacemide hydrochloride lasted at least 5 hours. We conclude that certain N-methyl-D -aspartate receptor antagonists have antiparkinsonian actions and low potential for side effects. Clinical trials of remacemide hydrochloride in patients with Parkinson's disease may be warranted.     

Intraction of the Anticonvulsant Ameltolide with standard Anticonvulsants

The newly characterized anticonvulsant ameltolide was studied in mice in combination with the standard antiepileptic drugs (AEDs), phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA). In combination with either PHT or CBZ, ameltolide produced dose-additive effects in the maximal electroshock (MES) test and in the horizontal screen (HS) test for neurologic impairment. The large separation between the doses for the anticonvulsant effects and the neurologically impairing effects (protective index, PI) were maintained as well in the combinations as in the individual compounds. VPA was impotent in the MES test and did not have a clear separation between the doses that produce the anticonvulsant effects and those that are neurologically impairing (low PI). When VPA and ameltolide were combined, the effects were less than additive by isobolographic analysis on both the MES and HS tests. At high oral doses (20 and 40 mg/kg, p.o.), ameltolide produced impairment on the HS test and decreased body temperature. The effects on the HS test were enhanced twofold, whereas the effects on body temperature were not markedly enhanced, by coadministration of the MES ED95 of PHT and CBZ. VPA (MES ED95) appeared to antagonize the temperature-lowering effects of ameltolide. These interaction studies suggest that ameltolide would be safe, with no unexpected effects, when used in epileptic patients concurrently receiving these standard AEDs. These studies also suggest that the effects of ameltolide would be lessened by simultaneous administration of VPA.     

Fluoxetine, a Selective Serotonin-Uptake Inhibitor, Enhances the Anticonvulsant Effects of Phenytoin, Carbamazepine, and Ameltolide (LY 201116)

Dose-response curves for the prototypical anticonvulsants phenytoin (PHT) and carbamazepine (CBZ), and a novel anticonvulsant, ameltolide (LY201116), were determined with and without pretreatment with the selective serotonin-uptake inhibitor fluoxetine by maximal electroshock seizure (MES) test in mice. Fluoxetine (2.5, 5, and 10 mg/kg intraperitoneally, i.p.) produced a dose-related decrease in the ED50 values for the anticonvulsants (i.p. administration) to protect against MES-induced tonic-extensor seizures. Fluoxetine (10 mg/kg i.p.) also decreased the intravenous (i.v.) ED50 doses of the three anticonvulsants by a factor of approximately 2. These data suggest that fluoxetine, through its selective inhibition of serotonergic reuptake, may have beneficial advantages as compared with common antidepressant drugs in treatment of depressed patients with epilepsy and may also enhance the seizure control of prototypical anticonvulsants in treatment of epilepsy.     

Influence of Different Methylxanthines on the Anticonvulsant Action of Common Antiepileptic Drugs in Mice

The protective activity of carbamazepine (CBZ, 60 min before testing), phenobarbital (PB, 120 min), phenytoin (PHT, 120 min), and valproate (VPA, 30 min) alone or concurrent with methylxanthine derivatives was evaluated against maximal electroshock-induced seizures (MES) in male mice. All drugs were administered intraperitoneally (i.p.), and the protection offered by antiepileptic drugs (AEDs) was expressed as ED50 in mg/kg. Caffeine sodium benzoate in doses of 0.0595-0.476 mmol/kg (11.55-92.4 mg/kg) distinctly reduced the anticonvulsant efficacy of PB, in the highest dose tested with an increase in ED50 value from 19.5 to 38 mg/kg. This methylxanthine derivative in the dose range of 0.119-0.476 mmol/kg (23.1-92.4 mg/kg) also efficiently inhibited the protective action of PHT. When combined with caffeine (0.238 and 0.476 mmol/kg), the ED50 of PHT was raised from 12 to 17 and 24 mg/kg, respectively. In doses of 0.238 and 0.476 mmol/kg, caffeine also diminished the efficacy of CBZ and VPA, and at the highest dose tested the methylxanthine elevated the respective ED50s from 13 to 20.5 mg/kg and from 270 to 420 mg/kg. Generally caffeine sodium benzoate (up to 0.476 mmol/kg) did not affect the plasma levels of studied AEDs, and only at 0.476 mmol/kg did it significantly decrease the level of PHT. Among the other methylxanthines, pentoxifylline (0.238-0.476 mmol/kg; 66.3-132.5 mg/kg) and diprophylline (0.952 mmol/kg; 242.1 mg/kg) inhibited the protective potential of PHT and the respective ED50s were raised from 12 to 16.5, 15.5, and 14 mg/kg. No significant alterations in PHT plasma levels were observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Furosemide potentiates the anticonvulsant action of valproate in the mouse maximal electroshock seizure model

Accumulating evidence indicates that furosemide (FUR, a loop diuretic) exerts the anticonvulsant action in various in vitro and in vivo experiments. Therefore, the aim of this study was to assess the influence of FUR on the protective action of numerous conventional and newer antiepileptic drugs (carbamazepine [CBZ], lamotrigine [LTG], oxcarbazepine [OXC], phenobarbital [PB], topiramate [TPM] and valproate [VPA]) in the mouse maximal electroshock seizure (MES) model. Results indicate that FUR (up to 100mg/kg, i.p., 30 min before the test) neither altered the threshold for electroconvulsions nor protected the animals against MES-induced seizures in mice. FUR (100 mg/kg, i.p.) enhanced the anticonvulsant effects of VPA in the MES test by reducing its ED(50) value from 230.4 to 185.4 mg/kg (P<0.05). In contrast, FUR at 100 mg/kg had no significant effect on the antielectroshock action of the remaining drugs tested (CBZ, LTG, OXC, PB, and TPM) in mice. Estimation of free plasma and total brain VPA concentrations revealed that the observed interaction between FUR and VPA in the MES test was pharmacodynamic in nature because neither free plasma nor total brain VPA concentrations were altered after i.p. administration of FUR. In conclusion, one can ascertain that the selective potentiation of the antielectroshock action of VPA by FUR and lack of any pharmacokinetic interactions between drugs, make this combination of pivotal importance for epileptic patients treated with VPA and received FUR from other than epilepsy reasons.     

Anticonvulsant profile and teratogenicity of 3,3-dimethylbutanoylurea: a potential for a second generation drug to valproic acid

Purpose: The purpose of this study was to evaluate the anticonvulsant activity and teratogenic potential of branched aliphatic acylureas represented by isovaleroylurea (IVU), pivaloylurea (PVU) and 3,3‐dimethylbutanoylurea (DBU), as potential second‐generation drugs to valproic acid (VPA). Methods: The anticonvulsant activity of IVU, PVU, and DBU was determined in mice and rats utilizing the maximal electroshock seizure (MES) and the pentylenetetrazole (scMet) tests. The ability of DBU to block electrical‐, or chemical‐induced seizures was further examined in three acute seizure models: the psychomotor 6 Hz model, the bicuculline and picrotoxin models and one model of chronic epilepsy (i.e., the hippocampal kindled rat model). The induction of neural tube defects (NTDs) by IVU, PVU, and DBU was evaluated after i.p. administration at day 8.5 of gestation to a mouse strain highly susceptible to VPA‐induced teratogenicity. The pharmacokinetics of DBU was studied following i.v. administration to rats. Results: DBU emerged as the most potent compound having an MES‐ED ₅₀ of 186 mg/kg (mice) and 64 mg/kg (rats) and an scMet‐ED ₅₀ of 66 mg/kg (mice) and 26 mg/kg (rats). DBU underwent further evaluation in the hippocampal kindled rat (ED ₅₀ = 35 mg/kg), the psychomotor 6 Hz mouse model (ED ₅₀ = 80 mg/kg at 32 mA and ED ₅₀ = 133 mg/kg at 44 mA), the bicuculline‐ and picrotoxin‐induced seizure mouse model (ED ₅₀ = 205 mg/kg and 167 mg/kg, respectively). In contrast to VPA, DBU, IVU, and PVU did not induce a significant increase in NTDs as compared to control. DBU was eliminated by metabolism with a half‐life of 4.5 h. Conclusions: DBU's broad spectrum and potent anticonvulsant activity, along with its high safety margin and favorable pharmacokinetic profile, make it an attractive candidate to become a new, potent, and safe AED.