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PubMed1993

Barbiturate anticonvulsants in refractory affective disorders.

Despite an increasing literature demonstrating both acute and long-term positive psychopharmacological effects of both valproate and carbamazepine, phenytoin has remained a controversial intervention, and barbiturate anticonvulsants have generally received poor press with regard to psychotropic effects. In the present investigation, 27 seizure-free, affectively ill patients who received therapeutic trials of primidone and/or mephobarbital after failing on antidepressants, lithium, carbamazepine, valproate, and phenytoin were analyzed with regard to effects on illness severity and affective cycle rate over a period of as long as four years. Nine (33%) of the patients had a sustained positive therapeutic effect on affective state and/or psychotic symptoms to primidone and three (11%) had positive effects on mephobarbital after primidone failure. Four (15%) had brief positive effects that were not sustained, and the remaining 11 (41%) had no effects or negative effects to these agents. The theoretical and practical implications of this new and unexpected finding are discussed.

Adult↗
PubMed1992

[The effect of monotherapy on concentration of selected blood serum hormones and upon cognitive function of children with epilepsy].

The studies included 64 children with newly diagnosed epilepsy, aged from 6 to 15 years of life. In 25 children with partial and secondary generalized seizures monotherapy with carbamazepine was introduced; in 19 children with primary generalized seizures--with phenobarbital, and in patients with both types of seizures--with primidone. Monotherapy was controlled by means of blood serum drug concentration level monitoring; the therapy was successful in all the children. The group did not include patients with mental retardation, and epilepsy was idiopathic. Prior to the institution of treatment, a single determination of blood serum triiodothyronine, thyroxine, TSH, prolactin, cortisol, LH and testosterone was made. Psychological test were carried out employing Wechsler's scale, Bender-Santucci test, rhythmic structures developed by Mira Stambak and test of manual dexterity (card display). In order to evaluate short-term effects of the employed drugs upon the blood serum concentration values of the studied hormones, a repeated determination was made one month after the initiation of therapy. The third determination was made one year after the onset of treatment in order to assess the long-term effects. The effect of drugs upon their cognitive functions was assessed in a follow-up psychological testing performed after one year of therapy. The studies combined with statistical analysis led to a conclusion that after one month of monotherapy there occurred a significant drop in thyroxine concentration levels, still augmented after one year. Patients treated with carbamazepine showed a significant decrease of T3 levels after one month and one year, whereas treatment with phenobarbital and primidone did not result in significant changes of T3 concentration. Yet, T3 and T4 concentration values did not exceed normal limits. No type of monotherapy resulted in significant long-term changes of TSH concentration levels. No clinical signs of hypothyroidism nor goiter were observed in the studied children. After one month of monotherapy with carbamazepine and phenobarbital there was observed a significant increase of prolactin and cortisol levels, which was absent after one year. The values observed did lie within normal limits. No significant changes were observed with respect to the effect of the studied drugs upon blood serum LH and testosterone levels. After a one-year monotherapy with primidone the children revealed a significant improvement of results measured on performance scale and by means of a full Wechsler scale. Carbamazepine and phenobarbital did not affect the intelligence quotient of the studied children.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1991

[Therapeutic and pharmacological monitoring of individual monotherapy of epilepsy with hexamidine].

The treatment with primidone alone of 53 epileptic patients with generalized tonic-clonic seizures, partial attacks with elementary symptomatology, and partial fits with complex symptomatology removed them completely in 75, 64.2, and 36.9% of the patients, respectively. The number of attacks was decreased as a result by 50% and over in 90, 78.6, and 73.7% of the patients, respectively. The attainment of such high efficacy of the monotherapy (called by the author intensive in contrast to routine or inadequate therapy carried out, as a rule, in standard doses) appeared possible only under the conditions of individualization of the drug doses which ranged within 250-2500 mg/day. The concentration of phenobarbital, the main end metabolite of primidone, in the blood serum of patients, in whom the attacks were completely arrested and who developed no clinical side effects with no toxic action on the internal organs, ranged from 14 to 59.1 mg/l. In partial fits with complex symptomatology, primidone appeared least effective for those types of fits in the treatment of which it was viewed as most adequate.

Adolescent↗
PubMed1982

The influence of antiepileptic drugs on the electroencephalogram: a review of controlled clinical studies.

The effect of antiepileptic drugs on the EEG was studied in a review of 23 controlled trials with therapeutic drug monitoring and serial EEG observations. There is a good correlation of suppression of paroxysmal discharges and an increase in the plasma concentrations of diazepam, phenobarbital, phenytoin, alone or in combination with phenobarbital or primidone. The correlation is variable during treatment with carbamazepine and in patients with focal discharge receiving sodium valproate or a delayed response to sodium valproate treatment. An increase in beta activity is correlated with a raised plasma concentration of clonazepam, phenytoin and phenobarbital, but not in all patients receiving these drugs. The degree and the localization of cerebral impairment seem to influence the drug-induced fast EEG response. Slowing of background occurs with high plasma concentrations of diazepam, phenytoin, alone or in combination with phenobarbital or primidone. The correlation of paroxysmal discharges with clinical seizure frequency is good for phenobarbital, phenytoin, alone or in combination. The correlation is variable for carbamazepine and the delayed response to sodium valproate. A slowing of background activity is correlated with clinical drug toxicity due to carbamazepine, phenytoin, phenobarbital and primidone treatment in most patients.

Anti-Anxiety Agents↗
PubMed1984

Compromised hepatic function in dogs treated with anticonvulsant drugs.

Hepatic function tests were performed on 48 dogs that had been given primidone, phenytoin, or a combination of anticonvulsant drugs for 6 months or longer. Except for histories of seizures, 44 of the dogs were healthy at the time the tests were performed. Abnormal test results were observed most frequently in dogs given only primidone and in dogs given combinations of anticonvulsant drugs. The test results that were abnormal most often were those for alanine transaminase and alkaline phosphatase activities, and sulfobromophthalein excretion. The dosage of anticonvulsant drug was found to modify certain test results. Statistically significant positive correlations were found between the dosage of primidone and serum alanine transaminase activity and between the dosage of phenytoin and serum alkaline phosphatase activity. Four of the dogs were examined because of signs of weakness and anorexia and 2 also had ascites. Three of the 4 dogs were euthanatized 2 to 49 days after admission with clinical signs compatible with hepatic failure, and cirrhosis of the liver was confirmed at necropsy. The fourth dog died at home and was not necropsied. Four of the remaining 44 dogs that apparently were healthy at the time of examination had abnormalities in hepatic biochemical test results that were comparable with those in the 4 dogs with clinical illness. We concluded that, although results of hepatic biochemical tests frequently may be abnormal in dogs given anticonvulsant drugs long-term, severe hepatic injury is observed less often.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

[Monitoring therapy by analysis of the drug concentration of saliva].

The distribution of a drug between blood and saliva depends on its physicochemical properties, e.g. binding to plasma proteins, apparent dissociation constant and lipid solubility. The clinical value of measuring salivary drug concentrations in therapeutic drug monitoring is demonstrated using anticonvulsant therapy in children as an example. For carbamazepine and phenytoin there is a close and constant saliva/serum ratio over a wide range of concentrations, which is influenced by the salivary flow rate only to an insignificant degree. Salivary concentrations of carbamazepine account for about 40%, of phenytoin for about 10% of the serum concentrations. In contrast, salivary levels of primidone and phenobarbital are significantly influenced by the rate of saliva flow. In resting saliva primidone levels slightly exceed those in serum and fall significantly below the corresponding serum values during forced stimulation of salivary flow. For phenobarbital in resting saliva the mean saliva/serum ratio is 0.3 and increases significantly during forced stimulation. Provided the conditions of sample collection are standardized saliva is suitable for monitoring primidone and phenobarbital therapy, too.

Anticonvulsants↗
PubMed1978

In vivo interaction of anticonvulsant drugs. The mathematical correlation of plasma levels of anticonvulsant drugs in epileptic patients.

The phenytoin plasma levels were measured in 45 epileptic patients whose only treatment was phenytoin. The plasma of 20 other patients receiving both phenytoin and phenobarbital was also tested for concentration of these two drugs and 18 patients treated with phenytoin, phenobarbital and primidone were investigated in the same way. The results were used to calculate the plasma levels of phenytoin in relation to dosage and to measure the effect of the simultaneous use of phenobarbital on the phenytoin plasma levels and of primidone together with phenobarbital on phenytoin concentration. The results led to the following conclusions: The population of epileptic patients can be divided into 2 groups. In the first group the patients reach equilibrium at the relatively high phenytoin plasma level for a given dose of phenytoin, and in the second group the phenytoin plasma level tends to be significantly lower for parallel dosages. Both groups, in their behavior, obey mathematically an exponential graph specific for each group. Phenobarbital tends to lower the plasma phenytoin level when the two drugs are used simultaneously. It is also possible, by the graphs produced, to calculate the expected phenytoin plasma levels when using the drugs together. Primidone and phenobarbital together decrease the phenytoin level much more than expected from the effect of phenobarbital alone.

Dose-Response Relationship, Drug↗
PubMed1999

Essential Tremor.

Multiple pharmacologic treatments have been studied, but propranolol and primidone have proven to be the most effective medications. It is unlikely that a patient will respond miraculously to another medication if his or her response to propranolol and primidone is minimal. Some subsets of essential tremor, however, such as the kinetic predominant type, may respond better to other medications. Mildly affected patients may not need treatment at all, and the potential benefits must always be weighed against the possible side effects. The main benefit of botulinum toxin injection is for head tremor, whereas its efficacy in hand tremor is variable. If a patient does not respond to adequate doses of propranolol or primidone, deep brain stimulation should be considered because it carries the lowest risk of the available surgical procedures; usually, it should be given preference over thalamotomy. It is important for the physician to realize the multitude of symptomatic treatments available. Beyond the conventional and often effective oral medications, use of newer treatments such as botulinum toxin, thalamotomy, and deep brain stimulation can often reduce tremor and lead to a greater quality of life for patients with ET.

Journal Article↗
PubMed1985

[Antiepileptic monotherapy and combination therapy of simple focal seizures].

According to present state of literature complete seizure control can be obtained in about 50% of patients with simple partial seizures. In several studies on previously untreated patients with simple partial seizures most patients became seizure-free with carbamazepine or phenobarbital or phenytoin or primidone or valproic acid used as monotherapy. Previous experience has shown that in patients whose seizures are not completely controlled by monotherapy drug combinations like carbamazepine with phenobarbital or primidone or valproic acid and phenytoin with phenobarbital or primidone or valproic acid should be initiated. Several animal experiments are suggestive for a synergistic effect of different antiepileptic drugs. In a previously published study on carbamazepine monotherapy, 6 out of 9 patients with simple partial seizures became seizure-free or improved markedly by this treatment.

Adolescent↗
PubMed1987

Serum concentrations of carbamazepine and its epoxide and diol metabolites in epileptic patients: the influence of dose and comedication.

The influence of carbamazepine (CBZ) dose, CBZ preparation used, comedication (phenobarbital, phenytoin, primidone, valproate), and factors such as age, weight, and sex on the concentration of CBZ and its metabolites carbamazepine-10,11-epoxide (CBZ-epoxide) and 10,11-dihydro-10,11-dihydroxy-carbamazepine (CBZ-diol) in serum was investigated. A non-linear regression analysis using the data of 609 patients shows that other anti-epileptic drugs can influence the metabolism of CBZ in various ways. The mean serum concentration of CBZ is lower when the drug is given in combination with phenytoin (59.4%), primidone (58.2%), phenobarbital (65.7%), and valproate (83.0%) than when CBZ is given alone (100%), whereas the mean concentration of CBZ-epoxide is increased by valproate (144.8%), by primidone (118.5%), and by a combination of the latter (167.4%). The CBZ-diol concentrations are also increased during concomitant treatment with the other antiepileptic drugs. Our results indicate a nonlinear relationship between the CBZ dose and the CBZ concentration, but a linear relationship between the CBZ dose and the CBZ-diol concentration.

Adult↗
PubMed2002

Fate of pharmaceuticals during indirect potable reuse.

The scope of this study was directed to examine different wastewater treatment technologies (activated sludge, trickling filter, nanofiltration, reverse osmosis) at full-scale facilities in Arizona and California leading to indirect potable reuse and their capability to remove pharmaceuticals. Additionally, the fate of selected pharmaceuticals was studied during soil-aquifer treatment (SAT) at sites where secondary and tertiary treated effluents are used for subsequent groundwater recharge. Facilities employing longer detention times during treatment (nitrifying and denitrifying plants) showed significant lower effluent concentration for analgesic drugs as compared to trickling filter or activated sludge facilities applying shorter detention times. A similar trend was observed for the lipid regulator gemfibrozil, which was significantly removed in denitrified effluents, whereas a trickling filter treated effluent exhibited concentration of 1,235 ng/L. Antiepileptic drugs, such as carbamazepine and primidone, showed no dependency on the wastewater treatment applied. None of the investigated drugs was detected in tertiary treated effluents after nanofiltration or reverse osmosis. After SAT, analgesic/anti-inflammatory drugs were efficiently removed after retention times of less than 6 months and remaining concentrations were near or below the detection limit of the analytical method. A high potential for biodegradation was also observed for anti-inflammatory drugs in groundwater recharge systems. The antiepileptics carbamazepine and primidone represented the most dominant of all investigated drugs in well treated domestic effluents (nitrifying/denitrifying plants). Removal of carbamazepine and primidone did not seem to occur during travel times of more than 6 years in the subsurface.

Biodegradation, Environmental↗
PubMed1988

[Pharmacokinetics of anticonvulsants in the perinatal period].

We have examined the concentration of a range of anticonvulsant drugs in serum, amniotic fluid and breast milk in 23 pregnant patients. Drug determinations were made during the last 3 months of pregnancy, at birth and during the first week postpartum. In the cord serum the range of concentrations, expressed as a percentage of the maternal serum concentration was: primidone (67-131%), phenobarbitone (80-108%), carbamazepine (60-76%), phenytoin (95-162%), ethosuximide (104%), and valproic acid (125-147%). In the amniotic fluid the corresponding ranges were: primidone (62-230%), phenobarbitone (28-59%), carbamazepine (18-45%), phenytoin (18-60%), ethosuximide (111%) and valproic acid (5-11%). In breast milk the corresponding percentages were: primidone (44-228%), phenobarbitone (20-50%), carbamazepine (32-80%), phenytoin (46-53%), ethosuximide (92%) and valproic acid (2-8%). Anticonvulsant drugs can be given in relatively high doses during pregnancy. Pregnant patients and neonates are patients with therapeutic problems. For this group of patients is recommendable a therapeutic drug monitoring.

Adolescent↗
PubMed1985

Evaluation of epileptic dogs as an animal model of human epilepsy.

In 126 epileptic dogs with spontaneously recurring generalized tonic-clonic (grand mal) seizures, epidemiological aspects and the efficacy of chronic oral treatment with common antiepileptic drugs were studied. Furthermore, the pharmacokinetics of antiepileptic drugs in dogs was compared with the values known for man. As in man, idiopathic epilepsy appeared to be more common than symptomatic epilepsy in dogs. There was a preponderance of male vs. female animals. When the breeds of the epileptic dogs were compared to the distribution of breeds in the hospital population, breed-related differences in the prevalence of epilepsy were found. The highest prevalence was seen in Cocker spaniels, Miniature schnauzers, Collies and Bassets. The total prevalence of dogs with epilepsy was 0.55%. Comparison of pharmacokinetics of antiepileptic drugs showed that some drugs were suited for maintenance therapy in dogs (primidone, phenobarbital, ethosuximide, trimethadione) whereas others appeared not to be ideally suited because of their short half-lives (phenytoin, carbamazepine, valproic acid, diazepam, clonazepam, nitrazepam). This was confirmed by the evaluation of antiepileptic drug efficacy in epileptic dogs. 46 dogs were treated with primidone at daily doses of 14-104 mg/kg for 6-60 months. During medication with primidone, effective plasma levels of its metabolite phenobarbital could be maintained. Complete control of seizures or a reduction of seizure frequency by at least 75% was achieved in 39% of the dogs at phenobarbital concentrations of 5-49 micrograms/ml. Similar figures were obtained during chronic treatment with phenobarbital at daily doses of 2.5-13 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1977

Rickets in children receiving anticonvulsant drugs. Biochemical and hormonal markers.

Forty-one epileptic children, aged 2 to 16 years, receiving combinations of phenobarbital, phenytoin, and primidone, and 39 control children were studied. The epileptics demonstrated slight but significant reductions in serum calcium, phosphorus, and 25-hydroxyvitamin D concentrations, and a significant increase in serum alkaline phosphatase values. No significant difference in serum immunoreactive parathyroid hormone levels was noted. Further analysis of the data revealed that patients whose drug therapy included primidone had the lowest serum levels of calcium and 25-hydroxyvitamin D. They had also received the largest number of drugs for the longest duration, and had serum phenobarbital levels that were significantly higher than those of other patients. The minimal degree of vitamin D deficiency in our epileptic children contrasts with the results of other investigations and warrants emphasis. The reasons for this difference are not apparent.

Adolescent↗
PubMed1977

Possible phenylethylmalondiamide (PEMA) intoxication.

We have encountered a case of apparent intoxication with primidone (Mysoline) in a patient with severe renal impairment. Of interest were high serum levels of phenylethyl-malondiamide (PEMA), a metabolite of primidone.

Adult↗
PubMed2004

Simple and rapid micellar electrokinetic capillary chromatographic method for simultaneous determination of four antiepileptics in human serum.

A very rapid and simple MEKC method was developed for the simultaneous determination of four antiepileptic drugs, ethosuximide (Etho), primidone (Pri), phenytoin (Pht) and carbamazepine (Cbz) in human serum. Sample analysis required only 100 microL of human serum which only needed to be centrifuged, decanted and combined with the running buffer [5.3 mM Na(2)HPO(4)/3.2 mM borax buffer (pH 9.5) containing 55 mM SDS and 3.5% (v/v) acetone]. The analysis was performed in only 10 min into fused-silica capillaries (57 cm total length with 50 microm i.d. and 50 cm to the detector) using the MEKC methodology with diode-array detection at 220 nm. The calibration graphs were established for ethoximide, primidone, phenytoin and carbamazepine between 0 and 20 mg/L. Recoveries were between 85 and 87%. The simplicity of the proposed methodology makes it suitable for routine clinical use, especially for epileptic patients on polytherapy.

Anticonvulsants↗
PubMed1983

Plasma arginine vasopressin concentrations in epileptics under monotherapy.

Plasma arginine vasopressin concentrations were determined by radio-immunoassay in 112 adult epileptics who were taking carbamazepine, phenytoin, primidone, or sodium valproate in long-term monotherapy, and in 19 controls. No significant difference was found between the groups, but some epileptics taking carbamazepine and primidone showed low values. Serum concentrations of carbamazepine did not correlate with the concentrations of plasma arginine vasopressin. In conclusion, there was no evidence of a stimulating effect of chronic carbamazepine medication or a special inhibiting effect of phenytoin on the release of vasopressin arginine from the posterior pituitary.

Adult↗
PubMed1975

Folate and monoamine metabolism in epilepsy.

In 27 drug-treated epileptics there was a significant fall in serum, red cell and CSF folate levels compared with 15 untreated epileptics and 22 neurological controls. The 3 folate parameters were positively correlated with each other and negatively correlated with serum phenobarbitone, diphenylhydantoin and primidone. There was also a significant elevation of CSF 5-hydroxyindoleacetic acid (5HIAA) in the drug-treated epileptics; but this was not seen until "therapeutic" serum levels of phenobarbitone and diphenylhydantoin had been achieved and was most marked in clinically intoxicated patients. Similar trends were observed in CSF homovanillic acid (HVA). CSF 5HIAA and HVA were positively correlated with each other, especially in the drug-treated patients, in whom both amine metabolites were also negatively correlated with CSF folate. A possible relationship between folate and monoamine metabolism is discussed with particular reference to the antiepileptic and toxic effects of phenobarbitone, diphenylhydantoin and primidone.

Adolescent↗