Gynecomastia in epileptics treated with phenobarbital, phenytoin and fluoresone: Two case reports

Gynecomastia developed in two epileptic patients some months after the addition of oral fluoresone 750 mg daily to the phenobarbital and phenytoin already being administered. The common systemic diseases that may give rise to gynecomastia were excluded. One of the patients presented hyperprolactinemia and a raised estrogen/androgen ratio but the hormone levels were not raised in the other. The onset of symptoms after fluoresone in both cases is highly suggestive, although the pathogenetic mechanism is not clear.

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Sommario Una ginecomastia insorta in due epilettici viene riportata. Il quadro si è sviluppato alcuni mesi dopo che ad un precedente trattamento con PB e PHT si era aggiunto fluoresone alla dose di 750 mg/die per os. Le comuni malattie sistemiche che possono determinare una ginecomastia sono state escluse. I rilievi ormonali hanno evidenziato soltanto in un caso un'iperprolattinemia ed un aumento del rapporto estrogeni-androgeni circolanti. La relazione temporale fra somministrazione del fluoresone e comparsa del quadro appare cruciate, tuttavia il meccanismo patogenetico resta da chiarire.

     

Serum elevation of high density lipoprotein (HDL) cholesterol in epileptic patients taking carbamazepine or phenytoin

Serum lipids and the cholesterol concentration in the high density lipoprotein (HDL) fraction were measured in epileptic patients taking either carbamazepine or phenytoin as single drug treatment. There was a significant increase in HDL-cholesterol levels in patients taking both phenytoin and carbamazepine. Serum total-cholesterol concentrations in patients taking both drugs did not differ significantly from those of controls. The ratio of HDL-cholesterol/total cholesterol was increased in both drugs and the increase reached significance in patients taking phenytoin. There was a significant increase in serum triglycerides in females taking carbamazepine.     

Side effects of phenobarbital and phenytoin during long-term treatment of epilepsy

ABSTRACT Phenobarbital and phenytoin have good antiepileptic effect, but clinically significant untoward effects occur during their long-term use. Phenobarbital may cause hyperactivity, behavioral problems, sedation, and even dementia; these effects are dose related to some extent. Side effects of phenytoin include sedation, a cerebellar syndrome, phenytoin encephalopathy, psychosis, locomotor dysfunction, hyperkinesia, megaloblastic anemia, decreased serum folate level, decreased bone mineral content, liver disease, IgA deficiency, gingival hyperplasia, and a lupus-like hypersensitivity syndrome. Especially susceptible to the neurotoxic effects of phenytoin are epileptic children with severe brain damage who are on multiple drugs. In those children, balance disturbance may develop and be followed by gradual loss of locomotion. Among 131 mentally retarded epileptic patients, phenytoin intoxication occurred in 73 (56 %), of whom 18 experienced persistent loss of locomotion. There is experimental evidence that the toxic action of phenytoin lies at the cellular level, predominantly in the cerebellum. Many experts avoid the long-term use of phenytoin because of its insidious and potentially dangerous side effects.     

Absence Seizures and Carbamazepine in Adults

Summary: Carbamazepine (CBZ) therapy was associated with development of absence seizures in 4 adults with generalized epilepsy. Two patients had new appearance of absence seizures and 2 patients had recrudesence of remote absence seizures. The seizures abated after discontinuation of CBZ therapy or addition of ethosuximide (ESM) in 1 patient intolerant of valproate (VPA).     

Serum phenytoin during pregnancy, labor and puerperium

111 pregnancies of epileptic women on phenytoin therapy were observed in a prospective study. Maternal serum phenytoin concentrations were measured monthly or bi-weekly during pregnancy, labor and puerperium. The concentration decreased towards the end of pregnancy and was lowest at delivery. In 48% of the patients the drug dosage had to be increased to combat the increased seizure frequency.     

Carbamazepine and phenytoin: combination versus single drug therapy

The records of 18 patients with intractable partial seizures who were observed on an in-patient epilepsy unit during single drug treatment with carbamezepine (CBZ) or phenytoin (PHT) and during combination therapy with both drugs were evaluated retrospectively. Seizure frequency was significantly lower during combination therapy (p < 0.01) and toxicity, as measured by an eight point objective scale, did not increase significantly (p > 0.10). In addition subjective signs of clinical toiicity (e.g. nausea, ataxia, etc.) increased only slightly during combination versus monotherapy. These findings were consistently seen whether the data were evaluated in total (i.e. treatment periods at least 7 weeks) or evaluated by using standardized 35 day treatment periods. In the absence of a blinded clinical trial evaluating PHT/CBZ combination, these findings support consideration of this combination in Intractable patients who have failed rigorously administered mono-therapy trials, recognizing however that only a small percentage of patients will improve on combination therapy.     

Cognitive effects of phenytoin during monotherapy and after withdrawal

We studied the psychomotor performance of 10 seizure-free epileptics during a fixed monotherapy with phenytoin and after its withdrawal. Our findings suggests some adverse effects of phenytoin which seem reversible after withdrawal.     

Effects of phenytoin and carbamazepine on cognitive functions in newly diagnosed epileptic patients

Phenytoin (PT) and carbamazepine (CBZ) are the two most prescribed anticonvulsants in Finland. Their effect on the cognitive functions of 43 newly diagnosed epileptic patients was examined. The medication was randomly assigned. The patients were tested before the medication was started, and after half a year's therapy. In order to estimate the practice effect in repeated testing a control group of 21 volunteers was similarly tested and retested. Both anticonvulsants, PT in particular, decrease the normal practice effect observed in neuropsychological testing. Compared to the CBZ group, patients with PT became somewhat slower, and their visual memory decreased. Within the PT group the motor slowing was more marked in female patients, and in patients having higher PT serum levels. In PT and CBZ groups there was an equal decrease in negative mood i.e. tension, depression, bewilderment and irritability.     

Cyclic AMP accumulation in cerebral cortical slices: effect of carbamazepine, phenobarbital, and phenytoin.

Recent investigations have suggested that abnormal increases in brain cyclic 3',5'-adenosine monophosphate (cAMP) may play a role in epileptogenesis. Therefore, the effect of three commonly used antiepileptic drugs on cAMP accumulation in rat cortex slices was investigated. Ouabain, a depolarizing agent which produces seizures when applied to rat cortex, produced a five- to sevenfold increase in cAMP accumulation, and both carbamazepine and and phenytoin inhibited this increase. Ouabain stimulation may be mediated by the release of endogenous adenosine, and carbamazepine antagonized adenosine stimulation of cAMP accumulation whereas phenytoin did not. Carbamazepine had no effect on adenosine efflux. The augmentation of cAMP accumulation by norepinephrine was inhibited by carbamazepine and phenobarbital but slightly increased by phenytoin. If increases in brain cAMP are involved in epileptogenesis, the antagonism of cAMP accumulation by antiepileptic drugs may play a role in their anticonvulsant action.     

Brain Distribution of Carbamazepine and Phenobarbital Given in Combination in Experimental Epilepsy

This study describes the brain distribution of carbamazepine (CBZ) and phenobarbital (PB) given intraperitoneally in combination to cats rendered epileptic by parenteral penicillin and by penicillin topically applied on neocortex. A control group of normal cats was also evaluated pharmacokinetically. Levels of both drugs were extremely low in brains of controls (CBZ 0.8 +/- 0.02 micrograms/g; PB 1.49 +/- 0.7 micrograms/g of fresh tissue), but higher levels were found in brains of epileptic cats with CBZ showing the greater increase (peak concentrations five- to sixfold higher than the corresponding CSF free fraction vs. three- to fourfold higher for PB). This might have been partially due to the ability of CBZ to prevent the metabolic alterations associated with severe convulsions, and hence the binding impairment. As this event had no effect of potentiation on CBZ anticonvulsant activity, the present data confirm previous reports indicating that there is no experimental evidence that two drugs are better than one in controlling epilepsy.     

Effects of withdrawal of phenytoin on cognitive and psychomotor functions in hospitalized epileptic patients on polytherapy

The effects of the withdrawal of phenytoin (PT) on cognitive and psychomotor functions of long-term patients in an epilepsy centre were studied. The patients had been treated for many years (31.1 +/- 10.8 yrs.) with PT in combination with other antiepileptic drugs. The serum concentration of PT was in the lower to middle therapeutic range (6.8 +/- 3.1 mg/l). Only patients in which the efficacy of PT was questionable were included in the study. PT was withdrawn in 17 patients. The PT dose was not changed in 12 patients (control group). Psychological tests were carried out immediately before the withdrawal of PT and about 10 weeks later. Tests were also carried out with the control group at the same time. A significantly improved performance (using a composite score) was noted after the withdrawal of PT. The statistical evaluation of the different tests showed an significant improvement in one test of concentration and two tests of psychomotor function (tapping and pursuit rotor with the dominant hand). There was no significant change in the frequency of seizures.     

Single photon emission computed tomography studies of partial epilepsies

Abstract At present, in the field of clinical epilepsy, it has been established that single photon emission computed tomography (SPECT) is useful for the regional determination of epileptic foci. In particular, it seems to be of great advantage to the field of clinical epilepsy that epileptic foci situated in the deep regions of the brain are detectable by the three-dimensional resolution power in SPECT, because such foci are not often represented on routine scalp electroencephalograph (EEG). In reference to our review published previously,¹ recent findings in SPECT studies of partial epilepsies are surveyed here.     

Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin

Objective – To evaluate the efficacy and tolerability of the treatment with valproic acid (VPA) in patients with status epilepticus (SE) or acute repetitive seizures (ARS) comparing it with phenytoin (PHT) treatment. Materials and methods – Patients with SE or ARS were treated in a consecutive manner with either VPA or PHT intravenously. The primary endpoint was defined as clinical seizure cessation; the secondary endpoint was evaluation of drug tolerability. Results – Seventy‐four adult patients with SE or ARS participated in the study, 49 with VPA i.v. and 25 PHT i.v. In 43 (87.8%) of the VPA patients, the seizures discontinued, and no rescue medication was needed. Similar results were found in the PHT group in which seizures of 22 (88%) patients were well controlled. Side effects were found in 12% of the PHT group, and in none of the VPA group. Conclusions – VPA i.v. seems to be effective and well tolerated in adult patients with SE or ARS.     

奥卡西平与卡马西平单药治疗儿童部分性癫的对照研究

目的比较奥卡西平与卡马西平单药治疗儿童部分性癫的疗效。方法71例新诊断的儿童部分性癫患者按单双号顺序分为奥卡西平组(35例)和卡马西平组(36例),并给予相应的药物治疗;6个月后进行疗效评价,观察不良反应。结果奥卡西平组和卡马西平组分别有25例及29例完成6个月治疗;脑电图改善率分别为44.0%及44.8%;显效率分别为92.0%及86.2%;不良反应发生率分别为22.2%及41.2%,两组间比较差异无统计学意义(均P>0.05);卡马西平组2例出现严重不良反应。结论奥卡西平与卡马西平单药治疗新诊断的儿童部分性癫均有很好的疗效,不良反应及耐受性相似,但奥卡西平组未见严重的不良反应。     

Interictal cerebral metabolism in partial epilepsies of neocortical origin

We performed interietal [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG PET) in 24 patients with partial epilepsy of neocortical origin. Two-thirds of patients had regions of hypometabolism. The zone of intracranially recorded electrographic ictal onset was always located in a region of hypometabolism, in those with hypometabolism. Hypometabolic regions in partial epilepsies of neocortical origin were usually associated with structural imaging abnormalities. Regional hypometabolism occasionally occurred without localizing ictal scalp EEG and cerebral magnetic resonance imaging findings, however. FDG PET may be useful in directing placement of intracranial electrodes for presurgical evaluation of refractory neocortical seizures.     

多药耐药蛋白对大鼠皮层细胞外液卡马西平和苯妥英钠影响的研究

目的观察多药耐药蛋白(multidrugresistance-associatedprotein,MRP)拮抗剂丙磺舒对大鼠大脑皮层细胞外液卡马西平和苯妥英钠含量的影响,证明MRP能够减少皮层内抗癫痫药物的浓度,探讨脑内表达MRP和难治性癫痫多药耐药的关系。方法在健康大鼠大脑皮层内安置微透析探针,腹腔注射卡马西平(20mg/kg)和苯妥英钠(50mg/kg),在给药后不同时间点收集透析液,并用高效液相检测其中的药物浓度,通过微透析探针局部给于丙磺舒,观察后者能否提高大鼠大脑皮层细胞外液卡马西平和苯妥英钠的浓度。结果丙磺舒升高了皮层细胞外液中卡马西平和苯妥英钠的药物浓度,前者在给药后45min～120min显著增高(P<0.05),后者在给药后30min～150min显著增高(P<0.05)。结论MRP具有限制卡马西平和苯妥英钠通过血脑屏障的作用,引起抗癫痫药物在大鼠大脑皮层细胞外液中分布减低,MRP表达增加可能参与了难治性癫痫多药耐药机制的形成。