No psychophysiological interactions between caffeine and stress?

In earlier studies, the predominantly-adrenergic effects of mental tasks and the -adrenergic effects of caffeine on cardiovascular functions were observed to be simply additive without interaction. In the present study, annoying electrical shocks were superimposed on a mental task affording either active coping, which specifically raises-adrenergic activation, or passive coping, and the 40 female subjects were preselected so as to differ in subjective stress susceptibility. Caffeine as well as the type of coping and the considered personality dimension produced significant effects, but almost no interactions were obtained. The stress resistant subjects, who tended toward more extraversion, emotional stability and more masculinity, had lower anxiety scores, rated their performance higher and had a greater cardiac output than the stress non-resistant subjects, who represented a rather normal population according to the FPI personality dimensions. Caffeine increased EEG alpha and beta frequency and delta power and decreased beta power, raised blood pressure and enhanced stress reactions in respiration amplitude and pre-ejection period. Active stress coping induced greater stress reactions in heart rate (increase), left ventricular ejection time (decrease) and ear pulse arrival time (decrease) than passive coping.     

Boiled or filtered coffee? Effects of coffee and caffeine on cholesterol, fibrinogen and C-reactive protein

Caffeine is the most widely consumed psychostimulant drug in the world that mostly is consumed in the form of coffee. Whether caffeine and/or coffee consumption contribute to the development of cardiovascular disease (CVD), the single leading cause of death in the US, is unclear.This article examines the effects of caffeine intake, both alone and via coffee consumption, on key blood markers of CVD risk: lipoproteins (cholesterol, triglycerides), fibrinogen (a biomarker of blood clotting) and C-reactive protein (CRP; a biomarker of inflammation). These blood markers and their role in the development of CVD are reviewed first. Studies examining caffeine and coffee effects on each of these blood markers are then presented. Next, biobehavioural moderators of the relationship between caffeine and/or coffee consumption and CVD are discussed, including genetics, sex and tobacco smoking.The literature indicates a strong relationship between boiled, unfiltered coffee consumption and elevated cholesterol levels; however, there is a critical gap in the literature regarding the effects of coffee or caffeine consumption on fibrinogen or CRP, which is an independent predictor of CVD risk. Available studies are limited by small samples sizes, inclusion of only men (or few women) and unrepresented age or ethnic groups. Thiere is a critical need for controlled laboratory and epidemiological studies that include fibrinogen and CRP markers of CVD risk before conclusions can be drawn regarding the health effects of caffeine and/or coffee in a normal, healthy population of men and women.     

Simultaneous quantitation of paracetamol,caffeine, pseudoephedrine,chlorpheniramine and cloperastine in human plasma by liquid chromatography–tandem mass spectrometry

A rapid and sensitive method based on liquid chromatography–tandem mass spectrometry (LC–MS/MS) for the simultaneous quantitation of paracetamol, caffeine, pseudoephedrine, chlorpheniramine and cloperastine in human plasma has been developed and validated. After sample preparation by liquid–liquid extraction, the analytes and internal standard (diphenhydramine) were analyzed by reversed-phase HPLC on a Venusil Mp-C₁₈ column (50 mm × 4.6 mm, 5 μm) using formic acid:10 mM ammonium acetate:methanol (1:40:60, v/v/v) as mobile phase in a run time of 2.6 min. Detection was carried out by electrospray positive ionization mass spectrometry in the multiple-reaction monitoring mode. The method was linear for all analytes over the following concentration (ng/ml) ranges: paracetamol 5.0–2000; caffeine 10–4000; pseudoephedrine 0.25–100; chlorpheniramine 0.05–20; cloperastine 0.10–40. Intra- and inter-day precisions (as relative standard deviation) were all ≤11.3% with accuracy (as relative error) of ±5.0%. The method was successfully applied to a study of the pharmacokinetics of the five analytes after administration of a combination oral dose to healthy Chinese volunteers.     

Cognitive and physiological effects of an “energy drink”: an evaluation of the whole drink and of glucose, caffeine and herbal flavouring fractions

Rationale Both glucose and caffeine can improve aspects of cognitive performance and, in the case of caffeine, mood. There are few studies investigating the effects of the two substances in combination.Objectives We assessed the mood, cognitive and physiological effects of a soft drink containing caffeine and glucose as well as flavouring levels of herbal extracts. The effects of different drink fractions were also evaluated.Methods Using a randomised, double-blind, balanced, five-way crossover design, 20 participants who were overnight fasted and caffeine-deprived received 250 ml drinks containing 37.5 g glucose; 75 mg caffeine; ginseng and ginkgo biloba at flavouring levels; a whole drink (containing all these substances) or a placebo (vehicle). Participants were assessed in each drink condition, separated by a 7-day wash-out period. Cognitive, psychomotor and mood assessment took place immediately prior to the drink then 30 min thereafter. The primary outcome measures included five aspects of cognitive performance from the Cognitive Drug Research assessment battery. Mood, heart rate and blood glucose levels were also monitored.Results Compared with placebo, the whole drink resulted in significantly improved performance on secondary memory and speed of attention factors. There were no other cognitive or mood effects.Conclusions This pattern of results would not be predicted from the effects of glucose and caffeine in isolation, either as seen here or from the literature addressing the effects of the substances in isolation. These data suggest that there is some degree of synergy between the cognition-modulating effects of glucose and caffeine which merits further investigation.     

Determination of caffeine and five metabolites simultaneously by HPLC and application on evaluating the activity of CYP1A2, CYP2A6, NAT2 and XO in Chinese healthy volunteers

HPLC同时检测咖啡因及其代谢产物并在健康中国人群中CYP1A2,CYP2A6,NATR和XO酶活性评价中的应用@陈尧$Pharmacogenetics Research Institute, Central South University!Changsha 410078, Hunan, China @欧阳冬生$Pharmacogenetics Research Institute, Central South Univer     

Does caffeine counteract alcohol-induced impairment? The ironic effects of expectancy

OBJECTIVE: Studies have shown that expectations of alcohol-induced impairment can produce adaptive responses to alcohol that reduce the degree of behavioral impairment displayed. The present study tested psychomotor performance following combined caffeine and alcohol administration in 42 social drinkers (23 men). Subjects were led to expect either that caffeine would antagonize alcohol-induced impairment or that it would have no effect. The study tested the hypothesis that drinkers who expected an antagonist effect of caffeine would display greater alcohol impairment than those who expected no antagonist effect. METHOD: Groups practiced a pursuit rotor task and received a moderate dose of alcohol (0.65 g/kg) combined with either 4.0 mg/kg caffeine or placebo caffeine. Some groups were led to expect that caffeine would counteract the impairing effect of alcohol and others were led to expect no counteracting effect. Psychomotor performance was then tested over a 3-hour period. RESULTS: In accord with the hypothesis, groups led to expect counteracting effects of caffeine displayed greater impairment than those led to expect no counteraction. Caffeine had no significant antagonist effect on alcohol impairment. CONCLUSIONS: The findings suggest that compensation for alcohol impairment occurs when drinkers hold clear expectations that the drug will disrupt performance. When no such clear expectation exists, no compensatory response occurs and the impairing effects of alcohol are observed.     

Hydrolysis of Carbonates,Thiocarbonates, Carbamates,and Carboxylic Esters of α-Naphthol, β-Naphthol,and p-Nitrophenol by Human,Rat, and Mouse Liver Carboxylesterases

Thirty carbonates, thiocarbonates, carbamates, and carboxylic esters of -naphthol, -naphthol, and p-nitrophenol were synthesized and tested as substrates for liver carboxylesterases from the crude microsomal fractions of human and mouse, and purified isozymes, hydrolases A and B, from rat liver microsomes. The carbonates, thiocarbonates, and carboxylic esters of -naphthol were cleaved more rapidly than the corresponding -naphthol isomers by the mammalian liver esterases. -Naphthyl esters of acetic, propionic, and butyric acids were among the best substrates tested for these enzymes. The majority of the substrates was consistently hydrolyzed at higher rates by hydrolase B compared with hydrolase A, although the Michaelis–Menten constant (K _m) values of selected substrates differed widely with these two isozymes. Malathion was a 15-fold better substrate for hydrolase B than for hydrolase A. Compared with the corresponding carboxylates, the carbonate moiety of - and -naphthol and p-nitrophenol lowered the specific activities of the enzymes by about fivefold but improved stability under basic conditions. The optimum pH of mouse liver esterase with the acetate, methylcarbonate, and ethylthiocarbonate of -naphthol was between pH 7.0 and pH 7.6. Human and mouse liver microsomal esterase activities were about five orders of magnitude lower than the esterase activities of purified rat liver hydrolase B. A relationship between the catalytic activity of the enzymes and the lipophilicity of the naphthyl substrates indicated that (i) in the - and -naphthyl carbonate series, an inverse relationship between enzyme activity and lipophilicity of the substrates was observed, whereas (ii) in the -naphthyl carboxylate series, an increase in enzyme activity with increasing lipophilicity of the substrates up to a log P value of about 4.0 was observed, after which the enzyme activity decreased.     

Methylene blue and vasoplegia: who, when, and how?

Systemic inflammatory response can be associated with clinically significant and, at times, refractory hypotension. Despite the lack of uniform definitions, this condition is frequently called vasoplegia or vasoplegic syndrome (VS), and is thought to be due to dysregulation of endothelial homeostasis and subsequent endothelial dysfunction secondary to direct and indirect effects of multiple inflammatory mediators. Vasoplegia has been observed in all age groups and in various clinical settings, such as anaphylaxis (including protamine reaction), sepsis, hemorrhagic shock, hemodialysis, and cardiac surgery. Among mechanisms thought to be contributory to VS, the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway appears to play a prominent role. In search of effective treatment for vasoplegia, methylene blue (MB), an inhibitor of nitric oxide synthase (NOS) and guanylate cyclase (GC), has been found to improve the refractory hypotension associated with endothelial dysfunction of VS. There is evidence that MB may indeed be effective in improving systemic hemodynamics in the setting of vasoplegia, with reportedly few side effects. This review describes the current state of clinical and experimental knowledge relating to MB use in the setting of VS, highlighting the potential risks and benefits of therapeutic MB administration in refractory hypotensive states.     

Does caffeine reverse the EAC cell‐induced immune suppression?

The aim of this study was to investigate the effect of long-term consumption of caffeine in the development of Ehrlich ascites carcinoma (EAC) cells in adult female mice, 25-30 g, in relation to immune response. Mice were treated with caffeine (20 mgkg(-1) daily, p.o.) for 22-27 consecutive days or inoculated with EAC cells (5 x 10(6) cells/mL, i.p.), or both. Control mice, corresponding to experimental groups, were treated with corresponding vehicles under similar conditions. The lymphocyte viability, mitogen-induced proliferating activity, cytotoxicity and DNA fragmentation from blood, spleen and thymus of both control and experimental groups were measured as immune response parameters. An immune response index, corticosterone, was also measured in adrenals and plasma under similar conditions. Results showed that development of EAC cells caused immune suppression with a reduction of lymphocyte viability, cytotoxicity and proliferative activity and induction of DNA fragmentation in those tissues, as well as an increase in plasma corticosterone. Though long-term caffeine treatment (which resulted in tolerance to caffeine) alone did not alter significantly any of the immune response parameters studied, including corticosterone status (immune biomarker), the continuation of caffeine treatment during the development of EAC cells either restored or reduced the EAC cell-induced alteration in these parameters, including the HPA axis biomarker. These results suggest that long-term caffeine intake may inhibit or reverse the EAC cell-induced immune suppression.     

Radiolabeled absorption, distribution, metabolism, and excretion studies in drug development: why, when, and how?

Absorption, distribution, metabolism, and excretion (ADME) studies are an integral part of the comprehensive safety evaluation of a new molecular entity, and they represent a standard suite of studies included in the registration package for all new small molecule drugs. In vivo studies in preclinical toxicology species and humans using radiolabeled ((3)H or (14)C) compound provide quantitative assessments of overall routes of excretion of drug-related material, pharmacokinetics of total drug-derived radioactivity in circulation, relative to parent compound and quantitation, and characterization of metabolites in excreta and circulation. These data serve as the starting point for metabolite in safety testing (MIST). These studies involve the administration of a radiolabeled drug to laboratory animals and humans followed by a quantitative collection of excreta and blood. Using appropriate plasma-pooling strategies, these studies could allow for modeling the metabolite exposure at the steady state. Information from the radiolabeled human study is used to design clinical drug-drug interaction (DDI) studies and to obtain a waiver for bioequivalence studies. This article describes the various aspects of conducting ADME studies and the use of radiolabeled analogues of drug candidates to investigate their metabolism and how to compare the exposures of metabolites in humans and toxicology species.     

Hexavalent chromium induced ROS formation,Akt, NF-κB,and MAPK activation,and TNF-α and IL-1α production in keratinocytes

In certain cell types, it has been found that, hexavalent chromium could increase ROS formation, activate cell signaling and stimulate the release of cytokines. But, in keratinocytes, these effects have not yet fully been demonstrated. Our aim is to observe the above effects of hexavalent chromium on keratinocytes. By utilizing HaCaT cells and the skin of albino guinea pigs, we showed that hexavalent chromium could increase ROS formation, activate the Akt, NF-kB, and MAPK pathways as well as increase the production of cytokines, including TNF-α and IL-1α. The release of these cytokines from keratinocytes is considered to be a key participant in the pathogenesis of contact hypersensitivity. Among cement workers, chromium hypersensitivity is an important occupational skin disease issue. Therefore, the observations of our study help us better understand the role of hexavalent chromium on the development of chromium hypersensitivity, which might provide clues for clinicians in the development of chemopreventative agents for the prevention of chromium hypersensitivity among cement workers.     

Review of synthesis, assay, and prediction of β and γ-secretase inhibitors

Alzheimer's disease (AD) is characterize with several pathologies this disease, amyloid plaques, composed of the β-amyloid peptide and β-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. AD is the most prevalent form of dementia, and current indications show that twenty-nine million people live with AD worldwide, a figure expected rise exponentially over the coming decades. Clearly, blocking disease progression or, in the best-case scenario, preventing AD altogether would be of benefit in both social and economic terms. However, current AD therapies are merely palliative and only temporarily slow cognitive decline, and treatments that address the underlying pathologic mechanisms of AD are completely lacking. While familial AD (FAD) is caused by autosomal dominant mutations in either amyloid precursor protein (APP) or the presenilin (PS1, PS2) genes. First, we revised Desing, synthesis, and Biological assay of β and γ-secretase inhibitors. Next, we review 2D QSAR, 3D QSAR, CoMFA, CoMSIA and Docking with different compound to find out the structural requirements. Next, we revised QSAR studies using method of Artificial Neural Network (ANN) in order to understand the essential structural requirement for binding with receptor for β and γ-secretase inhibitors.     

Biological actions and molecular effects of resveratrol,pterostilbene, and 3′-hydroxypterostilbene

Stilbenes are a class of polyphenolic compounds, naturally found in a wide variety of dietary sources such as grapes, berries, peanuts, red wine, and some medicinal plants. There are several well-known stilbenes including trans-resveratrol, pterostilbene, and 3′-hydroxypterostilbene. The core chemical structure of stilbene compounds is 1,2-diphenylethylene. Recently, stilbenes have attracted extensive attention and interest due to their wide range of health-beneficial effects such as anti-inflammation, -carcinogenic, -diabetes, and -dyslipidemia activities. Moreover, accumulating in vitro and in vivo studies have reported that stilbene compounds act as inducers of multiple cell-death pathways such as apoptosis, cell cycle arrest, and autophagy for chemopreventive and chemotherapeutic agents in several types of cancer cells. The aim of this review is to highlight recent molecular findings and biological actions of trans-resveratrol, pterostilbene, and 3′-hydroxypterostilbene.     

rac- and meso-Cyclohexanoids: Their α-, β-glycosidases,antibacterial, antifungal activities,and molecular docking studies

An efficient and versatile synthesis method has been postulated for hydroxymethylated rac - and meso-cyclohexanoid derivatives. The synthesis of these stereoisomers was achieved easily with traditional methods using hexahydroisobenzofuran 6 , prepared from commercially available cis-hydrophthalic anhydride. The study, involving diastereoselective epoxidation and cis-hydroxylation, was conducted to obtain epoxy-, cis-, and trans-diol-furans 7, 8 , and 9 . After sulfamic acid-catalyzed ring-opening reaction of the epoxide and furan rings, rac- and meso-tetraacetates 14, 15 , and 16 were afforded. Hydrolysis of acetate groups with ammonia in absolute methanol yielded the desired tetrols rac -17 , meso -18 , and meso -19 . All structures, after purification by chromatographic methods and elucidation by spectral techniques, were screened against α- and β-glucosidases. Compounds 7, 8, 10, 17, 18 , and 19 were also evaluated for their antibacterial and antifungal activity against some selected synthesized compounds with varying degrees of inhibitory effects on the growth of different pathogenic microorganisms by the well-diffusion method. In addition, Saccharomyces cerevisiae α-glucosidase molecular modeling studies were performed for all rac- and meso-compounds 7, 8, 10, 17, 18 , and 19 .     

Phytotherapeutic activity of curcumol: Isolation,GC–MS identification,and assessing potentials against acute and subchronic hyperglycemia,tactile allodynia,and hyperalgesia

Context: Curcumol has recently attracted special attention due to its potential activities in many chronic disorders. Moreover, the traditional role of turmeric [Curcuma longa L. (Zingiberaceae)] in suppression of hyperglycemia is of great interest.

Objectives: The present work explores the potential acute and subchronic antihyperglycemic, antinociceptive, and in vivo antioxidant effects of curcumol in alloxan-diabetic mice.

Materials and methods: Bio-guided fractionation, column-chromatography, and GC–MS were utilized to identify the most active compound of turmeric (curcumol). Turmeric (25, 50, and 100?mg/kg), the curcumol rich fraction (CRF) (7?mg/kg), and curcumol (20, 30, and 40?mg/kg) were assessed for their acute (6 h) and subchronic (8 d) antihyperglycemic potentials and antinociceptive effects (8 weeks) were measured, using hot-plate and tail-flick latencies and von-Frey filaments method and in vivo antioxidant effects in alloxan-diabetic mice.

Results: The most-active turmeric fraction was found to be rich in curcumol (45.5%) using GC–MS analysis method. The results proved that the highest dose levels of turmeric extract and curcumol exerted remarkable hypoglycemic activity with 41.4 and 39.3% drop in the mice glucose levels after 6 h, respectively. Curcumol (40?mg/kg) was found to be 9.4% more potent than turmeric extract (100?mg/kg) in subchronic management of diabetes. Curcumol also showed a significant improvement of peripheral nerve function as observed from the latency and tactile tests.

Discussion: The antioxidant potential of curcumol may cause its ability to ameliorate diabetes and diabetes-related complications.

Conclusions: Curcumol, a natural metabolite with a good safety-profile, showed results comparable with tramadol in reversing diabetes-induced tactile allodynia and hyperalgesia.