Plasma Caffeine Concentrations Research Articles

Caffeine pharmacokinetics following umbilical vein injection during delayed cord clamping in preterm lambs.

Spontaneous breathing during and after delayed cord clamping (DCC) stabilizes cardiopulmonary transition at birth. Caffeine stimulates breathing and decreases apnea in premature newborns. We evaluated the pharmacokinetics and physiological effects of early caffeine administration-direct injection into the umbilical vein (UV) during DCC or administered through a UV catheter (UVC) after delivery. Eighteen extremely premature lambs (125-127d, term gestation 145d) were exteriorized and instrumented. Lambs received caffeine-citrate at high (40 mg/kg) or standard-dose (20 mg/kg) via direct UV (DUV) injection during DCC, or via the UVC. Mean peak plasma caffeine concentrations were lower with high-dose DUV compared to UVC (18 ± 4.3 vs. 46 ± 12 mg/L, p < 0.05). With standard-dose caffeine, mean peak plasma levels were 7.48 ± 2.6 with DUV and 28.73 ± 9.4 mg/L with UVC. The volume of distribution was higher in the DUV group compared to UVC (2.5 ± 1.0 vs. 0.69 ± 0.15 L/kg) with an estimated 39 ± 18% entering the maternal circulation. Maternal peak concentrations were 0.79 ± 0.71 and 1.43 ± 0.74 mg/L with standard and high-dose DUV, respectively. Caffeine injected directly into the UV during DCC is feasible but achieves lower concentrations due to high volume of distribution including maternal circulation. Further trials evaluating DUV caffeine injection should use higher caffeine doses. Respiratory stimulation with early caffeine may reduce the need for intubation in preterm infants. In the preterm lambs, caffeine injection directly into the umbilical vein during delayed cord clamping is feasible. Plasma caffeine concentrations are less than half when administered directly into the umbilical vein during delayed cord clamping compared to administration via an umbilical venous catheter following birth likely attributed to a larger volume of distribution or injection site leak. There were no significant hemodynamic alterations following caffeine injection.

Concentration-effect relationships of plasma caffeine on EEG delta power and cardiac autonomic activity during human sleep.

Acute caffeine intake affects brain and cardiovascular physiology, yet the concentration-effect relationships on the electroencephalogram and cardiac autonomic activity during sleep are poorly understood. To tackle this question, we simultaneously quantified the plasma caffeine concentration with ultra-high-performance liquid chromatography, as well as the electroencephalogram, heart rate and high-frequency (0.15-0.4 Hz) spectral power in heart rate variability, representing parasympathetic activity, with standard polysomnography during undisturbed human sleep. Twenty-one healthy young men in randomized, double-blind, crossover fashion, ingested 160 mg caffeine or placebo in a delayed, pulsatile-release caffeine formula at their habitual bedtime, and initiated a 4-hr sleep opportunity 4.5 hr later. The mean caffeine levels during sleep exhibited high individual variability between 0.2 and 18.4 μmol L-1 . Across the first two non-rapid-eye-movement (NREM)-rapid-eye-movement sleep cycles, electroencephalogram delta (0.75-2.5 Hz) activity and heart rate were reliably modulated by waking and sleep states. Caffeine dose-dependently reduced delta activity and heart rate, and increased high-frequency heart rate variability in NREM sleep when compared with placebo. The average reduction in heart rate equalled 3.24 ± 0.77 beats per minute. Non-linear statistical models suggest that caffeine levels above ~7.4 μmol L-1 decreased electroencephalogram delta activity, whereas concentrations above ~4.3 μmol L-1 and ~ 4.9 μmol L-1 , respectively, reduced heart rate and increased high-frequency heart rate variability. These findings provide quantitative concentration-effect relationships of caffeine, electroencephalogram delta power and cardiac autonomic activity, and suggest increased parasympathetic activity during sleep after intake of caffeine.

Unraveling the link between plasma caffeine concentrations and inflammatory bowel disease risk through Mendelian randomization

BackgroundCaffeine is believed to possess anti-inflammatory properties, yet direct population-based evidence regarding its impact on inflammatory bowel disease (IBD) remains scarce. ObjectivesIn this study, we used 2-sample Mendelian randomization (MR) study to investigate the causal relationship between long-term plasma caffeine concentrations and IBD and its subtypes, ulcerative colitis (UC) and Crohn disease (CD). MethodsWe used single nucleotide polymorphisms (SNPs) associated with plasma caffeine concentrations at genome-wide significance within a ±100-kb range around the CYP1A2 or AHR genes as instrumental variables. Genome-wide association study (GWAS) data for IBD and its subtypes were obtained from FinnGen and International Inflammatory Bowel Disease Genetics Consortium. We conducted a meta-analysis of MR-related SNPs from both sources and used a multiplicative inverse variance–weighted random effects model to combine the effects of each SNP proxy on exposure to outcomes. ResultsIn our study, genetically predicted higher plasma caffeine concentrations were associated with a lower risk of IBD, with an odds ratio (OR) of 0.78 (95% confidence interval [CI]: 0.66, 0.91; PFDR = 0.004). This trend was also observed in UC and CD, with ORs of 0.79 (95% CI: 0.66, 0.94; PFDR = 0.014) and 0.78 (95% CI: 0.62, 0.98; PFDR = 0.032), respectively. ConclusionOur study indicates a potential causal link between genetically predicted higher plasma caffeine concentrations and a reduced risk of IBD, including its subtypes UC and CD.

Appraisal of the causal effect of plasma caffeine on adiposity, type 2 diabetes, and cardiovascular disease: two sample mendelian randomisation study

ObjectiveTo investigate the potential causal effects of long term plasma caffeine concentrations on adiposity, type 2 diabetes, and major cardiovascular diseases.DesignTwo sample mendelian randomisation study.SettingGenome-wide association study summary data for...

Association of Maternal Caffeine Consumption During Pregnancy With Child Growth

Greater caffeine consumption in pregnancy is associated with reduced birth size, but potential associations with childhood growth are unclear. To evaluate the associations of pregnancy caffeine and paraxanthine measures with child growth in a contemporary cohort with low caffeine consumption and a historical cohort with high caffeine consumption. The Environmental Influences on Child Health Outcomes cohort of the National Institute of Child Health and Human Development Fetal Growth Studies (ECHO-FGS; 10 sites, 2009-2013) was a pregnancy cohort with 1 child measurement between ages 4 and 8 years (follow-up in 2017-2019). The Collaborative Perinatal Project (CPP) was a pregnancy cohort (12 sites, 1959-1965) with child follow-up through 8 years (1960-1974). The current secondary analysis was conducted in 2021 and 2022. Concentrations of caffeine and its primary metabolite, paraxanthine, were quantified from plasma (ECHO-FGS) and serum (CPP) collected in the first trimester. Cut points for analyses were defined by quartiles in ECHO-FGS and quintiles in CPP. Child z scores for body mass index, weight, and height were evaluated, as well as fat mass index and percentage and obesity risk measured at 1 time between age 4 and 8 years in ECHO-FGS. In a secondary analysis of the CPP cohort, child z scores and obesity risk longitudinally through age 8 years were evaluated. In ECHO-FGS (median caffeine intake <50 mg/d), 788 children (mean [SD] age, 6.8 [1.0] years; 411 boys [52.2%]) of women in the fourth vs first quartile of plasma caffeine concentrations had lower height z scores (β = -0.21; 95% CI, -0.41 to -0.02), but differences in weight z scores were only observed in the third quartile (β = -0.27; 95% CI, -0.47 to -0.07). In CPP, beginning at age 4 years, 1622 children (805 boys [49.7%]) of women in the highest caffeine quintile group had lower height z scores than their peers from the lowest group, with the gap widening with each successive year of age (β = -0.16 [95% CI, -0.31 to -0.01] at 4 years; β = -0.37 [95% CI, -0.57 to -0.16] at 8 years). There were slight reductions in weight at ages 5 to 8 years for children in the third vs first caffeine quintile (β = -0.16 to -0.22). Results were consistent for paraxanthine concentrations in both cohorts. Intrauterine exposure to increasing levels of caffeine and paraxanthine, even in low amounts, was associated with shorter stature in early childhood. The clinical implication of reductions in height and weight is unclear; however, the reductions were apparent even with levels of caffeine consumption below clinically recommended guidelines of less than 200 mg per day.

Neurodegenerative Diseases: Can Caffeine Be a Powerful Ally to Weaken Neuroinflammation?

In recent years, there has been considerable research showing that coffee consumption seems to be beneficial to human health, as it contains a mixture of different bioactive compounds such as chlorogenic acids, caffeic acid, alkaloids, diterpenes and polyphenols. Neurodegenerative diseases (NDs) are debilitating, and non-curable diseases associated with impaired central, peripheral and muscle nervous systems. Several studies demonstrate that neuroinflammation mediated by glial cells-such as microglia and astrocytes-is a critical factor contributing to neurodegeneration that causes the dysfunction of brain homeostasis, resulting in a progressive loss of structure, function, and number of neuronal cells. This happens over time and leads to brain damage and physical impairment. The most known chronic NDs are represented by Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). According to epidemiological studies, regular coffee consumption is associated with a lower risk of neurodegenerative diseases. In this review, we summarize the latest research about the potential effects of caffeine in neurodegenerative disorders prevention and discuss the role of controlled caffeine delivery systems in maintaining high plasma caffeine concentrations for an extended time.

Caffeine dosing in premature neonates: impact of birth weight on a pharmacokinetic simulation study.

The optimal caffeine dosing in extremely premature neonates remains elusive. This study aimed to evaluate the impact of birth weight on caffeine pharmacokinetics and various dosing regimens. In this pharmacokinetic simulation study, we generated the body weights (0-49 days of postnatal age [PNA]) of neonates <28 weeks gestational age with different birth weights (550, 750, and 1050 g). Their pharmacokinetic parameters were determined based on published pharmacokinetic models. Then, we simulated and compared the caffeine base concentration-time profiles of standard versus off-label caffeine citrate dose regimens. The half-life decreased and the weight-adjusted clearance increased more significantly in neonates with lower birth weights, resulting in lower caffeine plasma concentrations. The neonate with the lowest birth weight did not achieve a threshold trough concentration of 15 mg/L after receiving the standard dose (5 mg/kg/day), while the higher-birth-weights (≥750 g) had trough concentrations below the threshold around the second week of life. Higher caffeine doses (10 mg/kg/day) resulted in peak concentrations of <36 mg/L by 10-14 days of PNA while maintaining trough concentrations above 15 mg/L throughout the 49 days PNA. Higher-than-standard caffeine dosing may be needed for extremely premature neonates, especially for those with lower birth weights. Extremely premature neonates with a lower birth weight may require a higher weight-based caffeine dosing due to their higher weight-adjusted clearance and shorter half-lives. Not only do these extremely premature neonates have a higher risk of developing bronchopulmonary dysplasia due to their structurally underdeveloped lungs, but the low birth weight-related underdosing may further contribute to the reduced caffeine effectiveness. Higher-than-standard caffeine citrate dosing (e.g., 10 mg/kg/day maintenance dose) may be needed to further prevent bronchopulmonary dysplasia.

Maternal caffeine consumption and child growth in the ECHO cohort of NICHD Fetal Growth Studies

Greater caffeine consumption during pregnancy is associated with smaller infant birth size, but little is known about its association with growth in childhood. Previous studies have found measures of childhood adiposity and growth linked to maternal caffeine consumption, but all used inherently limited self-reported caffeine measures. We have previously demonstrated that higher maternal plasma concentrations of caffeine and paraxanthine were associated with smaller neonatal anthropometrics. We now investigate whether the association of smaller birth size with higher maternal caffeine measures persists into childhood.

Pharmacokinetics of caffeine self-administered in overdose in a Japanese patient admitted to hospital

BackgroundCaffeine (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 presentationA 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.ConclusionsThe 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.

Test-retest reproducibility of cerebral adenosine A2A receptor quantification using [11C]preladenant.

To evaluate the reproducibility of cerebral adenosine A2A receptor (A2AR) quantification using [11C]preladenant ([11C]PLN) and PET in a test-retest study. Eight healthy male volunteers were enrolled. Dynamic 90min PET scans were performed twice at the same time of the day to avoid the effect of diurnal variation. Subjects refrained from caffeine from 12h prior to scanning, and serum caffeine was measured before radioligand injection. Arterial blood was sampled repeatedly during scanning and the fraction of the parent compound in plasma was determined. Total distribution volume (VT) was estimated using 1- and 2-tissue compartment models (1-TCM and 2-TCM, respectively) and Logan graphical analysis (Logan plot) (t* = 30min). Plasma-free fraction (fP) of [11C]PLN was measured and used for correction of VT values. Distribution volume ratio (DVR) was calculated from VT of target and reference regions and obtained by noninvasive Logan graphical reference tissue model (LGAR) (t* = 30min). Absolute test-retest variability (aTRV), and intra-class correlation coefficient (ICC) of VT and DVR were calculated as indexes of repeatability. Correlation between DVR and serum concentration of caffeine (a nonselective A2AR blocker) was analyzed by Pearson's correlation analysis. Regional time-activity curves were well described by 2-TCM models. Estimation of VT by 2-TCM produced some erroneous values; therefore, the more robust Logan plot was selected as the appropriate model. Global mean aTRV was 20% for VT and 14% for VT/fP (ICC, 0.72 for VT and 0.87 for VT/fP). Global mean aTRV of DVR was 13% for Logan plot and 10% for LGAR (ICC, 0.70 for Logan plot and 0.81 for LGAR). DVR estimates using LGAR and Logan plot were in good agreement (r2 = 0.96). Coefficients of variation for VT, VT/fP, DVR (Logan plot), and DVR (LGAR) were 47%, 47%, 27%, and 18%, respectively. Despite low serum caffeine levels, significant concentration-dependent effects on [11C]PLN binding to target regions were observed (p < 0.01). In this study, moderate test-retest reproducibility and large inter-subject differences were observed with [11C]PLN PET, possibly attributable to competition by baseline amount of caffeine. Analysis of plasma caffeine concentration is recommended during [11C]PLN PET studies. UMIN000030040.

Effects of Mixing Energy Drinks With Alcohol on Driving-Related Skills.

BackgroundEnergy drinks (EDs) reduce sleepiness and fatigue and improve driving performance whereas alcohol does just the opposite. Although it is a trendy combination among young people, the effects of alcohol mixed with EDs on driving performance have been poorly studied. The aim was to assess if there is an interaction between the effects of both drinks on driving-related skills as well as perceptions about driving ability.MethodsWe conducted a randomized, double-blind, and placebo-controlled 4-way crossover clinical trial. Participants were 16 healthy volunteers. Interventions of 60 g of ethanol and 750 mL of Red Bull (RB) were administered in 2 separated doses. Conditions were alcohol + RB placebo, alcohol + RB, alcohol placebo + RB, and both placebos. Objective performance was assessed using a tracking test and simple reaction time, N-Back, and movement estimation tasks. Additionally, willingness to drive, other subjective effects, and ethanol and caffeine blood concentrations were also measured.ResultsAlcohol increased the time outside the road in the tracking test and increased simple reaction time, but the addition of RB had no main or interaction effects on performance. Nonetheless, driving-related skills after alcohol + RB were better than after alcohol alone. Willingness to drive increased with the combination of drinks. RB also reduced alcohol-induced sedation whereas drunkenness did not change. These effects were seen even though alcohol + RB increased alcohol (14.8%) and caffeine plasma concentrations (17.6%).ConclusionsMixing EDs with alcohol predisposes consumers to drive under alcohol influence, perhaps in part because EDs counteract its detrimental effects on driving-related skills. Clinicaltrials.gov: NCT02771587.

Sex Differences and Caffeine Impact in Adenosine-Induced Hyperemia.

Caffeine consumption before adenosine stress myocardial perfusion imaging (MPI) is known to affect the hemodynamic response and, thus, reduce the stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) assessments. However, it is not clear if any sex-specific differences in the hemodynamic response after caffeine consumption exist. This study aimed to evaluate if such differences exist and, if so, their impact on MBF and MFR assessments. Methods: This study comprised 40 healthy volunteers (19 women). All volunteers underwent 4 serial rest/stress MPI sessions using 82Rb; 2 sessions were acquired without controlled caffeine consumption, and 2 sessions after oral ingestion of either 100 and 300 mg of caffeine or 200 and 400 mg of caffeine. For the caffeine imaging sessions, caffeine was ingested orally 1 h before the MPI scan. Results: Increase in plasma caffeine concentration (PCC) (mg/L) after consumption of caffeine was larger in women (MPI session without caffeine vs. MPI session with caffeine: women = 0.3 ± 0.2 vs. 5.4 ± 5.1, men = 0.1 ± 0.2 vs. 2.7 ± 2.6, both P < 0.001). Caffeine consumption led to reduced stress MBF and MFR assessments for men whereas no changes were reported for women (women [PCC < 1 mg/L vs. PCC ≥ 1 mg/L]: stress MBF = 3.3 ± 0.6 vs. 3.0 ± 0.8 mL/g/min, P = 0.07; MFR = 3.7 ± 0.6 vs. 3.5 ± 1.0, P = 0.35; men [PCC < 1 mg/L vs. PCC ≥ 1 mg/L]: stress MBF = 2.7 ± 0.7 vs. 2.1 ± 1.0 mL/g/min, P = 0.005; MFR = 3.8 ± 1.0 vs. 3.1 ± 1.4, P = 0.018). Significant differences in the stress MBF were observed for the 2 sexes (both P ≤ 0.001), whereas similar MFR was reported (both P ≥ 0.12). Conclusion: Associations between increases in PCC and reductions in stress MBF and MFR were observed for men, whereas women did not have the same hemodynamic response. Stress MBF was affected at lower PCCs in men than women.

Association Between Maternal Caffeine Consumption and Metabolism and Neonatal Anthropometry

Higher caffeine consumption during pregnancy has been associated with lower birth weight. However, associations of caffeine consumption, based on both plasma concentrations of caffeine and its metabolites, and self-reported caffeinated beverage intake, with multiple measures of neonatal anthropometry, have yet to be examined. To evaluate the association between maternal caffeine intake and neonatal anthropometry, testing effect modification by fast or slow caffeine metabolism genotype. A longitudinal cohort study, the National Institute of Child Health and Human Development Fetal Growth Studies-Singletons, enrolled 2055 nonsmoking women at low risk for fetal growth abnormalities with complete information on caffeine consumption from 12 US clinical sites between 2009 and 2013. Secondary analysis was completed in 2020. Caffeine was evaluated by both plasma concentrations of caffeine and paraxanthine and self-reported caffeinated beverage consumption measured/reported at 10-13 weeks gestation. Caffeine metabolism defined as fast or slow using genotype information from the single nucleotide variant rs762551 (CYP1A2*1F). Neonatal anthropometric measures, including birth weight, length, and head, abdominal, arm, and thigh circumferences, skin fold and fat mass measures. The β coefficients represent the change in neonatal anthropometric measure per SD change in exposure. A total of 2055 participants had a mean (SD) age of 28.3 (5.5) years, mean (SD) body mass index of 23.6 (3.0), and 580 (28.2%) were Hispanic, 562 (27.4%) were White, 518 (25.2%) were Black, and 395 (19.2%) were Asian/Pacific Islander. Delivery occurred at a mean (SD) of 39.2 (1.7) gestational weeks. Compared with the first quartile of plasma caffeine level (≤28 ng/mL), neonates of women in the fourth quartile (>659 ng/mL) had lower birth weight (β = -84.3 g; 95% CI, -145.9 to -22.6 g; P = .04 for trend), length (β = -0.44 cm; 95% CI, -0.78 to -0.12 cm; P = .04 for trend), and head (β = -0.28 cm; 95% CI, -0.47 to -0.09 cm; P < .001 for trend), arm (β = -0.25 cm; 95% CI, -0.41 to -0.09 cm: P = .02 for trend), and thigh (β = -0.29 cm; 95% CI, -0.58 to -0.04 cm; P = .07 for trend) circumference. Similar reductions were observed for paraxanthine quartiles, and for continuous measures of caffeine and paraxanthine concentrations. Compared with women who reported drinking no caffeinated beverages, women who consumed approximately 50 mg per day (~ 1/2 cup of coffee) had neonates with lower birth weight (β = -66 g; 95% CI, -121 to -10 g), smaller arm (β = -0.17 cm; 95% CI, -0.31 to -0.02 cm) and thigh (β = -0.32 cm; 95% CI, -0.55 to -0.09 cm) circumference, and smaller anterior flank skin fold (β = -0.24 mm; 95% CI, -0.47 to -0.01 mm). Results did not differ by fast or slow caffeine metabolism genotype. In this cohort study, small reductions in neonatal anthropometric measurements with increasing caffeine consumption were observed. Findings suggest that caffeine consumption during pregnancy, even at levels much lower than the recommended 200 mg per day of caffeine, are associated with decreased fetal growth.

The Pharmacokinetics of Caffeine in Preterm Newborns: No Influence of Doxapram but Important Maturation with Age

Background: Apnea of prematurity can persist despite caffeine therapy in preterm infants. Doxapram may additionally support breathing. Although multiple small studies have reported the efficacy of doxapram, the structural co-treatment with caffeine impedes to ascribe the efficacy to doxapram itself or to a pharmacokinetic (PK) interaction where doxapram increases the exposure to caffeine. We examined whether there is a PK drug-drug interaction between doxapram and caffeine by developing a PK model for caffeine including infants with and without doxapram treatment. Methods: In preterm neonates receiving caffeine, we determined caffeine plasma concentrations before, during, and directly after doxapram co-treatment and used these to develop a population PK model in NONMEM 7.3. Patient characteristics and concomitant doxapram administration were tested as covariates. Results: 166 plasma samples were collected from 39 preterm neonates receiving caffeine (median gestational age 25.6 [range 24.0–28.0] weeks) of which 65 samples were taken during co-treatment with doxapram (39%, from 32/39 infants). Clearance of caffeine was 9.99 mL/h for a typical preterm neonate with a birth weight of 0.8 kg and 23 days postnatal age and increased with birth weight and postnatal age, resulting in a 4-fold increase in clearance during the first month of life. No PK interaction between caffeine and doxapram was identified. Discussion: Caffeine clearance is not affected by concomitant doxapram therapy but shows a rapid maturation with postnatal age. As current guidelines do not adjust the caffeine dose with postnatal age, decreased exposure to caffeine might partly explain the need for doxapram therapy after the first week of life.

A systematic review of caffeine-related suicides and an analysis of the controversial role of caffeine consumption in suicidal risk.

Caffeine is the most widely consumed psychoactive compound worldwide. Its mechanisms of action are dose-dependent and when caffeine overdosing occurs, neurologic, cardiovascular and renal systems are mainly affected. Serious toxicities such as seizure and cardiac arrhythmias, seen with caffeine plasma concentrations of 15 mg/L or higher, have caused poisoning or, rarely, death. Caffeine concentrations of 80-100 mg/L are considered lethal. The aim of this systematic review is to summarize data regarding suicides by caffeine administration and analyze the controversial role of caffeine assumption and suicidal risk. We followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) indications in the identification and selection of studies and reviewed a series of fatal cases due intentional intoxication by caffeine. A total of 36 cases have been identified. Our results suggests caffeine seems to be negatively correlated with suicide. Even if some observations suggested that the consumption of caffeine may have beneficial effects against depression, and as a consequence against suicide risk, more in-depth studies are required. Data obtained from our study could support both clinicians and forensic pathologists in identifying possible unrecognized cases.

Quantification of Blood Caffeine Levels in Patients With Parkinson's Disease and Multiple System Atrophy by Caffeine ELISA.

Caffeine is considered to be a neuroprotective agent against Parkinson's disease (PD) and is expected to offer a blood-based biomarker for the disease. We herein investigated the ability of this biomarker to discriminate between PD and neurodegenerative diseases. To quantify caffeine concentrations in serum and plasma, we developed a specific competitive enzyme-linked immunosorbent assay (ELISA). To validate the diagnostic performance of the assay, we conducted a case control-study of two independent cohorts among controls and patients with PD and multiple system atrophy (MSA). Parallelism, recovery rate, and intra- and inter-assay precision of our assay were within the standard of acceptance. In the first cohort of 31 PD patients, 18 MSA patients and 33 age-matched controls, serum caffeine levels were significantly lower in PD patients than in Controls (p = 0.018). A similar trend was also observed in the MSA group, but did not reach the level of significance. In the second cohort of 50 PD patients, 50 MSA patients and 45 age-matched controls, plasma caffeine levels were significantly decreased in both PD and MSA groups compared to Controls (p < 0.001). This originally developed ELISA offered sufficient sensitivity to detect caffeine in human serum and plasma. We reproducibly confirmed decreased blood concentrations of caffeine in PD compared to controls using this ELISA. A similar trend was observed in the MSA group, despite a lack of consistent significant differences across cohorts.

Exploring the relation between methylxanthines and plasma lipids in two population-based studies

Abstract Background Chronic intake of caffeinated beverages might be associated with plasma lipids via disturbed lipid metabolism. Previous investigations have been limited by the use of self-reported caffeine intake instead of measured caffeine, whereas the associations between plasma lipids and other methylxanthines (paraxanthine, theobromine, theophylline) are unknown. Here, we investigated the associations of plasma lipids with caffeine and its metabolites in plasma and urine in two European populations. Methods Individuals were selected from the general population of North Belgium (FLEMENGHO) and Switzerland (SKIPOGH). Total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were measured in plasma using standard enzymatic methods. Plasma and 24h urinary caffeine, paraxanthine, theophylline, and theobromine excretions were measured using ultra-high performance liquid chromatography tandem mass spectrometry. We used mixed models to explore the associations of methylxanthines with plasma lipids while adjusting for major confounders. Results Overall, 1946 FLEMENGHO participants (911 men, age 45.9±15.2 years) and 990 SKIPOGH participants (467 men, age 47.1±17.3 years) were included. Mean plasma total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides in FLEMENGHO/SKIPOGH were 5.37/5.06, 3.12/3.12, 1.43/1.50, and 2.4/1.02 mmol/L. In both cohorts, adjusted mean total cholesterol, LDL cholesterol, and HDL cholesterol, increased with quartile of plasma caffeine, with stronger associations in men. Similar positive associations were observed for paraxanthine and theophylline. Similar associations were observed using 24h urine excretions in SKIPOGH. Conclusions Plasma and urinary caffeine, paraxanthine, and theophylline were positively associated with plasma lipids in men, whereas there were fewer meaningful associations in women. The increase in plasma lipids might mitigate the overall beneficial impact of caffeinated beverages on health. Key messages Caffeine constitutes one of the most widely consumed biological active substances. Plasma concentration and urinary excretion of caffeine and its derived metabolites is positively associated with plasma lipids.

Caffeine prevents hyperoxia-induced lung injury in neonatal mice through NLRP3 inflammasome and NF-\u03baB pathway

BackgroundBronchopulmonary dysplasia (BPD) is a common chronic lung disease in premature infants and hyperoxia exposure is a major cause. In hyperoxic lung injury animal model, alveolar simplification and pro-inflammatory cells infiltration are the main pathophysiologic changes. Caffeine is a drug used to treat apnea in premature infants. Early use of caffeine can decrease the rate and the severity of BPD while the mechanisms are still unclear. The purpose of this study was to evaluate the effects of caffeine on inflammation and lung development in neonatal mice with hyperoxic lung injury and to explore the possible mechanism.MethodsFollowing 14 d of 75% oxygen exposure in newborn mouse, the BPD model was established. Caffeine at a dose of 1 g/L was added in drinking water to nursing mouse. We measured the concentration of caffeine in serum and oxidative stress in lung by commercially available kits. Adenosine 2A receptor (A2AR) expression and lung inflammation were measured by Immunohistochemistry and western blotting. Apoptosis and surfactant protein-C (SFTPC) levels were measured by immunofluorescence. The inflammasome and NF-κB pathway proteins were assessed by western blotting.ResultsWe found that the caffeine concentration in plasma at present dose significantly decreased the expression of A2AR protein in mice lung. Caffeine treatment significantly reduced oxidative stress, improved weight gain, promoted alveolar development, attenuated inflammatory infiltration and lung injury in hyperoxia-induced lung injury mice. Moreover, caffeine decreased the cell apoptosis in lung tissues, especially the Type II alveolar epithelial cell. The expression of NLRP3 inflammasome protein and NF-κB pathway were significantly inhibited by caffeine treatment.ConclusionCaffeine treatment can protect hyperoxia-induced mice lung from oxidative injury by inhibiting NLRP3 inflammasome and NF-κB pathway.

Intestinal Permeability and Oral Absorption of Selected Drugs Are Reduced in a Mouse Model of Familial Alzheimer's Disease.

Compared with the significant number of studies reporting altered abundance and function of drug transporters at the blood-brain barrier (BBB) in Alzheimer's disease (AD), the impact of AD on the abundance of intestinal drug transporters and the subsequent effects on oral drug absorption have received little attention. We have reported the altered abundance of some small intestinal drug transporters in a familial mouse model of AD; however, whether this leads to altered oral drug absorption is unknown. The current study examined plasma concentrations of caffeine and diazepam (markers for transcellular passive transport), digoxin (P-glycoprotein substrate), and valsartan (multidrug resistance-associated protein 2 substrate) following oral administration to 8-10 month old female wild-type (WT) and APPswe/PSEN1dE9 (APP/PS1) transgenic mice, a commonly used mouse model of familial AD. The plasma exposure of valsartan and digoxin was significantly (p < 0.05) lower in APP/PS1 animals compared with WT mice, whereas the plasma concentrations of the passive transcellular markers caffeine and diazepam did not significantly differ between the two genotypes. To assess whether the reduced oral absorption of valsartan and digoxin was due to decreased intestinal transport, the ex vivo transport of the previously mentioned drugs and mannitol (a marker of paracellular transport) across the jejunum of WT and APP/PS1 mice was assessed over 120 min. In line with the in vivo absorption studies, the permeability of caffeine and diazepam did not significantly differ between WT and APP/PS1 mice. The permeability of 3H-digoxin through the APP/PS1 mouse jejunum was lower than that measured through the WT jejunum; the average amount (relative to dose applied) permeating the tissue over 120 min was 0.22 ± 0.11% (mean ± SD) for the APP/PS1 jejunum and 0.85 ± 0.3% for the WT jejunum. A 1.9-fold reduction in the average amount of valsartan permeating the jejunum of APP/PS1 mice relative to that of WT mice was also detected. Although no apparent morphological alterations were observed in the jejunal tissue of APP/PS1 mice, the permeability of 14C-mannitol across the jejunum from APP/PS1 mice was lower than that across the WT jejunum (Papp= 10.7 ± 3.7 × 10-6 and 6.0 ± 3.4 × 10-6 cm/s, respectively), suggesting tightened paracellular junctions in APP/PS1 mice. These studies are the first to demonstrate, in APP/PS1 mice, reduced intestinal permeability and the absorption of drugs commonly prescribed to people with AD for their comorbidities. If these findings translate to people with AD, then modified dosing regimens may be necessary for selected drugs to ensure that their plasma concentrations remain in the effective range.

Effects of caffeine on neuromuscular function in a non-fatigued state and during fatiguing exercise.

What is the central question of the study? What are the effects of caffeine on neuromuscular function in a non-fatigued state and during fatiguing exercise? What is the main finding and its importance? In a non-fatigued state, caffeine decreased the duration of the silent period evoked by transcranial magnetic stimulation. Caffeine-induced reduction of inhibitory mechanisms in the central nervous system before exercise was associated with an increased performance. Individuals who benefit from caffeine ingestion may experience lower perception of effort during exercise and an accelerated recovery of M-wave amplitude postfatigue. This study elucidates the mechanisms of action of caffeine and demonstrates that inter-individual variability of its effects on neuromuscular function is a fruitful area for further work. Caffeine enhances exercise performance, but its mechanisms of action remain unclear. In this study, we investigated its effects on neuromuscular function in a non-fatigued state and during fatiguing exercise. Eighteen men participated in this randomized, double-blind, placebo-controlled crossover trial. Baseline measures included plantarflexion force, drop jump, squat jump, voluntary activation of triceps surae muscle, soleus muscle contractile properties, M-wave, α-motoneuron excitability (H-reflex), corticospinal excitability, short-interval intracortical inhibition, intracortical facilitation, silent period evoked by transcranial magnetic stimulation (SP) and plasma potassium and caffeine concentrations. Immediately after baseline testing, participants ingested caffeine (6mg·kg-1 ) or placebo. After a 1-h rest, baseline measures were repeated, followed by a fatiguing stretch-shortening cycle exercise (sets of 40 bilateral rebound jumps on a sledge apparatus) until task failure. Neuromuscular testing was carried out throughout the fatigue protocol and afterwards. Caffeine enhanced drop jump height (by 4.2%) and decreased the SP (by 12.6%) in a non-fatigued state. A caffeine-related decrease in SP and short-interval intracortical inhibition before the fatiguing activity was associated with an increased time to task failure. The participants who benefitted from an improved performance on the caffeine day reported a significantly lower sense of effort during exercise and had an accelerated postexercise recovery of M-wave amplitude. Caffeine modulates inhibitory mechanisms of the CNS, recovery of M-wave amplitude and perception of effort. This study lays the groundwork for future examinations of differences in caffeine-induced neuromuscular changes between those who are deemed to benefit from caffeine ingestion and those who are not.