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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
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↗
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↗
PubMed1977

Time-dependent kinetics II: Diurnal oscillations in steady-state plasma ethosuximide levels in rhesus monkeys.

Morning steady-state (9 am) plasma levels were significantly higher than the corresponding evening (5 pm) plasma levels during a 3-week zero-order infusion of ethosuximide to six monkeys. These differences could not be explained by experimental variables such as GLC assay and infusion pump. Circadian periodicity in steady-state plasma levels was investigated in three monkeys over 4 months under controlled experimental conditions: blood sampling at 2-hr intervals for 26 hr, 1 day/week; fixed lighting, feeding, and noise schedules; and electroencephalogram monitoring. The plasma concentration-time curves showed two minima in the 12 noon-2 pm and 8 pm-12 midnight periods, and the later involved the largest percent change in plasma levels (4-8%). The plasma concentration-time data were subjected to cross-correlation analysis, which indicated a circadian rhythm in steady-state plasma levels with a period of 24-26 hr.

Animals↗
PubMed1977

Time-dependent kinetics III: diurnal oscillations in steady-state plasma valproic acid levels in rhesus monkeys.

Valproic acid was administered by constant rate intravenous infusion to catheterized chained rhesus monkeys for 8-10 weeks under controlled environmental conditions. Steady-state plasma levels were monitored at 2-hr intervals for 26 hr (10 am-12 noon on the following day), 1 day/week for 6 weeks. Individual steady-state plasma concentration-time plots exhibited the following characteristics. During Period A (10 am-6 pm), plasma levels remained stable or decreased. During Period B (6 pm-6 am), plasma levels increased, reached a maximum, and remained markedly higher than during Period A. The maximum concentrations were 40-140% higher than the observed minimum concentrations. During Period C (6 am-noon), plasma levels tended to decline from the maximum concentrations achieved in Period B. In most cases, plasma concentrations at 10 am and 12 noon of the 2nd experimental day fell within 10% of their respective values on the previous day. The mean (+/- SD) periods obtained by cross-correlation analysis of individual plasma concentration-time plots were 30.7 (+/- 3.7) and 22.8 (+/- 3.6) hr for Animals 903 and 923, respectively. The corresponding mean (+/- SD) amplitudes were 27.3 (+/- 12.6) and 17.4 (+/- 2.3)%. A circadian rhythm in total body clearance was hypothesized, and its pharmacokinetic implications are discussed.

Animals↗
PubMed1977

Diurnal variation of valproic acid plasma levels and day-night reversal in monkey.

Four normal monkeys each equipped with an EEG plug and two indwelling catheters for drug infusion and sampling, respectively, were administered valproic acid (VPA) before and after a 12-hr light, 12-hr dark phase shift. Before day-night reversal, diurnal oscillations of VPA plasma levels under steady-state intravenous constant-rate infusions were 30-50%, with maximum concentrations during the dark phase of the cycle. After reversal, maximum VPA plasma concentrations tended to follow the dark phase shift. The correlation was not perfect, nor was the sleep cycle completely reversed since the animals slept less after the phase shift. Possible mechanisms of the diurnal plasma level fluctuations and the importance of oscillations of this magnitude to clinical drug regimens are discussed.

Animals↗
PubMed1977

EEG operant conditioning in a monkey model: I. Seizure data.

EEG operant conditioning in an alumina-gel monkey model (N = 14) to decrease EMG, to increase 9 Hz or decrease 9 Hz, and to increase 23 Hz (18 Hz and 26 Hz in 2 pilot monkeys), respectively, was not consistently beneficial in reducing seizures. The data suggested: (1) that desynchronization of the EEG by reinforcing 18-26 Hz decreased in some animals the extent and severity of seizures while increasing seizure frequency; (2) that attending during conditioned EMG suppression reduced seizures somewhat; and (3) that the operant conditioning setting became stressful to the majority of monkeys under certain conditions, precipitating status epilepticus, gastrointestinal disturbances, and shock, which culminated in the death of 3 animals. Certain precautions are discussed in the therapeutic application of this technique to epileptic patients.

Animals↗
PubMed1977

EEG operant conditioning in a monkey model: II. EEG spectral analysis.

EEG power spectral analysis was studied from 14 (alumina-gel) chronically epileptic, undrugged monkeys during an EEG operant conditioning experiment. The composite profile of the average epileptic monkey shows the majority of power to be below 10 Hz. Because of the large variance in the data, no significant changes in the EEG power spectra could be detected as a function of conditioning. The possible reasons for this large variance are discussed. Hypothesis from previous human "biofeedback" studies would allow the prediction that those frequencies corresponding to the mu and sensory-motor-rhythm should negatively covary with seizure frequency. Data from this study did not support such assertions. The method of using spectral analysis for quantifying changes in the EEG which covary with operant conditioning is evaluated.

Animals↗