{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T03:34:08Z","timestamp":1775187248354,"version":"3.50.1"},"reference-count":377,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2016,7,27]],"date-time":"2016-07-27T00:00:00Z","timestamp":1469577600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BPD\/80451\/2011"],"award-info":[{"award-number":["SFRH\/BPD\/80451\/2011"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BPD\/108837\/2015"],"award-info":[{"award-number":["SFRH\/BPD\/108837\/2015"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"FEDER via Programa Operacional Fatores de Competitividade-COMPETE\/QREN &amp; FSE and POPH funds","award":["PestC\/SAU\/UI0709\/2014"],"award-info":[{"award-number":["PestC\/SAU\/UI0709\/2014"]}]},{"name":"FEDER via Programa Operacional Fatores de Competitividade-COMPETE\/QREN &amp; FSE and POPH funds","award":["Pest-OE\/SAU\/UI0215\/2014"],"award-info":[{"award-number":["Pest-OE\/SAU\/UI0215\/2014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Methylxanthines are a group of phytochemicals derived from the purine base xanthine and obtained from plant secondary metabolism. They are unobtrusively included in daily diet in common products as coffee, tea, energetic drinks, or chocolate. Caffeine is by far the most studied methylxanthine either in animal or epidemiologic studies. Theophylline and theobromine are other relevant methylxanthines also commonly available in the aforementioned sources. There are many disseminated myths about methylxanthines but there is increased scientific knowledge to discuss all the controversy and promise shown by these intriguing phytochemicals. In fact, many beneficial physiologic outcomes have been suggested for methylxanthines in areas as important and diverse as neurodegenerative and respiratory diseases, diabetes or cancer. However, there have always been toxicity concerns with methylxanthine (over)consumption and pharmacologic applications. Herein, we explore the structure-bioactivity relationships to bring light those enumerated effects. The potential shown by methylxanthines in such a wide range of conditions should substantiate many other scientific endeavors that may highlight their adequacy as adjuvant therapy agents and may contribute to the advent of functional foods. Newly designed targeted molecules based on methylxanthine structure may originate more specific and effective outcomes.<\/jats:p>","DOI":"10.3390\/molecules21080974","type":"journal-article","created":{"date-parts":[[2016,7,27]],"date-time":"2016-07-27T09:38:46Z","timestamp":1469612326000},"page":"974","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":158,"title":["Structure-Bioactivity Relationships of Methylxanthines: Trying to Make Sense of All the Promises and the Drawbacks"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9585-9632","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Monteiro","sequence":"first","affiliation":[{"name":"Laboratory of Cell Biology and Unit for Multidisciplinary Research in Biomedicine (UMIB), Department of Microscopy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7635-783X","authenticated-orcid":false,"given":"Marco","family":"Alves","sequence":"additional","affiliation":[{"name":"Health Sciences Research Centre (CICS\u2013UBI), University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4989-5699","authenticated-orcid":false,"given":"Pedro","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology and Unit for Multidisciplinary Research in Biomedicine (UMIB), Department of Microscopy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal"},{"name":"Institute of Health Research an Innovation, University of Porto, 4200-135 Porto, Portugal"}]},{"given":"Branca","family":"Silva","sequence":"additional","affiliation":[{"name":"Health Sciences Research Centre (CICS\u2013UBI), University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2016,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1078\/0176-1617-01169","article-title":"Purine and pyrimidine nucleotide metabolism in higher plants","volume":"160","author":"Stasolla","year":"2003","journal-title":"J. Plant Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1146\/annurev.arplant.57.032905.105421","article-title":"Pyrimidine and purine biosynthesis and degradation in plants","volume":"57","author":"Zrenner","year":"2006","journal-title":"Annu. Rev. Plant Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4145","DOI":"10.2174\/138161205774913255","article-title":"Uric Acid and Oxidative Stress","volume":"11","author":"Glantzounis","year":"2005","journal-title":"Curr. Pharm. Des."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1038\/417915a","article-title":"Pest Control: Caffeine as a repellent for slugs and snails","volume":"417","author":"Hollingsworth","year":"2002","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/0031-9422(86)88009-8","article-title":"Purine alkaloid formation in buds and developing leaflets of Coffea arabica: Expression of an optimal defence strategy?","volume":"25","author":"Frischknecht","year":"1986","journal-title":"Phytochemistry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1111\/j.1467-789X.2007.00389.x","article-title":"A short history of beverages and how our body treats them","volume":"9","author":"Wolf","year":"2008","journal-title":"Obes. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1007\/s11130-012-0281-5","article-title":"Chemical and nutritional composition of Tejate, a traditional maize and cacao beverage from the central valleys of Oaxaca, Mexico","volume":"67","author":"Sotelo","year":"2012","journal-title":"Plant Foods Hum. Nutr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/0278-6915(88)90007-5","article-title":"Methylxanthines: Toxicity to humans. 1. Theophylline","volume":"26","author":"Stavric","year":"1988","journal-title":"Food Chem. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.phytochem.2007.10.029","article-title":"Caffeine and related purine alkaloids: Biosynthesis, catabolism, function and genetic engineering","volume":"69","author":"Ashihara","year":"2008","journal-title":"Phytochemistry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/0165-0173(92)90012-B","article-title":"Caffeine and the central nervous system: Mechanisms of action, biochemical, metabolic and psychostimulant effects","volume":"17","author":"Nehlig","year":"1992","journal-title":"Brain Res. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0031-6997(24)01396-6","article-title":"Actions of caffeine in the brain with special reference to factors that contribute to its widespread use","volume":"51","author":"Fredholm","year":"1999","journal-title":"Pharmacol. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1136\/bjsm.26.4.276","article-title":"Effect of caffeine on maximal strength and power in \u00e9lite male athletes","volume":"26","author":"Jacobson","year":"1992","journal-title":"Br. J. Sports Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1007\/BF00705079","article-title":"Caffeine increases maximal anaerobic power and blood lactate concentration","volume":"65","author":"Anselme","year":"1992","journal-title":"Eur. J. Appl. Physiol. Occup. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1152\/jappl.1996.81.4.1658","article-title":"Metabolic, catecholamine, and endurance responses to caffeine during intense exercise","volume":"81","author":"Jackman","year":"1996","journal-title":"J. Appl. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2292","DOI":"10.1152\/jappl.1991.71.6.2292","article-title":"Performance and metabolic responses to a high caffeine dose during prolonged exercise","volume":"71","author":"Graham","year":"1991","journal-title":"J. Appl. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1152\/jappl.1998.85.2.709","article-title":"Effect of caffeinated drinks on substrate metabolism, caffeine excretion, and performance","volume":"85","author":"Kovacs","year":"1998","journal-title":"J. Appl. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1152\/jappl.2000.89.5.1837","article-title":"Comparison of caffeine and theophylline ingestion: Exercise metabolism and endurance","volume":"89","author":"Greer","year":"2000","journal-title":"J. Appl. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"97","DOI":"10.3810\/psm.2009.12.1747","article-title":"The effects of caffeine on ventilation and pulmonary function during exercise: An often-overlooked response","volume":"37","author":"Chapman","year":"2009","journal-title":"Phys. Sportsmed."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1164\/rccm.201302-0388PP","article-title":"Theophylline","volume":"188","author":"Barnes","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1007\/s001340050723","article-title":"Low-dose theophylline increases urine output in diuretic-dependent critically ill children","volume":"24","author":"Bell","year":"1998","journal-title":"Intensive Care Med."},{"key":"ref_21","first-page":"31","article-title":"DFT study and biological activity of some methylxanthines","volume":"42","year":"2014","journal-title":"Bull. Chem. Technol. Bosnia Herzeg."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15422119.2011.569047","article-title":"Analytical techniques used for determination of methylxanthines and their analogues\u2014Recent advances","volume":"41","author":"Talik","year":"2012","journal-title":"Sep. Purif. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1016\/0024-3205(82)90715-9","article-title":"Blood-brain barrier transport of caffeine: Dose-related restriction of adenine transport","volume":"31","author":"McCall","year":"1982","journal-title":"Life Sci."},{"key":"ref_24","unstructured":"Beale, J.M. (2011). Wilson and Gisvold\u2019s Textbook of Organic Medicinal and Pharmaceutical Chemistry, Lippincott Williams & Wilkins, Wolters Kuwer. [12th ed.]."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1021\/ed050p791","article-title":"Coffee, Tea, or Cocoa. A trio of experiments including the isolation of theobromine from cocoa","volume":"50","author":"Pavia","year":"1973","journal-title":"J. Chem. Educ."},{"key":"ref_26","unstructured":"Gardenhire, D.S. (2016). Rau\u2019s Respiratory Care Pharmacology, Elsevier Health Sciences. [9th ed.]."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.2741\/1367","article-title":"Distribution and biosynthesis of caffeine in plants","volume":"9","author":"Ashihara","year":"2004","journal-title":"Front. Biosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/S0065-2296(08)60228-1","article-title":"Biosynthesis and metabolism of caffeine and related purine alkaloids in plants","volume":"Volume 30","author":"Callow","year":"1999","journal-title":"Advances in Botanical Research"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/BF00025361","article-title":"Breeding for low seed caffeine content of coffee (Coffea L.) by interspecific hybridization","volume":"59","author":"Mazzafera","year":"1991","journal-title":"Euphytica"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.1021\/jf021066b","article-title":"Factors affecting the levels of tea polyphenols and caffeine in tea leaves","volume":"51","author":"Lin","year":"2003","journal-title":"J. Agric. Food Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1039\/a909219f","article-title":"HPLC determination of catechins and caffeine in tea. Differentiation of green, black and instant teas","volume":"125","author":"Fernandez","year":"2000","journal-title":"Analyst"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/0278-6915(88)90073-7","article-title":"Methylxanthines: Toxicity to humans. 3. Theobromine, paraxanthine and the combined effects of methylxanthines","volume":"26","author":"Stavric","year":"1988","journal-title":"Food Chem. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/0031-9422(94)00141-F","article-title":"Guaran\u00e1 (Paullinia cupana) rewards seed dispersers without intoxicating them by caffeine","volume":"39","author":"Baumann","year":"1995","journal-title":"Phytochemistry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/S0031-9422(03)00372-8","article-title":"Purine alkaloids in Paullinia","volume":"64","author":"Weckerle","year":"2003","journal-title":"Phytochemistry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0031-9422(99)00119-3","article-title":"Caffeine in Citrus flowers","volume":"52","author":"Kretschmar","year":"1999","journal-title":"Phytochemistry"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9824","DOI":"10.1021\/jf0721038","article-title":"Content of polyphenolic compounds in the nigerian stimulants Cola nitida ssp. alba, Cola nitida ssp. rubra A. Chev, and Cola acuminata Schott & Endl and their antioxidant capacity","volume":"55","author":"Atawodi","year":"2007","journal-title":"J. Agric. Food Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.jada.2004.10.027","article-title":"Food sources and intakes of caffeine in the diets of persons in the United States","volume":"105","author":"Frary","year":"2005","journal-title":"J. Am. Diet. Assoc."},{"key":"ref_38","first-page":"205","article-title":"Caffeine content of beverages as consumed","volume":"114","author":"Gilbert","year":"1976","journal-title":"Can. Med. Assoc. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"182","DOI":"10.2174\/2212798410901030182","article-title":"Recent patents on Camellia sinensis: Source of health promoting compounds","volume":"1","author":"Moderno","year":"2009","journal-title":"Recent Pat. Food Nutr. Agric."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1021\/jf052857r","article-title":"Catechin and caffeine content of green tea dietary supplements and correlation with antioxidant capacity","volume":"54","author":"Seeram","year":"2006","journal-title":"J. Agric. Food Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.foodchem.2010.02.014","article-title":"Green tea: A promising anticancer agent for renal cell carcinoma","volume":"122","author":"Carvalho","year":"2010","journal-title":"Food Chem."},{"key":"ref_42","first-page":"1","article-title":"White tea (Camellia sinensis L.): Antioxidant properties and beneficial health effects","volume":"11","author":"Dias","year":"2013","journal-title":"Int. J. Food Sci. Nutr. Diet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1007\/s00394-013-0640-5","article-title":"Effect of white tea (Camellia sinensis (L.)) extract in the glycolytic profile of Sertoli cell","volume":"53","author":"Martins","year":"2013","journal-title":"Eur. J. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"C541","DOI":"10.1111\/j.1750-3841.2010.01705.x","article-title":"White and green teas (Camellia sinensis var. sinensis): Variation in phenolic, methylxanthine, and antioxidant profiles","volume":"75","author":"Unachukwu","year":"2010","journal-title":"J. Food Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"75","DOI":"10.4103\/0973-1296.176061","article-title":"Theanine and caffeine content of infusions prepared from commercial tea samples","volume":"12","author":"Boros","year":"2016","journal-title":"Pharmacogn. Mag."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1039\/C1FO10240K","article-title":"Espresso coffees, caffeine and chlorogenic acid intake: Potential health implications","volume":"3","author":"Crozier","year":"2012","journal-title":"Food Funct."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1093\/jat\/30.8.611","article-title":"Caffeine content of decaffeinated coffee","volume":"30","author":"McCusker","year":"2006","journal-title":"J. Anal. Toxicol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5340","DOI":"10.1021\/jf010759+","article-title":"Factors affecting the caffeine and polyphenol contents of black and green tea infusions","volume":"49","author":"Astill","year":"2001","journal-title":"J. Agric. Food Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1111\/j.1365-2621.1983.tb14888.x","article-title":"HPLC determination of caffeine and theobromine in coffee, tea, and instant hot cocoa Mixes","volume":"48","author":"Blauch","year":"1983","journal-title":"J. Food Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1093\/chromsci\/40.1.45","article-title":"Simultaneous determination of caffeine, theobromine, and theophylline by high-performance liquid chromatography","volume":"40","author":"Bispo","year":"2002","journal-title":"J. Chromatogr. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/0963-9969(96)00038-5","article-title":"Tea preparation and its influence on methylxanthine concentration","volume":"29","author":"Hicks","year":"1996","journal-title":"Food Res. Int."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.foodchem.2016.03.116","article-title":"Assessment of flavanol stereoisomers and caffeine and theobromine content in commercial chocolates","volume":"208","author":"Castle","year":"2016","journal-title":"Food Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1021\/jf072153c","article-title":"Predictive relationship between polyphenol and nonfat cocoa solids content of chocolate","volume":"56","author":"Cooper","year":"2008","journal-title":"J. Agric. Food Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1007\/s00217-002-0565-3","article-title":"Optimized method for simultaneous determination of catechin, gallic acid, and methylxanthine compounds in chocolate using RP-HPLC","volume":"215","author":"Tokusoglu","year":"2002","journal-title":"Eur. Food Res. Technol."},{"key":"ref_55","unstructured":"Ashihara, H., Kato, M., and Crozier, A. (2011). Methylxanthines, Springer Berlin Heidelberg."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.2741\/1364","article-title":"Caffeine synthase and related methyltransferases in plants","volume":"9","author":"Misako","year":"2004","journal-title":"Front. Biosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/S0014-5793(01)02512-1","article-title":"A new caffeine biosynthetic pathway in tea leaves: Utilisation of adenosine released from the S-adenosyl-l-methionine cycle","volume":"499","author":"Koshiishi","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Zajac, M.A., Zarkzewski, A.G., Kowal, M.G., and Narayan, S. (2003). A Novel Method of Caffeine Synthesis from Uracil, Taylor & Francis.","DOI":"10.1002\/chin.200350205"},{"key":"ref_59","unstructured":"Kumar, N.S., Chandran, T.B., Namratha, S., Bharat, B.R., Kumar, C.H.P., and Kishore, V. (2013). Production of theobromine from Pseudomonas sp.. Int. Res. J. Pharm., 4."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1007\/s12010-015-1858-x","article-title":"Response surface optimization for decaffeination and theophylline production by Fusarium solani","volume":"178","author":"Nanjundaiah","year":"2015","journal-title":"Appl. Biochem. Biotechnol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1002\/bmc.736","article-title":"In vivo evaluation of CYP1A2, CYP2A6, NAT-2 and xanthine oxidase activities in a Greek population sample by the RP-HPLC monitoring of caffeine metabolic ratios","volume":"21","author":"Begas","year":"2007","journal-title":"Biomed. Chromatogr."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1177\/00912709922007930","article-title":"Salivary clearance and urinary metabolic pattern of caffeine in healthy children and in pediatric patients with hepatocellular diseases","volume":"39","author":"Shabib","year":"1999","journal-title":"J. Clin. Pharmacol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0378-4347(98)00016-4","article-title":"Analysis of urinary caffeine metabolites to assess biotransformation enzyme activities by reversed-phase high-performance liquid chromatography","volume":"709","author":"Krul","year":"1998","journal-title":"J. Chromatogr. B Biomed. Sci. Appl."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0378-4347(00)00325-X","article-title":"Liquid chromatographic method for the simultaneous determination of caffeine and fourteen caffeine metabolites in urine","volume":"746","author":"Bendriss","year":"2000","journal-title":"J. Chromatogr. B Biomed. Sci. Appl."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1152\/jappl.1996.80.3.999","article-title":"Acute effects of caffeine ingestion at rest in humans with impaired epinephrine responses","volume":"80","author":"Mohr","year":"1996","journal-title":"J. Appl. Physiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/BF00609587","article-title":"Plasma and salivary pharmacokinetics of caffeine in man","volume":"21","author":"Newton","year":"1981","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1081\/JLC-100100432","article-title":"IImproved micro-method for the HPLC analysis of caffeine and its demethylated metabolites in human biological fluids after SPE","volume":"23","author":"Georga","year":"2000","journal-title":"J. Liq. Chromatogr. Relat. Technol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1365\/s10337-006-0141-2","article-title":"Caffeine determination in human saliva and urine by TLC and ultraviolet absorption densitometry","volume":"65","author":"Fenske","year":"2006","journal-title":"Chromatographia"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1002\/bmc.341","article-title":"Simultaneous determination of caffeine, theophylline and theobromine in human plasma by on-line solid-phase extraction coupled to reversed-phase chromatography","volume":"18","author":"Emara","year":"2004","journal-title":"Biomed. Chromatogr."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/S0021-9673(01)94639-4","article-title":"Rapid high-performance liquid chromatography assay for salivary and serum caffeine following an oral load","volume":"385","author":"Setchell","year":"1987","journal-title":"J. Chromatogr. A"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1093\/chromsci\/46.2.144","article-title":"Simultaneous HPLC determination of caffeine, theobromine, and theophylline in food, drinks, and herbal products","volume":"46","author":"Srdjenovic","year":"2008","journal-title":"J. Chromatogr. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1016\/j.foodchem.2011.05.118","article-title":"Focused microwaves-assisted extraction of theobromine and caffeine from cacao","volume":"129","year":"2011","journal-title":"Food Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4820","DOI":"10.1021\/jf020128v","article-title":"Extraction of Methylxanthines from Guaran\u00e1 Seeds, Mat\u00e9 Leaves, and Cocoa Beans Using Supercritical Carbon Dioxide and Ethanol","volume":"50","author":"Zetzl","year":"2002","journal-title":"J. Agric. Food Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/S0963-9969(01)00077-1","article-title":"Improved analysis of theobromine and caffeine in chocolate food products formulated with cocoa powder","volume":"34","author":"Caudle","year":"2001","journal-title":"Food Res. Int."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1177\/108201329800400107","article-title":"Solid\/liquid extraction of caffeine from guaran\u00e1 with methylene chloride\/Extracci\u00f3n solido-liquido de cafeina de guarana con cloruro de metileno","volume":"4","author":"Hulbert","year":"1998","journal-title":"Food Sci. Technol. Int."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.foodres.2009.02.018","article-title":"Comparative study of commercially available cocoa products in terms of their bioactive composition","volume":"42","author":"Komes","year":"2009","journal-title":"Food Res. Int."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"4087","DOI":"10.1016\/j.foodchem.2013.06.121","article-title":"Simultaneous determination of caffeine, theophylline and theobromine in food samples by a kinetic spectrophotometric method","volume":"141","author":"Xia","year":"2013","journal-title":"Food Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1016\/j.talanta.2005.04.066","article-title":"Multivariate optimisation of the experimental conditions for determination of three methylxanthines by reversed-phase high-performance liquid chromatography","volume":"67","author":"Veloso","year":"2005","journal-title":"Talanta"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.jchromb.2013.01.011","article-title":"Development and validation of a rapid ultra high pressure liquid chromatographic method for the determination of methylxanthines in herbal infusions","volume":"927","author":"Zacharis","year":"2013","journal-title":"J. Chromatogr. B"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"304","DOI":"10.3358\/shokueishi.50.304","article-title":"Rapid determination of theophylline, theobromine and caffeine in dietary supplements containing guarana by ultra-performance liquid chromatography","volume":"50","author":"Hasegawa","year":"2009","journal-title":"Shokuhin Eiseigaku Zasshi"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0003-2670(99)00061-6","article-title":"Extraction of methylxanthines from human body fluids by solid-phase microextraction","volume":"387","author":"Kumazawa","year":"1999","journal-title":"Anal. Chim. Acta"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.chroma.2007.09.020","article-title":"Rapid determination of caffeine in one drop of beverages and foods using drop-to-drop solvent microextraction with gas chromatography\/mass spectrometry","volume":"1170","author":"Shrivas","year":"2007","journal-title":"J. Chromatogr. A"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1002\/jps.2600720512","article-title":"Gas chromatographic-mass spectrometric quantitation of theophylline and its metabolites in biological fluids","volume":"72","author":"Tserng","year":"1983","journal-title":"J. Pharm. Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1016\/j.foodchem.2006.07.035","article-title":"Simultaneous spectrophotometric determination of caffeine and theobromine in Iranian tea by artificial neural networks and its comparison with PLS","volume":"103","author":"Khanchi","year":"2007","journal-title":"Food Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.saa.2007.07.033","article-title":"Simultaneous spectrophotometric determination of paracetamol, ibuprofen and caffeine in pharmaceuticals by chemometric methods","volume":"70","author":"Khoshayand","year":"2008","journal-title":"Spectrochim. Acta Part A Mol. Biomol. Spectrosc."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.ab.2005.03.007","article-title":"Spectrophotometric determination of caffeine and theophylline in pure alkaloids and its application in pharmaceutical formulations","volume":"349","author":"Singh","year":"2006","journal-title":"Anal. Biochem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.aca.2005.05.032","article-title":"Solid-phase FT-Raman determination of caffeine in energy drinks","volume":"547","author":"Armenta","year":"2005","journal-title":"Anal. Chim. Acta"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.talanta.2005.02.004","article-title":"Solid-phase spectrofluorimetric determination of acetylsalicylic acid and caffeine in pharmaceutical preparations using partial least-squares multivariate calibration","volume":"67","author":"Moreira","year":"2005","journal-title":"Talanta"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.aca.2008.10.067","article-title":"Simultaneous determination of acetylsalicylic acid, paracetamol and caffeine using solid-phase molecular fluorescence and parallel factor analysis","volume":"642","author":"Alves","year":"2009","journal-title":"Anal. Chim. Acta"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0308-8146(02)00116-4","article-title":"Rapid determination of caffeine content in soft drinks using FTIR-ATR spectroscopy","volume":"78","author":"Paradkar","year":"2002","journal-title":"Food Chem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1016\/j.foodchem.2009.11.048","article-title":"Optimisation of a CE method for caffeine analysis in decaffeinated coffee","volume":"120","author":"Meinhart","year":"2010","journal-title":"Food Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1002\/jssc.200800634","article-title":"Separation of catechins and methylxanthines in tea samples by capillary electrochromatography","volume":"32","author":"Aturki","year":"2009","journal-title":"J. Sep. Sci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/S0021-9673(96)00764-9","article-title":"Simultaneous determination of qualitatively important components in green tea infusions using capillary electrophoresis","volume":"758","author":"Horie","year":"1997","journal-title":"J. Chromatogr. A"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/0021-9673(92)80296-7","article-title":"Determination of substituted purines in body fluids by micellar electrokinetic capillary chromatography with direct sample injection","volume":"593","author":"Thormann","year":"1992","journal-title":"J. Chromatogr."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0378-4347(96)00278-2","article-title":"Determination of caffeine and its metabolites by micellar electrokinetic capillary electrophoresis","volume":"688","author":"Zhao","year":"1997","journal-title":"J. Chromatogr. B Biomed. Sci. Appl."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1021\/jf020907b","article-title":"Fast determination of catechins and xanthines in tea beverages by micellar electrokinetic chromatography","volume":"51","author":"Bonoli","year":"2003","journal-title":"J. Agric. Food Chem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"8638","DOI":"10.1016\/j.electacta.2010.07.093","article-title":"Simultaneous voltammetric determination of acetaminophen, aspirin and caffeine using an in situ surfactant-modified multiwalled carbon nanotube paste electrode","volume":"55","author":"Sanghavi","year":"2010","journal-title":"Electrochim. Acta"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.jelechem.2009.11.025","article-title":"Nafion\/multi-wall carbon nanotubes composite film coated glassy carbon electrode for sensitive determination of caffeine","volume":"639","author":"Yang","year":"2010","journal-title":"J. Electroanal. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/S0022-3565(25)30729-9","article-title":"Caffeine in plasma and saliva by a radioimmunoassay procedure","volume":"199","author":"Cook","year":"1976","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/S0378-4347(00)84148-1","article-title":"Determination of plasma theophylline by straight-phase high-performance liquid chromatography: Elimination of interfering caffeine metabolites","volume":"222","author":"Moerman","year":"1981","journal-title":"J. Chromatogr."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1093\/chromsci\/45.5.251","article-title":"Simultaneous determination of caffeine, ergotamine, and metamizol in solid pharmaceutical formulation by HPTLC-UV-FLD with mass confirmation by online HPTLC-ESI-MS","volume":"45","author":"Aranda","year":"2007","journal-title":"J. Chromatogr. Sci."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"4385","DOI":"10.1021\/ac050488s","article-title":"Quantitative thin-layer chromatography\/mass spectrometry analysis of caffeine using a surface sampling probe electrospray ionization tandem mass spectrometry system","volume":"77","author":"Ford","year":"2005","journal-title":"Anal. Chem."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1007\/s11167-005-0531-5","article-title":"A new procedure for caffeine determination","volume":"78","author":"Khasanov","year":"2005","journal-title":"Russ. J. Appl. Chem."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1007\/s00216-005-3169-5","article-title":"Solid-phase ultraviolet sensing system for determination of methylxanthines","volume":"382","year":"2005","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1093\/clinchem\/22.11.1903","article-title":"More sensitive high-pressure liquid-chromatographic determiantion of theophylline in serum","volume":"22","author":"Adams","year":"1976","journal-title":"Clin. Chem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1007\/s0021663560284","article-title":"Determination of adenine, caffeine, theophylline and theobromine by HPLC with amperometric detection","volume":"356","author":"Meyer","year":"1996","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/S0731-7085(03)00605-8","article-title":"Simultaneous analysis of theanine, chlorogenic acid, purine alkaloids and catechins in tea samples with the help of multi-dimension information of on-line high performance liquid chromatography\/electrospray-mass spectrometry","volume":"34","author":"Zhu","year":"2004","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.jpba.2004.11.013","article-title":"Development and validation of a high-performance liquid chromatography-mass spectrometry assay for methylxanthines and taurine in dietary supplements","volume":"37","author":"Marchei","year":"2005","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.jchromb.2009.12.019","article-title":"Quantification of theobromine and caffeine in saliva, plasma and urine via liquid chromatography-tandem mass spectrometry: A single analytical protocol applicable to cocoa intervention studies","volume":"878","author":"Ptolemy","year":"2010","journal-title":"J. Chromatogr. B"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.aca.2005.01.064","article-title":"Analysis of caffeine, theobromine and theophylline in coffee by near infrared spectroscopy (NIRS) compared to high-performance liquid chromatography (HPLC) coupled to mass spectrometry","volume":"538","author":"Huck","year":"2005","journal-title":"Anal. Chim. Acta"},{"key":"ref_111","first-page":"31","article-title":"Simultaneous determination of methylxanthines and cotinine in human plasma by solid-phase extraction followed by LC-MS-MS","volume":"27","author":"Bech","year":"2015","journal-title":"Spectroscopy"},{"key":"ref_112","unstructured":"Gilman, L.G.A. (1980). In The Pharmacologic Basis of Therapeutics, Macmillan. [6th ed.]."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1111\/j.2042-7158.1986.tb03392.x","article-title":"Clarke\u2019s \u2018Isolation and Identification of Drugs\u2019 (2nd edition) Senior consulting editor: A.C. Moffat Reviewed by I A Blair","volume":"38","author":"Moffat","year":"1986","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"275","DOI":"10.3109\/10408448209037495","article-title":"The toxicology of cocoa and methylxanthines: A review of the literature","volume":"9","author":"Tarka","year":"1982","journal-title":"CRC Crit. Rev. Toxicol."},{"key":"ref_115","first-page":"292","article-title":"Purine receptors and heir pharmacological roles","volume":"Volume 18","author":"Jovanovic","year":"1989","journal-title":"Advances in Drug Research"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"3341","DOI":"10.1021\/jm00074a015","article-title":"Synthesis of paraxanthine analogs (1,7-disubstituted xanthines) and other xanthines unsubstituted at the 3-position: Structure-activity relationships at adenosine receptors","volume":"36","author":"Mueller","year":"1993","journal-title":"J. Med. Chem."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1111\/j.2042-7158.1992.tb03230.x","article-title":"Selective Bronchodilators from 1-(5\u2032-Oxohexyl)xanthines","volume":"44","author":"Miyamoto","year":"1992","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/S0021-5198(19)43290-3","article-title":"Structure-activity relationship in N3-alkyl-xanthine derivatives","volume":"46","author":"Takagi","year":"1988","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1016\/S0022-3565(25)20387-1","article-title":"Methylxanthines block antigen-induced responses in RBL-2H3 cells independently of adenosine receptors or cyclic AMP: Evidence for inhibition of antigen binding to IgE","volume":"258","author":"Ali","year":"1991","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/0006-2952(81)90062-9","article-title":"Adenosine antagonism by purines, pteridines and benzopteridines in human fibroblasts","volume":"30","author":"Bruns","year":"1981","journal-title":"Biochem. Pharmacol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1073\/pnas.80.7.2077","article-title":"Adenosine receptor binding: Structure-activity analysis generates extremely potent xanthine antagonists","volume":"80","author":"Bruns","year":"1983","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1021\/jm00382a018","article-title":"1,3-Dialkyl-8-(p-sulfophenyl)xanthines: Potent water-soluble antagonists for A1- and A2-adenosine receptors","volume":"28","author":"Daly","year":"1985","journal-title":"J. Med. Chem."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"4538","DOI":"10.1021\/jp201383y","article-title":"Is caffeine a good scavenger of oxygenated free radicals?","volume":"115","author":"Galano","year":"2011","journal-title":"J. Phys. Chem. B"},{"key":"ref_124","first-page":"105","article-title":"The influence of sodium fluoride and caffeine on the activity of antioxidative enzymes and the concentration of malondialdehyde in rat liver","volume":"42","author":"Chlubek","year":"2009","journal-title":"Fluoride"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1007\/s11064-008-9790-x","article-title":"The effects of caffeine on l-arginine metabolism in the brain of rats","volume":"34","author":"Ofluoglu","year":"2008","journal-title":"Neurochem. Res."},{"key":"ref_126","first-page":"BR325","article-title":"Antioxidant and prooxidant properties of caffeine, theobromine and xanthine","volume":"9","author":"Azam","year":"2003","journal-title":"Med. Sci. Monit. Int. Med. J. Exp. Clin. Res."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/0024-3205(88)90517-6","article-title":"Caffeine and theophylline analogues: Correlation of behavioral effects with activity as adenosine receptor antagonists and as phosphodiesterase inhibitors","volume":"43","author":"Choi","year":"1988","journal-title":"Life Sci."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/0896-6273(91)90070-G","article-title":"The brain ryanodine receptor: A caffeine-sensitive calcium release channel","volume":"7","author":"McPherson","year":"1991","journal-title":"Neuron"},{"key":"ref_129","unstructured":"Chen, J.-F., and Chern, Y. (2011). Methylxanthines, Springer."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"L334","DOI":"10.1152\/ajplung.00103.2012","article-title":"Caffeine relaxes smooth muscle through actin depolymerization","volume":"303","author":"Tazzeo","year":"2012","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1165\/ajrcmb.10.5.8179921","article-title":"Theophylline suppresses human alveolar macrophage respiratory burst through phosphodiesterase inhibition","volume":"10","author":"Dent","year":"1994","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1159\/000139480","article-title":"Structure-activity relationship of xanthines and skeletal muscle ryanodine receptor\/Ca2+ release channel","volume":"54","author":"Liu","year":"1997","journal-title":"Pharmacology"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/0265203021000007840","article-title":"Effects of caffeine on human health","volume":"20","author":"Nawrot","year":"2003","journal-title":"Food Addit. Contam."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/S0031-6997(24)01511-4","article-title":"International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors","volume":"53","author":"Fredholm","year":"2001","journal-title":"Pharmacol. Rev."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1146\/annurev.pa.35.040195.003053","article-title":"Adenosine receptor subtypes: Characterization and therapeutic regulation","volume":"35","author":"Olah","year":"1995","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/0006-2952(77)90127-7","article-title":"Elevation of cyclic amp in C-1300 murine neuroblastoma by adenosine and related compounds and the antagonism of this response by methylxanthines","volume":"26","author":"Green","year":"1977","journal-title":"Biochem. Pharmacol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/0304-3940(82)90290-7","article-title":"Effects of caffeine and theophylline on adenosine and benzodiazepine receptors in human brain","volume":"30","author":"Boulenger","year":"1982","journal-title":"Neurosci. Lett."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/S0006-2952(00)00570-0","article-title":"Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells","volume":"61","author":"Fredholm","year":"2001","journal-title":"Biochem. Pharmacol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/PL00005131","article-title":"Comparative pharmacology of human adenosine receptor subtypes\u2014Characterization of stably transfected receptors in CHO cells","volume":"357","author":"Klotz","year":"1997","journal-title":"Naunyn Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/BF00734999","article-title":"Subclasses of adenosine receptors in the central nervous system: Interaction with caffeine and related methylxanthines","volume":"3","author":"Daly","year":"1983","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/(SICI)1098-1128(200003)20:2<103::AID-MED1>3.0.CO;2-X","article-title":"A3 adenosine receptor ligands: History and perspectives","volume":"20","author":"Baraldi","year":"2000","journal-title":"Med. Res. Rev."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/0014-2999(82)90359-4","article-title":"Xanthine derivatives as adenosine receptor antagonists","volume":"81","author":"Fredholm","year":"1982","journal-title":"Eur. J. Pharmacol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"4159","DOI":"10.3390\/nu5104159","article-title":"Health benefits of methylxanthines in cacao and chocolate","volume":"5","author":"Franco","year":"2013","journal-title":"Nutrients"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1023\/A:1006901005925","article-title":"Chronic effects of xanthines on levels of central receptors in mice","volume":"19","author":"Shi","year":"1999","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/0024-3205(85)90386-8","article-title":"Discriminative stimulus properties of methylxanthines and their metabolites in rats","volume":"36","author":"Carney","year":"1985","journal-title":"Life Sci."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1007\/BF00572436","article-title":"Xanthine derivatives as antagonists at A1 and A2 adenosine receptors","volume":"330","author":"Schwabe","year":"1985","journal-title":"Naunyn Schmiedeberg Arch. Pharmacol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1002\/med.20048","article-title":"Progress in the pursuit of therapeutic adenosine receptor antagonists","volume":"26","author":"Moro","year":"2006","journal-title":"Med. Res. Rev."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1517\/17460441.2.9.1161","article-title":"Novel 8-heterocyclyl xanthine derivatives in drug development\u2014An update","volume":"2","author":"Baraldi","year":"2007","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"6641","DOI":"10.1016\/j.bmc.2015.09.012","article-title":"1,3,7-Triethyl-substituted xanthines\u2014Possess nanomolar affinity for the adenosine A1 receptor","volume":"23","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/0165-6147(96)10002-X","article-title":"Adenosine receptor ligands: Differences with acute versus chronic treatment","volume":"17","author":"Jacobson","year":"1996","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1161\/01.CIR.99.19.2499","article-title":"Caffeine alters A2A adenosine receptors and their function in human platelets","volume":"99","author":"Varani","year":"1999","journal-title":"Circulation"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1016\/S0022-3565(25)20409-8","article-title":"Caffeine and theophylline as adenosine receptor antagonists in humans","volume":"258","author":"Biaggioni","year":"1991","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1159\/000343174","article-title":"Caffeine\u2019s mechanisms of action and its cosmetic use","volume":"26","author":"Herman","year":"2013","journal-title":"Skin Pharmacol. Physiol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S0026-895X(25)15265-6","article-title":"Effects of xanthine derivatives on lipolysis and on adenosine 3\u2032,5\u2032-monophosphate phosphodiesterase activity","volume":"6","author":"Beavo","year":"1970","journal-title":"Mol. Pharmacol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1080\/01635581.2013.877497","article-title":"Theobromine, the primary methylxanthine found in Theobroma cacao, prevents malignant glioblastoma proliferation by negatively regulating phosphodiesterase-4, extracellular signal-regulated kinase, Akt\/mammalian target of rapamycin kinase, and nuclear factor-\u03baB","volume":"66","author":"Sugimoto","year":"2014","journal-title":"Nutr. Cancer"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.resp.2010.04.025","article-title":"Methylxanthine reversal of opioid-evoked inspiratory depression via phosphodiesterase-4 blockade","volume":"172","author":"Ruangkittisakul","year":"2010","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_157","doi-asserted-by":"crossref","unstructured":"Sassone-Corsi, P. (2012). The cyclic AMP pathway. Cold Spring Harb. Perspect. Biol., 4.","DOI":"10.1101\/cshperspect.a011148"},{"key":"ref_158","unstructured":"Francis, S.H., Sekhar, K.R., Ke, H., and Corbin, J.D. (2011). Methylxanthines, Springer."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1007\/s00018-007-7051-9","article-title":"Caffeine analogs: Biomedical impact","volume":"64","author":"Daly","year":"2007","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1183\/09031936.95.08040637","article-title":"Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants","volume":"8","author":"Rabe","year":"1995","journal-title":"Eur. Respir. J."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1016\/j.bmcl.2003.12.027","article-title":"SAR development of polycyclic guanine derivatives targeted to the discovery of a selective PDE5 inhibitor for treatment of erectile dysfunction","volume":"14","author":"Pissarnitski","year":"2004","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"2587","DOI":"10.1016\/S0960-894X(02)00480-8","article-title":"8-Aryl xanthines potent inhibitors of phosphodiesterase 5","volume":"12","author":"Arnold","year":"2002","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"13095","DOI":"10.1074\/jbc.M311556200","article-title":"Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor 3-isobutyl-1-methylxanthine suggest a conformation determinant of inhibitor selectivity","volume":"279","author":"Huai","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"6091","DOI":"10.1021\/bi049868i","article-title":"Crystal structure of human phosphodiesterase 3B: Atomic basis for substrate and inhibitor specificity","volume":"43","author":"Scapin","year":"2004","journal-title":"Biochemistry"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/0922-4106(89)90028-X","article-title":"Interaction of caffeine with the GABAA receptor complex: Alterations in receptor function but not ligand binding","volume":"172","author":"Lopez","year":"1989","journal-title":"Eur. J. Pharmacol. Mol. Pharmacol."},{"key":"ref_166","first-page":"489","article-title":"Inhibitory effect of theophylline on recombinant GABAA receptor","volume":"12","author":"Sugimoto","year":"2001","journal-title":"Neuro Rep."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1023\/A:1023688604792","article-title":"Caffeine analogs: Effects on ryanodine-sensitive calcium-release channels and GABAA receptors","volume":"23","author":"Shi","year":"2003","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/S0026-895X(25)13347-6","article-title":"Chronic caffeine or theophylline exposure reduces \u03b3-aminobutyric acid\/benzodiazepine receptor site interactions","volume":"33","author":"Roca","year":"1988","journal-title":"Mol. Pharmacol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/S0165-1838(00)00110-7","article-title":"Alkylxanthines as research tools","volume":"81","author":"Daly","year":"2000","journal-title":"J. Auton. Nerv. Syst."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/j.bbamem.2013.11.005","article-title":"Coupled gating modifies the regulation of cardiac ryanodine receptors by luminal Ca2+","volume":"1838","author":"Gaburjakova","year":"2014","journal-title":"Biochim. Biophys. Acta BBA Biomembr."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1016\/0006-2952(93)90589-O","article-title":"Stimulation of calcium release by caffeine analogs in pheochromocytoma cells","volume":"46","author":"Daly","year":"1993","journal-title":"Biochem. Pharmacol."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/0003-9861(88)90010-0","article-title":"Activation of the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum by caffeine and related compounds","volume":"267","author":"Rousseau","year":"1988","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.jep.2013.08.009","article-title":"Modulation effect of Smilax glabra flavonoids on ryanodine receptor mediated intracellular Ca2+ release in cardiomyoblast cells","volume":"150","author":"Shou","year":"2013","journal-title":"J. Ethnopharmacol."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"C1421","DOI":"10.1152\/ajpcell.1994.266.5.C1421","article-title":"Agonist-activated, ryanodine-sensitive, IP3-insensitive Ca2+ release channels in longitudinal muscle of intestine","volume":"266","author":"Kuemmerle","year":"1994","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1021\/jm980469t","article-title":"Potentiation of cADPR-induced Ca2+-release by methylxanthine analogues","volume":"42","author":"Cavallaro","year":"1999","journal-title":"J. Med. Chem."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1111\/j.0954-6820.1985.tb01650.x","article-title":"On the mechanism of action of theophylline and caffeine","volume":"217","author":"Fredholm","year":"1985","journal-title":"Acta Medica Scand."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/0024-3205(79)90369-2","article-title":"Purinergic inhibition of diazepam binding to rat brain (in vitro)","volume":"24","author":"Marangos","year":"1979","journal-title":"Life Sci."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0026-895X(25)15197-3","article-title":"The effect of adenosine and adenine nucleotides on the cyclic adenosine 3\u2032,5\u2032-phosphate content of guinea pig cerebral cortex slices","volume":"6","author":"Sattin","year":"1970","journal-title":"Mol. Pharmacol."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/0165-6147(80)90064-4","article-title":"Methylxanthines: Possible mechanisms of action in brain","volume":"1","author":"Cardinali","year":"1980","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1016\/S0021-9258(18)60316-3","article-title":"Adenosine 3\u2032,5\u2032-Phosphate in Biological Materials: I. Purification and properties of cyclic 3\u2032,5\u2032-nucleotide phosphodiesterase and use of this enzyme to characterize adenosine 3\u2032,5\u2032-phosphate in human urine","volume":"237","author":"Butcher","year":"1962","journal-title":"J. Biol. Chem."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1111\/j.1476-5381.1989.tb12029.x","article-title":"The ability of denbufylline to inhibit cyclic nucleotide phosphodiesterase and its affinity for adenosine receptors and the adenosine re-uptake site","volume":"97","author":"Nicholson","year":"1989","journal-title":"Br. J. Pharmacol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1016\/j.bcp.2006.06.023","article-title":"Caffeine metabolites are inhibitors of the nuclear enzyme poly(ADP-ribose)polymerase-1 at physiological concentrations","volume":"72","author":"Geraets","year":"2006","journal-title":"Biochem. Pharmacol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.chembiol.2005.07.009","article-title":"Methylxanthine drugs are chitinase inhibitors: Investigation of inhibition and binding modes","volume":"12","author":"Rao","year":"2005","journal-title":"Chem. Biol."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"8921","DOI":"10.1073\/pnas.132556899","article-title":"A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression","volume":"99","author":"Ito","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1084\/jem.20040416","article-title":"Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages","volume":"200","author":"Cosio","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"9873","DOI":"10.3390\/ijms14059873","article-title":"Caffeine inhibits acetylcholinesterase, but not butyrylcholinesterase","volume":"14","author":"Pohanka","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"543","DOI":"10.2174\/1389557514666140529223436","article-title":"The effects of caffeine on the cholinergic system","volume":"14","author":"Miroslav","year":"2014","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.lfs.2013.06.020","article-title":"The interactions of caffeine with monoamine oxidase","volume":"93","author":"Petzer","year":"2013","journal-title":"Life Sci."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.fluid.2011.06.006","article-title":"Quantitative study on the non-covalent interactions between ATP and caffeine, theophylline and theobromine in aqueous solution","volume":"308","author":"Gattuso","year":"2011","journal-title":"Fluid Phase Equilibria"},{"key":"ref_190","doi-asserted-by":"crossref","unstructured":"Johnson, I.M., Prakash, H., Prathiba, J., Raghunathan, R., and Malathi, R. (2012). Spectral analysis of naturally occurring methylxanthines (theophylline, theobromine and caffeine) binding with DNA. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050019"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1080\/07391102.2003.10506885","article-title":"RNA binding efficacy of theophylline, theobromine and caffeine","volume":"20","author":"Johnson","year":"2003","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_192","first-page":"1","article-title":"The relevance of theobromine for the beneficial effects of cocoa consumption","volume":"6","author":"Franco","year":"2015","journal-title":"Front. Pharmacol."},{"key":"ref_193","unstructured":"Arnaud, M.J. (2011). Methylxanthines, Springer."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1111\/j.1365-2125.1986.tb05246.x","article-title":"Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man","volume":"22","author":"Lelo","year":"1986","journal-title":"Br. J. Cl. Pharmacol."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/BF00613933","article-title":"The absolute bioavailability of caffeine in man","volume":"24","author":"Blanchard","year":"1983","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1111\/j.1742-7843.2005.pto960111.x","article-title":"Population pharmacokinetics of caffeine and its metabolites theobromine, paraxanthine and theophylline after inhalation in combination with diacetylmorphine","volume":"96","author":"Zandvliet","year":"2005","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1155\/2013\/147238","article-title":"Pharmacokinetics of caffeine following a single administration of coffee enema versus oral coffee consumption in healthy male subjects","volume":"2013","author":"Teekachunhatean","year":"2013","journal-title":"ISRN Pharmacol."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1002\/bmc.1419","article-title":"Caffeine and paraxanthine HPLC assay for CYP1A2 phenotype assessment using saliva and plasma","volume":"24","author":"Perera","year":"2010","journal-title":"Biomed. Chromatogr."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1056\/NEJM198403223101202","article-title":"The bronchodilator effects and pharmacokinetics of caffeine in asthma","volume":"310","author":"Becker","year":"1984","journal-title":"N. Engl. J. Med."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1185\/03007997909115902","article-title":"The pharmacokinetics of theophylline","volume":"6","author":"French","year":"1979","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/S0022-3476(77)81329-2","article-title":"Breast milk distribution of theobromine from chocolate","volume":"91","author":"Resman","year":"1977","journal-title":"J. Pediatr."},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1007\/s002280050205","article-title":"Absorption rate of methylxanthines following capsules, cola and chocolate","volume":"51","author":"Mumford","year":"1996","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1001\/jama.1984.03340370043028","article-title":"Caffeine as an analgesic adjuvant","volume":"251","author":"Laska","year":"1984","journal-title":"JAMA"},{"key":"ref_204","first-page":"1","article-title":"Caffeine as an analgesic adjuvant for acute pain in adults","volume":"12","author":"Derry","year":"2014","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.3748\/wjg.v20.i5.1127","article-title":"Novel methylxanthine derivative-mediated anti-inflammatory effects in inflammatory bowel disease","volume":"20","author":"Lee","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1159\/000082851","article-title":"Recovery after prolonged sleep deprivation: Residual effects of slow-release caffeine on recovery sleep, sleepiness and cognitive functions","volume":"51","author":"Beaumont","year":"2005","journal-title":"Neuropsychobiology"},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"225","DOI":"10.20882\/adicciones.303","article-title":"Cafe\u00edna: Un nutriente, un f\u00e1rmaco, o una droga de abuso","volume":"19","author":"Lozano","year":"2007","journal-title":"Adicciones"},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1007\/s00213-004-1898-3","article-title":"Methylxanthines are the psycho-pharmacologically active constituents of chocolate","volume":"176","author":"Smit","year":"2004","journal-title":"Psychopharmacology"},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.2741\/2870","article-title":"Adenosine receptor antagonists for cognitive dysfunction: A review of animal studies","volume":"13","author":"Takahashi","year":"2008","journal-title":"Front. Biosci."},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1590\/S0100-879X2002001000013","article-title":"Effects of caffeine on learning and memory in rats tested in the Morris water maze","volume":"35","author":"Angelucci","year":"2002","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/j.1753-4887.2001.tb06995.x","article-title":"The effects of ginseng, ephedrine, and caffeine on cognitive performance, mood and energy","volume":"59","author":"Lieberman","year":"2001","journal-title":"Nutr. Rev."},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1007\/s00213-004-2104-3","article-title":"Cognitive and mood improvements of caffeine in habitual consumers and habitual non-consumers of caffeine","volume":"179","author":"Haskell","year":"2005","journal-title":"Psychopharmacology"},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1007\/BF02246090","article-title":"Caffeine attenuates scopolamine-induced memory impairment in humans","volume":"122","author":"Riedel","year":"1995","journal-title":"Psychopharmacology"},{"key":"ref_214","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1046\/j.1468-1331.2002.00421.x","article-title":"Does caffeine intake protect from Alzheimer\u2019s disease?","volume":"9","author":"Maia","year":"2002","journal-title":"Eur. J. Neurol."},{"key":"ref_215","doi-asserted-by":"crossref","first-page":"S117","DOI":"10.3233\/JAD-2010-091249","article-title":"Caffeine and coffee as therapeutics against Alzheimer\u2019s disease","volume":"20","author":"Arendash","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"ref_216","doi-asserted-by":"crossref","first-page":"85","DOI":"10.3233\/JAD-2009-0920","article-title":"Midlife coffee and tea drinking and the risk of latelife dementia: A population-based CAIDE study","volume":"16","author":"Eskelinen","year":"2009","journal-title":"J. Alzheimers Dis."},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"RC143","DOI":"10.1523\/JNEUROSCI.21-10-j0001.2001","article-title":"Neuroprotection by caffeine and A2A adenosine receptor inactivation in a model of Parkinson\u2019s disease","volume":"21","author":"Chen","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"S221","DOI":"10.3233\/JAD-2010-091525","article-title":"Caffeine exposure and the risk of Parkinson\u2019s disease: A systematic review and meta-analysis of observational studies","volume":"20","author":"Costa","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1212\/WNL.0b013e318263570d","article-title":"Caffeine for treatment of Parkinson disease: A randomized controlled trial","volume":"79","author":"Postuma","year":"2012","journal-title":"Neurology"},{"key":"ref_220","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1016\/j.str.2011.06.014","article-title":"Structure of the adenosine A2A receptor in complex with ZM241385 and the xanthines XAC and caffeine","volume":"19","author":"Robertson","year":"2011","journal-title":"Structure"},{"key":"ref_221","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/1742-2094-5-12","article-title":"Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer\u2019s disease","volume":"5","author":"Chen","year":"2008","journal-title":"J. Neuroinflammation"},{"key":"ref_222","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1111\/j.1471-4159.2008.05697.x","article-title":"Caffeine protects against MPTP-induced blood-brain barrier dysfunction in mouse striatum","volume":"107","author":"Chen","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_223","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.neuroscience.2006.07.021","article-title":"Caffeine protects Alzheimer\u2019s mice against cognitive impairment and reduces brain \u03b2-amyloid production","volume":"142","author":"Arendash","year":"2006","journal-title":"Neuroscience"},{"key":"ref_224","doi-asserted-by":"crossref","first-page":"681","DOI":"10.3233\/JAD-2009-1071","article-title":"Caffeine suppresses \u03b2-amyloid levels in plasma and brain of Alzheimer\u2019s transgenic mice","volume":"17","author":"Cao","year":"2009","journal-title":"J. Alzheimer\u2019s Dis. JAD"},{"key":"ref_225","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1016\/j.foodchem.2012.04.148","article-title":"Crude caffeine reduces memory impairment and amyloid \u03b21-42 levels in an Alzheimer\u2019s mouse model","volume":"135","author":"Chu","year":"2012","journal-title":"Food Chem."},{"key":"ref_226","doi-asserted-by":"crossref","first-page":"661","DOI":"10.3233\/JAD-2009-1087","article-title":"Caffeine reverses cognitive impairment and decreases brain amyloid-beta levels in aged Alzheimer\u2019s disease mice","volume":"17","author":"Arendash","year":"2009","journal-title":"J. Alzheimers Dis."},{"key":"ref_227","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1093\/aje\/kwf074","article-title":"Risk factors for Alzheimer\u2019s disease: A prospective analysis from the Canadian Study of Health and Aging","volume":"156","author":"Lindsay","year":"2002","journal-title":"Am. J. Epidemiol."},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1212\/01.wnl.0000266670.35219.0c","article-title":"The neuroprotective effects of caffeine: A prospective population study (the Three City Study)","volume":"69","author":"Ritchie","year":"2007","journal-title":"Neurology"},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1093\/aje\/kwf119","article-title":"Coffee consumption and cognitive function among older adults","volume":"156","author":"Morton","year":"2002","journal-title":"Am. J. Epidemiol."},{"key":"ref_230","first-page":"226","article-title":"Coffee consumption is inversely associated with cognitive decline in elderly European men: The FINE Study","volume":"61","author":"Buijsse","year":"2006","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_231","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1016\/j.neuroscience.2007.11.020","article-title":"Chronic but not acute treatment with caffeine attenuates traumatic brain injury in the mouse cortical impact model","volume":"151","author":"Li","year":"2008","journal-title":"Neuroscience"},{"key":"ref_232","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.expneurol.2012.01.022","article-title":"Delayed caffeine treatment prevents nigral dopamine neuron loss in a progressive rat model of Parkinson\u2019s disease","volume":"234","author":"Sonsalla","year":"2012","journal-title":"Exp. Neurol."},{"key":"ref_233","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1212\/WNL.55.9.1350","article-title":"Smoking, alcohol, and coffee consumption preceding Parkinson\u2019s disease: A case-control study","volume":"55","author":"Benedetti","year":"2000","journal-title":"Neurology"},{"key":"ref_234","doi-asserted-by":"crossref","first-page":"2674","DOI":"10.1001\/jama.283.20.2674","article-title":"Association of coffee and caffeine intake with the risk of parkinson disease","volume":"283","author":"Ross","year":"2000","journal-title":"JAMA"},{"key":"ref_235","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/sj.ejcn.1602788","article-title":"Prospective study of coffee consumption and risk of Parkinson\u2019s disease","volume":"62","author":"Saaksjarvi","year":"2007","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_236","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1002\/ana.1052","article-title":"Prospective study of caffeine consumption and risk of Parkinson\u2019s disease in men and women","volume":"50","author":"Ascherio","year":"2001","journal-title":"Ann. Neurol."},{"key":"ref_237","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1002\/mds.25076","article-title":"Caffeine and risk of Parkinson disease in a large cohort of men and women","volume":"27","author":"Palacios","year":"2012","journal-title":"Mov. Disord."},{"key":"ref_238","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1111\/ggi.12123","article-title":"Dose-response meta-analysis on coffee, tea and caffeine consumption with risk of Parkinson\u2019s disease","volume":"14","author":"Qi","year":"2014","journal-title":"Geriatr. Gerontol. Int."},{"key":"ref_239","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1002\/ana.23866","article-title":"Caffeine and adenosine A2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado-Joseph disease","volume":"73","author":"Cunha","year":"2013","journal-title":"Ann. Neurol."},{"key":"ref_240","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.nbd.2013.05.013","article-title":"Association between caffeine intake and age at onset in Huntington\u2019s disease","volume":"58","author":"Simonin","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"ref_241","doi-asserted-by":"crossref","unstructured":"Henderson-Smart, D.J., and De Paoli, A.G. (2010). Methylxanthine treatment for apnoea in preterm infants. Cochrane Database Syst. Rev., 8.","DOI":"10.1002\/14651858.CD000140.pub2"},{"key":"ref_242","doi-asserted-by":"crossref","first-page":"61","DOI":"10.2165\/00128072-200103010-00005","article-title":"Caffeine citrate: A review of its use in apnoea of prematurity","volume":"3","author":"Comer","year":"2001","journal-title":"Paediatric Drugs"},{"key":"ref_243","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1177\/000992280003900602","article-title":"Current options in the management of apnea of prematurity","volume":"39","author":"Bhatia","year":"2000","journal-title":"Clin. Pediatr."},{"key":"ref_244","doi-asserted-by":"crossref","first-page":"20","DOI":"10.3109\/14767058.2010.517704","article-title":"Caffeine impact on neonatal morbidities","volume":"23","author":"Aranda","year":"2010","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_245","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s40272-013-0063-z","article-title":"Use of methylxanthine therapies for the treatment and prevention of apnea of prematurity","volume":"16","author":"Schoen","year":"2014","journal-title":"Pediatr. Drugs"},{"key":"ref_246","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1203\/00006450-198404000-00018","article-title":"Adenosine analogues depress ventilation in rabbit neonates. Theophylline stimulation of respiration via adenosine receptors?","volume":"18","author":"Lagercrantz","year":"1984","journal-title":"Pediatr. Res."},{"key":"ref_247","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/0034-5687(94)00124-I","article-title":"Theophylline and hypoxic ventilatory response in the rat isolated brainstem-spinal cord","volume":"100","author":"Kawai","year":"1995","journal-title":"Respir. Physiol."},{"key":"ref_248","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1111\/j.1748-1716.1983.tb07319.x","article-title":"Neonatal breathing control mediated via the central chemoreceptors","volume":"119","author":"Wennergren","year":"1983","journal-title":"Acta Physiol. Scand."},{"key":"ref_249","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1111\/j.1469-7793.1999.0159r.x","article-title":"Adenosinergic modulation of respiratory neurones in the neonatal rat brainstem in vitro","volume":"518","author":"Herlenius","year":"1999","journal-title":"J. Physiol."},{"key":"ref_250","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1152\/jappl.1985.59.5.1428","article-title":"Antagonism by theophylline of respiratory inhibition induced by adenosine","volume":"59","author":"Eldridge","year":"1985","journal-title":"J. Appl. Physiol."},{"key":"ref_251","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1159\/000242135","article-title":"Characterization of adenosine-induced respiratory depression in the preterm rabbit","volume":"47","author":"Hedner","year":"1985","journal-title":"Biol. Neonate"},{"key":"ref_252","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.resp.2014.06.002","article-title":"Methylxanthine reversal of opioid-induced respiratory depression in the neonatal rat: Mechanism and location of action","volume":"200","author":"Mosca","year":"2014","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_253","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1513\/pats.200504-024SR","article-title":"Theophylline in chronic obstructive pulmonary disease: New horizons","volume":"2","author":"Barnes","year":"2005","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_254","first-page":"69","article-title":"Adenosine receptor ligands as potential therapeutics in asthma","volume":"3","author":"Fozard","year":"2002","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_255","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/j.1472-8206.2005.00388.x","article-title":"Adenosine receptors: Promising targets for the development of novel therapeutics and diagnostics for asthma","volume":"20","author":"Russo","year":"2006","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_256","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1136\/thx.2006.061002","article-title":"Theophylline for COPD","volume":"61","author":"Barnes","year":"2006","journal-title":"Thorax"},{"key":"ref_257","doi-asserted-by":"crossref","unstructured":"Usmani, O.S., Belvisi, M.G., Patel, H.J., Crispino, N., Birrell, M.A., Korbonits, M., Korbonits, D., and Barnes, P.J. (2004). Theobromine inhibits sensory nerve activation and cough. FASEB J.","DOI":"10.1096\/fj.04-1990fje"},{"key":"ref_258","unstructured":"Smit, H.J. (2011). Methylxanthines, Springer."},{"key":"ref_259","unstructured":"Riksen, N.P., Smits, P., and Rongen, G.A. (2011). Methylxanthines, Springer."},{"key":"ref_260","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1016\/0024-3205(90)90174-P","article-title":"Caffeine and human cerebral blood flow: A positron emission tomography study","volume":"47","author":"Cameron","year":"1990","journal-title":"Life Sci."},{"key":"ref_261","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/S0021-5155(01)00498-1","article-title":"Effects of caffeine on microcirculation of the human ocular fundus","volume":"46","author":"Okuno","year":"2002","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_262","first-page":"318","article-title":"Reevaluation of the usefullness of theobromine calcium gluconate for the management of congestive heart failure and anginal syndrome","volume":"172","author":"Batterman","year":"1959","journal-title":"Int. Rec. Med. Gen. Pract. Clin."},{"key":"ref_263","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1093\/aje\/kwr226","article-title":"Coffee consumption and risk of stroke: A dose-response meta-analysis of prospective studies","volume":"174","author":"Larsson","year":"2011","journal-title":"Am. J. Epidemiol."},{"key":"ref_264","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1161\/CIRCULATIONAHA.113.005925","article-title":"Long-term coffee consumption and risk of cardiovascular disease: A systematic review and a dose-response meta-analysis of prospective cohort studies","volume":"129","author":"Ding","year":"2014","journal-title":"Circulation"},{"key":"ref_265","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1039\/c2fo10288a","article-title":"Effects of tea and coffee on cardiovascular disease risk","volume":"3","author":"Bohn","year":"2012","journal-title":"Food Funct."},{"key":"ref_266","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.numecd.2011.02.001","article-title":"Regular consumption of cocoa powder with milk increases HDL cholesterol and reduces oxidized LDL levels in subjects at high-risk of cardiovascular disease","volume":"22","author":"Khan","year":"2012","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_267","doi-asserted-by":"crossref","first-page":"1037S","DOI":"10.1093\/ajcn\/60.6.1037S","article-title":"Effects of a milk chocolate bar per day substituted for a high-carbohydrate snack in young men on an NCEP\/AHA Step 1 Diet","volume":"60","author":"Derr","year":"1994","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_268","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1016\/j.freeradbiomed.2004.06.002","article-title":"Dark chocolate consumption increases HDL cholesterol concentration and chocolate fatty acids may inhibit lipid peroxidation in healthy humans","volume":"37","author":"Mursu","year":"2004","journal-title":"Free Radic. Biol. Med."},{"key":"ref_269","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1093\/ajcn\/85.3.709","article-title":"Continuous intake of polyphenolic compounds containing cocoa powder reduces LDL oxidative susceptibility and has beneficial effects on plasma HDL-cholesterol concentrations in humans","volume":"85","author":"Baba","year":"2007","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_270","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1111\/j.1464-5491.2010.03108.x","article-title":"High-cocoa polyphenol-rich chocolate improves HDL cholesterol in Type 2 diabetes patients","volume":"27","author":"Mellor","year":"2010","journal-title":"Diabet. Med."},{"key":"ref_271","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.3945\/ajcn.112.047373","article-title":"Effect of cocoa and theobromine consumption on serum HDL-cholesterol concentrations: A randomized controlled trial","volume":"97","author":"Neufingerl","year":"2013","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_272","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1271\/bbb.70.1134","article-title":"Regulation of the body fat percentage in developmental-stage rats by methylxanthine derivatives in a high-fat diet","volume":"70","author":"Inoue","year":"2006","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_273","first-page":"439","article-title":"The lipotropic activity of caffeine, theobromine and theophylline","volume":"15","author":"Heppel","year":"1947","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_274","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/S0022-2275(20)42934-7","article-title":"Mobilization of fatty acids in genetically obese rats","volume":"11","author":"Bray","year":"1970","journal-title":"J. Lipid Res."},{"key":"ref_275","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1016\/S0021-9258(19)78219-2","article-title":"A comparison of the effects of lipolytic and antilipolytic agents on adenosine 3\u2032,5\u2032-monophosphate levels in adipose cells as determined by prior labeling with adenine-8-14C","volume":"244","author":"Kuo","year":"1969","journal-title":"J. Biol. Chem."},{"key":"ref_276","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1093\/ajcn\/79.1.40","article-title":"Metabolic effects of caffeine in humans: Lipid oxidation or futile cycling?","volume":"79","author":"Acheson","year":"2004","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_277","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1007\/s10068-010-0151-6","article-title":"Effect of caffeine on the metabolic responses of lipolysis and activated sweat gland density in human during physical activity","volume":"19","author":"Kim","year":"2010","journal-title":"Food Sci. Biotechnol."},{"key":"ref_278","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1093\/ajcn.83.3.674","article-title":"Changes in caffeine intake and long-term weight change in men and women","volume":"83","author":"Rajpathak","year":"2006","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_279","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1038\/oby.2005.142","article-title":"Body weight loss and weight maintenance in relation to habitual caffeine intake and green tea supplementation","volume":"13","author":"Lejeune","year":"2005","journal-title":"Obes. Res."},{"key":"ref_280","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1172\/JCI102211","article-title":"The effect of theophylline ethylene diamine on renal function in control subjects and in patients with congestive heart failure","volume":"28 Pt. 2","author":"Davis","year":"1949","journal-title":"J. Clin. Investig."},{"key":"ref_281","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/978-3-642-13443-2_15","article-title":"Methylxanthines and the kidney","volume":"200","author":"Osswald","year":"2011","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_282","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1681\/ASN.V104714","article-title":"Natriuretic and diuretic actions of a highly selective adenosine A1 receptor antagonist","volume":"10","author":"Wilcox","year":"1999","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_283","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1124\/jpet.104.080432","article-title":"Requirement of intact adenosine A1 receptors for the diuretic and natriuretic action of the methylxanthines theophylline and caffeine","volume":"313","author":"Rieg","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_284","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1016\/0006-2952(78)90199-5","article-title":"Effect of theophylline and other drugs on rabbit renal cyclic nucleotide phosphodiesterase, 5\u2032-nucleotidase and adenosine deaminase","volume":"27","author":"Fredholm","year":"1978","journal-title":"Biochem. Pharmacol."},{"key":"ref_285","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/S0022-3565(25)23742-9","article-title":"Xanthine effects on renal proximal tubular function and cyclic AMP metabolism","volume":"248","author":"Coulson","year":"1989","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_286","doi-asserted-by":"crossref","first-page":"155","DOI":"10.3945\/ajcn.112.048603","article-title":"Caffeinated and caffeine-free beverages and risk of type 2 diabetes","volume":"97","author":"Bhupathiraju","year":"2013","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_287","doi-asserted-by":"crossref","first-page":"S143","DOI":"10.3233\/JAD-2010-091228","article-title":"Caffeine, diabetes, cognition, and dementia","volume":"20","author":"Biessels","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"ref_288","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.1007\/s00125-006-0435-9","article-title":"Coffee consumption and risk of total and cardiovascular mortality among patients with type 2 diabetes","volume":"49","author":"Bidel","year":"2006","journal-title":"Diabetologia"},{"key":"ref_289","doi-asserted-by":"crossref","first-page":"162","DOI":"10.2174\/157339912800564016","article-title":"Coffee to reduce risk of type 2 diabetes? A systematic review","volume":"8","author":"Muley","year":"2012","journal-title":"Curr. Diabetes Rev."},{"key":"ref_290","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1016\/S0140-6736(02)11436-X","article-title":"Coffee consumption and risk of type 2 diabetes mellitus","volume":"360","author":"Feskens","year":"2002","journal-title":"Lancet"},{"key":"ref_291","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1001\/jama.294.1.97","article-title":"Coffee consumption and risk of type 2 diabetes: A systematic review","volume":"294","author":"Hu","year":"2005","journal-title":"JAMA"},{"key":"ref_292","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1093\/aje\/kwj323","article-title":"Coffee and sweetened beverage consumption and the risk of type 2 diabetes mellitus: The atherosclerosis risk in communities study","volume":"164","author":"Paynter","year":"2006","journal-title":"Am. J. Epidemiol."},{"key":"ref_293","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.3945\/ajcn.2009.28741","article-title":"Differential effects of coffee on the risk of type 2 diabetes according to meal consumption in a French cohort of women: The E3N\/EPIC cohort study","volume":"91","author":"Sartorelli","year":"2010","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_294","doi-asserted-by":"crossref","first-page":"569","DOI":"10.2337\/dc13-1203","article-title":"Caffeinated and decaffeinated coffee consumption and risk of type 2 diabetes: A systematic review and a dose-response meta-analysis","volume":"37","author":"Ding","year":"2014","journal-title":"Diabetes Care"},{"key":"ref_295","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1007\/s00125-009-1516-3","article-title":"Coffee and tea consumption and risk of type 2 diabetes","volume":"52","author":"Dieren","year":"2009","journal-title":"Diabetologia"},{"key":"ref_296","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1017\/S0007114513003887","article-title":"Tea consumption and risk of type 2 diabetes: A dose\u2013response meta-analysis of cohort studies","volume":"111","author":"Yang","year":"2014","journal-title":"Br. J. Nutr."},{"key":"ref_297","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1001\/archinte.166.12.1311","article-title":"Coffee consumption and risk of type 2 diabetes mellitus: An 11-year prospective study of 28,812 postmenopausal women","volume":"166","author":"Pereira","year":"2006","journal-title":"Arch. Intern. Med."},{"key":"ref_298","doi-asserted-by":"crossref","first-page":"398","DOI":"10.2337\/diacare.29.02.06.dc05-1512","article-title":"Coffee, caffeine, and risk of type 2 diabetes: A prospective cohort study in younger and middle-aged U.S. women","volume":"29","author":"Willett","year":"2006","journal-title":"Diabetes Care"},{"key":"ref_299","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.foodchem.2014.11.004","article-title":"Effects of bioactive constituents in functional cocoa products on cardiovascular health in humans","volume":"174","author":"Goya","year":"2015","journal-title":"Food Chem."},{"key":"ref_300","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1111\/j.1463-1326.2009.01108.x","article-title":"Roles of cAMP signalling in insulin granule exocytosis","volume":"11","author":"Seino","year":"2009","journal-title":"Diabetes Obes. Metab."},{"key":"ref_301","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cbi.2014.05.020","article-title":"Tadalafil inhibits the cAMP stimulated glucose output in the rat liver","volume":"220","author":"Vilela","year":"2014","journal-title":"Chem. Biol. Interact."},{"key":"ref_302","first-page":"2623","article-title":"Effects of tea, decaffeinated tea, and caffeine on UVB light-induced complete carcinogenesis in SKH-1 mice: Demonstration of caffeine as a biologically important constitutent of tea","volume":"57","author":"Huang","year":"1997","journal-title":"Cancer Res."},{"key":"ref_303","doi-asserted-by":"crossref","first-page":"12455","DOI":"10.1073\/pnas.182429899","article-title":"Topical applications of caffeine or (\u2212)-epigallocatechin gallate (EGCG) inhibit carcinogenesis and selectively increase apoptosis in UVB-induced skin tumors in mice","volume":"99","author":"Lu","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_304","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1093\/carcin\/bgl112","article-title":"Caffeine and caffeine sodium benzoate have a sunscreen effect, enhance UVB-induced apoptosis, and inhibit UVB-induced skin carcinogenesis in SKH-1 mice","volume":"28","author":"Lu","year":"2006","journal-title":"Carcinogenesis"},{"key":"ref_305","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1124\/jpet.106.114850","article-title":"Role of Adenosine Receptors in the Regulation of Angiogenic Factors and Neovascularization in Hypoxia","volume":"320","author":"Ryzhov","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_306","first-page":"4096","article-title":"Inhibition of lung carcinogenesis by black tea in fischer rats treated with a tobacco-specific carcinogen: Caffeine as an important constituent","volume":"58","author":"Chung","year":"1998","journal-title":"Cancer Res."},{"key":"ref_307","doi-asserted-by":"crossref","first-page":"11494","DOI":"10.1158\/0008-5472.CAN-06-1497","article-title":"Inhibition of adenoma progression to adenocarcinoma in a 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone\u2014Induced lung tumorigenesis model in A\/J mice by tea polyphenols and caffeine","volume":"66","author":"Lu","year":"2006","journal-title":"Cancer Res."},{"key":"ref_308","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1007\/s10585-004-8251-4","article-title":"Caffeine suppresses metastasis in a transgenic mouse model: A prototype molecule for prophylaxis of metastasis","volume":"21","author":"Yang","year":"2005","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_309","first-page":"287","article-title":"Effect of Caffeine, a xanthine derivative, in the inhibition of experimental lung metastasis induced by B16F10 melanoma cells","volume":"20","author":"Gude","year":"2001","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_310","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1124\/mol.106.032920","article-title":"Caffeine inhibits adenosine-induced accumulation of hypoxia-inducible factor-1\u03b1, vascular endothelial growth factor, and interleukin-8 expression in hypoxic human colon cancer cells","volume":"72","author":"Merighi","year":"2007","journal-title":"Mol. Pharmacol."},{"key":"ref_311","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1159\/000069785","article-title":"Potentiation of lipid peroxidation in B16F10 and B16F1 melanoma cells by caffeine, a methylxanthine derivative: Relationship to intracellular glutathione","volume":"49","author":"Shukla","year":"2003","journal-title":"Chemotherapy"},{"key":"ref_312","doi-asserted-by":"crossref","first-page":"3344","DOI":"10.1158\/0008-5472.CAN-03-3453","article-title":"Caffeine inhibits cell proliferation by G0\/G1 phase arrest in JB6 cells","volume":"64","author":"Hashimoto","year":"2004","journal-title":"Cancer Res."},{"key":"ref_313","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/BF02787362","article-title":"Therapeutic efficacy of theophylline in chronic lymphocytic leukemia","volume":"16","author":"Makower","year":"1999","journal-title":"Med. Oncol."},{"key":"ref_314","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1163\/156855900300109242","article-title":"Theophylline as a therapy for chronic lymphocytic leukemia: A case report and review of literature","volume":"30","author":"Basu","year":"2000","journal-title":"Haematologia"},{"key":"ref_315","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.bcp.2004.05.026","article-title":"Phosphodiesterase inhibitors as anti-cancer drugs","volume":"68","author":"Hirsh","year":"2004","journal-title":"Biochem. Pharmacol."},{"key":"ref_316","first-page":"517","article-title":"The influence of theobromine on angiogenic activity and proangiogenic cytokines production of human ovarian cancer cells","volume":"5","author":"Barcz","year":"1998","journal-title":"Oncol. Rep."},{"key":"ref_317","first-page":"1285","article-title":"Adenosine receptor antagonism causes inhibition of angiogenic activity of human ovarian cancer cells","volume":"7","author":"Barcz","year":"2000","journal-title":"Oncol. Rep."},{"key":"ref_318","first-page":"63","article-title":"Effect of purinergic receptor antagonists suramin and theobromine on tumor-induced angiogenesis in BALB\/c mice","volume":"39","author":"Gil","year":"1993","journal-title":"Folia Biol."},{"key":"ref_319","first-page":"4399","article-title":"Combined effect of CDDP and caffeine against human gastric cell line in vivo","volume":"18","author":"Takahashi","year":"1998","journal-title":"Anticancer Res."},{"key":"ref_320","first-page":"4375","article-title":"In vivo and in vitro enhanced antitumour effect by pentoxifylline in human cancer cells treated with Thiothepa","volume":"48","author":"Fingert","year":"1988","journal-title":"Cancer Res."},{"key":"ref_321","first-page":"2463","article-title":"Cytotoxic, cell cycle, and chromosomal effects of methylxanthines in human tumor cells treated with alkylating agents","volume":"46","author":"Fingert","year":"1986","journal-title":"Cancer Res."},{"key":"ref_322","first-page":"1681","article-title":"Caffeine Dose-dependently Potentiates the Antitumor Effect of Cisplatin on Osteosarcomas","volume":"28","author":"Kawahara","year":"2008","journal-title":"Anticancer Res."},{"key":"ref_323","first-page":"3769","article-title":"Desmoplastic small round cell tumour successfully treated with caffeine-assisted chemotherapy: A case report and review of the literature","volume":"30","author":"Miwa","year":"2010","journal-title":"Anticancer Res."},{"key":"ref_324","first-page":"2399","article-title":"Caffeine-potentiated chemotherapy for metastatic carcinoma and lymphoma of bone and soft tissue","volume":"25","author":"Hayashi","year":"2005","journal-title":"Anticancer Res."},{"key":"ref_325","doi-asserted-by":"crossref","first-page":"379","DOI":"10.2174\/1389200013338270","article-title":"Effect of methylxanthine derivatives on doxorubicin transport and antitumor activity","volume":"2","author":"Kakuyama","year":"2001","journal-title":"Curr. Drug Metab."},{"key":"ref_326","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1007\/BF01211797","article-title":"Effect of chemotherapy combined with caffeine for osteosarcoma","volume":"118","author":"Tsuchiya","year":"1992","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_327","doi-asserted-by":"crossref","first-page":"292","DOI":"10.2307\/3574780","article-title":"The action of caffeine on X-Irradiated HeLa cells: III. Enhancement of X-ray-induced killing during G2 arrest","volume":"76","author":"Busse","year":"1978","journal-title":"Radiat. Res."},{"key":"ref_328","first-page":"16","article-title":"Differential effect of selected methylxanthine derivatives on radiosensitization of lung carcinoma cells","volume":"28","author":"Malki","year":"2006","journal-title":"Exp. Oncol."},{"key":"ref_329","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1080\/09553000902741190","article-title":"1-Methylxanthine enhances the radiosensitivity of tumor cells","volume":"85","author":"Youn","year":"2009","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_330","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.canlet.2006.03.032","article-title":"The enigmatic effects of caffeine in cell cycle and cancer","volume":"247","author":"Bode","year":"2007","journal-title":"Cancer Lett."},{"key":"ref_331","doi-asserted-by":"crossref","first-page":"325","DOI":"10.2174\/138920108785161497","article-title":"Modulation of cellular response to anticancer treatment by caffeine: Inhibition of cell cycle checkpoints, DNA repair and more","volume":"9","author":"Sabisz","year":"2008","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_332","doi-asserted-by":"crossref","first-page":"10342","DOI":"10.1074\/jbc.275.14.10342","article-title":"Caffeine abolishes the mammalian G2\/M DNA damage checkpoint by inhibiting ataxia-telangiectasia-mutated kinase activity","volume":"275","author":"Zhou","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_333","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1158\/1535-7163.513.3.4","article-title":"G2 checkpoint abrogators as anticancer drugs","volume":"3","author":"Kawabe","year":"2004","journal-title":"Mol. Cancer Ther."},{"key":"ref_334","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1667\/0033-7587(2002)157[0026:CEGRIG]2.0.CO;2","article-title":"Caffeine eliminates \u03b3-ray-induced G2-phase delay in human tumor cells but not in normal cells","volume":"157","author":"Jha","year":"2002","journal-title":"Radiat. Res."},{"key":"ref_335","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.tox.2014.12.003","article-title":"Dose-dependent effects of caffeine in human Sertoli cells metabolism and oxidative profile: Relevance for male fertility","volume":"328","author":"Dias","year":"2015","journal-title":"Toxicology"},{"key":"ref_336","doi-asserted-by":"crossref","first-page":"5514","DOI":"10.1016\/S0021-9258(18)91042-2","article-title":"Characterization of basal and methylxanthine-stimulated Ca2+ transport in abalone spermatozoa","volume":"259","author":"Kopf","year":"1984","journal-title":"J. Biol. Chem."},{"key":"ref_337","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1095\/biolreprod26.4.745","article-title":"Regulation of protein phosphorylation and motility of sperm by cyclic adenosine monophosphate and calcium","volume":"26","author":"Tash","year":"1982","journal-title":"Biol. Reprod."},{"key":"ref_338","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1002\/jcb.240350302","article-title":"Regulation of sperm flagellar motility by calcium and cAMP-dependent phosphorylation","volume":"35","author":"Brokaw","year":"1987","journal-title":"J. Cell. Biochem."},{"key":"ref_339","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1021\/jf4049462","article-title":"White tea as a promising antioxidant medium additive for sperm storage at room temperature: A comparative study with green tea","volume":"62","author":"Dias","year":"2014","journal-title":"J. Agric. Food Chem."},{"key":"ref_340","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1262\/jrd.20238","article-title":"Improved fertility in gilts and sows after artificial insemination of frozen-thawed boar semen by supplementation of semen extender with caffeine and CaCl2","volume":"55","author":"Yamaguchi","year":"2009","journal-title":"J. Reprod. Dev."},{"key":"ref_341","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1111\/j.1872-034X.2011.00856.x","article-title":"Oral application of 1,7-dimethylxanthine (paraxanthine) attenuates the formation of experimental cholestatic liver fibrosis","volume":"41","author":"Klemmer","year":"2011","journal-title":"Hepatol. Res."},{"key":"ref_342","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1002\/hep.23279","article-title":"Increased caffeine consumption is associated with reduced hepatic fibrosis","volume":"51","author":"Modi","year":"2010","journal-title":"Hepatology"},{"key":"ref_343","doi-asserted-by":"crossref","unstructured":"Grases, F., Rodriguez, A., and Costa-Bauza, A. (2014). Theobromine inhibits uric acid crystallization. A potential application in the treatment of uric acid nephrolithiasis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0111184"},{"key":"ref_344","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1111\/j.1755-3768.2009.01688.x","article-title":"Effects of 7-methylxanthine on the sclera in form deprivation myopia in guinea pigs","volume":"89","author":"Cui","year":"2011","journal-title":"Acta Ophthalmol."},{"key":"ref_345","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s12177-008-9013-3","article-title":"Systemic 7-methylxanthine in retarding axial eye growth and myopia progression: A 36-month pilot study","volume":"1","author":"Trier","year":"2008","journal-title":"J. Ocul. Biol. Dis. Inform."},{"key":"ref_346","first-page":"59","article-title":"Influence of caffeine administered during pregnancy on the early differentiation of fetal rat ovaries and testes","volume":"13","author":"Pollard","year":"1990","journal-title":"J. Dev. Physiol."},{"key":"ref_347","first-page":"53","article-title":"Multiple effects of theobromine on fetus development and postnatal status of the immune system","volume":"26","author":"Sommer","year":"2004","journal-title":"Int. J. Tissue React."},{"key":"ref_348","first-page":"695","article-title":"The effects of prenatal exposure to methylxanthines","volume":"14","author":"Woronkowicz","year":"2011","journal-title":"Pol. J. Vet. Sci."},{"key":"ref_349","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1002\/bdra.20365","article-title":"Maternal caffeine consumption and risk of cardiovascular malformations","volume":"79","author":"Browne","year":"2007","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_350","first-page":"CD006965","article-title":"Effects of restricted caffeine intake by mother on fetal, neonatal and pregnancy outcome","volume":"2","author":"Jahanfar","year":"2013","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_351","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/0892-0362(91)90093-C","article-title":"Caffeine use during pregnancy and child outcome: A 7-year prospective study","volume":"13","author":"Barr","year":"1991","journal-title":"Neurotoxicol. Teratol."},{"key":"ref_352","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1136\/bmj.39062.520648.BE","article-title":"Effect of reducing caffeine intake on birth weight and length of gestation: Randomised controlled trial","volume":"334","author":"Bech","year":"2007","journal-title":"BMJ Br. Med. J."},{"key":"ref_353","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1002\/bdra.20752","article-title":"Maternal caffeine intake and risk of selected birth defects in the national birth defects prevention study","volume":"91","author":"Browne","year":"2011","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_354","doi-asserted-by":"crossref","first-page":"a2332","DOI":"10.1136\/bmj.a2332","article-title":"Maternal caffeine intake during pregnancy and risk of fetal growth restriction: A large prospective observational study","volume":"337","author":"Group","year":"2008","journal-title":"BMJ Br. Med. J."},{"key":"ref_355","doi-asserted-by":"crossref","first-page":"279.e1","DOI":"10.1016\/j.ajog.2007.10.803","article-title":"Maternal caffeine consumption during pregnancy and the risk of miscarriage: A prospective cohort study","volume":"198","author":"Weng","year":"2008","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_356","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1002\/bdra.20624","article-title":"Maternal caffeine consumption and risk of neural tube defects","volume":"85","author":"Schmidt","year":"2009","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_357","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1007\/s10995-013-1397-4","article-title":"Maternal caffeine consumption and small for gestational age births: Results from a population-based case-control study","volume":"18","author":"Hoyt","year":"2013","journal-title":"Matern. Child Health J."},{"key":"ref_358","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1002\/bdra.23050","article-title":"Maternal caffeine consumption and risk of congenital limb deficiencies","volume":"94","author":"Chen","year":"2012","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_359","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1007\/s00404-009-0991-6","article-title":"Caffeine in pregnancy","volume":"280","author":"Kuczkowski","year":"2009","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_360","first-page":"687","article-title":"Testicular atrophy and impaired spermatogenesis in rats fed high levels of the methylxanthines caffeine, theobromine, or theophylline","volume":"2","author":"Friedman","year":"1979","journal-title":"J. Environ. Pathol. Toxicol."},{"key":"ref_361","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/0278-6915(84)90365-X","article-title":"Comparative toxicities of dietary caffeine and theobromine in the rat","volume":"22","author":"Gans","year":"1984","journal-title":"Food Chem. Toxicol."},{"key":"ref_362","doi-asserted-by":"crossref","first-page":"71","DOI":"10.2174\/1570159X13666141210215655","article-title":"Caffeine: Cognitive and physical performance enhancer or psychoactive drug?","volume":"13","author":"Cappelletti","year":"2015","journal-title":"Curr. Neuropharmacol."},{"key":"ref_363","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1007\/7854_2011_187","article-title":"Genetic factors modulating the response to stimulant drugs in humans","volume":"12","author":"Hart","year":"2012","journal-title":"Curr. Top. Behav. Neurosci."},{"key":"ref_364","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.1038\/npp.2010.71","article-title":"Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption","volume":"35","author":"Rogers","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"ref_365","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1038\/sj.npp.1300232","article-title":"Association between A2A receptor gene polymorphisms and caffeine-induced anxiety","volume":"28","author":"Alsene","year":"2003","journal-title":"Neuropsychopharmacology"},{"key":"ref_366","unstructured":"(2014). Caffeine in Food and Dietary Supplements: Examining Safety: Workshop Summary, National Academies Press (US)."},{"key":"ref_367","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1016\/j.nut.2010.08.004","article-title":"Caffeine\u2014Not just a stimulant","volume":"26","author":"Glade","year":"2010","journal-title":"Nutrition"},{"key":"ref_368","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1331\/JAPhA.2008.07055","article-title":"Safety issues associated with commercially available energy drinks","volume":"48","author":"Clauson","year":"2003","journal-title":"J. Am. Pharm. Assoc."},{"key":"ref_369","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1111\/1556-4029.12387","article-title":"Fatal caffeine intoxication: A series of eight cases from 1999 to 2009","volume":"59","author":"Banerjee","year":"2014","journal-title":"J. Forensic Sci."},{"key":"ref_370","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/0278-6915(88)90236-0","article-title":"Methylxanthines: Toxicity to humans. 2. Caffeine","volume":"26","author":"Stavric","year":"1988","journal-title":"Food Chem. Toxicol."},{"key":"ref_371","doi-asserted-by":"crossref","first-page":"9","DOI":"10.4137\/CCRep.S4329","article-title":"Coffee-induced hypokalaemia","volume":"3","author":"Tajima","year":"2010","journal-title":"Clin. Med. Insights Case Rep."},{"key":"ref_372","doi-asserted-by":"crossref","unstructured":"Nehlig, A. (2004). Coffee, Tea, Chocolate, and the Brain, CRC Press.","DOI":"10.1201\/9780203618851"},{"key":"ref_373","doi-asserted-by":"crossref","first-page":"255","DOI":"10.31887\/DCNS.2010.12.2\/anehlig","article-title":"SPECT assessment of brain activation induced by caffeine: No effect on areas involved in dependence","volume":"12","author":"Nehlig","year":"2010","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_374","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s00213-013-3021-0","article-title":"Psychopharmacology of theobromine in healthy volunteers","volume":"228","author":"Baggott","year":"2013","journal-title":"Psychopharmacology"},{"key":"ref_375","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1023\/A:1007976831684","article-title":"Recent advances in caffeine and theobromine toxicities: A review","volume":"51","author":"Eteng","year":"1997","journal-title":"Plant Foods Hum. Nutr."},{"key":"ref_376","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/BF02021187","article-title":"Concerning the question of the biological effectiveness of methylxanthines in cocoa products","volume":"4","author":"Czok","year":"1974","journal-title":"Z. Ern\u00e4hrungswissenschaft"},{"key":"ref_377","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1111\/j.1476-5381.1993.tb13564.x","article-title":"The diuretic action of 8-cyclopentyl-1,3-dipropylxanthine, a selective A1 adenosine receptor antagonist","volume":"109","author":"Knight","year":"1993","journal-title":"Br. J. Pharmacol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/21\/8\/974\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:27:07Z","timestamp":1760210827000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/21\/8\/974"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,7,27]]},"references-count":377,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2016,8]]}},"alternative-id":["molecules21080974"],"URL":"https:\/\/doi.org\/10.3390\/molecules21080974","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,7,27]]}}}