Biomedical subjects

C E Lau

Publications and source records attributed to C E Lau.

At least 55 records · Page 3Linked to original sources

PubMed1995

Oral and IP caffeine pharmacokinetics under a chronic food-limitation condition.

For food-limited rats, serum caffeine was proportional to IP caffeine doses (10-40 mg/kg) for Cmax and area under the curve [AUC(0-24 h)], whereas the three dimethylxanthine (DMX) metabolites of caffeine were disproportional over the dose range. Steady-state concentrations of caffeine and the three metabolites were evident at the 11th day of chronic, daily caffeine IP 20 mg/kg doses. Both caffeine and the three metabolites were dose proportional for Cmax and AUC(0-24 h) by schedule-induced oral caffeine self-administration within the dose range taken (9-38 mg/kg). These results contrast with the nonlinear kinetics of caffeine reported for rats under ad lib conditions. Elimination rate constants (Kel) remained the same for the two routes, but apparent volume of distribution (AVd) and clearance (Cl) were different. The order of the Kel values was caffeine > paraxanthine > theophylline > theobromine. The effects of linear vs. nonlinear caffeine pharmacokinetics may have distinct implications for the resulting pharmacodynamics.

Administration, Oral↗

PubMed1995

Dose-dependent surmountability of locomotor activity in caffeine tolerance.

For two chronic intraperitoneal caffeine dose regimens (10 and 80 mg/kg per day), tolerance developed rapidly (2-3 days) to the stimulatory effects of caffeine on locomotor activity. However, surmountability of the tolerant activity rate levels by caffeine administration was dose dependent: Activity rate was restored fully by acute caffeine administration for the 10 mg/kg per day series, but not for the 80 mg/kg per day series. The extent of tolerance was also dose-dependent: Tolerance was incomplete for the low-dose daily caffeine series but complete for the high-dose series. Upon discontinuation of daily caffeine dosing, activity rate decreased to the original baseline levels for both chronic series. Caffeine tolerance and the quantification of its surmountability may be explained by the pharmacokinetics of caffeine and the upregulation of adenosine receptors.

Animals↗

PubMed1994

Determination of alprazolam and its major metabolites in serum microsamples by high-performance liquid chromatography and its application to pharmacokinetics in rats.

A high-performance liquid chromatographic method using a single-solvent extraction step is described for quantitating alprazolam and its metabolites in rat serum microsamples (50 microliters). The separation used a 2-mm I.D. reversed-phase Ultrasphere C18 column with a mobile phase of methanol-acetonitrile-sodium acetate buffer. By decreasing the methanol content in the mobile phase, triazolam and its metabolites can be extracted and separated using the same method. The detection limit was 5 ng/ml for all the compounds using an ultraviolet detector at 230 nm. The method showed the effect of aging on alprazolam pharmacokinetics following 0.8 mg/kg intravenous bolus alprazolam administration.

Acetates↗

PubMed1994

Acute and chronic nicotine effects on multiple-schedule behavior: oral and SC routes.

For rats responding on a 3 h FI 4 min FR 20 schedule of food reinforcement, presession SC nicotine doses (0.1-0.8 mg/kg) produced depression in all responding followed by stimulation of FI responding that was dependent upon both time and dose. With daily presession 0.8 mg/kg SC nicotine injections for 9 days, no tolerance to the depressive or stimulatory effects of nicotine occurred. When nicotine solutions were orally self-administered by presession exposure to 3 h of schedule-induced polydipsia, the subsequent FR responding was unaffected, but the degree of FI response stimulation and its duration occurred in a dose-related fashion (1.18-4.10 mg/kg). Prolonged daily sessions of oral nicotine self-administration provide a technique for investigating the effects of chronic exposure to nicotine. The postingestive effects of nicotine reveal stimulatory effects that last for at least 3 h.

Administration, Oral↗

PubMed1994

Tolerance to oral and IP caffeine: locomotor activity and pharmacokinetics.

Locomotor activity increase was a bitonic function of acute caffeine IP doses (2.5-40 mg/kg) in rats. When the schedule-induced polydipsic, orally self-administered dose of caffeine was increased over blocks of daily 3 h sessions from 9.3 to 36.5 mg/kg, postsession activity increased monotonically as a function of dose. The rate of tolerance development to the increase in locomotor activity produced by caffeine depended on the route of administration. Tolerance onset occurred on the fourth day of chronic IP doses, but remained incomplete after 21 doses. With the highest dose level of oral caffeine self-administration, tolerance developed on day 13, but remained incomplete even after 17 doses. Acute tolerance occurred for each of the IP doses, whereas a linear relation between locomotor activity and serum caffeine concentration was obtained after oral self-administration. There were two- to threefold higher locomotor activity AUCs(4 h) with oral caffeine at three dose levels compared to the activity AUCs(4 h) for IP doses.

Administration, Oral↗

PubMed1992

Determination of cocaethylene, cocaine and their metabolites in rat serum microsamples by high-performance liquid chromatography, and its application to pharmacokinetic studies in rodents.

A single-solvent extraction step high-performance liquid chromatographic method is described for quantitating cocaethylene in rat serum microsamples (50 microliters), a substance formed in vivo when cocaine and ethanol are present concurrently. The separation used a 2 mm I.D. reversed-phase Nova-Pak C18 column with a mobile phase of acetonitrile-phosphate buffer containing an ion-pairing reagent. With an ultraviolet detector operated at 230 nm, a linear response was observed from 0.05 to 2.0 micrograms/ml with a detection limit of 5 ng/ml for cocaethylene, cocaine and norcocaine. The method showed a longer half-life for cocaethylene than for cocaine in rat.

Administration, Oral↗

PubMed1992

Oral cocaine self-administration: relation of locomotor activity to pharmacokinetics.

Rats were exposed to daily schedule-induced polydipsia sessions in which solutions of cocaine HCl were available. Both cocaine solution concentration (0.08-0.32 mg/ml) and session duration (0.25-3 h) were varied to determine their effects on locomotor activity rate. Additional animals were used to determine the effect of session length on serum cocaine and metabolite levels when drinking 0.32 mg/ml cocaine solution. Changes in locomotor activity rate were related to serum cocaine concentration by a linear concentration-effect model. By estimation from the linear model, the serum cocaine concentration threshold for increasing locomotor activity was about 0.01 microgram/ml. Under these schedule-induction conditions, there was no evidence for the development of acute tolerance to the locomotor-stimulating activity of cocaine.

Animals↗

PubMed1992

Orally self-administered cocaine: reinforcing efficacy by the place preference method.

In three separate place preference conditioning (PPC) experiments, groups of rats were exposed to different modes of receiving cocaine: IP cocaine doses (7.5 mg/kg), PO cocaine self-administered bolus doses (15 mg/kg), and 1-h schedule-induced cocaine-solution drinking sessions (19.1 mg/kg). Oral cocaine self-administration of PO bolus and schedule induction took place in situations that preceded transfer into an apparatus for PPC sessions. Thus, the reinforcing efficacies of the pharmacological consequences of both oral cocaine self-administration methods were evaluated by a procedure separate from the self-administration behavior itself. The IP cocaine dose imposition and the two oral cocaine self-administration arrangements all resulted in dose-exposure conditions sufficient for the production of PPC. The serum and brain cocaine pharmacokinetics sufficient for the production of reinforcing efficacy were measured and related to previous data.

Administration, Oral↗

PubMed1991

Sustained synergism by chronic caffeine of the motor control deficit produced by midazolam.

To evaluate the effects of chronic caffeine on the impairment of discriminative fine motor control produced by midazolam, rats were trained to hold a force transducer steady to deliver food pellets. Chronic, daily doses of midazolam (3 mg/kg SC) led to a stable level of motor impairment. Chronic caffeine (20 mg/kg IP) alone usually produced a more moderate deficit or, for one animal, no deficit. Combined, chronic administration of these doses yielded a sustained synergism in motor performance impairment, which contrasted with the antagonism usually found between the benzodiazepines and methylxanthines when performance is evaluated by psychomotor tests not requiring fine motor control. The observed synergism was not explicable in terms of measured disposition of the drugs. The synergistic production of fine motor dyskinesia by the concurrent administration of caffeine and midazolam may be relevant to the triggering of anxiety attacks by caffeine observed in panic disorder patients.

Animals↗

PubMed1991

Midazolam withdrawal and discriminative motor control: effects of FG 7142 and Ro 15-1788.

Rats chronically drank either water or midazolam solution (0.1 mg/ml) in daily, 3-h schedule-induced polydipsia sessions and were evaluated in daily motor control sessions after polydipsia when midazolam metabolite levels had fallen to zero (withdrawal). Under midazolam polydipsia, animals orally self-administered between 21 and 38 mg/kg daily. The effect of acute drug administration [midazolam (0.75-3 mg/kg, SC), FG 7142 (1-8 mg/kg, IP), Ro 15-1788 (10-20 mg/kg, IP)] on motor control performance was similar after either chronic water or midazolam polydipsia. Thus chronic, oral midazolam self-administration did not lead to tolerance to the motor impairment produced by SC midazolam, nor did the daily discontinuation lead to impaired motor performance, nor had these performances, which occurred after daily elevated midazolam metabolite levels had reached zero (withdrawal), become sensitized to the effects of either the benzodiazepine inverse agonist FG 7142 or the agonist Ro 15-1788.

Animals↗

PubMed1991

Synergism by caffeine and by cocaine of the motor control deficit produced by midazolam.

To evaluate the effects of caffeine and cocaine on the impairment of discriminative motor control produced by midazolam, rats were trained to hold a force transducer operated with a paw so that it remained between upper and lower limits of a force band for a continuous 1.5-s period to deliver each food pellet. Acute doses of 3 mg/kg midazolam SC impaired motor performance. Except for one animal, caffeine (10-40 mg/kg IP) had little or no effect on performance, while cocaine (3.75-22.5 mg/kg IP) produced dose-related impairment. When each dose of caffeine was combined with 3 mg/kg midazolam, a marked synergism in motor performance impairment occurred. Cocaine plus midazolam produced mainly an additive synergism. The conspicuous synergistic action of caffeine on the motor control deficit produced by midazolam contrasts with the typical antagonism found between the benzodiazepines and methylxanthines when performance is evaluated by psychomotor tests not requiring fine motor control.

Animals↗

PubMed1991

Behavioral tolerance to flurazepam.

Rats were trained to earn 180 food pellets in daily, fixed-interval 1-min sessions. When performance had stabilized, a Before group was given a weekly 16 mg/kg flurazepam injection IP for 3 weeks immediately before the sessions, while an After group received their weekly injections immediately after the sessions. Then, the After group received 3 such weekly injections before the sessions. Behavioral tolerance developed by the 2nd flurazepam injection for the Before group, but for the After group, the 3 postsession flurazepam injections resulted in subsequent tolerance to presession flurazepam injection for session lever presses, but not for the time taken to earn 180 pellets. Dispositional tolerance to the serum elimination rate of flurazepam did not develop over the course of 3 injections. Behavioral suppression still evident in the initial portion of sessions with the 2nd and 3rd presession injection coincided with the duration of rising and high levels of serum flurazepam.

Animals↗

PubMed1991

Acute effects of cocaine on spontaneous and discriminative motor functions: relation to route of administration and pharmacokinetics.

Rats administered cocaine i.p. and p.o. (7.5-30 mg/kg) showed dose-related increases in locomotor (LM) and small-movement activities, with LM rates decreasing over the 2-hr session, except at the largest i.p. dose, for which rates were greater in the 2nd hr. Lidocaine p.o. (15-30 mg/kg) did not increase activity. Relating the area under the curve measures for serum cocaine (concentration-time) and LM activity (LM activity-time) for 2 hr postadministration indicated that cocaine was about twice as potent i.p., compared to p.o., in increasing LM activity. Cocaine (i.p. and p.o.) produced dose-related decrements in both discriminative motor control performance and in task work rate, whereas lidocaine p.o. did not. The motor control decrements produced by cocaine were approximately comparable by i.p. and p.o. routes, whereas effects on LM rates were much greater by i.p. than by p.o. administration. The effects of cocaine by both routes on LM rates were proportionally much greater than its effect on motor control performance. Changes in LM rates and motor control performance over the postadministration period were related to the pharmacokinetic features (maximum serum concentration, time to maximum serum concentration and elimination half-life) of cocaine observed for the routes explored (i.p., p.o. and s.c.). Tail-tip serum samples, although yielding conservative estimates of cocaine concentration, correlated well with trunk serum and brain cocaine levels.

Administration, Oral↗

PubMed1991

Chronic oral cocaine self-administration: pharmacokinetics and effects on spontaneous and discriminative motor functions.

Rats receiving repeated doses of oral cocaine (15 mg/kg) showed replicable increases in large-movement and small-movement activity rates, but sensitization to the repeated doses did not develop. With a schedule-induction procedure, as the daily, 3-hr, oral dose of self-administered cocaine increased, marked dose-related increases occurred in both large-movement locomotor activity rate and the time for which these elevations were sustained during the following daily 2-hr activity session. Sensitization developed. At the highest levels of self-administered oral cocaine (about 80 mg/kg), post-administration serum cocaine levels remained undiminished for the activity-session period, as did the large-movement activities of most animals, indicating no development of acute tolerance. Rats receiving repeated doses of oral cocaine (15 mg/kg) showed discriminative motor control deficits as well as increases in work rate. These changes were dose-related in animals self-administering oral cocaine under the schedule-induction procedure. Upon withdrawal of cocaine from the schedule-induction animals, motor behavior returned to precocaine base-line performance for most animals. The behavior of the animal with the largest cocaine intake did not return. After a schedule-induced oral cocaine intake session, the tail-tip and trunk serum measures for cocaine and its metabolites were approximately equivalent, while brain cocaine and norcocaine levels remained markedly elevated over serum values.

Animals↗

PubMed1990

Simultaneous determination of cocaine and its metabolites with caffeine in rat serum microsamples by high-performance liquid chromatography.

A single, isocratic high-performance liquid chromatographic method is described for the determination of cocaine and three of its metabolites along with caffeine in serum microsamples (50 microliters). The small sample size permits the tracking of pharmacokinetic data over time in individual, small animals. The method also was used to demonstrate that cocaine, benzoylecgonine and norcocaine in rat serum samples were stable for at least a month without the presence of sodium fluoride.

Animals↗

PubMed1990

Motor performance decrement by midazolam: antagonism by Ro 15-1788 and CGS 8216.

Rats were trained in a fine motor control performance that required operation by a paw of a force transducer so that it remained between upper and lower limits of a force band for a continuous 1.5-sec period to deliver each food pellet. Acute doses of midazolam (0.75-3.0 mg/kg, SC) impaired indices of motor performance in a graded, dose-related fashion. When administered alone, Ro 15-1788 (0.1-5.0 mg/kg, SC) had no effect on motor behavior while CGS 8216 (0.5 and 1.0 mg/kg, IP) alone had small effects. In general, the motor performance decrements produced by midazolam were antagonized in a dose-related fashion by both Ro 15-1788 and CGS 8216.

Animals↗

PubMed1990

Diazepam and discriminative motor control: acute, chronic and withdrawal effects.

Rats were trained to hold a force transducer operated with a paw so that it remained between upper and lower limits of a force band for a continuous 1.5-sec period to deliver each food pellet. Acute doses of diazepam impaired measures of this performance. Separate groups received chronic diazepam injections (6 mg/kg, IP) either presession (Before Group) or postsession (After Group), or presession vehicle (Vehicle Group). The After and Vehicle Groups demonstrated that neither chronic postsession diazepam, nor time alone, altered motor performance. The performance of the Before Group was affected by the daily diazepam, and although tolerance to the impairment developed, it was incomplete. Late in the chronic-administration phase (after 75 days) a toxic effect of the suspending agent became evident in all groups as a decrease in work rate, although the other performance indices were not affected. The withdrawal of diazepam from the Before Group led to improved performance which returned to the original baseline level.

Animals↗

PubMed1990

Schedule-induced cocaine drinking: choice between cocaine and vehicle.

Rats were exposed to daily 3-hr schedule-induced polydipsia sessions (fixed-time 1-min food-pellet delivery) with two drinking fluids available: cocaine solution and water. Fluid position was alternated daily. Polydipsia occurred mostly from a preferred-side spout (position preference) until cocaine solution concentration was increased to between 0.52 and 1.04 mg/ml and animals drank mostly water. Within a lower concentration range (0.28-0.6 mg/ml) maximum session cocaine intakes ranged from 54.3 to 120.1 mg/kg. Postsession serum cocaine levels were about 200 ng/ml. At individually chosen cocaine solution concentrations, the addition of saccharin to the solution did not increase cocaine intake, but a compound solution (saccharin plus glucose) did. With progressive dilution of the compound vehicle, an almost complete preference for cocaine solution was maintained. But with a return to water as the vehicle, animals reverted to a position preference after a few sessions, although one maintained a clear cocaine preference. Schedule-induced polydipsia produced chronic, oral self-administration of cocaine resulting in pharmacologically significant intakes and serum levels.

Animals↗