PubMed Health⌕ Search

Biomedical subjects

J A Ferrendelli

Publications and source records attributed to J A Ferrendelli.

At least 73 records · Page 4Linked to original sources
PubMed1982

Alpha-substituted gamma-butyrolactones: new class of anticonvulsant drugs.

Alkyl-Substituted gamma-butyrolactones were synthesized and tested for their convulsant and anticonvulsant actions in mice and guinea pigs. The alpha-substituted compounds, alpha, alpha-dimethyl-, and alpha-ethyl-alpha-methyl-gamma-butyrolactone were anticonvulsant compounds with a spectrum of activity similar to that of ethosuximide. In contrast, beta-substituted compounds were convulsant agents similar to picrotoxinin. The alpha-substituted-gama-butyrolactones represent a new class of anticonvulsant drug with experimental and clinical potential.

4-Butyrolactone↗
PubMed1982

Relationships between norepinephrine and cyclic nucleotides in brain and seizure activity.

To characterize further the roles of norepinephrine (NE) and cyclic nucleotides in seizure mechanisms, an examination was made of the effects of several drugs purported to depress noradrenergic influence in the CNS on pentylenetetrazol-induced seizure activity and regulation of cyclic AMP levels in the cerebral cortex and hippocampus in mice. Depletion of brain stores of NE with reserpine or treatment of neonatal mice with 6-hydroxy-dopamine decreased seizure latency and/or threshold and diminished seizure-induced accumulation of cyclic AMP in brain. Propranolol, a beta-adrenergic receptor antagonist, and yohimbine, an alpha 2-adrenergic receptor antagonist, had effects qualitatively similar to reserpine and 6-hydroxy-dopamine, but phentolamine, a mixed alpha-adrenergic antagonist, increased seizure threshold and latency and did not reduce the accumulation of cyclic AMP. None of the drugs tested had any consistent effect on the regulation of cyclic GMP levels in brain during seizures. These data are consistent with the hypothesis that cyclic AMP in brain may be mediating an inhibitory influence of NE on seizure activity.

Animals↗
PubMed1982

Adenylate cyclases in vertebrate retina: enzymatic characteristics in normal and dystrophic mouse retina.

Adenylate cyclase activity and the effects of various activators and inhibitors of this enzyme were measured in retinas from normal mice (C57BL/6J) and congenic animals with photoreceptor dystrophy. In normal retina, approximately 250 microM-ATP was required for half-maximal stimulation of the enzyme. Activity was supported by Mg2+ and Mn2+, but Ca2+ was ineffective. The enzyme was inhibited by EGTA and stimulated by 5'-guanylylimidodiphosphate (GPP(NH)P), dopamine, and NaF. The stimulatory effects of GPP(NH)P and dopamine were greater in the presence of EGTA. Examination of microdissected normal retinas revealed that the inner (neural) retina had adenylate cyclase activity four times that of the photoreceptor cell layers, and that EGTA inhibited activity in the inner retina, but had no effect in the outer retina. In dystrophic retinas basal enzyme activity was 60% higher than that in normal retina. The enzyme in this tissue was stimulated by EGTA, GPP(NH)P, and dopamine, and their effects were additive. These results indicate that adenylate cyclase activity in vertebrate retina is under complex regulation by substrate, divalent cations, guanine nucleotides, dopamine, and perhaps calmodulin. In addition, the data demonstrate that adenylate cyclase is not evenly distributed in the retina and that it is regulated differently in the inner and outer retina. Finally, the present results indicate that regulation of this enzyme in dystrophic retina may be qualitatively and quantitatively different from that in normal retina.

Adenylyl Cyclases↗
PubMed1982

Adenylate cyclases in the vertebrate retina: distribution and characteristics in rabbit and ground squirrel.

Adenylate cyclase activity and the effects of EGTA, 5'-guanylylimidodiphosphate (GPP(NH)P), and dopamine were measured in microdissected layers of rod-dominant (rabbit) and cone-dominant (ground squirrel) retinas, The distribution of basal enzyme activity was similar in both species, with the highest levels found in the inner plexiform and photoreceptor cell inner segment layers, EGTA inhibited adenylate cyclase in the inner retina of both species and stimulated activity in rabbit outer and inner segment layers, but had no effect in these layers from ground squirrel. Enzyme activity was stimulated in all regions by GPP(NH)P, except in the outer segments of the photoreceptors. Dopamine stimulated the enzyme in the outer and inner plexiform and inner nuclear layers in rabbit, but only in the inner plexiform layer in ground squirrel. These data demonstrate that the enzymatic characteristics of adenylate cyclase vary extensively from region to region in vertebrate retina and suggest that cyclic AMP may have multiple roles in this tissue. A model for the distribution of the different forms of adenylate cyclase in retina is proposed.

Adenylyl Cyclases↗
PubMed1982

Interactions between primidone, carbamazepine, and nicotinamide.

The effect of nicotinamide on the conversion of primidone to phenobarbital was studied in mice and in three epileptic patients. In mice, 200 mg per kilogram of nicotinamide increased the half-life of primidone by 47.6%, and the conversion to phenobarbital and phenylethylmalonamide was decreased by 32.4% and 14.5%, respectively. Nicotinamide also decreased the conversion of primidone to phenobarbital in patients. The dose of nicotinamide correlated directly with the primidone-phenobarbital ratio (r = 0.861, p less than 0.01). Nicotinamide also increased carbamazepine levels in two patients treated with this drug. The data demonstrate that nicotinamide inhibits metabolism of primidone in mice and metabolism of primidone and carbamazepine in humans. This probably occurs by inhibition of cytochrome P-450 by nicotinamide.

Animals↗
PubMed1982

Comparative actions of phenytoin and other anticonvulsant drugs on potassium- and veratridine-stimulated calcium uptake in synaptosomes.

The actions of phenytoin and several anticonvulsants drugs on veratridine-stimulated (Na-dependent) and K-stimulated (Na-independent) Ca uptake were studied in isolated nerve terminals (synaptosomes) from rat cerebral cortex. Phenytoin inhibits both veratridine- and K-induced Ca uptake but is more potent against veratridine. Inhibition of veratridine-stimulated Ca uptake by phenytoin appears to be a competitive relationship, whereas the interaction between K and phenytoin is noncompetitive. Hydroxyphenyl-phenylhydantoin, mephenytoin and ethylphenylhydantoin have actions similar to phenytoin but all are substantially less potent. Carbamazepine, phenobarbital, diazepam and lidocaine also inhibit veratridine- and K-stimulated Ca uptake, but ethosuximide and valproic acid are ineffective. Only carbamazepine and lidocaine have a relatively selective action against veratridine which is similar to phenytoin, and only these three drugs are active at concentrations which approximate their clinically effective anticonvulsant blood levels. The results of this study, in conjunction with reported data, suggest that phenytoin inhibits Na and Ca conductances in nervous tissue by separate and probably independent mechanisms. The present data also lead to the hypothesis that inhibition of Na uptake (perhaps associated with inhibition of Ca uptake) in nervous tissues is a mechanism of action responsible for some of the selective antiepileptic effects and/or analgesic effects of phenytoin, carbamazepine and lidocaine.

Animals↗
PubMed1982

Anticonvulsant properties of alpha, gamma, and alpha, gamma-substituted gamma-butyrolactones.

Derivatives of gamma-butyrolactone (GBL) substituted on the alpha- and/or gamma-positions were synthesized and tested for their effects on behavior in mice, on the electroencephalographs and blood pressure of paralyzed-ventilated guinea pigs, and on electrical activity of incubated hippocampal slices. Several compounds, including alpha-ethyl-alpha-methyl GBL (alpha-EMGBL), alpha, alpha-dimethyl GBL, alpha, gamma-diethyl-alpha, gamma-dimethyl GBL, and gamma-ethyl-gamma-methyl GBL, prevented seizures induced by pentylenetetrazol, beta-ethyl-beta-methyl-gamma-butyrolactone (beta-EMGBL), picrotoxin, or all three compounds in mice and guinea pigs but had no effect on seizures induced by maximal electroshock or bicuculline. Neither gamma-hydroxybutyrate (GHB) nor alpha-isopropylidine GBL had any anticonvulsant activity. The anticonvulsant alpha-substituted compounds had a potent hypotensive effect and antagonized the hypertensive effect of beta-EMGBL, alpha-EMGBL was tested in incubated hippocampal slices and was found to depress basal activity and antagonize excitation induced by beta-EMGBL. These results demonstrate that alpha-alkyl-substituted GBL and, to a lesser extent, gamma-substituted derivatives are anticonvulsant agents and that their effects are strikingly different from those of GHB or beta-alkyl-substituted GBLs, which are epileptogenic. Possibly beta- and alpha-substituted GBLs act at the same site as agonists and antagonists, respectively.

4-Butyrolactone↗
PubMed1981

Regionally selective metabolic effects of hypoglycemia in brain.

Regional CNS levels of glucose reserves, glycolytic intermediates, and high-energy phosphate reserves were measured in insulin-treated, hypoglycemic rats and correlated with EEG activity. Intravenous administration of insulin to paralyzed, ventilated animals causes concomitant reduction of blood glucose levels and progressive abnormality and eventual loss of EEG activity. In all regions of brain examined, glucose and glycogen levels decrease until they are essentially depleted, and glucose-6-phosphate and fructose-1,6-biphosphate fall approximately 80%. Pyruvate levels decrease 50% in cerebral cortex and brain stem and a lesser amount in striatum, hippocampus, thalamus, and cerebellum. Lactate levels fall 50-60% in all regions except cerebellum, where no change is observed. ATP and phosphocreatine levels remain normal until the EEG is isoelectric, and then decrease in all regions except cerebellum. These results demonstrate that hypoglycemia does not have a uniform effect on brain glucose and energy metabolism, and cerebellum seems to be relatively protected.

Adenosine Triphosphate↗
PubMed1981

Kainic acid-induced limbic seizures: electrophysiologic studies.

Surface and depth electroencephalograms (EEGs) were studied after intravenous injections of kainic acid (KA). High frequency oscillations and spikes appeared in the hippocampus at a dose (1 mg per kilogram) that did not affect other structures. Higher doses (greater than or equal to 4 mg per kilogram) led to electrical seizures in limbic structures, similar to those in temporal lobe epilepsy. In hippocampal slices maintained in vitro, 0.1 to 1.0 microM KA produced spontaneous epileptiform spikes, originating in CA3, and increased evoked potentials. Systemic KA is a potent means of inducing limbic seizures with a primary action in the hippocampus. We propose that this selective activation arises when KA augments excitatory glutamatergic synapses in critical epileptogenic areas, such as the CA3 region of the hippocampus.

Animals↗