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Caffeine is an ergogenic substance that is consumed globally in many forms. The use of buccally absorbable formulations instead of gastrointestinal uptake has become increasingly popular over the years, especially when accelerated absorption with minimal gastrointestinal stress is desired. This study investigated the impact of five different formulations and administration routes of caffeine on the whole blood concentrations of caffeine, paraxanthine, and theobromine: caffeinated capsules, tablets, shots, pouches, and chewing gums. A uniform dose of caffeine (200 mg) was administered to 16 healthy recreational athletes (26.0 ± 2.1 years) using a randomized crossover design. Samples were taken in the form of dried blood spots at 16 different time points in a 2-hr timeframe after drug administration. The samples were analyzed using a validated liquid chromatography–tandem mass spectrometry method. The results for caffeine showed no significant differences in the overall bioavailability (area under the concentration–time curve), maximal concentration, and time to maximum concentration. However, when analyzing the bioavailability of caffeine in the first 5, 10, and 15 min, the liquid caffeine formulation was superior to other administered forms (p <.05). This indicates that caffeine solubility has a major influence on its absorption rate. In sports, the rate of caffeine absorption must be considered, not only when ingesting anhydrous caffeine, but also when choosing buccal absorption. These findings imply that general guidelines for ergogenic caffeine use should consider the formulation used and, accordingly, the corresponding route of absorption. [ABSTRACT FROM AUTHOR]

Caffeine (CFF) is efficiently absorbed after ingestion, and approximately 80% of ingested CFF is metabolized to paraxanthine (PXT). Although PXT has approximately twice the adenosine receptor antagonist activity of CFF, there are few reports measuring the metabolite concentrations during CFF intoxication. Furthermore, no studies have examined the efficacy of hemodialysis (HD) on PXT or the indicators that contribute to treatment strategies for patients with acute CFF intoxication. This study analyzed the association between CFF and PXT blood levels, the blood biochemical data, and the vital signs of 27 cases with information on CFF intake and elapsed time data. It was found that HD was not as effective as CFF against PXT in CFF intoxication; however, HD was effective in cases with relatively high PXT concentrations (>10 μg/mL). Simultaneous analysis of CFF and PXT would make it possible to estimate the time elapsed from CFF intake and the risk of hyperCKemia, which may develop in cases left untreated for a prolonged period after ingestion. Therefore, the measurement of PXT, in addition to CFF, is expected to provide useful information for understanding the pathogenesis of CFF intoxication and the development of treatment strategies of acute CFF intoxication. [ABSTRACT FROM AUTHOR]

Importance and objective: Self-reported caffeine consumption has been widely used in research while it may be subject to bias. We sought to investigate the associations between self-reported caffeine consumption and plasma levels of caffeine and its two main metabolites (paraxanthine and theophylline) in the community. Methods: Data from two population-based studies (SKIPOGH1 and 2 (N = 1246) and CoLaus|PsyCoLaus (N = 4461)) conducted in Switzerland were used. Self-reported caffeine consumption was assessed using questionnaires. Plasma levels of caffeine and its metabolites were quantified by ultra-high performance liquid chromatography coupled to a tandem quadrupole mass spectrometer. Results: In both studies, mean log plasma levels of caffeine and its two metabolites were over 6.48 (plasma levels = 652 ng/ml) when no caffeine consumption was reported. Subsequently, nonlinear associations between log plasma levels and self-reported caffeine consumption were observed in SKIPOGH, with a change of the slope at 3–5 cups of espresso per day in SKIPOGH1 but not SKIPOGH2. In CoLaus|PsyCoLaus, increased daily consumption of caffeinated beverages was associated with increased log plasma levels with a change of the slope at 3 cups. In both studies, declared caffeine consumption higher than 3–5 cups per day was not associated with higher plasma levels of caffeine and its metabolites. Conclusion: Self-reports of no or low caffeine consumption and consumption of more than 3–5 cups of coffee should be interpreted with caution, with possible under- or over-estimation. Quantifying plasma levels of caffeine and its metabolites may contribute to a better estimation of caffeine intake. [ABSTRACT FROM AUTHOR]

The article presents a study which examined the effect of acute paraxanthine administration on the pentylenetetrazole (PTZ)-induced seizure threshold, focusing on the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway. Topics discussed include characteristics of epileptic seizure, finding on intravenous pentylenetetrazole test in mice, and effect of a high dose of paraxanthine on the nitric oxide metabolites (NOx) levels in brain tissues.

Simple Summary: Caffeine is a natural substance found in coffee (Coffea spp.), cocoa (Theobroma cacao), cola (Cola nitida), guaraná (Paullinia cupana), maté (Ilex paraguariensis), and tea plant (Camellia sinensis). These plant species are widely used to produce different drinks and foods, generating a large volume of by-products that may be used for animal feed. This article is part of a broad study that aims to evaluate the safety of using by-products containing caffeine to feed laying hens. In this study, we show that the eggs of laying hens fed caffeine contain this compound together with its primary metabolites: theophylline, theobromine, and paraxanthine. It is essential to highlight that the levels of these compounds found in eggs do not appear to pose any health risk to consumers. This study aimed to determine whether the eggs of laying hens fed caffeine contain this compound and its primary metabolites (theophylline, theobromine, and paraxanthine). Laying hens were distributed into four experimental groups fed rations containing 0 (control), 150, 300, or 450 μg/g of caffeine. For residual analysis, six eggs per group were collected after 4, 8, and 12 weeks. The concentrations of caffeine, theophylline, theobromine, and paraxanthine were determined in the white and yolk of each egg by a high-performance liquid chromatography with photodiode array detector (HPLC-PDA) method. All four compounds were detected in the white and yolk of eggs produced by hens fed caffeine, but their levels in the egg white were approximately twice those in the yolk. The major metabolite found in eggs was theophylline (57.5% of caffeine metabolites in the egg white and 58.5% in the yolk), followed by theobromine (39.9% in the egg white and 41.5% in the yolk), and paraxanthine (2.64% in the egg white and non-detected in the yolk). In summary, caffeine and its metabolites, theophylline, theobromine, and paraxanthine, are transferred to the chicken eggs. [ABSTRACT FROM AUTHOR]

This research aims to assess the influence of varying concentrations of caffeine (CA), one of the pharmaceutically active compounds, and its metabolites (i.e., paraxanthine (PX), theophylline (TP), and theobromine (TB)) on the growth of common marine phytoplankton (Isochrysis galbana and Thalassiosira pseudonana) under controlled laboratory conditions. Additionally, the study estimates the daily discharge of CA into marine ecosystems utilizing a developed model. The most effective metabolite inhibiting the proliferation of I. galbana was determined as TP (68.5%) at a concentration of 500 mg/L, while it was CA (65.8%) at the same concentration for T. pseudonana. After exposure to CA, the IC50 values for I. galbana and T. pseudonana were calculated as 107.3 mg/L and 136.8 mg/L, respectively after 96 hours. Furthermore, the lowest IC50 concentration was 7.4 mg/L in TP treatment in I. galbana. Based on a computational model developed in the paper, in a province with about 2 million inhabitants, where all wastewater is treated in wastewater treatment plants (WWTP), the quantity of CA discharged into the sea was computed as 8.11 kg/day. The CA amounts reaching the sea were potentially increased in regions devoid of wastewater treatment infrastructure. Consequently, WWTPs should undergo expansion and enhancement of their capacity, including advanced treatment for chemical removal for sustainable marine life. Additionally, further studies are needed to elucidate the mechanisms underlying the inhibition effects of CA on phytoplankton. [ABSTRACT FROM AUTHOR]

Melatonin (MEL) and caffeine (CA) are mediated by cytochrome P450 1A2 (CYP1A2), and the plasma concentration of MEL is reportedly affected by CA intake and CYP1A2 activity. Because the plasma concentrations of MEL and CA or paraxanthine (PX) differ by approximately 106, MEL, CA, and PX (a metabolite of CYP1A2) have not been quantified in a single-sample preparation. This study aimed to evaluate a liquid chromatography-tandem mass spectrometry method for quantification of MEL, CA, and PX in the same sample preparation. Initially, an injection volume of 10 µL produced a sharp peak for MEL, but the peaks for CA and PX were not suitable for quantification due to their asymmetric peaks. Therefore, CA and PX were separately quantified using 0.1 μL sample, which enabled measurement of both compounds with good peak symmetry. Under these conditions, the relative error for MEL, CA, and PX ranged from − 9.62% to 1.01%, 0.96% to 9.39%, and − 2.77% to 5.67%, with relative standard deviations of 7.23%, 4.95%, and 8.54%, respectively. In conclusion, the developed method is suitable for use in future studies on the relationship among MEL, CA, and PX. [ABSTRACT FROM AUTHOR]

Background In pregnancy, women are encouraged to cease smoking and limit caffeine intake. We employed objective definitions of smoking and caffeine exposure to assess their association with adverse outcomes. Methods We conducted a case cohort study within the Pregnancy Outcome Prediction study to analyse maternal serum metabolomics in samples from 12, 20, 28 and 36 weeks of gestational age. Objective smoking status was defined based on detectable cotinine levels at each time point and objective caffeine exposure was based on tertiles of paraxanthine levels at each time point. We used logistic and linear regression to examine the association between cotinine, paraxanthine and the risk of pre-eclampsia, spontaneous pre-term birth (sPTB), fetal growth restriction (FGR), gestational diabetes mellitus and birthweight. Results There were 914 and 915 women in the smoking and caffeine analyses, respectively. Compared with no exposure to smoking, consistent exposure to smoking was associated with an increased risk of sPTB [adjusted odds ratio (aOR) = 2.58, 95% CI: 1.14 to 5.85)] and FGR (aOR = 4.07, 95% CI: 2.14 to 7.74) and lower birthweight (β = –387 g, 95% CI: –622 g to –153 g). On univariate analysis, consistently high levels of paraxanthine were associated with an increased risk of FGR but that association attenuated when adjusting for maternal characteristics and objective—but not self-reported—smoking status. Conclusions Based on objective data, consistent exposure to smoking throughout pregnancy was strongly associated with sPTB and FGR. High levels of paraxanthine were not independently associated with any of the studied outcomes and were confounded by smoking. [ABSTRACT FROM AUTHOR]

This study aimed to determine whether the eggs of laying hens fed caffeine contain this compound and its primary metabolites (theophylline, theobromine, and paraxanthine). Laying hens were distributed into four experimental groups fed rations containing 0 (control), 150, 300, or 450 μg/g of caffeine. For residual analysis, six eggs per group were collected after 4, 8, and 12 weeks. The concentrations of caffeine, theophylline, theobromine, and paraxanthine were determined in the white and yolk of each egg by a high-performance liquid chromatography with photodiode array detector (HPLC-PDA) method. All four compounds were detected in the white and yolk of eggs produced by hens fed caffeine, but their levels in the egg white were approximately twice those in the yolk. The major metabolite found in eggs was theophylline (57.5% of caffeine metabolites in the egg white and 58.5% in the yolk), followed by theobromine (39.9% in the egg white and 41.5% in the yolk), and paraxanthine (2.64% in the egg white and non-detected in the yolk). In summary, caffeine and its metabolites, theophylline, theobromine, and paraxanthine, are transferred to the chicken eggs.

Caffeine is a trimethylxanthine found in coffee and several other foods and beverages. Its stimulatory effects make it an interesting strategy to boost performance for athletic populations. Scientific evidence supports its efficacy to improve high-intensity endurance exercise, explosive and high-intensity efforts, resistance exercise, team sports and combat sports, though individual variation in the ergogenic response to caffeine exists. Supplementation can be taken in many forms including dissolved in water, via capsules, coffee, energy drinks and caffeinated gum; ingestion via capsules, dissolved in water or in caffeinated gum appear to be most effective. Variability in the exercise response following caffeine supplementation may be explained by genetic factors or habitual caffeine consumption. Caffeine is an excellent supplement for athletes looking to improve their exercise performance, though some consideration of side-effects and impact on sleep are warranted. [ABSTRACT FROM AUTHOR]

Paraxanthine (PX), a major metabolite of caffeine, a protective agent against Alzheimer's and Parkinson's disease, and a promising drug for the treatment of post-COVID 2019 anosmia and ageusia, has been studied in the solid state and protein–ligand complex. Partial disorder in PX, caused by the methyl group at the N(7) position, has been modelled and discussed. The relationship between the unusual structural disorder and the propensity to form a specific system of non-covalent bonds was analyzed. Three 1H-14N NMR-NQR (nuclear magnetic resonance–nuclear quadrupole resonance) experimental techniques were used, namely multiple frequency sweeps, Larmor frequency scanning, and the two-frequency irradiation, followed by solid-state computational modelling (density functional theory, supplemented by quantum theory of atoms in molecules, 3D Hirshfeld surfaces, and reduced density gradient), and molecular docking approaches. New quantitative methods for estimating changes in the global pattern of interactions under the influence of rotation of the methyl group in N(7) based on the Pompeiu–Hausdorff and Bhattacharayya metrics and the Wasserstein distance have been proposed and applied. A spectrum consisting of 12 lines, indicating the presence of 4 chemically inequivalent nitrogen sites in the PX molecule, was recorded, and the lines' assignment to particular sites was made. The influence of the methyl rotation on the eigenvalues and eigenvectors of the electric field gradient tensor, NQR parameters, and resonance line positions was modelled in the solid (GGA/RPBE, m-GGA/RSCAN) and cluster (Minnesota M062X hybrid). Three factors have been found to determine structural disorder in PX: larger crystal voids near the methyl at N(7) than at N(1) (opening the path for the disorder), hyperconjugation strongly affecting the density distribution in the five-membered ring, and the involvement of the methyl group at N(7) in many non-covalent bonds that intercept (capture) subsequent jumping protons. The Pompeiu–Hausdorff and Bhattacharayya metrics and the Wasserstein distance confirmed the changes in the distribution and strength of non-covalent interactions throughout the molecule as a result of methyl rotation. This effect is clearly visible regardless of the type of metric, and its order of magnitude is consistent with the modulation effect of the NQR spectra (experimental and calculated). Through molecular docking, it was discovered that the PX moiety in protein–ligand complexes adopt the same methyl group conformation at N(7) as in the solid state. It was found that the cooperation–competition between the C-H⋯O hydrogen bonds and C-H⋯H-C dispersion interactions is the crucial factor that impedes methyl rotation and induces structural disorder, as well as being an important factor in the formation of the protein–ligand complexes. [ABSTRACT FROM AUTHOR]

Purine derivatives such as caffeine and uric acid have neuroprotective activities and are negatively correlated with the incidence of both Alzheimer's disease and Parkinson's disease. We have reported that an increment of intracellular glutathione (GSH) via cysteine uptake in neuronal cells is one of the mechanisms by which caffeine and uric acid confer neuroprotection. Here, we investigated whether caffeine metabolites such as paraxanthine, theophylline, theobromine, 1,7-dimethyluric acid and monomethylxanthines would increase cysteine uptake in mouse hippocampal slices. The metabolites were administered to hippocampal slices for 30 min at doses of 0, 10, or 100 μM, and then cysteine was added for 30 min. Paraxanthine, a major metabolite of caffeine, increased cysteine content in the slices, whereas the other metabolites did not. In vitro treatment with paraxanthine promoted cysteine uptake and increased GSH in HEK293 cells. The paraxanthine-induced cysteine uptake was inhibited by an excitatory amino-acid carrier-1 (EAAC1) inhibitor, and H2O2-induced cell damage was prevented by the paraxanthine treatment of SH-SY5Y cells. These results suggest that paraxanthine, an active metabolite of caffeine, acts to increase intracellular GSH levels via EAAC1 leading to neuroprotection.

Introduction: Caffeine, one of the most ubiquitous ingredients found in beverages and other ingested food products, has a long history of safe use. As a member of the methylxanthine class of stimulants, caffeine is not devoid of unwanted side effects at any serving level. Caffeine safety has been the subject of a safety workshop by FDA and the Institute of Medicine in the past decade. Thus, investigation into an alternate stimulant with similar pharmacology but improved safety is warranted. Paraxanthine (1,7-dimethylxanthine) is the predominant metabolite of caffeine in humans with similar stimulant properties. The few toxicity studies that are available for paraxanthine suggest that the molecule is relatively safe, although thorough characterization of its safety is required prior to widespread incorporation into foods/beverages.Methods: The aim of this study was to evaluate the toxicity of paraxanthine (Rarebird, Inc.) relative to caffeine through a battery of toxicological studies conducted in accordance with international guidelines. These studies evaluated the potential mutagenicity (bacterial reverse mutation, in vitro mammalian chromosomal aberration), genetic toxicity (in vitro mammalian cell gene mutation) and acute, sub-acute and sub-chronic oral toxicity of paraxanthine in Sprague Dawley rats.Results/Discussion: There was no evidence of genetic toxicity or mutagenicity in the in vitro studies. An acute oral LD50 of 829.20 mg/kg body weight (bw) was established. There was no mortality or treatment-related adverse effects in the 14-day repeat dose oral toxicity study, wherein rats received low, mid, or high doses of paraxanthine (50, 100, or 150 mg/kg bw, n = 5 rats/sex/group). The same findings were observed in the subchronic repeat-dose 90-day oral toxicity study at daily doses of paraxanthine of 100, 150, or 185 mg/kg bw which were compared to caffeine at 150 or 185 mg/kg bw (n = 10 animals/sex/group). However, mortality was reported in two animals in the high dose caffeine-treated animals. Therefore, the no observed adverse effect level (NOAEL) from the 90-day study was determined to be 150 mg/kg bw for caffeine and 185 mg/kg bw for paraxanthine for both male and female Sprague Dawley rats. These findings may suggest that paraxanthine could be a safer alternative to caffeine in humans.

Caffeine is a naturally occurring alkaloid and it is metabolized to paraxanthine, theophylline and theobromine. Analysis of caffeine and its metabolites is challenging since the metabolites theophylline and paraxanthine generate similar product and precursor ions. In this study, a new method was developed for the simultaneous analysis of caffeine, paraxanthine, theobromine and theophylline in horse urine using gas chromatography–mass spectrometry (GC–MS). Urine samples were treated using solid‐phase extraction followed by the elution with dichloromethane–isopropanol (90:10) after the pH was adjusted to 6, and then derivatization with N‐methyl‐N‐trimethylsilyl‐trifluoroacetamide–1% trimethylchlorosilane before analysis with GC–MS. Sample preparation and derivatization steps were optimized and the method permitted elution all of these analytes within 13 min. The method was fully validated according to Commission Decision, 2002/657/EC guidelines. The calibration curves were linear with a correlation coefficient of >0.99. Precision and accuracy were well within the 15% acceptance range and the method was robust. The validation results demonstrated that the method is highly reproducible, easily applicable and selective. The method was applied to urine samples collected from racehorses to demonstrate its applicability. [ABSTRACT FROM AUTHOR]

Abstract Background Caffeine (0.1 g) is used as a central nervous system stimulant and as a nontoxic phenotyping probe for cytochrome P450 1A2. However, an increasing number of suicide attempts by caffeine overdose have been recently reported. Case presentation A 25-year-old woman (body weight, 43 kg) who intentionally took an overdose of 5.9 g caffeine as a suicide attempt was emergently admitted to Kyoto Medical Center. The plasma concentrations of caffeine and its primary metabolite, N-demethylated paraxanthine, in the current case were 100 and 7.3 μg/mL, 81 and 9.9 μg/mL, 63 and 12 μg/mL, and 21 and 14 μg/mL, at 12, 20, 30, and 56 h after oral overdose, respectively. The observed apparent terminal elimination half-life of caffeine during days 1 and 2 of hospitalization was 27 h, which is several times longer than the reported normal value. This finding implied nonlinearity of caffeine pharmacokinetics over such a wide dose range, which could affect the accuracy of values simulated by a simplified physiologically based pharmacokinetic model founded on a normal dose of 100 mg. Low serum potassium levels (2.9 and 3.5 mM) on days 1 and 2 may have been caused by the caffeine overdose in the current case. Conclusions The patient underwent infusion with bicarbonate Ringer’s solution and potassium chloride and was discharged on the third day of hospitalization despite taking a potentially lethal dose of caffeine. The virtual plasma exposures of caffeine estimated using the current simplified PBPK model were higher than the measured values. The present results based on drug monitoring data and additional pharmacokinetic predictions could serve as a useful guide in cases of caffeine overdose.

Paraxanthine (1,7-dimethylxanthine), a purine alkaloid derivative of caffeine (1,3,7-trimethylxanthine), is a high-value biochemical with several applications in the pharmaceutical and cosmetic industries. However, chemical synthesis of paraxanthine requires harsh conditions and frequently results in low yield mixtures of non-specifically N-methylated compounds. We have recently demonstrated that the mutant bacterial N-demethylase NdmA4 with its partner reductase NdmD is capable of producing paraxanthine as the major metabolite from caffeine. Here, we report the construction and screening of several Escherichia coli strains to produce paraxanthine from caffeine by means of whole-cell biocatalysts using varying dosages of ndmA4, ndmD, and the frmAB formaldehyde dehydrogenase genes. Preliminary resting cell assay results with the best paraxanthine-producing strain, MBM019, showed a 33% molar conversion of caffeine, from 5 mM to 3.35 mM, resulting in approximately 0.90 mM paraxanthine. However, a small amount of 7-methylxanthine was unexpectedly produced at a concentration of approximately 0.35 mM. After optimizing reaction conditions to a cellular concentration of OD600 = 50 and a caffeine concentration of 5 mM, the reaction was scaled-up to a volume of 620 mL, producing 1.02 mM paraxanthine and consuming 2.49 mM caffeine. The purified paraxanthine was then isolated via preparatory scale chromatography, resulting in 104.1 mg of product at high purity. This is the first reported strain genetically optimized for the biosynthetic production of paraxanthine. [ABSTRACT FROM AUTHOR]

In the context of personalized medicine, the paraxanthine-to-caffeine ratio is an accepted standard for the optimization of the dose-response effect of many pharmaceuticals in individual patients. There is a strong drive towards the development of cheaper and portable devices for the detection of biomarkers, including paraxanthine and caffeine, which requires materials with high binding efficiency and specificity. We designed a recognition unit specific for paraxanthine which can discriminate molecules with small structural differences and can be used to increase the sensitivity of sensors. A number of functional units were screened by nuclear magnetic resonance for their ability to form specific binding interactions with paraxanthine in water and negligible interactions with its structural analogue caffeine. Imidazole was identified as the unit showing the most promising results and its two polymerizable derivatives were evaluated by isothermal titration calorimetry to identify the best monomer. The data suggested that 4-vinylimidazole was the most promising unit forming specific and strong binding interaction with paraxanthine. The calorimetry experiments allowed also the determination of the thermodynamic parameters of all interactions and the association constant values. Optimization of polymerization protocols in water, achieving high monomer conversions and chemical yields, demonstrate the suitability of the selected functional monomer for polymer preparations, targeting the detection of paraxanthine in aqueous environments. [ABSTRACT FROM AUTHOR]

Background Caffeine is the most frequently used psychoactive substance in the United States and >90% of reproductive-age women report some amount of intake daily. Despite biological plausibility, previous studies on caffeine and fecundability report conflicting results. Importantly, prior studies measured caffeine exposure exclusively by self-report, which is subject to measurement error and does not account for factors that influence caffeine metabolism. Objectives Our objective was to examine associations between preconception serum caffeine metabolites, caffeinated beverage intake, and fecundability. Methods Participants included 1228 women aged 18–40 y with a history of 1–2 pregnancy losses in the EAGeR (Effects of Aspirin in Gestation and Reproduction) trial. We prospectively evaluated associations of preconception caffeine metabolites (i.e. caffeine, paraxanthine, and theobromine) measured from 1191 serum samples untimed to a specific time of day, self-reported usual caffeinated beverage intakes at baseline, and time-varying cycle-average caffeinated beverage intake, with fecundability. Using Cox proportional hazards models, we estimated fecundability odds ratios (FORs) and 95% CIs according to each metabolite. Follow-up was complete for 89% (n  = 1088) of participants. Results At baseline, 85%, 73%, and 91% of women had detectable serum caffeine, paraxanthine, and theobromine, respectively. A total of 797 women became pregnant during ≤6 cycles of preconception follow-up. After adjusting for potential confounders, neither serum caffeine [tertile (T)3 compared with T1 FOR: 0.87; 95% CI: 0.71, 1.08], paraxanthine (T3 compared with T1 FOR: 0.92; 95% CI: 0.75, 1.14), nor theobromine (T3 compared with T1 FOR: 1.15; 95% CI: 0.95, 1.40) were associated with fecundability. Baseline intake of total caffeinated beverages was not associated with fecundability (>3 compared with 0 servings/d adjusted FOR: 0.99; 95% CI: 0.74, 1.34), nor was caffeinated coffee (>2 compared with 0 servings/d adjusted FOR: 0.93; 95% CI: 0.45, 1.92) or caffeinated soda (>2 servings/d adjusted FOR: 0.92; 95% CI: 0.71, 1.20). Conclusions Our findings are reassuring that caffeine exposure from usual low to moderate caffeinated beverage intake likely does not influence fecundability. This trial was registered at clinicaltrials.gov as NCT00467363. [ABSTRACT FROM AUTHOR]

Caffeine elicits widespread effects in the central nervous system and is the most frequently consumed psychostimulant worldwide. First evidence indicates that, during daily intake, the elimination of caffeine may slow down, and the primary metabolite, paraxanthine, may accumulate. The neural impact of such adaptions is virtually unexplored. In this report, we leveraged the data of a laboratory study with N = 20 participants and three within-subject conditions: caffeine (150 mg caffeine × 3/day × 10 days), placebo (150 mg mannitol × 3/day × 10 days), and acute caffeine deprivation (caffeine × 9 days, afterward placebo × 1 day). On day 10, we determined the course of salivary caffeine and paraxanthine using liquid chromatography-mass spectrometry coupled with tandem mass spectrometry. We assessed gray matter (GM) intensity and cerebral blood flow (CBF) after acute caffeine deprivation as compared to changes in the caffeine condition from our previous report. The results indicated that levels of paraxanthine and caffeine remained high and were carried overnight during daily intake, and that the levels of paraxanthine remained elevated after 24 h of caffeine deprivation compared to placebo. After 36 h of caffeine deprivation, the previously reported caffeine-induced GM reduction was partially mitigated, while CBF was elevated compared to placebo. Our findings unveil that conventional daily caffeine intake does not provide sufficient time to clear up psychoactive compounds and restore cerebral responses, even after 36 h of abstinence. They also suggest investigating the consequences of a paraxanthine accumulation during daily caffeine intake.

Background: Caffeine (0.1 g) is used as a central nervous system stimulant and as a nontoxic phenotyping probe for cytochrome P450 1A2. However, an increasing number of suicide attempts by caffeine overdose have been recently reported. Case presentation: A 25-year-old woman (body weight, 43 kg) who intentionally took an overdose of 5.9 g caffeine as a suicide attempt was emergently admitted to Kyoto Medical Center. The plasma concentrations of caffeine and its primary metabolite, N-demethylated paraxanthine, in the current case were 100 and 7.3 μg/mL, 81 and 9.9 μg/mL, 63 and 12 μg/mL, and 21 and 14 μg/mL, at 12, 20, 30, and 56 h after oral overdose, respectively. The observed apparent terminal elimination half-life of caffeine during days 1 and 2 of hospitalization was 27 h, which is several times longer than the reported normal value. This finding implied nonlinearity of caffeine pharmacokinetics over such a wide dose range, which could affect the accuracy of values simulated by a simplified physiologically based pharmacokinetic model founded on a normal dose of 100 mg. Low serum potassium levels (2.9 and 3.5 mM) on days 1 and 2 may have been caused by the caffeine overdose in the current case. Conclusions: The patient underwent infusion with bicarbonate Ringer's solution and potassium chloride and was discharged on the third day of hospitalization despite taking a potentially lethal dose of caffeine. The virtual plasma exposures of caffeine estimated using the current simplified PBPK model were higher than the measured values. The present results based on drug monitoring data and additional pharmacokinetic predictions could serve as a useful guide in cases of caffeine overdose. [ABSTRACT FROM AUTHOR]

In the context of personalized medicine, the paraxanthine-to-caffeine ratio is an accepted standard for the optimization of the dose-response effect of many pharmaceuticals in individual patients. There is a strong drive towards the development of cheaper and portable devices for the detection of biomarkers, including paraxanthine and caffeine, which requires materials with high binding efficiency and specificity. We designed a recognition unit specific for paraxanthine which can discriminate molecules with small structural differences and can be used to increase the sensitivity of sensors. A number of functional units were screened by nuclear magnetic resonance for their ability to form specific binding interactions with paraxanthine in water and negligible interactions with its structural analogue caffeine. Imidazole was identified as the unit showing the most promising results and its two polymerizable derivatives were evaluated by isothermal titration calorimetry to identify the best monomer. The data suggested that 4-vinylimidazole was the most promising unit forming specific and strong binding interaction with paraxanthine. The calorimetry experiments allowed also the determination of the thermodynamic parameters of all interactions and the association constant values. Optimization of polymerization protocols in water, achieving high monomer conversions and chemical yields, demonstrate the suitability of the selected functional monomer for polymer preparations, targeting the detection of paraxanthine in aqueous environments.

Background Neuroticism is a strong predictor for a variety of social and behavioral outcomes, but the etiology is still unknown. Our study aims to provide a comprehensive investigation of causal effects of serum metabolome phenotypes on risk of neuroticism using Mendelian randomization (MR) approaches. Methods Genetic associations with 486 metabolic traits were utilized as exposures, and data from a large genome-wide association study of neuroticism were selected as outcome. For MR analysis, we used the standard inverse-variance weighted (IVW) method for primary MR analysis and 3 additional MR methods (MR-Egger, weighted median, and MR pleiotropy residual sum and outlier) for sensitivity analyses. Results Our study identified 31 metabolites that might have causal effects on neuroticism. Of the 31 metabolites, uric acid and paraxanthine showed robustly significant association with neuroticism in all MR methods. Using single nucleotide polymorphisms as instrumental variables, a 1-SD increase in uric acid was associated with approximately 30% lower risk of neuroticism (OR: 0.77; 95% CI: 0.62–0.95; P IVW = 0.0145), whereas a 1-SD increase in paraxanthine was associated with a 7% higher risk of neuroticism (OR: 1.07; 95% CI: 1.01–1.12; P IVW = .0145). Discussion Our study suggested an increased level of uric acid was associated with lower risk of neuroticism, whereas paraxanthine showed the contrary effect. Our study provided novel insight by combining metabolomics with genomics to help understand the pathogenesis of neuroticism. [ABSTRACT FROM AUTHOR]

Background: Pre-exercise supplements containing low doses of caffeine improve endurance exercise performance, but the most efficacious time for consumption before intense endurance exercise remains unclear, as does the contribution of caffeine metabolism. Methods: This study assessed the timing of a commercially available supplement containing 200 mg of caffeine, 1600 mg of β-alanine and 1000 mg of quercetin [Beachbody Performance Energize, Beachbody LLC, USA] on exercise performance, perception of effort and plasma caffeine metabolites. Thirteen cyclists (V̇O2max 64.5 ± 1.4 ml kg− 1 min− 1 (± SEM)) completed four experimental visits consisting of 30 min of steady-state exercise on a cycle ergometer at 83 ± 1% V̇O2max followed by a 15-min time trial, with perceived exertion measured regularly. On three of the visits, participants consumed caffeine either 35 min before steady-state exercise (PRE), at the onset of steady-state (ONS) or immediately before the time trial (DUR) phases, with a placebo consumed at the other two time points (i.e. three drinks per visit). The other visit (PLA) consisted of consuming the placebo supplement at all three time points. The placebo was taste-, colour- and calorie-matched. Results: Total work performed during the time trial in PRE was 5% greater than PLA (3.53 ± 0.14 vs. 3.36 ± 0.13 kJ kg− 1 body mass; P = 0.0025), but not ONS (3.44 ± 0.13 kJ kg− 1; P = 0.3619) or DUR (3.39 ± 0.13 kJ kg− 1; P = 0.925), which were similar to PLA. Perceived exertion was lowest during steady-state exercise in the PRE condition (P < 0.05), which coincided with elevated plasma paraxanthine in PRE only (P < 0.05). Conclusion: In summary, ingestion of a pre-exercise supplement containing 200 mg caffeine 35 min before exercise appeared optimal for improved performance in a subsequent fatiguing time trial, possibly by reducing the perception of effort. Whether this was due to increased circulating paraxanthine requires further investigation. Trial registration: ClinicalTrials.Gov,NCT02985606; 10/26/2016. [ABSTRACT FROM AUTHOR]

Caffeine (CFF) is efficiently absorbed after ingestion, and approximately 80% of ingested CFF is metabolized to paraxanthine (PXT). Although PXT has approximately twice the adenosine receptor antagonist activity of CFF, there are few reports measuring the metabolite concentrations during CFF intoxication. Furthermore, no studies have examined the efficacy of hemodialysis (HD) on PXT or the indicators that contribute to treatment strategies for patients with acute CFF intoxication. This study analyzed the association between CFF and PXT blood levels, the blood biochemical data, and the vital signs of 27 cases with information on CFF intake and elapsed time data. It was found that HD was not as effective as CFF against PXT in CFF intoxication; however, HD was effective in cases with relatively high PXT concentrations (>10 μg/mL). Simultaneous analysis of CFF and PXT would make it possible to estimate the time elapsed from CFF intake and the risk of hyperCKemia, which may develop in cases left untreated for a prolonged period after ingestion. Therefore, the measurement of PXT, in addition to CFF, is expected to provide useful information for understanding the pathogenesis of CFF intoxication and the development of treatment strategies of acute CFF intoxication.

The enzyme CYP1A2 is responsible for the metabolism of numerous antioxidants in the body, including caffeine, which is transformed into paraxanthine, its main primary metabolite. Both molecules are known for their antioxidant and pro-oxidant characteristics, and the paraxanthine-to-caffeine molar ratio is a widely accepted metric for CYP1A2 phenotyping, to optimize dose–response effects in individual patients. We developed a simple, cheap and fast electrochemical based method for the simultaneous quantification of paraxanthine and caffeine in human saliva, by differential pulse voltammetry, using an anodically pretreated glassy carbon electrode. Cyclic voltammetry experiments revealed for the first time that the oxidation of paraxanthine is diffusion controlled with an irreversible peak at ca. +1.24 V (vs. Ag/AgCl) in a 0.1 M H2SO4 solution, and that the mechanism occurs via the transfer of two electrons and two protons. The simultaneous quantification of paraxanthine and caffeine was demonstrated in 0.1 M H2SO4 and spiked human saliva samples. In the latter case, limits of detection of 2.89 μM for paraxanthine and 5.80 μM for caffeine were obtained, respectively. The sensor is reliable, providing a relative standard deviation within 7% (n = 6). Potential applicability of the sensing platform was demonstrated by running a small scale trial on five healthy volunteers, with simultaneous quantification by differential pulse voltammetry (DPV) of paraxanthine and caffeine in saliva samples collected at 1, 3 and 6 h postdose administration. The results were validated by ultra-high pressure liquid chromatography and shown to have a high correlation factor (r = 0.994).

This study presents one of the most complete applications of probabilistic methodologies to the risk assessment of emerging contaminants. Perhaps the most data-rich of these compounds, caffeine, as well as its main metabolite (paraxanthine), were selected for this study. Information for a total of 29,132 individual caffeine and 7442 paraxanthine samples was compiled, including samples where the compounds were not detected. The inclusion of non-detect samples (as censored data) in the estimation of environmental exposure distributions (EEDs) allowed for a realistic characterization of the global presence of these compounds in aquatic systems. EEDs were compared to species sensitivity distributions (SSDs), when possible, in order to calculate joint probability curves (JPCs) to describe the risk to aquatic organisms. This way, it was determined that unacceptable environmental risk (defined as 5% of the species being potentially exposed to concentrations able to cause effects in > 5% of the cases) could be expected from chronic exposure to caffeine from effluent (28.4% of the cases), surface water (6.7% of the cases) and estuary water (5.4% of the cases). Probability of exceedance of acute predicted no-effect concentrations (PNECs) for paraxanthine were higher than 5% for all assessed matrices except for drinking water and ground water, however no experimental effects data was available for paraxanthine, resulting in a precautionary deterministic hazard assessment for this compound. Given the chemical similarities between both compounds, real effect thresholds, and thus risk, for paraxanthine, would be expected to be close to those observed for caffeine. Negligible Human health risk from exposure to caffeine via drinking or groundwater is expected from the compiled data. [ABSTRACT FROM AUTHOR]

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Background: Caffeine intake is generally estimated by self-reported consumption, but it remains unclear how well self-report associates with metabolite urinary excretion. We investigated the associations of self-reported consumption of caffeinated drinks with urinary excretion of caffeine and its major metabolites in an adult population. Methods: We used data from the population-based Swiss Kidney Project on Genes in Hypertension (SKIPOGH) study. Consumption of caffeinated coffee, decaffeinated coffee and other caffeinated beverages was assessed by self- administered questionnaire. Quantification of caffeine, paraxanthine, theobromine and theophylline was performed by ultra-high performance liquid chromatography tandem mass spectrometry in 24-h urine. Association of reported consumption of caffeinated drinks with urinary caffeine derived metabolites was determined by quantile regression. We then explored the association between urinary metabolite excretion and dichotomized weekly consumption frequency of caffeinated coffee, with Receiver Operator Characteristic (ROC) analysis. Results: In the present analysis, we included 598 individuals (52% women, mean age =46 ± 17 years). Self-reported caffeinated coffee intake was positively associated with 24-h urinary excretions of paraxanthine, theophylline and caffeine (p < 0.001), whereas reported intakes of decaffeinated coffee and other caffeinated beverages showed no association. In ROC analysis, optimal discrimination between individuals consuming less than one caffeinated coffee/ week, vs. at least one coffee, was obtained for 24-h urinary paraxanthine (Area Under Curve (AUC) = 0.868, 95% Confidence Interval (CI) [0.830;0.906]), with slightly lower performance for theophylline and caffeine, whereas theobromine did not allow any discrimination. Conclusion: Our results suggest that reported consumption of caffeinated coffee is positively associated with 24-h urinary excretion of caffeine, paraxanthine, and theophylline, and may be used as a marker of caffeine intake for epidemiological studies. [ABSTRACT FROM AUTHOR]

Background: Coffee consumption is a known inducer of cytochrome P450 1A2 (CYP1A2) enzyme activity. We recently observed that a group of type-2 diabetes patients consumed more caffeine (coffee) on a daily basis than non-type-2 diabetes controls. Here, we investigated whether type-2 diabetes cases may metabolize caffeine faster than non-type-2 diabetes controls. Methods: To estimate CYP1A2 enzyme activity, an established marker of caffeine metabolism, we quantified the paraxanthine/caffeine concentration ratio in saliva in 57 type-2 diabetes and 146 non-type-2 diabetes participants in a case-control field study. All participants completed validated questionnaires regarding demographic status, health and habitual caffeine intake, and were genotyped for the functional -163C > A polymorphism of the CYP1A2 gene. Results: In the diabetes group, we found a larger proportion of participants with the highly inducible CYP1A2 genotype. Furthermore, the paraxanthine/caffeine ratio, time-corrected to mitigate the impact of different saliva sampling times with respect to the last caffeine intake, was higher than in the control group. Participants who reported habitually consuming more caffeine than the population average showed higher CYP1A2 activity than participants with lower than average caffeine consumption. Multiple regression analyses revealed that higher caffeine intake was potentially an important mediator of higher CYP1A2 activity. Conclusions: Estimated CYP1A2 enzyme activity, and thus speed of caffeine metabolism, was higher in our type-2 diabetes group; this was possibly due to higher intake of caffeine, a known inducer of CYP1A2 enzyme activity. Given the fairly small sample sizes, the results need to be considered as preliminary and require validation in larger populations. [ABSTRACT FROM AUTHOR]

The salivary paraxanthine/caffeine molar ratio has been proposed as a novel dynamic liver function test to guide dose adjustments of drugs hepatically cleared by CYP1A2. Its usability requires an established population norm as well as the factors influencing the ratio and actual concentrations. To address this knowledge gap, salivary caffeine and paraxanthine concentrations were measured at 4 h post caffeine dose in healthy Chinese individuals who had undergone 24 h of caffeine abstinence. The metabolic ratio was calculated and statistical analysis was performed. From the 52 participants (26 males; 30 regular caffeine consumers) recruited, the salivary paraxanthine/caffeine molar ratio was normally distributed with a mean and SD of 0.5 ± 0.2. No statistically significant factors (BMI, body weight, gender and regularity of caffeine intake) affecting the metabolic ratio were found. The caffeine concentration and total caffeine plus paraxanthine concentrations were lower in males than in females, and lower in regular caffeine consumers than in non-regular caffeine consumers. The 4 h salivary metabolic ratio (mean: 0.5) was generally not significantly different from the literature reported salivary, serum and plasma ratios measured at 4-9 h in healthy individuals (mean range 0.4-0.7) but was significantly higher than the literature reported 6 h plasma ratio and salivary ratios measured at 1-6 h in patients with liver disease or mild abnormal liver function tests (mean range 0.03-0.2). Overall, the population norm of the salivary metabolic ratio in a Singaporean Chinese population established in this study is distinct from individuals with liver disease or mild abnormal liver function tests and provides the benchmark for dosage adjustments of drugs metabolized by CYP1A2. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Although caffeine is commonly consumed during pregnancy, there are few reports on the association of in utero caffeine exposure with offspring cognition or behavior during childhood. We evaluated the association of maternal serum paraxanthine, caffeine's primary metabolite, at <20 and ≥26 weeks' gestation with the child's intelligence quotient (IQ) and problem behaviors at ages 4 and 7 years among 2,197 mother-child pairs. The mothers were controls from a case-control study of caffeine metabolites and spontaneous abortion that was nested within the Collaborative Perinatal Project (multiple US sites, 1959-1974). Associations of paraxanthine (adjusted for maternal age, race, education, smoking, prepregnancy weight, gestational age at blood draw, and child sex) with mean IQ were assessed by linear regression and associations with problem behaviors by logistic regression. Paraxanthine concentration at ≥26 weeks' gestation manifested an inverted-J-shaped association with child's IQ at age 7 years, with a peak difference (vs. undetectable) of 0.65 points at 750 ug/L (66th percentile) and a decrement thereafter. Paraxanthine at <20 weeks was linearly associated with internalizing behavior at age 4 years (for a 500-ug/L increase, odds ratio = 1.3, 95% confidence interval: 1.1,1.5). None of the remaining 12 associations approached statistical significance. We conclude that over a range of values applicable to most pregnant women, there was no meaningful association of serum paraxanthine level with childhood IQ or problem behaviors. [ABSTRACT FROM AUTHOR]