Lever-pulling avoidance behavior of 24 monkeys was actively shaped with a manual shock-control box and a closed-circuit TV system. A negative reinforcement procedure was used wherein a periodically occurring body shock was postponed each time the subject moved toward the lever. All subjects were trainable with this method, two-thirds of them in fewer than five, 1- to 2-hr sessions. Negative reinforcement was more effective than a punishment procedure.

Journal Article↗

PubMed1967

Behavioral experimental epilepsy in monkeys. I. Clinical seizure recording apparatus and initial data.

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Animals↗

PubMedDate not supplied

A gestational monkey model: effects of phenytoin versus seizures on neonatal outcome.

In the present research, an animal model was developed to ascertain the potential effects of gestational drug concentrations and/or maternal seizures on the neonate. The rhesus monkey (Macaca mulatta) was the species of choice as previous research has demonstrated its validity as a model for partial epilepsy. Phenytoin (PHT) was tested because it is effective in the treatment of partial epilepsy in patients and is efficacious in nonpregnant monkeys with focal motor seizures. Data were obtained on the outcomes of nine pregnancies from five mothers, all of whom received PHT during gestation. Infant motor and social development and maternal/offspring interactions were systematically monitored for 12 weeks postnatally. Results indicated that impairment of infant motor development was directly correlated with greater drug exposure during the third trimester of pregnancy and unrelated to maternal seizure frequency during gestation. Also, developmental problems were more serious in infants exposed to higher drug levels, including difficulty nursing, grasping, and/or clasping; an upper lip anomaly; fetal death in one case; and infant death in another. Though the sample size of this study was small and the methodology experimental, the findings indicate that the gestational model is a valuable paradigm with potential clinical relevance. The results also support the notion that high third-trimester phenytoin levels may have significant impact on newborn reflexes and initial development of gross motor skills.

Animals↗

PubMedDate not supplied

Stiripentol in acute/chronic efficacy tests in monkey model.

Acute and chronic efficacy tests of stiripentol (4,4-dimethyl-1-[3,4-(methylenedioxy)-phenyl]-1-penten-3-ol) were conducted in alumina-gel rhesus monkeys. In the acute study (n = 6), discrete serial seizures precipitated by 150 mg/kg of 4-deoxypyridoxine hydrochloride were challenged by intravenous administration of stiripentol and the data compared with those obtained with valproate similarly tested in other monkeys (reported here) and with those from four other standard anticonvulsants (phenytoin, carbamazepine, phenobarbital, and diazepam--data published previously). In the acute challenge (Study 1), stiripentol performed comparably to valproate by delaying the onset of seizures but not eliminating them as did the other four drugs. In two separate chronic studies (at different doses, n = 6 each), stiripentol was given every 4 h by gastric catheter for 4 weeks, preceded and followed by 4 weeks of baseline. In these studies, stiripentol significantly reduced EEG interictal spike rates at mean plasma concentrations from 20 to 27 micrograms/ml in Study 2 and 11 to 14 micrograms/ml in Study 3. From these results, and those evinced in other studies, it appears that stiripentol should be evaluated for absence epilepsy and possible synergistic effects in polytherapy.

Animals↗

PubMedDate not supplied

Carbamazepine plus stiripentol: is polytherapy by design possible?

To test the idea that the combination of carbamazepine (CBZ) plus stiripentol (STP) is synergistic, an alumina-gel monkey model (N = 4) was used to compare polytherapy electroencephalographic (EEG) effects to those of CBZ monotherapy. The research design included five consecutive phases (2-3 weeks each): baseline, CBZ, CBZ + STP, CBZ, and postdrug baseline. Both drugs were administered in suspension through a chronic gastric catheter every 4 h (to minimize plasma level oscillations). Doses of CBZ were adjusted to maintain CBZ concentration at the same level in the drug periods (except during the initial polytherapy phase, where levels were allowed to increase prior to adjustment). Phased-reversed interictal spikes were manually counted (expressed as a rate per minute). Relative to baseline, CBZ (Cmin = 0.59; Cmax = 2.36 micrograms/ml) increased interictal EEG spikes by an average of 42%. Relative to CBZ monotherapy, the addition of STP (Cmin = 12.02; Cmax = 13.21 micrograms/ml) was associated with an average decrease in spike rate of 39%. This effect was reversible since removal of STP was associated with an increase in spike rate of 66%. The CBZ-epoxide/CBZ ratio decreased from 0.29 to 0.06 when STP was added and increased to 0.30 when STP was removed. The data fit a pharmacodynamic interpretation and suggest that in the case of CBZ + STP the benefits may outweigh the usual disadvantages of polytherapy.

Animals↗

PubMedDate not supplied

Phenytoin and/or stiripentol in pregnancy: infant monkey hyperexcitability.

A monkey (Macaca fascicularis) model was used to assess infant hyperexcitability after prenatal exposure to phenytoin (PHT, n = 4), stiripentol (STP, n = 5), or PHT + STP (n = 4). Adult female monkeys were equipped with tether systems and stomach catheters so that drug administration could start 1 month before mating and could be continued throughout gestation. During pregnancy, PHT and STP plasma levels were maintained between 4-12 and 4-10 micrograms/ml respectively (for both monotherapy and polytherapy). Infants were separated from mothers at birth and transferred to the University of Washington's (Seattle) Infant Primate Research Laboratory (IPRL) for postnatal care and testing. Data on a hyperexcitability scale were obtained during cognitive testing for visual and cross-modal recognition memory in 13 infant monkeys when they were between 2 weeks and 3 months of age. The data indicated that infants prenatally exposed to PHT, whether alone or in combination with STP, were at increased risk for hyperexcitability (screeching, refusing to attend to stimuli, lack of visual orientation). This was not true of infants prenatally exposed to STP monotherapy (drug group differences, p < 0.05).

Animals↗

PubMedDate not supplied

Metabolic fate of valproic acid in the rhesus monkey. Formation of a toxic metabolite, 2-n-propyl-4-pentenoic acid.

The metabolic fate of an iv bolus dose (13.5 mg kg-1) of valproic acid (VPA) was studied in adult male rhesus monkeys. Renal excretion proved to be the major route of elimination of the drug and a total of 17 metabolites, accounting collectively for some 82% of the administered dose, were identified in urine by GC-MS techniques. Many of these metabolites were present largely in the form of glucuronide conjugates, as was VPA itself. The principal pathways of VPA biotransformation were, in order of decreasing quantitative importance, ester glucuronide formation, omega-oxidation, beta-oxidation and (omega-1)-hydroxylation. In addition, three mono-unsaturated metabolites, identified as (E)-delta 2-, (E)-delta 3-, and delta 4-VPA, were detected in both plasma and urine. Quantitative analysis of these unsaturated VPA metabolites indicated that the delta 4 olefin, which is known to be a potent hepatotoxic agent, was the predominant isomer of the group.

Animals↗