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Biomedical subjects

J S Lockard

Publications and source records attributed to J S Lockard.

At least 19 recordsLinked to original sources
PubMed1998

Infant monkeys' visual responses to drawings of normal and distorted faces.

Face-like patterns attract attention from both human and nonhuman primates. The present study explored the facial preferences in infant pigtailed macaques (Macaca nemestrina). Twenty-five subjects looked at 20 paired drawings of adult conspecific monkey faces, and their looking time was recorded. The facial features in the drawings were arranged in positions ranging from a normal to a scrambled face. The subjects looked at the normal face more than expected by chance (P < .02), suggesting a preference, whereas the distorted faces were observed randomly. The normal face may have been preferred because the eyes were in a normal position within the facial outline.

Animals↗
PubMed1996

Infant monkey hyperexcitability after prenatal exposure to antiepileptic compounds.

PURPOSE: A monkey (Macaca fascicularis) model was previously used to assess infant hyperexcitability after prenatal exposure to phenytoin (PHT), stiripentol (STP) or PHT+STP. To explore this issue further, we studied additional monkey infants in those groups, as well as groups prenatally exposed to carbamazepine (CBZ) in monotherapy (n = 5) or CBZ+STP polytherapy (n = 10). METHODS: The drug-exposed groups were compared with a group of control infants (n = 10) for whom procedures were matched except that there was no prenatal drug exposure. All adult female monkeys were equipped with tether systems and stomach catheters so that drug administration (or water for controls) could be initiated before they were mated and continued throughout pregnancy. During pregnancy, PHT, STP, and CBZ plasma levels were maintained between 4-12, 4-10, and 1-6 micrograms/ ml, respectively (for both monotherapy and polytherapy). At birth, infants were separated from mothers and transferred to the University of Washington's (Seattle, WA, U.S.A.) Infant Primate Research Laboratory (IPRL) for postnatal care and follow-up testing. During tests of recognition memory administered between 2 weeks and 3 months of age, infants were rated on a hyperexcitability scale. RESULTS: Previously reported data indicated that infants prenatally exposed to PHT, in monotherapy or polytherapy with STP, were at increased risk for hyperexcitability (screeching, refusing to attend to stimuli, lack of visual orientation). This was not the case for infants prenatally exposed to STP monotherapy. CONCLUSIONS: Our results confirm previous findings and also demonstrate that infants prenatally exposed to CBZ or CBZ+STP, like controls, are not hyperexcitable during testing.

Animals↗
PubMed1990

Feasibility and safety of vagal stimulation in monkey model.

The feasibility, safety, and preliminary effects of chronic vagal stimulation were studied in an aluminagel monkey model. Pilot studies to perfect the equipment, determine stimulation thresholds, and insure the comfort and safety of the animals preceded this study. Four monkeys were equipped with an indwelling, 2-electrode cuff (titanium bands spaced 7 mm apart; silicone encased; 1.5 cm total length) in contact around the right vagus nerve; avoidance of the cardiac branch was confirmed by electrocardiograms. After postsurgical recovery, the intact and awake animals received constant-current stimulation (5 mA; 83 Hz, 143 Hz, or 50-250 Hz randomly; 0.5-ms pulse width) at the onset of every spontaneous seizure for the duration of the seizure or every 3 h for 40 s if stimulation had not occurred in the preceding hour. Stimulation periods of 2-6 weeks, with differing levels of stimulation, were preceded and followed by at least a 2-week baseline period of no stimulation. During the stimulation periods, the seizure rate decreased to zero in two monkeys and the interseizure intervals became invariable in the remaining two monkeys. These effects carried over temporarily into the poststimulation baseline periods. Vagal stimulation had no consistent effects on seizure severity or EEG interictal spikes. Histological studies of six vagus nerves were unable to separate electrode cuff damage from any direct effects stimulation may have had on the nerves. Although it appears that chronic vagal stimulation is feasible and that epileptogenic processes are influenced, the safety and efficacy of the procedure are still in question.

Action Potentials↗
PubMed1985

Diurnal oscillations of CSF valproate in monkey.

Valproate (VPA) was administered to four rhesus monkeys by constant-rate intravenous infusion for two weeks under controlled conditions. Plasma and CSF samples were collected for a period of 27 hours at 3-hour intervals during steady-state and post-infusion periods. The mean correlation coefficient between total plasma and CSF VPA concentrations was found to be 0.78 +/- 0.09. The CSF VPA levels reflected the changes in free VPA in plasma but the two were not equivalent. Diurnal fluctuations in CSF VPA concentration were similar to those found in plasma but the inter-animal variation was greater in CSF than in plasma.

Animals↗
PubMed1981

Absence of seizures or mirror foci in experimental epilepsy after excision of alumina and astrogliotic scar.

In 15 rhesus monkeys (Macaca mulatta) made epileptic by the sensorimotor cortical injection of alumina, the roles of alumina and of "mirror foci" were investigated by serial surgical excisions of the granuloma, surrounding epileptic focus, and contralateral homotopic sensorimotor cortex. Electroencephalographic and electrocorticographic recordings documented foci and transmitted contralateral epileptic activity. After the granuloma was removed, seizures continued but without alumina. After the epileptic cortex was removed, no seizure activity remained and no contralateral independent foci occurred. These findings indicate that the epilepsy incident to alumina injection into the sensorimotor cortex in monkey is not dependent on the continual presence of alumina and is not associated with independent or "mirror foci."

Aluminum Hydroxide↗
PubMed1981

Na+ + K+-ATPase in serially excised segments of epileptic monkey cortex.

The membrane-bound enzyme Na+ + K+-ATPase was measured in serially excised specimens of cerebral cortex in epileptic and control monkeys. Experimental chronic epileptic cortex showed significantly lower values than controls, as is seen in some other models and human epilepsy, but is different from the increased enzyme values in cobalt and freezing lesion epilepsy.

Aluminum Hydroxide↗
PubMed1980

Cinromide's metabolite in monkey model: gastric administration and seizure control.

In a previous study (Lockard et al., 1979) Cinromide (3 bromo-N-ethylcinnamamide), an experimental anticonvulsant (Burroughs-Wellcome Pharmaceutical Co.), was given a preliminary evaluation. Since that research was concerned primarily with EEG paroxysms, the present study was conducted to address drug efficacy in terms of clinical seizures. Cinromide's major metabolite (3-bromocinnamamide, BC) was the main focus. Eight alumina-gel monkeys were given by gastric bolus every 6 hr for 10 days (Phase I) either the solvent alone (Tween 80), Cinromide (BEC), or its synthetic metabolite (SBC). Subsequently (Phase II), four animals were given BEC or SBC by chronic gastric infusion for 20 days. In both phases Cinromide's metabolite (either via BEC or especially SBC) was effective in half of the animals in reducing seizure frequency and/or duration at plasma levels above 5 mcg/m. The data suggest that the drug's efficacy is individually specific. Another species of Cinromide metabolism, 3-bromocinnamic acid, is also discussed.

Animals↗
PubMed1980

Slow-speed EEG for chronic monitoring of clinical seizures in monkey model.

A method for utilizing slow-speed EEG (1/4 mm sec) to detect and quantify gross-motor clinical seizures in a chronic monkey model is described. The technique is particularly useful in the detection of small clinical seizures that may occur in studies of drug efficacy. It estimates the reams of paper generated by standard EEG recording (30 mm/sec) that heretofore precluded easy data collation and thereby essentially prevented continuous monitoring of EEG paroxysms. (This method, however, does not allow the detection of single or non-clumped interictal spikes.) The headplug and recording procedures employed in our laboratory are detailed. The technique can be used alone or, for greater precision, in conjunction with either the recording of motor-activity envelopes or a videotape seizure-confirmation system, or both (Lockard and Barensten, 1967; Lockard et al., 1976c). Unlike our motor-activity and closed-circuit TV method for detecting clinical seizures, the technique of slow-speed EEG could be easily employed in other laboratories already equipped with EEG polygraphs. This method also permits the simultaneous recording of slow-speed and standard-speed EEGs (on separate polygraphs) to facilitate periodically the discrimination between artifacts and clinical seizures.

Animals↗
PubMed1979

Efficacy and toxicity of the solvent polyethylene glycol 400 in monkey model.

Several antiepileptic drugs, such as carbamazepine and clonazepam, have low bioavailability in solid form and are insoluble in an aqueous solution. Alcohol solvents are often employed as vehicles when these drugs are studied in animal models. Secondary and particularly tertiary alcohols are suspected of some anticonvulsant activity. The present research evaluated the possibility that polyethylene glycol 400 (PEG 400) might be efficacious, toxic, or both. Monkeys (N = 11) rendered epileptic by aluminum-hydroxide were administered PEG 400 by constant rate (1 ml/hr) intravenous infusion for 3--4 weeks, preceded and followed by several weeks of baseline. At a concentration of 60%, PEG 400 significantly reduced seizure frequency, but also exhibited severe side effects. These findings suggest that experimental testing of anticonvulsants may be compromised when this or similar solvents are used chronically.

Aluminum Hydroxide↗
PubMed1979

The influence of attending on seizure activity in epileptic monkeys.

Six studies are presented on the influence of attending upon epileptic activity in the alumina-gel monkey model of focal motor and secondarily generalized tonic--clonic seizures. Seizure frequency and EEG paroxysms are reported during (a) scheduled feeding periods, (b) visual attending, and (c) three different operant tasks, including the conditioning of single neurons. An explanatory hypothesis of the cumulative data is proposed in terms of the different bursting behavior of group 1 (strongly epileptic) and group 2 (weakly epileptic) neurons of the epileptogenic focus. It is suggested that attending, or participation in operant tasks, results in a decrease in bursting of group 2 neurons and a disruption of synchrony between group 1 (pacemaker), group 2, and normal neurons. This desynchronization is said to lower the probability of an ictal event occurring either during or immediately following an operant task. Attending factors may be responsible for some of the conflicting findings in therapeutic studies of epilepsy which have not controlled for this parameter.

Aluminum Hydroxide↗
PubMed1979

Carbamazepine revisited in a monkey model.

In a previous study on carbamazepine (Lockard et al., 1974), the problem of its low bioavailability in solid form and its short half-life in monkey were addressed. The present research was designed to evaluate carbamazepine under constant-rate intravenous infusion in our alumina-gel monkey model. Since carbamazepine is insoluble in an aqueous solution, polyethylene glycol 400 was used as the vehicle for administration of this drug to a group of 8 epileptic monkeys. The attenuation of seizures by carbamazepine was not statistically significant since the serum levels of carbamazepine after enzyme induction were less than 2.0 micrograms/ml. This study (a) illustrates that some problems in drug evaluation may be insoluble with our present technology even though we are cognizant of them; (b) makes explicit the fact that the efficacy of carbamazepine is a function of adequate serum levels; (c) demonstrates endogenous oscillations of carbamazepine serum concentrations; and (d) reports simultaneous serum levels of carbamazepine and its 10--11 epoxide in the monkey model.

Animals↗
PubMed1979

Cerebellar stimulation in alumina-gel monkey model: inverse relationship between clinical seizures and EEG interictal bursts.

The efficacy of cerebellar stimulation was addressed in a chronic monkey model (N = 12) of spontaneous focal motor and secondarily generalized seizures using 24 hr seizure frequency monitoring and all-night EEG recording. The anterior cerebellar vermis was stimulated employing parameters similar to those used in man, 10 Hz, 1 msec pulses, 10 min on, 10 off, at an average current of 2.0 mA. Six weeks pre- and post-base-line periods were compared to a stimulation period of the same length. The results contribute to a clarification of conflicting findings of previous researchers by revealing an inverse relationship between seizure frequency and interictal EEG bursts during the weeks of stimulation. Seizure frequency increased significantly and interictal bursts decreased. Both of these effects (especially the former) were evident in the post-stimulation period, but for different reasons than hypothesized for the period of stimulation. Whereas the therapeutic value of cerebellar stimulation on seizures may be in question, its utilization in the study of mechanisms of epilepsy may be warranted.

Animals↗
PubMed1979

Experimental anticonvulsant cinromide in monkey model: preliminary efficacy.

Cinromide (3 brono-N-ethylcinnamide), an experimental anticonvulsant (Burroughs-Wellcome Pharmaceutical Co.), was given a preliminary evaluation in our alumina-gel monkey model. The parent drug has a biological half-life in monkey of 1-2 hr and its active metabolite, 3-bromocinnamide, a half-life of 4-6 hr. In phase 1, 6 chronically epileptic monkeys, with focal motor and secondarily generalized tonic-clonic seizures, received the drug in a vehicle of 65% polyethylene glycol 400 (PEG) by constant-rate intravenous infusion followed by baseline days of saline only and PEG only. Three different concentrations of Cinromide (12, 24, and 36 mg/ml/hr) were administered, respectively, to achieve mean steady state plasma levels of approximately 5, 10 and 20 micrograms/ml of the metabolite (0.5 to 5.0 micrograms/ml of the parent drug). In phase 2, Cinromide was administered for 7 days at the middle concentration to all monkeys. Baseline periods similar to those of phase 1 were used as controls. The data tentatively suggest that Cinromide is efficacious in the monkey model at a plasma concentration range of 7-14 micrograms/ml of the metabolite. With the exception of one animal, no secondarily generalized seizures were exhibited during drug administration (but were evident in the baseline periods), and EEG bursting decreased significantly in several monkeys. Minimal side effects were manifested at these plasma levels but withdrawal seizures were evinced with cessation of the drug. Further evaluation of Cinromide by gastric administration in our animal model is planned.

Animals↗
PubMed1979

Clonazepam in a focal-motor monkey model: efficacy, tolerance, toxicity, withdrawal, and management.

Since the clinical data have been equivocal in regard to the effects of clonazepam (CZP) in focal-motor seizures, an alumina gel monkey model was used to evaluate quantitatively its efficacy with respect to this seizure category. The insolubility of CZP and its short biological half-life in monkey necessitated its evaluation in the model via constant-rate intravenous administration in a solution of polyethylene glycol 400 (PEG). Two groups of monkeys were given CZP in PEG (N = 6) or a PEG solution alone as a control compound (N = 5) for 6 weeks; these treatments were bordered at both ends by 3 weeks of treatment with saline only in order to establish a baseline. CZP was administered at a concentration sufficient to achieve a plasma level of 30 ng/ml in drug step I (3 weeks) and at least double that level in drug step II (3 weeks). As a solute for CZP, and when given by itself, PEG was always administered at a concentration of 35%. The results indicate that CZP is effective for focal-motor seizures and secondarily generalized tonic-clonic seizures, particularly when its concentration in plasma is higher than 60 ng/ml. Withdrawal seizures were evident on cessation of CZP administration. CZP appears to be a useful broad-spectrum anticonvulsant when managed carefully. An unexpected finding was the irreversibility of the pharmacological effect of PEG. Cessation of PEG administration significantly reduced seizure frequency in subsequent weeks to a level below the initial baseline level.

Aluminum Hydroxide↗