Prolongation of the gastric residence time of caffeine after administration in fed state: Comparison of effervescent granules with an extended release tablet.

The aim of the present study was to investigate the gastroretentive capacity of different formulation principles. This was indirectly determined by the absorption behavior of caffeine from the dosage forms. A slow and continuous appearance of caffeine in the saliva of healthy volunteers was used as a parameter for a prolonged gastric retention time. For this purpose, a four-way study was conducted with twelve healthy volunteers using the following test procedures: (1) Effervescent granules with 240 mL of still water administered in fed state, (2) effervescent granules with 20 mL of still water in fed state, (3) extended release (ER) tablet with 240 mL of still water in fed state, and (4) effervescent granules with 240 mL of still water in fasted state. The initial rise of the caffeine concentrations was more pronounced after the intake of the effervescent granules in the fed state compared to that of the ER tablets. However, tmax tended to be shorter in the fed study arms following administration of the ER tablet compared to the granules. Overall, the application of active pharmaceutical ingredients formulated as effervescent granules seems to be a promising approach to increase their gastric residence time after intake in fed state.

Effects of Coffee on the Gastro-Intestinal Tract: A Narrative Review and Literature Update.

The objective of the present research was to review the state of the art on the consequences of drinking coffee at the different levels of the gastrointestinal tract. At some steps of the digestive process, the effects of coffee consumption seem rather clear. This is the case for the stimulation of gastric acid secretion, the stimulation of biliary and pancreatic secretion, the reduction of gallstone risk, the stimulation of colic motility, and changes in the composition of gut microbiota. Other aspects are still controversial, such as the possibility for coffee to affect gastro-esophageal reflux, peptic ulcers, and intestinal inflammatory diseases. This review also includes a brief summary on the lack of association between coffee consumption and cancer of the different digestive organs, and points to the powerful protective effect of coffee against the risk of hepatocellular carcinoma. This review reports the available evidence on different topics and identifies the areas that would most benefit from additional studies.

Pharmacokinetic, pharmacological, and genotoxic evaluation of deuterated caffeine.

Altering caffeine's negative physiological effects and extending its duration of activity is an active area of research; however, deuteration as a means of achieving these goals is unexplored. Deuteration substitutes one or more of the hydrogen atoms of a substance with deuterium, a stable isotope of hydrogen that contains an extra neutron. Deuteration can potentially alter the metabolic profile of a substance, while maintaining its pharmacodynamic properties. d9-Caffeine is a deuterated isotopologue of caffeine with the nine hydrogens contained in the 1, 3, and 7 methyl groups of caffeine substituted with deuterium. d9-Caffeine may prove to be an alternative to caffeine that may be consumed with less frequency, at lower doses, and with less exposure to downstream active metabolites of caffeine. Characterization of d9-caffeine's genotoxic potential, pharmacodynamic, and pharmacokinetic behavior is critical in establishing how it may differ from caffeine. d9-Caffeine was non-genotoxic with and without metabolic activation in both a bacterial reverse mutation assay and a human mammalian cell micronucleus assay at concentrations up to the ICH concentration limits. d9-Caffeine exhibited a prolonged systemic and brain exposure time in rats as compared to caffeine following oral administration. The adenosine receptor antagonist potency of d9-caffeine was similar to caffeine.

Acute Effect of Caffeine on the Synthesis of Pro-Inflammatory Cytokines in the Hypothalamus and Choroid Plexus during Endotoxin-Induced Inflammation in a Female Sheep Model.

This study was designed to determine the effect of acute caffeine (CAF) administration, which exerts a broad spectrum of anti-inflammatory activity, on the synthesis of pro-inflammatory cytokines and their receptors in the hypothalamus and choroid plexus (ChP) during acute inflammation caused by the injection of bacterial endotoxin-lipopolysaccharide (LPS). The experiment was performed on 24 female sheep randomly divided into four groups: control; LPS treated (iv.; 400 ng/kg of body mass (bm.)); CAF treated (iv.; 30 mg/kg of bm.); and LPS and CAF treated. The animals were euthanized 3 h after the treatment. It was found that acute administration of CAF suppressed the synthesis of interleukin (IL-1ß) and tumor necrosis factor (TNF)α, but did not influence IL-6, in the hypothalamus during LPS-induced inflammation. The injection of CAF reduced the LPS-induced expression of TNF mRNA in the ChP. CAF lowered the gene expression of IL-6 cytokine family signal transducer (IL6ST) and TNF receptor superfamily member 1A (TNFRSF1) in the hypothalamus and IL-1 type II receptor (IL1R2) in the ChP. Our study on the sheep model suggests that CAF may attenuate the inflammatory response at the hypothalamic level and partly influence the inflammatory signal generated by the ChP cells. This suggests the potential of CAF to suppress neuroinflammatory processes induced by peripheral immune/inflammatory challenges.

Habitual caffeine consumption moderates the antidepressant effect of dorsomedial intermittent theta-burst transcranial magnetic stimulation.

BACKGROUND: Potentiating current antidepressant treatment is much needed. Based on animal studies, caffeine may augment the effects of currently available antidepressants. OBJECTIVE: Here, we tested whether habitual caffeine consumption moderates the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS) using intermittent theta-burst stimulation (iTBS). METHODS: Forty patients with current depressive episodes were randomized to active iTBS (n = 19) or sham treatment (n = 21; shielded side of the coil and weak transcutaneous electrical stimulation) delivered two times per day for 10-15 weekdays. Neuronavigated stimulation was applied to the dorsomedial prefrontal cortex. Symptom improvement was measured using change in self-reported Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Pretreatment habitual caffeine consumption was quantified using self-reports of number of cups of coffee and energy drinks consumed the 2 days before the treatment starts. RESULTS: Habitual caffeine consumption was associated with symptom improvement following active iTBS (r = 0.51, 95% confidence interval (CI): 0.08-0.78, p = 0.025) but not following sham treatment (r = -0.02, 95% CI: -0.45 to 0.42, p = 0.938). A multiple regression analysis corroborated the findings by showing a significant caffeine consumption × treatment group interaction (ß = 0.62, p = 0.043), but no main effects of treatment group (ß = 0.22, p = 0.140) or caffeine consumption (ß = -0.01, p = 0.948). No group differences in pretreatment symptom scores or caffeine consumption were detected (p values > 0.86). CONCLUSION: Habitual caffeine consumption moderated the antidepressant effect of dorsomedial iTBS, consistent with caffeine improving antidepressant pharmacological treatments in animals. Caffeine is an antagonist of adenosine receptors and may enhance antidepressant effects through downstream dopaminergic targets.

A novel bedtime pulsatile-release caffeine formula ameliorates sleep inertia symptoms immediately upon awakening.

Sleep inertia is a disabling state of grogginess and impaired vigilance immediately upon awakening. The adenosine receptor antagonist, caffeine, is widely used to reduce sleep inertia symptoms, yet the initial, most severe impairments are hardly alleviated by post-awakening caffeine intake. To ameliorate this disabling state more potently, we developed an innovative, delayed, pulsatile-release caffeine formulation targeting an efficacious dose briefly before planned awakening. We comprehensively tested this formulation in two separate studies. First, we established the in vivo caffeine release profile in 10 young men. Subsequently, we investigated in placebo-controlled, double-blind, cross-over fashion the formulation's ability to improve sleep inertia in 22 sleep-restricted volunteers. Following oral administration of 160 mg caffeine at 22:30, we kept volunteers awake until 03:00, to increase sleep inertia symptoms upon scheduled awakening at 07:00. Immediately upon awakening, we quantified subjective state, psychomotor vigilance, cognitive performance, and followed the evolution of the cortisol awakening response. We also recorded standard polysomnography during nocturnal sleep and a 1-h nap opportunity at 08:00. Compared to placebo, the engineered caffeine formula accelerated the reaction time on the psychomotor vigilance task, increased positive and reduced negative affect scores, improved sleep inertia ratings, prolonged the cortisol awakening response, and delayed nap sleep latency one hour after scheduled awakening. Based on these findings, we conclude that this novel, pulsatile-release caffeine formulation facilitates the sleep-to-wake transition in sleep-restricted healthy adults. We propose that individuals suffering from disabling sleep inertia may benefit from this innovative approach.Trials registration: NCT04975360.

A MULTIFACTORIAL APPROACH FOR IMPROVING THE SURGICAL PERFORMANCE OF NOVICE VITREORETINAL SURGEONS.

PURPOSE: To quantitatively analyze and compare the novice vitreoretinal surgeons' performance after various types of external exposures. METHODS: This prospective, self-controlled, cross-sectional study included 15 vitreoretinal fellows with less than 2 years of experience. Surgical performance was assessed using the Eyesi simulator after each exposure: Day 1, placebo, 2.5, and 5 mg/kg caffeine; Day 2, placebo, 0.2, and 0.6 mg/kg propranolol; Day 3, baseline simulation, breathalyzer reading of 0.06% to 0.10% and 0.11% to 0.15% blood alcohol concentration; Day 4, baseline simulation, push-up sets with 50% and 85% repetition maximum; Day 5, 3-hour sleep deprivation. Eyesi-generated total scores were the main outcome measured (0-700, worst to best). RESULTS: Performances worsened after increasing alcohol exposure based on the total score (χ2 = 7; degrees of freedom = 2; P = 0.03). Blood alcohol concentration 0.06% to 0.10% and 0.11% to 0.15% was associated with diminished performance compared with improvements after propranolol 0.6 and 0.2 mg/kg, respectively (∆1 = -22 vs. ∆2 = +13; P = 0.02; ∆1 = -43 vs. ∆2 = +23; P = 0.01). Propranolol 0.6 mg/kg was positively associated with the total score, compared with deterioration after 2.5 mg/kg caffeine (∆1 = +7 vs. ∆2 = -13; P = 0.03). CONCLUSION: Surgical performance diminished dose dependently after alcohol. Caffeine 2.5 mg/kg was negatively associated with dexterity, and performance improved after 0.2 mg/kg propranolol. No changes occurred after short-term exercise or acute 3-hour sleep deprivation.

Caffeine-induced inversion of prostaglandin E2 effects on hepatic stellate cell activation.

BACKGROUND AND AIMS: Liver inflammation leads to the activation of hepatic stellate cells (HSCs), resulting in the development of liver fibrosis. The present study aimed to investigate the effects of prostaglandin E2 (PGE2), which is biosynthesized by Kupffer cells, hepatocytes, and HSCs during inflammation, on HSC activation, including its combinatory effect with caffeine. METHODS: HSCs isolated from mice were activated by culturing in a medium supplemented with 10% fetal bovine serum for 7 days on plastic plates. The activation of HSCs was evaluated by immunofluorescence of α-smooth muscle actin in HSCs. Comprehensive gene expression analysis was performed using mRNA-sequencing to compare HSCs cultured for 1 or 7 days, with or without PGE2, caffeine, or both. RESULTS: PGE2 (1 µM) facilitated the activation of HSCs but inhibited the HSC activation in the presence of caffeine (3 mM). Comprehensive gene expression analysis revealed that HSCs treated with PGE2 in the presence of caffeine were classified in the same class as HSCs cultured for 1 day, i.e., quiescent HSCs. In contrast, PGE2 did not exhibit an inhibitory effect on HSC activation when co-treated with any isoform-specific phosphodiesterase inhibitors. Although the adenylate cyclase inhibitor 2',5'-dideoxyadenosine suppressed the elevation of intracellular cAMP level induced by PGE2 in the presence of caffeine, it had no effect on the inhibition of HSC activation by PGE2 plus caffeine. CONCLUSION: The effect of PGE2 on HSC activation is changed from facilitatory to inhibitory when combined with caffeine, suggesting that caffeine may effectively suppress liver fibrosis during inflammation.

Health behaviours in 131,182 UK women planning pregnancy.

BACKGROUND: A woman's health at the time of conception lays the foundation for a healthy pregnancy and the lifelong health of her child. We investigated the health behaviours of UK women planning pregnancy. METHODS: We analysed survey data from the 'Planning for Pregnancy' online tool (Tommy's, UK). We described all women planning pregnancy and compared the frequency of non-adherence to preconception recommendations in women who had already stopped contraception (active planners) and those who had not (non-active planners). RESULTS: One hundred thirty-one thousand one hundred eighty-two women from across the UK were included, of whom 64.8% were actively planning pregnancy. Of the whole cohort, twenty percent were smokers and less than one third took folic acid supplements (31.5%). Forty two percent engaged in less than the recommended 150 min of weekly physical activity and only 53.3% consumed five portions of fruit or vegetables 4 days a week. Smokers were 1.87 times more likely to be active planners than non-smokers (95% CI 1.79-1.94), and women who took folic acid were 7 times more likely to be active planners (95% CI 6.97-7.59) compared to women who did not. Smoking, drug use and lack of folic acid supplementation were common in younger women and those who were underweight. CONCLUSIONS: This unique survey of UK women has identified poor adherence to preconception recommendations in those planning pregnancies and supports the need for a greater public health focus on preconception health. This study provides a contemporary basis from which to inform preconception health advice and a benchmark to measure changes over time.

Acute caffeine ingestion improves 3-km run performance, cognitive function, and psychological state of young recreational runners.

The current study aimed to assess the effects of caffeine administration on performance time, cognition, psychomotor state, and blood levels of oxidative stress markers following a 3-km run competition. Thirteen recreational runners performed two test sessions in a double-blind randomized order after placebo or 3 mg/kg of body mass of caffeine. At each session, subjects completed a 3-km running competition around a 400 m outdoor athletics track. Cognitive tasks (attention and reaction time), psychological tests (Feeling scale and Hooper), and blood collection were carried out before and after the run. In comparison with placebo, caffeine ingestion enhanced the 3-km performance time by 1.1% (p < 0.001) (10.13 ± 0.69 min versus 10.25 ± 0.72 min), improved attention by 15.6% (p < 0.001) and reaction-time by 5.9% (p < 0.05), increased good-feeling by 15.7% (p < 0.01), and lowered stress-feeling by 17.6% (p < 0.01) and pain-sensation by 11.3% (p < 0.05). However, no significant effects of caffeine were observed on oxidative stress markers. Only exercise resulted in increased levels of glutathione peroxidase (GPX) (12.2%, 8.8%) (p < 0.05), reduced glutathione (GSH) (17.6%, 10.1%) (p < 0.05), superoxide dismutase (SOD) (7.6%, 6.5%) (p < 0.05) and malondialdehyde (MDA) (10.3%, 9.6%) (p < 0.05), for both the placebo and caffeine groups respectively. In conclusion, our study highlighted that the consumption of 3 mg/kg caffeine could be an improving agent for the physical, cognitive, and psychological states without affecting the oxidative stress state during such a running competition.

Napabucasin Drug-Drug Interaction Potential, Safety, Tolerability, and Pharmacokinetics Following Oral Dosing in Healthy Adult Volunteers.

Napabucasin is an orally administered reactive oxygen species generator that is bioactivated by the intracellular antioxidant nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1. Napabucasin induces cell death in cancer cells, including cancer stem cells. This phase 1 study (NCT03411122) evaluated napabucasin drug-drug interaction potential for 7 cytochrome P450 (CYP) enzymes and the breast cancer resistance protein transporter/organic anion transporter 3. Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1-11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9). Drug-drug interaction potential was evaluated in 17 of 30 enrolled volunteers. Napabucasin coadministration increased the area under the plasma concentration-time curve from time 0 extrapolated to infinity (geometric mean ratio [90% confidence interval]) of caffeine (124% [109.0%-141.4%]), intravenous midazolam (118% [94.4%-147.3%]), repaglinide (127% [104.7%-153.3%]), and rosuvastatin (213% [42.5%-1068.3%]) and decreased the area under the plasma concentration-time curve from time 0 extrapolated to infinity of dextromethorphan (71% [47.1%-108.3%]), bupropion (79% [64.6%-97.0%]), and hydroxybupropion (45% [15.7%-129.6%]). No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree.

The Effects of Intraoperative Caffeine on Postoperative Opioid Consumption and Related Outcomes After Laparoscopic Surgery: A Randomized Controlled Trial.

BACKGROUND: Surgical patients are vulnerable to opioid dependency and related risks. Clinical-translational data suggest that caffeine may enhance postoperative analgesia. This trial tested the hypothesis that intraoperative caffeine would reduce postoperative opioid consumption. The secondary objective was to assess whether caffeine improves neuropsychological recovery postoperatively. METHODS: This was a single-center, randomized, placebo-controlled trial. Participants, clinicians, research teams, and data analysts were all blinded to the intervention. Adult (≥18 years old) surgical patients (n = 65) presenting for laparoscopic colorectal and gastrointestinal surgery were randomized to an intravenous caffeine citrate infusion (200 mg) or dextrose 5% in water (40 mL) during surgical closure. The primary outcome was cumulative opioid consumption through postoperative day 3. Secondary outcomes included subjective pain reporting, observer-reported pain, delirium, Trail Making Test performance, depression and anxiety screens, and affect scores. Adverse events were reported, and hemodynamic profiles were also compared between the groups. RESULTS: Sixty patients were included in the final analysis, with 30 randomized to each group. The median (interquartile range) cumulative opioid consumption (oral morphine equivalents, milligrams) was 77 mg (33-182 mg) for caffeine and 51 mg (15-117 mg) for placebo (estimated difference, 55 mg; 95% confidence interval [CI], -9 to 118; P = .092). After post hoc adjustment for baseline imbalances, caffeine was associated with increased opioid consumption (87 mg; 95% CI, 26-148; P = .005). There were otherwise no differences in prespecified pain or neuropsychological outcomes between the groups. No major adverse events were reported in relation to caffeine, and no major hemodynamic perturbations were observed with caffeine administration. CONCLUSIONS: Caffeine appears unlikely to reduce early postoperative opioid consumption. Caffeine otherwise appears well tolerated during anesthetic emergence.

Habitual Caffeine Consumption Does Not Interfere With the Acute Caffeine Supplementation Effects on Strength Endurance and Jumping Performance in Trained Individuals.

The long-standing caffeine habituation paradigm was never investigated in strength endurance and jumping exercise performance through a straightforward methodology. The authors examined if habitual caffeine consumption would influence the caffeine ergogenic effects on strength endurance and jumping performance as well as perceptual responses. Thirty-six strength-trained individuals were mathematically allocated into tertiles according to their habitual caffeine consumption: low (20 ± 11 mg/day), moderate (88 ± 33 mg/day), and high consumers (281 ± 167 mg/day). Then, in a double-blind, crossover, counterbalanced fashion, they performed a countermovement vertical jump test and a strength endurance test either after caffeine (6 mg/kg) and placebo supplementation or after no supplementation (control). Perceptual responses such as ratings of perceived exertion and pain were measured at the termination of the exercises. Acute caffeine supplementation improved countermovement vertical jump performance (p = .001) and total repetitions (p = .004), regardless of caffeine habituation. Accordingly, analysis of absolute change from the control session showed that caffeine promoted a significantly greater improvement in both countermovement vertical jump performance (p = .004) and total repetitions (p = .0001) compared with placebo. Caffeine did not affect the rating of perceived exertion and pain in any exercise tests, irrespective of tertiles (for all comparisons, p > .05 for both measures). Caffeine side effects were similar in low, moderate, and high caffeine consumers. These results show that habitual caffeine consumption does not influence the potential of caffeine as an ergogenic aid in strength endurance and jumping exercise performance, thus challenging recommendations to withdraw from the habitual caffeine consumption before supplementing with caffeine.

Caffeinated energy drinks in the Canadian context: health risk assessment with a focus on cardiovascular effects.

In Canada, caffeinated energy drinks (CEDs) currently sold under Temporary Marketing Authorizations must meet strict eligibility criteria. These criteria, which include compositional and labelling requirements, were developed based on the outcome of a health risk assessment conducted by Health Canada (HC) in 2013. HC updated its assessment by reviewing new information with the focus on potential cardiovascular effects associated with the consumption of CEDs available for sale in Canada. Due to limited data on CED consumption among Canadians to derive accurate exposure information, the composition of a typical CED was characterized to assess the potential effects of single ingredients and synergistic interactions between ingredients on the cardiovascular system. Surveillance data on potential adverse effects related to CED consumption was also analyzed. After extensive review, HC's updated assessment confirms the current risk management approach for CEDs is health protective for Canadian consumers, including the potential for cardiovascular effects. The available evidence supports that moderate consumption (up to 500 mL per day) of a typical CED authorized for sale in Canada is safe for the general population of healthy adults and adolescents. It also re-confirms that vulnerable sub-populations (i.e., children, pregnant and/or breastfeeding women, and caffeine-sensitive individuals) should not consume CEDs. Novelty: Consumption up to 500 mL per day of a typical CED is not associated with an increased risk of cardiovascular effects. Children, pregnant and/or breastfeeding women, and caffeine-sensitive individuals should not consume CEDs.

Consumption of caffeinated beverages and kidney function decline in an elderly Mediterranean population with metabolic syndrome.

It remains unclear whether caffeinated beverages could have deleterious renal effects in elderly population with underlying comorbid conditions. We investigated the associations between coffee, tea, or caffeine intake and 1-year changes in glomerular filtration rate (eGFR) in a large Spanish cohort of overweight/obese elderly with metabolic syndrome (MetS). This prospective analysis includes 5851 overweight/obese adults (55-75 years) with MetS from the PREDIMED-Plus study. We assessed coffee, tea, and caffeine consumption from a validated food-frequency questionnaire and creatinine-based eGFR using the Chronic Kidney Disease Epidemiology Collaboration equation. Multivariate-adjusted regression models were applied to test associations between baseline coffee, tea, or caffeine intake and 1-year eGFR changes. Caffeinated coffee (> 2 cups/day) and tea (at least 1 cup/day) drinkers had 0.88 and 0.93 mL/min/1.73 m2 greater eGFR decrease respectively, compared to those with less than 1 cup/day of coffee consumption or non-tea drinkers. Furthermore, caffeinated coffee consumption of > 2 cups/day was associated with 1.19-fold increased risk of rapid eGFR decline > 3 mL/min/1.73 m2 (95% CI 1.01-1.41). Similarly, individuals in the highest (median, 51.2 mg/day) tertile of caffeine intake had a 0.87 mL/min/1.73 m2 greater eGFR decrease. Decaffeinated coffee was not associated with eGFR changes. In conclusion, higher consumption of caffeinated coffee, tea, and caffeine was associated with a greater 1-year eGFR decline in overweight/obese adults with MetS.

Genetic Determinants of Neurobehavioral Responses to Caffeine Administration during Sleep Deprivation: A Randomized, Cross Over Study (NCT03859882).

This study investigated whether four single nucleotide polymorphisms (SNPs) moderated caffeine effects on vigilance and performance in a double-blind and crossover total sleep deprivation (TSD) protocol in 37 subjects. In caffeine (2 × 2.5 mg/kg/24 h) or placebo-controlled condition, subjects performed a psychomotor vigilance test (PVT) and reported sleepiness every six hours (Karolinska sleepiness scale (KSS)) during TSD. EEG was also analyzed during the 09:15 PVT. Carriers of the TNF-α SNP A allele appear to be more sensitive than homozygote G/G genotype to an attenuating effect of caffeine on PVT lapses during sleep deprivation only because they seem more degraded, but they do not perform better as a result. The A allele carriers of COMT were also more degraded and sensitive to caffeine than G/G genotype after 20 h of sleep deprivation, but not after 26 and 32 h. Regarding PVT reaction time, ADORA2A influences the TSD effect but not caffeine, and PER3 modulates only the caffeine effect. Higher EEG theta activity related to sleep deprivation was observed in mutated TNF-α, PER3, and COMT carriers, in the placebo condition particularly. In conclusion, there are genetic influences on neurobehavioral impairments related to TSD that appear to be attenuated by caffeine administration. (NCT03859882).

Arterial stiffness is not acutely modified by consumption of a caffeinated soft drink sweetened with high-fructose corn syrup in young healthy adults.

We tested the hypothesis that ingestion of a caffeinated soft drink sweetened with high-fructose corn syrup acutely increases arterial stiffness. In a randomized counterbalanced, crossover design, fourteen healthy adults (25 ± 3 years, 6 women) reported to the laboratory for two experimental visits where 500 ml of tap water (H2 O) or 500 ml of Mountain Dew® (a caffeinated soft drink sweetened with high-fructose corn syrup (HFCS)) were consumed. Arterial stiffness (carotid-to-femoral pulse wave velocity (cfPWV)), peripheral and central blood pressures were measured pre-consumption, 30 min post-consumption, and 120 min post-consumption. Prior to each measurement period, beat-to-beat hemodynamic measures were collected. Changes in heart rate, blood pressure, and cardiac output from pre-consumption did not differ between trials at any timepoint (p ≥ 0.06). Moreover, changes in peripheral or central blood pressures from pre-consumption did not differ between trials (p ≥ 0.84). Likewise, changes in cfPWV from pre-consumption to 30 min post-consumption (HFCS: 0.2 ± 0.3 m/s, H2 O: 0.0 ± 0.3 m/s, p = 0.34) and 120 min post-consumption (HFCS: 0.3 ± 0.4 m/s, H2 O: 0.2 ± 0.3 m/s, p = 0.77) did not differ. Changes in aortic augmentation pressure, augmentation index, augmentation index corrected to a heart rate of 75 bpm, and reflection magnitude did not differ between conditions at 30 min post- (p ≥ 0.55) or 120 min post- (p ≥ 0.18) consumption. In healthy young adults, ingesting 500 ml of a commercially available caffeinated soft drink sweetened with high-fructose corn syrup does not acutely change indices of arterial stiffness and wave reflection.

Pharmacodynamic Effects of Standard versus High Caffeine Doses in the Developing Brain of Neonatal Rats Exposed to Intermittent Hypoxia.

(1) Background: Caffeine citrate, at standard doses, is effective for reducing the incidence of apnea of prematurity (AOP) and may confer neuroprotection and decrease neonatal morbidities in extremely low gestational age neonates (ELGANs) requiring oxygen therapy. We tested the hypothesis that high-dose caffeine (HiC) has no adverse effects on the neonatal brain. (2) Methods: Newborn rat pups were randomized to room air (RA), hyperoxia (Hx) or neonatal intermittent hypoxia (IH), from birth (P0) to P14 during which they received intraperitoneal injections of LoC (20 mg/kg on P0; 5 mg/kg/day on P1-P14), HiC (80 mg/kg; 20 mg/kg), or equivalent volume saline. Blood gases, histopathology, myelin and neuronal integrity, and adenosine receptor reactivity were assessed. (3) Results: Caffeine treatment in Hx influenced blood gases more than treatment in neonatal IH. Exposure to neonatal IH resulted in hemorrhage and higher brain width, particularly in layer 2 of the cerebral cortex. Both caffeine doses increased brain width in RA, but layer 2 was increased only with HiC. HiC decreased oxidative stress more effectively than LoC, and both doses reduced apoptosis biomarkers. In RA, both caffeine doses improved myelination, but the effect was abolished in Hx and neonatal IH. Similarly, both doses inhibited adenosine 1A receptor in all oxygen environments, but adenosine 2A receptor was inhibited only in RA and Hx. (4) Conclusions: Caffeine, even at high doses, when administered in normoxia, can confer neuroprotection, evidenced by reductions in oxidative stress, hypermyelination, and increased Golgi bodies. However, varying oxygen environments, such as Hx or neonatal IH, may alter and modify pharmacodynamic actions of caffeine and may even override the benefits caffeine.

Coffee Consumption and Cancer Risk: An Assessment of the Health Implications Based on Recent Knowledge.

A significant number of studies suggest that coffee consumption reduces cancer risk. This beneficial effect is usually ascribed to the presence of polyphenolic antioxidants and anti-inflammatory agents, including caffeine, cafestol, kahweol, and chlorogenic acids. To summarize recent literature on this subject, we performed a bibliographic search in PubMed and Embase over the period January 2005 to December 2020 to identify cohort studies and meta-analysis (with data collection ensuring quality of selected reports) that could provide quantitative data on the relationship between coffee consumption and common cancers. The totality of eligible scientific articles supports the evidence that coffee intake is inversely associated with risk of hepatocellular cancer and, to a slight extent, risk of breast cancer among postmenopausal women. As to the association with other organs, including the esophagus, pancreas, colorectum, kidneys, bladder, ovaries, and prostate, the results are less clear as reports reveal conflicting results or statistically nonsignificant data. Therefore, this overview does not provide broad-based conclusions. Important uncertainties include general study design, inhomogeneous patient sampling, different statistical analysis (deliberate), misreporting of socioeconomic status, education, coffee-brewing methods, consumption of caffeinated or decaffeinated coffee, smoking habits, and alcohol intake. Clearly, more epidemiologic research needs to be conducted before solid science-based recommendations can be made with regard to coffee consumption.

Methylxanthines and Neurodegenerative Diseases: An Update.

Methylxanthines (MTX) are purine derived xanthine derivatives. Whereas naturally occurring methylxanthines like caffeine, theophylline or theobromine are widely consumed in food, several synthetic but also non-synthetic methylxanthines are used as pharmaceuticals, in particular in treating airway constrictions. Besides the well-established bronchoprotective effects, methylxanthines are also known to have anti-inflammatory and anti-oxidative properties, mediate changes in lipid homeostasis and have neuroprotective effects. Known molecular mechanisms include adenosine receptor antagonism, phosphodiesterase inhibition, effects on the cholinergic system, wnt signaling, histone deacetylase activation and gene regulation. By affecting several pathways associated with neurodegenerative diseases via different pleiotropic mechanisms and due to its moderate side effects, intake of methylxanthines have been suggested to be an interesting approach in dealing with neurodegeneration. Especially in the past years, the impact of methylxanthines in neurodegenerative diseases has been extensively studied and several new aspects have been elucidated. In this review we summarize the findings of methylxanthines linked to Alzheimer´s disease, Parkinson's disease and Multiple Sclerosis since 2017, focusing on epidemiological and clinical studies and addressing the underlying molecular mechanisms in cell culture experiments and animal studies in order to assess the neuroprotective potential of methylxanthines in these diseases.