Biomedical subjects

C E Lau

Publications and source records attributed to C E Lau.

At least 37 records · Page 2Linked to original sources

PubMed1999

Dose independent pharmacokinetics of caffeine after intravenous administration under a chronic food-limited regimen.

Several studies have shown that caffeine follows non-linear pharmacokinetics in both rats and humans. Recent data have demonstrated that caffeine may following linear pharmacokinetics when administered orally and intraperitoneally to food-limited rats. In this study the pharmacokinetics of caffeine was analyzed following intravenous (i.v.) administration to rats under a food-limited regimen. Four rats were administered four doses of caffeine and a standard dose of the caffeine metabolites, paraxanthine, theobromine, and theophylline. Caffeine pharmacokinetic parameters were dose independent following intravenous doses ranging from 1 to 20 mg/kg. Furthermore, the caffeine area under the curve (AUC) increased linearly as a function of dose. The mean fraction of caffeine converted to paraxanthine, theobromine, and theophylline was 16%, 16%, and 7%, respectively. The linear pharmacokinetics demonstrated in the present study may be attributed to the induction of hepatic metabolism under a chronic food-limited regimen.

Animals↗

PubMed1999

A double-peak phenomenon in the pharmacokinetics of alprazolam after oral administration.

The pharmacokinetics of alprazolam (ALP) after i.v. and p.o. administration in rats were characterized. ALP decayed biexponentially after the i.v. dose (1.25 mg/kg), but the concentration-time profiles after the p.o. doses (7 and 12.5 mg/kg) exhibited a double-peak phenomenon. The presence of two peaks was confirmed by statistical analysis of the serum concentration data of ALP, as well as by observed double peaks in the serum concentration-time profiles of the two active metabolites (alpha-hydroxyalprazolam and 4-hydroxyalprazolam). An absorption model incorporating a delay site is proposed to describe the data, and the absolute oral bioavailability is estimated to be about 30%. The two peaks were approximately 80 to 115 min apart, and there was a delay in the absorption of close to 80% of oral ALP, regardless of dose. We hypothesize that the mechanism underlying the double-peak phenomenon is due to reduction in gastric motility caused by the muscle relaxant effect of ALP. This hypothesis is supported by the observed longer delay in the appearance of the second peak at the higher p.o. dose. Enterohepatic recycling is precluded from being the underlying mechanism, because of the presence of double peaks after the p.o. doses but not after the i.v. dose. This is the first reported case of double peaks for oral ALP, and this phenomenon has not been reported for other benzodiazepines. The double-peak phenomenon caused by the hypothesized mechanism may have important therapeutic and drug interaction implications, especially because benzodiazepines are commonly coadministered with other drugs.

Administration, Oral↗

PubMed1999

Pharmacokinetic-pharmacodynamic modeling of the psychomotor stimulant effect of cocaine after intravenous administration: timing performance deficits.

We investigated dose-response cocaine pharmacokinetic and metabolite profiles in a within-subject design after intravenous bolus cocaine administration (1-4 mg/kg) in rats under a food-limited regimen. Cocaine was rapidly distributed (T1/2beta = 1.09 min) and eliminated (T1/2alpha = 14.93 min). Norcocaine was not detected. The free fraction of cocaine was 31.3-33.1% for serum cocaine concentrations of 0.5 to 1 microg/ml. Parallel pharmacodynamics was studied using performance on a contingency-controlled timing behavior, a differential reinforcement of low rate schedule (45 s) in 3-h sessions. Cocaine increased the shorter-response rate and decreased the density of reinforcement in a dose- and time-related fashion. The increased shorter-response rate is the stimulatory effect herein reported. The changes in shorter-response rate and the density of reinforcement were directly interpretable as functions of cocaine concentrations in the respective hypothetical effect compartments by using sigmoidal Emax and inhibitory Emax models, respectively. Because the concentration at half of Emax for the shorter-response rate (EC50 = 0.467 microg/ml) was greater than that for density of reinforcement (IC50 = 0.070 microg/ml), the former began to return toward baseline sooner than the latter. Only as cocaine concentration decreased to values smaller than the EC50 did the density of reinforcement begin to return toward baseline. Thus, the density of reinforcement is an index for evaluating the deficit in timing performance. The concentration-effect plot confirmed that the intensity of the effects of cocaine depends solely on concentration regardless of the dose. These results demonstrated that the pharmacokinetic-pharmacodynamic analysis allows the identification of the stimulant action of cocaine, which in turn delineates its consequence on timing performance.

Animals↗

PubMed1998

Determination of clozapine and its metabolite, N-desmethylclozapine, in serum microsamples by high-performance liquid chromatography and its application to pharmacokinetics in rats.

A single solvent extraction step high-performance liquid chromatographic method is described for quantitating clozapine and its metabolite, N-desmethylclozapine, in rat serum microsamples (50 microl). The separation used a 2.1-mm I.D. reversed-phase Symmetry C18 column with an isocratic mobile phase consisting of methanol-acetonitrile-28.6 mM sodium acetate buffer, pH 2.6 (10:20:70, v/v/v). The detection limit was 2.5 ng/ml for all the compounds using an ultraviolet detector operated at 230 nm. The method was used to study the pharmacokinetics of clozapine after an intravenous bolus dose (2.5 mg/kg).

Animals↗

PubMed1998

Pharmacokinetic-pharmacodynamic modeling of the coexistence of stimulatory and sedative components for midazolam.

Midazolam increased the shorter-response rate and decreased the reinforcement rate of a contingency-controlled timing behavior--a differential-reinforcement-of-low-rate 45-s schedule. The responding rate changes observed were immediately interpretable as functions of midazolam concentration during a 3-h session--a period for investigating the onset, peak, and disappearance of midazolam effect--in rats. That the midazolam pharmacokinetic-pharmacodynamic model was a direct application of our alprazolam pharmacokinetic-pharmacodynamic model implies that both drugs exhibit similar pharmacological effects. The two peaks of the shorter-response rate increases produced by midazolam were modeled as a stimulation-sedation model that consisted of two opposing effect-link sigmoidal Emax functions. The stimulation-sedation model suggested that midazolam possesses both stimulatory and sedative effects in a continuous but sequential fashion, and hypothesizes the coexistence of stimulation and sedation components for midazolam; this model may help delineate possible mechanisms for rebound side effects and of tolerance in humans. The reinforcement rate was, then, an index for evaluating the deficit in timing performance.

Algorithms↗

PubMed1998

Caffeine has similar pharmacokinetics and behavioral effects via the i.p. and p.o. routes of administration.

Caffeine administered intraperitoneally (i.p.) or orally (p.o.) decreased the reinforcement rate and increased the nonreinforced response rate in a dose-related fashion under a differential reinforcement of low rate schedule (DRL 45-s) in 3-h sessions. These effects were similar following both routes of caffeine administration. The parallel pharmacokinetics for i.p. and p.o. caffeine were each determined and related to the respective effects of caffeine on reinforcement rate. Serum caffeine concentrations were similar across the session after the absorption phase for a given dose. Consequently, the effect remained in approximately the same range within a dose, and no single dose possessed a full concentration-effect relation for the two routes. The effects of i.p. and p.o. caffeine on reinforcement rate plateaued at doses higher than 40 mg/kg, which produced a serum caffeine concentration of approximately 25 microg/ml regardless of the route of administration. The EC50 values were 7.34 and 9.93 microg/ml for i.p. and p.o. caffeine, respectively. This study as well as our previous studies demonstrated that the i.p. route is dependable for studying caffeine dose response relations but not for studying other drugs (e.g., midazolam). The possible mechanism accounting for this difference is discussed.

Administration, Oral↗

PubMed1997

Establishing preference for oral cocaine without an associative history with a reinforcer.

Using schedule-induced polydipsia (SIP), a stable, oral, preference for cocaine solution to water presented concurrently can be established by first presenting cocaine in a preferred vehicle, and subsequently fading the vehicle to water. The present study showed that rats exposed to a history of choosing 0.48 mg/ml cocaine in preference to concentrated lidocaine (2 mg/ml) under SIP conditions subsequently maintained this preference when the lidocaine concentration was progressively decreased to zero (water). Preference for lidocaine was tested by fixing it at 0.38 mg/ml (equimolar with 0.48 mg/ml cocaine) while subsequently increasing cocaine from 0.48 mg/ml to 2.5 mg/ml. Lidocaine preference did not occur, rather, preference for concentrated cocaine persisted. The results suggest that the avoidance of lidocaine solution may force the discrimination of the relation between high oral cocaine intake and its reinforcing effects, thereby instituting a stable preference for cocaine.

Administration, Oral↗

PubMed1997

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

A single-solvent extraction step high-performance liquid chromatographic method is described for quantitating cocaine and its three metabolites in rat serum microsamples (50 microl). The separation used a 2.1-mm I.D. reversed-phase Brownlee C18 column with an isocratic mobile phase consisting of methanol-acetonitrile-25.8 mM sodium acetate buffer, pH 2.2, containing 1.29-10(-4) M tetrabutylammonium phosphate (12.5:10:77.5, v/v/v). The detection limit was 2.5 ng/ml for all the compounds using an ultraviolet detector operated at 235 nm. The method was used to study the pharmacokinetics of cocaine after an intravenous (i.v.) bolus dose (4 mg/kg).

Animals↗

PubMed1997

Independent interaction of alprazolam and caffeine under chronic dose regimens on differential reinforcement of low-rate (DRL 45-s) performance.

In previous research, we found an independent interaction of alprazolam and caffeine in rats under acute dose regimens using two measures (reinforcement rate and shorter-response rate) of a differential reinforcement of low rate performance (DRL 45-s) in 3-h sessions. Applying the same behavioral endpoints, the present study investigated the alprazolam-caffeine interaction under chronic dose regimens. Both drugs were administered by the oral route. Acute alprazolam and caffeine dose-response curves (DRCs) were characterized and were then used to determine the maintenance dose for the respective chronic dose regimens. Both drugs decreased the reinforcement rate and increased the shorter-response rate in a dose-related fashion. An alprazolam DRC also was determined during chronic-caffeine, chronic-alprazolam, and concurrent chronic-caffeine-alprazolam dose regimens. Complete tolerance to caffeine-induced rate changes was observed on the second day. Incomplete tolerance occurred only at higher alprazolam doses (7-12.5 mg/kg). Cross tolerance was not found between alprazolam and caffeine. Upon discontinuation of both drugs, performance progressively returned to baseline. The four alprazolam DRCs as well as the effect-time profiles demonstrated that caffeine altered neither the magnitudes nor the patterns of alprazolam effects on the two rates under chronic dose regimens. The Pöch DRC method further confirmed the independent interaction of alprazolam and caffeine. Thus, the independence of the interaction held for both the acute and chronic dose regimens despite the development of tolerance in the latter regimens.

Alprazolam↗

PubMed1997

Schedule induction conditions not only exaggerate intake but also enhance drug solution choice.

In previous research, rats exposed to daily, 3 h sessions of schedule-induced polydipsia (SIP) self-administered high doses of cocaine orally. However, a strong and durable preference for cocaine solution to water requires training in addition to mere oral self-administration exposure. If cocaine is dissolved in a preferred vehicle solution, and the vehicle is subsequently faded to water, then a strong preference for cocaine remains. A similar preference can be instituted for lidocaine solution. Such preferences may develop because the gustatory property of a drug becomes associated with the preferred vehicle and remains to function as a durable conditioned reinforcer after vehicle fading. To determine if drug preference is solely a function of this posited conditioning mechanism, or whether it also depends upon the SIP condition, rats were exposed to daily, 3 h sessions of single-ration feeding, rather than the SIP condition. A preferred vehicle (glucose/saccharin solution) was slowly faded from a 0.19 mg/ml lidocaine solution, which was presented concurrently with a choice for water. Although a preference for lidocaine solution to water could be generated, it occurred for only 5 out of 9 rats, and the preference was relatively unstable. By contrast, in two previous studies using SIP, 26 out of 27 rats maintained a preference for lidocaine solution. Thus, SIP not only exaggerates the amount of drug solution ingested but also contributes to the fixation of the associative drug solution choice.

Animals↗

PubMed1997

Differential reinforcement of low rate performance, pharmacokinetics and pharmacokinetic-pharmacodynamic modeling: independent interaction of alprazolam and caffeine.

To investigate the interaction between alprazolam and caffeine, performance on a differential reinforcement of low-rate behavior schedule and the respective pharmacokinetics (PK) were explored in concurrent studies. Alprazolam PK was not altered by caffeine, but alprazolam retarded caffeine absorption indirectly, as inferred by the lack of i.v. drug administration PK interaction, thereby decreasing serum methylxanthine concentrations. Inasmuch as alprazolam was more potent and short-lived than caffeine in decreasing the reinforcement rate (consonant with their respective t(1/2) values, 0.44 and 3.1 hr), the alprazolam/caffeine potency ratio decreased across the session time, which determined the expression of the combined effects. Thus, the decreased methylxanthine level yielded slightly less disruption in performance for the observed combined effect, compared to the expected calculated effect, only near the end of a session. The interaction was PK linked and mainly not distinguishable from independence as indicated by the Poch dose-response curve method and the integration of PK and pharmacodynamics. The sigmoid maximal effect-link pharmacodynamic model indicated that caffeine did not alter the concentration at half of the maximal effect value of alprazolam and suggested that the interaction is not competitive, but independent. Although the nature of the benzodiazepine-methylxanthine interaction has been controversial in other behavioral studies, as is the role of PK in determining behavior, this and our previous study make it evident that the interaction is independent not only across doses and routes of administration, but also with respect to two indices of differential reinforcement of low rate performance.

Alprazolam↗

PubMed1997

Pharmacokinetic-pharmacodynamic modeling of stimulatory and sedative effects of alprazolam: timing performance deficits.

Alprazolam decreased the reinforcement rate and increased the shorter-response rate of contingency-controlled timing behavior under a differential reinforcement of low-rate schedule (DRL 45-s) in rats. An integrated pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe and characterize the effects of i.v. and s. c. administration of alprazolam. The onset, peak and disappearance of alprazolam effects were evaluated during a 3-hr session. After s. c. alprazolam administration, two peak increases in shorter-response rate occurred at moderate alprazolam serum levels, first in the ascending and then in the descending limb of the concentration-time profile. We used a stimulation-sedation PD model incorporating two opposing effect-link sigmoidal Emax functions to model the two peaks after s.c. alprazolam administration. The model suggested that alprazolam possesses both stimulatory and sedative effects in a continuous but sequential fashion, which corresponded to low- and high-concentration effects as indicated by the EC50 values of 0.09 and 0.18 microg/ml, respectively. Owing to the rapid onset of i.v. administration, the first peak (a transition phase before the onset of the sedative effect) was absent, with the presence of the second peak again coinciding with the offset of the sedative effect. The reinforcement rate (IC50 = 0.02 microg/ml) characterized by the indirect response model to account for the initial hysteresis is an index for evaluating the deficit in timing performance. Although the effects of alprazolam can be described in behavioral terms, simultaneous PK-PD optimization numerically defines the performance and hypothesizes the coexistence of stimulation and sedation components for alprazolam. The stimulation-sedation model may help in delineating the possible mechanisms for adverse rebound side effects and of tolerance in humans.

Alprazolam↗

PubMed1996

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

A single-solvent extraction step high-performance liquid chromatographic method is described for quantitating midazolam and its two hydroxy metabolites in rat serum microsamples (50 microliters). The separation used a 2 mm I.D. reversed-phase Symmetry C18 column with an isocratic mobile phase consisting of methanol-acetonitrile-14.9 mM sodium acetate in water at pH 3.0 (10:23:67, v/v). The detection limit was 10 ng/ml for all the compounds using an ultraviolet detector operated at 230 nm. The method was used to study the pharmacokinetics of midazolam after an intravenous bolus dose (0.75 mg/kg).

Animals↗

PubMed1996

Alprazolam, caffeine and their interaction: relating DRL performance to pharmacokinetics.

Three-hour sessions of differential reinforcement of low-rate behavior (DRL 45-s) in rats were used to investigate alprazolam, caffeine, and their interactions at the onset, peak and disappearance of serum alprazolam, while caffeine level remained constant. The dose-response curve (DRC) method of Pöch permitted an extensive evaluation of the kind (additivity or independence) of interactions occurring in combined drug effects. The alprazolam and caffeine DRCs were used to derive theoretical additive and independent relations, and the observed combined effects compared to these functions. Behavior-time profiles of the combined effects were similarly compared. Serum alprazolam and caffeine concentrations correlated with their respective behavior-time profiles. No acute tolerance was observed either for the individual drugs or their combinations. Alprazolam was more potent than caffeine in disrupting DRL behavior. Because alprazolam is much shorter-lived (t1/2 = 32 min) than caffeine (t1/2 = 3 h) in rats, potency ratios between alprazolam and caffeine changed across session time (from 123 to 4), which determined the expression of the combined effects. Although the combined effects were not distinguishable in terms of additivity or independence in both the DRCs and in the behavior-time profiles, they showed neither synergism nor antagonism. The pharmacokinetics of alprazolam were not altered by caffeine, but those of caffeine were affected by alprazolam.

Alprazolam↗

PubMed1996

Pharmacokinetics and bioavailability of midazolam after intravenous, subcutaneous, intraperitoneal and oral administration under a chronic food-limited regimen: relating DRL performance to pharmacokinetics.

The effects of midazolam on animal behavior often are evaluated under a chronically food-limited regimen, which is used to implement food-reinforced performance, but the corresponding pharmacokinetics are lacking. The present study investigated the pharmacokinetics of midazolam after i.v., s.c., i.p., and p.o. administration in food-limited rates. A two-compartment model best described the concentration-time profiles for the four routes of administration. The rate of midazolam absorption was rapid, and peak concentrations were attained in less than 7 min for the three extravascular routes. The mean volume of distribution of the central compartment and clearance were 0.77 l/kg and 2.03 l/h per keg, respectively. Midazolam elimination half-lives for the four routes of administration ranged from 23.1 to 49.5 min, and metabolites could not be detected. The mean absolute bioavailability was route-dependent: 39.3% (s.c.) 19.2% (i.p.) and 4.6% (p.o.). The markedly low oral bioavailability found in food-limited rats contrasted to the value reported for free-feeding rates (45%). Although the i.p. route yielded the highest maximum concentration on occasion, serum midazolam concentration-time profiles were variable, but did correspond to respective sedative responses. DRL 45-s performance after s.c., i.p., and p.o. administration further supported the advisability of using the s.c. route of administration, as opposed to the i.p. route, for studying midazolam dose-response relations. The bioavailability values assessed from DRL performance also agree with the measured pharmacokinetic values.

Administration, Oral↗

PubMed1996

Conditions sufficient for the production of oral cocaine or lidocaine self-administration in preference to water.

Groups of rats were given a chronic history of drinking cocaine solutions of different concentrations in daily, 3-h schedule induced polydipsia sessions. Animals failed to develop a preference for cocaine solution to concurrently presented water. Schedule-induction conditions were maintained, and the animals were divided into separate groups, drinking either cocaine or lidocaine placed in a highly acceptable vehicle (glucose-saccharin solution). Animals preferred their respective drug solutions to concurrently presented water, and these preferences remained stable after the glucose-saccharin vehicle was gradually faded to water, leaving only cocaine or lidocaine, respectively, in the solution. Thus a stable preference for drug solution to water could be instituted in rats for either cocaine or lidocaine solution (putative reinforcing and nonreinforcing agents, respectively) given an appropriate associative history, with high intakes maintained by schedule-induction. Conditions sufficient for the initiation of an oral preference and high intake for a putatively reinforcing drug cannot be assumed to occur owing to the drug's reinforcing property in the absence of demonstrating the ineffectiveness of an appropriate negative control substance.

Administration, Oral↗

PubMed1996

Tolerance to the anxiolytic effects of the triazolobenzodiazepines triazolam and alprazolam, as measured by the ingestion of a hypertonic sodium chloride solution in rats.

Rats were adapted to a water-deprivation regimen that allowed daily 1-hr drinking sessions of a single fluid, either 1.5% NaCl solution or water. Oral, presession, acute doses of triazolam (0.05-1.6 mg/kg) or alprazolam (0.4-6.4 mg/kg) produced dose-related increases in session NaCl solution ingestion. The relative potencies found for these two drugs approximated their relative Ki values reported in the literature. The increased ingestion produced in this and other experiments by anxiolytic agents is presented as an alternative way of evaluating punishment attenuation, and hence anxiolytic activity. Chronic oral dosing (every 2nd day) with triazolam (0.2 mg/kg) or alprazolam (1.2 mg/kg) led, after several weeks, to partial, but surmountable, tolerance to the increased NaCl solution ingestion produced by these drugs, which was confirmed by a rightward shift in the dose-effect relations. During chronic dosing, no corresponding declines in the independently evaluated increases in water intake produced by these drugs occurred. Abrupt drug discontinuation produced a precipitous decrease in NaCl solution intake, with subsequent recovery. For triazolam, the initial discontinuation decrease in intake to below the original base line suggested the possible accrual of a mild physiological dependence under this moderate chronic dose regimen.

Alprazolam↗

PubMed1995

Stimulus control of addictive behavior: persistence in the presence and absence of a drug.

Rats were exposed daily to a food schedule-induced polydipsia condition, in which water and 0.16 mg/ml cocaine solution were available concurrently, with the cocaine solution indicated by a discriminative stimulus (SD) light. The cocaine solution was preferred, and the preference was maintained when the SD was gradually eliminated by fading its intensity. For a second group, if cocaine concentration was the stimulus gradually eliminated, preference for the resulting solution (water) indicated by the SD was stably maintained. For two additional groups, if either the light SD or the cocaine stimulus was removed abruptly rather than gradually, few animals retained preferences. These studies reveal the importance of establishing strong stimulus control for the initiation and persistence of drug abuse behavior.

Animals↗