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PubMed1986

Human coffee drinking: reinforcing and physical dependence producing effects of caffeine.

In a residential research ward coffee drinking was studied in nine volunteer human subjects with histories of heavy coffee drinking. The presence or absence of caffeine in the coffee was manipulated under double-blind conditions by using caffeinated (C) or decaffeinated (D) coffee. When subjects were switched alternately for 10 or more consecutive days between C and D, the daily number of cups consumed tended to be relatively stable. In a different experiment, preference for C vs. D was assessed. After experimenter-scheduled exposures, subjects were given choices between C and D. When subjects were presumably caffeine tolerant/dependent, C was rated as being better liked than D and was reliably preferred to D in choice tests. When subjects were not caffeine tolerant/dependent, C was not reliably preferred to D, nor were there pronounced differences in ratings of liking. Under these conditions, some subjects preferred D to C, citing adverse symptoms (suggesting caffeine toxicity) as reasons for avoiding C. The effects of caffeine withdrawal were studied by abruptly substituting D for C for 10 or more days. This resulted in an orderly withdrawal syndrome, having an onset latency of 19 hr, peaking on days 1 and 2, and decreasing progressively over the next 5 or 6 days. The withdrawal syndrome, which was detected on subject-rated, staff-rated and objective behavioral measures, was characterized by increased headache, sleepiness and laziness and decreased alertness and activeness. The present study demonstrates the reinforcing effects of caffeine in humans and also documents the severity of the caffeine withdrawal syndrome. It is concluded that caffeine has the cardinal features of a prototypic drug of abuse.

Adult↗
PubMedDate not supplied

Maternal caffeine use before, during and after pregnancy and effects upon offspring.

Prospective information gathered through the course of pregnancy, perinatal measurements, and retrospective data collected postnatally were used to investigate the changing patterns and effects of caffeine use of 286 women participating in the Ottawa Prenatal Prospective Study. Data were collected on maternal use of tea, coffee, caffeinated soft-drinks, chocolate bars and drinks and caffeinated medication. The volume and analysed caffeine concentration of 53 samples of coffee and tea, prepared by subjects as they usually consumed it, were used to examine the predictive potential of the women's subjective description of the beverages. Self-reports of volume and beverage strength were found to be valid predictors; the method of coffee preparation held little predictive power. An algorithm for estimating caffeine intake retrospectively over time was developed. During pregnancy most women continued to consume caffeine but usually at lower intake levels. After pregnancy, caffeine consumption tended to persist at reduced levels for several months and then returned to prepregnancy patterns. Maternal caffeine intake of more than 300 mg daily during pregnancy was associated with lowered birth weight and smaller head circumference of the infant after accounting for maternal nicotine use. No relationship was apparent between maternal caffeine use and the incidence of caesarian sections, breech births, miscarriages or premature births.

Adult↗
PubMed1984

Behavioral effects of caffeine, N6-(L-phenylisopropyl) adenosine and their combination in the squirrel monkey.

The behavioral effects of caffeine, N6-(L-phenylisopropyl)adenosine (PIA) and the two drugs in combination were studied in squirrel monkeys. Monkeys responded by pressing a lever under different schedules of reinforcement involving either food or electric shock. The effects of caffeine depended primarily on the type of schedule that controlled responding and were largely independent of the type of consequent event. When responding was maintained at high rates under fixed-ratio schedules of either food presentation or stimulus-shock termination, caffeine (1-56 mg/kg) typically decreased responding in a dose-dependent manner. When responding was maintained at moderate rates under fixed-interval schedules involving either event, intermediate doses of caffeine (3-10 mg/kg) slightly increased responding, whereas higher doses decreased responding. When responding was maintained under a fixed-interval schedule of stimulus-shock termination and concurrently suppressed by response-produced shock, intermediate doses of caffeine (3-30 mg/kg) markedly increased responding. PIA (0.03-1 mg/kg) only decreased responding under all schedules. Caffeine (1-30 mg/kg) antagonized the rate-decreasing effects of PIA under each schedule. PIA (0.03-1 mg/kg) reduced or eliminated the rate-increasing effects of intermediate doses of caffeine under the fixed-interval schedules but did not attenuate the rate-decreasing of high doses of caffeine under any schedule. Thus, the rate-increasing and rate-decreasing effects of caffeine differed in their susceptibility to modification by PIA.

Adenosine↗
PubMed1983

Lack of pharmacological active saliva levels of caffeine in breast-fed infants.

Caffeine, which is used for the treatment of apnoea in premature newborns, is known to be excreted into breast milk. However data on the amount of caffeine transferred to the breast-fed infant and on caffeine concentrations in the baby are lacking. In 18 healthy breast-feeding women caffeine concentrations in breast milk were measured 2 and 4 hours after the intake of coffee (145.8 mg caffeine, mean +/- sd, n = 18). For an estimation of kinetic parameters (eg, AUC), additional saliva samples were collected up to 6 hours after coffee intake. The daily caffeine intake of the infants was calculated from the average breast-milk concentration (AUCsaliva X milk/saliva ratio/24 hours) as average milk concentration X daily milk volume. From nine of the babies (aged 20 days to 19 weeks) at least one saliva sample could be obtained. The ratio milk/saliva was found to be 0.90 +/- 0.20 (mean +/- sd, n = 18) and the average breast-milk concentration was 0.82 +/- 0.29 mg/L (mean +/- sd, n = 18). The daily caffeine intake of the infants was calculated to range from 0.027 to 0.203 mg/kg/day. The caffeine concentrations measured in the babies ranged from less than 0.05 to 0.75 mg/L. Hence it can be concluded that the amount of caffeine ingested by the children is small compared to the therapeutic dose if usual amounts of coffee are taken by the mothers.

Adult↗
PubMed1983

Pharmacology, pharmacokinetics, and behavioral effects of caffeine in horses.

Caffeine (4 mg/kg) was given by rapid IV injection to 4 horses. Plasma concentrations of the drug peaked at 10 micrograms/ml and decreased rapidly at first, and then more slowly, with an apparent beta-phase half-life of 18.2 hours. Urinary concentrations of caffeine were remarkably consistent at about 3 times plasma values of the drug. Caffeine was detectable in both plasma and urine of the horses for up to 9 days after dosing. After oral administration, caffeine was absorbed poorly with an apparent bioavailability of 39%. Although blood concentrations of caffeine peaked rapidly after oral administration, its apparent plasma half-life by this route was about 42 hours. These observations identify the possible existence of a slowly absorbed pool of caffeine in the gastrointestinal tract after oral administration. When caffeine-treated horses were given fentanyl, the locomotor response to fentanyl was enhanced. This potentiation of the fentanyl response peaked at between 0 and 4 hours after dosing and was gone by 72 hours after caffeine dosing. The data indicate that the probability of behavioral stimulation due to caffeine by 72 hours after dosing may be small.

Administration, Oral↗
PubMed1995

Effect of caffeine on myocardial blood flow at rest and during pharmacological vasodilation.

UNLABELLED: Stress testing with intravenous injection of dipyridamole is frequently used for noninvasive detection of coronary artery disease (CAD) with PET or SPECT. Dietary intake of caffeinated food, beverages or medication might alter both resting and dipyridamole-induced hyperemic blood flow, thereby compromising the diagnostic sensitivity of dipyridamole stress testing. METHODS: To quantify the effect on myocardial blood flow at rest and during intravenous injection of dipyridamole, 12 healthy volunteers (mean age 27 +/- 6 yr) with low risk for CAD were studied with dynamic PET and a tracer kinetic model for 13N-ammonia after 24 hr of caffeine abstinence and after caffeine intake. RESULTS: Caffeine tended to increase the rate pressure product from 6873 +/- 1494 to 7566 +/- 1102 (p = 0.051), whereas resting myocardial blood flow remained unchanged (0.61 +/- 0.13 versus 0.58 +/- 0.07 ml/g/min, p = ns). The heart rate response to dipyridamole was inversely related to serum caffeine levels. Hyperemic blood flow (2.01 +/- 0.46 versus 1.31 +/- 0.0.38 ml/g/min; p < 0.001) and flow reserve (3.4 +/- 0.8 versus 2.3 +/- 0.7; p < 0.001) were inversely related to the caffeine dose. Coronary vascular resistance at rest tended to increase (132 +/- 32 versus 147 +/- 25 mmHg/ml/g/min; p = 0.06), whereas minimal coronary vascular resistance was significantly higher after caffeine (41 +/- 9 to 69 +/- 25 mmHg/ml/g/min; p < 0.01). CONCLUSION: Caffeine intake alters the coronary vasomotor tone at rest, which might lower the threshold for ischemic events in patients with CAD. It reduces hyperemic blood flow and flow reserve and the dipyridamole-induced increase in heart rate in a dose-dependent fashion. These findings emphasize the importance of carefully screening patients for intake of caffeinated food, beverages or medication prior to dipyridamole stress testing.

Adult↗
PubMed1995

Intravenous caffeine in stimulant drug abusers: subjective reports and physiological effects.

The present study was conducted to examine the self-reported (i.e., subjective) and physiological effects of intravenous caffeine in 10 subjects with histories of stimulant drug abuse. Under double-blind conditions, subjects received each dose of caffeine (0, 37.5, 75, 150 or 300 mg/70 kg) twice according to a latin-square design; injections were 10 sec in duration and separated by at least 24 hr. Effects were measured before injection and repeatedly afterward for 60 min. Caffeine dose-dependently increased ratings of positive mood (e.g., increased ratings of drug liking and high), which peaked at 2 min after injection and progressively decreased. Caffeine also dose-dependently increased the frequency of stimulant identifications on the Pharmacological Class Identification Questionnaire (e.g., like cocaine, amphetamine). Caffeine also produced negative-mood effects (e.g., increased ratings of bad effects) and increases in self-reported desire for cocaine. In contrast to the positive-mood effects, the negative-mood effects were of smaller magnitude and only significant at the highest dose. Caffeine increased reports of unusual smells and tastes. Caffeine decreased heart rate (7 bpm) and skin temperature (4 degrees C), and increased systolic and diastolic blood pressures (8 and 6 mm Hg, respectively). The mood effects but not the physiological effects of intravenous caffeine were similar to those previously observed with cocaine in studies using similar methods and subjects. Intravenous caffeine administration may provide a useful model system for investigating factors relevant to the use and abuse of stimulant drugs.

Adult↗
PubMed1994

Caffeine as a probe for CYP1A2 activity: potential influence of renal factors on urinary phenotypic trait measurements.

Two established caffeine-based urinary methods for measuring CYP1A2 activity were compared with each other, and also with the systemic clearance of caffeine which served as a standard of reference for such activity. Following a standardized dose, caffeine (137X) and its metabolites were measured in urine and plasma of 39 healthy subjects. The measurements allowed determinations of: (1) systemic caffeine clearance (CL(caff)); (2) the caffeine metabolite ratio (AFMU + 1X + 1U)/17U determined in an overnight-urine specimen and referred to as CMR, and (3) the ratio (17X + 17U)/137X measured in urine collected between 4 and 5 h after caffeine intake and referred to as PCUR for 'paraxanthine-caffeine urinary ratio'. The PCUR showed a bimodal distribution and a relatively wide variation, CL(caff) and CMR were both normally distributed. The correlation between CL(caff) and CMR was r = 0.77 (p < 0.001), between CLcaff and PCUR r = 0.46 (p < 0.01), and between CMR and PCUR r = 0.40 (p < 0.02). The difference between the correlation coefficients 0.77 and 0.46 was statistically significant (z-test; p < 0.05). The well established decrease of caffeine metabolism by oral contraceptive use was observed with both CL(caff) and CMR but not with PCUR. Examination of possible explanations for the differences between PCUR and CMR led to the finding of a correlation between PCUR and the renal clearance of caffeine (CLr) with r = -0.47 (p < 0.01). Further scrutiny demonstrated that a bimodal or non-normal frequency distribution as shown by PCUR was also shown by CLr and by urine flow rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Effects of caffeine on the metabolic and catecholamine responses to exercise in 5 and 28 degrees C.

The influence of caffeine on the metabolic and catecholamine responses to mild exercise in a cold and a warm environment was studied in eight healthy males. The subjects performed 60 min of cycling at 50% VO2max in a cold environment (5 degrees C and 70% relative humidity) and a warm environment (28 degrees C and 50% relative humidity) 30 min after ingesting caffeine (5 mg.kg-1 body weight) or placebo (dextrose). Caffeine ingestion prior to exercise in the warm environment resulted in increased plasma epinephrine, with no effect on plasma norepinephrine. Neither lipid nor carbohydrate metabolism was altered by caffeine in the warm trial. Exercise in the cold environment (placebo) produced increased VO2 and carbohydrate metabolism, decreased lipid metabolism, and no difference in plasma catecholamines compared with the warm-placebo trial. Responses to the combination of caffeine ingestion and the cold environment did not differ from cold-placebo responses in VO2 during the cycling bout. However, in the cold-caffeine trial plasma epinephrine was elevated. In addition, fat oxidation and serum free fatty acids were elevated in the cold-caffeine condition. Carbohydrate oxidation was depressed, while serum glucose and blood lactate were elevated in this trial compared to cold-placebo. Thus, caffeine increases plasma epinephrine; cold increases oxygen consumption and carbohydrate metabolism, while decreasing lipid metabolism; and the combination of caffeine and cold during exercise increases plasma epinephrine and lipid metabolism, but decreases carbohydrate metabolism.

Adult↗
PubMedDate not supplied

Fetal loss associated with caffeine intake before and during pregnancy.

OBJECTIVE: To determine if caffeine intake before and during pregnancy was associated with an increased risk for fetal loss. DESIGN: Incidence-density case-control study. SETTING: University-affiliated obstetric and pediatric hospital in Montréal, Québec. PARTICIPANTS: A total of 331 women with fetal loss and 993 controls with a normal pregnancy at the same period of pregnancy as the case. OUTCOME MEASURES: Crude and adjusted odds ratios (ORs) for fetal loss were estimated using conditional logistic regression. A trend test for increasing caffeine intake was also used. RESULTS: Caffeine intake was divided into quartiles; the baseline for comparison was less than 48 mg per day. The adjusted ORs for fetal loss associated with caffeine intake before pregnancy were 1.29 (95% confidence interval [CI], 0.85 to 1.95) for 48 to 162 mg; 1.37 (95% CI, 0.92 to 2.04) for 163 to 321 mg; and 1.85 (95% CI, 1.18 to 2.89) for more than 321 mg. The same comparisons were made for caffeine intake during pregnancy, and the respective adjusted ORs were 1.15 (95% CI, 0.82 to 1.63), 1.95 (95% CI, 1.29 to 2.93), and 2.62 (95% CI, 1.38 to 5.01). After controlling for confounding factors, there was a strong association of caffeine intake during pregnancy and fetal loss, compatible with a linear trend on the logistic scale in which ORs increased by a factor of 1.22 (1.10 to 1.34) for each 100 mg of caffeine ingested daily during pregnancy. CONCLUSIONS: Caffeine intake before and during pregnancy was associated with an increased risk of fetal loss, supporting the US Food and Drug Administration recommendation to pregnant women, largely based on animal studies, to reduce their caffeine intake.

Abortion, Spontaneous↗
PubMed1996

Caffeine induces cytochrome P4501A2: induction of CYP1A2 by tea in rats.

Previous reports indicated that treatment of rats with green tea or black tea extracts increased CYP1A2 activity, but such an induction was not observed with decaffeinated green tea in our preliminary study. Herein we report a comparative study on the induction of CYP1A2 with different tea preparations and caffeine as an inducer. When green tea (2%) or black tea (2%) was given to male Fischer 344 rats as the sole source of drinking fluid for 21 days, a 2.4- or 2.7-fold induction, respectively, of CYP1A2-dependent O-methoxyresorufin demethylase (MROD) activity in liver microsomes was observed. Treating rats with caffeine (0.04%) also resulted in an 1.9-fold increase in the MROD activity, but decaffeinated green tea (0.8%) did not cause such an induction. Rats treated with green tea (2%) or caffeine (0.055%) as the sole source of drinking fluid for 1, 3, and 7 days also showed comparable induction (from 1.7- to 2.1-fold) of the MROD activity. The induction was also shown by intragastric administration of caffeine (100 mg/kg). The induced MROD activity caused by consumption of green tea, black tea, and caffeine corresponded to the increase in liver microsomal CYP1A2 protein, as determined by immunoblot analysis. The concentrations of tea polyphenols and caffeine in plasma were also measured. Close correlation of the increase in the MROD activity was observed only with the plasma caffeine level (r = 0.736, n = 10, p = 0.015), not with the combined tea polyphenol level (r = 0.058, n = 6, p = 0.913). The present study establishes caffeine as an inducer of CYP1A2 and demonstrates that caffeine, not tea polyphenols, is the component in tea responsible for the induction of this enzyme.

Animals↗
PubMed1998

[Is caffeine addictive? The most widely used psychoactive substance in the world affects same parts of the brain as cocaine].

Caffeine is the most widely used psychoactive substance in the world. In Western society, at least 80 per cent of the adult population consumes caffeine in amounts large enough to have an effect on the brain. Is this due to caffeine dependence? The article reviews the abuse potential of caffeine in relation to its mechanisms of action. Caffeine affects the same parts of the brain as cocaine, but in completely different ways. There is evidence for caffeine withdrawal symptoms, and caffeine does act as a weak reinforcer, but neither effect is as pronounced as those associated with cocaine. Nor does caffeine use appear to pose any threat to the individual or to society. There is thus no need to add diagnosis "caffeine dependence" to the psychiatric manuals.

Adult↗
PubMed2001

The effects of caffeine on simulated driving, subjective alertness and sustained attention.

There is evidence that caffeine increases alertness and reduces fatigue. This may be especially so in low arousal situations (e.g. working at night or for prolonged hours). Caffeine has also been found to improve performance on vigilance tasks and simple tasks requiring sustained response. Again, these effects are often clearest when alertness is reduced, although there is evidence that benefits may still occur when the individual is unimpaired. Most studies to date have investigated the behavioural effects of caffeine in laboratory experiments using artificial tasks. In the current study 3 mg/kg caffeine was found to improve steering accuracy in a 1 h simulated drive. Measures of mood and performance on a sustained attention task also showed the benefits of caffeine. These findings suggest that laboratory results reflect a general benefit of caffeine that may also be observed in real-life situations. Other evidence examining the effects of caffeine on performance efficiency over the working day has shown the benefits of caffeine consumption on measures of sustained attention and alertness. This study also provided evidence suggesting that caffeine is often consumed when alertness is low to maximise alertness and performance efficiency. The implications of these findings for road safety are also considered. Copyright 2001 John Wiley & Sons, Ltd.

Journal Article↗
PubMed2000

Dietary caffeine intake and the risk for detrusor instability: a case-control study.

OBJECTIVE: To determine whether there is an association in women between caffeine intake and risk for detrusor instability. METHODS: Women were included if they had symptoms of urinary incontinence, completed a 48-hour voiding diary detailing fluid and caffeine intake, and had undergone standardized multichannel urodynamics. The study group had 131 women with detrusor instability on provocative cystometry and maximum urethral closure pressure greater than 20 cm of water. The control group had 128 women without detrusor instability on provocative cystometry and maximum urethral closure pressure greater than 20 cm of water. For statistical comparison, women were divided into the following three groups on the basis of caffeine intake: minimal (< 100 mg/day), moderate (100-400 mg/day), and high (> 400 mg/day). RESULTS: The mean caffeine intake of women with detrusor instability (484 +/- 123 mg/day) was significantly higher than that of controls (194 +/- 84 mg/day, P =.002). On univariate analysis, significant risk factors for detrusor instability were age, smoking status, and caffeine intake. On multivariate analysis, the statistically significant association between high caffeine intake and detrusor instability persisted after controlling for age and smoking (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.1, 6.5, P =.018). When women with moderate caffeine intake were compared with those with minimal caffeine intake, the risk for detrusor instability was lower and did not reach significant levels (OR 1.5, 95% CI 0.1, 7.2, P =.093). CONCLUSION: An association between high caffeine intake and detrusor instability was seen in this population. Larger studies are required to determine whether the association is causal.

Case-Control Studies↗
PubMed1993

Separate de Novo and Salvage Purine Pools Are Involved in the Biosynthesis of Theobromine but Not Caffeine in Leaves of Coffea arabica L.

In Coffea arabica leaves, the purine ring of theobromine (3,7-dimethylxanthine) and caffeine (1,3,7-trimethylxanthine) is provided by de novo purine biosynthesis: (a) [14C]glycine, [14C]bicarbonate, and [14C]formate were incorporated into inosine 5[prime]- monophosphate (IMP), sum of adenine nucleotides ([sigma]Ade), theobromine, and caffeine; and (b) incorporation of [14C]formate into IMP, [sigma]Ade, theobromine, and caffeine was inhibited by azaserine, a known inhibitor of de novo purine biosynthesis. Capacity of coffee leaves to salvage added purines was demonstrated by incorporation of [14C]hypoxanthine into [sigma]Ade and the incorporation of [14C]adenosine, [14C]adenine, [14C]inosine, and [14C]hypoxanthine into both theobromine and caffeine. Consistent with synthesis of theobromine from two separate purine nucleotide pools, one synthesized de novo and one via salvage, added xanthine 5[prime]-monophosphate (XMP), inosine, or hypoxanthine failed to reduce the incorporation of [14C]formate into theobromine but diluted the specific radioactivity of [14C]adenosine and [14C]adenine incorporated into theobromine. Evidence that theobromine is not the immediate precursor of caffeine is provided: (a) [14C]xanthine was incorporated into caffeine but not into theobromine; (b) exogenous xanthine diluted the specific radioactivity of caffeine synthesized from [14C]adenine and [14C]hypoxanthine but caused accumulation of radiolabel in theobromine; (c) allopurinol, a known inhibitor of the conversion of hypoxanthine to xanthine, reduced incorporation of [14C]adenine and [14C]hypoxanthine into caffeine but caused accumulation of radiolabel in theobromine; and (d) incorporation of [14C]formate into caffeine, but not into theobromine, was reduced by added XMP, inosine, or hypoxanthine.

Journal Article↗
PubMed1976

The time-dependent and dose-dependent effects of caffeine on the contraction of the ferret heart.

1. Trabeculae isolated from ferret heart and from other mammalian hearts have been mounted in a way that enables the tension generated to be measured while the composition of the bathing fluid is rapidly altered.2. Application of caffeine to these trabeculae initiates a rapid transient contracture and depresses the strength of regularly evoked heart beats.3. The strength of the contractures, the rate of tension development and the rate of spontaneous relaxation are all increased by raising the concentration of the applied caffeine.4. The strength of the caffeine contracture is relatively unaffected by changes in the bathing Na(+), K(+) or Ca(2+) concentrations, but is reduced by exposure to the free-base form of local anaesthetics.5. Lowering of the temperature has complex effects on the amplitude of the caffeine contracture due to the differing temperature sensitivities of the contraction and spontaneous relaxation.6. Following a caffeine contracture, a period of perfusion by caffeinefree solution is required before a full-sized contracture can be evoked by the re-application of caffeine. This re-priming of the caffeine contracture has a sigmoidal time course that can be fitted by a two compartment model. The rate constants of the filling of each of the compartments can be obtained analytically, and are found to be increased by raising the extracellular calcium concentration, [Ca](o), by stimulating the preparation or by raising the temperature. Reducing the [Na](o) or raising the [K](o) has little effect on these processes.7. The presence of traces of caffeine in the perfusing fluid between the conditioning and test challenges with the caffeine contracture solution reduces the extent of the re-priming without much affecting its rate.8. The behaviour of several model systems have been compared with that of the heart with the aid of an analogue computer. A four compartment closed system has been found to simulate the results presented in this paper.9. It appears that caffeine has its effects by acting to increase the rate of release of activator calcium from one part of a non-homogeneous intracellular relaxing system present within the mammalian heart, which is likely to be the sarcoplasmic reticulum.

Journal Article↗
PubMed2002

Evaluation of gastrointestinal transit characteristics of oral patch preparation using caffeine as a model drug in human volunteers.

Salivary caffeine excretion rate test has been proposed for the evaluation of gastrointestinal transit characteristics of an oral patch preparation after administration to human volunteers instead of measuring the plasma or serum concentration in the early stages of formulation development. Patches having a diameter of 3.0 mm and containing caffeine as a model drug were prepared. The patches consisted of 1) the backing layer made of a water-insoluble polymer, 2) the drug-carrying layer composed of caffeine and a gel-forming polymer, and 3) the enteric polymer membrane. These three layer patches were filled into enteric capsules. Caffeine solution in an enteric capsule was used as the control preparation. After oral administration of each preparation to human volunteers at a dose of 50 mg of caffeine in a cross-over study with a wash-out period of two weeks, saliva samples were collected over 1 min at every sampling time for 12 h and salivary caffeine concentration was determined by a HPLC assay method. Salivary caffeine excretion rate (ER) was used for pharmacokinetic analysis. Mean residence time (MRT) and first-appearance time of caffeine into the saliva (T(i)) were determined. To characterize the pharmacokinetics of caffeine, MRT-T(i) values of patch and solution preparations were compared. Patch preparations had a T(i) value of 2.33+/-0.33 h and showed significantly longer MRT-T(i), 3.87+/-0.21 h, as compared to the control preparation (MRT-T(i)=1.04+/-0.38 h) under fasting condition (p<0.05). Food intake prolonged the gastric emptying time (GET) of the preparations with T(i) values of 5.00+/-1.15 h for control preparation and 4.67+/-1.20 h for patch preparation. The MRT-T(i) values were 0.62+/-0.20 h (control) and 2.45+/-0.73 h (patch). The results of this study indicate that the parameter, MRT-T(i), was useful in characterizing the transit characteristics of oral patch preparations than MRT itself and the presence of food affects the performance of the patch system.

Journal Article↗
PubMed1995

The effects of dopamine agonists on rotational behavior in non-tolerant and caffeine-tolerant rats.

Tolerance develops to caffeine-induced stimulation of both locomotor activity and rotational behavior. The role of dopamine in tolerance to the locomotor stimulant effects of caffeine has been documented. However, the role of dopamine in caffeine-induced turning behavior remains to be elucidated. Therefore, the present study determined the role of dopamine receptors in tolerance to caffeine-induced rotational behavior. Rats with a unilateral lesion of the nigrostriatal tract, induced by 6-hydroxydopamine (6-OHDA), were treated chronically with either caffeine (1.0mg/ml) or with drug-free tap water, by a method of scheduled access. Agonists with and without selectivity for dopamine receptor sub-types were tested in both groups of rats (nonselective: apomorphine, d-amphetamine; D1 selective: SKF-38393, SKF-77434; D2 selective: R(-)-propylnorapomorphine (NPA), quinpirole). All drugs produced dose-dependent increases in turning that, with the exception of quinpirole, were comparable in both groups. Quinpirole produced a smaller effect in rats treated with caffeine than in control rats. Thus, there was significant cross-tolerance only to the effects of quinpirole. The concurrent administration of SKF-38393 with NPA produced a synergistic interaction on rotational behavior in control rats, to which cross-tolerance did not develop in caffeine-treated rats. In contrast to what occurs with locomotor activity, in control rats the selective D1 dopamine receptor antagonist SCH 23390 completely blocked SKF-38393-induced turning behavior and the selective D2 dopamine receptor antagonist eticlopride partially attenuated this effect. NPA-induced turning behavior was blocked only by eticlopride; SCH 23390 was without effect. Both SCH 23390 and eticlopride blocked d-amphetamine-induced rotational behavior. The results of this study suggest that D1 dopamine receptors are not involved in tolerance to caffeine-induced rotational behavior. The role of D2 dopamine receptors in this effect is unresolved. Results obtained from rotational behavior studies generally do not parallel those obtained from locomotor activity studies, suggesting that different mechanisms underlie the effects of caffeine on these two behaviors.

Journal Article↗