Plasma Caffeine Research Articles

Therapy for Apnoea of Prematurity: A Retrospective Study on Effects of Standard Dose and Genetic Variability on Clinical Response to Caffeine Citrate in Chinese Preterm Infants.

Apnoea of prematurity (AOP) is among the most common diagnoses in the neonatal intensive care unit. Caffeine treatment is a preferred treatment choice. However, neonatal caffeine therapy results in significant intersubject variability. This study aimed to determine the effects of plasma caffeine levels based on standard dose and genetic variability on clinical response to caffeine citrate in Chinese preterm infants. This single-center and retrospective study examined data from 112 preterm infants (< 35weeks gestational age) between July 2017 and July 2018. Subjects were divided into apnoea-free (n = 48) and apnoeic (n = 64) groups, and their clinical outcomes were summarized. Liquid chromatography-tandem mass spectrometry was used to measure levels of caffeine and its primary metabolites. Eighty-eight single-nucleotide polymorphisms were chosen for genotyping by a MassARRAY system. Preterm infants in the apnoea-free group were associated with a reduction in the incidence of bronchopulmonary dysplasia and a reduced requirement for patent ductus arteriosus ligation. No significant association was observed between plasma-trough-concentration-to-dose (C0/D) ratio and birth weight, gestational age, or postnatal age in either group. Polymorphisms in CYP1A2 and aryl hydrocarbon receptor (AHR) genes did not affect plasma caffeine levels. Polymorphisms in adenosine receptor genes ADORA1 (rs10920568 and rs12744240), ADORA2A (rs34923252 and rs5996696), and ADORA3 (rs10776727 and rs2298191), especially in AHR (rs4410790) and adenosine deaminase (rs521704), play critical roles in the interindividual response to caffeine therapy. Genetic polymorphisms in caffeine's target receptors, but not the exposure levels based on the standard dosing, were associated with variable responses to caffeine therapy in preterm neonates. Future studies are needed to uncover how these genetic variants affect responses to caffeine therapy in this patient population.

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.

Dietary Caffeine Synergizes Adverse Peripheral and Central Responses to Anesthesia in Malignant Hyperthermia Susceptible Mice.

Ryanodine receptor (RYR) mutations confer stress-triggered malignant hyperthermia (MH) susceptibility. Dietary caffeine (CAF) is the most commonly consumed psychoactive compound by humans. CAF-triggered Ca2+ release and its influences on skeletal muscle contractility are widely used as experimental tools to study RYR function/dysfunction and diagnose MH susceptibility. We hypothesize that dietary CAF achieving blood levels measured in human plasma exacerbates the penetrance of RYR1 MH susceptibility mutations triggered by gaseous anesthetic, affecting both central and peripheral adverse responses. Heterozygous R163C-RYR1 (HET) MH susceptible mice are used to investigate the influences of dietary CAF on both peripheral and central responses before and after induction of halothane (HAL) maintenance anesthesia under experimental conditions that maintain normal core body temperature. HET mice receiving CAF (plasma CAF 893 ng/ml) have significantly shorter times to respiratory arrest compared with wild type, without altering blood chemistry or displaying hyperthermia or muscle rigor. Intraperitoneal bolus dantrolene before HAL prolongs time to respiratory arrest. A pilot electrographic study using subcutaneous electrodes reveals that dietary CAF does not alter baseline electroencephalogram (EEG) total power, but significantly shortens delay to isoelectric EEG, which precedes respiratory and cardiac arrest. CAF ± HAL are studied on RYR1 single-channel currents and HET myotubes to define molecular mechanisms of gene-by-environment synergism. Strong pharmacological synergism between CAF and HAL is demonstrated in both single-channel and myotube preparations. Central and peripheral nervous systems mediate adverse responses to HAL in a HET model of MH susceptibility exposed to dietary CAF, a modifiable lifestyle factor that may mitigate risks of acute and chronic diseases associated with RYR1 mutations. SIGNIFICANCE STATEMENT: Dietary caffeine at a human-relevant dose synergizes adverse peripheral and central responses to anesthesia in malignant hyperthermia susceptible mice. Synergism of these drugs can be attributed to their actions at ryanodine receptors.

Development of a liquid chromatography-tandem mass spectrometry (LC–MS/MS) method for characterizing caffeine, methylliberine, and theacrine pharmacokinetics in humans

Coffea liberica possesses stimulant properties without accumulating the methylxanthine caffeine. The basis for this peculiar observation is that methylurates (e.g., theacrine and methylliberine) have replaced caffeine. The stimulant properties of methylurates, alone and in combination with caffeine, have recently been investigated. However, human pharmacokinetics and LC-MS/MS methods for simultaneous measurement of methylxanthines and methylurates are lacking. To address this deficiency, we conducted a pharmacokinetic study in which subjects (n = 12) were orally administered caffeine (150 mg), methylliberine (Dynamine™, 100 mg), and theacrine (TeaCrine®, 50 mg) followed by blood sampling over 24 h. Liquid-liquid extraction of plasma samples containing purine alkaloids and internal standard (13C-Caffeine) were analyzed using a C18 reversed-phase column and gradient elution (acetonitrile and water, both containing 0.1% formic acid). A Waters Xevo TQ-S tandem mass spectrometer (positive mode) was used to detect caffeine, methylliberine, theacrine, and IS transitions of m/z 195.11 → 138.01, 225.12 → 168.02, 225.12 → 167.95, and 198.1 → 140.07, respectively. The method was validated for precision, accuracy, selectivity, and linearity and was successfully applied to characterize the oral pharmacokinetics of caffeine, methylliberine, and theacrine in human plasma. Successful development and application of LC-MS/MS-based methods such as ours for the simultaneous measurement of methylxanthines and methylurates are essential for the characterization of potential pharmacokinetic and pharmacodynamic interactions.

A Randomised, Placebo-Controlled, Crossover Study Investigating the Optimal Timing of a Caffeine-Containing Supplement for Exercise Performance

BackgroundPre-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.MethodsThis 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.ResultsTotal 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).ConclusionIn 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 registrationClinicalTrials.Gov,NCT02985606; 10/26/2016.

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.

Comparison of Plasma Caffeine Concentration After Oral Consumption of Caffeinated Beverages With Varied Bioactive Compounds in Healthy Volunteers

This website is for sale! casemedicalresearch.com is your first and best source for all of the information you’re looking for. From general topics to more of what you would expect to find here, casemedicalresearch.com has it all. We hope you find what you are searching for!

Simultaneous Determination of Six Alkaloids in Rat Plasma with On-line SPE–HPLC Using a Homemade Four-Hydrogen Furfuryl-Based Polymer Monolithic Sorbent

A four-hydrogen furfuryl-based polymer monolithic column for solid-phase extraction was prepared via in situ radical polymerization, using tetrahydrofurfuryl methacrylate as the monomer. The monolith was characterized by scanning electron microscopy, Fourier-transform infrared spectroscopy and nitrogen adsorption–desorption method, showing relatively uniform porous structure with micro-, meso- and macro-pores and a relatively high surface area of 54.99 m2 g−1. Online solid-phase extraction–high-performance liquid chromatography was carried out to quantitatively analyze six alkaloids, including caffeine, hydroxy-α-sanshool, hydroxy-β-sanshool, hydroxy-γ-sanshool, hydroxy-γ-isosanshool and γ-sanshool in rat plasma. The results show that the prepared polymer monolithic sorbent exhibits good clean-up ability for bio-matrix, as well as good extractive ability for the six concerning alkaloids in rat plasma. Method validation shows that the correlation coefficients of the linear regressions are higher than 0.998 and the accuracy represented by spiked recovery ranges in 94.37–100.7%, 99.52–101.1%, 98.93–100.8%, 98.36–101.6%, 99.22–101.2% and 99.86–101.4% for the six alkaloids, respectively, as well as the LOD ranges in 2.10–3.90 ng mL−1 and the LOQ in 6.35–10.14 ng mL−1. Compared to the reference works, the present work is a simple and effective method for online extraction and simultaneous determination of six alkaloids in plasma with high accuracy and low cost.

Features of chromatographic separation on heteropaternal sorbents

The possibility of using a short 20x4 mm chromatographic column with a heterosurface sorbent for direct determination of theophylline and caffeine in blood plasma and a 120x4 mm column for determination of tetracycline antibiotics in cow’s milk was studied. Complete separation of tetracycline peaks was not achieved. Determination of caffeine and theophylline was performed successfully in plasma filtrates without long and time-consuming stages of preliminary preparation of the sample without protein deposition. Before backwashing, unfiltered blood plasma can be injected in an amount equivalent to 50 mg of dry matter. Retention characteristics of caffeine and theophylline are practically stable: the retention factor of theophylline for k = 4,0 + 0,1 for caffeine k = 8,5 + 0,4 eluent in composition of 0.02 M sodium hydrogen phosphate (pH = 6,0) – acetonitrile (90:10).

Acute Ingestion of a Mixed Flavonoid and Caffeine Supplement Increases Energy Expenditure and Fat Oxidation in Adult Women: A Randomized, Crossover Clinical Trial.

This randomized, double-blinded, crossover study measured the acute effect of ingesting a mixed flavonoid-caffeine (MFC) supplement compared to placebo (PL) on energy expenditure (EE) and fat oxidation (FATox) in a metabolic chamber with premenopausal women (n = 19, mean ± SD, age 30.7 ± 8.0 year, BMI 25.7 ± 3.4 kg/m2). The MFC supplement (658 mg flavonoids, split dose 8:30, 13:00) contained quercetin, green tea catechins, and anthocyanins from bilberry extract, and 214 mg caffeine. Participants were measured twice in a metabolic chamber for a day, four weeks apart, with outcomes including 22 h EE (8:30–6:30), substrate utilization from the respiratory quotient (RQ), plasma caffeine levels (16:00), and genotyping for the single-nucleotide polymorphism (SNP) rs762551. Areas under the curve (AUC) for metabolic data from the MFC and PL trials were calculated using the trapezoid rule, with a mixed linear model (GLM) used to evaluate the overall treatment effect. The 22 h oxygen consumption and EE were significantly higher with MFC than PL (1582 ± 143, 1535 ± 154 kcal/day, respectively, p = 0.003, trial difference of 46.4 ± 57.8 kcal/day). FATox trended higher for MFC when evaluated using GLM (99.2 ± 14.0, 92.4 ± 14.4 g/22 h, p = 0.054). Plasma caffeine levels were significantly higher in the MFC versus PL trial (5031 ± 289, 276 ± 323 ng/mL, respectively, p < 0.001). Trial differences for 22 h EE and plasma caffeine were unrelated after controlling for age and body mass (r = −0.249, p = 0.139), and not different for participants with the homozygous allele 1, A/A, compared to C/A and C/C (p = 0.50 and 0.56, respectively). In conclusion, EE was higher for MFC compared to PL, and similar to effects estimated from previous trials using caffeine alone. A small effect of the MFC on FATox was measured, in contrast to inconsistent findings previously reported for this caffeine dose. The trial variance for 22 h EE was not significantly related to the variance in plasma caffeine levels or CYP1A2*1F allele carriers and non-carriers.

Effective quantification of 11 tyrosine kinase inhibitors and caffeine in human plasma by validated LC-MS/MS method with potent phospholipids clean-up procedure. Application to therapeutic drug monitoring

Therapeutic drug monitoring (TDM) help to improve treatment efficacy and safety. Therefore, a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous monitoring of 11 tyrosine kinase inhibitors (TKIs) in human plasma. TKIs included in the assay are used in the treatment of chronic myeloid leukemia (CML: imatinib, dasatinib, nilotinib, bosutinib, ponatinib), polycythemia vera (ruxolitinib), chronic lymphocytic leukemia (ibrutinib) and rheumatoid arthritis (filgotinib, tofacitinib, baricitinib, peficitinib). Caffeine was also included in the method. Caffeine increases the acidity of the stomach and decreases its pH as well as is a competitive inhibitor of cytochrome P450 isoenzymes. Thus, it may influence absorption and metabolism of some TKIs, by modifying their plasma levels. The analytes of interest and their stable isotope-labeled internal standards were extracted from 200 μL of human plasma. Microelution-solid phase extraction (μ-SPE) was optimized for method validation and compared to simple protein precipitation (PPT). A gradient elution on a Poroshell 120 EC-C18 column at 60 °C and a flow rate of 0.5 mL/min was applied for analyte separation. The analytical run lasted 8 min and it was followed by a re-equilibration time of 4 min. Dynamic multiple reaction monitoring scan in the positive ionization mode was applied to improve method sensitivity. Endogenous plasma phospholipids can strongly affect MS analysis. Hence, the monitoring of endogenous phospholipids was included in the assay. Full validation of the method was achieved, including tests of precision, accuracy, trueness, linearity, extraction recovery, matrix effect, process efficiency, stability, sensitivity (with excellent LLOQs), selectivity, identity confirmation and carry-over effect. Regarding sample cleanup, more than 91% of early eluting and more than 96% of late eluting endogenous phospholipids were eliminated by μ-SPE when compared to PPT. This method enables the simultaneous plasma monitoring of 11 TKIs and caffeine and ensures high effectiveness in phospholipids elimination. The present approach is currently used in our clinical practice, being applied to TDM of dasatinib, imatinib, nilotinib and ponatinib. TKIs plasma monitoring helps to individualize dose adjustment and manage adverse effects in CML patients.

Preliminary Studies on Genetic Profiling of Coffee and Caffeine Consumption

Regular coffee intake has been associated with reduced risk of developing serious chronic diseases. The hypothesis of this study is that coffee consumers present a particular pattern/trend of genotypes that ultimately will shed light on new gene targets to treat the diseases, from which regular coffee intake has preventive effects. Sixteen SNPs identified at genome-wide association studies (GWAS) on coffee and caffeine consumption were genotyped using real-time restriction-fragment length polymorphism-polymerase chain reaction (RT-PCR). The DNA samples were the same from a previous pilot study where 15 healthy volunteers donated two blood samples collected before and after drinking a standard cup of coffee and had caffeine plasma levels and CYP 1A2 genotype (rs762551) determined. The cross-examination of the data showed that six of the sixteen SNPs exhibited a negative allelic effect direction and nine of them showed a positive effect direction of which three of them had results confirmed by a recent GWAS. There is a need of a more in-depth study to understand the effects of the presence or absence of specific variant alleles as players to benefit the health of coffee consumers.

Beverage Intake in U.S. Women Across Pregnancy and Gestational Diabetes Risk (P11-010-19)

ObjectivesSugar and artificially sweetened beverages (SSB/ASB), coffee, and tea are commonly consumed among U.S. pregnant women, but there is limited data on their use in pregnancy and gestational diabetes (GDM) risk and cardiometabolic profile. Our aim was to examine longitudinal associations between SSB, ASB, coffee, and tea intake in pregnancy with GDM risk. In two separate sub-samples, we also examined 1) associations between these beverages and cardiometabolic biomarkers and 2) plasma caffeine metabolites and GDM risk. MethodsWe used data collected from pregnant women at 12 U.S. clinical centers (2009-2013; N = 2802) in the NICHD Fetal Growth Studies. Women completed a food frequency questionnaire at enrollment at 8–13 gestational weeks (GW) regarding 1st trimester diet, and an Automated Self-Administered 24-Hour dietary recall was completed at 16–22, 24–29, 30–33, and 34–37 GW (N = 1993). Plasma caffeine and paraxanthine were measured at 8–13 GW in a sub-sample of women without obesity (N = 2106). GDM (N = 85; 4.3%) was ascertained from medical records. Cardiometabolic biomarkers were measured in a sub-sample at 8–13 and 16–22 GW (N = 221). All models were adjusted for relevant confounders including diet quality. ResultsDaily SSB, ASB, coffee, and tea intake was uncommon (Figure). No significant associations between 1st trimester SSBs (≥ 1 serving/day vs. none, adjusted RR = 1.16 [95% CI 0.59, 2.28]), ASBs (RR = 0.53 [0.16, 1.80]), coffee (RR = 1.04 [0.53, 2.07]), or tea (RR = 1.23 [0.57, 2.63]) and GDM risk were observed. Results were similar for intake at 16–22 and 24–29 GW. No consistent associations were observed with cardiometabolic markers. There was no association between plasma caffeine (Quartile 4 vs Quartile 1, RR = 0.94 [0.47, 1.88]), paraxanthine (RR = 0.81 [0.41, 1.60]) or their sum (RR = 0.86 [0.45, 1.66]) at 8–13 GW and GDM risk. ConclusionsIn this diverse U.S. cohort of low-risk pregnant women with relatively low consumption of SSBs, ASBs, coffee, and tea, no significant associations were observed with GDM risk or cardiometabolic profile. In addition, plasma caffeine metabolites were not significantly associated with GDM risk. Funding SourcesThis study was support by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Supporting Tables, Images and/or Graphs▪

Acute Ingestion of a Mixed Flavonoid and Caffeine Supplement Increases Energy Expenditure and Fat Oxidation in Adult Women: A Randomized, Crossover Clinical Trial (OR29-07-19)

ObjectivesThis randomized, double-blinded, crossover study measured the acute effect of ingesting a mixed flavonoid-caffeine (MFC) supplement compared to placebo (PL) on energy expenditure (EE) and fat oxidation (FATox) in a metabolic chamber with pre-menopausal women (N = 19, mean ± SD, age 30.7 ± 8.0 y, BMI 25.7 ± 3.4 kg/m2). MethodsThe MFC supplement (678 mg flavonoids, split dose 8:30 am, 1:00 pm) contained quercetin (200 mg), green tea catechins (368 mg, 180 mg EGCG), and anthocyanins (128 mg) from bilberry extract, and 214 mg caffeine. Participants were measured twice in a metabolic chamber for a day, 4 weeks apart, with primary outcomes including EE for 5 defined time segments and 22 h (22hEE, 8:30–6:30 am), substrate utilization from the respiratory quotient (RQ), physical activity counts, and plasma caffeine levels (4:00 pm). Areas under the curve (AUC) for metabolic data from the MFC and PL trials were calculated for 5 time segments using the trapezoid rule, with a mixed linear model (GLM) used to evaluate the overall treatment effect, and paired t-tests used to compare data for each time segment. ResultsEE and oxygen consumption for the MFC trial were significantly higher than PL (p < 0.001) when AUCs were compared as a whole and for each defined segment except during sleep. 22hEE with MFC was significantly higher than PL (1582 ± 143, 1535 ± 154 kcal/d, respectively, P = 0.003), with an average trial difference of 46.4 ± 57.8 kcal/d. Activity counts were not significantly different between trials (P = 0.671). RQ values were similar between the MFC and PL trials (0.819 ± 0.021, 0.826 ± 0.022, respectively, P = 0.281). FATox trended higher for MFC when evaluated using GLM (99.2 ± 14.0, 92.4 ± 14.4 grams/22 h, P = 0.054). Plasma caffeine levels were significantly higher in the MFC versus PL trial (5031 ± 289, 276 ± 323 ng/ml, respectively, P < 0.001). The trial differences for 22hEE and plasma caffeine were unrelated after controlling for age and body mass (r = –0.249, P = 0.139). ConclusionsEE was higher for MFC compared to PL, and similar to effects estimated from previous trials using caffeine alone. A small effect of the MFC on FATox was measured, in contrast to inconsistent findings previously reported for this caffeine dose. The trial variance for 22hEE was not related to the large variance in plasma caffeine levels. Funding SourcesReoxcyn LLC.

Women Experience the Same Ergogenic Response to Caffeine as Men.

This study aimed to determine whether 1) consumption of caffeine improves endurance cycling performance in women and 2) sex differences exist in the magnitude of the ergogenic and plasma responses to caffeine supplementation. Twenty-seven (11 women and 16 men) endurance-trained cyclists and triathletes participated in this randomized, double-blind, placebo-controlled, crossover study. Participants completed an incremental exercise test to exhaustion, two familiarization trials, and two performance trials. Ninety minutes before the performance trials, participants ingested opaque capsules containing either 3 mg·kg body mass of anhydrous caffeine or a placebo. They then completed a set amount of work (75% of peak sustainable power output) in the fastest possible time. Plasma was sampled at baseline, preexercise, and postexercise for caffeine. Strict standardization and verification of diet, hydration, training volume and intensity, and contraceptive hormone phase (for women) were implemented. Performance time was significantly improved after caffeine administration in women (placebo: 3863 ± 419 s, caffeine: 3757 ± 312 s; P = 0.03) and men (placebo: 3903 ± 341 s, caffeine: 3734 ± 287 s; P < 0.001). The magnitude of performance improvement was similar for women (mean = 4.3%, 95% CI = 0.4%-8.2%) and men (4.6%, 2.3%-6.8%). Plasma caffeine concentrations were similar between sexes before exercise, but significantly greater in women after exercise (P < 0.001). Ingestion of 3 mg·kg body mass of caffeine enhanced endurance exercise performance in women. The magnitude of the performance enhancement observed in women was similar to that of men, despite significantly greater plasma caffeine concentrations after exercise in women. These results suggest that the current recommendations for caffeine intake (i.e., 3-6 mg·kg caffeine before exercise to enhance endurance performance), which are derived almost exclusively from studies on men, may also be applicable to women.

A genome-wide association study of bitter and sweet beverage consumption.

Except for drinking water, most beverages taste bitter or sweet. Taste perception and preferences are heritable and determinants of beverage choice and consumption. Consumption of several bitter- and sweet-tasting beverages has been implicated in development of major chronic diseases. We performed a genome-wide association study (GWAS) of self-reported bitter and sweet beverage consumption among ~370 000 participants of European ancestry, using a two-staged analysis design. Bitter beverages included coffee, tea, grapefruit juice, red wine, liquor and beer. Sweet beverages included artificially and sugar sweetened beverages (SSBs) and non-grapefruit juices. Five loci associated with total bitter beverage consumption were replicated (in/near GCKR, ABCG2, AHR, POR and CYP1A1/2). No locus was replicated for total sweet beverage consumption. Sub-phenotype analyses targeting the alcohol, caffeine and sweetener components of beverages yielded additional loci: (i) four loci for bitter alcoholic beverages (GCKR, KLB, ADH1B and AGBL2); (ii) five loci for bitter non-alcoholic beverages (ANXA9, AHR, POR, CYP1A1/2 and CSDC2); (iii) 10 loci for coffee; six novel loci (SEC16B, TMEM18, OR8U8, AKAP6, MC4R and SPECC1L-ADORA2A); (iv) FTO for SSBs. Of these 17 replicated loci, 12 have been associated with total alcohol consumption, coffee consumption, plasma caffeine metabolites or BMI in previous GWAS; none was involved in known sweet and bitter taste transduction pathways. Our study suggests that genetic variants related to alcohol consumption, coffee consumption and obesity were primary genetic determinants of bitter and sweet beverage consumption. Whether genetic variants related to taste perception are associated with beverage consumption remains to be determined.

Evaluating the effect of Ganoderma lucidum polysaccharides on five cytochrome P450 isozymes with cocktail probe drugs in rats by LC–MS/MS

Ganoderma lucidum polysaccharides (GLPs) are commonly used as health-promoting medicine and dietary supplement due to the positive effects in immune modulation, antitumor and antioxidant activities. However, whether GLPs executes other uncharacterized effects is largely unclear. The rats were pre-primed with GLPs and then administrated with canonical “cocktail probes” of cytochrome P450 (CYP450) isozymes including caffeine, tolbutamide, dextromethorphan, omeprazole, and midazolam. The plasma concentrations of probes at each indicated time point were simultaneously detected using the designed high-performance liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. The results suggested that GLPs could increase the accumulated levels of caffeine, tolbutamide and midazolam in plasma as compared to control group. Besides, GLPs reduced the concentration of dextromethorphan in blood at high dose, while elevated it at low dose. GLPs could inhibit the activities of CYP1A2, and CYP3A4, additionally; GLPs at low dose suppressed the activity of CYP2D6, which demonstrated that drugs co-administrated with GLPs might require strictly evaluating the dose relation.

Simultaneous determination of six antipsychotics, two of their metabolites and caffeine in human plasma by LC-MS/MS using a phospholipid-removal microelution-solid phase extraction method for sample preparation

A simple and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated in human plasma for the simultaneous determination of aripiprazole (ARI) and its metabolite dehydro-aripiprazole (DARI); olanzapine (OLA), risperidone (RIS), paliperidone (PAL), quetiapine (QUE), clozapine (CLO) and caffeine (CAF). CAF is included to the method because it can have an influence on drug metabolism due to competitive inhibition. The above mentioned compounds and their isotope-labeled internal standards were extracted from 200 µL human plasma samples by both, effective phospholipids-eliminating three-step microelution-solid-phase extraction (µ-SPE) and protein precipitation (PPT) for comparison. A combination of formic acid (0.2%)-acetonitrile (pH 3.0; 65:35, v/v) was used as mobile phase and the chromatogram was run under gradient conditions at a flow rate of 0.6 mL/min. Run time lasted 6 min, followed by a re-equilibration time of 3 min. All analytes were monitored by mass spectrometric detection operating in multiple reaction monitoring mode and the method was validated covering the corresponding therapeutic ranges: 0.18–120 ng/mL for ARI, 0.25–80 ng/mL for DARI, 1.00–100 ng/mL for OLA, 0.70–60 ng/mL for RIS, 0.20–30 ng/mL for PAL, 0.50–160 ng/mL for QUE, 0.50–1000 ng/mL for CLO, and finally 1200–3700 ng/mL for CAF. The method was validated based on the recommendations of regulatory agencies through tests of precision, accuracy, extraction recovery, identity confirmation, trueness, matrix effect, process efficiency, stability, selectivity, linearity and carry-over effect fulfilling the guideline requirements. Our µ-SPE method results in the elimination of more than 99% of early eluting and more than 92% of late-eluting phospholipids compared to PPT. Additionally, the method was successfully applied for quantifying ARI and OLA plasma concentrations from healthy volunteers.

No Relevant Pharmacokinetic (PK) Interaction between Rezafungin and Nine Probe Drugs: Results from a Drug-Drug Interaction (DDI) Study

Introduction Rezafungin (RZF) is a new echinocandin being developed to treat patients with systemic fungal infections and to prevent invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients and other patients at high risk of infection. RZF is differentiated by stable and efficacy-driving pharmacokinetics (PK) that allow for once-weekly dosing. Several in vitro studies have been conducted to assess the potential for rezafungin to alter the PK of other drugs. Based on the results, possible interactions were identified in which the risk of drug-drug interactions (DDIs) could not be ruled out relative to the assumed Ph3 dose of 400 mg once weekly and known PK exposure in healthy subjects. Clinical in vivo evaluations of drug interaction potential were performed proactively. Methods This was an open-label, inpatient study of 26 healthy subjects to assess DDIs between RZF and probe drugs selected for known interactions with CYP enzymes and transporters (and consequently commonly used in evaluations of PK interaction), as well as drugs likely to be coadministered with RZF. A loading dose of RZF 600 mg was administered on the first dosing day, to approximate a steady state plasma concentration of multiple once-weekly 400-mg doses, followed by 400-mg doses on days 10 and 15. Probe drugs were administered as part of a cocktail containing ≥2 drugs, once prior to and once after receiving RZF on a schedule designed to allow for washout between doses and to limit interactions with other drugs (Figure 1). Samples were analyzed to determine RZF, tacrolimus, repaglinide, metformin, rosuvastatin, pitavastatin, caffeine, efavirenz, midazolam and digoxin concentrations in plasma (except for tacrolimus which was in whole blood) to characterize the PK profile of each analyte. PK exposure parameters (area under curve [AUC] and maximum concentration [Cmax]) were calculated from the plasma concentration-time profiles by noncompartmental analysis. Results When rezafungin was dosed concomitantly with metformin, pitavastatin, caffeine, efavirenz, midazolam, digoxin, tacrolimus, repaglinide, and rosuvastatin, no relevant change in systemic concentrations of these probe drugs was observed (Figure 2). PK exposure of all drugs were similar with or without RZF. Maximum changes in mean Cmax or AUC were Conclusion No meaningful PK interactions occurred between RZF and the 9 probe drug substrates tested, providing evidence that no RZF dose adjustment is expected when co-administered with these commonly used drugs.

Physiologically Based Pharmacokinetic/Pharmacodynamic Model for Caffeine Disposition in Pregnancy.

Caffeine is the most consumed active stimulant. About 80% of pregnant women consume caffeine orally on a daily basis. Many reports indicated consumption of >200 mg caffeine during pregnancy could increase the likelihood of miscarriage. In this article, we developed a pregnancy physiological-based pharmacokinetic/pharmacodynamic (PBPK/PD) model for caffeine to examine association between maternal caffeine consumption during pregnancy and caffeine plasma levels at doses lower and higher than 200 mg to predict changes in caffeine concentrations across the 3 trimesters, and to predict associated changes in caffeine PD parameters. Two models were successfully developed using GastroPlus software, a nonpregnant model for validation purposes and a pregnant model for validation and prediction of maternal caffeine plasma concentrations following single and multiple dosing. Using observed and predicted data, we were able to validate and simulate PK changes of caffeine in nonpregnant women and the PD effect of caffeine on certain enzymes and catecholamines associated with caffeine intake. Furthermore, the pregnancy PBPK model successfully predicted changes in caffeine PK across the three trimesters. Caffeine increased exposure during pregnancy was related to reduced activity of caffeine metabolizing enzyme CYP1A2. The model also predicted increased levels of caffeine in the fetoplacental compartment (FPC) due to increased maternal caffeine plasma concentrations. Increased caffeine levels in maternal blood was accompanied by greater inhibition of the phosphodiesterase enzyme, higher cyclic adenosine monophosphate, and greater increase of epinephrine levels, which could increase the risk of pregnancy loss. The application of the developed PBPK model to predict the PD effect could provide a useful tool to help define potential cut-offs for caffeine intake in various stages of pregnancy.