Plasma Caffeine Levels Research Articles

Comparison of caffeine consumption behavior with plasma caffeine levels as exposure measures in drug-target Mendelian randomization.

Mendelian randomization is an epidemiological technique that can explore the potential effect of perturbing a pharmacological target. Plasma caffeine levels can be used as a biomarker to measure the pharmacological effects of caffeine. Alternatively, this can be assessed using a behavioral proxy, such as average number of caffeinated drinks consumed per day. Either variable can be used as the exposure in a Mendelian randomization investigation, and to select which genetic variants to use as instrumental variables. Another possibility is to choose variants in gene regions with known biological relevance to caffeine level regulation. These choices affect the causal question that is being addressed by the analysis, and the validity of the analysis assumptions. Further, even when using the same genetic variants, the sign of Mendelian randomization estimates (positive or negative) can change depending on the choice of exposure. Some genetic variants that decrease caffeine metabolism associate with higher levels of plasma caffeine, but lower levels of caffeine consumption, as individuals with these variants require less caffeine consumption for the same physiological effect. We explore Mendelian randomization estimates for the effect of caffeine on body mass index, and discuss implications for variant and exposure choice in drug target Mendelian randomization investigations.

The relationship between coffee-related factors and cortical and hippocampal structure: a triangulation of evidence approach and Mendelian randomization research.

Existing studies have reported sustained changes in the cortical structure of rats due to coffee-related factors, which are speculated to occur in the human body. However, there is a lack of research on this topic. Additionally, previous observational studies have found the impact of diseases on cortical structure and the potential therapeutic effects of coffee on these diseases. Our aim was to study the causal effects of coffee-related factors on the human brain using SNPs (single nucleotide polymorphisms). We will connect these discovered causal effects to the impact of diseases on the brain. Through triangulating evidence, we will reveal the potential active areas of coffee in preventing diseases. We utilized GWAS data from multiple cohorts and their databases, selecting instrumental variables for genetic prediction of coffee intake and plasma levels of caffeine and its direct metabolites. We applied these instrumental variables to individual data on cortical thickness and surface area, as well as hippocampal volume, from the ENIGMA and CHARGE consortium for Mendelian randomization analysis (MR). Triangular evidence was obtained by integrating existing evidence through a specified retrieval strategy, calculating the overlap between coffee's effects on brain regions and disease-related brain regions to identify potential regions of action. The MR analysis yielded 93 positive results for 9 exposures, among which theobromine, a metabolite in the caffeine pathway, was found to be associated with increased hippocampal volume. For cortical structure, theobromine in the caffeine pathway was associated with a decrease in total surface area, while theobromine and caffeine in the pathway were associated with an increase in total thickness. The overlap rate of triangular evidence showed no difference in both overall and subgroup analyses, indicating a high overlap between the effects of coffee on brain regions and disease. From predicted outcomes from causal effects, coffee intake-related factors may have lasting effects on cortical structure. Additionally, theobromine and theophylline have the greatest impact on certain brain gyri, rather than caffeine. Triangulation evidence indicates that disease and coffee intake-related factors act on the same cortical regions, suggesting the presence of potential shared or antagonistic pathways.

Self-reported caffeine consumption miss-matched consumption measured by plasma levels of caffeine and its metabolites: results from two population-based studies

Importance and objectiveSelf-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.MethodsData 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.ResultsIn 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.ConclusionSelf-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.

Coffee Intake, Plasma Caffeine Levels, and Kidney Function: Two-Sample Mendelian Randomization Among East Asian and European Ancestries

IntroductionPrevious Mendelian randomization (MR) studies for the coffee-kidney association have reported inconsistent relationships in European populations and never examined mediators of this association. We aimed to evaluate this causal relationship using two-sample MR among both East Asian and European ancestries and to explore underlying mechanisms using plasma caffeine levels. MethodsAmong East Asians, the largest genome-wide association study (GWAS) results for coffee intake, plasma caffeine levels, and kidney outcomes were obtained from 152,634, 8,940, and 47,070 Japanese adults. Among Europeans, summary statistics were acquired from European GWAS with 428,860, 7,719, and 564,470 adults for each trait. We applied different MR methods (inverse-variance weighted with random effects, weighted median, weighted mode, and MR-Egger). ResultsAfter excluding possible pleiotropic variants, among East Asian ancestry, drinking an extra coffee intake per week showed a protective association on eGFRcre (β=0.077; 95% CI=0.003 to 0.150). Analysis in European ancestry also showed a causal relationship between drinking an extra coffee intake per day and eGFRcre (β=0.052; 95% CI=0.027 to 0.078). These results were consistent across different MR methods accounting for invalid instruments. Higher plasma caffeine levels were associated with lower eGFRcre among both East Asian (β=–0.071; 95% CI=–0.137 to –0.006) and European ancestries (β=–0.048; 95% CI=–0.057 to –0.040). ConclusionsOur cross-ancestry MR study found beneficial effects of coffee intake on eGFRcre. However, given the possible adverse effects of plasma caffeine levels on eGFRcre, results interpretation should be carefully considered and further investigations on non-caffeine and biological pathways are needed.

Caffeine Intake, Plasma Caffeine Level, and Kidney Function: A Mendelian Randomization Study.

Caffeine is a psychoactive substance widely consumed worldwide, mainly via sources such as coffee and tea. The effects of caffeine on kidney function remain unclear. We leveraged the genetic variants in the CYP1A2 and AHR genes via the two-sample Mendelian randomization (MR) framework to estimate the association of genetically predicted plasma caffeine and caffeine intake on kidney traits. Genetic association summary statistics on plasma caffeine levels and caffeine intake were taken from genome-wide association study (GWAS) meta-analyses of 9876 and of >47,000 European ancestry individuals, respectively. Genetically predicted plasma caffeine levels were associated with a decrease in estimated glomerular filtration rate (eGFR) measured using either creatinine or cystatin C. In contrast, genetically predicted caffeine intake was associated with an increase in eGFR and a low risk of chronic kidney disease. The discrepancy is likely attributable to faster metabolizers of caffeine consuming more caffeine-containing beverages to achieve the same pharmacological effect. Further research is needed to distinguish whether the observed effects on kidney function are driven by the harmful effects of higher plasma caffeine levels or the protective effects of greater intake of caffeine-containing beverages, particularly given the widespread use of drinks containing caffeine and the increasing burden of kidney disease.

Lifestyle factors, serum parameters, metabolic comorbidities, and the risk of kidney stones: a Mendelian randomization study.

The early identification of modifiable risk factors is important for preventing kidney stones but determining causal associations can be difficult with epidemiological data. We aimed to genetically assess the causality between modifiable factors (lifestyle factors, serum parameters, and metabolic comorbidities) and the risk of kidney stones. Additionally, we aimed to explore the causal impact of education on kidney stones and its potential mediating pathways. We conducted a two-sample Mendelian randomization (MR) study to explore the causal association between 44 modifiable risk factors and kidney stones. The FinnGen dataset initially explored the causal relationship of risk factors with kidney stones and the UK Biobank dataset was used as the validation set. Then, a meta-analysis was conducted by combining discovery and validation datasets. We used two-step MR to assess potential mediators and their mediation proportions between education and kidney stones. The combined results indicated that previous exposures may increase the risk of kidney stones, including sedentary behavior, urinary sodium, the urinary sodium/potassium ratio, the urinary sodium/creatinine ratio, serum calcium, 25-hydroxyvitamin D (25OHD), the estimated creatinine-based glomerular filtration rate (eGFRcrea), GFR estimated by serum cystatin C (eGFRcys), body mass index (BMI), waist circumference, type 2 diabetes mellitus (T2DM), fasting insulin, glycated hemoglobin, and hypertension. Coffee intake, plasma caffeine levels, educational attainment, and the urinary potassium/creatinine ratio may decrease the risk of kidney stones. Ranked by mediation proportion, the effect of education on the risk of kidney stones was mediated by five modifiable risk factors, including sedentary behavior (mediation proportion, 25.7%), smoking initiation (10.2%), BMI (8.2%), T2DM (5.8%), and waist circumference (3.2%). This study provides MR evidence supporting causal associations of many modifiable risk factors with kidney stones. Sedentary lifestyles, obesity, smoking, and T2DM are mediating factors in the causal relationship between educational attainment and kidney stones. Our results suggest more attention should be paid to these modifiable factors to prevent kidney stones.

Immediate effect of caffeine on sympathetic nerve activity: why coffee is safe? A single-centre crossover study

PurposesHabitual coffee drinking is ubiquitous and generally considered to be safe despite its transient hypertensive effect. Our purpose was to determine the role of the sympathetic nervous system in the hypertensive response.MethodsIn a single-centre crossover study, medical caregivers were studied after consumption of standard coffee (espresso), water and decaffeinated coffee (decaff) given in random order at least 1 month apart. Plasma caffeine levels, mean arterial pressure, heart rate, total peripheral resistance and muscle sympathetic activity were recorded. Baroreflex activity was assessed using burst incidence and RR interval changes to spontaneous blood pressure fluctuations.ResultsA total of 16 subjects (mean [± standard error] age 34.4 ± 2 years; 44% female) were recruited to the study. Three agents were studied in ten subjects, and two agents were studied in six subjects. Over a 120-min period following the consumption of standard coffee, mean (± SE) plasma caffeine levels increased from 2.4 ± 0.8 to 21.0 ± 4 µmol/L and arterial pressure increased to 103 ± 1 mmHg compared to water (101 ± 1 mmHg; p = 0.066) and decaff (100 ± 1 mmHg; p = 0.016). Peripheral resistance in the same period following coffee increased to 120 ± 4% of the baseline level compared to water (107 ± 4; p = 0.01) and decaff (109 ± 4; p = 0.02). Heart rate was lower after both coffee and decaff consumption: 62 ± 1 bpm compared to water (64 bpm; p = 0.01 and p = 0.02, respectively). Cardio-vagal baroreflex activity remained stable after coffee, but sympathetic activity decreased, with burst frequency of 96 ± 3% versus water (106 ± 3%; p = 0.04) and decaff (112 ± 3%; p = 0.001) despite a fall in baroreflex activity from – 2.2 ± 0.1 to – 1.8 ± 0.1 bursts/100 beats/mmHg, compared to water (p = 0.009) and decaff (p = 0.004).ConclusionThe hypertensive response to coffee is secondary to peripheral vasoconstriction but this is not mediated by increased sympathetic nerve activity. These results may explain why habitual coffee drinking is safe.

Appraising the causal relationship between plasma caffeine levels and neuropsychiatric disorders through Mendelian randomization

BackgroundCaffeine exposure modifies the turnover of monoamine neurotransmitters, which play a role in several neuropsychiatric disorders. We conducted a Mendelian randomization study to investigate whether higher plasma caffeine levels are causally associated with the risk of anorexia nervosa, bipolar disorder, major depressive disorder (MDD), and schizophrenia.MethodsSummary-level data on the neuropsychiatric disorders were obtained from large-scale genome-wide association studies (GWASs) of European ancestry participants (n = 72,517 to 807,553) and meta-analyzed with the corresponding data from the FinnGen study (n = 356,077). Summary-level data on plasma caffeine were extracted from a GWAS meta-analysis of 9876 European ancestry individuals. The Mendelian randomization analyses estimated the Wald ratio for each genetic variant and meta-analyzed the variant-specific estimates using multiplicative random effects meta-analysis.ResultsAfter correcting for multiple testing, genetically predicted higher plasma caffeine levels were associated with higher odds of anorexia nervosa (odds ratio [OR] = 1.124; 95% confidence interval [CI] = 1.024–1.238, pFDR = 0.039) and a lower odds of bipolar disorder (OR = 0.905, 95% CI = 0.827–0.929, pFDR = 0.041) and MDD (OR = 0.965, 95% CI = 0.937–0.995, pFDR = 0.039). Instrumented plasma caffeine levels were not associated with schizophrenia (OR = 0.986, 95% CI = 0.929–1.047, pFDR = 0.646).ConclusionsThese Mendelian randomization findings indicate that long-term higher plasma caffeine levels may lower the risk of bipolar disorder and MDD but increase the risk of anorexia nervosa. These results warrant further research to explore whether caffeine consumption, supplementation, or abstinence could render clinically relevant therapeutic or preventative psychiatric effects.

Determination of temporal changes in hepatic drug-oxidizing capacity using plasma metabolite/caffeine ratios in non-pregnant and pregnant goats.

Caffeine (CF) is a metabolic probe drug used in the determination of the hepatic drug-oxidizing capacity. The aim of this study was to investigate temporal changes in the hepatic drug-oxidizing capacity using plasma metabolite/CF ratios in non-pregnant goats (n = 11) and pregnant goats (n = 23). CF (5 mg/kg, intravenous) was administered in six periods (Period 1-6) with 45 days between two periods. The plasma levels of CF and its metabolites, theophylline (TP), theobromine (TB) and paraxanthine (PX), were determined by HPLC-UV. To evaluate hepatic drug-oxidizing capacity in terms of enzymes that play a role in CF metabolism, the plasma metabolic ratios including TB/CF, PX/CF, TP/CF and TB + PX + TP/CF were determined at 10 h following CF administration. Plasma metabolite/CF ratios were similar between non-pregnant and pregnant goats. However, plasma metabolite/CF ratios in Period 3 (45 days in pregnant goats) were significantly higher than those other periods in both pregnant and non-pregnant goats. The effect of pregnancy may not be observed on drugs that are substrates of enzymes involved in CF metabolism in goats.

Early-life fecal metabolomics of food allergy.

Intestinal microenvironmental perturbations may increase food allergy risk. We hypothesize that children with clinical food allergy, those with food sensitization, and healthy children can be differentiated by intestinal metabolites in the first years of life. In this ancillary analysis of the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we performed untargeted metabolomic profiling in 824 stool samples collected at ages 3-6months, 1year and 3 years. Subjects included 23 with clinical food allergy at age 3 and/or 6 years, 151 with food sensitization but no clinical food allergy, and 220 controls. We identified modules of correlated, functionally related metabolites and sought associations of metabolite modules and individual metabolites with food allergy/sensitization using regression models. Several modules of functionally related intestinal metabolites were reduced among subjects with food allergy, including bile acids at ages 3-6months and 1year, amino acids at age 3-6months, steroid hormones at 1year, and sphingolipids at age 3 years. One module primarily containing diacylglycerols was increased in those with food allergy at age 3-6months. Fecal caffeine metabolites at age 3-6months, likely derived from breast milk, were increased in those with food allergy and/or sensitization (beta=5.9, 95% CI 1.0-10.8, p=.02) and were inversely correlated with fecal bile acids and bilirubin metabolites, though maternal plasma caffeine levels were not associated with food allergy and/or sensitization. Several classes of bioactive fecal metabolites are associated with food allergy and/or sensitization including bile acids, steroid hormones, sphingolipids, and caffeine metabolites.

Plasma Caffeine Levels and Risk of Alzheimer's Disease and Parkinson's Disease: Mendelian Randomization Study.

We leveraged genetic variants associated with caffeine metabolism in the two-sample Mendelian randomization framework to investigate the effect of plasma caffeine levels on the risk of Alzheimer’s disease and Parkinson’s disease. Genetic association estimates for the outcomes were obtained from the International Genomics of Alzheimer’s Project, the International Parkinson’s Disease Genomics consortium, the FinnGen consortium, and the UK Biobank. Genetically predicted higher plasma caffeine levels were associated with a non-significant lower risk of Alzheimer’s disease (odds ratio 0.87; 95% confidence interval 0.76, 1.00; p = 0.056). A suggestive association was observed for genetically predicted higher plasma caffeine levels and lower risk of Parkinson’s disease in the FinnGen consortium. but not in the International Parkinson’s Disease Genomics consortium; no overall association was found (odds ratio 0.92; 95% confidence interval 0.77, 1.10; p = 0.347). This study found possible suggestive evidence of a protective role of caffeine in Alzheimer’s disease. The association between caffeine and Parkinson’s disease requires further study.

Dysmetabolism and Sleep Fragmentation in Obstructive Sleep Apnea Patients Run Independently of High Caffeine Consumption.

Daytime hypersomnolence, the prime feature of obstructive sleep apnea (OSA), frequently leads to high coffee consumption. Nevertheless, some clinicians ask for patients’ caffeine avoidance. Caffeinated drinks are sometimes associated with more severe OSA. However, these effects are not consensual. Here we investigated the effect of caffeine consumption on sleep architecture and apnea/hypopnea index in OSA. Also, the impact of caffeine on variables related with dysmetabolism, dyslipidemia, and sympathetic nervous system (SNS) dysfunction were investigated. A total of 65 patients diagnosed with OSA and 32 without OSA were included after given written informed consent. Polysomnographic studies were performed. Blood was collected to quantify caffeine and its metabolites in plasma and biochemical parameters. 24 h urine samples were collected for catecholamines measurement. Statistical analyses were performed by SPSS: (1) non-parametric Mann-Whitney test to compare variables between controls and OSA; (2) multivariate logistic regression testing the effect of caffeine on sets of variables in the 2 groups; and (3) Spearmans’ correlation between caffeine levels and comorbidities in patients with OSA. As expected OSA development is associated with dyslipidemia, dysmetabolism, SNS dysfunction, and sleep fragmentation. There was also a significant increase in plasma caffeine levels in the OSA group. However, the higher consumption of caffeine by OSA patients do not alter any of these associations. These results showed that there is no apparent rationale for caffeine avoidance in chronic consumers with OSA.

Effect of Caffeine on Time to Anesthetic Emergence after Laparoscopic Cholecystectomy: Randomized-Controlled Trial

Background: The aim of this study was to examine the effect of caffeine on the time to emerge from sevoflurane anesthesia for laparoscopic cholecystectomy. Methods: Prospective, randomized, double-blind study conducted between July 2021 and October 2021. ASA I and II patients proposed for laparoscopic cholecystectomy were included and randomized into 2 groups at the end of the surgery to receive either 300mg of caffeine citrate infusion (C) or saline infusion (S). The main endpoint was to compare anesthetic recovery times. The secondary endpoints were recovery scales, postoperative pain, time to the first flatus, fatigue, occurrence of cardiovascular adverse events, and plasma caffeine levels one and twenty-four hours after intravenous infusion. Results: Sixty patients were included. Both groups were comparable regarding demographic characteristics and anesthesia parameters. All average times to emergence were shorter in group C with significant differences (p <0.05) for time to spontaneous ventilation (p= 0.002, -2.86 min) and time to extubation (P= 0.004, -3.51 min). In group C the modified Aldrete scale and the Richmond agitation-sedation scale were significantly higher. Fatigue was significantly lower 4 hours postoperatively with caffeine (p = 0.049). There was no difference regarding postoperative pain, headache incidence, nausea and vomiting, time to the first flatus and satisfaction at discharge from hospital. Plasma levels of caffeine were well below the toxicity threshold. Conclusion: Caffeine administration following laparoscopic cholecystectomy reduced the time to emergence and sedation. Cardiovascular adverse events were not reported and plasma levels were well below the toxicity threshold.

Associations Between High Plasma Methylxanthine Levels, Sleep Disorders and Polygenic Risk Scores of Caffeine Consumption or Sleep Duration in a Swiss Psychiatric Cohort.

Objective: We first sought to examine the relationship between plasma levels of methylxanthines (caffeine and its metabolites) and sleep disorders, and secondarily between polygenic risk scores (PRS) of caffeine consumption or sleep duration with methylxanthine plasma levels and/or sleep disorders in a psychiatric cohort.Methods: Plasma levels of methylxanthines were quantified by ultra-high performance liquid chromatography/tandem mass spectrometry. In inpatients, sleep disorder diagnosis was defined using ICD-10 “F51.0,” sedative drug intake before bedtime, or hospital discharge letters, while a subgroup of sedative drugs was used for outpatients. The PRS of coffee consumption and sleep duration were constructed using publicly available GWAS results from the UKBiobank.Results: 1,747 observations (1,060 patients) were included (50.3% of observations with sleep disorders). Multivariate analyses adjusted for age, sex, body mass index, setting of care and psychiatric diagnoses showed that patients in the highest decile of plasma levels of methylxanthines had more than double the risk for sleep disorders compared to the lowest decile (OR = 2.13, p = 0.004). PRS of caffeine consumption was associated with plasma levels of caffeine, paraxanthine, theophylline and with their sum (β = 0.1; 0.11; 0.09; and 0.1, pcorrected = 0.01; 0.02; 0.02; and 0.01, respectively) but not with sleep disorders. A trend was found between the PRS of sleep duration and paraxanthine levels (β = 0.13, pcorrected = 0.09).Discussion: Very high caffeine consumption is associated with sleep disorders in psychiatric in- and outpatients. Future prospective studies should aim to determine the benefit of reducing caffeine consumption in high caffeine-consuming patients suffering from sleep disorders.

Pharmacokinetic profile of a novel sustained-release caffeine with extended benefits on alertness and mood: A randomized, double-blind, single-dose, active-controlled, crossover study

• Xtenergy™ demonstrated a slow absorption and sustained plasma caffeine levels based on T max , t 1/2 and AUC data. • T max was 325.53% higher ( p < 0.05) and t 1/2 was 21.34% higher ( p < 0.05) for Xtenergy™ as compared to immediate release caffeine. • Xtenergy™ demonstrated similar total exposure as IRC based on the 90% CI of 84.63% - 114.45% for AUC 0–24. • Slow-Release caffeine showed significant beneficial effects ( p < 0.05) at several of the time points on alertness, tiredness, overall mood, jitteriness and less tenseness without any safety issues. Oral consumption of caffeine typically leads to its instant release and subsequent rapid absorption, high plasma caffeine levels followed by a quick steep decline reducing its beneficial effects which is frequently referred to as “caffeine crash”. To overcome this limitation, we developed a new slow and sustained-release caffeine (SRC) formulation, Xtenergy™. The primary objective was to compare the plasma pharmacokinetic profile of SRC with immediate-release caffeine (IRC). Secondary objectives included the use of caffeine research visual analogue scales (Caff - VAS) to evaluate some of the nootropic benefits of SRC and safety assessments. This was a randomized, double-blind, single-dose, active-controlled, crossover study. Twenty-six subjects were randomized to receive 200 mg caffeine from SRC and IRC in a crossover fashion as per the randomization schedule. Blood samples were collected at -4, 0, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 h in each period. Plasma caffeine levels were analyzed by a validated LC-MS/MS method. The changes in Caff-VAS relaxed, alert, jittery, tired, tense, headache, overall mood from baseline i.e., 0 to 1, 2, 4, 6, 8, 10, and 12 h were evaluated. Twenty-four male subjects with mean age 32.71±6.18 years completed the study. The median T max was 325.53% higher ( p < 0.05) for SRC as compared to IRC (4.00 vs. 0.94 h) and mean t 1/2 was 21.34% higher ( p < 0.05) for SRC as compared to IRC (9.± 4.56 vs. 7.61± 3.98 h). SRC demonstrated similar total exposure as IRC based on the 90% CI of 84.63% - 114.45% for ln-transformed AUC 0–24 . AUC 4–8 and AUC 6–12 were 6.80% and 22.84% higher for SRC as compared to IRC, respectively. Compared to IRC, SRC showed significant beneficial effects ( p < 0.05) on feelings of being more alert, less tired, better overall mood, less jittery and less tense at several of the study time points. No safety concerns were observed. SRC showed a slow absorption and sustained plasma caffeine levels. Compared to IRC, we saw significant benefits of SRC at several of the time points on alertness, tiredness, overall mood, jitteriness and tenseness without any safety concerns.

Comparative Pharmacokinetics of a Novel, Patented Sustained Release Caffeine Versus Immediate Release Caffeine and Their Effects on Alertness & Mood

ObjectivesOral caffeine consumption results in rapid absorption with high blood levels followed by its sharp decline and is typically associated with reduction in beneficial effects of caffeine. To help extend the benefits of caffeine over a six-eight hour time period, we developed a new sustained release caffeine (SRC) formulation called XtenergyTM. The primary study objective was to compare the pharmacokinetic profile of SRC with immediate release caffeine (IRC). Secondary objectives were comparing the effects of SRC and IRC using caffeine research visual analogue scales (Caff - VAS) and evaluate its safety. MethodsTwenty-six subjects were randomized to receive 200 mg of caffeine from SRC and IRC in a double blind, single-dose, two-period, crossover study in healthy subjects under fasting state. A washout duration of 7 days was followed between the two periods. Blood samples were collected at –4, 0, 0.25, 0.50, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 & 24 hours in each period. Plasma caffeine levels were analysed using a validated LCMS/MS method. The changes in Caff-VAS for relaxed, alert, jittery, tired, tense, headache & overall mood from baseline (0) to 1, 2, 4, 6, 8, 10 & 12 hrs were evaluated. ResultsTwenty-four male subjects with mean age 32.71 ± 6.18 yrs completed the study. Median tmax was 325.53% higher (4.00 vs 0.94 hrs) and mean t1/2 was 21.34% higher (9.24 ± 4.56 vs 7.61 ± 3.98 hrs) for SRC (P < 0.05) compared to IRC, respectively. Geometric least squares means (GLSM) for AUC4–8 (11,673.52 vs 10,930.25 hr.ng/mL) & AUC6–12 (14,043.79 vs 11,432.41 hr.ng/mL) were 6.80% and 22.84% higher for SRC compared to IRC, respectively. SRC showed an equivalent total absorption as IRC based on 90% CI for AUC0–24 (43,312.07 vs 44,009.64 hr*ng/mL). SRC demonstrated significant effects (P < 0.05) on feelings of being more alert, less tired, better overall mood, less jittery & less tense compared to IRC. SRC was well tolerated with no adverse events. ConclusionsThe SRC formulation resulted in slow & sustained levels of plasma caffeine associated with feelings of being more alert, less tired, better overall mood, less jittery and less tense for longer time periods without any safety concerns. SRC could be beneficial for those involved in sustained operations demanding peak cognitive & physical performance for a longer time. Funding SourcesOmniActive Health Technologies Ltd.

Prediction of pharmacokinetic values of two various dosages of caffeine in premature neonates with apnea.

OBJECTIVES:Despite extensive caffeine use in preterm infants, the pharmacokinetics (PKs) data are limited because of the studies are complicated to do in these patients. This research was investigated the PK profile of two various dosages of caffeine in premature neonates.MATERIALS AND METHODS:The PK values of caffeine in premature neonates with Apnea were predicted by using all of computer-based simulation (Simcyp®), population-based PK, and modeling (P-Pharm®). We assayed the plasma levels of caffeine in two groups. The information was analyzed utilizing nonlinear mixed-effects modeling approach. The PK parameters were assessed simulating virtual clinical considers with subjects got 20 mg. kg−1 of caffeine in both groups, which was followed by a 5 mg. kg−1 once daily in Group 1 or 2.5 mg. kg−1 twice daily in Group 2. All statistical analysis was executed utilizing SSPS issue 19 and a P value of 0.05 was chosen significance.RESULTS:In the present study, the means CL, volume of distribution, and T1/2 of caffeine in preterm infants were 0.0476 L. h−1, 1.1081 L, 16.2284 h, respectively. Whereas our simulated means by Simcyp were 0.090 L. h−1, 1.841 L, and 14.653 h in Group 1 and 16.223 h in Group 2, respectively.CONCLUSIONS:There was overall good agreement between predicted and measured PK values in our study. This study provides an initial demonstration of Simcyp simulation advantage on anticipating of PK parameters.

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.

Study protocol: treatment with caffeine of the very preterm infant in the delivery room: a feasibility study

IntroductionEarly treatment with caffeine in the delivery room has been proposed to decrease the need for mechanical ventilation (MV) by limiting episodes of apnoea and improving respiratory mechanics in preterm...

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.