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PubMed1998

Effects of caffeine and caffeine-associated stimuli on the human startle eyeblink reflex.

An experiment was performed (n = 19) that investigated the effect of caffeine and expectancy of caffeine on the eyeblink component of the startle reflex. Nineteen habitual caffeine users received caffeinated coffee, caffeinated juice, decaffeinated coffee, or decaffeinated juice in four sessions spaced 1 week apart. Twenty-five to 30 min after ingestion of the liquid, 30 acoustic startle stimuli were presented. The results showed that caffeine increased startle eyeblink amplitude. Startle reflex onset latency was significantly longer in the decaffeinated coffee condition than in the other three conditions. This may have been due to the activation of a compensatory slowing of the reflex by the anticipation of caffeine, a slowing that was then overridden by caffeine speeding the response.

Acoustic Stimulation↗

PubMed1975

Biosynthesis of caffeine by tea-leaf extracts. Enzymic formation of theobromine from 7-methylxanthine and of caffeine from theobromine.

1. Extracts prepared from tea leaves with Polyclar AT (insoluble polyvinylpyrrolidine) contained two methyltransferase activities catalysing the transfer of methyl groups from S-adenosylmethionine to 7-methylxanthine, producing theobromine, and to theobromine, producing caffeine. 2. The methyltransferases exhibited the same pH optimum (8.4) and a similar pattern of effects by metal ions, thiol inhibitors and metal-chelating reagents, both for theobromine and caffeine synthesis. Mg2+, Mn2+ and Ca2+ slightly stimulated enzyme activity but they were not essential. Paraxanthine was shown to be most active among methylxanthines, as the methyl acceptor. However, the formation of paraxanthine from 1-methylxanthine was very low and that from 7-methylxanthine was nil, suggesting that the synthesis of caffeine from paraxanthine is of little importance in intact plants. Xanthine, xanthosine, XMP and hypoxanthine were all inactive as methyl acceptors, whereas [2(-14)C]xanthine and [8(-14)C]hypoxanthine were catabolized to allantoin and urea by tea-leaf extracts. The apparent Km values are as follows: 7-methylxanthine, 1.0 times 10(-14)M; theobromine, 1.0 times 10(-3)M; paraxanthine, 0.2 times 10(-3)M; S-adenosylmethionine, 0.25 times 10(-4)M (with each of the three substrates). 3. The results suggest that the pathway for caffeine biosynthesis is as follows: 7-methylxanthine leads to theobromine leads to caffeine. In contrast, it is suggested that theophylline is synthesized from 1-methylxanthine. The methyl groups of the purine ring of caffeine are all derived directly from the methyl group of S-adenosylmethionine. Little is known about the pathways leading to the formation of 7-methylxanthine. 4. A good correlation between caffeine synthesis and shoot formation or growth of tea seedlings was shown, suggesting that the methylating systems in caffeine synthesis are closely associated with purine nucleotide and nucleic acid metabolism in tea plants.

Caffeine↗

PubMed1992

Caffeine in sport. Influence of endurance exercise on the urinary caffeine concentration.

This study was conducted to evaluate the influence of excessive sweating during long-distance running on the urinary concentration of caffeine after the intake of a large amount of caffeine. Nine endurance-trained athletes participated in a randomised cross-over study in which 450 mg caffeine were taken with and without exercise. Exercise consisted of running for 30 min on a treadmill at 75% of maximum heart rate, one hour after intake of caffeine. This endurance exercise caused a decrease in the urine flow as well as in the amount of caffeine excreted in urine. The combined effect of both these decreases is that the concentrations of caffeine detected in urine were similar with and without exercise. The maximum caffeine concentration detected in any urine sample was 11.9 micrograms/ml without exercise and 10.4 micrograms/ml with exercise. It can be concluded that excessive sweating during long-distance running did not enhance the urinary caffeine concentration.

Adolescent↗

PubMed1968

The relationship between caffeine contracture of intact muscle and the effect of caffeine on reticulum.

At concentrations between 1 to 10 mM, caffeine reduced the Ca-accumulating capacity of fragmented reticulum obtained from frog and rabbit muscle. With 8 mM caffeine enough Ca was released from frog reticulum to account for the force of the contracture. Caffeine did not affect all reticulum membranes equally. The fraction which was spun down at 2000 g was more sensitive than the lighter fractions. The percentage of the total accumulated Ca released by caffeine decreased with decreasing Ca content of the reticulum. In parallel with their known effects on the caffeine contracture, a drop in temperature increased the caffeine-induced Ca release while procaine inhibited it. Caffeine also inhibited the rate of Ca uptake, which may in part account for the prolongation of the active state caused by caffeine.

Animals↗

PubMedDate not supplied

Caffeine and its dimethylxanthine metabolites in two cases of caffeine overdose: a cause of falsely elevated theophylline concentrations in serum.

Two children ingested over-the-counter medications containing caffeine, resulting in significant caffeine overdose. Measured concentrations of caffeine were as high as 176 and 128 mg/L. We have described the elimination of caffeine and its dimethylxanthine metabolites, paraxanthine, theophylline, and theobromine in these cases. The apparent theophylline concentrations determined after caffeine ingestion were dependent upon the method of measurement. Use of one published reversed-phase HPLC method, which does not separate theophylline from paraxanthine, resulted in overestimation of theophylline by 225 to 513%. Use of an enzyme immunoassay procedure resulted in a lesser degree of overestimation (142-383%), which was due, in part, to cross-reactivity with extremely high concentrations of caffeine and paraxanthine. The measurement of caffeine concentrations in the management of caffeine overdose is of limited clinical usefulness; likewise, measurement of theophylline concentrations is generally not indicated, and may be misleading unless a highly specific assay is used.

Caffeine↗

PubMedDate not supplied

Caffeine effects on cardiovascular and neuroendocrine responses to acute psychosocial stress and their relationship to level of habitual caffeine consumption.

The effects of a moderate dose of caffeine on cardiovascular and neuroendocrine stress reactivity were examined in 25 healthy male subjects selected as habitual or light consumers of caffeine. Measurements were taken under resting conditions before and after administration of caffeine (3.5 mg/kg) or placebo, during a stressful laboratory task, and in a post-stress recovery period. Caffeine elevated blood pressure and plasma norepinephrine levels at rest, effects which added significantly to the effects of stress. Caffeine potentiated stress-related increases in plasma epinephrine and cortisol stress, more than doubling the responses observed in the control condition. These effects were present in both habitual and light consumers and level of habitual caffeine consumption did not affect their magnitude. Results indicate that caffeine can potentiate both cardiovascular and neuroendocrine stress reactivity and that the habitual use of caffeine is not necessarily associated with the development of tolerance to these effects.

Adaptation, Psychological↗

PubMed1987

In vitro diagnosis of susceptibility to malignant hyperthermia: evaluation of tests with halothane-caffeine, potassium chloride, suxamethonium and caffeine-suxamethonium.

Susceptibility to MH was determined in 77 patients according to the protocol of the European MH Group. Additional muscle bundles were used for diagnostic in vitro tests with caffeine in the presence of 1% halothane, potassium chloride, suxamethonium, and caffeine-suxamethonium. Significant differences between MH-susceptible (MHS) and MH-negative (MHN) patients were obtained with the halothane-caffeine test and the potassium chloride test, whereas no differences were found with the suxamethonium test. In the test with caffeine-suxamethonium, a different response to caffeine but not to suxamethonium was obtained. In all tests there was an overlap in results between MHS and MHN groups, and the predictive values of the tests ranged between 63 and 95%. Prior small doses of caffeine followed by a 4 mmol/l dose of caffeine elicited significantly smaller contractures than 4 mmol/l given as the first dose of caffeine. This underlines the necessity of a common protocol for performance and interpretation of diagnostic tests for MH.

Caffeine↗

PubMed2006

Naringin does not alter caffeine pharmacokinetics, energy expenditure, or cardiovascular haemodynamics in humans following caffeine consumption.

1. Naringin, a grapefruit constituent interacts with many medications including caffeine, a popular weight loss supplement. The purpose of the current study was to identify changes in caffeine pharmacokinetics, resting energy expenditure (REE), oxygen consumption (VO(2)) and respiratory exchange ratio (RER) after an acute dosage of caffeine and naringin. 2. Using a double-blinded, counterbalanced design, REE, VO(2), and RER were measured before and systematically for 8 h after a single dosage of caffeine (CAF, 200 mg) with and without naringin (100 mg (CN100) or 200 mg (CN200)) in 10 apparently healthy individuals. A standardized meal was provided following 240-minute measurements (400 kcals; 35 g carbohydrate; 27 g protein; 7 g fat). 3. Caffeine, CN100, CN200 did not alter VO(2) or VO(2) area under the curve (137 301 +/- 8318, 139 729 +/- 9300, 134 297 +/- 8318, mL/480 min). Resting energy expenditure (k/cals) was 10.0 +/- 1.4% higher with CAF versus CN200 (6.0 +/- 1.4%) and CN100 (6 +/- 1.5%) at 240 min (P = 0.07) which was then negated following a standardized meal. Percent change in RER from pre to 240 min and pre to 480 min was not different between the CAF, CN100, or CN200 (-0.2 +/- 1.7%, 1.7 +/- 1.7%, -2.8 +/- 1.9%). 4. Although caffeine alone suggests a trend of increased REE, the results of the present study indicate that concurrent consumption of caffeine with naringin in acute dosages does not affect RER, VO(2), and prevents the increase of REE in adult humans. The results suggest that the interaction of grapefruit juice and caffeine may be due to constituents of grapefruit juice other than naringin or in addition to naringin.

Adolescent↗

PubMed2006

Acute effects of caffeine on heart rate variability in habitual caffeine consumers.

During the last years, heart rate variability (HRV) has become a promising risk factor for cardiovascular events. However, the effect of caffeine on HRV in habitual caffeine consumers has barely been investigated. Therefore, we treated 30 male habitual caffeine users in a randomized double-blinded crossover study design with either placebo, 100 or 200 mg caffeine orally and determined parameters of HRV under resting conditions and metronomic breathing. As result, we could not detect significant differences in HRV parameters up to 90 min after drug ingestion. We conclude that modest amounts of caffeine do not reveal negative nor positive effects on HRV within the first 90 min after drug ingestion in young and healthy habitual caffeine consumers. However, further research is necessary to determine the effects of caffeine on HRV in habitual caffeine users, healthy as well as suffering from diabetes, hypertension and postmyocardial infarction.

Adult↗

PubMed2002

Effect of a divided caffeine dose on endurance cycling performance, postexercise urinary caffeine concentration, and plasma paraxanthine.

This study compared the effects of a single and divided dose of caffeine on endurance performance and on postexercise urinary caffeine and plasma paraxanthine concentrations. Nine male cyclists and triathletes cycled for 90 min at 68% of maximal oxygen uptake, followed by a self-paced time trial (work equivalent to 80% of maximal oxygen uptake workload over 30 min) with three randomized, balanced, and double-blind interventions: 1) placebo 60 min before and 45 min into exercise (PP); 2) single caffeine dose (6 mg/kg) 60 min before exercise and placebo 45 min into exercise (CP); and 3) divided caffeine dose (3 mg/kg) 60 min before and 45 min into exercise (CC). Time trial performance was unchanged with caffeine ingestion (P = 0.08), but it tended to be faster in the caffeine trials (CP: 24.2 min and CC: 23.4 min) compared with placebo (PP: 28.3 min). Postexercise urinary caffeine concentration was significantly lower in CC (3.8 micro g/ml) compared with CP (6.8 micro g/ml). Plasma paraxanthine increased in a dose-dependent fashion and did not peak during exercise. In conclusion, dividing a caffeine dose provides no ergogenic effect over a bolus dose but reduces postexercise urinary concentration.

Adult↗

PubMed1991

Caffeine modulates the effects of DNA-intercalating drugs in vitro: a flow cytometric and spectrophotometric analysis of caffeine interaction with novantrone, doxorubicin, ellipticine, and the doxorubicin analogue AD198.

Exposure of L1210 cells to DNA-intercalating antitumor drugs Novantrone (mitoxantrone; 20 ng/ml), doxorubicin (0.5 micrograms/ml), ellipticine (5 micrograms/ml), or the doxorubicin analogue AD198 (0.4 micrograms/ml), for 1 h, results in inhibition of cell proliferation, arrest of cells in the G2 phase of the cell cycle, and an increase in the number of cells entering higher DNA ploidy. These effects are significantly reduced when 5 mM concentrations of the methylxanthines caffeine or pentoxifylline are present either simultaneous with, or, in some cases, when added for 1 h immediately following pulse exposure to the drug. Both caffeine and pentoxifylline alone (5 mM) have little effect on cell growth or cell cycle progression. The possible mechanism of cell protection against intercalating drugs provided by caffeine was studied spectrophotometrically by measuring the interaction between Novantrone and the caffeine chromophore and in a model system using permeabilized L1210 cells and measuring the effect of caffeine in reducing binding of the intercalating dye acridine orange to cellular DNA and RNA. The data indicate that the observed protection of cells against intercalating drugs by caffeine or pentoxifylline is most likely a consequence of the direct interaction between the methylxanthines and the planar aromatic molecules of the intercalating drugs: formation of caffeine-drug complexes in solution effectively lowers the concentration of the free drug and thereby reduces its pharmacological activity. The principle of selective entrapment of the intercalator by compounds like caffeine may be considered in designing strategies to modulate the activity of intercalating drugs in vivo, e.g., in lowering drug toxicity when inadvertently applied at too high doses.

Acridine Orange↗

PubMed2004

Rapid determination method of caffeine and application to monitoring of caffeine-assisted chemotherapy.

Caffeine-assisted chemotherapy for bone and soft tissue tumours is very effective. However, high serum caffeine concentrations cause severe side effects, so monitoring of the serum level during therapy is important. For this purpose, a rapid determination method was established by high-performance liquid chromatography after solid-phase extraction. This method can measure caffeine and its three major metabolites in serum samples within 8 min. The mean serum caffeine concentrations of patients were 34.6+/-7.8, 54.5+/-11.9 and 73.0+/-12.8 microg/ml at 24, 48 and 72 h, respectively, after the start of a 1500 mg/m2/day continuous infusion for 72 h. The distribution volume of caffeine was 0.65+/-0.23 l/kg, and the total body clearance was 0.025+/-0.011 l/h/kg, which was one-third of the reported low dose clearance. The appropriate infusion rate was calculated to avoid severe side effects in the final phase of the infusion by using a one-compartment constant infusion model based on the serum levels measured at 24 and 48 h. Caffeine clearance did not correlate with the metabolite/caffeine ratio in serum at any time. It is concluded that individual monitoring with this method for the purpose of dose adjustment is useful for avoiding the side effects of caffeine-assisted chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1982

Blood levels of caffeine and results of fetal examination after oral administration of caffeine to pregnant rats.

Pregnant FDA-strain Osborne-Mendel rats were administered repeated doses of caffeine by oral intubation (gavage) and by administration in the drinking water (ad libitum sipping). When [1-methyl-14C]caffeine was administered at a dosage of 80 mg per kg per day by ad libitum sipping on days 12 to 15 of gestation, the amounts of radioactivity in blood were variable; the highest level on day 12 was 0.2% of the dose per ml of blood. The highest blood level of caffeine observed during a 24-h sampling period averaged 5.7 micrograms ml-1. When [14C]caffeine was administered by gavage at a dosage of 80 mg kg-1 on day 12, the blood level of radioactivity reached a peak of 0.4% of the dose per ml of blood and declined rapidly thereafter. The highest amount of caffeine observed in blood averaged 63.1 micrograms ml-1, 1 h after gavage. The overall blood elimination half-life of radioactivity in pregnant rats treated by gavage was 2.6 h, and the half-life of caffeine in blood was 1.7 h. The levels of radioactivity in the fetus and maternal muscle per unit weight were comparable after each method of administration. A comparison of autopsy results from both groups indicated that resorptions were increased when compared with rats that did not receive caffeine; this effect was more marked in the gavage group than in the ad libitum sipping group. Ectrodactyly was observed only in offspring of the gavage group. The incidences of ectrodactyly or resorptions did not appear to be directly related to nutrition or fluid intake.

Administration, Oral↗

PubMed1994

Serum caffeine levels after 24 hours of caffeine abstention: observations on clinical patients undergoing myocardial perfusion imaging with dipyridamole or adenosine.

Although caffeine attenuates the vasodilatation produced by dipyridamole and adenosine, and is therefore contraindicated when these agents are used for myocardial perfusion scintigraphy, caffeine levels in clinical patients undergoing standard imaging protocols have not been studied. Eight-six patients undergoing clinically indicated intravenous dipyridamole (n = 75) or adenosine (n = 11) thallium-201 myocardial perfusion scintigraphy, all of whom reported abstention from products containing caffeine for 24 h, were studied prospectively. Blood samples were drawn prior to initiation of the pharmacologic infusion, and serum caffeine levels were determined using an enzyme immunoassay technique. Results of these determinations were correlated with maximum pulse and blood pressure changes measured during and immediately after the stressor infusion, and thallium imaging findings. Detectable caffeine levels were found in 34 patients (40%), ranging from 0.1 to 5.0 mg/l. There was no significant difference in mean systolic blood pressure decrease or mean pulse increase between patients with caffeine levels > 1.0 mg/l (20.4 +/- 18.2 mmHg, 11.0 +/- 8.9 BPM; n = 5) and those with lower (0.1 to 0.9 mg/l) (15.4 +/- 9.5 mmHg, 14.4 +/- 8.2 BPM; n = 29) or no detectable caffeine levels (18.0 +/- 11.5 mmHg, 16.6 +/- 10.1 BPM; n = 52). Redistribution on thallium imaging was also identified with a similar frequency in these three groups (2/5, 40%; 8/29, 28%; 22/52, 42% respectively).

Adenosine↗

PubMed1981

Relationship between caffeine discrimination and caffeine plasma levels.

Rats, trained to discriminate 32 mg/kg caffeine from saline in a two-lever operant task, were tested for the presence of caffeine-appropriate lever responding at various intervals after the intraperitoneal injection of 32 mg/kg caffeine. Following completion of all behavioral tests, caffeine plasma levels were determined in the same animals at the same intervals after caffeine administration. After injection, both caffeine levels and caffeine-appropriate responding showed rapid increases followed by a differential decline.

Animals↗

PubMed2006

Distribution of caffeine levels in urine in different sports in relation to doping control before and after the removal of caffeine from the WADA doping list.

Caffeine concentrations were measured in the urine of 4633 athletes tested for doping control in the Ghent Doping Control Laboratory in 2004. Determination of these concentrations was done using an alkaline extraction with a mixture of dichloromethane and methanol (9 : 1; v/v) followed by high performance liquid chromatography and ultraviolet detection (HPLC-UV). The method was validated according to ISO 17 025 standards (International Organisation for Standardisation). Quantification was done by using a linear calibration curve in the range from 0 to 20 microg/ml. The limit of quantification (LOQ) was 0.10 microg/ml. Because the results were not normally distributed, transformation of the data was done to evaluate the difference in detected concentrations in several sports. This resulted in an overall average concentration of 1.12 +/- 2.68 microg/ml. Comparison of the most frequently tested sports in 2004 demonstrated that caffeine concentrations in samples originating from power lifters are significantly higher in comparison to urines taken in other sports. Also, a significant difference between caffeine concentrations found in cycling and concentrations found in other sports, including athletics and some ball sports, was observed. A comparison was made between results obtained in 2004 and results obtained before the removal of caffeine from the WADA (World Anti-Doping Agency) doping list indicating that average caffeine concentrations decreased after the withdrawal of caffeine from the list of prohibited substances. The overall percentage of positive samples between the two periods remained the same although the percentage of positive samples noticed in cycling increased after the removal of caffeine from the doping list.

Bicycling↗

PubMed1986

Influence of alcohol and caffeine consumption on caffeine elimination.

Ten healthy male volunteers were each studied on four separate occasions to assess the role of regular caffeine and alcohol intake on caffeine elimination. Antipyrine disappearance was also studied as an established quantitative test of hepatic microsomal function. Regular caffeine intake in high doses for 1 week failed to alter either antipyrine or caffeine pharmacokinetics. In contrast, alcohol intake of 50 g/day significantly prolonged caffeine half-life by 72% (P less than 0.005) and diminished caffeine clearance by 36% (P less than 0.0005). However, antipyrine kinetics were unaltered. These results demonstrate that alcohol, in amounts commonly consumed, is a strong inhibitor of caffeine metabolism.

Adult↗

PubMed2002

Exercise endurance 1, 3, and 6 h after caffeine ingestion in caffeine users and nonusers.

The purpose of the present study was to examine the duration of caffeine's ergogenic effect and whether it differs between users and nonusers of the drug. Twenty-one subjects (13 caffeine users and 8 nonusers) completed six randomized exercise rides to exhaustion at 80% of maximal oxygen consumption after ingesting either a placebo or 5 mg/kg of caffeine. Exercise to exhaustion was completed once per week at either 1, 3, or 6 h after placebo or drug ingestion. Exercise time to exhaustion differed between users and nonusers with the ergogenic effect being greater and lasting longer in nonusers. For the nonusers, exercise times 1, 3, and 6 h after caffeine ingestion were 32.7 +/- 8.4, 32.1 +/- 8.6, and 31.7 +/- 12.0 min, respectively, and these values were each significantly greater than the corresponding placebo values of 24.2 +/- 6.4, 25.8 +/- 9.0, and 23.2 +/- 7.1 min. For caffeine users, exercise times 1, 3, and 6 h after caffeine ingestion were 27.4 +/- 7.2, 28.1 +/- 7.8, and 24.5 +/- 7.6 min, respectively. Only exercise times 1 and 3 h after drug ingestion were significantly greater than the respective placebo trials of 23.3 +/- 6.5, 23.2 +/- 7.1, and 23.5 +/- 5.7 min. In conclusion, both the duration and magnitude of the ergogenic effect that followed a 5 mg/kg dose of caffeine were greater in the nonusers compared with the users.

Administration, Oral↗