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PubMedDate not supplied

[Epilepsy and pregnancy].

A total of 132 women with epilepsy were confined in the period from 1978-1989. Their pregnancies and outcomes were analysed. The special aim was to find out if the anticonvulsive therapy has any correlation with the occurrence of fetal malformations in the studied group of women. In 43.9% of pregnant women with epilepsy, methyl-phenobarbitone as an anticonvulsive drug was administered, while carbamazepine was applied in 13.6% cases. A combination of phenytoin and phenobarbitone was prescribed in 18.9% of cases. Primidone was the drug of choice in 8% cases and 5.3% of patients were treated with various combinations of anticonvulsive drugs. Hyperemesis, threatened spontaneous abortion and premature labor complicated significantly more pregnancies in patients with epilepsy than on controls. Pregnancies from the studied group were terminated by the cesarean section in significantly more cases (11.2%) than in the control group (5.4%). Newborns from mothers with epilepsy had a statistically lower birthweight (3173 +/- 575 g) than those born from healthy mothers (3376 +/- 510g). Fifteen newborns or 11.2% were born with congenital malformations, while among the control group of newborns only two were malformed. It is noticed that the newborns from mothers treated with phenitoin and phenobarbitone had dysmorphic anomalies of the face more frequently. The drugs mentioned above interfere with the metabolism of K vitamin and as a result of this interreaction, mothers and newborns can suffer from coagulation disorders. In conclusion it is important to mention that no anticonvulsant drug seems to be absolutely safe when used during pregnancy since each of them has a teratogenic effect on the fetus.

Abnormalities, Drug-Induced↗
PubMed1990

[Psychoses in epilepsy].

The heterogenous psychoses in epilepsies, caused by well known conditions, are not rare but associated with regularly a few of seizure-types not with the nature and development of attacks. Polar transitional ranks and converging courses of schizophrenic (accentuated) syndromes in epilepsies and idiopathic schizophrenias are rather frequent. Also (sub-)acute schizophrenic psychoses are corresponding to the complete palette of first and second rank symptoms (K. Schneider) of idiopathic schizophrenias. After manifestations of epilepsy these syndromes can appear at any time. It is given a profile of risks. Progressive avoidance of a. phenylaceturea, b. mixtures of antiepileptics did not put an end to psychotic syndromes: Long-term therapies with 1. Polytherapy, 2. Primidone and Phenytoin (dosedependant) as well as 3. Ethosuximide (-monotherapy) cause a disorder of feed back mechanisms, especially a disturbed regulation of vigilance and sleeping-waking-cycle and their psychological correlates. Carbamazepine and Sodium Valproate are, plasma-level-controlled of preventive antipsychotic effect. Selected neuroleptics of rather slight epileptogenic potency are of going down importance. Benzodiazepines are required mostly in prepsychotic syndromes, Lithium compounds in selected cases. There is no more alternative seizures or psychosis.

Anticonvulsants↗
PubMed1991

[Therapeutic ranges of anti-epileptic drugs in monotherapy of children].

Relationship between steady-state plasma concentrations of phenobarbitone (PB), phenytoin (PHT), primidone (PRM), carbamazepine (CBZ) and sodium valproate (VPA) and their efficacy and toxicity, were studied in 392 pediatric outpatients, long-term treated in monotherapy for epileptic seizures or febrile convulsions, in order to establish "target" values which may be used, as reference, in clinical practice. The concentration-efficacy and toxicity curves suggest target values of 20, 15, 9, 10, 6 and 70 mg/l for PB, PB derived from PRM, PRM, PHT, CBZ and VPA respectively. Above 25 mg/l of PB, 20 of PHT and 100 of VPA, markedly decreased the probability of response in refractory patients, and a clear increase in toxicity was shown. Above 7 mg/l of CBZ a decrease in the percentage of seizure-free patients was observed, without an increase of toxicity. For PRM no efficacy "ceiling" was found but side effects increased. The target values proposed may be helpful as a reference for the initial dosage of antiepileptic drugs in children, during monotherapy. Nevertheless, final doses should be adjusted according to clinical response of each patient.

Anticonvulsants↗
PubMed1990

Drug therapy in cats: a systems approach.

In the second part of this 4-part series, drug therapy in cats is discussed by use of a systems approach. Specifically, drugs that can be used safely for treatment of disorders affecting the feline gastrointestinal, central nervous, respiratory, cardiovascular, and urogenital systems are described. Many drugs that are used in dogs can be safely used in cats according to the same or similar dosing regimens. Several drugs that have traditionally been considered inappropriate (eg, morphine derivatives, primidone) can probably also be used, if cautiously, in cats. In contrast, use of several drugs that are safely used in other species should be avoided in cats (eg, selected emetics and antiemetics, phosphate salt enemas, and selected urinary antiseptics). Cats are more sensitive than dogs to the adverse side effects of a variety of drugs (eg, aspirin, digoxin, selected antiarrhythmics), and extra precautions must be taken when these drugs are used in cats. Finally, several drugs are used for the treatment of illnesses that tend to be unique to cats (eg, taurine and calcium-channel blockers in selected feline cardiovascular disorders).

Animals↗
PubMed1990

Hematologic values and plasma and tissue folate concentrations in dogs given phenytoin on a long-term basis.

During earlier investigations of the hepatic effects in dogs of long-term administration of phenytoin alone or in combination with primidone, erythrocytic macrocytosis, neutropenia, neutrophilic hypersegmentation, and thrombocytopenia were observed. Such abnormalities were observed most often in dogs given phenytoin and resembled those known to be attributable to folate deficiency in human beings with epilepsy treated with phenytoin. To pursue the theory that these hematologic aberrations were caused by drug-induced folate deficiency, 12 dogs were given a diet specifically formulated to contain a minimally adequate concentration of folate. After 2 weeks, phenytoin was administered daily (400 mg, PO, q 8 h) to 8 of the 12 dogs for 54 weeks. A CBC, bone marrow aspiration biopsy, and measurement of plasma and RBC folate concentrations were done every 3 weeks. Bone marrow aspirates were examined by transmission electron microscopy after 24 and 36 weeks, and at the end of the treatment period. Hepatic folate concentration was also determined in all dogs before and after treatment. Excretion of formiminoglutamic acid, as a marker of folate deficiency, was measured in all dogs at the end of the study. All dogs remained healthy throughout the treatment phase. Consistent abnormalities were not observed in the blood or bone marrow of treated dogs. Plasma and RBC folate concentrations decreased in control and treated dogs as a result of dietary restriction (P less than or equal to 0.02), and remained stable until the end of the study. The RBC folate content decreased further in treated dogs (P less than or equal to 0.02), although the hepatic folate content was similar in control and treated dogs. Treated dogs did not excrete formiminoglutamic acid more rapidly than did control dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

A comprehensive gas chromatography procedure for measurement of drugs in biological materials.

Procedures have been developed for the determination in serum and urine of 21 drugs which include all of the barbiturates, methyprylon, glutethimide, meprobamate, propoxyphene, methaqualone, primidone, diphenylhydantoin, methadone, codeine, morphine, amphetamine and methamphetamine. The method involves pipeting 1.0 ml of serum or urine into an extraction tube, adding an internal standard together with either a pH 4.9 or pH 8.3 buffer and extracting with chloroform. The drugs in the extract are concentrated by exaporation of the organic layer and identified and quantitated by gas-liquid chromatography (GLC) using a column packed with 3 percent OV 17. GLC analysis times are kept below seven minutes by using temperature programming which allows good separations of drugs of widely varying volatilities. All calculations are based on peak areas determined by an electronic integrator. Losses of drugs during extraction, evaporation and chromatography steps are compensated for by the use of internal standards. Actual extraction efficiencies of drugs from serum or urine range from 75 to 100 percent although recoveries, based on standards carried through the entire procedures, are quantitative. Precision (s.d.) based on replicate determinations is approximately plus or minus 0.2 mg per dl.

Alkaloids↗
PubMed1978

Simultaneous liquid-chromatographic determination of 12 common sedatives and hypnotics in serum.

We present a method for simultaneously determining 12 hypnotics and sedatives (primidone, methyprylon, phenobarbital, butabarbital, butalbital, ethchlorvynol, pentobarbital, amobarbital, phenytoin, glutethimide, secobarbital and methaqualone) in 200 microliter of serum. Serum proteins are precipitated with an acetonitrile solution containing 5-(4-methylphenyl)-5-phenylhydantoin, the internal standard. The drugs are eluted from a reversed-phase column with a mobile phase consisting of an acetonitrile/phosphate buffer, at a flow rate of 3.0 ml/min. The eluted drugs are detected by their absorption at 195 nm; their quantities are estimated from their peak heights. Each analysis requires no longer than 30 min at the optimum column temperature of 50 degrees C. The lower limit of detection for all of these drugs is less than 10 ng/sample for drug standard. A sensitivity of 1.0 mg/liter of serum is attained routinely for each of the drugs. Analytical recoveries for the 12 drugs varied from 94 to 112%, with good day-to-day precision (CV between 3.8 and 10.4%). Of more than 35 drugs tested for possible interference, only ethotoin interferes with the analysis of phenobarbital.

Chromatography, Liquid↗
PubMedDate not supplied

Anticonvulsant drugs used in the treatment of epilepsy.

The pharmacology of anticonvulsant drugs is reviewed with emphasis placed on the treatment of canine and feline epilepsy. Due to pharmacokinetic reasons, only phenobarbital, primidone, and, with certain limitations, the benzodiazepines can be used in dogs. Bromides may be given additionally in cases that cannot be controlled with phenobarbital or promidone therapy. In cats, diazepam has been shown to be very useful because no tolerance develops to the antiepileptic effect in this species.

Animals↗
PubMedDate not supplied

Feline epilepsy.

In approximately two-thirds of the epileptic cats in this article, an idiopathic epilepsy had to be assumed. It began between six and 36 months of age with a single seizure, which usually occurred during rest or sleep. Symptomatic epilepsy was frequently observed during the first two years of life and in old age, beginning frequently with multiple seizures or status epilepticus and less often during sleep or rest. In both types, grand mal seizures are predominant. Seizure clusters or status epilepticus caused extensive neuron necroses and scleroses in Ammon's horn. Diazepana and phenobarbital are antiepileptics of first choice for the cat; primidone and phenytoin are less suitable.

Animals↗
PubMed1989

Trunkal tremor: orthostatic or essential?

A sixty two year old man who presented with tremors of trunk and lower limbs, appearing only on standing, is reported. The tremor frequency was 14-16 Hz and there was co-contraction of antagonistic muscles. No therapeutic benefit was noted with propranolol, primidone and diazepam. The possible pathogenesis of this rare orthostatic trunkal tremor and its relationship with essential tremor are discussed.

Aged↗
PubMed1978

Drug therapy in the treatment of minimal brain dysfunction.

The pharmacotherapy of minimal brain dysfunction (MBD) is reviewed. Studies using central nervous system (CNS) stimulants (amphetamines and methylphenidate, deanol, pemoline, caffeine), antidepressants (imipramine and desipramine), anticonvulsants (phenytoin and primidone), antianxiety agents (chlordiazepoxide, hydroxyzine, meprobamate), antipsychotic agents (phenothiazines, thioxanthenes, butyrophenones) and miscellaneous agents (benztropine, thyrotropin-releasing hormone, megavitamins) are discussed. When drugs are indicated, the CNS stimulants are the agents of choice in the treatment of MBD. The use of tricyclic antidepressants in MBD is regarded as investigational and warrants careful monitoring to minimize toxicities. Anticonvulsants have been ineffective in controlling behavior problems; however, phenytoin may be helpful in auditory perception problems. Anti-anxiety and antipsychotic agents are not as desirable as the CNS stimulants for treatment since they do not decrease distractibility or increase attention spans.

Anti-Anxiety Agents↗
PubMed1989

Tremor disorders of aging: diagnosis and management.

Tremor disorders are commonly encountered in the elderly. Physiological tremor is present in all of us and may be enhanced by drugs or other circumstances to cause symptomatic dysfunction. Essential tremor consists of postural and kinetic tremors which may involve the hands, head, and voice. Approximately 50% of cases are hereditary. Significant disability may occur. Propranolol and primidone provide effective treatment for some patients. The tremor of Parkinson's disease occurs in resting and postural positions. Treatment with levodopa usually reduces the tremor. Anticholinergics may also decrease tremor but often cause mental side effects in the elderly. Disturbances of the cerebellum may cause a kinetic tremor of the extremities or shakiness of the trunk. Tremors may also occur on a psychogenic basis. Proper classification of tremor disorder will lead to appropriate diagnosis and, often, effective treatment.

Aged↗
PubMed1987

Characterization and inhibition of mephenytoin 4-hydroxylase activity in human liver microsomes.

The in vivo metabolism in humans of the anticonvulsant mephenytoin exhibits stereoselectivity as well as genetic polymorphism of the 4-hydroxylation pathway. The characteristics of the involved cytochrome P-450 isozyme are, however, not known completely. Accordingly, the ability of human liver microsomes to metabolize mephenytoin and its enantiomers was investigated in vitro, and the ability of related anticonvulsants and other compounds to inhibit 4-hydroxylation was studied. Marked stereoselectivity was observed in the conversion of S-mephenytoin to its 4-hydroxy metabolite, but N-demethylation was essentially similar for both enantiomers. The intrinsic clearance (Vmax/Km) for 4-hydroxymephenytoin formation showed an almost 10-fold range in five livers and was 150- to 1000-fold greater than that for N-demethylation. Competitive inhibition of 4-hydroxylation was observed with ethotoin, mephobarbital, methsuximide and phensuximide, but not other commonly used anticonvulsants such as ethosuximide, phenobarbital, phenytoin and primidone. However, synthetic N-alkyl analogs of the latter compounds were found to be inhibitory. An aryl residue alpha to the carbonyl carbon of an N-alkyl lactam in a 5- or 6-membered ring, therefore, appears to be a minimal requirement for strong interaction with the 4-hydroxylase. Warfarin, but not diazepam, ketoconazole or iodochlorohydroxyquin, were also competitive inhibitors, but at much higher concentrations than the anticonvulsants. Competitive inhibition at concentrations similar to the Km of 4-hydroxymephenytoin formation (30-350 microM) may indicate that the isozyme is involved in the metabolism of the substrates under consideration and, therefore, their in vivo metabolism may be regulated to some extent by the same genetic factor(s) that determine mephenytoin's biotransformation.

Anticonvulsants↗
PubMedDate not supplied

Pharmacological treatment of epilepsy today.

The pharmacological treatment of epilepsy has not gone through remarkable changes in recent years. Treatment is based on few first choice drugs, the mechanism of action of which we do not yet know exactly. These include: phenobarbital, primidone, phenytoin, carbamazepine, valproic acid, ethosuximide, clonazepam. Choice of drug is determined by the kind of seizures presented by the patient, while successful treatment is determined by the kind of epilepsy. The present trend is the use of first line drugs in monotherapy, fixing individually the dosage according to the plasma levels. The results obtained with the GABA-agonists (progabide, gamma-vinyl GABA) and with some of the calcium-antagonists (flunarizine) seem promising.

Anti-Anxiety Agents↗
PubMedDate not supplied

Lymphocyte changes after long-term therapy of some neurological diseases.

Hematologic investigations were carried out in 50 patients with various forms of epilepsy, aged 20 to 50 years, who had been treated for different periods of time with antiepileptic and neuroleptic drugs such as primidon, luminal and prasine. All the cytomorphological and cytochemical studies concerned the white blood cells, especially lymphocytes, and their transformation into plasma cells and histiomonocytes. The cytochemical investigations referred particularly to nucleolar-RNA, glycogen and lipid cellular content. The results obtained showed that the lymphocyte count and mostly that of the large and medium lymphocytes, may reach twice the normal or more. The transition forms towards histiomonocytes and plasma cells were quite frequent. Cytochemically, a variable state of reactivity of the nucleolar apparatus was demonstrated, as well as certain changes of the carbohydrate and lipid metabolism. The influence of such changes on the cellular and humoral immunity of the respective patients is discussed. Emphasis is also laid on the utility of such investigations for the detection of the untoward effects of antiepileptic and neuroleptic drugs on hematopoiesis.

Adult↗
PubMedDate not supplied

Effects of antiepileptics on the hepatic storage of retinol.

The effect of various antiepileptics on the retinol storage in rat liver was tested. We observed a dose- and time-dependent reduction in the hepatic storage of retinol after the administration of several of these drugs. Administration for 11 weeks of phenobarbital, primidone and carbamazepine in doses comparable to those used in humans reduced the retinol concentration in the Liver by 17-33% compared to control rats. The plasma retinol levels remained unaffected in all the rats. Plasma retinol from 31 epileptic children had plasma levels between 0.7 and 2.4 nmol/ml, which is regarded as normal.

Animals↗
PubMed1986

Hyperammonaemia and hepatotoxicity during chronic valproate therapy: enhancement by combination with other antiepileptic drugs.

Erythrocyte (ENH3) and plasma (PNH3) ammonia levels, liver function tests and plasma valproate concentration were measured in 81 epileptic patients, comprising three therapeutic groups: Group 1 (23 patients) received sodium valproate (VPA) monotherapy, group 2 (33 patients) received sodium valproate combined with phenytoin, carbamazepine, phenobarbitone and/or primidone and group 3 (25 patients) received one or more of these anti-epileptic drugs without sodium valproate. The mean ENH3 and PNH3 of patients in group 1 (41.1 +/- 30.7 mumol l-1 and 37.1 +/- 31.8 mumol l-1, respectively) and group 2 (44.5 +/- 21.3 and 37.6 +/- 21.4 mumol l-1, respectively) were significantly (P less than 0.01) higher than those in group 3 (28.7 +/- 10.6 and 21.5 +/- 7.8 mumol l-1, respectively) and the reference range (30.1 +/- 7.9 and 20.8 +/- 5.7 mumol l-1, respectively). Hyperammonaemia was more prevalent amongst patients in group 2, for both ENH3 (45.5%) and PNH3 (54.6%), than amongst patients in group 1 (30.4% and 52.2%, respectively) and group 3 (8% and 8%, respectively). There was a significant (P less than 0.05) positive correlation between plasma VPA and total bilirubin concentrations. Chronic VPA therapy was also associated with an increase in bilirubin concentrations measured on average four months apart.

Adolescent↗
PubMed1977

High-pressure liquid chromatography and enzyme immunoassay compared with gas chromatography for determing phenytoin.

We compared a gas-chromatographic method for determination of phenytoin with a high-pressure liquid chromatographic technique and with enzyme immunoassay by three instrumental procedures. More than 100 sera from patients being treated with this drug were assayed by all these techniques. The coefficient of variation was the lowest (4.0%) with liquid chromatography, but all methods gave a CV of less than 10%. The correlation coefficients for all methods exceeded 0.97 when compared to gas chromatography. Operation costs varied with the number of tests per batch, reagent costs, and operator labor costs. All assays gave comparable values for the therapeutic range, so it would be plausible to use more than one method in a situation where (e.g.) satellite laboratories handle different quantities of assays. In any of these techniques, interferences from carbamazepine, mephenytoin, phenobarbital, and primidone were negligible.

Chromatography, Gas↗