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)

The mechanisms underlying the induction of afterdischarges at presynaptic nerve terminals by convulsant aminopyridines and their suppression by the anticonvulsant drug phenytoin were studied at the frog neuromuscular preparation. Addition of aminopyridine to the perfusing solution induced the appearance of afterdischarges in motor nerve fibres following their primary response to a single nerve stimulus. The afterdischarges seemed to originate at or near the nerve terminals and to propagate both antidromically and orthodromically. The latter resulted in repetitive activation of the neuromuscular synapse. Focal recordings of nerve terminal potentials suggested that aminopyridines may induce afterdischarges by slowing spike repolarization and thereby producing a prolonged depolarization of nerve terminals. Phenytoin suppressed the aminopyridine-induced afterdischarges and the resultant repetitive excitation of the postsynaptic muscle fibres. This effect of phenytoin was associated with a depression of the action potential at the motor nerve terminals but not at their parent axons. These results single the presynaptic nerve terminals as preferential sites for convulsant and anticonvulsant actions.
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PMID:Suppression by phenytoin of convulsant-induced afterdischarges at presynaptic nerve terminals. 299 98

Phenytoin is one of the most commonly used anticonvulsants in pregnant epileptic women. Unrelatedly, the drug is also an inducer of hepatic drug metabolizing enzymes. Considering these facts, we wanted to determine if maternal treatment with therapeutic-like doses for the rat of phenytoin would produce long-term defects in the metabolism and action of drugs in the dams' adult offspring. We found that peripartum exposure to phenytoin resulted in a significant depression in the maximal velocities of hepatic microsomal aminopyrine N-demethylase in the 28-day-old male and female offspring. When the animals were 4-to-5-month old adults, the maximal velocities for the demethylase and hexobarbital hydroxylase remained subnormal in the males but were elevated in the females exposed to the highest therapeutic-like dose of phenytoin. Hexobarbital-induced sleeping time measurements were in agreement with enzyme kinetic analyses. Lastly, the hepatic monooxygenases of the adult male and female rats exposed, perinatally, to all but the lowest dose of phenytoin, were much less responsive to the inductive effects of several low doses of phenobarbital. The results suggest that levels of phenytoin that may be therapeutic for the mother can produce defects in the developing hepatic monooxygenase system of the perinates, which can then permanently affect drug metabolism and action in adulthood. Furthermore, by disrupting the development of hepatic enzyme induction mechanisms, perinatal exposure to phenytoin may irreversibly alter an important homeostatic mechanism that is normally responsive to daily exposure to low levels of various endogenous and exogenous inducing agents.
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PMID:Persistent defects in the hepatic monooxygenase system of adult rats exposed, perinatally, to maternally administered phenytoin. 372 6

The Corvac integrated serum separator tube (TM Monoject Scientific) has been examined for use in processing specimens for drug analysis. This study was undertaken because the SST serum separator tube (Becton-Dickinson) was shown to cause decreases in drug levels of lidocaine, pentobarbital, and phenytoin, which were dependent upon blood volume and time of contact with the gel. Pools of donor blood were spiked with lidocaine or phenytoin and processed in Corvac tubes and red top tubes. Lidocaine levels were depressed by 5.2% when Corvac was used. Phenytoin levels were unchanged. The lidocaine depression was independent of blood volume, time of gel contact, or tube lot number. Paired patient specimens for quinidine, lidocaine, or theophylline analysis were obtained in Corvac and red top tubes. Lidocaine levels were depressed by 6.0% (p less than 0.01). Quinidine and theophylline levels were unchanged. All drug analyses were carried out using the Syva enzyme multiplied immunoassay technique. The Corvac tube has been shown to cause decreased levels of lidocaine but not of the other drugs tested. Corvac (silicone gel) results differ from SST (polyester gel) results because of the different construction of these tubes.
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PMID:Assessment of the Corvac blood collection tube for drug specimen processing. 372 42

63 patients on long-term oral therapy with phenytoin sodium (sodium diphenylhydantoin) were screened for abnormalities of immunological function. They were compared with 92 controls and 28 patients with lymphoma. Depression of cellular or humoral immunity, or both, was found in a significant number of phenytoin-treated and lymphoma subjects. Phenytoin therapy was associated with low immunoglobulin A (21%), failure of antibody response to Salmonella typhi antigen (9%), absence of delayed hypersensitivity (D.H.S.) to three common skin-test antigens (22%), and depression of in-vitro lymphocyte transformation by phytohaemagglutinin (27%). Lymphoma patients manifested low IgM (22%), and inability to make antibody to S. typhi (11%) and to tetanus toxoid (21%). D.H.S. was absent in 36%; lymphocyte transformation was depressed in 17%. Abnormal lymphocyte transformation did not correlate with depression of cellular or humoral immunity in either group.
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PMID:Depression of immunological function in patients treated with phenytoin sodium (sodium diphenylhydantoin). 414 95

The effects of delta 9-tetrahydrocannabinol (delta 9-THC), two of its metabolites, 8 beta-hydroxy-delta 9-THC and 11-hydroxy-delta 9-THC, and cannabidiol were comparatively studied by means of an iron-induced cortical focal epilepsy in conscious rats with chronically implanted electrodes. delta 9-Tetrahydrocannabinol produced depression of the spontaneously firing epileptic focus, excitatory behavior, generalized after-discharge-like bursts of epileptiform polyspikes and frank convulsions. The pharmacological profiles of the two metabolites differed from that of the parent compound: 11-Hydroxy-delta 9-THC did not precipitate convulsions, but it did elicit all the other effects of delta 9-THC; the 8 beta-hydroxy derivative, on the other hand, exerted only two delta 9-THC-like effects; that is, it evoked polyspike bursts and convulsions. In contrast, cannabidiol, even in large doses (100 mg/kg) was devoid of all the effects of delta 9-THC. Furthermore, pretreatment with cannabidiol markedly altered the responses to delta 9-THC in the following ways: focal depression was partially blocked, polyspike activity was enhanced and convulsions abolished. Phenytoin pretreatment elicited similar effects, but it failed to block the delta 9-THC-induced convulsions. In general, the cannabinoids exhibit a wide spectrum of CNS effects ranging from focal depression to convulsions; specifically, however, the pharmacological profile of each agent can differ markedly; for example, the convulsant properties of delta 9-THC are not a universal characteristic of this class of drugs.
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PMID:Central excitatory properties of delta 9-tetrahydrocannabinol and its metabolites in iron-induced epileptic rats. 627 53

In order to use antiarrhythmic drugs safely, one must understand their hemodynamic effects. Quinidine and the calcium antagonists have direct cardiac effects and frequently opposing autonomically mediated or indirect cardiac effects. Lidocaine is exceptionally well tolerated, even by patients with severe left ventricular dysfunction. Phenytoin and procainamide have the potential for serious adverse effects, but are generally well tolerated at usual doses. Disopyramide causes serious depression of left ventricular function in many patients because of its direct myocardial depressant and peripheral vasoconstricting actions. Although bretylium causes an immediate increase in contractility, it can ultimately result in important hypotension. In this review the in vitro and in vivo hemodynamic effects of these and other antiarrhythmic drugs are discussed to provide information that will assist the clinician in using these drugs properly.
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PMID:Hemodynamic effects of antiarrhythmic drugs. 641 78

Phenytoin (diphenylhydantoin, Dilantin, PHT), an anticonvulsant and antiarrhythmic drug, is teratogenic to A/J mice, producing an increased incidence of cleft lip with or without cleft palate [CL(P)] and cardiac defects. Although its mechanism of teratogenic action remains unclear, one possibility may involve uterine ischemia resulting from an exaggerated depressant effect on maternal cardiovascular function. To test this hypothesis, the heart rate response of susceptible A/J and resistant C57Bl/6J mice was monitored following intraperitoneal injection of doses of PHT of known teratogenic potential. Heart rate (HR) was obtained electrocardiographically from unanesthetized, pregnant mice on day 10 of gestation via previously implanted subcutaneous electrodes. The HR of A/J mice was significantly depressed relative to vehicle-injected controls following doses of 40, 60, and 75 mg/kg, with the greatest effect occurring in the high-dose group. In C57Bl/6J mice, the HR response of the group treated with 75 mg/kg was not different from that of the vehicle-treated controls. At the same dose level, the depression of HR of A/J mice was significantly greater in magnitude and duration than that of C57Bl/6J mice. A proposed maternally mediated mechanism of CL(P) in A/J mice involving low placental/embryonic oxygen delivery is discussed. The results of the present study indicate the potential significance that changes in maternal physiology may have on embryonic development.
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PMID:Effect of phenytoin on maternal heart rate in A/J mice: possible role in teratogenesis. 663 88

Lidocaine, Mexiletine, Procainamide, and Phenytoin were administered intravenously to anaesthesized rabbits. BERA alterations showed two different patterns. If the intoxication dose was exceeded, amplitude depression, threshold elevation, desynchronization, and severe cumulative prolongation of all latencies and interpeak latencies appeared. Below this dose Lidocaine and Mexiletine induced a single, reversible, dose related, cumulative prolongation of all latencies and interpeak latencies. Procainamide induced counterrelated shiftings of interpeak latencies I-III and III-V, whereas Phenytoin showed no influence. One should, therefore, take into account these effects when BERA is used clinically, since otherwise serious errors can occur. On the other hand, there are diagnostic and therapeutic aspects for the tinnitus patient.
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PMID:[Effect of membrane-effective drugs (anti-arrhythmia agents) on acoustically evoked brain-stem potentials]. 670 Mar 43

Sodium valproate is often used with phenytoin when epilepsy cannot be controlled by a single drug. Sodium valproate depresses phenytoin protein binding and so invalidates plasma phenytoin monitoring as a means of determining precise phenytoin dosage requirements. Plasma and saliva phenytoin and plasma valproate concentrations were measured in 42 patients with epilepsy receiving both drugs. Phenytoin protein binding was also measured by ultrafiltration in 19 of these patients and 19 patients taking phenytoin alone. Saliva phenytoin concentration bore the same close correlation to unbound (therapeutically active) phenytoin in patients receiving both drugs as it did in patients receiving phenytoin alone, whereas plasma total phenytoin did not. The same therapeutic range for saliva phenytoin (4-9 mumol/1; 1-2 microgram/ml) was therefore valid in both groups. The depression of phenytoin binding was directly related to the plasma concentration of valproate both in random samples taken from the 42 patients and in samples taken throughout the day in two of these patients. This was confirmed in vitro. Even when the concentration of valproate is known the degree of binding cannot be predicted. Saliva rather than plasma monitoring of phenytoin treatment is therefore valuable in the presence of valproate and with reduced phenytoin binding from any cause.
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PMID:Phenytoin-valproate interaction: importance of saliva monitoring in epilepsy. 679 18

Effect of 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810) on kindled seizures in the neocortex, hippocampus and amygdala was studied in comparison with that of clinically proved antiepileptics, and the differences in kindled seizure development in the three areas were also studied. The amygdala more rapidly developed a generalized seizure (kindled seizure) than the hippocampus and the neocortex. Although more days of stimulation were needed, the neocortex also developed a kindled seizure similar to limbic kindled seizures. Phenobarbital, carbamazepine, dipropylacetate and diazepam showed a depressant effect on the neocortical kindled seizures. Phenytoin showed a depressant effect only when it was administered intravenously. Phenobarbital and carbamazepine depressed the hippocampal kindled seizures, while phenytoin and diazepam had little effect. Phenobarbital and diazepam caused marked depression on the amygdaloid kindled seizures, but the effect of phenytoin, carbamazepine and dipropylacetate on them was weak or negligible. AD-810 showed a depressant effect on neocortical and hippocampal kindled seizures, but not on amygdaloid ones. The profile of AD-810 is similar to that seen with carbamazepine.
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PMID:Effects of 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810) and some antiepileptics on the kindled seizures in the neocortex, hippocampus and amygdala in rats. 722 18


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