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[Caffeine intake and food sources of caffeine and prematurity: a case-control study].

Caffeine (1,3,7-trimethylxanthine) is an alkali that easily crosses the placental barrier and can interfere in the growth and development of fetal cells and compromise fetal oxygenation. Considering the widespread consumption of foods containing caffeine in Brazil, the aim of this study was to evaluate the association between total caffeine consumption (including its food sources) and prematurity. A case-control study of 140 cases (newborns with gestational age less than 37 weeks) and 162 controls (newborns with 37 weeks gestational age or greater) evaluated caffeine consumption during pregnancy. Intake measurement used a semi-quantitative food frequency questionnaire based on the following foods: coffee, tea, and powdered chocolate. Total caffeine consumption (including food sources) during pregnancy was not associated with prematurity, and most intakes were less than 300 mg/ day. Caffeine consumption in the present study does not support guidelines against caffeine consumption by Brazilian pregnant women.

Adolescent↗

Nonparametric expectation maximisation (NPEM) population pharmacokinetic analysis of caffeine disposition from sparse data in adult caucasians: systemic caffeine clearance as a biomarker for cytochrome P450 1A2 activity.

OBJECTIVE: To explore the ability of the nonparametric expectation maximisation (NPEM) method of population pharmacokinetic modelling to deal with sparse data in estimating systemic caffeine clearance for monitoring and evaluation of cytochrome P450 (CYP) 1A2 activity. DESIGN AND PARTICIPANTS: Nonblind, single-dose clinical investigation in 34 non-related adult Bulgarian Caucasians (18 women and 16 men, aged between 18 and 62 years) with normal and reduced renal function. METHODS: Each participant received oral caffeine 3 mg/kg. Two blood samples per individual were taken according to the protocol for measuring caffeine plasma concentrations. A total of 67 measured concentrations were used to obtain NPEM estimates of caffeine clearance. Paraxanthine/caffeine plasma ratios were calculated and correlated with clearance estimates. Graphical methods and tests for normality were applied and parametric and nonparametric statistical tests were used for comparison. RESULTS: NPEM median estimates of caffeine absorption and elimination rate constants, k(a) = 4.54 h(-1) and k(el) = 0.139 h(-1), as well as of fractional volume of distribution and plasma clearance, V(S1) = 0.58 L/kg and CL(S1) = 0.057 L/h/kg, agreed well with reported values from more 'data rich' studies. Significant correlations were observed between paraxanthine/caffeine ratios at 3, 8 and 10 hours and clearance (Spearman rank correlation coefficients, r(s), >0.74, p </= 0.04). Sex or renal function caused no significant differences in clearance. Heavy smokers and drinkers showed 2-fold higher CYP1A2 activity. Normality tests and graphical methods of analysing caffeine clearance supported a non-Gaussian and multicomponent distribution of CYP1A2 activity. CONCLUSIONS: Collectively, the results show that the NPEM method is suitable and relevant for large-scale epidemiological studies of population phenotyping for cancer susceptibility and for abnormal liver function by monitoring CYP1A2 activity based on sparse caffeine data.

Adult↗

Physiological responses to caffeine during endurance running in habitual caffeine users.

Several studies have found that caffeine improved endurance exercise performance, but the factors which are responsible for this are not fully understood. Possibilities include an increased free fatty acid (FFA) oxidation and a resultant sparing of muscle glycogen as well as an enhancement of neuromuscular function during exercise. In order to further examine these factors, six varsity level runners (VO2max = 63.3 ml.kg-1.min-1) were studied over 90 min of treadmill running (70% VO2max) in a thermoneutral environment in order to determine the metabolic and neuromuscular effects of caffeine (6 mg.kg-1) administered in a randomized, crossover, double-blind manner. Subjects were habitual caffeine consumers (200 mg.d-1) and were given identical diets during each 3-d testing period. Caffeine administration, 60 min prior to exercise, significantly (P less than 0.05) increased plasma FFA levels both prior to and during exercise. Caffeine administration did not alter any of the other variables examined: VO2, HR, RER, rating of perceived exertion; plasma levels of glucose, lactate, epinephrine, and norepinephrine; or neuromuscular function (maximal voluntary strength, peak twitch torque, and motor unit activation). We conclude that caffeine administration (6 mg.kg-1) in athletic, habitual caffeine consumers increased plasma FFA levels but had neither metabolic nor neuromuscular effects that would be of potential ergogenic benefit in endurance running.

Adult↗

Direct effects of caffeine on osteoblastic cells metabolism: the possible causal effect of caffeine on the formation of osteoporosis.

BACKGROUND: Caffeine consumption has been reported to decrease bone mineral density (BMD), increase the risk of hip fracture, and negatively influence calcium retention. In this study, we investigated the influence of caffeine on the osteoblasts behaviour. METHOD: Osteoblasts derived from newborn Wistar-rat calvaria was used in this study. The effects of various concentrations of caffeine on bone cell activities were evaluated by using MTT assay. Alkaline phosphatase (ALP) staining, von Kossa staining and biochemical parameters including ALP, lactate dehydrogenase (LDH), prostaglandin E2 (PGE2) and total protein were performed at day 1, 3, and 7. DNA degradation analysis under the caffeine influence was also performed. RESULTS AND DISCUSSION: The results showed that the viability of the osteoblasts, the formation of ALP positive staining colonies and mineralization nodules formation in the osteoblasts cultures decreased significantly in the presence of 10 mM caffeine. The intracellular LDH, ALP and PGE2 content decreased significantly, the LDH and PGE2 secreted into the medium increased significantly. The activation of an irreversible commitment to cell death by caffeine was clearly demonstrated by DNA ladder staining. CONCLUSION: In summary, our results suggest that caffeine has potential deleterious effect on the osteoblasts viability, which may enhance the rate of osteoblasts apoptosis.

Journal Article↗

Behavioral effects of caffeine in children. Relationship between dietary choice and effects of caffeine challenge.

From a survey of 24-hour caffeine intake of 798 grade-school children (mean age, 10.3 years), 19 "high consumers" (reported intake of 500 mg/day or more) and a matched group of 19 "low consumers" were recruited for a double-blind, placebo-controlled, caffeine challenge study. Children received 5 mg/kg of caffeine twice a day or placebo for two weeks each, using a crossover design. While not receiving caffeine, high consumers had higher scores on an anxiety questionnaire and tended to have lower autonomic arousal (less frequent spontaneous skin conductance response and lower skin conductance level). While receiving caffeine, low consumers were perceived by their parents as more emotional, inattentive, and restless, while high consumers were not rated as changed. These differences cannot be attributed to tolerance, withdrawal, or subject selection, and suggest a possible physiological basis in children for dietary caffeine preference.

Adolescent↗

Adenosine A1 receptors determine effects of caffeine on total fluid intake but not caffeine appetite.

Adenosine A1 receptor wild-type (+/+) and knockout (-/-) mice were used to elucidate the role of adenosine A1 receptors in caffeine self-administration in a two-bottle choice test and in the effect of caffeine on total fluid intake and plasma renin concentration. With access to water only, adenosine A1 receptor -/- mice showed greater basal fluid intake and greater plasma renin concentration than +/+ mice. Free access to both water and a caffeinated solution (30 mg/100 ml) for 14 days increased total fluid intake only in adenosine A1 receptor +/+ mice (by 23+/-3%), and both total fluid intake and plasma renin concentration were no longer different between genotypes. Mean intake of water and caffeinated solution was not different between adenosine A1 receptor +/+ and -/- mice. These data reveal that adenosine A1 receptors do not contribute to caffeine consumption, but determine the effects of caffeine on fluid intake and plasma renin concentration.

Animals↗

Caffeine withdrawal symptoms following brief caffeine deprivation.

The effects of short-term caffeine deprivation on mood, withdrawal symptoms and psychomotor performance were studied in habitual coffee drinkers. Thirty-one male and female coffee drinkers were tested twice at midday (1130 to 1330 h) 4 h after double-blind administration of 250 mg of caffeine or placebo. Mood and withdrawal symptoms reports were collected by questionnaires. Psychomotor performance was tested with a brief computerized test battery, and causal blood pressure was measured. Caffeine deprivation was associated with decreased vigor and increased fatigue and with symptoms including sleepiness and yawning. Blood pressure was lower by 5-6 mm Hg. No changes in psychomotor performance were observed. Even short periods of caffeine deprivation, equivalent in length to missing regular morning coffee, can produce noticeable unpleasant caffeine withdrawal symptoms in habitual coffee drinkers. Such symptoms may be common side effects of habitual caffeine consumption that contribute to the maintenance of this behavior.

Adolescent↗

Repeated co-administration of caffeine and bromocriptine prevents tolerance to the effects of caffeine in the turning behavior animal model.

The present study examined the effects of repeated co-administrations of caffeine and bromocriptine for 9 consecutive days on contralateral turning in unilateral nigrostriatal 6-hydroxydopamine denervated rats. In agreement with previous data, our results showed that on the first administration, both caffeine and bromocriptine injected plus saline produced a significant increase in contralateral rotational behavior as compared to saline-saline injections. However, with repeated administrations, tolerance was observed to caffeine, but not to bromocriptine. The combination of different doses of bromocriptine (0.1, 0.2, 0.4 and 0.8 mg/kg) with caffeine (40 mg/kg) significantly enhanced the effects of either drug injected with saline on rotational behavior, and no tolerance was observed with repeated treatment. The continuous co-administration of both substances was necessary to maintain elevated levels of rotational behavior, since withdrawing one or the other drug led to decreased contralateral turning. These results demonstrate that when caffeine is administered repeatedly in combination with bromocriptine, tolerance to its psychostimulant effects is not observed, suggesting that caffeine could be used as an adjunctive therapeutic agent with dopamine agonists for the treatment of Parkinson's disease.

Adrenergic Agents↗

Efficacy of caffeine versus expectancy in altering caffeine-related symptoms.

The study investigated the independent and interactive effects of caffeine and expectancy on caffeine-related symptoms. High- and low-caffeine consumers were randomly assigned to either an expectancy or nonexpectancy instructional set and one of four caffeine doses. Subjects were administered the State-Trait Anxiety Inventory, (Spielberger & Gorsuch, 1970) and a Symptom Questionnaire (Christensen, White, Krietsch, & Steele, 1990) prior to and 45 min following consumption of one of the four caffeine doses. An analysis of covariance identified a significant main effect for the State-Trait Anxiety Inventory scores and significant main and interaction effects for four Symptom Questionnaire items. However, when the alpha levels were corrected for the increased probability of Type I error, using the Bonferroni procedure, these effects failed to achieve significance. These results suggest that previous reports of subjective caffeine effects are also suspect because of their failure to control for the increased probability of Type I error.

Adult↗

Comparison of caffeine-induced changes in cerebral blood flow and middle cerebral artery blood velocity shows that caffeine reduces middle cerebral artery diameter.

Changes in cerebral blood flow (CBF) can be assessed directly with xenon clearance (XeC) or indirectly by measuring changes in middle cerebral artery blood velocity (Vmca) with transcranial Doppler (TCD). The aim of this study was to compare the changes in CBF and Vmca following caffeine ingestion. Nineteen patients (age 48-86, recovering from an acute stroke) and ten controls (age 52-85) were each studied twice. Bilateral measurements of CBF and Vmca were made before and after ingestion of 250 mg caffeine or matched placebo. The percentage change in CBF and Vmca after caffeine was calculated. Full results (CBF and Vmca) were obtained from 14 patients and 9 controls. There was no significant difference between patients and controls, so results were combined. Caffeine reduced CBF by 22% (95% confidence interval (CI) = 17% to 28%) and reduced Vmca by 13% (95% CI = 10% to 17%). The fall in Vmca was significantly less than that in CBF (p = 0.0016), showing that caffeine reduces mca diameter. Analysis based on Poiseuille flow in the arterioles suggests that caffeine reduced arteriole diameter by 5.9% (95% CI = 4.6% to 7.3%) and mca diameter by 4.3% (95% CI = 2.0% to 6.6%). TCD is being used as an alternative to XeC for assessing the effect of vasoconstrictors and vasodilators on CBF. This study has demonstrated that in mca diameter can be changed by the vasoactive agents, and that changes in Vmca do not necessarily reflect changes in CBF.

Aged↗

Paraxanthine (metabolite of caffeine) mimics caffeine's interaction with sympathetic control of thermogenesis.

The notion that paraxanthine (the major dimethylated by-product of caffeine) may be a biologically active metabolite that could mediate some of the effects of caffeine was tested in relation to the well-established property of caffeine as a thermogenic stimulant. From studies measuring the in vitro respiration rates of rat brown adipose tissue in the basal state and in response to ephedrine (an enhancer of norepinephrine release from sympathetic nerve endings), it is shown that paraxanthine has the same potency as its parent compound, caffeine, in interacting with the adrenergic system to potentiate thermogenesis. These data provide the first direct demonstration of a physiological effect of the main metabolite of caffeine and raise the possibility that paraxanthine may contribute importantly to the ability of caffeine to potentiate the thermogenic effects of well-known stimuli of the sympathetic nervous system such as cold exposure, moderate exercise, and sympathomimetic drugs.

Adipose Tissue, Brown↗

Slowly relaxing caffeine responses in rat ventricle: relationships of ryanodine and caffeine actions.

Contractile responses to 20 mM caffeine were compared in arterially perfused rat right ventricle as tension, in intact rat myocytes as shortening, and in Triton X-100-"skinned" rat myocytes as shortening and stiffness. Responses in intact quiescent ventricle and membrane-disrupted myocytes at -log molar Ca concentration (pCa) of 7.0-6.8 were similar; force and stiffness rose quickly on application of caffeine and declined incompletely toward base line over 20 min. Subsequent caffeine responses were blunted. By contrast, in freshly isolated rat myocytes, rapid caffeine exposures induced large phasic contractures, which relaxed for the most part in 2-5 s. These responses were largely suppressed by 0.2 microM ryanodine pretreatment at 35 degrees C but not by high ryanodine concentrations (10 microM). Ryanodine was without effect on slowly relaxing contractile responses in both intact ventricle and Triton X-100-treated myocytes. The results are discussed in relation to the predicted effects of a calcium store leak in a simple model of cardiac excitation-contraction coupling. The results suggest that slowly relaxing caffeine contractures can be caused entirely by direct actions of caffeine on myofilaments.

Alkaloids↗

Antagonism of adenosine receptors by caffeine and caffeine metabolites in equine forebrain tissues.

OBJECTIVE: To determine the presence of adenosine receptor subtypes A1 and A2a in equine forebrain tissues and to characterize the interactions of caffeine and its metabolites with adenosine receptors in the CNS of horses. SAMPLE POPULATION: Brain tissue specimens obtained during necropsy from 5 adult male research horses. PROCEDURE: Membrane-enriched homogenates from cerebral cortex and striatum were evaluated by radioligand binding assays with the A1-selective ligand [3H]DPCPX and the A2a-selective ligand [3H]ZM241385. Functional responses to adenosine receptor agonists and antagonists were determined by a nucleotide exchange assay using [35S]-guanosine 5'-(gamma-thio) triphosphate ([35S]GTPgammaS). RESULTS: Saturable high affinity [3H]DPCPX binding (A1) sites were detected in cerebral cortex and striatum, whereas high-affinity [3H]ZM241385 binding (A2a) sites were detected only in striatum. Caffeine and related methylxanthines had similar binding affinities at A1 and A2a sites with rank orders of drug binding affinities (theophylline > paraxanthine > or = caffeine >> theobromine) similar to other species. [35S]GTPgammaS exchange revealed that caffeine and its metabolites act as pure adenosine receptor antagonists at concentrations that correspond to A1 and A2a receptor binding affinities. CONCLUSIONS AND CLINICAL RELEVANCE: Results of our study affirm the presence of guanine nucleotide binding protein linked adenosine receptors (ie, high-affinity A1 and A2a adenosine receptors) in equine forebrain tissues and reveal the antagonistic actions by caffeine and several biologically active caffeine metabolites. Antagonism of adenosine actions in the equine CNS by these stimulants may be responsible for some central actions of methylxanthine drugs, including motor stimulation and enhanced racing performance.

Animals↗

Caffeine consumption questionnaire: a standardized measure for caffeine consumption in undergraduate students.

Undergraduate students (N=691) were given the 1992 Caffeine Consumption Questionnaire of Landrum and provided information on age, sex, and year in school. A subset (n = 168) of those completing the questionnaire were also given the Morningness-Eveningness Questionnaire of Horne and Ostberg. Analysis indicated that the average intake of caffeine was roughly 1,600 mg, i.e., a range from 13 mg to 21,840 mg per week. Older students consumed more caffeine than younger ones, and students with an Evening personality preference consumed more caffeine in the evening and nighttime hours than those with a Morning personality preference. These results are discussed in the context of other caffeine studies. Caffeine consumption is an important issue, and a consistent measurement system should be used by various researchers testing different populations.

Adolescent↗

[Caffeine as an inhibitor of the conjugation transfer of R-factors. A study of the quantitative effect of caffeine on the conjugation transfer of R-factors].

The effect of caffeine on the conjugation transfer of R-factors was studied using a standartized kinetic conjugation system described earlier. It was shown that caffeine had a pronounced inhibitory effect on R-factor transfer. The inhibition coefficients at a caffeine concentration of 2000 gamma/ml were from 2.5 (when using strain CSH-2 R222 of E. coli as the donor) to 13.8 (when using strain J5-3 RI drd of E. coli as the donor). Higher concentrations of caffeine induced a significant increase in the coefficient. Since R-transfer inhibition was induced by rather high concentrations of caffeine, the effect of equivalent concentrations of some normal metabolites of the purine and pyrimidine series, such as ATP, guanine, cytosine and thymine was studied. It was shown that the substances had no inhibitory effect on R-factor transfer. Inhibition of P-transfer by caffeine did not depend on either the type of R-factor or the microbial host.

Bacteriological Techniques↗

Caffeine and caffeinism.

Caffeine is a widely ingested and generally beneficial drug. However, when taken in excess, anxiety related symptoms become increasingly apparent. A case of caffeinism, which presented as a paranoid delusion, is reported as an extreme example of this. A study of 60 hospital inpatients revealed that about 40% of them consumed sufficient caffeine to produce symptoms of caffeinism. It is thus recommended that all patients should be questioned on their caffeine intake. Also, caffeinism should be considered as a differential diagnosis of anxiety states.

Adult↗

The action of caffeine on X-irradiated HeLa cells. VII. Evidence that caffeine enhances expression of potentially lethal radiation damage.

HeLa cells irradiated with 2 Gy of 220-kV X rays suffer a 60-70% loss of colony-forming ability which is increased to 90% by postirradiation treatment with 10 mM caffeine for 6 hr. The detailed postirradiation patterns of cell death and sister-cell fusion in such cultures and in cultures in which the colony-forming ability was brought to about the same level by treatment with a larger (4 Gy) X-ray dose alone or by longer (48 hr) treatment with 10 mM caffeine alone were recorded by time-lapse cinemicrography. Because the patterns of cell death and fusion differ radically in irradiated and in caffeine-treated cultures, the response of the additional cells killed by the combined treatment can be identified as X-ray induced rather than caffeine induced. The appearance of cultures after several days of incubation confirms the similarity of the post-treatment patterns of proliferation in cultures suffering enhanced killing to those occurring in cultures treated with larger doses of X rays alone. It is concluded that X rays do not sensitize cells to caffeine, but rather that caffeine enhances the expression of potentially lethal radiation-induced damage.

Caffeine↗

Caffeine and its metabolites in caffeine overdose cause falsely elevated serum theophylline measurements.

In two cases of caffeine overdose, the elimination of caffeine appeared to be non-linear. Measurements of theophylline concentrations after caffeine overdose were method-dependent. After caffeine overdose, quantitation of caffeine is not clinically indicated, because of the variable correlation between concentration and toxic effects. Our data suggest that the measurement of theophylline concentrations after caffeine overdose is also not clinically indicated, and may be misleading if a nonspecific method is used.

Caffeine↗