piperidines and ilepcimide

Antieplepsirine (AES) is a new antiepileptic drug (AED) which was originally extracted from a Chinese folk remedy, and is now chemically characterized and synthesized. Its chemical structure is different from those of other available AEDs. Animal experiments involving AES demonstrated significant antiepileptic activity. Only a few clinical studies of AES with open trial have been resorted, none of which were on children. A 6.5 month, add-on, double-blind, placebo-controlled, randomized, cross-over study on AES (10 mg/kg per day) was conducted on epileptic children (aged 1-14 years) refractory to treatment with standard AEDs. The seizure frequency was recorded, and the blood levels of AES and other co-medicated AEDs (phenobarbital, phenytoin, carbamazepine and valproate) were determined. Although not planned, patients or parents were allowed to refuse to cross-over to the alternate therapy. The results were compared to the children who crossed-over as well as for the entire group during the first 3 months of randomized treatment. A total of 58 children entered, but only 34/58 children completed the cross-over study. The 24 children whose parents refused to let them be crossed-over continued the original study treatment (AES or placebo) for the entire 6 months. There was no statistically significant difference in seizure control when the entire group of 58 patients was compared to a parallel study group for the first 3 months of therapy (P = 0.178). There was a significant difference (P<0.01) in seizure control between AES and placebo treatment for the 34 patients who completed the entire cross-over study. No significant changes were seen in the blood level of other AEDs, and no serious acute side effects were observed. The results of the present study indicate the efficacy of AES for epileptic children with refractory seizures.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Electroencephalography; Epilepsy; Female; Humans; Infant; Male; Piperidines; Treatment Outcome

Antiepilepsirine (AES) is one of the derivatives of a Chinese folk prescription. It is a new antiepileptic drug (AED) synthesized in cooperation by Chinese medical and pharmaceutical workers. Pharmacological experiments on animal models prove that its antiepileptic action is marked, but there has been little evaluation of its clinical effects. We used the double-blind placebo-controlled crossover study which is generally acceptable as a proper method for new drug study. This study covered 58 epileptic children treated with classical AEDs and observed 6.5 months. Every patient took AES and placebo for 3 months each by random crossover on the basis of add-on therapy. The blood levels of AES and other antiepileptic drugs were determined regularly. The results show that there are no significant differences in clinical effects between AES and placebo in pediatric epilepsies as a whole, but AES is effective in tonic-clonic seizures (P less than 0.05), the most common type of seizure in the series. There are no significant differences in AED blood levels between the AES effective and ineffective groups. AES has no effect on the blood levels of other AEDs. AES is very safe, children given large doses (10 mg/kg/day) demonstrate no serious side-effects. It is suggested that there is potential improvement in patient psychological and cognitive status. This article also discusses the evaluation of new drugs for clinical effects, subject sampling, the criteria for efficacy evaluation and relationship between animal information and human outcome. The AES chemical structure is different from other well-known AEDs, this is a unique advantage.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Clinical Trials as Topic; Double-Blind Method; Epilepsy, Tonic-Clonic; Female; Humans; Infant; Male; Piperidines

Ilepcimide (ICM), a clinically effective antiepileptic drug, has been used in China for decades; however, its antiepileptic mechanism remains unclear. ICM is structurally similar to antiepileptic drug lamotrigine (LTG). LTG exerts its anticonvulsant effect by inhibiting voltage-gated Na

Topics: Action Potentials; Animals; Anticonvulsants; Hippocampus; Lamotrigine; Mice; Neurons; Piperidines; Sodium; Sodium Channels

Objective To observe changes of serum neuron specific enolase (NSE) level in children patients with epilepsy by additional use of ilepcimide (piperine derivative). Methods Totally 107 epilepsy children patients were assigned to the test group (77 cases) and the control group (30 cases) ac- cording to random digit table. Children patients in the control group received anti-epileptic Western drugs only. Those in the test group additionally took ilepcimide, 5 mg/kg per day as initial dose, taken in two times. The dose was gradually added to those without control of epilepsy attack. Added dose within a week should not exceed 10 mg/kg per day. The therapeutic course for all was one year. Electoencephalo- gram (EEG) was performed before treatment, half a year after treatment, and one year after treatment, respectively. Serum NSE level was detected using electrochemiluminescence. Efficacy was assessed after 1-year treatment. Results The total effective rate was 65. 0% (50177) in the test group, with statistical difference as compared with that in the control group [30. 0% (9/30), P <0. 01 ]. Compared with before treatment, serum NES-level obviously decreased in the test group after 0. 5-year treatment and 1- year treatment respectively (P <0. 05, P <0. 01). Besides, serum NES level was lower after 1-year treatment than after 0. 5-year treatment (P <0. 05, P <0. 01). There was no statistical difference in serum NES level between the test group and the control group at each time point (P >0. 05). Results of EEG were obviously superior in the test group (3 with normal range EEG, 5 critically abnormal EEG, 69 abnormal EEG) to the control group (2 with normal range EEG and 75 abnormal EEG) after 1-year treatment, with statistical difference (Z= -2. 33, P <0. 05). There was no statistical difference in EEG results of the control group between before treatment (all abnormal EEG) and after 1-year treatment (3 critically abnormal EEG and 27 abnormal EEG) (Z = -1. 732, P > 0. 05). Conclusion Adding ilepcimide (piperine derivative) for epilepsy children patients could lower serum NSE level and the frequency of seizures, and improve results of EEG.

Topics: Child; Drugs, Chinese Herbal; Electroencephalography; Epilepsy; Humans; Phosphopyruvate Hydratase; Piperidines; Seizures

Together with apigenine dimethylether and piperchabamide A, a new amide alkaloid, Kaousine and the Z form of antiepilepsirine were isolated from the aerial part of Piper capense L.f (Piperaceae). Their structures were elucidated by spectrometric methods and their in vitro antiparasitic activities were evaluated on Plasmodium falciparum.

Topics: Alkaloids; Amides; Antimalarials; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Epoxy Compounds; Humans; Microbial Sensitivity Tests; Molecular Structure; Piper; Piperidines; Plant Extracts; Plants, Medicinal

Antiepilepsirine (AES) is a new antiepileptic drug developed in China. Anticonvulsant effects of AES were studied in both pentylenetetrazol (PTZ, n = 20) and amygdala kindled (n = 10) rats. AES was given once per day by oral gavage for 4 weeks. On days 7, 14, 21 and 28, all rats were tested 2 h after daily AES administration: PTZ and amygdala kindled rats were given a PTZ injection (30 mg/kg, i.p.) or amygdala stimulation (400 microA, 1 s), respectively. Behavior was observed, and seizures were graded. AES (300 or 500 mg/kg) produced sustained, dose dependent, protective effects against PTZ induced seizures in PTZ kindled rats, while AES (500 mg/kg) had no effects in amygdala kindled rats.

Topics: Amygdala; Animals; Anticonvulsants; Epilepsy; Kindling, Neurologic; Male; Pentylenetetrazole; Piperidines; Rats; Rats, Sprague-Dawley

Antiepilepsirine is a kind of new antiepileptic drug. In this paper, a new method, adsorptive voltammetry (ADV) has been established for the determination of antiepilepsirine. In 0.20 mol/L H2SO4 solution, a sensitive reduction wave of antiepilepsirine was obtained by ADV after preconcentration on the surface of hanging mercury drop electrode (HMDE) (Ei = 0.7V, v = 100 mV/s), the peak potential was -0.94V (vs Ag/AgCl). The linear range between the peak current and the concentration of antiepilepsirine was 3.0 x 10(-9)-3.0 x 10(-6) mol/L with a detection limit of 1.0 x 10(-9) mol/L. Antiepilepsirine in tablet and urine samples was determined by using this method. The electrochemical behaviour of the system and its electrode reaction mechanism were studied by means of linear sweep and cyclic voltammetry, constant potential coulometry, normal pulse polarography (NPP), etc. The diffusion coefficient D was 7.7 x 10(-6) cm2/s. The electrode reaction rate constant was 1.5 x 10(-3) cm/s. The number of reduction electron n was 2. The electron transfer coefficient was 0.52. The electrode reduction process was shown to be irreversible with the adsorptive characteristics.

Topics: Anticonvulsants; Electrochemistry; Electrodes; Humans; Piperidines; Tablets

In order to investigate the mechanism of action of anticonvulsant drugs, we examined the effects of carbamazepine (CBZ) and antiepilepsirine (AE) on convulsions and on brain biogenic amines in genetically epilepsy-prone rats (GEPR). AE was an effective anticonvulsant in moderate seizure GEPR (GEPR-3, ED50 = 65.5 mg/kg) and in severe seizure GEPR (GEPR-9, ED50 = 68.5 mg/kg). Because GEPR are known to have deficiencies in brain norepinephrine (NE) and serotonin (5-HT), which are of etiologic significance in their seizure predisposition, we evaluated the effects of anticonvulsant doses of CBZ and AE on dialyzable NE, 5-HT and their metabolites. Dialysis probes were stereotaxically inserted into hippocampi of awake and unrestrained GEPR-3 and GEPR-9. Either AE (100 mg/kg in GEPR-3; 100 mg/kg in GEPR-9) or CBZ (45 mg/kg in GEPR-3; 6 mg/kg in GEPR-9) was administered i.p. after establishing basal release. Significant increases in dialyzable 5-HT, but not NE, were seen at the approximate time to peak anticonvulsant effect for each drug in both strains. The changes in 5-HT release remained closely associated with the anticonvulsant actions after i.v. administration of either AE (40 mg/kg) or CBZ (25 mg/kg) in GEPR-3. Pretreatment of GEPR-9 with p-chlorophenylalanine depleted brain 5-HT and greatly diminished the anticonvulsant effectiveness of both drugs. We conclude that both CBZ and AE are effective anticonvulsants in GEPR and that enhancement of serotonergic transmission may contribute to the anticonvulsant effect of these drugs.

Topics: Animals; Anticonvulsants; Brain; Carbamazepine; Chromatography, High Pressure Liquid; Epilepsy; Female; Hydroxyindoleacetic Acid; Injections, Intraperitoneal; Male; Neurons; Piperidines; Rats; Rats, Inbred Strains; Serotonin

The metabolism of antiepilepserine, 3,4-methylene dioxycinnamyl piperidine, was studied in isolated perfused rat liver. Two metabolites were separated and purified by means of HPLC. They were identified as 3,4-methylene dioxycinnamyl hydroxypiperidine and 4-hydroxy-3-methoxycinnamyl piperidine by UV and MS. The latter was further confirmed by chemical synthesis. The pharmacokinetics of antiepilepserine in isolated perfused liver was also studied. Parameters obtained include a first order elimination constant, k = 0.0157 +/- 0.0043 min-1, and a half-life, t 1/2 = 46.7 +/- 11.9 min, (n = 6). The amount of antiepilepserine lost during the perfusion could not be compensated by the increased amount of metabolites. Antiepilepserine was found to be tightly bound and stored in the liver. This might be one of the explanations of the first pass effect of antiepilepserine after oral administration.

Topics: Animals; Anticonvulsants; Chromatography, High Pressure Liquid; Cinnamates; In Vitro Techniques; Liver; Perfusion; Piperidines; Rats

Topics: Anticonvulsants; Chromatography, High Pressure Liquid; Photochemistry; Piperidines; Stereoisomerism

Topics: Animals; Anticonvulsants; Brain; Corpus Striatum; Hydroxyindoleacetic Acid; Limbic System; Male; Piperidines; Rats; Serotonin

Piperine and two of its derivatives, antiepilepsirine (AE or 3,4-methylendioxycynnamoylpiperine) and compound 7448 (N-isopropyl 3 (4 chloro-phenyl) propenoylamide) are very effective in stimulating serotonin (5HT) synthesis. AE raises the ratio of free-to-bound tryptophan (TP) in plasma and induces a long-lasting increase of this aminoacid in brain. At the same time in striatum and limbic area it causes a lasting increase in 5 hydroxyindolacetic acid (5HIAA) a 5HT metabolite and to a lesser extent, an increase in the levels of the monoamine itself. Together with this action on 5HT metabolism we found that AE caused release of 3H-5HT from an in vitro synaptosomal preparation. It thus appears that piperine and its derivatives AE and compound 7148 affect the central serotonergic system.

Topics: Animals; Anticonvulsants; Brain; Corpus Striatum; Hydroxyindoleacetic Acid; Kinetics; Limbic System; Male; Piperidines; Rats; Rats, Inbred Strains; Serotonin; Tryptophan

Topics: Animals; Anticonvulsants; Cytochrome P-450 Enzyme System; Enzyme Induction; Female; Humans; Male; Mice; Phenobarbital; Phenytoin; Piperidines; Rats

Piperine and its derivatives are effective anticonvulsant drugs that antagonize convulsions induced by physical and chemical methods. Their major anticonvulsant activity as shown in animal tests lies in modification of the maximal electroshock seizure pattern. They also have sedative-hypnotic, tranquilizing, and muscle-relaxing actions and can intensify the depressive action of other depressants, when used in combination. Antiepilepsirine, one of the derivatives of piperine, is used as an antiepileptic drug in treating different types of epilepsy. It has been proved effective and is being widely used in China. The anticonvulsant action of 7446, 7448, and 7903 is more potent than that of antiepilepsirine. The chemical structure of piperine and its derivatives is different from that of prototype antiepileptic drugs, and, therefore, these may become a new group of antiepileptic drugs.

Topics: Anticonvulsants; Chemical Phenomena; Chemistry; Humans; Piperazines; Piperidines; Seizures