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Biomedical subjects

J S Lockard

Publications and source records attributed to J S Lockard.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1977

Seizure severity and acquisition and performance of operant tasks in a monkey model.

Several studies utilizing an alumina-gel monkey model demonstrated a relationship between degree of epileptic activity and learning difficulty. Three operant tasks were employed: single-unit, gross-motor positive reinforcement, and avoidance conditioning. The data indicated that the number of hours needed to learn any one of the tasks increased with seizure frequency and/or number of EEG interictal bursts. The learning impairment appeared to be a function of the relevance of the required response to the site of the epileptogenic focus.

Animals↗
PubMed1976

Conditioned EEG desynchronization and seizure occurrence in patients.

Five patients with seizures poorly controlled by standard anticonvulsant medication, underwent EEG operant conditioning. The operant paradigm reinforced the production of low voltage fast activity while decreasing frequencies below 10 c/sec. Seizure frequency decreased in 2 patients, seizure severity was attenuated in 2 others, and one patient who was only given reinforecement for scalp EMG suppression whowed no change in seizure parameters. Pseudoconditioning and control periods ruled out placebo effects. A rationale for this phenomenon is proposed.

Adult↗
PubMed1976

Prophylaxis with diphenylhydantoin and phenobarbital and alumina-gel monkey model. I. Twelve months of treatment: seizure, EEG, blood, and behavioral data.

Utilizing an alumina-gel epileptic monkey model, with instrumentation for continuous monitoring of all overt, spontaneous motor seizures, the efficacy of pharmacologic prophylactic treatment of posttraumatic epilepsy was explored. The alumina-gel model provides a relatively standardized brain trauma from monkey to monkey, resulting in virtually complete assurance that all animals will manifest, in time, electrical and clinical seizures if not treated. Thirteen rhesus monkeys were divided into two groups of 8 drug-treated and 5 placebo animals, respectively. Administration of diphenylhydantoin and phenobarbital in a combined regimen commenced within 48 hr of the alumina-gel injections. After 1 year the monkeys were withdrawn from either their drugs or placebo and followed for a subsequent 4 month period. The data for the first 12-month period indicate that anticonvulsant treatment of potentially epileptic monkeys decreased both the frequency and severity of seizures they would have had without treatment. All animals manifested an electrical focus and overt seizures, but the drug monkeys had only partial seizures whereas the placebo monkeys exhibited secondarily generalized tonic-clonic seizures. The follow-up, no-treatment data of 4 months are reported in the following paper.

Aluminum Hydroxide↗
PubMed1976

Prophylaxis with diphenylhydantoin and phenobarbital in alumina-gel monkey model. II. Fourth-month follow-up period: seizure, EEG, blood and behavioral data.

This study, a 4-month follow-up period of a 12-month treatment study by the present authors, was concerned with the permanent effects of treatment with diphenylhydantoin and phenobarbital in the alumina-gel monkey model. Whereas the 8 drug animals during withdrawal increased their seizure frequency, duration, and severity, those 4 animals having received 120 mg/kg/day DPH in weeks 6-12 had one-half the number of seizures of the 4 placebo monkeys in the follow-up period. The other 4 drug animals who had continued to receive 60 mg/kg/day DPH during those weeks had two to four times the number of seizures of the placebo group during posttreatment. (All drug monkeys received 80 mg/kg/day of DPH from weeks 13-52 and 6 mg/kg/day of phenobarbital throughout the 12-month treatment period). The results reaffirm the problems of drug withdrawal and the importance of altering seizure mechanisms with sufficiently high doses of efficacious anticonvulsants rather than merely treating epileptic manifestations at lower doses.

Aluminum Hydroxide↗
PubMed1976

Valproic acid: reversibly acting drug?

Valproic acid [dipropylacetic acid (DPA)] was evaluated in an alumina-gel monkey model (N = 12) by constant-rate intravenous infusion. The data indicated: (a) a statistically significant decrease in seizure frequency the first 2 days of drug Step I (45-55 mug/ml) and drug Step II (90-110 mug/ml) which was temporary, lasting 2 days only; (b) a later, more permanent decrease in siezure frequency which was not apparent until drug Setp III (130-170 mug/ml); and a delayed return of the seizure frequency to predrug levels for 2 weeks after drug administration was discontinued, with no DPA detectable in plasma after the initial postdrug day. Whether DPA will behave as a reversibly acting drug was discussed.

Animals↗
PubMed1976

Interactions of phenytoin and phenobarbital in terms of order and temporal spacing of administration in monkeys.

The present study investigated order and temporal spacing interactions of phenytoin and phenobarbital in terms of plasma levels during multiple dosing in monkeys. Phenytoin at a dose of 30 mg/kg and pehnobarbital at a dose of 3 mg/kg and phenobarbital at a dose of 3 mg/kg were administered separately to 4 animals (control group) by nasogastric intubation daily for 10 days. In four subsequent 10-day periods the drugs were administered together in 4 other animals (interaction group) at different times of the day (immediately following one another, 1/2 hr apart, and 6 hr apart) and in a different order of administration (either phenobarbital first and phenytoin later, or the reverse). Blood samples were obtained on the 5th, 8th, and 10th day of each 10-day period. The plasma data indicated: (a) phenytoin is capable of autoinduction, (b) phenobarbital lowers the levels of phenytoin under the four methods of administration studied here, and (c) phenytoin can affect the levels of phenobarbital. The latter interaction is a function of order and temporal spacing of drug administration.

Animals↗
PubMed1976

Avoidance behavior and ileum motility post-cingulumotomy in monkey.

Two experiments were conducted utilizing rhesus monkeys to determine (i) the effects of cingulumotomy on conditioned-avoidance acquisition and extinction and (ii) the effects of avoidance learning on distal ileum motility in control- and cingulum-lesioned animals. Active (AAR) and passive (PAR) avoidance schedules singly or in combination were employed during short daily periods (less than 2 hr) of "shaping," training, acquisition, and extinction. The data indicated that the control-lesion and cingulum groups did not differ in the acquisition or extinction of an AAR. The cingulum group, however, showed a significant deficit in the acquisition of a PAR and a noticeably slower rate of lever pulling during avoidance trials in the combined avoidance training sessions. The results also suggested that ileum motility and avoidance behavior parallel on another, i.e., if either changed the other often changed in the same direction; that cingulum monkeys seemed to be less "reactive" than control-lesion monkeys; and that cingulum animals may been somewhat more regular in their percent daily motility patterns than the control animals.

Animals↗
PubMed1975

Pharmacokinetics of carbamazepine in monkeys following intravenous and oral administration.

The pharmacokinetics of carbamazepine were evaluated in four male rhesus monkeys. A 20-mg/kg dose was administered by intravenous (5-min) infusion and orally (nasal-gastric intubation) in a propylene glycol-ethanol-water solvent. Plasma and urine determinations were performed by GLC. All semilogarithmic intravenous curves exhibited an irregular decay behavior in the first 3-hr period, followed by a linear disappearance phase (T 1/2 equals 1.0-2.4 hr). Urinary excretion measurements confirmed the short elimination half-life and showed that less than 1% of the dose was excreted unchanged. Oral studies also yielded a short elimination half-life (1.0-1.60 hr), which was confirmed by urinary excretion measurements. The oral curves were analyzed pharmacokinetically. The fraction of the dose reaching the systemic circulation ranged between 58 and 87%. Measurable (but insignificant) amounts of drug were found in the feces after intravenous and oral administrations.

Administration, Oral↗
PubMed1975

Efficacy of standard anticonvulsants in monkey model with spontaneous motor seizures.

Monkeys were rendered chronically epileptic by injection of alumina gel into the pre- and postcentral gyrus. To test the validity of this primate model, the effects of diphenylhydantoin (DPH), phenobarbital, and primidone on spontaneous seizures evaluated for 8 months with a Latin-Squar experimental design. All three drugs were effective, the frequency of seizures being reduced by at least one-half during 6 weeks with treatment as compared with 6 weeks without. In most monkeys the frequency and severity of seizures were correlated to the number of interictal spikes in the EEG, and were inversely related to the level of drug in plasma. During withdrawal of phenobarbital and primidone, epileptic activity increased over that during control periods. Side effects were minimal with all three drugs. Patterns of behavior, although they differed from one monkey to the next, exhibited trends specific to each drug but particularly DPH. The seizures of some animals seemed to be related to the sleep-waking cycle.

Aluminum↗