Effect of reduction of anticonvulsants on wellbeing.

An attempt was made over a period of a year to reduce the number of anticonvulsants used to treat epilepsy in a hospital for the mentally handicapped. At least one drug was withdrawn for each of 20 patients, without loss of seizure control. Effect on wellbeing was assessed by a behavioural scale completed before and after withdrawal, and in the 20 cases of successful withdrawal wellbeing was significantly improved.     

Age-dependent increase in the threshold for pentylenetetrazole induced maximal seizure in mice

The thresholds for inducing the maximal seizure by pentylenetetrazole (PTZ) were compared for BDF1 mice of both sexes with varying ages after intraperitoneal administration of various doses of PTZ. The minimal effective PTZ concentrations (MECs) in the brain for inducing the maximal seizure were significantly higher in 24-month or older mice than in 6-month-old animals of both sexes. Some mice of 30 months did not demonstrate the maximal seizure but died within the 15-min observation period, a phenomenon never observed in mice of 24 months or younger. The relationship between plasma and brain concentrations of PTZ changed little during aging. It was concluded that the brain becomes less sensitive to PTZ with age in regard to its convulsant activity, as was previously shown for electroshock by the authors. This observation, coupled with our earlier observations on anticonvulsants, appears to support the classical hypothesis that age has a dual effect on drug sensitivity i.e. a decrease for stimulants but an increase for sedative (or depressant) drugs.     

One drug for epilepsy.

We performed prospective trials of phenytoin and carbamazepine, assisted by blood level monitoring, in untreated patients newly referred with grand mal or partial seizures, or both, to a neurological clinic. At the time of follow-up (mean 28.5 months for phenytoin; 12 months for carbamazepine) 76-88% of patients were completely controlled. Twelve per cent of the patients on each drug had further seizures, despite an optimum blood level. When the blood drug concentration was in the optimum range there was a 98% reduction in grand mal attack rate and 92-93% reduction in partial seizure rate. These results suggest that polypharmacy is largely, and possibly totally, unnecessary in newly diagnosed adult epileptics.     

The genetically epilepsy-prone rat: an overview of seizure-prone characteristics and responsiveness to anticonvulsant drugs

The Genetically Epilepsy-Prone Rat (GEPR) is rapidly gaining support as a model of epilepsy. In addition to a marked sensitivity to both sound-induced and hyperthermic seizures, GEPRs exhibit unusual sensitivity to a number of seizure-provoking modalities, including various forms of electrical and chemical stimulation. The existence of a moderate seizure colony (GEPR-3) and a severe seizure colony (GEPR-9) allows pathophysiological studies of seizure susceptibility and severity. The consistency of seizures within each colony allows for comparisons in seizure naive GEPRs and seizure experienced GEPRs. The consistent seizure responses of the GEPR are also ideal for the testing of anticonvulsant drugs. Further, the relative potencies of anticonvulsant drugs between the two colonies of GEPRs predict the clinical efficacies of traditional antiepileptic drugs and may be able to predict novel anticonvulsants.     

Increasing anticonvulsant effect of AD-810 (zonisamide) in aging BDF1 mice

The anticonvulsant efficacy of a newly developed anticonvulsant, AD-810 (zonisamide, 3-sulfamoylmethyl-1,2-benzisoxazole) was examined in relation to mouse age in three different age groups of female BDF1 mice (7-, 25- and 29-month-old). The minimal effective concentration (MEC) of AD-810 in both plasma and brain for abolishing the electroshock-induced maximal seizure steadily decreased with age, the 25- and 29-month values being 50 and 30% of respective 7-month values. The observation in the present study was almost identical to previous observations by the authors on phenytoin, phenobarbital and oxazepam. The present results support our previous contention that the dose and plasma concentration of anticonvulsants can (and probably should) be reduced in the elderly regardless of the drug. Since the anticonvulsant mechanism of AD-810 has been reported to differ from those of previously examined drugs (phenobarbital and oxazepam), the results also suggest that the apparent increase in the pharmacological effect of these anticonvulsants may be due to old animals' lowered response capability for seizures rather than a specific age effect on the pharmacological reaction sites for individual anticonvulsants.     

Pentylenetetrazole induced changes in cerebellar energy metabolism

Pentylenetetrazole was administered to Swiss-Albino mice, producing clonic-tonic seizures. Other groups were pretreated with one of the three anticonvulsants: phenytoin, clonazepam, or sodium valproate. Mice were sacrificed during the preseizure (1 minute) stage and at the onset of clonic-tonic seizures (2 minutes). Glucose, glycogen, ATP, and phosphocreatine were measured in layers of the parietal cortex and cerebellar vermis. Cortical metabolites were unchanged, or increased slightly, suggesting decreased utilization. In both cerebellar layers, glucose and glycogen were significantly decreased, and phosphocreatine was decreased in the molecular layer. These results indicate a regionally selective effect for pentylenetetrazole on cerebral energy metabolites. Pretreatment with anticonvulsants reduced the severity of the seizure, and eliminated the effect of pentylenetetrazole on glucose and glycogen.     

Effects of pregnancy on seizure threshold and the disposition and efficacy of antiepileptic drugs in the mouse

The effects of pregnancy on seizure excitability as well as antiepileptic drug disposition and efficacy were studied in the mouse during late gestation. Phenytoin and carbamazepine concentrations in brain were increased in pregnant animals, which was related to increased free concentrations in plasma. Little changes were observed for valproic acid and phenobarbital. The seizure threshold in untreated pregnant mice was significantly higher than in the nonpregnant group. The efficacy of carbamazepine and valproic acid in the pregnant animals was increased as compared to the control group; little changes were observed for phenobarbital and phenytoin. Our study indicates that - in contrast to the general clinical opinion - pregnancy has little influence or even a slight beneficial effect on the seizure propensity as well as the efficacy of antiepileptic drugs.     

Interaction of phenytoin and primidone.

The ratio of derived phenobarbitone to unmetabolized primidone in the serum was significantly higher in 50 epileptic patients on a combination of primidone and phenytoin than in 12 patients on primidone alone, though the dose and serum levels of primidone were similar in the two groups. Out of 253 patients attending a seizure clinic 47% were taking a combination of these two anticonvulsants. The effect of phenytoin on the metabolism of primidone may have clinical implications in view of the frequency of their combined use.     

Propranolol concentrations in plasma after insertion into the vagina.

Six healthy women participated in a study of the concentrations of propranolol achieved in plasma after insertion of the drug into the vagina. In four of the women the concentrations were also determined after administration by mouth. The area under the concentration curve for propranolol administered per vaginam was significantly greater than that after oral administration. There were small significant reduction in systolic blood pressure, pulse rate, and forced expiratory volume in one second after vaginal administration but these did not cause any symptomatic side effects. The tolerability of the vagina to drugs and the safety of this form of treatment remain to be determined. Probably further studies of the contraceptive effects of propranolol should be conducted with the dextro isomer of the drug.     

Anticonvulsant activity of 2,4(1H)-diarylimidazoles in mice and rats acute seizure models

2,4(1H)-Diarylimidazoles have been previously shown to inhibit hNa(V)1.2 sodium (Na) channel currents. Since many of the clinically used anticonvulsants are known to inhibit Na channels as an important mechanism of their action, these compounds were tested in two acute rodent seizure models for anticonvulsant activity (MES and scMet) and for sedative and ataxic side effects. Compounds exhibiting antiepileptic activity were further tested to establish a dose response curve (ED(50)). The experimental data identified four compounds with anticonvulsant activity in the MES acute seizure rodent model (compound 10, ED(50)=61.7mg/kg; compound 13, ED(50)=46.8mg/kg, compound 17, ED(50)=129.5mg/kg and compound 20, ED(50)=136.7mg/kg). Protective indexes (PI=TD(50)/ED(50)) ranged from 2.1 (compound 10) to greater than 3.6 (compounds 13, 17 and 20). All four compounds were shown to inhibit hNa(V)1.2 in a dose dependant manner. Even if a correlation between sodium channel inhibition and anticonvulsant activity was unclear, these studies identify four Na channel antagonists with anticonvulsant activity, providing evidence that these derivatives could be potential drug candidates for development as safe, new and effective antiepileptic drugs (AEDs).     

Human Brain γ-Aminobutyric Acid Levels and Seizure Control Following Initiation of Vigabatrin Therapy

Abstract: Vigabatrin is a novel antiepileptic drug designed to control seizures by raising brain γ-aminobutyric acid (GABA) concentrations. Seizure control is not improved significantly when the daily dose is increased beyond 50 mg/kg. Serial, in vivo measurements of GABA levels in human occipital lobe were made using ¹H NMR spectroscopy before and after the start of vigabatrin treatment. We used a 2.1-T magnetic resonance imagerspectrometer and an 8-cm surface coil to examine serially a 14-cm³ volume in the occipital lobe of 26 patients with complex partial seizures. Brain GABA content increased following the start of vigabatrin treatment up to a daily dose of 60 mg/kg. Additional increases in dose failed to increase brain GABA content further. GABA synthesis may decrease with sustained elevations of human brain GABA levels. Starting vigabatrin treatment reduced seizure frequency by >50%, from six to seven per month to three. Improved seizure control was not associated with further increases of vigabatrin dose. Increased brain GABA concentration was associated with improved seizure control. Starting vigabatrin treatment improved seizure control twofold when GABA levels increased above 1.8 mmol/kg. Further increases in brain GABA content above 2.5 mmol/kg provided less protection. Measuring occipital lobe GABA concentrations may predict improved seizure control when using antiepileptic drugs designed to increase brain GABA levels.     

Cyclosporin A as prophylaxis against graft-versus-host disease in 36 patients.

Oral cyclosporin A was used as prophylaxis against graft-versus-host disease in (a) 31 patients with acute leukaemia or aplastic anaemia given transplants of HLA-matched bone marrow and (b) five patients with inborn errors of metabolism given transplants of haplotype-identical (parental) bone marrow. Twenty-six patients survived longer than two months after the operation. Despite the cyclosporin A, 31 patients (86%) suffered an acute form of graft-versus-host disease and 22 (61%) a chronic form. Nevertheless, the disease was usually treatable with immunosuppressive agents and caused the death of only one patient. Cyclosporin A caused renal toxicity in all cases; occasionally this was associated with a "capillary leak" syndrome, fatal in two patients. In children hypertension, fits, and fluid retention were common side effects. Blood concentrations of cyclosporin A correlated with blood urea values and blood pressure but did not predict the occurrence of graft-versus-host disease. Four different dose schedules were used to find the optimum way to administer this drug. Oral cyclosporin A is extremely effective at reducing the severity of graft-versus-host disease, but prevention of the disease is limited by toxicity of the drug and variable absorption. Better results might be achieved with parenteral administration or by using the drug in combination with other methods.     

Treatment of Epilepsy

The main clinical types of epilepsy and their treatment are described. The treatment of choice in petit mal epilepsy is trimethadione (Trimedone) 0.3 g., three to six times a day, or acetazolamide (Diamox) 125-250 mg., three to four times a day. Phenobarbital is usually given as well to prevent grand mal seizures. Diphenylhydantoin sodium (Dilantin Sodium), 100 mg., and/or phenobarbital, 30-100 mg., three to four times a day, is recommended in patients with focal and grand mal epilepsy. Psychomotor automatisms are a form of focal seizure. Primidone (Mysoline), in doses of 125-250 mg. two to three times a day, is a very useful anticonvulsant in patients with myoclonic features, psychomotor automatisms and grand mal seizures. Primidone should be started in small doses. Drug reactions, especially cerebellar ataxia in the case of diphenylhydantoin and blood dyscrasias in the case of some drugs, should be recognized. Excessive drowsiness can be avoided by proper dosage and proper timing of drug administration. Patients should be seen regularly at least two to three times a year. The objective of treatment is to achieve optimum control of seizures by using the appropriate drug in adequate dosage. Social adaptation is good in the majority of patients, who should be encouraged to carry on their life independently, usually free to marry and have children. Attention to special occupational hazards has to be considered. Education of employers and employees is often necessary. Special work arrangements are occasionally indicated for selected patients. Patients should be seizure-free for two to three years before permission is given to drive an automobile.     

The Effects of Dextrothyroxine in Diabetes

Eighteen diabetic patients were treated with dextrothyroxine (from 2 mg to 8 mg daily) for varying periods up to six months. This produced a decided reduction of serum cholesterol levels. Statistically valid comparisons were made of their fasting blood sugar levels before and after two weeks of dextrothyroxine treatment. Administration of this drug was associated with a significant elevation of fasting blood sugar levels. Good diabetic control did not preclude this adverse effect.After more prolonged treatment with the drug, 8 of the 18 patients experienced progressive deterioration of their diabetic control, necessitating increased amounts of insulin or oral drugs. Despite close observation, one patient developed acidosis.When dextrothyroxine was discontinued, there was a significant drop in blood sugar levels in these patients. Two patients had hypoglycemic reaction.When the fasting blood sugar values of the 18 patients, studied while they were receiving significant doses of dextrothyroxine, are compared with a control series of blood sugar determinations obtained on these same patients before dextrothyroxine administration was begun, the diabetogenic effect of this drug is confirmed by the highly significant difference demonstrated.Four patients were given dextrothyroxine a second time, and again experienced deterioration of diabetic control.     

Ubiquitin Carboxy-Terminal Hydrolase L1 (UCH-L1) is increased in cerebrospinal fluid and plasma of patients after epileptic seizure

ABSTRACT: BACKGROUND: Clinical and experimental studies have demonstrated that seizures can cause molecular and cellular responses resulting in neuronal damage. At present, there are no valid tests for assessing organic damage to the brain associated with seizure. The aim of this study was to investigate cerebrospinal fluid (CSF) and plasma concentrations of Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a sensitive indicator of acute injury to brain neurons, in patients with tonic--clonic or partial secondarily generalized seizures due to various etiologies. METHODS: CSF and plasma concentrations of UCH-L1 were assessed in 52 patients within 48 hours after epileptic seizure and in 19 controls using ELISA assays. RESULTS: CSF obtained within 48 hours after seizure or status epilepticus (SE) presented significantly higher levels of UCH-L1 compared to controls (p = 0.008). Plasma UCH-L1 concentrations were negatively correlated with time to sample withdrawal. An analysis conducted using only the first 12 hours post-seizure revealed significant differences between concentrations of UCH-L1 in plasma and controls (p = 0.025). CSF and plasma concentrations were strongly correlated with age in patients with seizure, but not in control patients. Plasma UCH-L1 levels were also significantly higher in patients after recurrent seizures (n = 4) than in those after one or two seizures (p = 0.013 and p = 0.024, respectively). CONCLUSION: Our results suggest that determining levels of neuronal proteins may provide valuable information on the assessment of brain damage following seizure. These data might allow clinicians to make more accurate therapeutic decisions, to identify patients at risk of progression and, ultimately, to provide new opportunities for monitoring therapy and targeted therapeutic interventions.     

Metabolic Changes in Cerebral Cortex, Hippocampus, and Cerebellum During Sustained Bicuculline-Induced Seizures

Abstract— The objective of the present experiments was to study metabolic correlates to the localization of neuronal lesions during sustained seizures. To that end, status epilepticus was induced by i.v. administration of bicuculline in immobilized and artificially ventilated rats, since this model is known to cause neuronal cell damage in cerebral cortex and hippocampus but not in the cerebellum. After 20 or 120 min of continuous seizure activity, brain tissue was frozen in situ through the skull bone, and samples of cerebral cortex, hippocampus, and cerebellum were collected for analysis of glycolytic metabolites, phosphocreatine (PCr), ATP, ADP, AMP, and cyclic nucleotides. After 20 min of seizure activity, the two “vulnerable” structures (cerebral cortex and hippocampus) and the “resistant” one (cerebellum) showed similar changes in cerebral metabolic state, characterized by decreased tissue concentrations of PCr, ATP, and glycogen, and increased lactate concentrations and lactate/ pyruvate ratios. In all structures, though, the adenylate energy charge remained close to control. At the end of a 2-h period of status epilepticus, a clear deterioration of the energy state was observed in the cerebral cortex and the hippocampus, but not in the cerebellum. The reduction in adenylate energy charge in the cortex and hippocampus was associated with a seemingly paradoxical decrease in tissue lactate levels and with failure of glycogen resynthesis (cerebral cortex). Experiments with infusion of glucose during the second hour of a 2-h period of status epilepticus verified that the deterioration of tissue energy state was partly due to reduced substrate supply; however, even in animals with adequate tissue glucose concentrations, the energy charge of the two structures was significantly lowered. The cyclic nucleotides (cAMP and cGMP) behaved differently. Thus, whereas cAMP concentrations were either close to control (hippocampus and cerebellum) or moderately increased (cerebral cortex), the cGMP concentrations remained markedly elevated throughout the seizure period, the largest change being observed in the cerebellum. It is concluded that although the localization of neuronal damage and perturbation of cerebral energy state seem to correlate, the results cannot be taken as. evidence that cellular energy failure is the cause of the damage. Thus, it appears equally probable that the pathologically enhanced neuronal activity (and metabolic rate) underlies both the cell damage and the perturbed metabolic state. The observed changes in cyclic nucleotides do not appear to bear a causal relationship to the mechanisms of damage.     

Blood manganese levels in children with convulsive disorder

Manganese deficiency syndromes have been well described in animals and include among a wide variety of metabolic aberrations the heightened susceptibility to convulsions induced by electroshock or drugs. We have measured manganese blood levels in two populations of children: (1) a reference group of 120 ambulatory patients without neurologic disease, (2) 197 patients with convulsive disorder. Blood manganese was found to be age related in infants under 1 year of age. Highly significant was the lower mean blood manganese found in the convulsive disorder group as compared to the reference group. There was also a slight trend in the convulsive group for blood manganese to decrease from 1 to 22 years of age. No significant differences in manganese levels were found related to sex, type of seizure disorder, type of anticonvulsant drug therapy, or serum level of drug. Although this study does not demonstrate a causal relation between manganese and seizure disorder, and cannot be used as the basis for altering current approaches to therapy, it provides insight into the potentially important role of previously unrecognized factors in the pathophysiology of this syndrome.     

Tolerated drugs in subjects with severe cutaneous adverse reactions (SCARs) induced by anticonvulsants and review of the literature

Background

Anticonvulsant hypersensitivity syndrome represents a rare but potentially fatal kind of adverse drug reaction. This clinical picture often hampers the flexibility with which alternative anticonvulsants or even other classes of drugs are prescribed in these patients, negatively affecting the efficacy of treatment and the course of the disease. The aim of this study was to analyse a group of six patients with severe cutaneous drug reactions induced by anticonvulsants and to report which alternative antiepileptic drugs and which drugs of other classes were tolerated.

Case presentation

A total of six patients (2 males and 4 females, age 11–73 years) are described in this study. In all the patients the onset of the severe cutaneous drug reactions was 2–4 weeks after initiating the anticonvulsant therapy: 2 out of 6 patients presented with a drug reaction with eosinophilia and systemic symptoms under therapy with phenytoin; 2 out of 6 presented with Stevens–Johnson syndrome under therapy with lamotrigine; and 2 out of 6 presented with a toxic epidermal necrolysis, one of them under therapy with valproic acid, and the other one under therapy with lamotrigine. Alternative anticonvulsants tolerated after the reaction were: clonazepam, levetiracetam, diazepam, delorazepam and lormetazepam.

Conclusions

In our cases we observed that non aromatic anticonvulsants and benzodiazepines were well tolerated as alternative treatments in six patients with reactions to aromatic anticonvulsivants and that the risk of hypersensitivity reactions to other drug classes was not increased as compared to general population.

     

An indirect method for absorption rate estimation: Flurothyl-induced seizures

This paper develops a method to estimate a minimal amount of flurothyl necessary to induce the seizures (the seizure threshold). A simple mathematical model is proposed which permits one to determine the drug absorption rate from the amount which has been administered and from the measured latency to onset of seizure. Experimental animal (rats) were exposed to a continuous intake of flurothyl in two different situations: either being alone in the airtight chamber or sharing it in a pair. In the latter case, we assume that the two rats uniformly share the infused drug. Our calculations estimate that approximately 20 μl of flurothyl is necessary to induced twitches, whereas 25 μl of flurothyl is the dose required for the induction of clonic seizures. The model can be used to estimate the threshold amounts of any drug producing obvious behavioral changes irrespective of the route of administration.     

Pharmacokinetics and pharmacodynamics of hydroxychloroquine enantiomers in patients with rheumatoid arthritis receiving multiple doses of racemate

Hydroxychloroquine, a slow acting antirheumatic drug, is administered as the racemic mixture. Blood concentrations of the two enantiomers of hydroxychloroquine were measured in two studies, one study of eight patients, in whom blood and urine concentrations were measured during the first 6 months of therapy with rac-hydroxychloroquine, and one of 43 patients who had received rac-hydroxychloroquine therapy for at least 6 months. In the latter study rheumatoid disease activity was also measured. The pharmacokinetics of hydroxychloroquine were found to be enantioselective. The concentrations of (?)-(R)-hydroxychloroquine were higher than those of the (+)-(S)-antipode in all patients at all time points, although the ratios of the two enantiomers did display a two to three fold variability between patients. Both total and renal clearance were greater for the (+)-(S)-enantiomer. From the observational, cross-sectional study design used, it was not possible to differentiate concentration–effect relationships of the two enantiomers. The 11-fold range of drug concentrations swamped any effect of variability between patients in enantiomer proportions. Blood concentrations of both enantiomers were significantly higher in groups of patients with less active disease. © 1994 Wiley-Liss, Inc.