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Mice were injected with intracerebroventricular (i.c.v.) kainic acid (KA; 0.1 micrograms per animal) and the pentetrazol test was carried out on the fifth day after the administration of the amino acid. The following antiepileptic drugs were tested for anticonvulsant activity in mice lesioned with KA: diazepam (0.4 mg/kg), phenobarbital (12.5 and 25 mg/kg), trimethadione (200 and 400 mg/kg), depakine (200 and 400 mg/kg), carbamazepine (10 and 20 mg/kg), lefadol (bromophenylsuccinimide; 20 mg/kg), and acetazolamide (320 mg/kg). All drugs were given intraperitoneally, except for carbamazepine, which was also given orally in doses of 100 and 200 mg/kg. Pentetrazol was administered subcutaneously in a dose of 110 mg/kg, and the animals were subsequently observed for the occurrence of clonic and tonic convulsions within 30 min. The protective effects of diazepam and phenobarbital were significantly reduced in the KA-lesioned animals, while the actions of the remaining anticonvulsants were unaltered. Moreover, a substantial loss of pyramidal cells in the CA 3 field of the hippocampus was noted after i.c.v. injection of KA. It may therefore be concluded that the mechanism of the action of diazepam and phenobarbital are partially dependent on the intact functions of the hippocampal formation.

Permanent freedom from fits can be achieved in a large proportion of children with a history of epilepsy through precise individual adjustment and careful maintenance of the therapeutic regimen. A review of the cases treated at the Pediatric Clinic, out-Patient-Department for Epileptics, University of Vienna, reveals that at present about 70% of the patients have a good prognosis (the figures vary from 50 to 85%, depending on the seizure type). An important question which has received only scant attention in the literature arises in the case of patients who have remained free from epileptic fits over a period of many years, namely whether longterm antiepileptic therapy can be terminated and, if so, then when and how. Only very few studies deal specifically with this problem and even these do not provide entirely satisfactory answers to all the posed questions, not only with regard to the optimum time and mode of drug reduction, but also with regard to the principles underlying the choice of apparently suitable candidates for attempted termination of therapy. An attempt is made in this retrospective study comprising 375 patients who have been followed up over a period of at least 5 years, to throw some light on these problems. Indeed, results of statistical significance were obtained by the use of a new mathematical technique, which enables the formulation of new guiding principles in the resolution of all three above-mentioned questions. In consequence, it now appears within the power of the pediatrician to markedly reduce the risk of relapse, which in the case of childhood epilepsies, is about 20%, at present. In general, several basic principles must be adhered to. Total freedom from convulsions over an uninterrupted period of at least 3 years' duration is an absolute prerequisite for consideration of cessation of therapy. Reduction in antiepileptic drug dosage should be carried out as a stepwise procedure over a period of about 2 years. Regular clinical and EEG follow-up examinations should be performed over this period of drug reduction and for 5 years subsequently, in order to recognise and counteract promptly any early signs of possible relapse. The prerequisite convulsionfree period is raised to 4 to 5 years or even longer and the time over which therapy is tailed off increased accordingly in the presence of any of the following criteria: 1. "Endogenous" tendency to relapse, 2. persistence of paroxysmal EEG abnormalities or deterioration of the EEG during the attempt to reduce the dosage of antiepileptic drugs, 3. inveterate epilepsy. The cessation of fits and the termination of medication do not yet signify that all the after-effects of epilepsy are overcome. Social integration must also be achieved before this goal is reached. The psychopathological symptomatology of the patient plays an important role in determining the outcome, whereby the level of intelligence of the patient is the decisive factor...

On the basis of a study of 156 patients the authors with the aid of a computer convened a dispersion analysis of interaction found in the process of treatment by conditional optimal doses of trimetin and succilep with 23 clinical parameters of the disease. It was established that on a statistically significant level the largest dose of trimetin (per 1 kg of body weight) was required in the treatment of myoclonic forms of seizures, with duration less that one year, pathological changes in the craniogram, signs of hypertension and the absence of prenatal noxious factors and pathology in the neurological state. The interaction of optimal doses of succilep with the cliniel characteristics is less expressed than for Trimetin and on a significant level is detected only for two of them: a larger dosage in longer duration of the disease and in the existence of prenatal noxious factors in the past history. It was established that with years the used amount of trimetin adn saccilep (per 1 kg of body weight) declines, while the therapeutical effectiveness does not drop.

The causes of hypercalciuria and simple diagnostic criteria for the various forms of hypercalciuria are outlined. Indications, effectiveness, limitations, and side effects of cellulose phosphate are described. Emphasis is placed on the biochemical pathogenesis and classification of hyperoxaluria. The problems of measuring and controlling oxalate excretion in patients with hyperoxaluria and calcium oxalate stones are discussed. Succinimide offers a partly successful approach to the reduction of endogenous oxalate synthesis.

Dietary and drug treatments of calcium nephrolithiasis depend mainly on the mineral composition of renal stones: calcium oxalate, phosphate or mixed stones. The association with an hypercalciuria is an important factor which must be taken into account because oxalates and phosphates precipitate as calcium crystals in case of urinnary oversaturation. Despite many therapies have been proposed, their efficiency seems to be rather small when they are used alone. Usually, it is necessary to act on several factors with a combination of therapeutic methods. Absorptive hypercalciuria are improved with both low calcium diets and inhibitors of calcium absorption. In renal hypercalciuria, the treatment is based on the administration of thiazide diuretics which enhance calcium renal tubular reabsorption. The other therapeutic methods depend on the nature of renal stones: urinary acidification for calcium phosphate; administration of succinimide, oral phosphate or organic phosphonates for calcium oxalate stones; association with purine biosynthesis inhibitors in case of the presence of urates in renal calculi.

Cholinergic deficiency is the most consistent transmitter system abnormality in Alzheimer's disease. To test the acute therapeutic efficacy of cholinergic replacement, seven patients with presenile onset of Alzheimer's type dementia received maximum tolerated doses (10 mg/d) of the selective muscarinic agonist, RS-86, in combination with a peripherally active anticholinergic glycopyrrolate (6 mg/d), in a double-blind placebo-controlled design. No consistent, clinically significant cognitive improvement could be discerned in these mild to moderately demented patients, despite attainment of central RS-86 levels approximating those that affect behavior in the experimental animal. Muscarinic agonist monotherapy may thus be inadequate to benefit Alzheimer's type dementia.

The muscarinic agonist RS 86 was administered to patients with Alzheimer's disease (AD) and senile dementia of the Alzheimer type (SDAT) in a series of controlled clinical trials. Daily doses were up to 3.0 mg orally for a maximum duration of 18 weeks. RS 86 produced typical peripheral cholinergic effects, but appeared to be better tolerated than similar drugs, such as physostigmine and arecoline. Positive clinical changes with regard to cognitive functions, mood, and social behavior were seen in a minority of AD and SDAT patients. Psychometric tests suggested improvement of functions entailing a speed component. RS 86 is a suitable drug for further clinical experiments in AD and SDAT.

Epileptic paroxystic headache consists of an episode of pain that starts suddenly, in a varying area that is usually the same for the same patient, of medium to high intensity, lasting from a few seconds to minutes and, rarely, hours; the episode subsides spontaneously and tends to recur. This was found in 32 of 125 patients studied by the author. Average age of onset was 11 years, with 80% of cases presenting it in the first or second decade of life. Once diagnosed, the condition was present a maximum of 41 years and a minimum of one month, with an average of six years. Headache lasted from 30 seconds to 4 hours; in 62% of cases it was 15 minutes or less. Pain was severe in 24 patients and moderate in 8. Epileptic paroxystic headache can be the only epileptic symptom (31%) or be associated with other ictal manifestations, independently (56.2%) or simultaneously (12.5%). EEG studies showed focalization in temporal lobe (56%), in the midbrain (12.5%) or in other areas. Treatment with hydantoine, primidone and methylsuccimide gave excellent results. Differential diagnosis with other paroxystic headaches is noted.

Some common conservative treating methods of urolithiasis are critically discussed. Based on physico-chemical relationships of solubility and cristallisation of stone-forming compounds our own methods of conservative treatment of urolithiasis is presented.

Interictal spikes with a configuration similar to that occurring in grand mal epilepsy were generated by the application of penicillin to a hippocampal slice preparation. This slice preparation has potential value for screening anticonvulsant drugs and for studying epileptic activity. The effect of anticonvulsant drugs on seizure activity was tested at concentrations comparable to reported clinical serum concentrations. Phenytoin and diazepam were maximally effective at concentrations of 20 microgram/ml and 3-4 microgram/ml, respectively, in good agreement with their effective concentrations in clinical practice. Phenobarbital was more potent (5 microgram/ml) and mesuximide (50% potent at 80 microgram/ml) was least effective.

The synthesis of succinimide derivatives in which alkylating groups have been attached to the imide nitrogen or to the 3 position of the ring is described. The synthesis of one bis-alkylating derivative 19 is also described. The alkylating groups used were (a) alpha-haloacetyl, (b) alpha-haloacetamido, (c) maleamyl, and (d) maleimido. These compounds were prepared as potential long-acting anticonvulsants. None of the compounds showed activity against maximal electroshock or metrazole-induced seizures.

Twelve patients who met Research Diagnostic Criteria for Alzheimer's disease (AD) completed a double-blind crossover study comparing oral RS 86, a long-acting and specific muscarinic agonist, with placebo. Cognitive and noncognitive effects were assessed with the Alzheimer's Disease Assessment Scale (ADAS). RS 86 was found to improve ADAS test scores consistently (both cognitive and noncognitive subscales) in seven patients, with a clinically obvious improvement in only two patients. RS 86 produced a significant increase in peak nocturnal cortisol levels, and this increase correlated with improvement on ADAS testing. Similarly, there was a 38% increase in amplitude of the P300 evoked potential with RS 86. The biological findings suggest that RS 86 was effective only to the extent that it enhanced central cholinergic activity.

Rana esculenta tadpoles that are fed spinach develop an oxalic calculogenesis. The addition of cholestyramine, orthophosphate, citrate, allopurinol and tungstate to the tank water prevented calculi formation while succinimide, magnesium oxide, hydrochlorothiazide and tetracycline were ineffective. Methylene blue proved lethal to tadpoles, and its anti-lithogenic activity could not be assessed. These findings, except for the non-effectiveness of magnesium oxide, are in agreement with both the theoretical expectations and the results obtained in other experimental models. Experimental frog calculogenesis seems to be a simple and valid method for evaluating anti-lithogenic activity.

Fifteen epileptic patients with mild seizures of the narcolepsy type were treated with a combination of succinimide (average dose 750 mg) and dipropylacetate (average dose 1,200 mg), medication with each drug alone having brought no success. The combination of drugs stopped the seizures in eleven patients, in three they almost stopped and in one the frequency of seizures was halved. An E.E.G. was recorded in twelve, with improvement in each. Side effects occurred in five patients (nausea, vomiting, singultus and fatigue), but the drug had to be discontinued in only one instance.

Hyperoxaluria, alone or associated with hypercalciuria, has been detected in 69 of 450 patients with recurrent stones (15.3 per cent). The 3 main findings associated with hyperoxaluria were 1) oxalate hyperabsorption, 2) hyperoxalemia and 3) increased or decreased oxalate clearance. Correction of oxalate hyperabsorption by administration of diethylaminoethanol cellulose showed good results through a 5-year followup. Succinimide, given to the hyperoxalemic group, and a combination of phosphate and magnesium, given to the group with altered clearances, showed poorer results.

In 8 patients who had clinically diagnosed presenile dementia (Alzheimer's disease) the cerebral glucose metabolism was repeatedly determined via FDG-PET under therapy with a muscarinergic choline agonist. The pattern of glucose metabolism disturbance characteristic of Alzheimer's disease, which had been determined previously by examining the metabolism, was confirmed. Whereas the total cortical glucose metabolism was significantly reduced, the regions of the parietal and the adjacent regions of the temporal and occipital association cortex were preferably affected. The primary somatosensory and visual cortex were largely excepted from the reduction in metabolism or showed slightly enhanced metabolic rates, as for example the cerebellum. The disturbance was not equilaterally pronounced and correlated with the neuropsychological deficiency. Despite biochemically "on target" therapy the glucose metabolism decreased progressively (mean value with large interindividual and intraindividual variations. No relationship between the degree of reduced metabolism and the clinical pattern was seen. Rather, it appears that the clinical pattern is much more strongly influenced by mutual adjustment of metabolic differences in various areas of the brain. Results obtained by the authors are communicated besides a review of update knowledge and interpretation of pathophysiological and biochemical linkups in Alzheimer's disease, taking into consideration the glucose metabolism studies published in the literature.

A gas-chromatographic analysis for the succinimide anticonvulsant drugs--ethosuximide, methsuximide, and phensuximide--in 1.0 ml of serum was modified to improve its reliability, speed, and precision. A separate procedure for 10-100 mul of serum was also developed. Neither method requires an initial preparation of derivatives. The working range of each method is about 10-100 mg/liter for the macro-method, 2-100 mg/liter for the micro-method. The methsuximide metabolite, N-desmethylmethsuximide, is included in both methods. Concentrations of N-desmethylmethsuximide in the blood of two patients with petit mal epilepsy are reported.

Cholinergic projections to the cerebral cortex from certain basal forebrain nuclei degenerate in Alzheimer's disease. Nevertheless, attempts to alleviate this disorder through the administration of drugs that increase the availability of acetylcholine to postsynaptic receptor sites have generally yielded disappointing results. In an attempt to evaluate the therapeutic efficacy of cholinomimetics that act independently of the presynaptic cholinergic terminals, a double-blind, placebo-controlled trial of the muscarinic agonist RS-86 (2-ethyl-8 methyl-2,8 diazospiro [4.5]-decane-1,3-dione hydrobromide) was undertaken. Eight patients with Alzheimer's disease with mild to moderately advanced dementia received RS-86 orally at maximum individually tolerated dose levels for eight days. Although some verbal and visuospatial tests showed slight alterations, no consistent overall change in cognitive performance could be discerned. These results lend further support to the view that short-term administration of cholinomimetic monotherapies may fail in the symptomatic treatment of Alzheimer's dementia.

The clinical efficacy of phensuximide and methsuximide was studied in relation to plasma concentrations of these compounds and their desmethyl metabolites. Single- and chronic-dose studies of each drug were carried out in five patients with intractable seizures. Patients were evaluated before and during treatment by 6-hour simultaneous video and telemetered electroencephalographic recordings to characterize the seizure type and by daily determinations of plasma antiepileptic drug concentrations. Phensuximide had a mean half-life of 7.8 hours and accumulated to an average fasting level of only 5.7 micrograms per milliliter. Desmethylphensuximide averaged only 1.7 micrograms per milliliter with a similar half-life. Methsuximide had an even shorter half-life, averaging 1.4 hours, but its desmethyl metabolite had a mean half-life of 38 hours and therefore accumulated to levels in excess of 40 micrograms per milliliter. The addition of phensuximide to their regimens benefited none of the patients, but two had an excellent response to methsuximide. The failure of phensuximide and its desmethyl metabolite to accumulate to reasonable levels is the likely explanation for the relatively weak antiepileptic effect of phensuximide as compared with methsuximide.

The efficacy of second-line antiepileptic drugs (AEDs) was evaluated in the treatment of 66 patients with complex partial seizures who had previously failed first-line AEDs. Methsuximide, valproate, or clorazepate had eliminated seizures in 11% of the patients at the end of the study. However, these good results deteriorated on longer follow-up and were not expected to be permanent. It is recommended that suitable patients with partial epilepsy be referred for surgical evaluation after failing the first-line AEDs, and that second-line AEDs be reserved for nonsurgical candidates.