Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In rats anesthetized with methoxyflurane, phenytoin (DPH) and medazepam (MDZ) were administered iontophoretically to pyramidal and granule cells discharging spontaneously or being driven by acetylcholine or glutamic acid. The objectives were to determine if: 1) these anticonvulsant agents exert direct effects on the rates of discharge of hippocampal neurons; 2) similarities exist between responses elicited by DPH and MDZ; and 3) pyramidal and granule cells differ in their responsiveness to the drugs. The firing rates of 38% of spontaneously active neurons were reduced by iontophoretic DPH. The incidence of depression by DPH depended upon the pretest discharge rates of the cells. Only 5% of cells with spontaneous rates less than 12/sec were depressed by DPH, but 80% with rates faster than 12/sec were inhibited. MDZ depressed 79% of spontaneously firing neurons regardless of pretest discharge rate. A majority of neurons whose firing rates were facilitated by either acetylcholine or glutamate were depressed by DPH or MDZ ejected iontophoretically. Pyramidal and granule cells responded similarly to putative transmitters, but differentially to the drugs. MDZ depressed a much greater proportion of spontaneously active granule cells then DPH. Phenytoin and MDZ differed with regard to the incidence of depression of spontaneous discharges, inhibition of slow firing cells, the proportion of granule cells depressed, and the duration of effect. These differences may be due to potency and pharmacokinetic factors or dissimilar mechanisms of action when the compounds are applied directly to single neurons.
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PMID:Actions of iontophoretic phenytoin and medazepam on hippocampal neurons. 1 97

Post-tetanic potentiation (PTP) of monosynaptic reflex was estimated in spinal cords in the drug-free state after the administration of a convulsant dose of penicillin and after the administration of phenytoin. There was no apparent correlation between the degree of depression of PTP and the efficacy of controlling seizure activity by phenytoin. Extracellular potassium levels were measured with ion-selective microelectrodes. The post-stimulation clearing of [K+]0 was not accelerated by phenytoin, and frequently it was slowed. Post-stimulus undershooting of [K+]0 was diminished. Oxidation of NADH in cortex and of cytochrome a, a3 in spinal cord were measured by optical methods. Stimulus-evoked transient oxidation responses evoked by electrical stimulation were depressed by phenytoin. It is concluded that systemic administration of phenytoin in therapeutic doses does not stimulate Na+-K+-activated membrane ATPase in cortex and spinal cord. Unlike other depressants, phenytoin did not cause a reduction of "resting" redox levels of respiratory enzymes. The local regulation of blood flow remained unaltered after phenytoin administration. Phenytoin caused a moderate but consistent depression of the stimulus-evoked responses of potassium activity, electric potential, and oxidative enzymes, consistent with diminished outflow of potassium from cells, owing either to lesser activation of cells or to a lesser exchange of ions.
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PMID:Phenytoin, electric, ionic, and metabolic responses in cortex and spinal cord. 19 41

Diphenylhydantoin (DPH, phenytoin sodium, Dilantin) inhibited the growth of cultured human astrocytoma cells in 7 of the 10 cell lines studied. This inhibition, determined by a microtiter assay, was dose-dependent; DPH levels of 20 micrograms/ml and above produced significant depression of growth in astrocytoma cultured cells. However, normal cultured human astrocytes were not affected until DPH levels of 60 micrograms/ml and above were added to the cells; normal fibroblasts also showed no growth inhibition up to 100 micrograms/ml. We have confirmed that DPH is 1.5 times as concentrated in tumor tissue as it is in normal tissue and serum. These findings suggest that DPH has properties that inhibit the growth of human astrocytoma cells in tissue culture at levels that are achievable clinically.
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PMID:Growth-inhibitory effects of diphenylhydantoin on human brain tumor cells in culture. 21 34

Four prototypic anticonvulsants were tested for their effectiveness against barbiturate withdrawal in cats. The effects were evaluated on a total of over 20 motor, autonomic and behavioral withdrawal signs. The animals were made physically dependent by 5 weeks of twice daily "maximally tolerable" sodium pentobarbital dosing intragastrically. Anticonvulsants were administered by intravenous infusion 25 hours after the final dose of chronic pentobarbital treatment when all withdrawal signs had become severe and grand mal type withdrawal convulsions were observed. Phenobarbital blocked withdrawal signs quite effectively at doses that caused no significant acute central nervous system depression. Trimethadione also reversed most withdrawal signs, but some signs persisted even at doses causing overt acute toxicity. Dimethadione was less effective than the parent compound, trimethadione, in reversing withdrawal but caused greater acute toxicity. Phenytoin was in effective for most withdrawal signs and some signs were made worse. The clonic phase of withdrawal convulsions was accentuated and the overall condition of the animals worsened. During withdrawal, the animals were less sensitive (tolerant) to phenobarbital but were more sensitive to acute toxicity from the other drugs tested.
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PMID:Evaluation of anticonvulsants in barbiturate withdrawal. 56 Apr 73

Veratridine, ouabain, glutamate and high concentrations of K+, agents which cause depolarization of excitable cells, markedly elevate levels of adenosine 3':5'-monophosphate (cyclic AMP) and guanosine 3':5'-monophosphate (cyclic GMP) in brain tissue, in vitro. Phenytoin inhibits veratridine (5 micron)- and ouabain (100 micron)-induced accumulations of both cyclic nucleotides in slices of mouse cerebral cortex. As little as 10 to 30 micron phenytoin produces a statistically significant depression, and 100 to 400 micron inhibits more than 90%. In contrast, at concentrations up to 400 micron, the drug has little or no effect on elevations of cyclic AMP or cyclic GMP caused by glutamate (10 mM) or K+ (64 mM). The inhibitory action of phenytoin on ouabain-induced elevations of cyclic nucleotides appears to be noncompetitive; inhibition of the veratridine effects probably is also noncompetitive. Tetrodotoxin also inhibits ouabain- and veratridine-induced elevations of cyclic nucleotides in brain slices, but it is 3 orders of magnitude more potent than phenytoin. Like phenytoin, tetrodotoxin does not inhibit the effects of glutamate or K+ on cyclic nucleotide regulation. These data suggest that, similar to tetrodotoxin phenytoin blocks sodium channels in excitable membranes. Possibly this mechanism is responsible for the antiepileptic action of phenytoin.
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PMID:Similar effects of phenytoin and tetrodotoxin on cyclic nucleotid regulation in depolarized brain tissue. 73 31

Depression of one or more parameters of cellular and/or humoral immune responses was found in 60% of general hospital patients treated with phenytoin and 47% of patients treated with carbamazepine. Phenytoin-treated patients failed to manifest delayed hypersensitivity (DHS) reactions to common antigens, and to make antibody to Salmonella typhi and tetanus toxoid. Serum levels of IgA and IgM, DNA synthesis in circulating leucocytes, and phytohaemagglutinin (PHA) induced deoxyribonucleic acid synthesis were also low. Depression of IgA, DHS reactivity and antibody responsiveness to S. typhi were shown to develop after the commencement of phenytoin therapy in a study of eleven patients. The presence of immunological defects was independent of the dosage of drug, its serum concentration, the duration of therapy and the sex of the subject. Studies in vitro provided evidence that immunosuppression was the result of a direct effect of phenytoin on the metabolism of lymphoid cells. Carbamazepine was shown to have a similar but less potent direct effect. Pharmacological concentrations of phenytoin caused a significant depression of DNA synthesis in PHA-stimulated and non-stimulated blood cell cultures in vitro. High concentrations in addition caused depression of cell counts, lymphocyte blastogenesis, ribonucleic acid and protein synthesis. Phenytoin was not cytocidal at concentrations of up to 125 mug/ml. Depression of DNA synthesis by phenytoin was maximal when phenytoin was added within 4-8 hr of the addition of PHA. PHA-induced DNA synthesis was not significantly affected by pre-incubation with phenytoin. In vivo, the presence of immunological defects was not related to phenytoin-induced folic acid deficiency. High concentrations of carbamazepine, but not phenobarbitone or diazepam caused a significant depression of PHA-stimulated DNA synthesis in blood cell cultures. The data show that immunosuppression is a common side-effect of phenytoin therapy, and that lymphoma is rare. They suggest that in the presence of phenytoin-induced immunosuppression another factor, or factors are required to induce the formation of lymphoma.
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PMID:Depression of immune competence by phenytoin and carbamazepine. Studies in vivo and in vitro. 121 10

The influence of diazepam, an agonist, and flumazenil (Ro 15-1788), an antagonist of the benzodiazepine receptor, on repetitive firing of action potentials in cultured spinal neurons and on voltage-dependent Na+ currents in cultured N2A neuroblastoma cells was examined. The effects were compared to those of the antiepileptics phenytoin and carbamazepine and the local anesthetic lidocaine. The whole-cell configuration of the patch-clamp technique was used for potential and current recording. Diazepam (10 microM) or phenytoin (10 microM) reduced the duration of repetitive action potential discharges in 50 or 67% of the spinal neurons, respectively. At a concentration of 100 microM repetitive firing was completely blocked. Flumazenil (100 microM) had no effect. In N2A neuroblastoma cells diazepam, phenytoin, carbamazepine and lidocaine, but not flumazenil, at a concentration of 100 microM reduced the Na+ current to 60-67% of control. At 10 microM no or only a weak depression was seen with any drug. In the presence of diazepam (100 microM) the Na+ channel inactivation curve was shifted in the hyperpolarizing direction by -4.8 +/- 0.5 mV. Phenytoin, carbamazepine and lidocaine (all 100 microM) caused stronger shifts of -17.4 +/- 2.1, -10.6 +/- 0.9 and -17.0 +/- 2.1 mV, respectively. Inhibition of the Na+ current by diazepam increased use-dependently over 9 depolarizing pulses repeated at high frequency (200 Hz), whereas use-dependent effects of the other compounds developed less rapidly. At a low stimulation rate (7 Hz) use-dependent block was pronounced with lidocaine, but weak or absent with diazepam and carbamazepine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Action of diazepam on the voltage-dependent Na+ current. Comparison with the effects of phenytoin, carbamazepine, lidocaine and flumazenil. 165 Nov 46

Dilantin toxicity has been well described and has generally been noted to include signs and symptoms of nystagmus, ataxia, nausea, and vomiting. Dilantin's depressive effects are seldom mentioned. Two patients are presented who, although stable while on the rehabilitation unit, developed vegetative signs of depression soon after discharge. Both were found to have toxic levels of Dilantin. Neither revealed the classic neurologic or gastrointestinal complaints. Although one patient had documented family and social stressors, the other had a stable home life. Both patients recovered remarkably once their Dilantin dosages were adjusted. In such patients who present with change in mood, sleeping, and eating patterns, Dilantin toxicity should be suspected. Serum blood levels should be checked, and dosage adjusted before the addition of antidepressant medication. Possible causes for Dilantin-associated depression are discussed in detail.
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PMID:Dilantin toxicity and vegetative depression: a report of two cases. 224 39

The action of phenytoin on the inward calcium current (ICa) was studied in cells of the clonal mouse neuroblastoma X rat glioma hybrid line 108CC5 by the suction pipette technique for internal perfusion and voltage clamp. The ICa was recorded after suppression of Na+ and K+ currents. Phenytoin, applied externally in concentrations of 50 to 500 microM, depressed the ICa in the investigated potential range of -60 to +30 mV in a concentration-dependent manner. When the cells were stimulated by depolarizing clamp steps, the extent of the ICa depression increased with the frequency and duration of the activating pulses. ICa was also inhibited on intracellular application of phenytoin.
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PMID:Calcium channel block by phenytoin in neuroblastoma x glioma hybrid cells. 241 95

Phenytoin (10-100 microM) was studied on excitatory synaptic transmission and post-tetanic potentiation (PTP) in the in vitro rat hippocampus. Synaptic potentials were studied using extracellular, intracellular and single-electrode voltage clamp techniques. Field excitatory postsynaptic potentials were recorded from the apical dendrites of CA1 pyramidal cells after Schaffer collateral stimulation. Intracellularly recorded excitatory postsynaptic potentials and excitatory postsynaptic currents were recorded in CA3 pyramidal cells after mossy fiber stimulation and in the presence of 10 microM picrotoxinin. In the CA1 region, phenytoin elicited a reversible depression of field excitatory postsynaptic potentials as well as reduced the time constant of decay of PTP from 79 sec to 47 sec with no change in the magnitude of potentiation. Higher concentrations of phenytoin (100 microM) had a general depressant effect on both the amplitude and time course of PTP. In CA3 cells, phenytoin (10 microM) reduced the mossy fiber synaptic conductance but did not change its reversal potential. Phenytoin (10 microM) also reduced the time constant of decay of PTP of the mossy fiber to CA3 synapse, while having no effect on the magnitude of potentiation. These results show that therapeutically relevant concentrations of phenytoin depress both low-frequency synaptic transmission and the time course of short-term potentiation. Both actions may be involved in the anticonvulsant properties of phenytoin.
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PMID:Phenytoin reduces excitatory synaptic transmission and post-tetanic potentiation in the in vitro hippocampus. 284 32


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