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call loadScript javascripts\jsmol\core\package.js call loadScript javascripts\jsmol\core\core.z.js -- required by ClazzNode call loadScript javascripts\jsmol\J\awtjs2d\WebOutputChannel.js Jmol JavaScript applet jmolApplet0_object__2655854346404043__ initializing getValue debug = null getValue logLevel = null getValue allowjavascript = null AppletRegistry.checkIn(jmolApplet0_object__2655854346404043__) call loadScript javascripts\jsmol\core\corestate.z.js viewerOptions: { "name":"jmolApplet0_object","applet":true,"documentBase":"https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI%3A27732","platform":"J.awtjs2d.Platform","fullName":"jmolApplet0_object__2655854346404043__","display":"jmolApplet0_canvas2d","signedApplet":"true","appletReadyCallback":"Jmol._readyCallback","statusListener":"[J.appletjs.Jmol.MyStatusListener object]","codeBase":"https://www.ebi.ac.uk/chebi/javascripts/jsmol/","syncId":"2655854346404043","bgcolor":"#000" } (C) 2012 Jmol Development Jmol Version: 13.2.7 $Date: 2013-10-01 11:35:15 -0500 (Tue, 01 Oct 2013) $ java.vendor: j2s java.version: 0.0 os.name: j2s Access: ALL memory: 0.0/0.0 processors available: 1 useCommandThread: false appletId:jmolApplet0_object (signed) starting HoverWatcher_1 getValue emulate = null defaults = "Jmol" getValue boxbgcolor = null getValue bgcolor = #000 backgroundColor = "#000" getValue ANIMFRAMECallback = null getValue APPLETREADYCallback = Jmol._readyCallback APPLETREADYCallback = "Jmol._readyCallback" getValue ATOMMOVEDCallback = null getValue CLICKCallback = null getValue ECHOCallback = null getValue ERRORCallback = null getValue EVALCallback = null getValue HOVERCallback = null getValue LOADSTRUCTCallback = null getValue MEASURECallback = null getValue MESSAGECallback = null getValue MINIMIZATIONCallback = null getValue PICKCallback = null getValue RESIZECallback = null getValue SCRIPTCallback = null getValue SYNCCallback = null getValue STRUCTUREMODIFIEDCallback = null getValue doTranslate = null language=en_US getValue popupMenu = null getValue script = null Jmol applet jmolApplet0_object__2655854346404043__ ready call loadScript javascripts\jsmol\core\corescript.z.js call loadScript javascripts\jsmol\J\script\FileLoadThread.js starting QueueThread0_2 script 1 started starting HoverWatcher_3 starting HoverWatcher_4 The Resolver thinks Mol Marvin 02080816533D starting HoverWatcher_5 Time for openFile( Marvin 02080816533D 24 25 0 0 0 0 999 V2000 -0.8679 0.6241 -0.3283 C 0 0 0 0 0 0 0 0 0 4 0 0 0.4615 0.7009 0.0829 C 0 0 0 0 0 0 0 0 0 5 0 0 -1.5328 -0.5430 -0.4078 N 0 0 0 0 0 0 0 0 0 3 0 0 0.4263 -1.6660 0.3115 N 0 0 0 0 0 0 0 0 0 1 0 0 -0.8724 -1.6645 -0.0706 C 0 0 0 0 0 0 0 0 0 2 0 0 1.0847 -0.4998 0.4105 C 0 0 0 0 0 0 0 0 0 6 0 0 0.8268 2.0015 0.0556 N 0 0 0 0 0 0 0 0 0 7 0 0 -1.2810 1.8740 -0.5971 N 0 0 0 0 0 0 0 0 0 9 0 0 -0.2509 2.6938 -0.3617 C 0 0 0 0 0 0 0 0 0 8 0 0 -1.4930 -2.7256 -0.1152 O 0 0 0 0 0 0 0 0 0 0 0 0 2.2466 -0.4019 0.7856 O 0 0 0 0 0 0 0 0 0 0 0 0 -2.8808 -0.5274 -0.8405 C 0 0 0 0 0 0 0 0 0 0 0 0 2.0890 2.5724 0.3917 C 0 0 0 0 0 0 0 0 0 0 0 0 1.0842 -2.8976 0.5960 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.3058 3.7063 -0.4907 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.5287 -0.9307 -0.0601 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.9888 -1.1295 -1.7447 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.2978 0.4525 -1.0903 H 0 0 0 0 0 0 0 0 0 0 0 0 2.8617 2.1595 -0.2585 H 0 0 0 0 0 0 0 0 0 0 0 0 2.3281 2.3436 1.4313 H 0 0 0 0 0 0 0 0 0 0 0 0 2.1008 3.6589 0.2773 H 0 0 0 0 0 0 0 0 0 0 0 0 1.0715 -3.5477 -0.2828 H 0 0 0 0 0 0 0 0 0 0 0 0 0.5843 -3.4214 1.4149 H 0 0 0 0 0 0 0 0 0 0 0 0 2.1343 -2.8322 0.8911 H 0 0 0 0 0 0 0 0 0 0 0 0 8 1 4 0 0 0 0 2 1 4 0 0 0 0 7 2 4 0 0 0 0 3 1 1 0 0 0 0 5 4 1 0 0 0 0 5 3 1 0 0 0 0 10 5 2 0 0 0 0 6 2 1 0 0 0 0 6 4 1 0 0 0 0 11 6 2 0 0 0 0 9 7 4 0 0 0 0 9 8 4 0 0 0 0 9 15 1 0 0 0 0 12 3 1 0 0 0 0 13 7 1 0 0 0 0 14 4 1 0 0 0 0 12 16 1 0 0 0 0 12 17 1 0 0 0 0 12 18 1 0 0 0 0 13 19 1 0 0 0 0 13 20 1 0 0 0 0 13 21 1 0 0 0 0 14 22 1 0 0 0 0 14 23 1 0 0 0 0 14 24 1 0 0 0 0 M APO 3 12 1 13 1 14 1 M STY 3 1 SUP 2 SUP 3 SUP M SAL 1 4 12 16 17 18 M SBL 1 1 14 M SMT 1 Me M SDS EXP 1 1 M SAL 2 4 13 19 20 21 M SBL 2 1 15 M SMT 2 Me M SDS EXP 1 2 M SAL 3 4 14 22 23 24 M SBL 3 1 16 M SMT 3 Me M SDS EXP 1 3 M END): 14 ms reading 24 atoms ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false 1 model in this collection. Use getProperty "modelInfo" or getProperty "auxiliaryInfo" to inspect them. Default Van der Waals type for model set to Babel 24 atoms created ModelSet: not autobonding; use forceAutobond=true to force automatic bond creation Script completed Jmol script terminated
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Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class and is the most commonly consumed psychoactive substance globally. It is mainly used for its eugeroic (wakefulness promoting), ergogenic (physical performance-enhancing), or nootropic (cognitive-enhancing) properties. Caffeine acts by blocking binding of adenosine at a number of adenosine receptor types, inhibiting the centrally depressant effects of adenosine and enhancing the release of acetylcholine. Caffeine has a three-dimensional structure similar to that of adenosine, which allows it to bind and block its receptors. Caffeine also increases cyclic AMP levels through nonselective inhibition of phosphodiesterase, increases calcium release from intracellular stores, and antagonizes GABA receptors, although these mechanisms typically occur at concentrations beyond usual human consumption.
Caffeine is a bitter, white crystalline purine, a methylxanthine alkaloid, and is chemically related to the adenine and guanine bases of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). It is found in the seeds, fruits, nuts, or leaves of a number of plants native to Africa, East Asia and South America and helps to protect them against herbivores and from competition by preventing the germination of nearby seeds, as well as encouraging consumption by select animals such as honey bees. The best-known source of caffeine is the coffee bean, the seed of the Coffea plant. People may drink beverages containing caffeine to relieve or prevent drowsiness and to improve cognitive performance. To make these drinks, caffeine is extracted by steeping the plant product in water, a process called infusion. Caffeine-containing drinks, such as coffee, tea, and cola, are consumed globally in high volumes. In 2020, almost 10 million tonnes of coffee beans were consumed globally. Caffeine is the world's most widely consumed psychoactive drug. Unlike most other psychoactive substances, caffeine remains largely unregulated and legal in nearly all parts of the world. Caffeine is also an outlier as its use is seen as socially acceptable in most cultures with it even being encouraged.
Caffeine has both positive and negative health effects. It can treat and prevent the premature infant breathing disorders bronchopulmonary dysplasia of prematurity and apnea of prematurity. Caffeine citrate is on the WHO Model List of Essential Medicines. It may confer a modest protective effect against some diseases, including Parkinson's disease. Some people experience sleep disruption or anxiety if they consume caffeine, but others show little disturbance. Evidence of a risk during pregnancy is equivocal; some authorities recommend that pregnant women limit caffeine to the equivalent of two cups of coffee per day or less. Caffeine can produce a mild form of drug dependence – associated with withdrawal symptoms such as sleepiness, headache, and irritability – when an individual stops using caffeine after repeated daily intake. Tolerance to the autonomic effects of increased blood pressure and heart rate, and increased urine output, develops with chronic use (i.e., these symptoms become less pronounced or do not occur following consistent use).
Caffeine is classified by the U.S. Food and Drug Administration (FDA) as generally recognized as safe. Toxic doses, over 10 grams per day for an adult, are much higher than the typical dose of under 500 milligrams per day. The European Food Safety Authority reported that up to 400 mg of caffeine per day (around 5.7 mg/kg of body mass per day) does not raise safety concerns for non-pregnant adults, while intakes up to 200 mg per day for pregnant and lactating women do not raise safety concerns for the fetus or the breast-fed infants. A cup of coffee contains 80–175 mg of caffeine, depending on what "bean" (seed) is used, how it is roasted, and how it is prepared (e.g., drip, percolation, or espresso). Thus it requires roughly 50–100 ordinary cups of coffee to reach the toxic dose. However, pure powdered caffeine, which is available as a dietary supplement, can be lethal in tablespoon-sized amounts. |
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InChI=1S/C8H10N4O2/c1-10-4-9-6-5(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3 |
RYYVLZVUVIJVGH-UHFFFAOYSA-N |
Cn1cnc2n(C)c(=O)n(C)c(=O)c12 |
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Mus musculus
(NCBI:txid10090)
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Source: BioModels - MODEL1507180067
See:
PubMed
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Theobroma cacao
(NCBI:txid3641)
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See:
DOI
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Camellia sinensis
(NCBI:txid4442)
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See:
PubMed
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Claviceps sorghicola
(NCBI:txid83213)
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See:
DOI
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Homo sapiens
(NCBI:txid9606)
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Found in
blood serum
(BTO:0000133).
See:
MetaboLights Study
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environmental contaminant
Any minor or unwanted substance introduced into the environment that can have undesired effects.
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EC 3.1.4.* (phosphoric diester hydrolase) inhibitor
An EC 3.1.* (ester hydrolase) inhibitor that interferes with the action of a phosphoric diester hydrolase (EC 3.1.4.*).
mouse metabolite
Any mammalian metabolite produced during a metabolic reaction in a mouse (Mus musculus).
EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor
An EC 2.7.11.* (protein-serine/threonine kinase) inhibitor that interferes with the action of non-specific serine/threonine protein kinase (EC 2.7.11.1), a kinase enzyme involved in phosphorylation of hydroxy group of serine or threonine.
ryanodine receptor agonist
A ryanodine receptor modulator which activates the receptor. Ryanodine receptors (RyRs) act as selective ion channels, modulating the release of calcium. Activating the receptors causes the release of calcium, so depleting internal calcium and ultimately preventing further muscle contraction.
fungal metabolite
Any eukaryotic metabolite produced during a metabolic reaction in fungi, the kingdom that includes microorganisms such as the yeasts and moulds.
adenosine A2A receptor antagonist
An antagonist at the A2A receptor.
food additive
Any substance which is added to food to preserve or enhance its flavour and/or appearance.
adenosine receptor antagonist
An antagonist at any adenosine receptor.
plant metabolite
Any eukaryotic metabolite produced during a metabolic reaction in plants, the kingdom that include flowering plants, conifers and other gymnosperms.
human blood serum metabolite
Any metabolite (endogenous or exogenous) found in human blood serum samples.
xenobiotic
A xenobiotic (Greek, xenos "foreign"; bios "life") is a compound that is foreign to a living organism. Principal xenobiotics include: drugs, carcinogens and various compounds that have been introduced into the environment by artificial means.
mutagen
An agent that increases the frequency of mutations above the normal background level, usually by interacting directly with DNA and causing it damage, including base substitution.
metabolite
Any intermediate or product resulting from metabolism. The term 'metabolite' subsumes the classes commonly known as primary and secondary metabolites.
(via alkaloid )
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geroprotector
Any compound that supports healthy aging, slows the biological aging process, or extends lifespan.
psychotropic drug
A loosely defined grouping of drugs that have effects on psychological function.
diuretic
An agent that promotes the excretion of urine through its effects on kidney function.
food additive
Any substance which is added to food to preserve or enhance its flavour and/or appearance.
adjuvant
Any pharmacological or immunological agent that modifies the effect of other agents such as drugs or vaccines while having few if any direct effects when given by itself.
central nervous system stimulant
Any drug that enhances the activity of the central nervous system.
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View more via ChEBI Ontology
1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione
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1,3,7-trimethyl-2,6-dioxopurine
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ChemIDplus
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1,3,7-trimethylpurine-2,6-dione
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IUPHAR
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1,3,7-Trimethylxanthine
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KEGG COMPOUND
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1,3,7-trimethylxanthine
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NIST Chemistry WebBook
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1-methyltheobromine
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ChemIDplus
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3,7-Dihydro-1,3,7-trimethyl-1H-purin-2,6-dion
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NIST Chemistry WebBook
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7-methyltheophylline
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NIST Chemistry WebBook
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anhydrous caffeine
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KEGG DRUG
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cafeína
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ChemIDplus
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caféine
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ChEBI
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CAFFEINE
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PDBeChem
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Caffeine
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KEGG COMPOUND
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caffeine
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UniProt
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Coffein
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ChemIDplus
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guaranine
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IUPHAR
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Koffein
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ChemIDplus
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mateína
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ChemIDplus
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methyltheobromine
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IUPHAR
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teína
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ChEBI
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Thein
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ChemIDplus
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theine
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NIST Chemistry WebBook
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103040
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Gmelin Registry Number
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Gmelin
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17705
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Reaxys Registry Number
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Reaxys
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58-08-2
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CAS Registry Number
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KEGG COMPOUND
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58-08-2
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CAS Registry Number
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NIST Chemistry WebBook
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58-08-2
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CAS Registry Number
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ChemIDplus
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Rallis C, Codlin S, Bähler J (2013) TORC1 signaling inhibition by rapamycin and caffeine affect lifespan, global gene expression, and cell proliferation of fission yeast. Aging cell 12, 563-573 [PubMed:23551936] [show Abstract] Target of rapamycin complex 1 (TORC1) is implicated in growth control and aging from yeast to humans. Fission yeast is emerging as a popular model organism to study TOR signaling, although rapamycin has been thought to not affect cell growth in this organism. Here, we analyzed the effects of rapamycin and caffeine, singly and combined, on multiple cellular processes in fission yeast. The two drugs led to diverse and specific phenotypes that depended on TORC1 inhibition, including prolonged chronological lifespan, inhibition of global translation, inhibition of cell growth and division, and reprograming of global gene expression mimicking nitrogen starvation. Rapamycin and caffeine differentially affected these various TORC1-dependent processes. Combined drug treatment augmented most phenotypes and effectively blocked cell growth. Rapamycin showed a much more subtle effect on global translation than did caffeine, while both drugs were effective in prolonging chronological lifespan. Rapamycin and caffeine did not affect the lifespan via the pH of the growth media. Rapamycin prolonged the lifespan of nongrowing cells only when applied during the growth phase but not when applied after cells had stopped proliferation. The doses of rapamycin and caffeine strongly correlated with growth inhibition and with lifespan extension. This comprehensive analysis will inform future studies into TORC1 function and cellular aging in fission yeast and beyond. | Romano GH, Harari Y, Yehuda T, Podhorzer A, Rubinstein L, Shamir R, Gottlieb A, Silberberg Y, Pe'er D, Ruppin E, Sharan R, Kupiec M (2013) Environmental stresses disrupt telomere length homeostasis. PLoS genetics 9, e1003721 [PubMed:24039592] [show Abstract] Telomeres protect the chromosome ends from degradation and play crucial roles in cellular aging and disease. Recent studies have additionally found a correlation between psychological stress, telomere length, and health outcome in humans. However, studies have not yet explored the causal relationship between stress and telomere length, or the molecular mechanisms underlying that relationship. Using yeast as a model organism, we show that stresses may have very different outcomes: alcohol and acetic acid elongate telomeres, whereas caffeine and high temperatures shorten telomeres. Additional treatments, such as oxidative stress, show no effect. By combining genome-wide expression measurements with a systematic genetic screen, we identify the Rap1/Rif1 pathway as the central mediator of the telomeric response to environmental signals. These results demonstrate that telomere length can be manipulated, and that a carefully regulated homeostasis may become markedly deregulated in opposing directions in response to different environmental cues. | Roux A, Xu Y, Heilier JF, Olivier MF, Ezan E, Tabet JC, Junot C (2012) Annotation of the human adult urinary metabolome and metabolite identification using ultra high performance liquid chromatography coupled to a linear quadrupole ion trap-Orbitrap mass spectrometer. Analytical chemistry 84, 6429-6437 [PubMed:22770225] [show Abstract] Metabolic profiles of biofluids obtained by atmospheric pressure ionization mass spectrometry-based technologies contain hundreds to thousands of features, most of them remaining unknown or at least not characterized in analytical systems. We report here on the annotation of the human adult urinary metabolome and metabolite identification from electrospray ionization mass spectrometry (ESI-MS)-based metabolomics data sets. Features of biological interest were first of all annotated using the ESI-MS database of the laboratory. They were also grouped, thanks to software tools, and annotated using public databases. Metabolite identification was achieved using two complementary approaches: (i) formal identification by matching chromatographic retention times, mass spectra, and also product ion spectra (if required) of metabolites to be characterized in biological data sets to those of reference compounds and (ii) putative identification from biological data thanks to MS/MS experiments for metabolites not available in our chemical library. By these means, 384 metabolites corresponding to 1484 annotated features (659 in negative ion mode and 825 in positive ion mode) were characterized in human urine samples. Of these metabolites, 192 and 66 were formally and putatively identified, respectively, and 54 are reported in human urine for the first time. These lists of features could be used by other laboratories to annotate their ESI-MS metabolomics data sets. | Lublin A, Isoda F, Patel H, Yen K, Nguyen L, Hajje D, Schwartz M, Mobbs C (2011) FDA-approved drugs that protect mammalian neurons from glucose toxicity slow aging dependent on cbp and protect against proteotoxicity. PloS one 6, e27762 [PubMed:22114686] [show Abstract] Screening a library of drugs with known safety profiles in humans yielded 30 drugs that reliably protected mammalian neurons against glucose toxicity. Subsequent screening demonstrated that 6 of these 30 drugs increase lifespan in C. elegans: caffeine, ciclopirox olamine, tannic acid, acetaminophen, bacitracin, and baicalein. Every drug significantly reduced the age-dependent acceleration of mortality rate. These protective effects were blocked by RNAi inhibition of cbp-1 in adults only, which also blocks protective effects of dietary restriction. Only 2 drugs, caffeine and tannic acid, exhibited a similar dependency on DAF-16. Caffeine, tannic acid, and bacitracin also reduced pathology in a transgenic model of proteotoxicity associated with Alzheimer's disease. These results further support a key role for glucose toxicity in driving age-related pathologies and for CBP-1 in protection against age-related pathologies. These results also provide novel lead compounds with known safety profiles in human for treatment of age-related diseases, including Alzheimer's disease and diabetic complications. | Chen GQ, Chen YY, Wang XS, Wu SZ, Yang HM, Xu HQ, He JC, Wang XT, Chen JF, Zheng RY (2010) Chronic caffeine treatment attenuates experimental autoimmune encephalomyelitis induced by guinea pig spinal cord homogenates in Wistar rats. Brain research 1309, 116-125 [PubMed:19879252] [show Abstract] Dysfunction of adenosinergic systems has been implicated in the development of multiple sclerosis in humans and experimental autoimmune encephalomyelitis (EAE) in animals. Caffeine, a non-selective antagonist of adenosine receptors, has been shown to provide protection against myelin oligodendroglia glycoprotein (MOG)-induced EAE in mice. In this study, we showed that chronic caffeine similarly imparts neuroprotection against EAE induced in rats by guinea pig spinal cord homogenates (GPSCH). GPSCH-induced EAE is characterized by extensive tissue inflammation with a typical chronic disease course. We showed that caffeine decreases the incidence of EAE and attenuates EAE pathology at behavioral, histological (inflammatory cell infiltration and demyelination) and neurochemical (expression of inflammatory cytokines) levels. The attenuation of GPSCH-induced pathology by chronic caffeine treatment was observed at doses of 10 and 30 mg/kg and during both peak and recovery phases of EAE. Furthermore, it was showed that chronic treatment with caffeine up-regulated A1 receptor and TGF-beta mRNAs and suppressed interferon-gamma mRNA in EAE rats. Together with previous reports, our data demonstrates that chronic treatment with caffeine exerts a neuroprotective effect against EAE, possibly through an A(1) receptor-mediated shift from Th1 to Th2 cell function, and provides a neurobiological basis for epidemiological investigation into the possible relationship between caffeine consumption and development of multiple sclerosis in humans. | Chen X, Ghribi O, Geiger JD (2010) Caffeine protects against disruptions of the blood-brain barrier in animal models of Alzheimer's and Parkinson's diseases. Journal of Alzheimer's disease : JAD 20 Suppl 1, S127-41 [PubMed:20164568] [show Abstract] Sporadic Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common neurodegenerative diseases and as such they represent major public health problems. Finding effective treatments for AD and PD represents an unmet and elusive goal largely because these diseases are chronic and progressive, and have a complicated and ill-understood pathogenesis. Although the underlying mechanisms are not fully understood, caffeine, the most commonly ingested psychoactive drug in the world, has been shown in human and animal studies to be protective against AD and PD. One mechanism implicated in the pathogenesis of AD and PD is blood-brain barrier (BBB) dysfunction and we reported recently that caffeine exerts protective effects against AD and PD at least in part by keeping the BBB intact. The present review focuses on the role of BBB dysfunction in the pathogenesis of AD and PD, caffeine's protective effects against AD and PD, and potential mechanisms whereby caffeine protects against BBB leakage. | Goldstein E, Jacobs PL, Whitehurst M, Penhollow T, Antonio J (2010) Caffeine enhances upper body strength in resistance-trained women. Journal of the International Society of Sports Nutrition 7, 18 [PubMed:20470411] [show Abstract]
BackgroundResearch has indicated that low-to-moderate dosages of caffeine supplementation are ergogenic for sustained endurance efforts as well as high-intensity exercise. The effects of caffeine supplementation on strength-power performance are equivocal, with some studies indicating a benefit and others demonstrating no change in performance. The majority of research that has examined the effects of caffeine supplementation on strength-power performance has been carried out in both trained and untrained men. Therefore, the purpose of this study was to determine the acute effects of caffeine supplementation on strength and muscular endurance in resistance-trained women.MethodsIn a randomized manner, 15 women consumed caffeine (6 mg/kg) or placebo (PL) seven days apart. Sixty min following supplementation, participants performed a one-repetition maximum (1RM) barbell bench press test and repetitions to failure at 60% of 1RM. Heart rate (HR) and blood pressure (BP) were assessed at rest, 60 minutes post-consumption, and immediately following completion of repetitions to failure.ResultsRepeated measures ANOVA indicated a significantly greater bench press maximum with caffeine (p ConclusionsThese findings indicate a moderate dose of caffeine may be sufficient for enhancing strength performance in resistance-trained women. | Kasture S, Barhate S, Mohan M, Ballero M, Sanna C, Maxia A (2009) Caffeine withdrawal retains anticataleptic activity but Withania somnifera withdrawal potentiates haloperidol-induced catalepsy in mice. Natural product research 23, 724-728 [PubMed:19418355] [show Abstract] The previous study showed that chronic treatment with Withania somnifera extract (WS) inhibited haloperidol-induced catalepsy. It is suggested that caffeine and WS may be useful adjuvants in pharmacotherapy of Parkinson's disease. There are no studies on the effect of haloperidol on mice withdrawn from caffeine or W. somnifera. We therefore studied the effect of a single administration of standardised WS containing 5.1% total withanolides (WS, 30 or 100 mg kg(-1) i.p.) and/or caffeine (3 mg kg(-1) i.p.) and withdrawal from 6 days treatment with WS and/or caffeine, on haloperidol-induced catalepsy in albino mice. Single administration of both WS and caffeine, used either alone or in combination, significantly inhibited catalepsy. Mice withdrawn from caffeine significantly inhibited haloperidol-induced catalepsy, but mice withdrawn from WS showed increased catalepsy. The study indicated that withdrawal from WS does not retain anticataleptic activity, and caffeine but not WS may be a good adjuvant in pharmacotherapy of Parkinson's disease. | Chavez-Valdez R, Wills-Karp M, Ahlawat R, Cristofalo EA, Nathan A, Gauda EB (2009) Caffeine modulates TNF-alpha production by cord blood monocytes: the role of adenosine receptors. Pediatric research 65, 203-208 [PubMed:19047957] [show Abstract] Caffeine, a nonspecific adenosine receptor (AR) antagonist is widely used to treat apnea of prematurity. Because adenosine modulates multiple biologic processes including inflammation, we hypothesized that AR blockade by caffeine would increase cytokine release from neonatal monocytes. Using cord blood monocytes (CBM), we investigated 1) the changes in AR mRNA profile by real time quantitative reverse-transcription polymerase-chain-reaction (qRT-PCR) and protein expression (western blot) after in vitro culture, caffeine or lipopolysaccharide (LPS) exposure, and 2) the modulation of cytokine release and cyclic adenosine monophosphate (cAMP) production by enzyme-linked immunosorbent assay (ELISA) induced by caffeine and specific AR antagonists: DPCPX(A1R), ZM241385(A2aR), MRS1754(A2bR), and MRS1220(A3R). After 48 h in culture, A2aR and A2bR gene expression increased 1.9 (p = 0.04) and 2.5-fold (p = 0.003), respectively. A1R protein expression directly correlated with increasing LPS concentrations (p = 0.01), with minimal expression preexposure. Only caffeine (50 microM) and DPCPX (10 nM) decreased tumor necrosis factor-alpha (TNF-alpha) release from LPS activated-CBM by 20 and 25% (p = 0.01) and TNF-alpha gene expression by 30 and 50%, respectively, in conjunction with a > or =2-fold increase in cAMP (p < 0.05). AR blockade did not modulate other measured cytokines. The induction of A1R after LPS exposure suggests an important role of this receptor in the control of inflammation in neonates. Our findings also suggest that caffeine, via A1R blockade, increases cAMP production and inhibits pretranscriptional TNF-alpha production by CBM. | Hume JR, McAllister CE, Wilson SM (2009) Caffeine inhibits InsP3 responses and capacitative calcium entry in canine pulmonary arterial smooth muscle cells. Vascular pharmacology 50, 89-97 [PubMed:19084078] [show Abstract] Caffeine is a well described and characterized ryanodine receptor (RyR) activator. Previous evidence from independent research studies also indicate caffeine inhibits InsP3 receptor functionality, which is important to activation of capacitative Ca2+ entry (CCE) in some cell types. In addition, RyR activation elicits excitatory-coupled Ca2+ entry (ECCE) in skeletal muscle myotubes. Recent studies by our group show that canine pulmonary arterial smooth muscle cells (PASMCs) have functional InsP3 receptors as well as RyRs, and that CCE is dependent on InsP3 receptor activity. The potential for caffeine to activate ECCE as well as inhibit InsP3 receptor function and CCE was examined using fura-2 fluorescent imaging in canine PASMCs. The data show caffeine causes transient as well as sustained cytosolic Ca2+ increases, though this is not due to CCE or ECCE activity as evidenced by a lack of an increase in Mn2+ quench of fura-2. The experiments also show caffeine reversibly inhibits 5-HT elicited-InsP3 mediated Ca2+ responses with an IC50 of 6.87x10(-4) M and 10 mM caffeine fully inhibits CCE. These studies provide the first evidence that caffeine is an inhibitor of InsP3 generated Ca2+ signals and CCE in PASMCs. | Graham TE, Battram DS, Dela F, El-Sohemy A, Thong FS (2008) Does caffeine alter muscle carbohydrate and fat metabolism during exercise? Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme 33, 1311-1318 [PubMed:19088793] [show Abstract] Caffeine, an adenosine receptor antagonist, has been studied for decades as a putative ergogenic aid. In the past 2 decades, the information has overwhelmingly demonstrated that it indeed is a powerful ergogenic aid, and frequently theories have been proposed that this is due to alterations in fat and carbohydrate metabolism. While caffeine certainly mobilizes fatty acids from adipose tissue, rarely have measures of the respiratory exchange ratio indicated an increase in fat oxidation. However, this is a difficult measure to perform accurately during exercise, and small changes could be physiologically important. The few studies examining human muscle metabolism directly have also supported the fact that there is no change in fat or carbohydrate metabolism, but these usually have had a small sample size. We combined the data from muscle biopsy analyses of several similar studies to generate a sample size of 16-44, depending on the measure. We examined muscle glycogen, citrate, acetyl-CoA, glucose-6-phosphate, and cyclic adenosine monophosphate (cAMP) in resting samples and in those obtained after 10-15 min of exercise at 70%-85% maximal oxygen consumption. Exercise decreased (p < 0.05) glycogen and increased (p < 0.05) citrate, acetyl-CoA, and glucose-6-phosphate. The only effects of caffeine were to increase (p < 0.05) citrate in resting muscle and cAMP in exercise. There is very little evidence to support the hypothesis that caffeine has ergogenic effects as a result of enhanced fat oxidation. Individuals may, however, respond differently to the effects of caffeine, and there is growing evidence that this could be explained by common genetic variations. | Moore MT, Greenway SL, Farris JL, Guerra B (2008) Assessing caffeine as an emerging environmental concern using conventional approaches. Archives of environmental contamination and toxicology 54, 31-35 [PubMed:17957400] [show Abstract] Organic wastewater contaminants, including pharmaceuticals, caffeine, and nicotine, have received increased scrutiny because of their detection in water bodies receiving wastewater discharge. Despite recent measurement in United States streams, caffeine's effect on freshwater organisms is not well documented. The present study measured caffeine's lethal and sublethal effects on the freshwater species, Ceriodaphnia dubia, Pimephales promelas, and Chironomus dilutus. These organisms, which are used in standard testing or effluent monitoring, were exposed to aqueous caffeine solutions under static exposure for 48 hours and daily renewed static exposure for 7 days. Averaged responses of 48-hour acute end points indicated that C. dubia was more sensitive to caffeine exposures (LC50 = 60 mg/L) than either P. promelas (LC50 = 100 mg/L) or C. dilutus (LC50 = 1,230 mg/L). Exposure-response slopes confirmed these findings (3% mortality/mg/L for C. dubia; 0.5% mortality/mg/L for P. promelas; and 0.07% mortality/mg/L for C. dilutus). Comparative 7-day responses between C. dubia and P. promelas (LC50 = 46 and 55 mg/L, respectively) were more similar than the broad range of acute values. Sublethal effects measured for caffeine exposure included impaired C. dubia reproduction (IC50 = 44 mg/L) and inhibited P. promelas growth (IC50 = 71 mg/L). According to the results of this study, combined with earlier studies reporting environmental concentrations and product half-lives, caffeine should pose negligible risk for most aquatic vertebrate and invertebrate organisms. | Díaz-Reval MI, Galván-Orozco R, López-Muñoz FJ, Carrillo-Munguía N (2008) [Synergism of caffeine on antinociceptive effects of metamizole]. Cirugia y cirujanos 76, 241-246 [PubMed:18647558] [show Abstract]
BackgroundCombinations of analgesic drugs have been used as an option for treating pain because some types of pain are difficult to relieve with conventional analgesics. This group of drugs has been combined with analgesics or drugs without analgesic effect and is called adjuvant. One such drug is caffeine.MethodsWe undertook the present study to analyze if caffeine is able to potentiate the antinociceptive effect of metamizole in the formalin model.ResultsMetamizole produced a dose-dependent antinociceptive effect with ED(50) = 329.61 mg/kg in the formalin model. Caffeine at the following doses (3.16, 10.0, 17.8 and 31.6 mg/kg) also showed antinociceptive effect. When a subeffective dose of metamizole (100 mg/kg) was combined with caffeine (3.16, 10.0, 17.8 or 31.6 mg/kg), higher antinociceptive effects were produced than the corresponding effects produced by metamizole alone. One combination presented potentiation effect; the other combination showed antinociceptive effect that was not different from the effects of metamizole alone. Two combinations showed an effect lower than the corresponding effect produced by metamizole alone.ConclusionsAdjuvant caffeine is able to change the effect of metamizole in the inflammatory pain model, in which caffeine also presents an antinociceptive effect. | Shapiro RE (2008) Caffeine and headaches. Current pain and headache reports 12, 311-315 [PubMed:18625110] [show Abstract] Caffeine is the most widely consumed psychostimulant drug in the world. With intermittent exposures, caffeine may act as a mild analgesic for headache or as an adjuvant for the actions of other analgesics. Chronic repetitive exposures to caffeine increase the risks for development of analgesic-overuse headache, chronic daily headache, and physical dependency. Cessation of caffeine use after chronic exposures leads to a withdrawal syndrome with headache as a dominant symptom. At dosages achieved by common dietary intake, caffeine acts as a potent antagonist of central and peripheral nervous system adenosine receptors. The complex effects of caffeine on headache disorders suggest important roles for adenosine in these disorders and in the induction of caffeine dependency. | da Silva RS, Richetti SK, da Silveira VG, Battastini AM, Bogo MR, Lara DR, Bonan CD (2008) Maternal caffeine intake affects acetylcholinesterase in hippocampus of neonate rats. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 26, 339-343 [PubMed:18258404] [show Abstract] Transcriptional factors and signalling molecules from intracellular metabolism modulate a complex set of events during brain development. Neurotransmitter and neuromodulator synthesis and their receptor expressions vary according to different stages of brain development. The dynamics of signalling systems is often accompanied by alterations in enzyme expression and activity. Adenosine is a neuromodulator that controls the release of several neurotransmitters, including acetylcholine, which is an important neurotransmitter during brain development. Caffeine is a non-specific antagonist of adenosine receptors and can reach the immature brain. We evaluated the effects of rat maternal caffeine intake (1g/L) on acetylcholine degradation and acetylcholinesterase expression from hippocampus of 7-, 14- and 21-day-old neonates in caffeine-treated and control groups. Caffeine was not able to change the age-dependent increase of acetylcholinesterase activity or the age-dependent decrease of acetylcholinesterase expression. However, caffeine promoted an increase of acetylcholinesterase activity (42%) without modifications on the level of acetylcholinesterase mRNA transcripts in 21-day-old rats. Considering the high score of phosphorylatable residues on acetylcholinesterase, this profile can be associated with a possible regulation by specific phosphorylation sites. These results highlight the ability of maternal caffeine intake to interfere on cholinergic neurotransmission during brain development. | Chin JM, Merves ML, Goldberger BA, Sampson-Cone A, Cone EJ (2008) Caffeine content of brewed teas. Journal of analytical toxicology 32, 702-704 [PubMed:19007524] [show Abstract] Caffeine is the world's most popular drug and can be found in many beverages including tea. It is a psychostimulant that is widely used to enhance alertness and improve performance. This study was conducted to determine the concentration of caffeine in 20 assorted commercial tea products. The teas were brewed under a variety of conditions including different serving sizes and steep-times. Caffeine was isolated from the teas with liquid-liquid extraction and quantitated by gas chromatography with nitrogen-phosphorus detection. Caffeine concentrations in white, green, and black teas ranged from 14 to 61 mg per serving (6 or 8 oz) with no observable trend in caffeine concentration due to the variety of tea. The decaffeinated teas contained less than 12 mg of caffeine per serving, and caffeine was not detected in the herbal tea varieties. In most instances, the 6- and 8-oz serving sizes contained similar caffeine concentrations per ounce, but the steep-time affected the caffeine concentration of the tea. These findings indicate that most brewed teas contain less caffeine per serving than brewed coffee. | Yang R, Wang J, Chen Y, Sun Z, Wang R, Dai Y (2008) Effect of caffeine on erectile function via up-regulating cavernous cyclic guanosine monophosphate in diabetic rats. Journal of andrology 29, 586-591 [PubMed:18421070] [show Abstract] Erectile dysfunction (ED) is a common complication of diabetes mellitus. Phosphodiesterase-5 (PDE5) inhibitors, which inhibit the breakdown of intracellular cyclic guanosine monophosphate (cGMP), are used to treat diabetic ED. Caffeine, a nonselective PDE inhibitor used in our daily diet, is controversial regarding its effect on erectile function. To investigate the effect of caffeine on erectile function in diabetic rat models and explore the mechanism, male Sprague-Dawley rats were injected with streptozotocin to induce diabetes mellitus. The rats with blood glucose levels above 300 mg/dL were selected for the study. The rats were divided into 4 groups: group A (normal control rats), group B (diabetic rats treated with normal saline), group C (diabetic rats treated with caffeine, 10 mg/kg per day), and group D (diabetic rats treated with caffeine, 20 mg/kg per day). After 8 weeks of treatment, intracavernous pressure (ICP) was measured to assess erectile function. The radioimmunoassay was used to evaluate the level of cGMP in the cavernosum. The ICP and the cavernous cGMP decreased significantly in the diabetic rats compared with normal controls. An 8-week administration of caffeine at the given dosages increased the ICP and cavernous cGMP in diabetic rats. Caffeine consumption improved the erectile function of diabetic rats by up-regulating cavernous cGMP. | Ravi D, Muniyappa H, Das KC (2008) Caffeine inhibits UV-mediated NF-kappaB activation in A2058 melanoma cells: an ATM-PKCdelta-p38 MAPK-dependent mechanism. Molecular and cellular biochemistry 308, 193-200 [PubMed:17932622] [show Abstract] Mammalian ultraviolet (UV) radiation response is a gene induction cascade activated by several transcription factors, including NF-kappaB. Although NF-kappaB is induced by UV radiation, the signal transduction mechanism remains relatively unclear. In the present study, we show that UV-induced NF-kappaB activation is mediated by the activation of Ataxia telangiecia mutated (ATM) and protein kinase C (PKC). We also show that caffeine specifically inhibits UV-mediated NF-kappaB activation, but not TNFalpha-mediated NF-kappaB activation. In addition, our study shows that ATM, but not ATM-Rad3-related (ATR) or DNA-dependent protein kinase (DNA-PK) is involved in UV-induced NF-kappaB activation. Because SB203580 (a p38 MAPK inhibitor), or Calphostin C or rottlerin (PKC inhibitors) was able to inhibit UV-mediated NF-kappaB activation, we evaluated whether caffeine could inhibit p38 MAPK or PKC activity. Caffeine or rottlerin inhibited UV-induced phosphorylation of p38 MAPK, but not anisomycin-induced phosphorylation of p38 MAPK, suggesting that p38 MAPK is downstream of PKC. Additionally, caffeine could effectively inhibit UV-induced increases in PKC activity. Taken together, our study demonstrates that caffeine is a potent inhibitor of UV-induced NF-kappaB activation. Additionally, this inhibition occurs due to the inhibitory action of caffeine on ATM and PKC, resulting in the inhibition of p38 MAPK activation. | Wanke V, Cameroni E, Uotila A, Piccolis M, Urban J, Loewith R, De Virgilio C (2008) Caffeine extends yeast lifespan by targeting TORC1. Molecular microbiology 69, 277-285 [PubMed:18513215] [show Abstract] Dietary nutrient limitation (dietary restriction) is known to increase lifespan in a variety of organisms. Although the molecular events that couple dietary restriction to increased lifespan are not clear, studies of the model eukaryote Saccharomyces cerevisiae have implicated several nutrient-sensitive kinases, including the target of rapamycin complex 1 (TORC1), Sch9, protein kinase A (PKA) and Rim15. We have recently demonstrated that TORC1 activates Sch9 by direct phosphorylation. We now show that Sch9 inhibits Rim15 also by direct phosphorylation. Treatment of yeast cells with the specific TORC1 inhibitor rapamycin or caffeine releases Rim15 from TORC1-Sch9-mediated inhibition and consequently increases lifespan. This kinase cascade appears to have been evolutionarily conserved, suggesting that caffeine may extend lifespan in other eukaryotes, including man. | Ashihara H, Sano H, Crozier A (2008) Caffeine and related purine alkaloids: biosynthesis, catabolism, function and genetic engineering. Phytochemistry 69, 841-856 [PubMed:18068204] [show Abstract] Details of the recently elucidated biosynthetic pathways of caffeine and related purine alkaloids are reviewed. The main caffeine biosynthetic pathway is a sequence consisting of xanthosine-->7-methylxanthosine-->7-methylxanthine-->theobromine-->caffeine. Genes encoding N-methyltransferases involved in three of these four reactions have been isolated and the molecular structure of N-methyltransferases investigated. Pathways for the catabolism of caffeine have also been studied, although there are currently no reports of enzymatic and genetic studies having been successfully carried out. Metabolism of purine alkaloids in species including Camellia, Coffea, Theobroma and Ilex plants is summarised, and evidence for the involvement of caffeine in chemical defense and allelopathy is discussed. Finally, information is presented on metabolic engineering that has produced coffee seedlings with reduced caffeine content, and transgenic caffeine-producing tobacco plants with enhanced disease resistance. | Pardo Lozano R, Alvarez García Y, Barral Tafalla D, Farré Albaladejo M (2007) [Caffeine: a nutrient, a drug or a drug of abuse]. Adicciones 19, 225-238 [PubMed:17724925] [show Abstract] Coffee, tea, chocolate and caffeinated drinks are the main sources of caffeine, which is consumed in almost all ages and socioeconomic levels. Caffeine acts as a non-selective adenosine receptor antagonist in the central nervous system. Its main effects are as psychostimulant, acting in addition on the respiratory, muscular and cardiovascular systems. Basically, caffeine is metabolized by the hepatic cytochrome P-450 1A2 enzymes (CYP1A2). Several drugs can interact with its metabolism. The observed interindividual differences of its effects can be explained by variations in its metabolism. The main therapeutic use of caffeine is bronchodilator in respiratory diseases. Other possible uses are under investigation. Acute or chronic consumption of caffeine can induce several adverse effects, including intoxication that can be lethal. Finally, caffeine can be considered a drug of abuse. It has positive reinforcing actions, produces tolerance, and a withdrawal syndrome after stopping its consumption. Caffeine can cause different mental disorders such as dependence, which is not included in the DSM-IV-R, withdrawal syndrome and intoxication. Depending on its use, caffeine can be considered a nutrient, a drug or a drug of abuse. | Bode AM, Dong Z (2007) The enigmatic effects of caffeine in cell cycle and cancer. Cancer letters 247, 26-39 [PubMed:16709440] [show Abstract] Caffeine may very well be the most frequently ingested neuroactive drug in the world. Mechanistically, caffeine has been reported to affect cell cycle function, induce programmed cell death or apoptosis and perturb key cell cycle regulatory proteins. Although the effects of caffeine have been heavily investigated, much of the research data regarding caffeine's effects on cell cycle and proliferation seem ambiguous. One important factor may be that caffeine has been used experimentally in numerous cell types under a variety of conditions at concentrations ranging from micromolar to high millimolar. Physiologically, achieving experimental blood levels of caffeine would be extremely difficult without adverse side effects. Therefore, the relevance of experimental data obtained by using high concentrations of caffeine is not clear and may account for some of the discrepancies in the literature. This review attempts to reconcile data regarding the cellular effects of caffeine by examining reported effects on cell cycle, proliferation and apoptosis with careful attention to differences in experimental conditions and caffeine concentration utilized. | Judd K, Shugert E, Vélez SJ (2007) Depressing effects of caffeine at crayfish neuromuscular synapses I. Dosage response and Ca++ gradient effects. Cellular and molecular neurobiology 27, 367-380 [PubMed:17387608] [show Abstract] The response of crayfish synaptic terminals to drugs began to be studied to characterize the terminal's physiological characteristics. Caffeine, the first drug to be studied, was selected to enhance synaptic transmission because of its ability to increase calcium release from internal stores.1. The largest excitor neuron to the superficial flexor muscle system of Procambarus clarkii was stimulated at 10 Hz while recording junction potentials from several lateral muscle fibers.2. Caffeine unexpectedly decreased synaptic transmission in this system in a dosage-dependent manner. The depressing effect of caffeine was observed at 5 mM caffeine and junction potentials disappeared completely at 50 mM. Washing the preparation in fresh control Ringers did not restore the amplitudes of the junction potentials.3. Changes in extracellular calcium concentrations delayed or depressed the caffeine effect depending on the calcium gradient across the membrane or the caffeine dosage. The data suggest that calcium is involved in caffeine's response in this system in a way yet to be determined. | Shapiro RE (2007) Caffeine and headaches. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 28 Suppl 2, S179-83 [PubMed:17508167] [show Abstract] Caffeine is the most widely consumed psychostimulant drug. It is a potent antagonist of adenosine receptors at dosages consistent with common dietary intake. With infrequent exposure, caffeine may act as an analgesic for headache or an adjuvant for the actions of other analgesics. With chronic repetitive intake, caffeine is associated with an increased risk of development of analgesicoveruse headache, chronic daily headache and physical dependency. Cessation of caffeine use following chronic exposures leads to a withdrawal syndrome, with headache as a dominant symptom. | McCusker RR, Fuehrlein B, Goldberger BA, Gold MS, Cone EJ (2006) Caffeine content of decaffeinated coffee. Journal of analytical toxicology 30, 611-613 [PubMed:17132260] [show Abstract] Caffeine is the most widely consumed drug in the world with coffee representing a major source of intake. Despite widespread availability, various medical conditions necessitate caffeine-restricted diets. Patients on certain prescription medications are advised to discontinue caffeine intake. Such admonition has implications for certain psychiatric patients because of pharmacokinetic interactions between caffeine and certain anti-anxiety drugs. In an effort to abstain from caffeine, patients may substitute decaffeinated for caffeinated coffee. However, decaffeinated beverages are known to contain caffeine in varying amounts. The present study determined the caffeine content in a variety of decaffeinated coffee drinks. In phase 1 of the study, 10 decaffeinated samples were collected from different coffee establishments. In phase 2 of the study, Starbucks espresso decaffeinated (N=6) and Starbucks brewed decaffeinated coffee (N=6) samples were collected from the same outlet to evaluate variability of caffeine content of the same drink. The 10 decaffeinated coffee samples from different outlets contained caffeine in the range of 0-13.9 mg/16-oz serving. The caffeine content for the Starbucks espresso and the Starbucks brewed samples collected from the same outlet were 3.0-15.8 mg/shot and 12.0-13.4 mg/16-oz serving, respectively. Patients vulnerable to caffeine effects should be advised that caffeine may be present in coffees purported to be decaffeinated. Further research is warranted on the potential deleterious effects of consumption of "decaffeinated" coffee that contains caffeine on caffeine-restricted patients. Additionally, further exploration is merited for the possible physical dependence potential of low doses of caffeine such as those concentrations found in decaffeinated coffee. | Conde SV, Obeso A, Vicario I, Rigual R, Rocher A, Gonzalez C (2006) Caffeine inhibition of rat carotid body chemoreceptors is mediated by A2A and A2B adenosine receptors. Journal of neurochemistry 98, 616-628 [PubMed:16805851] [show Abstract] Caffeine, an unspecific antagonist of adenosine receptors, is commonly used to treat the apnea of prematurity. We have defined the effects of caffeine on the carotid body (CB) chemoreceptors, the main peripheral controllers of breathing, and identified the adenosine receptors involved. Caffeine inhibited basal (IC50, 210 microm) and low intensity (PO2 approximately 66 mm Hg/30 mm K+) stimulation-induced release of catecholamines from chemoreceptor cells in intact preparations of rat CB in vitro. Opposite to caffeine, 5'-(N-ethylcarboxamido)adenosine (NECA; an A2 agonist) augmented basal and low-intensity hypoxia-induced release. 2-p-(2-Carboxyethyl)phenethyl-amino-5'-N-ethylcaboxamido-adenosine hydrochloride (CGS21680), 2-hexynyl-NECA (HE-NECA) and SCH58621 (A2A receptors agents) neither affected catecholamine release nor altered the caffeine effects. The 8-cycle-1,3-dipropylxanthine (DPCPX; an A1/A2B antagonist) and 8-(4-{[(4-cyanophenyl)carbamoylmethyl]-oxy}phenyl)-1,3-di(n-propyl)xanthine (MRS1754; an A2B antagonist) mimicking of caffeine indicated that caffeine effects are mediated by A2B receptors. Immunocytochemical A2B receptors were located in tyrosine hydroxylase positive chemoreceptor cells. Caffeine reduced by 52% the chemosensory discharges elicited by hypoxia in the carotid sinus nerve. Inhibition had two components with pharmacological analysis indicating that A2A and A2B receptors mediate, respectively, the low (17 x 10(-9) m) and high (160 x 10(-6) m) IC50 effects. It is concluded that endogenous adenosine, via presynaptic A2B and postsynaptic A2A receptors, can exert excitatory effects on the overall output of the rat CB chemoreceptors. | Vavra-Hadziahmetović N, Hadziahmetović Z (2006) [The effects of physical therapy in prevention of deep vein thrombosis (DVT) in the "syndrome of economy class"]. Medicinski arhiv 60, 115-116 [PubMed:16528931] [show Abstract] "Economy class syndrome" made headline news in Australia when young girl died from blood clot caused by deep vein thrombosis shortly after getting off a Sydney to London flight. Although medical research is yet to prove a link between long distance travelling and DVT, consumers sholud take precautions. Pain and swelling in one leg is usually the first sign of a DTV, although sometimes there won, t be any symptoms. In one to two percent of cases the blood clot can break away from the vein and travel to other major organs. If it s big enough it may cause breathing problems (pulmonary embolism), and in rare cases--around one in a thousand people with a DVT-death. During the flight: Change your position regularly and be aware of positions which might block your circulation. Regular excercise will help restore blood flow to your legs if you've been sitting for long period of time or in an awkward position. Dehydratation can cause the blood to thiceken. Alcohol and caffeine are known diuretics which may accentuate the effect of dry cabin air and immobility on blood flow. Drink 200 mls (a standards glass) of non-alcoholic fluids every hour and use the need to go to the toilet as an opportunity to change your posture. | Wu WP, Hao JX, Fredholm BB, Wiesenfeld-Hallin Z, Xu XJ (2006) Effect of acute and chronic administration of caffeine on pain-like behaviors in rats with partial sciatic nerve injury. Neuroscience letters 402, 164-166 [PubMed:16644114] [show Abstract] Caffeine, used in many pain medications as an adjuvant analgesic, is an adenosine A1 and A2A receptor antagonist. Here we examined the effects of acute or chronic caffeine administration in rats after partial sciatic nerve injury. The hindpaw response to mechanical or cold stimulation was assessed following photochemically induced sciatic nerve injury which leads to hypersensitivity to these stimuli. Caffeine was administered i.p. acutely or in the drinking water chronically. The mechanical and cold hypersensitivity of sciatic nerve-injured rats was dose-dependently alleviated by acute systemic administration of caffeine (10-80 mg/kg). The effect of caffeine was, however, associated with side effects including locomotor stimulation or depression. Chronic oral administration (average daily doses 27.5 mg/kg/day or 61.5 mg/kg/day for 2 weeks) of caffeine starting at the time of nerve injury did not significantly affect the development of pain-like behaviors. Thus, acute, but not long term, caffeine intake reduced neuropathic pain state in nerve-injured rats, but only at very high doses. The potential hyperalgesic effect of chronic A1 adenosine receptor blockade may have been compensated for by an antinociceptive effect of caffeine through antagonism of A2A receptors and tolerance development. | Al-Wadei HA, Takahashi T, Schuller HM (2006) Caffeine stimulates the proliferation of human lung adenocarcinoma cells and small airway epithelial cells via activation of PKA, CREB and ERK1/2. Oncology reports 15, 431-435 [PubMed:16391865] [show Abstract] The incidence of pulmonary adenocarcinoma (PAC) has increased dramatically over the last three decades. Recent studies have shown that human PAC cells with phenotypic features of bronchiolar Clara cells and experimentally induced PAC of Clara cell origin are under beta-adrenergic growth control. The phosphodiesterase inhibitor, theophylline, which is contained in tea, asthma/allergy medications and numerous dietary supplements selectively stimulated the growth of this cancer type in vivo and in vitro. The current study has tested the hypothesis that another environmentally prominent phosphodiesterase inhibitor, caffeine, has similar effects. Using a cell line derived from a human PAC with Clara cell features (PACC) and immortalized human small airway epithelial cells (SAECs), our data show that caffeine activated protein kinase A (PKA), the mitogen-activated kinases ERK1/2, the nuclear transcription factor cyclic AMP response element binding protein (CREB) and stimulated cell proliferation in these cell lines. These findings suggest that exposure to caffeine may contribute to the prevalence of PAC observed today. | Rodrigues IM, Klein LC (2006) Boiled or filtered coffee? Effects of coffee and caffeine on cholesterol, fibrinogen and C-reactive protein. Toxicological reviews 25, 55-69 [PubMed:16856769] [show Abstract] 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. | Varani K, Portaluppi F, Gessi S, Merighi S, Vincenzi F, Cattabriga E, Dalpiaz A, Bortolotti F, Belardinelli L, Borea PA (2005) Caffeine intake induces an alteration in human neutrophil A2A adenosine receptors. Cellular and molecular life sciences : CMLS 62, 2350-2358 [PubMed:16143823] [show Abstract] Caffeine is the most widely used drug in the world and acts mainly through antagonism of the effects mediated by the adenosine receptor subtypes A1, A2A, A2B and A3. We determined whether repeated caffeine administration at different doses and for different periods of time (400 or 600 mg/day for 1 week and 400 mg/day for 2 weeks) alters human neutrophil A2A adenosine receptor density and function. Saturation binding assays showed an increase in affinity (K(D)) and density (B(max)) of A2A adenosine receptors after caffeine intake. These changes were accompanied by increases in cAMP accumulation and decreases in superoxide anion production after stimulation of the A2A receptor subtype using the agonist 5'-N-ethylcarboxamidoadenosine (NECA). Binding and functional changes of A2A receptors returned to baseline after 48 h of caffeine withdrawal. The findings are consistent with a potential anti-inflammatory effect of caffeine mediated by neutrophil A2A receptors. | Daniel R, Marusich E, Argyris E, Zhao RY, Skalka AM, Pomerantz RJ (2005) Caffeine inhibits human immunodeficiency virus type 1 transduction of nondividing cells. Journal of virology 79, 2058-2065 [PubMed:15681408] [show Abstract] Caffeine is an efficient inhibitor of DNA repair and DNA damage-activated checkpoints. We have shown recently that caffeine inhibits retroviral transduction of dividing cells, most likely by blocking postintegration repair. This effect may be mediated at least in part by a cellular target of caffeine, the ataxia telangiectasia-mutated and Rad3-related (ATR) kinase. In this study, we present evidence that caffeine also inhibits efficient transduction of nondividing cells. We observed reduced transduction in caffeine-treated growth-arrested cells as well as caffeine-treated terminally differentiated human neurons and macrophages. Furthermore, this deficiency was observed with a human immunodeficiency virus type 1 (HIV-1) vector lacking Vpr, indicating that the effect is independent of the presence of this viral protein in the infecting virion. Finally, we show that HIV-1 transduction of nocodazole-arrested cells is reduced in cells that express an ATR dominant-negative protein (kinase-dead ATR [ATRkd]) and that the residual transduction of ATRkd-expressing cells is relatively resistant to caffeine. Taken together, these data suggest that the effect(s) of caffeine on HIV-1 transduction is mediated at least partly by the inhibition of the ATR pathway but is not dependent on the caffeine-mediated inhibition of cell cycle checkpoints. | Prediger RD, Batista LC, Takahashi RN (2005) Caffeine reverses age-related deficits in olfactory discrimination and social recognition memory in rats. Involvement of adenosine A1 and A2A receptors. Neurobiology of aging 26, 957-964 [PubMed:15718055] [show Abstract] Caffeine, a non-selective adenosine receptor antagonist, has been suggested as a potential drug to counteract age-related cognitive decline since critical changes in adenosinergic neurotransmission occur with aging. In the present study, olfactory discrimination and short-term social memory of 3, 6, 12 and 18 month-old rats were assessed with the olfactory discrimination and social recognition tasks, respectively. The actions of caffeine (3.0, 10.0 and 30.0 mg/kg, i.p.), the A1 receptor antagonist DPCPX (1.0 and 3.0 mg/kg, i.p.) and the A2A receptor antagonist ZM241385 (0.5 and 1.0 mg/kg, i.p.) in relation to age-related effects on olfactory functions were also studied. The 12 and 18 month-old rats exhibited significantly impaired performance in both models, demonstrating deficits in their odor discrimination and in their ability to recognize a juvenile rat after a short period of time. Acute treatment with caffeine or ZM241385, but not with DPCPX, reversed these age-related olfactory deficits. The present results suggest the participation of adenosine receptors in the control of olfactory functions and confirm the potential of caffeine for the treatment of aged-related cognitive decline. | Nunnari G, Argyris E, Fang J, Mehlman KE, Pomerantz RJ, Daniel R (2005) Inhibition of HIV-1 replication by caffeine and caffeine-related methylxanthines. Virology 335, 177-184 [PubMed:15840517] [show Abstract] Human immunodeficiency virus type I (HIV-1) DNA integration is an essential step of viral replication. We have suggested recently that this stage of HIV-1 life-cycle triggers a cellular DNA damage response and requires cellular DNA repair proteins for its completion. These include DNA-PK (DNA-dependent protein kinase), ATR (ataxia telangiectasia and Rad3-related), and, at least in some circumstances, ATM (ataxia telangiectasia mutated). Host cell proteins may constitute an attractive target for anti-HIV-1 therapeutics, since development of drug resistance against compounds targeting these cellular cofactor proteins is unlikely. In this study, we show that an inhibitor of ATR and ATM kinases, caffeine, can suppress replication of infectious HIV-1 strains, and provide evidence that caffeine exerts its inhibitory effect at the integration step of the HIV-1 life-cycle. We also demonstrate that caffeine-related methylxanthines including the clinically used compound, theophylline, act at the same step of the HIV-1 life-cycle as caffeine and efficiently inhibit HIV-1 replication in primary human cells. These data reveal the feasibility of therapeutic approaches targeting host cell proteins and further support the hypothesis that ATR and ATM proteins are involved in retroviral DNA integration. | Chiarella P, Puglisi R, Sorrentino V, Boitani C, Stefanini M (2004) Ryanodine receptors are expressed and functionally active in mouse spermatogenic cells and their inhibition interferes with spermatogonial differentiation. Journal of cell science 117, 4127-4134 [PubMed:15280431] [show Abstract] Ryanodine receptors (RyRs) are intracellular calcium release channels that are highly expressed in striated muscle and neurons but are also detected in several non-excitable cells. We have studied the expression of the three RyR isoforms in male germ cells at different stages of maturation by western blot and RT-PCR. RyR1 was expressed in spermatogonia, pachytene spermatocytes and round spermatids whereas RyR2 was found only in 5- to 10-day-old testis but not in germ cells. RyR3 was not revealed at the protein level, although its mRNA was detected in mixed populations of germ cells. Caffeine, a known agonist of RyRs, was able to induce release of Ca(2+) from intracellular stores in spermatogonia, pachytene spermatocytes and round spermatids, but not spermatozoa. Treatment with high doses of ryanodine, which are known to block RyR channel activity, reduced spermatogonial proliferation and induced meiosis in in vitro organ cultures of testis from 7-day-old mice. In conclusion, the results presented here indicate that RyRs are present in germ cells and that calcium mobilization through RyR channels could participate to the regulation of male germ maturation. | Landolt HP, Rétey JV, Tönz K, Gottselig JM, Khatami R, Buckelmüller I, Achermann P (2004) Caffeine attenuates waking and sleep electroencephalographic markers of sleep homeostasis in humans. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 29, 1933-1939 [PubMed:15257305] [show Abstract] Prolonged wakefulness increases electroencephalogram (EEG) low-frequency activity (< 10 Hz) in waking and sleep, and reduces spindle frequency activity (approximately 12-16 Hz) in non-rapid-eye-movement (nonREM) sleep. These physiologic markers of enhanced sleep propensity reflect a sleep-wake-dependent process referred to as sleep homeostasis. We hypothesized that caffeine, an adenosine receptor antagonist, reduces the increase of sleep propensity during waking. To test this hypothesis, we compared the effects of caffeine and placebo on EEG power spectra during and after 40 h of wakefulness. A total of 12 young men underwent two periods of sleep deprivation. According to a randomized, double-blind, crossover design, they received two doses of caffeine (200 mg) or placebo after 11 and 23 h of wakefulness. Sleep propensity was estimated at 3-h intervals by measuring subjective sleepiness and EEG theta (5-8 Hz) activity, and polysomnographic recordings of baseline and recovery nights. Saliva caffeine concentration decreased from 15.7 micromol/l 16 h before the recovery night, to 1.8 micromol/l 1 h before the recovery night. Compared with placebo, caffeine reduced sleepiness and theta activity during wakefulness. Compared with sleep under baseline conditions, sleep deprivation increased 0.75-8.0 Hz activity and reduced spindle frequency activity in nonREM sleep of the recovery nights. Although caffeine approached undetectable saliva concentrations before recovery sleep, it significantly reduced EEG power in the 0.75-2.0 Hz band and enhanced power in the 11.25-20.0 Hz range relative to placebo. These findings suggest that caffeine attenuated the build-up of sleep propensity associated with wakefulness, and support an important role of adenosine and adenosine receptors in the homeostatic regulation of sleep. | Waldvogel SR (2003) Caffeine--a drug with a surprise. Angewandte Chemie (International ed. in English) 42, 604-605 [PubMed:12574990] | Cherif A, Marrakchi Z, Klouz A, Chaouachi S, Belkahia C, Boukef-Larguèche S (2003) [Pharmacologic study of monohydrated caffeine in the treatment of apnoea of premature infant]. Archives de pediatrie : organe officiel de la Societe francaise de pediatrie 10, 517-520 [PubMed:12915014] [show Abstract]
UnlabelledMonohydrated caffeine was the only respiratory xanthine available in our country to treat apnea of premature infant. The aim of this study was to evaluate plasma levels of this molecule at dosages of 20 mg/kg (equal to 18 mg/kg of caffeine base) as a loading dose and 5 mg(-1) kg(-1) (equal to 4.5 mg(-1) kg(-1) of caffeine base) as a maintenance dose.Patients and methodsThe study was prospective including premature infants less than 34 weeks of gestational age born between the 1st of july 2001 and 15th december 2001 and receiving monohydrated caffeine to prevent apnea. Each premature infant has received orally a loading dose of 20 mg/kg in the first hours of life followed, 24 h after, by a maintenance dose orally once a day of 5 mg/kg until 35 weeks of post-conceptional age. Caffeinemia plasma levels were measured by high performance liquid chromatography immediately before the second dose to determine the loading residual rate and immediately before the sixth dose to determine the maintenance residual rate.ResultsTwenty-one premature infants were included. Their medium term was 31.4 weeks (27.4-33.3 weeks), birth weight was 1684 g (1000-2800 g) and sex-ratio M/F was 1.3. Fifteen infants (71.4%) have presented apnea with an average of 4.1 episodes per infant and per day. Tolerance of the medicament was good in all cases. The medium loading residual rate was 3.26 microg/ml (1.75-7.80) and the medium maintenance residual rate was 4.26 microg/ml (2.13-7.64).ConclusionPrescribed at a dosage close to twice the recommendations of the literature, monohydrated caffeine does not provide efficient plasma rates. This is probably due to a difference in its oral bio-availability compared with caffeine citrate and further study with greater dosages is needed to appreciate its efficacy. | McCusker RR, Goldberger BA, Cone EJ (2003) Caffeine content of specialty coffees. Journal of analytical toxicology 27, 520-522 [PubMed:14607010] [show Abstract] Caffeine is the world's most widely consumed drug with its main source found in coffee. We evaluated the caffeine content of caffeinated and decaffeinated specialty coffee samples obtained from coffee shops. Caffeine was isolated from the coffee by liquid-liquid extraction and analyzed by gas chromatography with nitrogen-phosphorus detection. In this study, the coffees sold as decaffeinated were found to have caffeine concentrations less than 17.7 mg/dose. There was a wide range in caffeine content present in caffeinated coffees ranging from 58 to 259 mg/dose. The mean (SD) caffeine content of the brewed specialty coffees was 188 (36) mg for a 16-oz cup. Another notable find is the wide range of caffeine concentrations (259-564 mg/dose) in the same coffee beverage obtained from the same outlet on six consecutive days. | Murphy JA, Deurveilher S, Semba K (2003) Stimulant doses of caffeine induce c-FOS activation in orexin/hypocretin-containing neurons in rat. Neuroscience 121, 269-275 [PubMed:14521986] [show Abstract] Although caffeine is a commonly used CNS stimulant, neuronal mechanisms underlying its stimulatory effect are not fully understood. Orexin (hypocretin)-containing neurons play a critical role in arousal and might be activated by acute administration of caffeine. We examined this possibility by using dual-immunostaining for orexin B and c-Fos protein as a marker for neuronal activation. Rats were administered intraperitoneally with 10, 30 or 75 mg/kg caffeine, or saline. As previously reported, caffeine increased locomotion at 10 and 30 mg/kg, but not at 75 mg/kg. The numbers of orexin-immunoreactive and non-orexin-immunoreactive neurons expressing c-Fos were analysed using three counting boxes within the orexin field in the posterior hypothalamus. Compared with saline, all doses of caffeine increased the number of cells immunoreactive for both orexin and c-Fos. The average magnitude of this increase across doses in orexin neurons differed amongst regions; c-Fos expression increased by 343% in the perifornical area and by 158% in the more medial, dorsomedial nucleus. In the lateral hypothalamic area, c-Fos expression increased by 226% at 10 and 30 mg/kg but no change was seen at 75 mg/kg. In contrast, caffeine significantly increased the number of non-orexin-immunoreactive neurons expressing c-Fos only in the dorsomedial nucleus. These results indicate that systemically administered caffeine preferentially activates orexin neurons over non-orexin neurons in the same field, and that this activation is most pronounced in the perifornical region where orexin neurons are most concentrated. The activation of orexin neurons might play a role in the behavioural activation by caffeine. | Al Moutaery K, Al Deeb S, Ahmad Khan H, Tariq M (2003) Caffeine impairs short-term neurological outcome after concussive head injury in rats. Neurosurgery 53, 704-11; discussion 711-2 [PubMed:12943586] [show Abstract]
ObjectiveAdenosine is an endogenous neuroprotective agent that is released during ischemia, hypoxia, epilepsy, and ischemic brain injury. Caffeine is a receptor antagonist for adenosine that might interfere with the neuroprotective effect of adenosine in ischemic-hypoxic conditions. An investigation was undertaken to study the effect of caffeine on neurological function, edema formation, and blood-brain barrier permeability after experimental head injury in rats.MethodsAdult female Wistar rats classified into different groups received caffeine intraperitoneally at doses of 0, 50, 100, and 150 mg/kg body weight. Thirty minutes after the caffeine treatment, the animals were subjected to concussive head injury (CHI) administered by a controlled cortical impact device. Neurological severity score was recorded in each rat at 2 hours after CHI. Specific gravity, water content (as an indicator of edema), and blood-brain barrier impairment were analyzed in the cortical tissue surrounding the injury site. The levels of myeloperoxidase and malondialdehyde in the cortical region were measured as indicators of neutrophil infiltration and lipid peroxidation, respectively.ResultsA significant increase in righting latency and neurological deficiency after CHI was observed in caffeine-treated rats as compared with untreated animals. Although no deaths occurred in the rats exposed to CHI after pretreatment with saline, pretreatment with caffeine caused significant mortality of animals after trauma in a dose-dependent manner. Caffeine also exacerbated neutrophil infiltration, edema, and disruption of blood-brain barrier in the traumatic cortex. Light microscopy of brain revealed more severe hemorrhage and neuronal degeneration in the injured hemisphere of caffeine-treated rats as compared with rats in the injury-alone group. A significant increase in malondialdehyde in the brain of injured rats treated with caffeine before CHI clearly indicated the role of oxidative stress.ConclusionCaffeine adversely affects outcome after CHI, possibly as a result of blockade of adenosine receptors. The findings also point toward the involvement of free radical-mediated neuronal damage in caffeine-induced exacerbation of neurotrauma. | Keijzers GB, De Galan BE, Tack CJ, Smits P (2002) Caffeine can decrease insulin sensitivity in humans. Diabetes care 25, 364-369 [PubMed:11815511] [show Abstract]
ObjectiveCaffeine is a central stimulant that increases the release of catecholamines. As a component of popular beverages, caffeine is widely used around the world. Its pharmacological effects are predominantly due to adenosine receptor antagonism and include release of catecholamines. We hypothesized that caffeine reduces insulin sensitivity, either due to catecholamines and/or as a result of blocking adenosine-mediated stimulation of peripheral glucose uptake.Research design and methodsHyperinsulinemic-euglycemic glucose clamps were used to assess insulin sensitivity. Caffeine or placebo was administered intravenously to 12 healthy volunteers in a randomized, double-blind, crossover design. Measurements included plasma levels of insulin, catecholamines, free fatty acids (FFAs), and hemodynamic parameters. Insulin sensitivity was calculated as whole-body glucose uptake corrected for the insulin concentration. In a second study, the adenosine reuptake inhibitor dipyridamole was tested using an identical protocol in 10 healthy subjects.ResultsCaffeine decreased insulin sensitivity by 15% (P < 0.05 vs. placebo). After caffeine administration, plasma FFAs increased (P < 0.05) and remained higher than during placebo. Plasma epinephrine increased fivefold (P < 0.0005), and smaller increases were recorded in plasma norepinephrine (P < 0.02) and blood pressure (P < 0.001). Dipyridamole did not alter insulin sensitivity and only increased plasma norepinephrine (P < 0.01).ConclusionsCaffeine can decrease insulin sensitivity in healthy humans, possibly as a result of elevated plasma epinephrine levels. Because dipyridamole did not affect glucose uptake, peripheral adenosine receptor antagonism does not appear to contribute to this effect. | Keogh E, Chaloner N (2002) The moderating effect of anxiety sensitivity on caffeine-induced hypoalgesia in healthy women. Psychopharmacology 164, 429-431 [PubMed:12457274] [show Abstract]
RationaleCaffeine is an analgesic adjuvant, but also has panicogenic properties. Anxiety sensitivity is a trait vulnerability factor related to negative responses to pain, and is known to moderate negative psychological responses to caffeine.ObjectivesThe current study sought to investigate whether anxiety sensitivity moderates the effect caffeine has on the pain responses of healthy women.MethodsCaffeine (250 mg) was administered to women pre-selected as high, medium or low in anxiety sensitivity. Measures of arousal and mood were taken before and after drug administration. The cold pressor pain task was used to induce pain. Pain threshold, tolerance, sensory and affective pain responses were also recorded.ResultsCaffeine increased systolic blood pressure and mood. Additionally, those low in anxiety sensitivity exhibited caffeine-induced improvement in negative mood (less depressed) and caffeine-related hypoalgesia.ConclusionsThese results suggest that the analgesic effects of caffeine may depend on anxiety sensitivity status, and that the fear of bodily sensations should be considered in pain management programmes. | Hoesch RE, Weinreich D, Kao JP (2001) A novel Ca(2+) influx pathway in mammalian primary sensory neurons is activated by caffeine. Journal of neurophysiology 86, 190-196 [PubMed:11431501] [show Abstract] Single-cell microfluorimetry and electrophysiology techniques were used to identify and characterize a novel Ca(2+) influx pathway in adult rabbit vagal sensory neurons. Acutely dissociated nodose ganglion neurons (NGNs) exhibit robust Ca(2+)-induced Ca(2+) release (CICR) that can be triggered by 10 mM caffeine, the classic agonist of CICR. A caffeine-induced increase in cytosolic-free Ca(2+) concentration ([Ca(2+)](i)) is considered diagnostic evidence of the existence of CICR. However, when CICR was disabled through depletion of intracellular Ca(2+) stores or pharmacological blockade of intracellular Ca(2+) release channels (ryanodine receptors), caffeine still elicited a significant rise in [Ca(2+)](i) in approximately 50% of NGNs. The same response was not elicited by pharmacological agents that elevate cyclic nucleotide concentrations. Moreover, extracellular Ca(2+) was obligatory for such caffeine-induced [Ca(2+)](i) rises in this population of NGNs, suggesting that Ca(2+) influx is responsible for this rise. Simultaneous microfluorimetry with whole cell patch-clamp studies showed that caffeine activates an inward current that temporally parallels the rise in [Ca(2+)](i). The inward current had a reversal potential of +8.1 +/- 6.1 (SE) mV (n = 4), a mean peak amplitude of -126 +/- 24 pA (n = 4) at E(m) = -50 mV, and a slope conductance of 1.43 +/- 0.79 nS (n = 4). Estimated EC(50) values for caffeine-induced CICR and for caffeine-activated current were 1.5 and approximately 0.6 mM, respectively. These results indicate that caffeine-induced rises in [Ca(2+)](i), in the presence of extracellular Ca(2+), can no longer be interpreted as unequivocal diagnostic evidence for CICR in neurons. These results also indicate that sensory neurons possess a novel Ca(2+) influx pathway. | Donovan JL, DeVane CL (2001) A primer on caffeine pharmacology and its drug interactions in clinical psychopharmacology. Psychopharmacology bulletin 35, 30-48 [PubMed:12397877] [show Abstract] Caffeine in the form of various beverages and as an additive in numerous drug formulations is the most widely consumed drug in the world. Its psychostimulant properties account for much of its popularity. Caffeine has multiple pharmacological effects that influence normal physiological functioning, and it has been suspected of contributing to morbidity. Drug interactions of caffeine with other psychoactive drugs are described. This review summarizes the pharmacology of caffeine and its drug interactions relevant to the practice of clinical psychopharmacology. The impact of caffeine consumption should be considered in planning and assessing responses to pharmacotherapy for mental illness. | Christian MS, Brent RL (2001) Teratogen update: evaluation of the reproductive and developmental risks of caffeine. Teratology 64, 51-78 [PubMed:11410911] [show Abstract] Caffeine is a methylated xanthine that acts as a mild central nervous system stimulant. It is present in many beverages, including coffee, tea, and colas, as well as chocolate. Caffeine constitutes 1-2% of roasted coffee beans, 3.5% of fresh tea leaves, and approximately 2% of mate leaves (Spiller, '84; Graham, '84a,b). Many over-the-counter medications, such as cold and allergy tablets, headache medicines, diuretics, and stimulants also contain caffeine, although they lead to relatively minimal intake (FDA, '86). In epidemiological studies, it is assumed that one cup of coffee contains < or =100 mg of caffeine, and soft drinks, such as colas, contain 10-50 mg of caffeine per 12-ounce serving. The per-capita consumption of caffeine from all sources is estimated to be about 3-7 mg/kg per day, or approximately 200 mg/day (Barone and Roberts, '96). Consumption of caffeinated beverages during pregnancy is quite common (Hill et al., '77) and is estimated to be approximately 144 mg/day, or 2.4 mg/kg for a 60-kg human (Morris and Weinstein, '81). However, pregnant women appear to consume slightly less than do other adults, approximately 1 mg/kg per day (Barone and Roberts, '96). This decrease may be interrelated with taste aversion (Hook, '76; Little, '82). The medical literature contains many varied references that appear to indicate that human adverse reproductive/developmental effects are produced by caffeine. If caffeine indeed causes such effects, the reproductive consequences could be very serious because caffeine-containing foods and beverages are consumed by most of the human populations of the world, and consumption in the United States is estimated to be 4.5-kg/person/year (Narod et al., '91). Therefore, the medical literature dealing with developmental and reproductive risks of caffeine was reviewed, and the biological plausibility of the epidemiological and animal findings, as well as the methods and conclusions of previous investigators, were evaluated. The epidemiological studies describe exposures of women to caffeine during pregnancy, as well as the occurrence of congenital malformations, fetal growth retardation, small-for-date babies, miscarriages (spontaneous abortions), behavioral effects, and maternal fertility problems that presumably resulted from the caffeine consumption. A few epidemiological studies were concerned with the genetic effects of preconception exposures to caffeine. Animal studies, conducted mostly in pregnant rats and mice, were designed to produce malformations. The objectives of the present review are to summarize the findings from the various clinical and animals studies, objectively discuss the merits and/or faults inherent in the studies and establish a global reproductive risk assessment for caffeine consumption in humans during pregnancy. It should be noted that evaluation of the developmental risks of caffeine based solely on epidemiological studies is difficult because the findings are inconsistent. Even more important, is the fact that caffeine users are subject to multiple confounding factors that make analyses difficult and prevent investigators from reaching definitive conclusions. For example, the caffeine content of foods and beverages can vary considerably, which can interfere with obtaining valid interpretations from many human studies. Isolated epidemiological studies dealing with the risk of abortion, without evaluating other developmental and reproductive effects, are the most difficult to interpret, because they present special problems that are sometimes ignored in epidemiological studies. The results of animal studies are probably most helpful in solving some of the dilemmas created by the epidemiological studies. An animal study reported in 1960 first focused our attention on the potential developmental effects of caffeine. However, the exposure reported by Nishimura and Nakai ('60) was an intraperitoneal dosage of 250 mg/kg in the mouse, an extremely high dosage that would result in a blood plasma level that could never be obtained from consuming caffeine containing products. More recent animal studies have demonstrated, that depending on the method of administration and species, the developmental NOEL in rodents is approximately 30 mg/kg per day, the teratogenic NOEL is 8,100 mg/kg per day, and the reproductive NOEL approximately 80-120 mg/kg per day. Lack of biological plausibility to support the concept that caffeine has been responsible for human malformations is another important part of this analysis. For example, no one has described the Caffeine "teratogenic syndrome," a cluster of malformations associated with caffeine ingestion. Proven human teratogens have an identifiable syndrome. The malformations described in the animal studies at very high doses fit the description of vascular disruptive types of malformations. (ABSTRACT TRUNCATED) | Rayburn AL, Bouma J, Northcott CA (2001) Comparing the clastogenic potential of atrazine with caffeine using Chinese hamster ovary (CHO) cells. Toxicology letters 121, 69-78 [PubMed:11312039] [show Abstract] The agronomically important herbicide atrazine has been reported to cause damage to animal chromosomes at levels of atrazine found contaminating drinking water supplies. While documenting potential chromosome damage is important it is equally important to compare the damage with the potential consequences of compounds readily found in our food and water supply. In this study atrazine and caffeine, a ubiquitous food additive, were compared at equal levels and at real exposure levels for their ability to damage animals chromosomes in cell culture. Nuclei and chromosomes from treated and control cells were analyzed by flow cytometry. At extremely low levels, atrazine was found to be a more potent clastogen. Caffeine had no effect on the chromosomes at the lower levels. Both chemicals were genotoxic at the potential exposure levels with caffeine being more disruptive than atrazine. Atrazine appears to be a more potent damaging agent than caffeine at similar levels of exposure; however, the levels of caffeine one is exposed to during everyday life appears to be more damaging on the endpoints analyzed in this study than the levels of atrazine found contaminating water supplies. The advantages and limitations of whole cell clasotgenicity are also presented in light of these results. | Dager SR, Friedman SD (2000) Brain imaging and the effects of caffeine and nicotine. Annals of medicine 32, 592-599 [PubMed:11209966] [show Abstract] Caffeine and nicotine are the most common psychostimulant drugs used worldwide. Structural neuroimaging findings associated with caffeine and nicotine consumption are limited and primarily reflect the putative relationship between smoking and white matter hyperintensities (WMH), a finding that warrants further appraisal of its clinical implications. The application of newer brain imaging modalities that measure subtle haemodynamic changes or tissue-based chemistry in order to better elucidate brain functional processes, including mechanisms underlying addiction to nicotine and caffeine and the brain functional consequences, provide intriguing findings. Potential influences of caffeine and nicotine on the functional contrast, or metabolic response, to neural activation also necessitates the careful appraisal of the effects that these commonly used drugs may have on the results of functional imaging. | Cavalcante JW, Santos PR, Menezes MG, Marques HO, Cavalcante LP, Pacheco WS (2000) Influence of caffeine on blood pressure and platelet aggregation. Arquivos brasileiros de cardiologia 75, 97-105 [PubMed:10983026] [show Abstract]
ObjectiveStudies have demonstrated that methylxanthines, such as caffeine, are A1 and A2 adenosine receptor antagonists found in the brain, heart, lungs, peripheral vessels, and platelets. Considering the high consumption of products with caffeine in their composition, in Brazil and throughout the rest of the world, the authors proposed to observe the effects of this substance on blood pressure and platelet aggregation.MethodsThirteen young adults, ranging from 21 to 27 years of age, participated in this study. Each individual took 750 mg/day of caffeine (250 mg tid), over a period of seven days. The effects on blood pressure were analyzed through the pressor test with handgrip, and platelet aggregation was analyzed using adenosine diphosphate, collagen, and adrenaline.ResultsDiastolic pressure showed a significant increase 24 hours after the first intake (p<0.05). This effect, however, disappeared in the subsequent days. The platelet aggregation tests did not reveal statistically significant alterations, at any time during the study.ConclusionThe data suggest that caffeine increases diastolic blood pressure at the beginning of caffeine intake. This hypertensive effect disappears with chronic use. The absence of alterations in platelet aggregation indicates the need for larger randomized studies. | Esser MJ, Sawynok J (2000) Caffeine blockade of the thermal antihyperalgesic effect of acute amitriptyline in a rat model of neuropathic pain. European journal of pharmacology 399, 131-139 [PubMed:10884512] [show Abstract] In the present study, we sought to determine whether administration of caffeine, a non-selective adenosine receptor antagonist, would affect the thermal antihyperalgesic efficacy of acute amitriptyline in a rat model of neuropathic pain. Rats were rendered neuropathic by unilateral tight ligation of the fifth and sixth lumbar spinal nerves, and tested for thermal hyperalgesia using a focused beam of light. Systemic administration of caffeine (1.5-7.5 mg/kg), at the same time as amitriptyline, blocked the thermal antihyperalgesic effect of 10 mg/kg amitriptyline. The greatest degree of block exerted by caffeine was observed with 3.75 mg/kg (100% block), a dose that had no observable intrinsic effect. Spinal administration of amitriptyline (60 microg) exhibited a mild antihyperalgesic effect that was unaffected by pretreatment with intrathecal caffeine (100 microg). Peripheral administration of amitriptyline into the neuropathic paw (under brief anesthesia) produced an antihyperalgesic effect at both 30 and 100 nmol, with a greater effect being observed at 100 nmol. Coadministration of caffeine (1500 nmol) partially antagonized the effects of both doses of amitriptyline. The results of this study suggest that the thermal antihyperalgesic effect of acute amitriptyline in this model may involve enhancement of an endogenous adenosine tone. This involvement is important in light of the widespread consumption of caffeine, which may potentially act to reduce the benefits of amitriptyline in the treatment of neuropathic pain. | Temple JG, Warm JS, Dember WN, Jones KS, LaGrange CM, Matthews G (2000) The effects of signal salience and caffeine on performance, workload, and stress in an abbreviated vigilance task. Human factors 42, 183-194 [PubMed:11022879] [show Abstract] In 2 experiments, a 12-min computerized vigilance task was demonstrated to reproduce the vigilance decrement, high workload (NASA-TLX), and stressful character (Dundee Stress State Questionnaire) of vigilance tasks lasting 30 min or more. In Experiment 1, the abbreviated task was also shown to duplicate the signal salience effect, a major finding associated with long-duration vigilance tasks. Moreover, Experiment 2 showed that performance on the abbreviated task can be enhanced by caffeine - a drug that benefits long-duration tasks. This enhancement effect was limited to performance, however, suggesting that caffeine influences factors that control signal detection but not those that control task-induced stress. The results parallel those obtained with long-duration tasks and support a resource-depletion model of the vigilance decrement. The abbreviated task might be useful in situations in which long-duration tasks are precluded (e.g., performance assessment batteries, neuropsychological testing, and brain imaging). | Gannon BA (2000) Theophylline or caffeine: which is best for apnea of prematurity? Neonatal network : NN 19, 33-36 [PubMed:11949272] [show Abstract] Apnea of prematurity is a common problem of the premature infant under 30 weeks gestation. Theophylline and caffeine, two methylxanthines, are widely used to treat this condition. The drugs are equally effective in preventing apnea in the premature infant. Caffeine citrate has many advantages over theophylline, however, including once-a-day dosing, more predictable plasma concentrations, earlier onset of action, and minimal side effects. Caffeine is therefore the initial drug of choice for apnea of prematurity. | Bogo A, Mantle PG (2000) Caffeine: also a fungal metabolite. Phytochemistry 54, 937-939 [PubMed:11014293] [show Abstract] Caffeine has been found to occur as a fungal metabolite and to be the principal alkaloid in sclerotia of Claviceps sorghicola, a Japanese ergot pathogen of Sorghum spp. | Tofovic SP, Rominski BR, Bastacky S, Jackso EK, Kost CK (2000) Caffeine augments proteinuria in puromycin-aminonucleoside nephrotic rats. Renal failure 22, 159-179 [PubMed:10803761] [show Abstract] Several studies indicate that increased intrarenal adenosine concentrations may attenuate puromycin-aminonucleoside (PAN)-induced nephropathy in rats. The purpose of this study was to investigate the chronic effects of caffeine, a nonselective adenosine receptor antagonist, on renal function and structure in PAN-induced nephropathy. Animals were randomized to receive drinking water or 0.1% caffeine solution. PAN was administered in two doses to a subset from each group at 1 week (100 mg/kg, s.c.; Purom-1) and 15 wks (80 mg/kg, s.c.; Purom-2) after initiating caffeine treatment (PAN and CAFF-PAN groups). The remaining animals served as time controls (CON and CAFF groups). Renal excretory function was followed for 23 wks. Caffeine consumption significantly augmented PAN-induced proteinuria after both PAN injections (Purom-1 and Purom-2, p<0.05 and p<0.001 respectively; CAFF-PAN vs. PAN). In addition, caffeine potentiated the transient reduction in creatinine clearance (CrCl) induced by PAN. Caffeine consumption for 23 wks significantly reduced CrCl in conscious nephrotic animals (4.76 +/- 0.98 vs. 8.51 +/- 1.55 L/kg/day, CAFF-PAN vs. PAN). Seven days after both PAN injections, increased plasma renin activity was detected in animals that were consuming caffeine as compared with corresponding control groups (CAFF and CAFF + PAN vs CON and PAN, respectively). Eight weeks after the second injection of PAN, acute measures of renal hemodynamic and excretory function were compared in anesthetized animals and renal samples were analyzed for histological changes. In PAN-rats, caffeine treatment for 23 weeks significantly reduced inulin clearance (0.28 +/- 0.09 vs. 0.57 +/- 0.12 mL/min/gr kidney. CAFF-PAN vs PAN, p<0.05), tended to increase renal vascular resistance (59.0 +/- 9.5 vs. 42.9 +/- 5.5 mmHg/mL/min/gr kidney, CAFF-PAN vs. PAN, p < 0.06), potentiated the development of more severe tubulointerstitial damage (tubular atrophy, presence of proteinaceous material, tubular dilatation, interstitial inflammation, interstitial fibrosis), and tended to increase glomerulosclerosis. In conclusion, this study indicates that caffeine adversely affects renal function in PAN-nephrotic rats, and that this effect may be due, in part, to increased activity of the renin angiotensin system. | Bara AI, Barley EA (2000) Caffeine for asthma. The Cochrane database of systematic reviewsCD001112 [PubMed:10796597] [show Abstract]
BackgroundCaffeine has a variety of pharmacological effects. It is chemically related to the drug theophylline which is used to treat asthma. Accordingly, interest has been expressed in its potential role as an asthma treatment. A number of studies have explored the effects of caffeine in asthma, this is the first review to systematically examine and summarise the evidence.ObjectivesCaffeine is a weak bronchodilator and it also reduces respiratory muscle fatigue. It has been suggested that caffeine may reduce asthma symptoms. The objective of this review was to assess the effects of caffeine on lung function and identify whether there is a need to control for caffeine consumption prior to lung function testing.Search strategyWe searched the Cochrane Airways Group trials register and the reference lists of articles. We also contacted study authors.Selection criteriaRandomised trials of oral caffeine compared to placebo in adults with asthma.Data collection and analysisTrial quality assessment and data extraction were done independently by two reviewers.Main resultsSix trials involving a total of 55 people were included. The studies were all of cross-over design and of high quality. In comparison with placebo, caffeine appears to improve lung function for up to two hours after consumption. Forced expiratory volume in one minute showed a small improvement up to two hours after caffeine use (standardised mean difference -0.73, 95% confidence interval -1.20 to -0.25). Mid-expiratory flow rates also showed a small improvement with caffeine and this was sustained up to four hours.Reviewer's conclusionsCaffeine appears to improve airways function modestly in people with asthma for up to four hours. People may need to avoid caffeine for at least four hours prior to lung function testing. | Sinclair CJ, Geiger JD (2000) Caffeine use in sports. A pharmacological review. The Journal of sports medicine and physical fitness 40, 71-79 [PubMed:10822912] [show Abstract] Caffeine is the most widely ingested psychoactive drug in the world. As many know, chronic use of caffeine leads to dependence, tolerance, drug craving, and upon abrupt cessation unpleasant withdrawal symptoms. Thus, caffeine fulfills pharmacological criteria by which agents are classified as drugs of abuse. Nevertheless, its use is legal and only at high, but readily attainable, levels is it banned from sport. Its use is widespread by athletes as young as 11 years of age who are seeking athletic advantage over fellow competitors. It is likely that its use will not decline any time soon because it is inexpensive, readily available, medically quite safe, socially acceptable, and by most measures legal. However, at levels allowed in sport, caffeine through its wide-ranging physiological and psychological effects increases endurance in well-trained athletes. If the goal of drug-testing and education programs in sport is to protect the health of athletes, prevent unfair advantage (cheating) and encourage ethical behavior then it seems obvious that the allowable levels of caffeine ingestion should be decreased. The alternative is to continue with policies designed largely to punish only those that get caught. | Granados-Soto V, Castañeda-Hernández G (1999) A review of the pharmacokinetic and pharmacodynamic factors in the potentiation of the antinociceptive effect of nonsteroidal anti-inflammatory drugs by caffeine. Journal of pharmacological and toxicological methods 42, 67-72 [PubMed:10924888] [show Abstract] Caffeine is an effective analgesic adjuvant because it increases the antinociceptive effect of NSAIDs while reducing the probability of side effects. The mechanism by which caffeine increases the antinociceptive action of NSAIDs does not appear to include a pharmacokinetic interaction. The potentiation appears to be due to a pharmacokinetic mechanism including actions at the central and the peripheral levels. Because caffeine shifts the effect-compartment concentration-effect relation of NSAIDs to the left and this relationship is sigmoidal, there is no potentiation if the NSAID concentrations are too high or too low with respect to EC(50). The best potentiation can be observed if the NSAID doses used yield effect-compartment concentrations in the vicinity of EC(50). Therefore further investigation of the PK/PD relations of caffeine-NSAID combinations for different pain states and intensities is needed to optimize the therapeutic use of these mixtures. | Dassesse D, Vanderwinden JM, Goldberg I, Vanderhaeghen JJ, Schiffmann SN (1999) Caffeine-mediated induction of c-fos, zif-268 and arc expression through A1 receptors in the striatum: different interactions with the dopaminergic system. The European journal of neuroscience 11, 3101-3114 [PubMed:10510174] [show Abstract] Adenosine and the adenosine receptor antagonist, caffeine, modulate locomotor activity and striatal neuropeptide expression through interactions with the dopaminergic system by mechanisms which remain partially undetermined. We addressed this question by using quantitative immunocytochemistry and in situ hybridization, combined with retrograde tracing of striatal neurons, to characterize the mechanism(s) leading to the striatal increase in the immediate early genes (IEG), c-fos, zif-268 and arc, following a single injection of caffeine or the A1 antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). Caffeine and DPCPX induced c-fos, zif-268 and arc expression, both at mRNA and protein levels, in large proportions of striatonigral and striatopallidal neurons. The involvement of dopamine systems was evaluated by manipulations of the dopaminergic transmission. Quinpirole, a D2 agonist, almost completely blocked the caffeine-induced IEG increase in both striatopallidal and striatonigral neurons. Conversely, the lesion of the nigrostriatal pathway and the D1 antagonist SCH23390 abolished the caffeine effects in striatonigral neurons but had no or slight effect, respectively, on its action in striatopallidal neurons. These observations demonstrate that caffeine- and DPCPX-mediated IEG inductions involved different mechanisms in striatonigral and striatopallidal neurons through blockade of A1 receptors. Immediate early gene inductions result from a stimulation of dopamine release in striatonigral neurons and from activation of glutamate release and probably also acetylcholine release in striatopallidal neurons. These results also support the idea that, besides A2A receptors, adenosine acting at the A1 receptor plays pivotal functions in the basal ganglia physiology and that blockade of these receptors by specific or nonspecific antagonists, DPCPX and caffeine, may influence a broad range of neuronal functions in the striatum. | Okada M, Kiryu K, Kawata Y, Mizuno K, Wada K, Tasaki H, Kaneko S (1997) Determination of the effects of caffeine and carbamazepine on striatal dopamine release by in vivo microdialysis. European journal of pharmacology 321, 181-188 [PubMed:9063686] [show Abstract] The effects of carbamazepine and caffeine on adenosine receptor subtypes were determined using in vivo microdialysis in an attempt to elucidate their different psychotropic mechanisms of action. Adenosine and a selective adenosine A1 receptor agonist decreased the striatal extracellular dopamine level, whereas caffeine, carbamazepine and a selective adenosine A1 receptor antagonist increased it, but neither an adenosine A2 receptor agonist nor an antagonist affected it. Under conditions of adenosine A1 receptor blockade, adenosine, carbamazepine and a selective adenosine A2 receptor agonist increased the striatal extracellular dopamine level, whereas caffeine and a selective adenosine A2 receptor antagonist decreased it. These results suggest that adenosine A1 receptor stimulation reduces the striatal extracellular dopamine level, and that adenosine A2 receptor stimulation under conditions of adenosine A1 receptor blockade increases it. Therefore, caffeine is an antagonist of both adenosine A1 and A2 receptor subtypes, and carbamazepine is an adenosine A1 receptor antagonist as well as an adenosine A2 receptor agonist. These properties support the hypothesis that the central actions of both carbamazepine and caffeine result from effects on both adenosine A1 and A2 receptors. | Garrett BE, Griffiths RR (1997) The role of dopamine in the behavioral effects of caffeine in animals and humans. Pharmacology, biochemistry, and behavior 57, 533-541 [PubMed:9218278] [show Abstract] Dopamine has been proposed to mediate some of the behavioral effects of caffeine. This review discusses cellular mechanisms of action that could explain the role of dopamine in the behavioral effects of caffeine and summarizes the results of behavioral studies in both animals and humans that provide evidence for a role of dopamine in these effects. Caffeine is a competitive antagonist at adenosine receptors and produces a range of central and physiological effects that are opposite those of adenosine. Recently, caffeine has been shown to enhance dopaminergic activity, presumably by competitive antagonism at adenosine receptors that are colocalized and interact functionally with dopamine receptors. Thus, caffeine, as a competitive antagonist at adenosine receptors, may produce its behavioral effects by removing the negative modulatory effects of adenosine from dopamine receptors, thus stimulating dopaminergic activity. Consistent with this interpretation, preclinical behavioral studies show that caffeine produces behavioral effects similar to classic dopaminergically mediated stimulants such as cocaine and amphetamine, including increased locomotor activity, increased turning behavior in 6-hydroxydopamine-lesioned animals, stimulant-like discriminative stimulus effects, and self-administration. Furthermore, caffeine potentiates the effects of dopamine-mediated drugs on these same behaviors, and some of caffeine's effects on these behaviors can be blocked by dopamine receptor antagonists. Although more limited in scope, human studies also show that caffeine produces subjective, discriminative stimulus and reinforcing effects that have some similarities to those produced by cocaine and amphetamine. | Ercan-Fang N, Nuttall FQ (1997) The effect of caffeine and caffeine analogs on rat liver phosphorylase a activity. The Journal of pharmacology and experimental therapeutics 280, 1312-1318 [PubMed:9067318] [show Abstract] Liver phosphorylase a is stimulated by adenosine monophosphate. It is inhibited by adenosine diphosphate, adenosine triphosphate and glucose. Using these effectors as well as other potential in vivo effectors at concentrations approximating those present in hepatocytes, we previously reported that the net effect was nil, i.e., at estimated in vivo concentration, the inhibitors neutralized the stimulatory effect of adenosine monophosphate in a phosphorylase a preparation. In addition, a concentration dependent inhibition by glucose was not present. Therefore, we were interested in determining if addition of caffeine, an inhibitor that synergizes with glucose, would result in a reduction in activity in the presence of the other effectors and restore regulation by physiological concentrations of glucose. The effect of xanthine and xanthine analogs also were studied. Purified liver phosphorylase a was used. Activity was measured in the direction of glycogenolysis at 37 degrees, pH 7.0 and under initial rate conditions. Caffeine (1 mM) was added to individual and various combinations of other effectors. The interactions among the potential in vivo effectors when caffeine was present were complex. However, when caffeine was present glucose again regulated activity. This most likely was due to a synergistically facilitated reduction in binding affinity for AMP by caffeine and glucose. Theophylline and adenosine did not inhibit activity but reduced AMP stimulation and facilitated glucose inhibition. Xanthine and the other xanthine derivatives all strongly inhibited activity and the inhibition was independent of other effectors. | Devasagayam TP, Kamat JP, Mohan H, Kesavan PC (1996) Caffeine as an antioxidant: inhibition of lipid peroxidation induced by reactive oxygen species. Biochimica et biophysica acta 1282, 63-70 [PubMed:8679661] [show Abstract] Caffeine (1,3,7-trimethyl xanthine), an ingredient of coffee, has been investigated for its potential antioxidant activity against oxidative damage to rat liver microsomes. Such damage was induced by three reactive oxygen species of cardinal importance in causing membrane damage in vivo namely hydroxyl radical (.OH), peroxyl radical (ROO.) and singlet oxygen (1O2). The results obtained showed that caffeine was an effective inhibitor of lipid peroxidation, at millimolar concentrations, against all the three reactive species. The extent of inhibition was high against peroxidation induced by .OH, medium against 1O2 and low against ROO. In general, the antioxidant ability of caffeine was similar to that of the established biological antioxidant glutathione and significantly higher than ascorbic acid. Investigations into the possible mechanisms involved in the observed antioxidant effect reveal that the quenching of these reactive species by caffeine may be one of the possible factor responsible. The rate constant of caffeine with .OH was 7.3 x 10(9) M-1 s-1 and with 1O2 it was 2.9 x 10(7) M-1 s-1. Considering their potential for damage, half-life estimates and generation in biological systems, the ability of caffeine to inhibit oxidative damage induced by these reactive species in membranes suggest one more positive attribute of caffeine, whose daily intake as coffee may be considerable in most populations. | Tarnopolsky MA (1994) Caffeine and endurance performance. Sports medicine (Auckland, N.Z.) 18, 109-125 [PubMed:9132918] [show Abstract] Caffeine is consumed in many beverages and foods throughout the world. It is the most commonly used drug in North America and, probably, in many other countries. The short term consumption of caffeine may result in increased urination, gastrointestinal distress, tremors, decreased sleep, and anxiety symptoms in certain individuals. The long term consumption of caffeine at < 5 cups/day does not appear to increase the risk of cancer, cardiovascular disease, peptic ulcer disease or cardiac arrhythmias. At the cellular level, caffeine is a competitive antagonist of adenosine receptors and probably acts directly on the ryanodine receptor (Ca++ release channel) to potentiate Ca++ release from skeletal muscle sarcoplasmic reticulum. As a result of these 2 cellular mechanisms of action, caffeine causes increased lipolysis, a facilitation of central nervous system transmission, a reduction in plasma potassium during exercise, an increased force of muscle contraction at lower frequencies of stimulation, and a sparing of muscle glycogen (partially or wholly due to an increase in free fatty acid oxidation). These mechanisms of action would predict that caffeine should be of ergogenic benefit during endurance exercise performance, especially when glycogen depletion would be rate limiting to performance. A review of the literature suggests that caffeine at doses of approximately 6 mg/kg is not of ergogenic benefit to high intensity exercise performance, but similar doses are ergogenic in endurance exercise performance. These doses (approximately 6 mg/kg) would result in urinary caffeine concentrations less than the current International Olympic Committee restricted level of 12 mg/L, and consideration should be given to lowering this level. | Jaw S, Jeffery EH (1993) Interaction of caffeine with acetaminophen. 1. Correlation of the effect of caffeine on acetaminophen hepatotoxicity and acetaminophen bioactivation following treatment of mice with various cytochrome P450 inducing agents. Biochemical pharmacology 46, 493-501 [PubMed:8347173] [show Abstract] The combination of caffeine with acetaminophen (APAP) is used widely in the treatment of headache. The effects of caffeine on APAP-induced hepatotoxicity and APAP bioactivation by liver microsomes from uninduced mice and from mice pretreated with various agents that induce cytochrome P450 were studied. When 1 mM caffeine was included, the rate of glutathione-APAP conjugate (GS-APAP) formation was increased significantly by 33 and 39% in microsomes from phenobarbital (PB)- and dexamethasone (DEX)-treated mice, respectively, whereas this parameter was decreased 39 and 12% by caffeine in microsomes from beta-naphthoflavone (beta NF)- and acetone-treated mice, respectively. A 5 mM concentration of caffeine increased GS-APAP formation by 47, 107 and 117% in microsomes from control, PB-, and DEX-treated mice, respectively, and decreased it 39 and 25% in microsomes from beta NF- and acetone-treated mice, respectively. Caffeine was a competitive inhibitor of APAP bioactivation in microsomes from beta NF- and acetone-treated mice. While caffeine increased APAP bioactivation in microsomes from uninduced, PB-, and DEX-treated mice, the apparent Km values for APAP were increased by caffeine, indicating that this enhancement was not due to a direct effect of caffeine on APAP binding to cytochrome P450 but may be due to an effect of caffeine on the substrate-enzyme complex. The variable effect of caffeine on APAP hepatotoxicity correlated with the effect of caffeine on APAP bioactivation by liver microsomes, regardless of pretreatment. Lack of correlation of aminopyrine N-demethylase, but good correlation of erythromycin N-demethylase activity with the extent of caffeine enhancement of APAP bioactivation following PB or DEX treatment suggests that a murine P450 subfamily similar to the rat P450 3A subfamily may be the candidate in mediating the stimulatory effect of caffeine on APAP bioactivation and APAP-induced hepatotoxicity. | Schiffmann SN, Vanderhaeghen JJ (1993) Caffeine regulates neurotensin and cholecystokinin messenger RNA expression in the rat striatum. Neuroscience 54, 681-689 [PubMed:8332255] [show Abstract] Interactions between dopamine and neurotensin or dopamine and cholecystokinin have been demonstrated in the basal ganglia. Disruption of nigrostriatal dopaminergic transmission results in a dramatic increase in neurotensin messenger RNA and in an induction of cholecystokinin messenger RNA in the striatum. Interaction between striatal dopaminergic and adenosinergic systems have also been reported. Adenosine and the adenosine receptor antagonist, caffeine, regulate gene expression in the striatum. In the present study, in situ hybridization histochemistry was used to investigate the putative regulation of neurotensin and cholecystokinin messenger RNA expression by caffeine in the rat striatum. Using this method, cholecystokinin messenger RNA was undetectable and neurotensin messenger RNA very sparse in the normal striatum. Chronic caffeine administration induced a dramatic increase in neurotensin messenger RNA in the subcallosal region of the caudate-putamen and a moderate increase in the shell sector of the accumbens nucleus. Similarly, caffeine induced a significant striatal expression of cholecystokinin messenger RNA in the dorsolateral and ventrolateral quadrants but was not restricted to the subcallosal area. At the cellular level, this corresponded to a significant labeling of a moderate to high density of medium-sized striatal neurons. These distributions were identical to those of neurotensin and cholecystokinin messenger RNAs observed in the case of disruption of dopaminergic transmission. We therefore concluded that in the intact striatum normally innervated by dopaminergic fibers, caffeine, probably acting through a presynaptic A2 receptor, induced a relative dopamine depletion which in turn led to the induction of neurotensin and cholecystokinin expression in subsets of striatal neurons. | Howell LL (1993) Comparative effects of caffeine and selective phosphodiesterase inhibitors on respiration and behavior in rhesus monkeys. The Journal of pharmacology and experimental therapeutics 266, 894-903 [PubMed:7689104] [show Abstract] The effects of caffeine and several selective phosphodiesterase (PDE) inhibitors on ventilation and on schedule-controlled behavior were studied in rhesus monkeys. In seated, unanesthetized monkeys prepared with a head plethysmograph, ventilation during exposure to air (normocapnia) and to elevated levels of CO2 (3, 4 and 5%) mixed in air (hypercapnia) was measured after cumulative doses of each drug. In other monkeys, behavioral effects were studied by administering cumulative doses preceding sequential periods of fixed-ratio or fixed-interval responding. The nonselective PDE inhibitors, caffeine and 3-isobutyl-1-methylxanthine, and the type IV-selective PDE inhibitors, rolipram and Ro 20-1724, had pronounced respiratory-stimulant effects during conditions of normocapnia and hypercapnia, and their potencies in increasing ventilation corresponded with their potencies as PDE inhibitors. The type III-selective PDE inhibitor, CI-930, had only modest respiratory-stimulant effects at the highest dose studied, and the type V-selective PDE inhibitor, zaprinast, had no respiratory effect. CGS 15943, a selective adenosine antagonist lacking PDE-inhibitory effects, also had only modest respiratory-stimulant effects at the highest dose studied. In contrast to their relative potencies and efficacies in stimulating respiration, caffeine and 3-isobutyl-1-methylxanthine were less efficacious than CGS 15943 in increasing fixed-interval responding, and CI-930, rolipram and Ro 20-1724 only decreased fixed-interval responding. Zaprinast had little or no behavioral effect. The results support the interpretation that inhibition of type IV PDE plays a prominent role in the respiratory-stimulant effects of xanthines, whereas the behavioral-stimulant effects are more closely related to antagonism of adenosine receptors. | D'Ambrosio SM, Setlow RB (1980) Modulation by caffeine of enhanced postreplication repair in mammalian cells treated with N-acetoxy-acetylaminofluorene. Journal of environmental pathology and toxicology 4, 181-191 [PubMed:7441110] [show Abstract] As shown previously, newly synthesized DNA from Chinese hamster, excision proficient and excision deficient xeroderma pigmentosum (XP) cells treated with split doses of N-acetoxy-acetylaminofluorene (AAAF) or ultraviolet radiation (uv) is larger in size than DNA from cells treated with only the single dose. In this report we determined the effects of caffeine, an inhibitor of postreplication repair, upon enhancement of repair by a split dose treatment with AAAF. Caffeine was added to cells either immediately following the first or the second dose of AAAF and the size of newly synthesized DNA was determined by alkaline sucrose gradient sedimentation. Results showed that: (a) the DNA from V79 and XP cells incubated with caffeine between the first and second dose of AAAF was smaller in size than DNA from cells not incubated with caffeine; (b) caffeine exhibited a lesser effect when added after the second dose during the pulse-chase; and (c) caffeine has little effect upon daughter DNA of normal human cells treated with single or split doses of AAAF. These data indicate that caffeine interferes with the enhancement of postreplication repair in V79 and XP cells treated with AAAF. |
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