Effects of anticonvulsant drugs on substantia nigra pars reticulata neurons

Enhancement of gamma-aminobutyric acid transmission within the substantia nigra has been shown to prevent the motor manifestations of chemically induced and kindled seizures. These findings raise the possibility that the substantia nigra might constitute a site of anticonvulsant drug action if these drugs share an ability to suppress propagation of seizure activity from the nigra to motor effector sites. The current studies monitored effects of a diverse group of anticonvulsant drugs on the extracellular, single unit activity of nondopaminergic neurons of the substantia nigra pars reticulata in awake, paralyzed and locally anesthetized male rats. Intravenous phenytoin (1.25-160 mg/kg) and carbamazepine (1.25-40 mg/kg) did not alter neuronal firing at any dose. Conversely, both diazepam (31.25-8,000 micrograms/kg) and clonazepam (2-500 micrograms/kg) partially inhibited firing (to 46 +/- 11% and 59 +/- 6% of base-line rates, respectively), although clonazepam was approximately 16 times more potent in eliciting equivalent degrees of inhibition. Valproic acid (5-640 mg/kg) and phenobarbital (1.25-80 mg/kg) also slowed firing to 65 to 70% of base-line rates, but did so only at the highest doses administered. However, the anesthetic barbiturate pentobarbital (0.3125-80 mg/kg) completely suppressed firing by the highest dose tested. Of those drugs used exclusively for treatment of absence seizures, trimethadione (12.5-800 mg/kg) caused dose-related inhibitions to 37.6 +/- 9.8% of base-line, whereas ethosuximide (12.5-800 mg/kg) markedly stimulated firing, nearly doubling firing rates after the 200 mg/kg dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulation of the behavioral effects of anticonvulsant drugs by an external discriminative stimulus in the pigeon

The effects of the anticonvulsant drugs valproic acid, phenytoin, phenobarbital and diazepam were examined in pigeons performing under a fixed-consecutive-number schedule with and without an added external discriminative stimulus. Under these schedules, a reinforced response run consisted of responding between eight and 12 times on one response key (work key) and then responding once on a second response key (reinforced key). For one group of pigeons, an external discriminative stimulus signaled completion of the response requirement on the work key, whereas no stimulus change was programmed for the other group. Phenobarbital (5-60 mg/kg) and diazepam (0.5-6 mg/kg) produced large decreases in reinforced response runs (accuracy) and rates of responding. The magnitude of these accuracy- and rate-decreasing effects was larger in the group without the external discriminative stimulus. Under both schedules, these drugs produced pronounced increases in the probability of switching to the reinforcement key before completion of the minimal response requirement on the work key. Valproic acid (20-160 mg/kg) and phenytoin (1.25-10 mg/kg) also decreased both accuracy and rates of responding. Although the accuracy-decreasing effects of these drugs were relatively small in magnitude, they were consistently larger in the group without the external discriminative stimulus. These data suggest that the addition of an external discriminative stimulus attenuates the disruptive behavioral effects of anticonvulsant drugs.     

Clearance of phenytoin and valproic acid is affected by a small body weight reduction in an epileptic obese patient: a case study

The interaction between clearance of phenytoin, valproic acid, phenobarbital and carbamazepine, and changes in body weight was determined in a 19-year-old obese woman with epilepsy (body weight 93 kg, BMI 36.3 kg/m²). The patient, who was given daily oral doses of 100 mg phenobarbital, 350 mg phenytoin, 800 mg valproic acid and 800 mg carbamazepine over 5 months was hospitalized for obesity treatment. The daily dosage of each drug was held constant during treatment of the obesity. Blood samples were taken five times. Weight reduction was 7 kg (7.5%) over 46 days. Estimation of the pharmacokinetic parameters in each drug was performed by Higuchi's Bayesian program, PEDA Pearson's correlation coefficient ( r ) between clearance and body weight was calculated for each drug. High positive correlations were found between clearance and body weight for phenytoin ( r = 0.800) and valproic acid ( r = 0.785), but not for phenobarbital ( r = - 0.227) and carbamazepine ( r = 0.152). Clearance of phenytoin and valproic acid may be potentially affected by small changes in body weight.     

Genetic differences in anticonvulsant sensitivity in mouse lines selectively bred for ethanol withdrawal severity

WSP (withdrawal seizure-prone) mice exhibit approximately 10-fold more severe withdrawal convulsions than WSR (withdrawal seizure-resistant) mice after identical chronic ethanol exposure. Although WSP and WSR mice do not differ in threshold for seizures elicited by electroconvulsive shock (ECS), WSR mice are more sensitive to ethanol-induced elevation of ECS seizure thresholds. The current experiments demonstrated that WSR mice showed more ECS-induced seizure threshold elevation than WSP mice when tested after the administration of C1-C5 straight-chain alcohols. Whereas the brain concentrations of the C1 and C2 alcohols did not differ between the lines, WSP mice tended to have higher brain concentrations than WSR mice of the C3-C5 alcohols, even though they exhibited the smaller behavioral response in all cases. Thus, the difference between WSP and WSR mice was one of neurosensitivity and could not be attributed to pharmacokinetic differences. The WSR line was also more sensitive to ethchlorvynol, methyprylon, barbital, phenobarbital, pentobarbital, diazepam, valproic acid and phenytoin in this test. Examining loss of righting reflex (RR), we found that WSP and WSR mice did not differ in ED50, latency to lose RR or duration of loss of RR. Thus, the genetic anticonvulsant sensitivity difference is not simply a genetic difference in sensitivity to central nervous system depression between the lines. In summary, WSR mice were more sensitive to the anticonvulsant effects of a variety of compounds than WSP mice, suggesting that some genes influence both ethanol withdrawal seizures and ethanol's anticonvulsant effects.     

Antikonvulsiva beim Nervenschmerz

The anticonvulsants, carbamazepine, clonazepam, phenytoin, and valproic acid are capable of depressing attacks of shooting pain in neuralgia. Shooting pain is perceived in trigeminal, intercostal, and other neuralgias, as a consequence of infectious diseases such as herpes zoster, and in the course of polyneuropathies of various causes. It is due to injury of nociceptive afferents, which generate bursts of activity in response to appropriate environmental changes. The anticonvulsant agents have no analgesic property per se, so that background pain remains unchanged. The depression of shooting pain results from the anticonvulsant action of the compounds. Both carbamazepine and phenytoin block synaptic transmission of neuronal hyperactivity by a direct depressant action that includes reduction of sodium conductance and by activation of inhibitory control. Clonazepam and valproic acid act by enhancing GABA-mediated inhibition of synaptic transmission. Carbamazepine is by far the most widely used compound; phenytoin, clonazepam, and valproic acid are not so popular because of their side effects.     

Kinetics of drug action in disease states. XVI. Pharmacodynamics of theophylline-induced seizures in rats

Seizures, often with fatal outcome, are a manifestation of pronounced theophylline intoxication. The purpose of this investigation was to characterize the relationship between theophylline concentrations and theophylline-induced convulsions and to develop an animal model suitable for exploring conditions that might predispose theophylline-treated individuals to seizures. Female Lewis rats (approximately 170 g) received an i.v. infusion of theophylline (as aminophylline) at one of three different rates (1.03-5.1 mg/min/rat) until the animals exhibited a maximal seizure (which occurred after 11 +/- 1 to 42 +/- 3 min of infusion). The total dose, the serum concentration (both total and unbound drug) and the brain concentration of theophylline at onset of seizures increased with increasing infusion rate. The theophylline concentration in cerebrospinal fluid at onset of seizures (mean +/- S.D., 232 +/- 17 mg/l, n = 41) was not affected by the infusion rate. The theophylline metabolites 1-methyluric acid and 1,3-dimethyluric acid were found in serum but at very much lower concentrations than those of theophylline. 1-Methylxanthine and caffeine were not detected in any serum sample, 3-methylxanthine was present in low concentrations in only some serum samples and 1-methyluric acid and 3-methylxanthine were found in the brain in low concentrations (less than 10 mg/kg). Theophylline metabolites were not detected in cerebrospinal fluid. Direct i.v. infusion of either 1-methyluric acid, 1,3-dimethyluric acid or 3-methylxanthine did not produce seizures despite high concentrations in serum. Ethylenediamine infusions also did not cause seizures.(ABSTRACT TRUNCATED AT 250 WORDS)     

Massive theophylline dosing in a heavy smoker receiving both phenytoin and phenobarbital.

OBJECTIVE: To report unusually high theophylline dosing requirements in a smoker receiving concomitant therapy with phenytoin and phenobarbital. DESIGN: Single case report. SETTING: 517-bed, university teaching hospital. PATIENT: 29-year-old woman with newly diagnosed asthma, heavy smoking history, and a seizure disorder. RESULTS: The additive influence of smoking, phenytoin, and phenobarbital greatly increased the theophylline dosing requirements. Doses of up to 4 g/d (59 mg/kg/d) were required to achieve adequate symptomatic relief of her asthma as well as to provide therapeutic serum theophylline concentrations. CONCLUSIONS: Multiple polymorphisms may additively influence theophylline metabolism and exceptionally large theophylline doses may be required in some patients who smoke and are comedicated with phenytoin and phenobarbital.     

Effects of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3.2-e]-1,3-thiazin-4-one (YM928), an orally active alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, in models of generalized epileptic seizure in mice and rats

The anticonvulsant activity of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3.2-e]-1,3-thiazin-4-one (YM928), a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, was studied in animal models of generalized seizure. YM928 exerted significant anticonvulsant effects in the maximal electroshock (MES) seizure test (ED50 = 7.4 mg/kg p.o.), pentylenetetrazol (PTZ)-induced seizure test (ED50 = 9.6 mg/kg p.o.), AMPA-induced seizure test (ED50 = 5.5 mg/kg p.o.), and strychnine-induced seizure test (ED50 = 14.0 mg/kg p.o.) in mice. Effects in rats were detected in the MES seizure test (ED50 = 4.0 mg/kg p.o.) and PTZ-induced seizure test (ED50 = 6.2 mg/kg p.o.). The profile of YM928 was compared with that of established antiepileptics. Valproate showed beneficial effects in all tests used. In contrast, carbamazepine, phenytoin, lamotrigine, phenobarbital, diazepam, ethosuximide, and gabapentin were not active against seizures induced by at least one stimulant. In the rotarod test, YM928 impaired motor coordination (TD50 = 22.5 mg/kg p.o.). The protective index (TD50 value of the rotarod test/ED50 value of MES seizure) was 3.0, suggesting that YM928 can exert antiepileptic effects with only minor motor disturbances. YM928 at doses of 2, 4, and 8 mg/kg p.o. did not significantly affect the threshold of electroshock seizure in rats after 16 days of repeated administration. These data indicate that YM928 does not induce tolerance after subchronic administration. These results indicate that YM928 is a broad-spectrum anticonvulsant that would prove useful for the treatment of generalized seizure in human epileptic patients.     

Kinetics of drug action in disease states. XVIII. Effect of experimental renal failure on the pharmacodynamics of theophylline-induced seizures in rats

Theophylline, the bronchodilating agent, can cause life-threatening, generalized seizures when plasma concentrations exceed the usual therapeutic concentration range. However, the plasma concentrations of theophylline associated with this neurotoxic effect vary widely between patients. To determine the reasons for the wide variation, and thereby to facilitate prevention or early treatment of theophylline-induced neurotoxicity, an animal model of theophylline-induced seizures was developed and has now been used to determine the effect of experimental renal failure on the concentrations of theophylline that cause convulsions. Adult female rats were subjected to bilateral ureteral ligation or injected with uranyl nitrate to produce renal failure or dysfunction. Sham-operated and saline-injected rats, respectively, served as controls. Theophylline was infused i.v. at either 1.03 or 2.06 mg/min until the onset of maximal seizures. Renal failure due to ureter ligation was associated with a substantial reduction of the dose of drug required to produce seizures, the concentrations of total and free (unbound) theophylline in serum and the concentrations of theophylline in the brain and cerebrospinal fluid at onset of seizures. The concentrations of theophylline metabolites were very low and did not account for the enhanced neurotoxicity. No apparent change in the neurotoxicity of theophylline was observed in rats with uranyl nitrate-induced renal dysfunction. The results of the investigation on ureter-ligated rats are consistent with recent clinical findings of a higher incidence of theophylline-induced neurotoxicity in azotemic patients. The experimental methodology may therefore be suitable for the prospective identification of other potential clinical risk factors for theophylline neurotoxicity.     

Pharmacoepidemiologic investigation of a clonazepam-valproic acid interaction by mixed effect modeling using routine clinical pharmacokinetic data in Japanese patients

Non-linear Mixed Effects Modeling (NONMEM) was used to estimate the effects of clonazepam-valproic acid interaction on clearance values using 576 serum levels collected from 317 pediatric and adult epileptic patients (age range, 0.3-32.6 years) during their clinical routine care. Patients received the administration of clonazepam and/or valproic acid. The final model describing clonazepam clearance was CL = 144.0 TBW-0.172 1.14VPA, where CL is total body clearance (mL/kg/h); TBW is total body weight (kg); VPA = 1 for concomitant administration of valproic acid and VPA = zero otherwise. The final model describing valproic acid clearance was CL (mL/kg/h) = 17.2 TBW-0.264 DOSE0.159 0.821CZP 0.896GEN, where DOSE is the daily dose of valproic acid (mg/kg/day); CZP = 1 for concomitant administration of clonazepam and CZP = zero otherwise; GEN = 1 for female and GEN = zero otherwise. Concomitant administration of clonazepam and valproic acid resulted in a 14% increase in clonazepam clearance, and a 17.9% decrease in valproic acid clearance.     

Anticonvulsant and adverse effects of avermectin analogs in mice are mediated through the gamma-aminobutyric acid(A) receptor

Twenty-five avermectin analogs were assessed in a mouse seizure model. The ED(50) against pentylenetetrazole-induced tonic seizures ranged from 0.48 mg/kg (L-676,893) to >160 mg/kg (L-685,869) cf. 0. 26 mg/kg for diazepam. Although avermectins are without acute toxic effects, they have been historically shown to have relative low LD(50) values in mammals. The mechanisms involved in the anticonvulsant effect and the toxicity were investigated. A series of avermectin analogs displaced [(3)H]ivermectin binding to rat brain membranes and recombinant GABA(A) receptors (alpha1beta3gamma2-subtype) with the same affinities, strongly suggesting that [(3)H]ivermectin labels the GABA(A) receptor in rodent brain. Avermectins, which were anticonvulsant, were also potent inhibitors of [(3)H]ivermectin binding in rat brain. However, the rank order for anticonvulsant activity did not parallel the rank order for affinity at the [(3)H]ivermectin site and it was reasoned that avermectins may have differential affinity or efficacy at subtypes of the GABA(A) receptor. All the active compounds tested potentiated the effects of GABA at recombinant GABA(A) receptors in oocytes and at native cortical GABA(A) receptors and the efficacy of avermectins at the GABA(A) receptor correlated best with their anticonvulsant potency. Although avermectins weakly inhibited [(3)H]strychnine binding in rat spinal cord, and inhibited glycine responses on primary cultured cortical neurons, activity at glycine receptors did not correlate with either anticonvulsant activity or toxicity. Because both anticonvulsant activity and toxicity correlated best with activity at GABA(A) receptors, it is unlikely that these effects can be separated, which may contraindicate the potential use of avermectins as anticonvulsants.     

Effects of phenytoin and phenobarbital on schedule-controlled responding and seizure activity in the amygdala-kindled rat

The purpose of the present study was to examine whether doses of phenytoin and phenobarbital that blocked kindled seizures in rats also disrupted operant behavior. Subjects initially were exposed to a kindling procedure in which repeated electrical stimulation of the amygdala evoked generalized seizures. After kindling, they were trained under a multiple fixed-ratio 30 interresponse-time-greater than 10-sec schedule of food delivery. Once each day, 6 days per week, 30-min exposures to this schedule were followed immediately by amygdaloid stimulation which occurred at no other time. Response rate, reinforcement rate and duration of forelimb clonus were recorded. When response rates were stable, 5 rats were tested with phenytoin (25, 50, 75 and 100 mg/kg) and 5 others were tested with phenobarbital (10, 25 and 40 mg/kg). Results indicated that doses of phenytoin that controlled kindled seizures also affected operant behavior. For this drug, the ED50 for forelimb clonus was 62 mg/kg. For response rate under the fixed-ratio and interresponse-time components, it was 48 and 58.2 mg/kg, respectively. Dose-response curves for the behavioral and antiseizure effects of phenobarbital were similar. However, for this drug the ED50 for forelimb clonus (18.9 mg/kg) was significantly lower than for response rate under the fixed ratio component (37.4 mg/kg).     

Status epilepticus

Convulsive status epilepticus is a life-threatening disorder. Every emergency room that treats patients with this problem should have a treatment protocol prepared in advance to allow for prompt and appropriate therapy. The recommended treatment is an intravenous infusion of 20 mg/kg of phenytoin. Lorazepam or diazepam may be used to stop a convulsion in progress. If seizures persist, the second step may be an intravenous infusion of phenobarbital. If convulsions persist beyond the first hour and have not responded to the above, a barbiturate coma should be induced.     

Anti-convulsant therapy

Treatment for seizures during acute encephalopathy and encephalitis is not so different from those for seizures due to other etiologies. However, it is sometimes accompanied with intensive care and we also have to pay attention to consciousness disturbance, because it is difficult to determine whether consciousness disturbance is caused by encephalopathy itself, or effect of anticonvulsant therapy, especially in early stage of acute encephalopathy. In Japanese guideline of treatment for influenza encephalopathy, an intravenous administration of diazepam or midazolam as first-line agent, phenobarbital or phenytoin as second-line agent, and midazolam (continuous) or thiopental as third-line agent, were recommended for therapy for status epilepticus.     

Pharmacokinetic modeling of the anticonvulsant action of phenobarbital in rats

The aim of this study was to develop a model for the relationship between concentration and anticonvulsant effect of phenobarbital in the rat. The method of quantitating the anticonvulsant response on the basis of plasma pentylenetetrazol threshold concentrations, was optimized by application of a longitudinal study design. The pharmacokinetics of phenobarbital were studied in a separate set of rats (elimination half-life 11 +/- 2 hr). The anticonvulsant effect was measured 1 hr after i.v. administration. Concentration-effect relationships were assessed for serum (total and free), cerebrospinal fluid and brain concentrations on the basis of the sigmoid maximum effect model. The EC50 for total serum was 76 +/- 9 mg/l and for free serum, cerebrospinal fluid and brain 44 +/- 5, 43 +/- 7 and 50 +/- 8 mg/l and mg/kg, respectively (means +/- S.E.). The maximum effect was about 120 mg/l of pentylenetrazol. The respective EC50 ratios corresponded closely with the concentration ratios between the different compartments as determined by orthogonal regression analysis. For the greater part of the concentration range the concentration-effect relationship also could be fitted accurately to a simple linear model. Such relationships were not perturbed by the occurrence of seizures as these did not alter the distribution profile of phenobarbital. The pharmacokinetics and pharmacodynamics of p-hydroxyphenobarbital, the main metabolite of phenobarbital, also were investigated. This compound is eliminated very rapidly and has neither anticonvulsant activity of its own nor influences the anticonvulsant effect of phenobarbital at serum concentrations up to 30 mg/l. The described experimental strategies allow the study of factors influencing the concentration-anticonvulsant effect relationship of phenobarbital.     

Anticonvulsant drugs effective against human temporal lobe epilepsy prevent seizures but not neurotoxicity induced in rats by quinolinic acid: electroencephalographic, behavioral and histological assessments

Intrahippocampal injection of quinolinic acid (QUIN) in rats caused an epileptic-like syndrome reminiscent of human temporal lobe epilepsy. By electroencephalographic (EEG) analysis, the authors assessed whether QUIN seizures were responsive to anticonvulsants effective in the treatment of the human disease. Anticonvulsants used in clinical practice to control partial seizures, such as carbamazepine, diphenylhydantoin, sodium phenobarbital, sodium valproate and diazepam, prevented QUIN-induced EEG seizures, whereas ethosuximide, which is specifically used to control absence attacks, and chlorpromazine, a sedative with no anticonvulsant properties, were ineffective. QUIN seizures showed particular sensitivity to carbamazepine (5 mg/kg) but were resistant to diphenylhydantoin unless a relatively high dose was used (100 mg/kg). None of the effective anticonvulsants completely suppressed EEG paroxysmal events like spikes and fast activity. Animals injected with QUIN displayed chewing, sniffing and rearing; no clear correlation was found between the ability of drugs to prevent QUIN-induced EEG seizures and effects on stereotypies, suggesting that these behavioral signs are not sensitive measures of anticonvulsant activity in this model. The anticonvulsants that protected animals from QUIN seizures did not prevent nerve cell degeneration induced by the excitotoxin, thus indicating that nerve cell death can occur even in the absence of sustained seizure activity. The data show that, in this animal model of epilepsy, the EEG seizure activity is specifically sensitive to anticonvulsants effective in partial epilepsy, thus suggesting that it could be used to test potential new drugs for this human disorder.     

Long-term use of the major anticonvulsant drugs.

The specific type of epilepsy must be identified. The history and the EEG provide the evidence. Drug selection is then based on the classification of the patient's epilepsy. Major drugs used in the management of epilepsy are phenytoin, phenobarbital, primidone, carbamazepine, ethosuximide and valproic acid. The physician should know their kinetics, interactions and side effects, and the value of monitoring blood levels of these anticonvulsant agents.     

Seizure prophylaxis in patients with brain tumors: a meta-analysis

OBJECTIVE: To assess whether antiepileptic drugs (AEDs) should be prescribed to patients with brain tumors who have no history of seizures. METHODS: We performed a meta-analysis of randomized controlled trials (1966-2004) that evaluated the efficacy of AED prophylaxis vs no treatment or placebo to prevent seizures in patients with brain tumors who had no history of epilepsy. Summary odds ratios (ORs) were calculated using a random-effects model. Three subanalyses were performed to assess pooled ORs of seizures in patients with primary glial tumors, cerebral metastases, and meningiomas. RESULTS: Of 474 articles found in the initial search, 17 were identified as primary studies. Five trials met inclusion criteria: patients with a neoplasm (primary glial tumors, cerebral metastases, and meningiomas) but no history of epilepsy who were randomized to either an AED or placebo. The 3 AEDs studied were phenobarbital, phenytoin, and valproic acid. Of the 5 trials, 4 showed no statistical benefit of seizure prophylaxis with an AED. Meta-analysis confirmed the lack of AED benefit at 1 week (OR, 0.91; 95% confidence interval [CI], 0.45-1.83) and at 6 months (OR, 1.01; 95% CI, 0.51-1.98) of follow-up. The AEDs had no effect on seizure prevention for specific tumor pathology, including primary glial tumors (OR, 3.46; 95% CI, 0.32-37.47), cerebral metastases (OR, 2.50; 95% CI, 0.25-24.72), and meningiomas (OR, 0.62; 95% CI, 0.10-3.85). CONCLUSIONS: No evidence supports AED prophylaxis with phenobarbital, phenytoin, or valproic acid in patients with brain tumors and no history of seizures, regardless of neoplastic type. Subspecialists who treat patients with brain tumors need more education on this issue. Future randomized controlled trials should address whether any of the newer AEDs are useful for seizure prophylaxis.     

Chlormethiazole: effectiveness against toxic effects of cocaine in mice

Chlormethiazole positively modulates the gamma-aminobutyric acid (GABA)(A) receptor complex and is primarily used to treat certain life-threatening neurological events (e.g., refractory seizures and ethanol withdrawal syndrome). On account of several experimental and clinical studies reporting effectiveness against the toxic effects of heroin and methamphetamine, chlormethiazole was systematically tested in the present study for its effectiveness against cocaine-induced seizures and lethality in mice. The protective effects of chlormethiazole were evaluated against single, submaximal convulsive (75 mg/kg) or lethal (110 mg/kg) doses of cocaine. Chlormethiazole also was tested against the expression (anticonvulsant effect) and development (antiepileptogenic effect) of cocaine-kindled seizures, and against fully developed kindled seizures. Cocaine-kindled seizures were produced by a total of five daily treatments with 60 mg/kg cocaine. The inverted-screen test was used to assess behavioral side effects of chlormethiazole. Chlormethiazole protected against acute cocaine-induced convulsions (ED(50) = 7.0 mg/kg) and lethality (ED(50)= 21.8 mg/kg) with a robust separation [protective index (PI) = TD(50)/ED(50) = 22.3 and 7.2, respectively] from doses producing behavioral side effects (TD(50) = 156 mg/kg). Chlormethiazole suppressed the behavioral expression of cocaine-kindled seizures and prevented the development of sensitization to the convulsant effects of cocaine. It was also effective in suppressing fully developed kindled seizures. Relative to cocaine seizures in naive mice, chlormethiazole was equieffective, less potent (ED(50) = 22.3 mg/kg), and had a reduced protective index (PI = 3.7) against cocaine-induced seizures in kindled mice. The protective profile and protective index of chlormethiazole were superior to those of the benzodiazepines clonazepam and diazepam, which were of limited efficacy and had low protective indices (PI = approximately 1). The results of this study predict the potential utility of chlormethiazole for the treatment of life-threatening complications of cocaine abuse for which no specific treatment has yet been identified.     

Phenytoin antagonism of electrically induced maximal seizures in frogs and mice and effects on central nervous system levels of adenosine 3',5'-monophosphate and guanosine 3',5'-monophosphate

Phenytoin antagonized the electroshock-induced increase in levels of cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) in cerebrum and cerebellum, respectively, from CF-1 mice. However, the effective dose range of phenytoin for significant reduction of the elevated levels of cAMP and cGMP was 2 to 5 times higher than that for prevention of tonic hindlimb extension in 95% of mice. The effective dose range of phenytoin for alteration of cyclic nucleotide levels was nearer to that for preventing tonic flexion and clonus; endpoints which are less relevant to anticonvulsant efficacy than is prevention of tonic hindlimb extension. Also , the greatest reduction in cyclic nucleotide levels occurred at a dose (100 mg/kg) which produced toxic signs in mice. Quaking mice (qk/qk), a mutant strain which exhibits spontaneous seizures, did not have abnormal levels of cAMP or cGMP in cerebrum or cerebellum, and a dose of phenytoin (15 mg/kg) which abolished all seizure activity did not alter levels of these cyclic nucleotides. In frogs, the electroshock-associated increase in levels of cAMP in the central nervous system was not altered by phenytoin even when the doses administered were up to twice the ED95 for prevention of tonic hindlimb extension. Because these data from mice and frogs show that the anticonvulsant effect of phenytoin is dissociated, by dose, from effects on central nervous system cyclic nucleotide levels, it is doubtful that the alteration of cyclic nucleotide levels is a mechanism by which phenytoin exerts its anticonvulsant effect