Serum anticonvulsant concentrations and the risk of drug induced skin eruptions.

In two prospective studies of anticonvulsant therapy there was a high incidence of drug-induced skin reactions to phenytoin (7%) and carbamazepine (16.6%). High initial serum concentrations of these drugs appeared to be a factor influencing the occurrence of such skin reactions.     

Prevalence of toxic anticonvulsant drug concentrations in mentally retarded persons with epilepsy

Anticonvulsant drug concentrations in retarded individuals (117 hospital residents, 58 community-based) were surveyed. Concentrations of carbamazepine (CBZ, Tegretol) and phenytoin (Dilantin) were determined in salivary samples collected before morning medication (premedication sample) and 4 hours later (postmedication sample). Of 146 individuals receiving CBZ, 16% had salivary concentrations above the therapeutic range on at least one sample, whereas 2% exceeded the range on both samples. Of the 54 subjects prescribed phenytoin, 28% had at least one salivary concentration exceeding the therapeutic range, and 15% surpassed the therapeutic range on both samples. These data suggest the desirability of using regular therapeutic drug monitoring and neurological assessments to avoid the possibility of toxic drug levels in this population. A variety of subject and pharmacological variables (sex, severity of retardation, number of seizures in the last year, and dose) were also examined for their relationship to drug concentrations.     

Episodic nocturnal wanderings responsive to anticonvulsant drug therapy

Six patients between the ages of 17 and 32 years presented with unusual sleep-walking episodes characterized by screaming or unintelligible vocalizations; complex, often violent automatisms; and ambulation. Two or more attacks could occur in a single night and were most common in the early morning hours. Family and personal histories did not show epilepsy, psychiatric disorders, or (with 1 exception) previous somnambulism. Electrographic investigation revealed that all patients had normal waking-sleep cycles but that 4 of them had epileptiform abnormalities on their electroencephalograms. All patients were treated with either phenytoin or carbamazepine, with cessation of the abnormal nocturnal behavior during follow-up periods ranging from 9 to 48 months. This syndrome appears to be distinct from more typical non–rapid eye movement dyssomnias and suggests an atypical form of epilepsy.     

Long-term consequences of neonatal exposure to chlordecone

Neonate, female rats pups were injected with varying doses of chlordecone in cotton seed oil or with 1 mg chlordecone in dimethylsulfoxide. The effects of these neonatal treatments on vaginal opening, persistent vaginal estrus and adult sexual behavior were examined. Females treated with chlordecone showed earlier onset of vaginal opening and developed persistent vaginal estrus in adulthood. Sexual behavior of intact adult females was irregular but after ovariectomy and estrogen plus progesterone hormonal priming, chlordecone treated females showed normal lordosis responding. Females did not appear to have been defeminized by the neonatal chlordecone. After treatment with testosterone in adulthood, chlordecone treated females exhibited high levels of mounting behavior indicating that the neonatal treatments may have masculinized the developing hypothalamus. No significant effects of the vehicle were detected.     

Microencephaly and hyperactivity in adult rats can be induced by neonatal exposure to high blood alcohol concentrations

To investigate whether or not blood alcohol concentration during the brain growth spurt has an influence on the permanency of alcohol-induced central nervous system damage, an artificial rearing technique was used to administer a daily dose of alcohol (6.6 g/kg/day) to neonatal rats during postnatal days 4 to 10. The alcohol was administered either in a condensed pattern over 8 h resulting in cyclic blood alcohol concentrations with high peaks, or uniformly over each 24-h period resulting in stable, but low peaks. The condensed alcohol exposure resulted in considerable microencephaly (20% to 25%), with significant growth deficits in the cerebrum, cerebellum, and brain stem of rats of either sex at day 10; there still was significant microencephaly (16% to 19%) in adult rats that received the condensed alcohol exposure as neonates. Furthermore, activity at day 90 in rats of either sex that had condensed alcohol exposure was elevated compared with that of the gastrostomy control group. In contrast, the rats having uniform alcohol exposure had only nonsignificant changes in brain weight both on day 10 and day 90 and did not exhibit hyperactivity at day 90. Thus, neonatal alcohol exposure producing high blood alcohol concentrations caused permanent deficits in brain growth and significant changes in activity, whereas the same daily dose of alcohol administered in a pattern that resulted in consistently low blood alcohol concentrations failed to produce either permanent microencephaly or increased activity. These data support the hypothesis that patterns of alcohol exposure that produce high concentrations in the blood, such as "binge-drinking," increase the risk of permanent damage to the developing brain.     

Neuronal deficits after neonatal exposure to phenobarbital

Heterogeneous Sabra mice pups were injected daily with 50 mg/kg (B50) phenobarbital or 40 mg/kg (B40) from age 2 to 21 days. Control litter mates (C) received vehicle injection. Brain phenobarbital concentrations attained 50 μg/g. The brains of C, B40, and B50 mice were removed at age 50 days, fixed, sectioned, and stained with hematoxylin and eosin. Matching sagittal sections were selected for the study of the cerebellum, hippocampus, and the cerebral cortex. Brain weight was reduced 8 to 12% compared with control among the phenobarbital-treated animals. There were reductions of about 20% in the area of the cerebellar layers in B50-treated mice but no significant differences in B40-treated mice. In both groups Purkinje and granule cell numbers were reduced by about one-third, the packing density of the cerebellar cells was also reduced (18% to 20%), and the area of the hippocampal layers was reduced by about 15 to 20%. There were one-third fewer pyramidal cells in B50- and B40-treated mice than in controls and 22 to 25% fewer granule cells. Therefore, the ratio granule:pyramidal cells was significantly different in the hippocampus. The cortical area was smaller than control in the B50 group (14%) and the B40 group (20%). The neuronal deficits in the cortex were less extensive than in the other brain parts studied (B50, 9%; B40, 19%). The resuls suggest that unlike many neonatal insults including undernutrition, neonatal administration of relatively small doses of phenobarbital destroys even brain cells which are already formed.     

Clinical implications of increased antipsychotic plasma concentrations upon anticonvulsant cessation

Plasma antipsychotic concentrations were measured in five patients when their anticonvulsant medications were discontinued. Plasma antipsychotic concentrations increased by two- to five-fold at 4 weeks after cessation. All patients demonstrated either moderate or marked improvement as antipsychotic plasma concentrations increased. Four patients experienced extrapyramidal side effects within 30 days of anticonvulsant discontinuation. Careful monitoring of clinical symptoms, adverse effects, and plasma antipsychotic concentrations is recommended.     

Second-line anticonvulsant treatment of neonatal seizures: a video-EEG monitoring study

The authors conducted a randomized trial of second-line anticonvulsant treatments for neonates. The response to treatment was assessed using continuous video-EEG because the clinical diagnosis of seizure in neonates is known to be unreliable. Of 27 neonates with EEG-confirmed seizures, 5 were excluded because of protocol violations, and 11 responded to phenobarbitone in a dose of 40 mg/kg as first line. Three of five neonates treated with lignocaine responded. Six neonates were treated with benzodiazepines as second line: None responded, and their neurodevelopmental outcome was poor.     

Sensitivity of cerebellar glutathione system to neonatal ionizing radiation exposure

Reactive oxygen species (ROS) are relevant components of living organisms that, besides their role in the regulation of different important physiological functions, when present in excess are capable to affect cell oxidative status, leading to damage of cellular molecules and disturbance of normal cell function. ROS accumulation has been associated with a variety of conditions such as neurodegenerative diseases and ionizing radiation exposure. Cell ability to counteract ROS overproduction depends on the capacity of the endogenous antioxidant defenses--which includes the glutathione (GSH) system--to cope with. Since developing central nervous system (CNS) is especially sensitive to ROS-induced damage, the aim of the present work was to evaluate ROS, reduced GSH and oxidized glutathione (GSSG) levels in the cerebellum at different developmental ages after irradiation, in order to test if any changes were induced on these key oxidative stress-related cellular markers that might explain the high cerebellar vulnerability to radiation-induced injury. Since intracellular levels of GSH are maintained by glutathione reductase (GSHr), this enzymatic activity was also evaluated. Newborn Wistar rats were irradiated in their cephalic ends and the different parameters were measured, from 1h to 90 days post-irradiation. Results showed that an early transient increase in ROS levels followed by a decrease in cerebellar weight at 3-5 days post-irradiation were induced. An increase in cerebellar GSH levels was induced at 30 days after irradiation, together with a decrease in GSHr activity. These results support the hypothesis that ROS may represent a marker of damage prior to radiation-induced cell death. In contrast, it would be suggested that GSH system might play a role in the compensatory mechanisms triggered to counteract radiation-induced cerebellar damage.     

Progressive anticonvulsant hypersensitivity syndrome associated with change of drug product

This report describes the laboratory and physical manifestations of lamotrigine-like toxicity in a young man with refractory epilepsy receiving lamotrigine presenting as anticonvulsant hypersensitivity syndrome (AHS) associated with an abrupt change of drug product.     

Reduction of voltage-operated sodium currents by the anticonvulsant drug sulthiame

The effect of the sulfonamide derivative sulthiame (Ospolot^®) on voltage-operated sodium channels was investigated in acutely isolated neurons from the guinea pig hippocampus using the whole-cell patch-clamp technique. Sulthiame in a concentration of 10 μg/ml reduced the inactivating sodium currents without affecting potassium currents. The effect was not dependent on voltage. At therapeutic concentration of 1 to 10 μg/ml sodium currents were reduced by 13 to 25% of control. Reductions of this size (induced by the specific sodium channel blocker tetrodotoxin or by 10 μg/ml sulthiame itself) impaired repetitive generation of action potentials and reduced the maximum discharge frequency by 20 to 40%. In summary, the anticonvulsant drug sulthiame exerts blocking effects on sodium channels which can be assumed to be anticonvulsant and to be different from the effects induced by blockade of carbonic anhydrase.     

Melatonin increases following convulsive seizures may be related to its anticonvulsant properties at physiological concentrations

Melatonin ( N-acetyl-5-methoxytryptamine, aMT) is an indoleamine produced by several organs and tissues including the pineal gland. Melatonin (aMT) modulates the activity of the brain, mainly acting on both GABA and glutamate receptors. Previous studies have shown the participation of melatonin in the control of convulsive crises, suggesting that aMT concentration increases during seizures, and that patients with seizures of diverse origins show an alteration of the aMT rhythm. However, what is not known is the duration of the aMT response to seizures, and whether aMT changes during seizures could be a marker of the disease. For this reason, the serum levels of aMT in 54 children with a convulsive crisis, febrile and epileptic, were analyzed during the crisis, as well as at 1 h and 24 hours after the seizure. The results show that aMT significantly increases during the seizure (Day group, 75.64+/-45.91 and Night group, 90.69+/-51.85 pg/mL), with normal values being recovered 1 h later (Day group, 26.33+/-10.15 and Night group, 27.78+/-7.82 pg/mL) and maintained for up to 24 hours, when the circadian variation of aMT returns to the normal acrophase. Due to the interindividual variation of aMT levels among healthy people, a single determination of the indoleamine concentration is not a suitable marker of the existence of a convulsive crisis unless the circadian profile of aMT secretion in the patient is known. The results obtained also support the view that the stimulation of aMT production by the convulsive crisis may participate in the response of the organism against the seizures.     

Value of therapeutic drug level monitoring and unbound (free) levels.

Therapeutic drug monitoring (TDM) has declined with newer anti-epileptic drugs (AEDs) having no therapeutic window. Use of unbound (free) fraction has almost completely disappeared. The case reported highlights its importance and offers sound reason for its retention. A 66-year-old Caucasian man with known epilepsy was admitted with vomiting, ataxia and nystagmus presumably due to AED toxicity. Medications included valproate (VPA) 1g bd; phenytoin (PHT) 200mg tds; carbamazepine (CBZ) 400mg mane, 200mg midi, 400mg nocte; levetiracetam (LEV) 250mg bd. Initial AED-TDM revealed total serum levels of CBZ: 27mumol/L; PHT: 37mumol/L; VPA 499mumol/L, therapeutic or subtherapeutic. Free levels were subsequently measured demonstrating CBZ: 8.2mumol/L; PHT: 5mumol/L; VPA 93mumol/L. Consequently, VPA was initially omitted and dosage reduced with cessation of toxicity. AED regimen was greatly simplified and remained efficacious. This case highlights the value of TDM with polypharmacy and suggested AED toxicity. Total AED levels failed to identify the cause, which the unbound, free fraction identified. While total PHT was borderline subtherapeutic (37mumol/L; range: 40-80) the free level was therapeutic (5mumol/L; range: 4-8) and while VPA was therapeutic (VPA 499mumol/L; range: 300-750) the free level was supratherapeutic (93mumol/L; range: 30-75). Acknowledgement of discordance between total and free levels for highly protein-bound AED is highlighted.     

Protein synthesis in rat brain following neonatal exposure to lead

(1) Suckling rats were exposed to lead through the milk of their dams who received a diet of 4% lead carbonate and weanling rats were exposed to 2 injections of 5.0 mg Pb2+/100 g body weight. The brains were used to prepare the following homogenate fractions: postmitochondrial supernatant, postmicrosomal supernatant, ribosomes, initiation factors. (2) The postmitochondrial supernatant fractions were tested in vitro for protein synthesizing activity using the incorporation of labelled phenylalanine, and phenylalanyl-tRNA into peptide. The preparations from the lead-exposed rats had a significant reduction in activity. (3) Peptide formation with the brain ribosomes was not changed in the lead-exposed rats. (4) The aminoacyl-tRNA synthetase reaction was significantly reduced and accounted for most of the reduced peptide formation with brain homogenates from lead-exposed rats. (5) The binding of methionyl-tRNAfMet to ribosomes was increased using initiation factor preparations from the brain of lead-exposed rats.