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Retrobenzamides [N-(nitrophenyl) benzamides and N-(aminophenyl)benzamides] were developed in the perpective of a design for phenytoinergic agents. Anticonvulsant and neurotoxic properties of these compounds were evaluated in mice and rats in two seizure models (maximal electroshock-induced seizures [MES] and seizures induced by subcutaneous administration of pentylenetetrazole [scPtz]) and in the rotorod test. Data obtained were compared with those recorded on carbamazepine and phenytoin (antiepileptic drugs widely utilized in human clinics), ameltolide (anticonvulsant compound recently developed by Eli Lilly in human clinical trials) and other compounds previously reported by our research group. Studies on retrobenzamides in mice administered by intraperitoneal route point out a good anticonvulsant potential in the MES test for the amino derivatives (N-(aminophenyl)benzamides) and moderate activity in the case of the corresponding "nitro" derivatives. In rats dosed orally, aminoretrobenzamides were less active in the MES test than in mice dosed intraperitoneally.

The density and collagen content of fibroblasts were measured in the gingiva of rats injected intraperitoneally with sodium 5,5-diphenylhydantoinate (Dilantin). An analysis using a point-counting procedure on stained histologic sections, was performed. The effect of Dilantin was studied in normal gingiva and in gingivitis provoked by a silk-ligature placed around the first lower molars. The silk ligature alone did not modify the number of fibroblasts in the gingiva, but affected the collagen content. Dilantin associated with this irritant caused not only an alteration of the collagen content but also had a statistically significant effect (p less than 0.1) on the number of fibroblasts. The results indicate an interaction of the effects of Dilantin and a gingival irritant.

During chronic hypoxia at sea level (FiO2 : 0,08) the liver concentrations of cytochrome P 450 and b5 decreased. Phenytoin administration induces an increase in cytochrome P 450 and b5 liver content. The hydroxylation of phenytoin that was decreased at low level of cytochrome P 450 and oxygen, reached again a normal level after induction of cytochrome P 450 in spite of the persistency of a low level of available oxygen. Liver cytochrome P 450 concentration is the main limiting factor of phenytoin hydroxylation.

In order to study the action of sodium diphenylhydantoinate (DPH) on bone repair and during apical scars, vitallium implants were included in four maxillary and mandibular bony cavities in Sprague-Dawley rats. After one month, the implants were removed. In half the cavities, selected as the experimental group bleeding was avoided. In the controls, the bony walls were perforated in order to induce formation of a good-quality clot. The day before the implants were removed and everyday until sacrifice, the animals were injected with sodium hydantoinate (10 mg/100g b/w) ip. They were sacrificed 1d, 4d, 8d, 16d, 28d and 56 days after the implants had been removed. The jaws were isolated, prepared for paraffin sections, and the areas of bone repair cut serially and studied under the photonic microscope. Another series of animals without sodium hydantoinate treatment, was studied for comparison. It was concluded that, in animals under DPH treatment: the bone repair was consistently delayed; a good-quality clot led to a better repair than a poor-quality clot which led cogeneralised collagen formation; the bony defects were proportional to the dose of the injected drug; the bony defects were qualitative including: thin bone traceculae, large osteocytes, collagen overgrowth; foreign bodies included in the bony repair areas were often encapsulated and tolerated; the percentage of collagenous bony defects (tapical scars) increased after sodium hydantoine treatment.

Rattus norvegicus females were treated by diphenylhydantoin (D.P.H.), all along pregnancy and lactation. 4 groups were constituted: a 100 mg DPH/kg/day group, a 50 mg DPH/kg/day group; a placebo group (treated with pure water), and control group. D.P.H. was given twice a day by a gastric tube. The cerebellar Purkinje cells studied through light microscopy and transmission electron microscopy in young rats (25 days old) showed no visible alteration. 2 motorcoordination tests were applied to the young rats, during their 2nd and 3rd weeks of post-natal life. Young rats of DPH 100, DPH 50 and placebo groups showed a backwardness relatively to control. This backwardness may be attributed to the maternal forced feeding stress, but not to a specific action of the DPH.

The electropharmacological action of imolamine was studied using Hiss bundle electrography. In dogs with spontaneous sinusal rhythm, imolamine decreases Hiss-Purkinje and total intraventricular conduction, without affecting auriculoventricular conduction time. In dogs with paced sinusal rhythm (180/min), imolamine increases atrial and ventricular thresholds and atrial refractory period, and decreases intra-atrial and intraventricular conduction; no significant modification of auriculoventricular conduction was noted at therapeutic dosages. In ouabaïn-intoxicated dogs, imolamine suppresses digitalis rhythm disorders and antagonizes the action of the glycoside on A-V node, as does diphenylhydantoïne, but, in contrast to this drug, it increases slightly intraventricular conductivity.

Morphological changes in the anatomical structures of the limbic system induced by phenytoin and ethosuximide administered in effective doses for 1, 3 and 6 months in rats were analyzed. The clinical symptoms consisted of some vegetative and behavioral disorders, mostly transitory. Differences in gain of body weight depending on the sex of the animal and the drug administered were observed. The morphological changes in the parenchymal and mesenchymal nervous tissue elements were not specific with regard to their topography or to the type of pathological process. Some morphological differences depending on the drug and its period of administration were observed only in rats treated for 1 and 3 months. The neuropathological picture in rats treated with both drugs for 6 months showed a great similarity. The pathological process in the ganglionic cells had the character of degeneration. Morphological changes in the myelin sheaths were due to edema which appeared to be vasculogenic and situated in the white matter. Focal and diffuse proliferation of cellular glia appeared after administration of both drugs for 1 and 3 months while in those treated for 6 months the degenerative changes were seen. The anatomo-comparative study of the neuropathological picture in the rats treated with both drugs and the morphological picture of the limbic system structures in patients with chronic epilepsy indicates that the drugs examined could play some role in the pathogenesis of the limbic system lesions encountered in epileptics.

Pediatric chronopharmacological findings until now have been limited to circadian changes in children 6 to 15 years old. This means that (a) data in neonates and even in infants of one year is not available and (b) other bioperiodicities with periods of several hours (ultradian rhythms) as well as several months and about one year (infradian rhythms) have not been explored in older children. Biologic time-related changes have been documented for phenytoin and theophylline with regards to pharmacokinetics and for orciprenaline and methylprednisolone with regards to effectiveness (bronchodilatation). Despite the limited number of experiments performed to date, it is already possible to admit that, (a) a chronopharmacological approach provides better precision of pharmacologic study than the conventional approach not using time-related data; (b) better therapeutics can be achieved with the help of chronopharmacological facts since an appropriate timing in administration of a medicine usually enhances its desired effects and/or reduces its undesired effects.

Phenytoin (diphenylhydantoin) was used in doses of 300 mg/24 hours to treat severe motor diarrhoea in 5 diabetic patients. The patients had been insulin-dependent for 2 to 17 years and had advanced neuropathy. In each case, malabsorption, lesions of the colon or small bowel, endocrine tumour or parasitic, infectious and inflammatory causes could be excluded. Under phenytoin the diarrhoea ceased in all 5 patients within 24 to 48 hours. It recurred in 4 of them within 48 hours when treatment was withdrawn to disappear within the same length of time when it was reintroduced. No relapse was observed for periods of 3 months to 5 years under phenytoin maintenance treatment. The mechanism of action of phenytoin may suggest that diabetic diarrhoea is hormone-mediated or caused by an effect on the autonomous nervous system or on the peptidergic system, but no definite conclusion can be reached in the present state of our knowledge.

In young male rats, long-term treatment with phenytoïn reduces the amount of calcium and magnesium in the femurs and provokes a stimulation of the parathyroiïds witnessed by the hypertrophy and hyperplasy of the parathyroid cells. Neither plasma calcium nor plasma and erythrocyte magnesium are modified.