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At least 487 records · Page 27Linked to original sources
PubMed1988

Epileptic phenomena produced by kainic acid in laboratory rats during ontogenesis.

Because of its preferential neuroexcitatory effects on the hippocampal neurones kainic acid (KA) is used for inducing partial seizures with a complex symptomatology. In this study the authors investigated the effect of intraperitoneal administration of KA, in doses of 2-16 mg/kg, on the laboratory rat during ontogenesis. The experimental animals were males aged 7, 12, 18, 25 and 90 days. The first signs of an effect in adult rats were automatisms; in young animals, jerks also appeared. The most important automatisms were wet dog shakes, which preponderated in 25-day-old and older animals, whereas in the young rats they consisted chiefly of intensive scratching. Minimal seizures with a motor pattern identical to minimal metrazol seizures were observed in all the age groups and so were generalized tonic-clonic convulsions, which appeared after large doses of KA. The systemic administration of KA is a convenient model of temporal seizures and their progressive generalization and could act as a model for testing broad spectrum antiepileptics.

Age Factors↗
PubMed1986

Effects of thioglucoses on sensitivity to insulin hypoglycemic convulsions.

Based on the effects of gold thioglucose (GTG), we have previously proposed a regulatory center in brain which adjusts the convulsive response to insulin hypoglycemia. The sensitivity to insulin hypoglycemic convulsions is decreased 24 hr and increased 1 week after a single i.p. injection of GTG. The differences are in the brain's convulsive response to equal hypoglycemia, as the blood glucose response to insulin is unchanged. The generalized convulsive threshold, reflected in the sensitivity to nonmetabolic pentylenetetrazol (Metrazol) convulsions, is not altered. Despite its systemic administration, GTG causes lesions focused in the ventromedial hypothalamus. In the present study, this regulatory center was explored further by the ability of two thioglucoses to substitute for GTG. beta-D-Thioglucose had no effect. 5-Thioglucose simulated the early (24 hr) action of GTG but had no effect at 1 week. However, unlike GTG, 5-thioglucose did not cause the ventromedial hypothalamus lesion. The early (24 hr) and late (1 week) components are thus dissociated. The early effect on insulin hypoglycemic convulsions does not require a ventromedial hypothalamus lesion. Structure-activity relationships and relationships to glucoregulatory systems are discussed.

Animals↗
PubMed1986

[Effect of antidepressants on the convulsive action of thiosemicarbazide, strychnine and corasol].

Orally administered amitryptiline (25 and 50 mg/kg) protected animals against fatal convulsions induced by thiosemicarbazide, strychnine and metrazole. Vilaxazine had a protecting effect against death induced by strychnine. Impramine, maprotiline, mianserine and pirlindole (pyrazidol) only somewhat prolonged the latend period of convulsions and death, while incazane, caroxazone, nomifenzine and trazodone had practically no effect on the action of the three convulsants under study.

Animals↗
PubMed1986

Effect of theophylline treatment on the functional hyperaemic and hypoxic responses of cerebrocortical microcirculation.

The purpose of the present study was to elucidate the importance of extracellular adenosine (ADO) in the regulation of cerebrocortical microcirculation during rest, hypoxia, and brain activation. Cerebrocortical microcirculation and fluorescence of reduced nicotinamide adenine dinucleotide (NADH) were measured by surface fluororeflectometry through a cranial window. Arterial hypoxia and brain activation were produced by respirating the animals with a gas mixture containing 6-7% O2 and by injecting 4-6 mg/kg metrazol into the lingual artery, respectively. These reactions were used as test before and after theophylline (THEO) treatment. In some of the experiments only the cortical area beneath the cranial window was treated with THEO (10(-4) M), in others 2 X 10(-4) mol/kg THEO was injected intraperitoneally. Potency of THEO in antagonizing the cerebral blood flow (CBF) increasing effect of topically applied ADO was also tested. It was found that superfusion of the brain cortex with artificial cerebrospinal fluid (mock CSF) containing 10(-4) M THEO does not alter resting CBF, but inhibits the CBF increasing effect of 10(-6) M and 10(-5) M ADO by approximately 70% and 40%, respectively. Intraperitoneally injected THEO increased CBF by approximately 60%, which has been attributed mostly to its action on the systemic circulation. Under control conditions, arterial hypoxia and epileptic seizures increased CBF by approximately 150% and 300%, respectively. Since neither topical nor systemic THEO treatment altered the vasodilatory and CBF increasing potency of arterial hypoxia and attenuated these effects of epilepsy slightly, it was concluded that extracellular ADO is not a critical factor in the regulation of cerebrocortical microcirculation.

Adenosine↗
PubMed1985

Kinetics of drug action in disease states. XIV. Effect of infusion rate on pentylenetetrazol concentrations in serum, brain and cerebrospinal fluid of rats at onset of convulsions.

The purpose of this investigation was to develop a method which can be used to determine the effect of various diseases on the concentration-pharmacologic activity relationship of the central nervous system stimulant pentylenetetrazol (PTZ, Metrazol) in a manner that excludes or accounts for pharmacokinetic variables. Adult female rats (approximately 170 g) received an i.v. infusion of PTZ at one of four different rates (0.155-1.53 mg/min) until the animals exhibited the first myoclonic jerk. This occurred after an average of 4.9 to 52 min of infusion. The PTZ concentrations in serum, brain and cerebrospinal fluid at this pharmacologic endpoint were independent of infusion rate. Other groups of rats were infused at three different rates (0.155-1.53 mg/min) to the onset of maximal seizures. Again, the PTZ concentrations in serum, brain and cerebrospinal fluid were not significantly affected by the rate of infusion of the drug. The average (+/- S.D.) PTZ concentration in cerebrospinal fluid was 46 +/- 5 mg/l (n = 22) at the onset of the first myoclonic jerk and 109 +/- 13 mg/l (n = 12) at the onset of maximal seizure. PTZ concentrations in brain and serum were similar to those in cerebrospinal fluid. The total serum clearance of a 20-mg/kg i.v. bolus dose of PTZ was 5.36 +/- 0.34 ml/min/kg, the terminal half-life was 116 +/- 25 min and the apparent volume of distribution was 896 +/- 134 ml/kg (all values are mean +/- S.D.). Serum protein binding was negligible (less than 10%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Effect of stimulus intensity on the profile of anticonvulsant activity of phenytoin, ethosuximide and valproate.

The relative ability of phenytoin, ethosuximide and valproate to prevent minimal (clonic) threshold, maximal (tonic extension of the hindlimbs) threshold and supramaximal (tonic extension of the hindlimbs) seizures elicited by electrical and chemical (Metrazol, bicuculline, and picrotoxin) stimulation was determined. Ethosuximide and valproate were effective against minimal (clonic) threshold seizures, whereas phenytoin was ineffective and even activated them. All three anticonvulsants were effective against maximal (tonic extension of the hindlimbs) threshold seizures. Phenytoin and valproate, but not ethosuximide, were effective against supramaximal (tonic extension of the hindlimbs) seizures. The results suggest that the specificity of experimental models of epilepsy used in the evaluation of potential antiepileptic drugs is primarily due to the intensity rather than the nature of the stimulus used or the kind of seizure component evoked. Models based only on maximal (tonic extension of the hindlimbs) threshold seizures may identify anticonvulsant activity, but do not differentiate between substances that prevent seizure spread and those that increase seizure threshold.

Animals↗
PubMed1985

Antiepileptic drugs: detection, quantification, and evaluation.

The anticonvulsant potential of chemical substances can be identified with test procedures that act at various biological levels, ranging from subcellular elements to the normal or modified intact animal. All of these procedures modify either some minimal overt threshold electrochemical or neurochemical event or a suprathreshold manifestation such as seizure spread. This suggests that laboratory tests for the detection, quantification, and evaluation of antiepileptic drugs should be designed to identify substances that elevate seizure threshold and/or prevent seizure spread. The s.c. Metrazol (pentylenetetrazol) seizure threshold test and the supramaximal electroshock seizure test are commonly used to achieve this objective. Additional chemoshock tests may be used to delineate further the mechanisms of anticonvulsant action. Numerous variables, such as experimental animals, electroshock apparatus, parameters of electrical and chemical stimulus, and routes of drug administration, must be controlled to ensure accurate, reliable, and reproducible results. The in vivo procedures described are reliable and reproducible, and predict clinical utility of the drugs tested. New models for testing anticonvulsant activity are evaluated against clinically effective antiepileptic drugs originally identified by these same procedures.

Age Factors↗
PubMedDate not supplied

[Cortical diffusion characteristics of seizure induced in the horm of Ammoni: II. Chemical stimulation].

We have studied the cortical diffusion characteristics of seizures induced at cornu Ammonis by toppical application of:pentilenetetrazol (Metrazol), acetylcholine and stricnine. We have observed that cerebral cortex synchronise with cornu ammonis showing similar morphology, which is characteristic for the differents drugs applied. We have found similar characteristics in the cortical diffusion to those described in a previous paper 4 for the mechanical stimulation. Hence we must conclue that the variability of the discharges depends onto the position of the electrode in the anteroposterior axes. As far as the electrodes are situated backwards the activity is slower with spikes of higher amplitude and without cortical propagation.

Acetylcholine↗
PubMed1979

[Chemical and pharmacological research on pyran derivatives. XIV. 3-alkylaminoaphtho/2,1-b/pyran-1-ones and derivatives].

3-Alkyl(phenyl)aminoaphtho[2,1-b]pyran-1-ones (III) were prepared from N-alkyl or N-phenylethoxycarbonylacetamides and 2-naphthol in the presence of phosphorus oxychloride, in order to evaluate their pharmacological activity on the CNS in comparison with previously described 3-dialkylaminoaphtho[2,1-b]pyran-1-ones. Compounds (III) gave 2-morpholinomethyl derivatives as well as N-acetyl and N-ethtoxycarbonyl derivatives. The reaction of (III) in which R = alkyl and N,N-dimethylformamide-POCl3 afforded 2-formyl derivatives and in some cases also 8-alkyl-9,10-bisdimethylaminoaphtho[1',2':5,6]pyrano[2,3-b]pyrrol-11(8H)-ones; when R = phenyl, only naphtho[1',2':5,6]pyrano[2,3-b]quinolin-14-one was obtained from the same reaction. Pharmacological evaluation showed that compounds (III) had a weak CNS depressant activity. Some of them also exhibited antagonist effect on reserpine-induced blepharospasm and hypothermia and on metrazole-induced seizures in the mouse. Within the limits of these activities a special behavior was found for the compound 3-ethylaminoaphtho[2,1-b]pyran-1-one [(III b) - K 12479].

Amphetamines↗
PubMed1977

Charge-transfer complexes of hematoporphyrin having a pharmacological interest.

Complexes formed by hematoporphyrin with donor molecules were prepared and isolated. Among these complexes particular attention is given to that formed by reacting dimethylaminoethanol with hematoporphyrin. Some data are reported on the chemical evidence of formation like u.v. spectra. The product, named Hematodeanol, determines some sufficiently specific effects on the CNS; it remarkably cuts down the depression induced by pentobarbital, moderately hinders convulsions by metrazole, delays hypothermia by reserpine, facilites the learning of conditioned avoidance response (CAR) and improves the learning of a sound discrimination at variable interval. The actions become evident when tests are carried out after a continuous treatment for 7 days and according to the data of the investigation of pharmacokinetic kind, the phenomenon may be attributed to the fact that the drug concentration in the nervous tissue, when it is administered several times at intervals of 24 h, inclines to increase progressively.

Animals↗
PubMed1984

Modification of drug action by hyperammonemia.

Pretreatment with ammonium acetate (NH4Ac) (6 mmol/kg s.c.) approximately doubled the time morphine-treated mice remained on a hot surface and similarly increased muscular incoordination by diazepam, but NH4Ac treatment alone had no effect. Thus, hyperammonemia is capable of altering drug action and must be considered along with impaired drug metabolism in enhanced drug responses associated with liver disease. Experiments in vitro showed that acetylcholine-induced catecholamine release from bovine adrenal medulla is depressed as much as 50% by 0.3 mM NH4Ac and KCl-induced contractions of guinea-pig ileum were inhibited 20% by 5 mM NH4Ac. Addition of excess calcium reversed the depression in both tissues, but calcium-independent catecholamine release by acetaldehyde was not blocked by NH4Ac. These results suggested that ammonia blocks calcium channels. Parallels in the actions of NH4Ac and the calcium channel blocker verapamil support this concept. Both verapamil (10 mg/kg i.p.) and NH4Ac pretreatment enhanced morphine analgesia- and diazepam-induced muscular incoordination and antagonized amphetamine-induced motor activity, and neither verapamil nor NH4Ac affected the convulsant action of metrazol. The data suggest that hyperammonemia exerts a calcium channel blocking action which enhances the effects of central nervous system depressants and certain opioid analgesics.

Acetates↗
PubMed1983

Central nervous system supersensitivity and withdrawal from long-term diphenylhydantoin treatment.

The effects of withdrawal from long-term treatment with increasing doses of diphenylhydantoin (DPH) were studied in rats. The dose of DPH was increased from 5 to 200 mg/kg over 20 days and the animals were tested 72 h after withdrawal. DPH withdrawal induced a leftward displacement of the dose-response curves obtained for the convulsive effects of both picrotoxin and metrazol and decreased the latency of 3-mercaptopropionic acid-induced seizures. These effects were interpreted to be a consequence of supersensitivity of the central nervous system induced by long-term DPH depression.

Animals↗
PubMed1980

Post-ictal resistance to audiogenic seizures in inbred mice.

Inbred audiosensitive mice exposed to a prolonged auditory signal recovered and remained refractory to further audiogenic seizures as long as the signal was continued. Susceptibility to audiogenic seizures returned upon cessation of sound. The rate of return was the same whether the sound stimulus was brief or prolonged. In a small proportion of test animals, which failed to become fully refractory, the continuing auditory stimulus proved lethal. Mice maintained in the post-seizure refractory state were fully susceptible to Metrazol-induced seizures.

Acoustic Stimulation↗
PubMed1980

Anticonvulsive activity of indenoimidazolidinones and related heterocyclic compounds in mice.

A series of substituted cyclic ureides and related compounds, one of them a thio analog, were synthesized by condensing ninhydrin with urea, thiourea, dimethylurea or other aromatic or bifunctional agents. When tested against seizures induced in mice by the chemoconvulsant Metrazol or against audiogenic seizures, four compounds decreased either the incidence or the severity of convulsive manifestations and protected from mortality in seizures. The effective compounds were not toxic at the administered level (150 mg/kg) and produced few observable sedative effects.

Acoustic Stimulation↗
PubMed1995

Anticonvulsant efficacy/safety properties of 2-amino-N-(1,2-diphenylethyl)acetamide hydrochloride.

2-Amino-N-(1,2-diphenylethyl)-acetamide-hydrochloride (FPL 13950) was profiled preclinically in rodents for efficacy against convulsions, as well as for acute safety/behavioral observations. FPL 13950 exhibited good oral efficacy and duration of action with respect to prevention of seizures elicited by maximal electroshock-shock in both rats and mice. Tolerance to protection against maximal electroshock and hexobarbital-induced sleep-time was not evident after subchronic drug administration. FPL 13950 also prevented convulsions/mortality in mice after i.v. dosing with N-methyl-D, L-aspartate, however, it was ineffective against other types of chemically induced convulsions, as well as bicorneal kindling. High oral doses produced neural impairment in both mice and rats and hyperactivity in rats. Sequential administration of yet higher doses elicited tonic/clonic convulsions culminating in death. During i.v. infusion of metrazol in mice, high i.p. doses of FPL 13950 shortened the latency to first twitch and clonus. No increase in the startle response or phencyclidine-like behavior was evident after oral dosing in rats.

Acetamides↗
PubMed1994

Synthesis of some N-arylazole acetamide derivatives and their anticonvulsant and antimicrobial activities.

Some new N-arylazole acetamide derivatives have been prepared by the reaction of alpha-bromo-N-arylacetamide with imidazole, pyrazole and 1,2,4-triazole. The structures of these compounds have been confirmed by UV, IR, 1H-NMR and elementary analysis. Their anticonvulsant activities were determined by maximal electroshock (MES) and subcutaneous metrazol (Scmet) tests. Most of the compounds showed anticonvulsant activity with significantly low neurotoxicity according to Phase I tests. Compound 6 carrying alpha-naphthyl and 1,2,4-triazole was found active in the MES test with ED50 = 64.9 mg/kg and TD50 = 221.0 mg/kg but it was not active in corneally stimulated rats. Antibacterial and antifungal activities of the compounds were determined against S. aureus, E. coli, P. aeruginosa, C. albicans, C. parapsilosis, C. pseudotropicalis and C. stellatoidea by using the microdilution broth method. Compounds 8 and 10 showed significant activity (MIC < 32 micrograms/ml) against various Candida species.

Acetamides↗
PubMed1994

Is the site of action of ethosuximide in the hindbrain?

The action of ethosuximide, valproate and clonazepam against pentylenetetrazol-induced epileptic EEG phenomena was studied in acute experiments in rats with intercollicular brainstem transection. Ethosuximide lost its action against both rhythmic metrazol activity (model of human absences) and EEG seizures. On the contrary, the action of valproate and clonazepam in cerveau isolé rats was the same as in intact animals. The site of anticonvulsant action of ethosuximide may be localized in hindbrain structures, whereas the actions of both valproate and clonazepam may be demonstrated even if hindbrain structures had been eliminated.

Animals↗