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PubMed2002

Caffeine use and dependence in adolescents: one-year follow-up.

The objectives were to conduct a 1-year follow-up of daily caffeine-using adolescents to further describe caffeine dependence symptoms and to determine whether caffeine dependence is associated with other substance dependence disorders. Twenty-one of 36 (58.3%) adolescents who participated in a study of caffeine dependence returned for follow-up. The previous study was a case series of adolescents who consumed caffeine daily and met some Diagnostic and Statistical Manual of Mental Disorders (fourth edition) substance dependence criteria as applied to caffeine. At follow-up, caffeine consumption from beverages was 179.9 +/- 151.8 mg/day. Of the 21 teenagers, 23.8% (n = 5) met criteria for caffeine dependence. Four of these participants developed caffeine dependence during the follow-up period. Other substance dependence disorders were not overrepresented in the caffeine dependent group compared to the caffeine nondependent group. The most commonly reported withdrawal symptoms in dependent teenagers (at baseline and follow-up combined) were feeling drowsy/tired, fatigued, or sluggish/slowed down (83.3% each) and headache (75.0%). Caffeine dependence occurs in some adolescents who drink caffeine daily and is marked by symptoms similar to those found in adults.

Adolescent↗
PubMed2006

Epigallocatechin gallate and caffeine differentially inhibit the intestinal absorption of cholesterol and fat in ovariectomized rats.

We conducted this study to determine whether green tea constituents, (-)-epigallocatechin gallate (EGCG) and caffeine, affect the intestinal absorption of cholesterol (CH), fat, and other fat-soluble compounds. Ovariectomized rats with lymph cannula were infused intraduodenally with a lipid emulsion containing 14C-labeled CH (14C-CH), alpha-tocopherol (alpha TOH), triolein, and sodium taurocholate, without (control) or with EGCG, caffeine, or EGCG plus caffeine, in PBS, pH 6.5. The lymphatic total 14C-CH was significantly lowered by EGCG (21.1 +/- 2.1% dose), caffeine (27.9 +/- 1.7% dose), and EGCG plus caffeine (19.3 +/- 0.9% dose), compared with the control (32.4 +/- 1.6% dose). The lymphatic output of esterified CH also was significantly lower in rats infused with EGCG (7.9 +/- 0.7 micromol), caffeine (7.6 +/- 0.2 micromol), and EGCG plus caffeine (7.5 +/- 0.6 micromol) than rats in the control group (11.6 +/- 1.7 micromol). Also, EGCG and caffeine significantly lowered the absorption of alpha TOH, another highly hydrophobic lipid. However, the lymphatic outputs of oleic acid (exogenous fatty acid marker) and other fatty acids of endogenous origin were not affected by EGCG but were markedly lowered by caffeine and EGCG plus caffeine. Caffeine significantly lowered the amount of lymph flow, regardless of whether it was infused alone (14.2 +/- 3.9 mL) or with EGCG (18.6 +/- 2.0 mL), compared with EGCG (22.2 +/- 2.2 mL) alone and the control group (23.2 +/- 3.8 mL). The caffeine-induced decline in lymph flow was associated with the lowering of lipid absorption. The results indicate that both EGCG and caffeine inhibit lipid absorption and that the inhibitory effects of the 2 tea constituents are not synergistic but mediated by distinctly different mechanisms.

Animals↗
PubMed2003

The effect of caffeine on peripheral vascular resistance in isolated perfused guinea pig hind limbs.

BACKGROUND: The role of caffeine in cardiovascular disease is controversial. Most of its pharmacologic actions are attributed to its role as an adenosine antagonist. Adenosine is one of the most important endogenous vasodilatative substances and is released under ischemic conditions, for example, in the skeletal muscle of patients with peripheral arterial occlusive disease. We aimed to investigate the influence of caffeine on peripheral vascular resistance and on the beneficial vasodilatory effect of adenosine in isolated perfused guinea pig hind limbs. MATERIALS AND METHODS: (1) Caffeine was administered at 0.5, 5, and 50 micromol/L under normoxic conditions. (2) The vasculature of the perfused guinea pig hind limb was precontracted with noradrenaline (3 micromol/L), followed by adenosine (10 micromol/L) under normoxic conditions. When vascular resistance (VR) had reached a steady state, caffeine was administered additionally at dosages of 0.5, 5, and 50 micromol/L. (3) This protocol was repeated using iloprost 0.1 micromol/L instead of adenosine as vasodilatory substance. (4) Under hypoxia, caffeine was again administered at the above dosages. (5) Under hypoxia, experiments with adenosine A2-receptor antagonists (alloxazine 10 micromol/L and ZM 241385 100 nmol/L) were done. RESULTS: Under normoxic conditions, 0.5 and 5 micromol/L caffeine had nearly no effect on vascular resistance compared with baseline conditions. A slight, but statistically not significant decrease in VR was achieved with 50 micromol/L caffeine. In the presence of noradrenaline, the vasodilatory effect of adenosine was reduced by 7.6 +/- 1.6% after the addition of 0.5 micromol/L caffeine, and by 37.3 +/- 3.8% at a dosage of 5 micromol/L caffeine. A dosage of 50 micromol/L caffeine completely abolished the vasodilatative effect of adenosine. In the presence of iloprost, only a slight but statistically insignificant inhibitory influence (0.9%) of caffeine at a dosage of 50 micromol/L could be seen. Hypoxia significantly reduced VR. Caffeine at 0.5 micromol/L diminished this effect by about 53.2 +/- 4.6% and abolished it at 5 and 50 micromol/L. The hypoxia-induced adenosine-mediated vasodilatation seems to be an adenosine A2A-receptor-mediated effect. CONCLUSIONS: The observed effect of hypoxia-induced vasodilatation in peripheral arteries may be the result of the vasodilatory effect of elevated endogenous adenosine during hypoxia. For patients with peripheral arterial disease, drinking of caffeine-containing beverages may reduce the beneficial vasodilatory effect of elevated endogenous adenosine levels.

Adenosine↗
PubMed1997

Caffeine in saliva after peroral intake: early sample collection as a possible source of error.

The influence of collection time on the correlation of caffeine concentrations in saliva and serum was examined in six healthy adults after peroral administration of 5 mg/kg caffeine citrate. Saliva was obtained from three different salivary glands (sublingual, right parotid, and left parotid) and evaluated separately. Caffeine concentrations in saliva and serum samples were determined by high-performance liquid chromatography. There were no differences in the caffeine concentrations in saliva from the three investigated glands (alpha = 0.05). Saliva samples collected earlier than 2 hours after caffeine intake showed higher caffeine concentrations than could be expected from the corresponding serum samples. Gingiva contamination was shown to be responsible for the higher caffeine concentrations in saliva, and it was concluded that saliva is a feasible matrix for therapeutic drug monitoring of caffeine. If caffeine is administered orally, saliva samples should be taken at least 2 hours after caffeine intake. If caffeine-containing beverages are used as the source of caffeine or if subjects do not cooperate by rinsing the mouth of caffeine contamination, an additional 60 minutes should be added before saliva sampling.

Administration, Oral↗
PubMed1991

Caffeine-sensitive calcium stores in bovine adrenal chromaffin cells.

Caffeine was used to study the intracellular Ca2+ pools of bovine chromaffin cells. Its effects on cytosolic Ca2+ concentration ([Ca2+]i) were examined using fura-2. Caffeine caused a transient increase in [Ca2+]i in the presence or absence of extracellular Ca2+. In the former case, the caffeine-induced [Ca2+]i increase was higher and stayed above the basal value for several minutes. In the latter case, the [Ca2+]i rise was lower and fell to the basal level within 1 min. These results suggest that caffeine increases [Ca2+]i by causing both Ca2+ influx and Ca2+ release from intracellular pools. In the absence of extracellular Ca2+, ionomycin but not caffeine caused a further increase in [Ca2+]i in cells that had been treated with caffeine. Apparently there are at least two intracellular Ca2+ pools, only one of which is sensitive to caffeine. The caffeine-induced [Ca2+]i rise became smaller when the cells were pretreated with the inositol trisphosphate-generating agonists, methacholine and bradykinin. In addition, methacholine was unable to initiate a [Ca2+]i transient after the cells had been treated with caffeine. The results indicate that the caffeine-sensitive Ca2+ pools overlap with the inositol trisphosphate-sensitive pool and that the size of the latter pool is smaller than that of the former. The caffeine-sensitive Ca2+ pools were refilled after high K+ treatment, which suggests that the caffeine-sensitive Ca2+ pools may be important in buffering the cytosolic Ca2+. The effect of caffeine on [Ca2+]i is not due to inhibition of phosphodiesterase. Our results support a Ca2+ entry model in which depletion of intracellular Ca2+ pools controls the rate of Ca2+ entry across the plasma membrane.

Adrenal Glands↗
PubMed1994

Effects of caffeine on intracellular sodium activity in cardiac Purkinje fibres: relation to force.

1. An increase in cytoplasmic calcium by caffeine would lead to Ca extrusion via the Na/Ca exchange. The hypotheses were investigated that, as a consequence, caffeine might increase intracellular sodium activity (aiNa) and that the relation between aiNa and force might be conditioned by the Ca load. 2. Action potential, aiNa and contractile force were recorded in sheep Purkinje fibres during exposure to caffeine under conditions that decrease or increase the Ca load by different mechanisms. 3. In Tyrode solution, caffeine (8 mM) increased aiNa from 8.05 +/- 0.20 to 10.52 +/- 0.40 mM (+30.5%) and had a triphasic effect on force: an initial transient increase (+93.6%), a subsequent decrease (-37.1%) (negative inotropy) and slow partial recovery (+8.9%). 4. Decreasing the Ca load by means of manganese (1 mM) decreased aiNa and force. Adding caffeine re-increased aiNa and no longer caused a negative inotropic action. Cadmium (0.2 mM) also decreased aiNa, and caffeine reincreased it although far less than in Tyrode solution. 5. High [K]o (10 mM) and tetrodotoxin (5 microM) decreased aiNa as well as force. In their presence, caffeine re-increased aiNa and no longer had a negative inotropic action. 6. Increasing the Ca load by means of high [Ca]o (8.1 mM) increased force (+195%) and decreased aiNa, (-20.3%). Adding caffeine re-increased aiNa (+28.1%), but immediately decreased force (-32.3%). 7. Addition of pyruvate (10 mM) to caffeine increased force, as it does in the presence of Ca overload. 8. Noradrenaline (0.1-1 microM) decreased aiNa and increased contractile force. In its presence, caffeine decreased aiNa further and increased force. 9. It is concluded that caffeine increases aiNa, even during the negative inotropic effect. The decrease in force appears to depend on Ca load. Thus, caffeine no longer decreases force under conditions that decrease Ca load (Mn, high [K]0, TTX) and immediately decreases force when the Ca load is increased(high [Ca]0). However, in the presence of noradrenaline, caffeine decreases aiNa and markedly increases force, as the Ca load is increased, but Ca can be removed from the cytoplasm into the SR.

Animals↗
PubMed1986

Caffeine potentiation of calcium release in frog skeletal muscle fibres.

The effects of caffeine at concentrations up to 3 mM were studied on Ca signals obtained using the metallochromic Ca indicator dyes Arsenazo III and Antipyrylazo III in cut frog skeletal muscle fibres mounted in a triple Vaseline-gap chamber and stimulated by voltage clamp or action potential. The peak amplitude of the transient absorbance change due to Ca2+ release following action potential stimulation is potentiated by an amount dependent on caffeine concentration up to 0.5 mM, and by a concentration-independent amount between 0.5 and 2 mM. At 3 mM-caffeine, the potentiation is reduced, and the Ca signal can have a smaller amplitude than under the control condition. The time course of the rising phase of the Ca signal is preserved by the potentiating effect of caffeine; however, the decay rate of the Ca signal is increasingly slowed at caffeine concentrations greater than 0.5 mM. No substantial change was found in the resting myoplasmic Ca2+ level at caffeine concentrations near 0.5 mM. Even if the free Ca2+ concentration in the presence of this level of caffeine were to increase by 0.04 microM (the threshold of detectability), the calculated potentiation of the Ca signal due to increased partial saturation of intracellular Ca2+ buffers would amount to only about 7%. This value is significantly less than the amount of potentiation observed (up to 40%) following action potentials at caffeine levels of 0.5 mM and above. Experiments made with the impermeant potentiometric dye NK2367 show no alteration by caffeine of the electrical properties of the tubular system. Caffeine at up to moderate concentrations causes a substantial increase in the maximal Ca2+ release obtained following large depolarizations. The voltage dependence of the Ca2+ release is characterized by a caffeine concentration-dependent shift towards more negative membrane potentials. The potentiation of Ca2+ release by caffeine was found to be independent of the external free Ca2+ level. The potentiation of the Ca2+ release process by caffeine is likely to occur at a step subsequent to the depolarization of the transverse tubule membrane, and suggests the presence of an intermediate step, or second messenger, in the excitation-contraction coupling process.

Action Potentials↗
PubMed1992

Caffeine-induced release and reuptake of Ca2+ by Ca2+ stores in myocytes from guinea-pig urinary bladder.

1. Voltage-clamped isolated smooth muscle cells from guinea-pig urinary bladder were studied with 3.6 mM extracellular Ca2+ at 36 degrees C. The fluorescence of the Ca(2+)-sensitive dye Indo-1 was used to monitor the cytosolic calcium concentration ([Ca2+]i) and its changes ([Ca2+]i transient). Fast application of caffeine (10 mM) to the cell was used to release the intracellular Ca2+ from a 'caffeine-sensitive Ca2+ store'. 2. At the holding potential -60 mV, a short (1 s) caffeine application increased [Ca2+]i within less than 1 s from the resting 118 +/- 22 nM to 1490 +/- 332 nM. Following the caffeine wash-out, [Ca2+]i fell from this peak to a subresting level of 47 +/- 12 nM, i.e. an 'undershoot' of [Ca2+]i occurred. Subsequent caffeine-induced [Ca2+]i transients had attenuated peaks suggesting that the caffeine-sensitive Ca2+ store had lost a part of the releasable Ca2+. 3. In the continuous presence of caffeine, [Ca2+]i decayed from its peak to control resting [Ca2+]i values. The wash-out of caffeine following prolonged (10-30 s) treatment also resulted in [Ca2+]i undershoot. Subsequent caffeine-induced [Ca2+]i transients were largely abolished as if the caffeine-sensitive Ca2+ store had lost a large part of releasable Ca2+. During the undershoot, hyperpolarization to -100 mV did not affect [Ca2+]i. In most cells studied, recovery of [Ca2+]i from the undershoot to the resting level required depolarizations inducing Ca2+ influx through L-type Ca2+ channels. 4. Block of plasmalemmal Ca(2+)-ATPase (PMCa) with extracellular La3+ (3 mM) did not modify the decay of the [Ca2+]i transients induced by depolarization or by a 1 s caffeine application suggesting that decay rate of both is not limited by PMCa rate. La3+ abolished the undershoot of [Ca2+]i. In the continuous presence of caffeine, La3+ largely prevented the decay of [Ca2+]i. 5. When the depolarizing steps from -60 to 0 mV (160 ms duration) were applied during the period of [Ca2+]i undershoot, the half-time of decay of the corresponding [Ca2+]i transients was up to three times faster than in control. Repetitive depolarizations restored the rate of decay and [Ca2+]i recovered to the resting value. Both processes recovered along a similar time course. 6. Application of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX; 0.1 mM) or of 8-Br-cAMP (0.1 mM) did not mimic the above caffeine effects suggesting that stimulation of sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCa) by cAMP-dependent phosphorylation is not the underlying mechanism.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1985

Caffeine in human milk and in serum of breast-fed infants.

A study was carried out to determine the caffeine concentration in milk of lactating women ingesting known amounts of caffeine and to determine serum concentration of caffeine of their infants. 9 lactating women and their infants were studied for 9 days. For the first 5 days, the women ingested 750 mg of caffeine daily, and for the next 4 days they ingested no caffeine and avoided coffee and other caffeine-containing products. The concentration of caffeine in samples of milk obtained by pooling aliquots from each feeding on day 5 averaged 4.3 micrograms/ml for 7 mothers who were 11-22 days after delivery on the 1st day of study. Values ranged from nondetectable (less than 0.25 micrograms/ml) to 15.7 micrograms/ml. No caffeine was detected in milk samples obtained on day 9. The mean concentration of caffeine in sera of the infants on day 5 was 1.4 micrograms/ml (range: nondetectable to 2.8 micrograms/ml). Caffeine was still detectable in 2 infants' sera obtained on day 9. Concentrations had decreased only slightly since day 5. 2 older infants and their mothers were studied as described except that on days 5 and 9 samples of milk were obtained from each feeding and analyzed individually. The average caffeine concentrations in milk consumed on day 5 were 13.4 and 28.6 micrograms/ml, respectively. The concentrations of caffeine in infants' sera on day 5 were less than 0.25 and 3.2 micrograms/ml. On day 9 milk and serum caffeine levels were below the limits of detectability.

Adult↗
PubMed2003

Pilot dose-escalation study of caffeine plus ethanol (caffeinol) in acute ischemic stroke.

BACKGROUND AND PURPOSE: In animal models, the combination of caffeine and ethanol (caffeinol) provides robust neuroprotection at blood levels that should be easily and safely achieved in humans. This study was designed to determine the safety and tolerability of ascending doses of this combination in stroke patients. METHODS: This Food and Drug Administration-approved open-label, single-arm, dose-escalation study had 3 original dose groups: group 1, caffeine 6 mg/kg plus ethanol 0.2 g/kg; groups 2 and 3, incremental increases of caffeine and ethanol by 2 mg/kg and 0.2 g/kg, respectively. Intravenous thrombolysis was encouraged if patients qualified. Drug was started within 6 hours of stroke onset, and blood levels of caffeine and ethanol were drawn at baseline and end of infusion. The target blood caffeine and ethanol ranges were 8 to 10 microg/mL and 30 to 50 mg/dL, respectively. Clinical outcome measurements included the National Institutes of Health Stroke Scale at the end of infusion, at 24 hours, and at discharge. Potential complications from caffeine and ethanol were recorded. Cases were reviewed by an independent stroke neurologist for safety. RESULTS: A total of 23 patients were recruited. Target blood caffeine and ethanol levels were reached in 0 of the 4 patients in the first group. The second dose group (caffeine 8 mg/kg plus ethanol 0.4 g/kg) included 8 patients. The median end-of-infusion caffeine and ethanol levels were within the desired target ranges. Two days after infusion, 1 patient in this group with preexisting cardiac disease and end-of-infusion caffeine and ethanol levels of 10.7 microg/mL and 69 mg/dL developed reversible congestive heart failure and required transfer to an intensive care unit. The original third dose group was canceled given achievement of target blood caffeine and ethanol levels in group 2. However, 3 new dose groups were created in an attempt to minimize the dose of ethanol. Although blood levels were proportional to dose, none of these new dose groups provided optimal blood levels. Congestive heart failure occurred in 1 other patient with previously asymptomatic cardiomyopathy. No other side effects were noted. Concomitant thrombolytic therapy was given in 8 patients, 1 of whom died of intracerebral hemorrhage. CONCLUSIONS: Caffeinol alone or combined with intravenous tissue plasminogen activator can be administered safely. Caffeine 8 mg/kg plus ethanol 0.4 g/kg produces target caffeine and ethanol levels of 8 to 10 microg/mL and 30 to 50 mg/dL, respectively. A randomized, placebo-controlled trial is needed to determine the neuroprotective effect of this combination.

Adult↗
PubMed2000

Effects of caffeine on muscle glycogen utilization and the neuroendocrine axis during exercise.

To examine the effect of caffeine ingestion on muscle glycogen utilization and the neuroendocrine axis during exercise, we studied 20 muscle glycogen-loaded subjects who were given placebo or caffeine (6 mg/kg) in a double blinded fashion 90 min before cycling for 2 h at 65% of their maximal oxygen consumption. Exercise-induced glycogen depletion in the thigh muscle was noninvasively measured by means of 13C nuclear magnetic resonance spectroscopy (NMR) spectroscopy, and plasma concentrations of substrates and neuroendocrine hormones, including beta-endorphins, were also assessed. Muscle glycogen content was increased 140% above normal values on the caffeine trial day (P < 0.001). After cycling for 2 h, caffeine ingestion was associated with a greater increase in plasma lactate (caffeine: +1.0 +/- 0.2 mmol/L; placebo, +0.1 +/- 0.2 mmol/L; P < 0.005), epinephrine (caffeine, +223 +/- 82 pg/mL; placebo, +56 +/- 26 pg/mL; P < 0.05), and cortisol (caffeine, +12 +/- 3 mg/mL; placebo, +2 +/- 2 mg/mL; P < 0.001) levels. However, plasma free fatty acid concentrations increased (caffeine, +814 +/- 133 mmol/L; placebo, +785 +/- 85 mmol/L; P = NS), and muscle glycogen content decreased (caffeine, -57 +/- 6 mmol/L muscle; placebo, -53 +/- 5 mmol/L muscle; P = NS) to the same extent in both groups. At the same time, plasma beta-endorphin levels almost doubled (from 30 +/- 5 to 53 +/- 13 pg/mL; P < 0.05) in the caffeine-treated group, whereas no change occurred in the placebo group. We conclude that caffeine ingestion 90 min before prolonged exercise does not exert a muscle glycogen-sparing effect in athletes with high muscle glycogen content. However, these data suggest that caffeine lowers the threshold for exercise-induced beta-endorphin and cortisol release, which may contribute to the reported benefits of caffeine on exercise endurance.

Adult↗
PubMed2001

Intravenous nicotine and caffeine: subjective and physiological effects in cocaine abusers.

The subjective and physiological effects of intravenously administered caffeine and nicotine were compared in nine subjects with histories of using caffeine, tobacco, and cocaine. Subjects abstained from tobacco cigarette smoking for at least 8 h before each session. Dietary caffeine was eliminated throughout the study; however, to maintain consistency with the nicotine intake, subjects were administered caffeine (150 mg/70 kg b.i.d.) in capsules, with the last dose administered 15 to 18 h before each session. Under double-blind conditions, subjects received placebo, caffeine (100, 200, and 400 mg/70 kg), and nicotine (0.75, 1.5, and 3.0 mg/70 kg) in mixed order. Physiological and subjective data were collected before and repeatedly after drug or placebo administration. Compared with the highest dose of caffeine, the highest dose of nicotine produced greater subjective ratings on a number of scales. At doses that produced comparable ratings of drug effect (1.5 mg/70 kg of nicotine and 400 mg/70 kg of caffeine), both drugs produced similar increases in ratings of good effect, liking, high, stimulated, and bad effect. Nicotine showed a somewhat faster time to peak subjective effects than caffeine (2 versus 4 min). Subjective ratings that differentiated caffeine and nicotine were ratings of rush, blurry vision, and stimulant identification (elevated by nicotine) and ratings of unusual smell and/or taste (elevated by caffeine). Both caffeine and nicotine decreased skin temperature and increased diastolic blood pressure; however, caffeine decreased whereas nicotine increased heart rate. The study documents both striking similarities and some notable differences between caffeine and nicotine, which are among the most widely used mood-altering drugs.

Adult↗
PubMed1992

Ethanol enhances, but diazepam and pentobarbital reduce the ambulation-increasing effect of caffeine in mice.

The interactions of caffeine (10 mg/kg p. o.) with various doses of ethanol, diazepam or pentobarbital were investigated by observing the ambulatory activity of mice. The ambulatory activities after the coadministration of caffeine with ethanol (1.6, 2.4 and 3.2 g/kg p. o.) were significantly higher than those after the single administration of the corresponding doses of individual drugs. Ethanol alone significantly increased the activity with ataxia at 2.4 and 3.2 g/kg, suggesting that 1.6 g/kg of ethanol was an optimum dose for studying the interaction of caffeine with ethanol. Although diazepam (0.25, 0.5 and 2 mg/kg s. c.) and pentobarbital (1, 3 and 10 mg/kg s. c.) alone did not change the activity, they significantly reduced the effect of caffeine. Naloxone (1 and 5 mg/kg s. c.) did not modify the effect of caffeine alone, but, at 5 mg/kg, it was effective in significantly reducing the ambulation-increasing effect of caffeine with ethanol (1.6 g/kg) to nearly the level of caffeine alone. Ca-cyanamide (5 mg/kg p. o., pretreatment 30 min before), reserpine (1 mg/kg s. c., pretreatment 4 hr before) and alpha-methyl-p-tyrosine (200 mg/kg i. p., pretreatment 1 hr before) reduced the ambulation increment induced by caffeine alone or combination of caffeine with ethanol. Ethanol, diazepam and pentobarbital are classified as CNS depressants, and caffeine as a CNS stimulant. However, the present experiment demonstrated that the interaction of caffeine with ethanol was very different from that of caffeine with diazepam or pentobarbital. In the enhancing interaction of caffeine and ethanol, both dopaminergic and endogenous opioid systems may be involved.

Animals↗
PubMed2004

Daily caffeine intake among Osijek High School students: questionnaire study.

AIM: To assess caffeine intake habits of Osijek high school students and identify the most important sources of caffeine intake. METHODS: Adjusted Wisconsin University Caffeine Consumption Questionnaire was administered to 571 high school students (371 boys and 200 girls in the ninth grade) from Osijek, the largest town in eastern Croatia. The level of caffeine in soft drinks was determined by the high pressure liquid chromatography method, and in chocolate and coffee from the literature data. RESULTS: Only 10% of our participants did not use foodstuffs containing caffeine. The intake of caffeine originated from soft drinks (50%), coffee (37%), and chocolate (13%). The mean caffeine concentration in soft drinks was 100-/+26.9 mg/L. The mean estimated caffeine intake was 62.8-/+59.8 mg/day. There was no statistically significant difference between boys and girls in caffeine consumption (1.0-/+0.9 mg/kg bw for boys vs 1.1-/+1.4 mg/kg bw for girls). Daily caffeine intake of 50-100 mg was recorded in 32% of girls and 29% of boys, whereas intake greater than 100 mg/day was recorded in 18% of girls and 25% of boys. CONCLUSION: Soft drinks containing caffeine were the major source of caffeine intake in high school students. Large-scale public health measures are needed to inform the public on health issues related to excessive intake of caffeine-containing foodstuffs by children and adolescents.

Adolescent↗
PubMed2004

Effect of caffeine intake on myocardial hyperemic flow induced by adenosine triphosphate and dipyridamole.

UNLABELLED: The aims of this study were (a). to compare absolute myocardial blood flow (MBF) during adenosine triphosphate (ATP) infusion with that after dipyridamole administration without caffeine intake and (b). to evaluate the effect of caffeine intake on the hyperemic flow induced by these coronary vasodilator agents. METHODS: MBF was quantified with (15)O-labeled water and PET at rest, during ATP infusion (0.16 mg/kg/min for 9 min), and after dipyridamole administration (0.56 mg/kg over 4 min) after a 24-h abstinence from caffeine (baseline evaluation) in 10 healthy volunteers. Within 2 wk, the same PET studies were repeated after caffeine intake to evaluate the effect of caffeine on the hyperemic flow induced by these pharmacologic agents (caffeine study). Myocardial flow reserve (MFR), defined as the ratio of hyperemic to resting blood flow, was also evaluated. RESULTS: Resting MBF in baseline and caffeine studies did not differ significantly (0.79 +/- 0.29 vs. 0.75 +/- 0.31 mL/min/g, P = 0.88). Without caffeine intake, MBF during ATP infusion was significantly higher than that after dipyridamole administration (3.70 +/- 0.67 vs. 3.00 +/- 0.79 mL/min/g, P = 0.003), whereas there was no significant difference in MFR between ATP and dipyridamole stress (5.15 +/- 1.64 vs. 4.11 +/- 1.44, P = 0.07). After caffeine intake, the hyperemic flows induced by ATP and dipyridamole were not significantly different (1.68 +/- 0.37 vs. 1.52 +/- 0.40 mL/min/g, P = 0.50). MFR estimated by ATP and dipyridamole also did not differ significantly in the caffeine studies (2.44 +/- 0.88 vs. 2.25 +/- 0.94, P = 0.73). MBF during ATP infusion and after dipyridamole administration were significantly lower in the caffeine studies than that in the baseline evaluation (1.68 +/- 0.37 vs. 3.70 +/- 0.67 mL/min/g, P < 0.0001, and 1.52 +/- 0.40 vs. 3.00 +/- 0.79 mL/min/g, P < 0.0001, respectively). CONCLUSION: This study demonstrates that ATP has the potential to induce greater hyperemia than dipyridamole, whereas hyperemic responses to ATP and dipyridamole are similarly attenuated after caffeine intake. These findings suggest that abstinence from caffeine before ATP stress testing may be needed.

Adenosine Triphosphate↗
PubMed1991

Influence of caffeine on development of benign and carcinomatous mammary gland tumors in female rats treated with the carcinogens 7,12-dimethylbenz(a)anthracene and N-methyl-N-nitrosourea.

The effect of chronic caffeine consumption (500 mg/liter of drinking water) on the initiation and promotion stages of 7,12-dimethylbenz(a)anthracene (DMBA) (a low dose, 0.5 mg/100 g body weight, i.v.) and N-methyl-N-nitrosourea (MNU) (a standard dose, 2.5 mg/100 g body weight, i.v.) induced mammary gland tumorigenesis in female Sprague-Dawley rats was determined. In the initiation studies, caffeine was administered for 30 days prior to and for 3-4 days after carcinogen treatment (carcinogens administered at 55-57 days of age); in the promotion studies, caffeine was administered beginning 3-4 days after carcinogen treatment and until experiment termination (DMBA study and MNU study, 48 and 26 weeks after carcinogen treatment, respectively). In the DMBA study, there were 62-73 rats/group, in the MNU study, 40 rats/group. Eighty-nine % of the mammary tumors induced by DMBA were benign (adenomas, fibroadenomas, often with cystic secretory activity), 11% were carcinomas (intraductal and invasive); virtually all of the MNU-induced mammary tumors were carcinomas (approximately 99%). Caffeine consumption during the initiation stage in the DMBA-treated rats resulted in a significant decrease in the mean number of mammary carcinomas per rat (50% reduction, P less than 0.01) and mean number of benign mammary tumors per rat (28% reduction, P less than 0.05); caffeine consumption during the promotion stage significantly decreased the mean number of benign mammary tumors per rat (57% reduction, P less than 0.001) while not significantly influencing mammary carcinoma number. In contrast, caffeine consumption during either the initiation or promotion stages of MNU-treated rats did not significantly influence this tumorigenic process. The influence of caffeine on urinary and fecal excretion of tritiated DMBA and on rat mammary gland development at the time of carcinogen treatment also was determined. Slightly reduced levels of tritium in 24-h urinary samples were observed in caffeine-treated animals (P = 0.06). No significant effect of caffeine on 24- to 96-h fecal or 48- to 96-h urinary excretion of the isotope was observed. No apparent effect of caffeine on rat mammary gland development (number of ducts, degree of lobuloalveolar development) was observed. That caffeine significantly suppresses the initiation stage of DMBA-induced rat mammary gland tumorigenesis, while not influencing this stage when MNU is used as a carcinogen, suggests that caffeine acts via an alteration in carcinogen (DMBA) activation. The lack of a pronounced effect of caffeine on tritiated DMBA excretion, however, does cast some doubt on this mechanism.(ABSTRACT TRUNCATED AT 400 WORDS)

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Influence of caffeine and/or coffee consumption on the initiation and promotion phases of 7,12-dimethylbenz(a)anthracene-induced rat mammary gland tumorigenesis.

The effect of caffeine and/or coffee consumption (via the drinking water) during the initiation phase and promotion phase of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary gland tumorigenesis in female Sprague-Dawley rats fed a commercial laboratory animal chow was examined. In the initiation studies, DMBA was administered once at 53-55 days of age; caffeine (100-860 mg/liter of drinking water) and/or coffee (moderate or high dose, sole source of drinking water) treatments were for 32 consecutive days, commencing 29 days prior to DMBA treatment and terminating 3 days after DMBA treatment. In the promotion studies, DMBA was administered once at 54-55 days of age; caffeine and/or coffee treatments were daily from 57-58 days of age to termination of experiments (12-21 weeks after carcinogen treatment). In the initiation studies, either moderate (100-400 mg) or high (860 mg) dose levels of caffeine or moderate to high dose levels of caffeinated coffee significantly (P less than 0.05) reduced mammary carcinoma multiplicity (number of tumors/rat). Consumption of high or moderate dose levels of decaffeinated coffee did not significantly alter mammary carcinoma multiplicity. The addition of caffeine to the moderate dose level of decaffeinated coffee resulted in a significant (P less than 0.05) reduction in mammary carcinoma multiplicity. In the promotion studies, prolonged consumption of moderated dose levels of caffeine or moderate or high dose levels of caffeinated coffee or decaffeinated coffee did not significantly effect mammary carcinoma multiplicity. In the early stages of promotion, however, a significant (p less than 0.05) stimulatory effect of caffeine on mammary carcinoma multiplicity was observed; an effect that was temperate and transitory. In both the initiation and promotion studies caffeine and/or coffee consumption did not significantly affect the incidence of mammary carcinomas (percentage of rats bearing mammary carcinomas) or the mean latency period of mammary tumor appearance. These results provide evidence that caffeine and/or caffeinated coffee consumption can significantly influence mammary carcinoma multiplicity in female rats treated with DMBA, an effect that is dependent upon the dose level, duration, and time-span of caffeine administration.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

Caffeine pharmacokinetics in obesity and following significant weight reduction.

OBJECTIVES: To compare caffeine pharmacokinetics (200 mg single oral dose) between obese and lean subjects and in obese subjects prior to and following weight reduction. In the obese group antipyrine (1000 mg single oral dose) pharmacokinetics were also evaluated one week before caffeine administration. SETTING: Teaching university hospital. DESIGN: Single dose, open study. SUBJECTS: Twenty obese subjects (Group A) (BMI exceeding 30 kg/m2), referred from the outpatient metabolic clinic and 14 lean (Group B) subjects participated in the study. Weight (mean +/- s.d.) and BMI were significantly greater in the obese than the lean subjects (110.4 +/- 19.2 vs 66.9 +/- 13.3 kg respectively, and 38.5 +/- 5.8 vs 22.6 +/- 1.7 kg/m2 respectively, P < 0.001). INTERVENTIONS: Single dose oral administration of caffeine (200 mg) and antipyrine (1000 mg) in Group A and only caffeine in Group B. Twice single dose oral administrations of caffeine (200 mg) in six subjects (Group C), prior to and following weight loss. MAIN OUTCOME MEASURES: Caffeine and antipyrine pharmacokinetics were derived from the plasma concentrations-time curves. RESULTS: Caffeine elimination half-life (T1/2) and clearance (CLo) were similar in obese and lean subjects (6.54 +/- 2.85 vs 6.08 +/- 2.23 h respectively and 100.7 +/- 49.5 vs 82.6 +/- 34.0 ml/min respectively, P > 0.05). Caffeine Varea was greater in group A than in Group B (48.3 +/- 11.4 vs 40.1 +/- 13.0 L respectively, P = 0.06) but when corrected for body weight significantly reduced values were obtained in the obese group (0.44 +/- 0.06 vs 0.59 +/- 0.10 L/kg respectively, P < 0.001). In group A subjects caffeine and antipyrine Varea were similar (48.3 +/- 11.4 vs 49.9 +/- 9.3 L respectively, P > 0.3). Caffeine T1/2 and CLo were not significantly altered by the 30.2 +/- 12.3 kg weight loss obtained in Group C subjects, but caffeine Varea was significantly reduced (55.6 +/- 9.3 L before, 47.8 +/- 9.5 L after, P < 0.04) and Varea corrected for body weight was significantly increased (0.46 +/- 0.03 L/kg before, 0.52 +/- 0.05 L/kg after, P < 0.05). CONCLUSIONS: Caffeine pharmacokinetics are only minimally altered by obesity. The use of caffeine containing drugs in obese subjects does not necessitate significant dosage modification.

Administration, Oral↗