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7 Other Compounds Impacting Caffeine Effects Caffeinated food and beverage products on the market contain multi- ple compounds, with different products containing different types of compounds, which can have implications for the range and severity of health effects related to exposure. In the Day 2, Session 1, panel, moder- ated by Stephen Schaffer, Ph.D., University of South Alabama, Mobile, panelists considered whether and how those other compounds impact the health effects of caffeine on behavior and physiology. This chapter summarizes Schafferâs opening remarks, the panelistsâ remarks, and the discussion that followed. Although all caffeinated foods and beverages contain other ingredients, the focus of the session was on caffeine- containing energy drinks and other products with added sources of caf- feine. Box 7-1 reviews key points made by speakers. INTERACTION BETWEEN ENERGY DRINK INGREDIENTS AND CAFFEINE Presented by Stephen Schaffer, Ph.D., University of South Alabama Several times throughout the workshop, participants considered whether the health effects of caffeine-containing energy drinks and other products with added caffeine are different from those of coffee and other products with naturally existing caffeine. Answering that question re- quires, first, knowing what the ingredients are. Stephen Schaffer provid- ed an overview of common ingredients in caffeine-containing energy 129
130 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS BOX 7-1 Key Points Made by Individual Speakers â¢ In Stephen Schafferâs opinion, evidence reported in the scientific liter- ature suggests that most other ingredients in caffeinated energy drinks (i.e., ingredients besides caffeine) appear to inhibit the poten- tial adverse effects of caffeine. Clinical studies are rare, however. â¢ Carl Keen emphasized the âmoving targetâ nature of caffeinated en- ergy drink ingredients as a result of competitive marketing. He also reminded the workshop audience of the complex mixtures of ingredi- ents in coffee, tea, cocoa, and other products with naturally existing caffeine. The food industry is constantly changing not just the ingredi- ents being used in those other types of products but also the way those products are processed. He warned against extrapolating re- sults from studies of caffeine (or any other ingredient) conducted in one product to other products. â¢ John Higgins emphasized that results from in vivo studies often differ from in vitro study results. He echoed other calls for more clinical studies. â¢ While clinical studies on the effects of combinations of caffeine and other ingredients are rare, they are even rarer in the context of preg- nancy. Christina Chambers called for more research in pregnant pop- ulations. Although it is unethical to conduct randomized clinical trials among pregnant women, she said, âWe can do a much better job of conducting observational studies.â â¢ Given the lack of data on whether and how caffeinated energy drink ingredients are associated with cardiac death, for Jeffrey Goldberger the question is: how can those data be collected? He called for a clin- ical assessment to determine whether the reported observations of cardiac death create a signal suggesting that there might be an asso- ciation. Then, if an association exists, is it causal? What are the po- tential mechanisms? Given the likely rare risk of cardiac death, a sur- rogate risk biomarker (i.e., a biomarker associated with the end point of interest) would be a useful tool for conducting clinical studies. drinks and what is knownâand not knownâabout those ingredients and their interactions with caffeine. He focused on glucuronolactone, taurine, vitamins, and herbal extracts (e.g., ginseng, guarana, and ginko biloba). In sum, he concluded that, in his view, these other ingredients inhibit some of the potential adverse effects of caffeine. But clinical studies are rare, he said, and more are needed.
OTHER COMPOUNDS IMPACTING CAFFEINE EFFECTS 131 Glucuronolactone There is not much known about glucuronolactone, according to Schaffer. It was initially added to energy drinks to improve mood and diminish fatigue. Glucuronolactone is a naturally occurring substance and is a major component of connective tissue. Derived from glucose, glucuronolactone is metabolized in humans via the pentose pathway, with some of the products of that pathway, xylitol in particular, having important physiological effects. Xylitol is a pancreatic secretagogue of insulin. In rodents, but not in humans, xylitol is converted into ascorbic acid. Normally, humans are exposed to about 38 mg per day, with average energy drink consumers exposed to about 126 mg per day. Among heavy energy drink consumers, that is, those in the 95th percentile, exposure is quite high, about 840 to 900 mg per day. With respect to toxicity, accord- ing to Schaffer there has been only one real study, a 13-week oral toxici- ty study in rats conducted in Europe by the Scientific Committee on Food. The researchers found that, at higher doses, vacuoles formed in the kidneys. In a follow-up study, the researchers did not detect any vacuoli- zation but did observe some focal inflammation of the kidney. On the basis of those results, the committee concluded that exposure below 300 mg per kg of body mass is completely safe. Schaffer observed that levels of glucuronolactone in energy drinks are well below that level. He was not aware of any studies examining the interaction between glucuro- nolactone and caffeine. Taurine Schaffer described taurine as a âvery simple compoundâ formed from cysteine via decarboxylation and oxidation of the sulfhydryl group. Taurine has several physiological functions: bile acid conjugation, osmo- regulation (with tremendous amounts of taurine present in the heart and brain, as high as 10 millimolar concentrations, but micromolar concen- trations in plasma), neural modulation, inflammation, and mitochondrial function. Schaffer emphasized the important role that taurine serves in the mitochondria, where it conjugates with uridines at the wobble posi- tion on tRNA and thereby enhances codon-anticodon interactions and synthesis of respiratory chain proteins. Taurine deficiency leads to poor respiratory chain flux, which in turn leads to decreased oxygen consump-
132 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS tion and decreased adenosine triphosphate synthesis. In addition, elec- trons are diverted from the respiratory chain to oxygen, resulting in the formation of super oxide and the creation of oxidated stress. Ultimately, taurine deficiency is associated with a number of pathological condi- tions: retinopathy, cardiomyopathy, myopathy, immune deficiency, and development defects. Furthermore, noted Schaffer, children, adolescents, and adults eating omnivorous diets consume anywhere from 40 to 400 mg of taurine per day. Average energy drink consumers are exposed to about 270â280 mg daily, and heavy energy drink consumers (i.e., in the 95th percentile) are exposed to 1,400â2,300 mg daily. Schaffer described the elimination of taurine, which is dose depend- ent. If administered 30 mg per kg of body mass within the first 6 hours, 20 to 30 percent is eliminated in the urine; if administered 300 mg per kg body mass, 40 to 50 percent is eliminated in the urine (Sved et al., 2007). Only a small amount of ingested taurine enters tissues. Even after 14 days of 300 mg per day exposure, the levels of taurine in the brain and heart remain constant (Sved et al., 2007). In 2009, the European Food Safety Authority (EFSA) stated that taurine (3â6 g) had been adminis- tered daily to a large group of patients, including adults, children, and even infants, with no noted no adverse health effects (EFSA, 2009). With respect to potential interactions between taurine and caffeine, probably the best studied, in Schafferâs opinion, is diuresis and natriure- sis. Taurine was demonstrated to be a weak diuretic and natriuretic by Mozaffari and Schaffer (2001), in a comparison of fluid and sodium excre- tion rates between taurine-depleted and taurine-supplemented animals. Nonetheless, he also opined that Mozaffari and Schaffer (2001) tested tau- rine levels that one would not ordinarily see among individuals consuming energy drinks. With respect to the diuretic potential of a taurine-caffeine combination, Schaffer identified Riesenhuber et al. (2006) as an especial- ly well-designed clinical study and encouraged more such studies. The researchers administered energy drinks to study participants, with some energy drinks lacking caffeine, some lacking taurine, and some lacking both. They found that taurine did not significantly impact urine output or natruresis. According to Schaffer, there has been concern expressed in the lit- erature about the potential effects of taurine on blood pressure and heart rate. Using taurine-deficient rats, Mozaffari et al. (2006) showed that taurine deficiency leads to increased blood pressure. In humans, Yamori et al. (2010) showed that increased taurine excretion led to decreased
OTHER COMPOUNDS IMPACTING CAFFEINE EFFECTS 133 blood pressure among individuals with higher blood pressure but that increased taurine excretion had no impact on blood pressure in individu- als with normal heart rates. In addition, studies with spontaneous hyper- tensive animals have demonstrated that the addition of taurine leads to decreased blood pressure. With respect to the combined effect of taurine and caffeine on blood pressure and heart rate, Bichler et al. (2006) demonstrated decreased heart rate without a change in blood pressure when taurine and caffeine were administered in combination. Neverthe- less, according to Schaffer, it is difficult to extract a lot of information from the study because the researchers did not examine taurine and caf- feine individually, only in combination. Schaffer pointed out that cardiac arrhythmias are another potential effect of concern. Although the ingestion of caffeine is a common cause of ectopic heart beats, arrhythmias are also produced by nutrient defi- ciencies, including taurine deficiency (Eby and Halcomb, 2006). Basal spasms, he said, have been identified in the literature as yet another potential problem. Calcium antagonists are one way to treat basal spasms. Abebe (2008) demonstrated in rats that taurine does not affect aortic tension, regardless of whether calcium is present, except in the case of diabetes. In rats with diabetes, taurine actually reduced vascular tension. Finally, some researchers have expressed concern that taurine- caffeine interactions may affect seizures. LâAmoreaux et al. (2010) found that taurine prolonged latency to seizure when both injected subcutane- ously (43 mg per kg) and fed to animals (water containing 0.05 percent taurine). According to Schaffer, that is good range of exposure levels. The researchers found that the effect was related to chlorine transports, with taurine actually interacting or competing with picrotoxin at the GABA receptor. El Idrissi et al. (2003) had previously found that chronic feed- ing of taurine led to an increase in GABA. Schaffer explained that either GABA itself acts as an inhibitor, thereby decreasing seizures, or, as El Idrissi et al. (2003) suggested, the GABA receptor is down-regulated. Herbal Supplements Schaffer described herbal supplements in caffeinated energy drinks, including guarana, the seeds of which contain greater amounts of caf- feine than coffee beans do (Woods, 2012). When added to energy drinks, guarana increases the amount of metabolized caffeine.
134 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS Another herbal supplement, ginseng, contains a number of steroids, one of which is ginsenoside-Rg1, which can bind to the glucocorticoid receptor and displace dexamethasone (Lee et al., 1997). At the right con- centration, ginseng may have an anti-inflammatory effect. Hong et al. (2012) demonstrated a concentration-dependent reduction in blood pres- sure, but at doses too high to be relevant. Lian et al. (2005) demonstrated a concentration-dependent increased latency to seizures. Finally, Schaffer sought evidence for the effects of ginkgo biloba. He did not find much. Krieglstein et al. (1986) reported increased cerebral blood flow in rats, and Braquet (1993) reported inhibited platelet activa- tion. But again, the effects were at concentrations too high to be relevant, according to Schaffer. PANELIST REMARKS Carl L. Keen, Ph.D., University of California, Davis Carl Keen stressed the importance of the fact that, although Schaffer covered some of the major compounds of todayâs energy drinks, âthis will be a very moveable target.â Because of market competition, energy drinks on the market 6 months or 1 year from now may have very differ- ent compositions. Already he has seen energy drinks with ingredients such as beet root and pomegranate juice, added for their vasodilation ef- fects. He cautioned against pigeonholing energy drinks with respect to other compounds that may or may not interact with caffeine. Keen also called attention to the fact that energy drinks are not the only caffeinated food or dietary supplement. Coffee, tea, and cocoa are just three examples of the many others. All of those are complex mix- tures with thousands of compounds, many of which can have synergistic, neutral, or antagonistic effects with caffeine. For example, some of the catechins and the theobromine present in coffee, tea, and cocoa have very potent vascular effects that typically increase endothelial relaxation. Those potential effects are important to keep in mind when evaluating the epidemiological literature, in Keenâs opinion. Studies that report only on coffee consumption, for example, ignore the fact that the processing of that coffee, as well as the temperature at which it is served, can change the profile of some of the other compounds, particularly the catechins. The catechins could end up having either very strong endothelial relaxa-
OTHER COMPOUNDS IMPACTING CAFFEINE EFFECTS 135 tion properties or zero endothelial relaxation properties. Plus, the food industry is always trying to develop new methodologies that might alter the profiles of some of these compounds. In Keenâs opinion, not only do these new methodologies have implications for how older epidemiology studies are interpreted, but they also have implications for how future controlled intervention studies are designed. Keen echoed other workshop participant cautionary calls that extrap- olating results from studies on caffeine in isolation to caffeine in food products is, as he said, âfraught with error.â Indeed, it is opposite to what a recent Institute of Medicine study on biomarkers recommended, that is, when evaluating compounds, whether it be caffeine or something else, it should be done within the framework of the food being evaluated (IOM, 2010). John P. Higgins, M.D., M.B.A. University of Texas Medical School, Houston John Higgins reiterated what Schaffer had stated about the lack of clinical studies on many of the other compounds present in caffeine- containing energy drinks. A lesson learned in cardiology is that findings from in vitro studies do not always hold true in clinical trials. Effects are often very different in the human system than in a test tube. Moreover, not only is the human system different from a test tube, but human sys- tem dynamics vary among individuals in numerous ways; variables in- clude, for example, genetically, by age, sex, exposure (e.g., exposure to pure caffeine versus coffee versus energy beverage), and other toxicities that the body may also be dealing with at the time. As an example of different results obtained in vitro versus in vivo, Higgins mentioned a study of 9 individuals who consumed either an en- ergy drink with 80 mg of caffeine and 1,000 mg of taurine or a control containing 80 mg pure caffeine (Franks et al., 2012). The researchers reported that blood pressure was significantly greater among individuals who consumed the energy drink versus pure caffeine. In another study, researchers compared the cardiovascular effects during exercise of the energy drink with taurine to the effects of another similar energy bever- age but without any taurine (Baum and Weiss, 2001). They reported a significant increase in contractility and a higher stroke volume in the group that had the energy drink with taurine, which meant, as Higgins explained, that the heart had to work harder, that is, cardiac work (and its
136 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS maximal oxygen consumption) is proportional to contractility, so greater contractility means greater work for the heart. Finally, Higgins men- tioned a case report of a 28-year-old motocross cycle rider in Australia who was drinking energy beverages throughout the day and experienced a ventricular cardiac arrest (Berger and Alford, 2009). Tests conducted in the hospital indicated that he had experienced some kind of abnormal vascular functioning. It was postulated that the combination of exercise and the consumption of a caffeine- and taurine-containing beverage had interacted and led to a heart attack. Higgins encouraged more human studies on the interactions between caffeine and other compounds. Such studies may also help researchers understand why some individuals are more vulnerable to various types of caffeine exposures. Christina Chambers, Ph.D., M.P.H. University of California, San Diego Building on what Keen and Higgins said, Christina Chambers re- marked that, in the context of pregnancy, âI can sum it up by saying thereâs almost no data.â The lack of data during pregnancy is typical for most prescription medicines, let alone for herbal and other products, de- spite that an estimated one-quarter to one-third of all pregnant women consume some type of herbal product. It makes it difficult to say any- thing about the safety, or lack of safety, during human pregnancy of any of these compounds either by themselves or in combination with caf- feine. Compounding the challenge, Chambers noted, is what Keen had said about the moving-target nature of the research, and she remarked that the (caffeinated energy drink) products are âchanging probably as we speak.â Chambers called for more human data on the effects of such products as energy drinks that contain multiple compounds. Although it would be unethical to conduct randomized clinical trials in the pregnant popula- tion, she said, âWe can do a much better job of conducting observational studies.â Chambers also raised an additional issue: the consumption of ener- gy drinks in combination with alcohol. She observed that the use of energy drinks in combination with alcohol appears to attenuate the de- pressant effects of alcohol, with one recent study reporting that adults who consume energy drinks in combination with alcohol are more likely
OTHER COMPOUNDS IMPACTING CAFFEINE EFFECTS 137 to binge drink. Given that more than half of all pregnancies in the United States are unplanned, the potential for a woman to drink like that, that is, to consume alcohol in combination with an energy drink, raises some concern. Jeffrey Goldberger, M.D. Northwestern University, Chicago, Illinois Jeffrey Goldberger reiterated what he had said earlier during his presentation about the lack of data suggesting an elevated risk of cardiac arrhythmia following the consumption of an energy beverage, but he framed his claim differently. He explained what he referred to as the sta- tistical basis for that statement. That is, studies are conducted that com- pare the number of events that occur in people who are exposed to a sub- stance versus people who are not exposed to that substance, and odds ratios are calculated that indicate whether the people exposed have an increased, decreased, or no difference in risk. The important thing to keep in mind is that, regardless of the calculated odds ratio, researchers also calculate what is known as a 95 percent confidence interval, that is, a range of odds ratio values within which one can be 95 percent sure that the true odds ratio is somewhere in that interval. For example, if a study shows absolutely no difference in risk of sudden cardiac death between those exposed to coffee and those not exposed to coffee, then the odds ratio would be 1. Suppose further that the researchers calculated a very tight 95 percent confidence interval: 0.99â1.01. That means that, accord- ing to the data, one can be 95 percent sure that the true odds ratio is be- tween 0.99 and 1.01. But one cannot be 100 percent sure. Goldberger observed that, at this point, it remains a huge question whether any caffeinated energy beverages are associated with an in- creased risk of sudden cardiac death. If an increased risk exists, in Goldbergerâs opinion, it is âprobably very small.â Otherwise, given how much exposure there has been to caffeinated energy beverages, it would already be detectable. âIf one is concerned about the small potential in- crease in risk related to sudden cardiac death,â he said, âone has to come up with a strategy that would be able to address that very, very small in- creased risk.â He stressed the importance of collecting observations, such as the case report mentioned by Higgins, and then conducting clinical assess- ments to evaluate those observations and determine whether together
138 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS they create a signal to suggest that there might be an association. Then, if there is an association, is it causal? Goldberger encouraged the identifi- cation of surrogate markers for risk, given that surrogate markers associ- ated with end points of interest are especially helpful for very rare events. As an example, he pointed to the association between liquid pro- tein diets and sudden cardiac death and how researchers discovered that liquid protein diets cause QT prolongation and that QT prolongation was identified as a marker for the risk of sudden cardiac death. PANELIST DISCUSSION WITH THE AUDIENCE Following the panelistsâ remarks, audience members were invited to ask questions of the panelists. Topics covered ranged from the challenge of detecting a small health risk (i.e., sudden cardiac death) to the âde- monizingâ of energy drinks and the need for an assessment of the science of the safety of caffeine exposure to consider all of the many different types of food and beverages that contain caffeine. The Challenge of Detecting a Small Health Risk A member of the audience commented on the large number of ener- gy drinks being sold compared to the very small number of sudden cardi- ac deaths being reported. He said, âIâm concerned about trying to match the magnitude of a phenomenon as large as the number sold against mi- nor anecdotes and basic research that is not related to whatâs happening in the clinical arena.â According to the commenter, there are 350,000 sudden cardiac deaths annually. Among those, he said, âyou could find somebody who had an energy drink that day.â In his opinion, âthereâs no disease.â Another audience member questioned why, with 50 billion en- ergy drinks being sold worldwide and 20 million being sold in the United States, no clusters [of effects] are being seen, for example, on college campuses. In response, Goldberger reiterated that if there is a risk, it is a small risk. The lack of an apparent large signal does not rule out the possibility of, in Goldbergerâs words, a âvery, very small effect.â He speculated that data related to coffee consumption in adult populations, which he identi- fied as the largest collection of data (related to the health effects of caf- feine exposure), are probably consistent with a one-tenth of 1 percent
OTHER COMPOUNDS IMPACTING CAFFEINE EFFECTS 139 increased risk in sudden cardiac death (but has not been demonstrated). That same risk (if real) would probably also exist in relation to other forms of caffeine. The challenge to detecting the possibility of low-level risks is lack of data. He considered it âreasonableâ to begin to track events associated with different forms of caffeine and continue to collect information and then decide whether the formulations are different. There were several calls for a registry to track adverse effects associ- ated with the consumption of energy drinks and other caffeine-containing foods and beverages. For example, Steven Lipshultz suggested that sud- den cardiac death be tracked via postmarketing surveillance. Effects of Taurine on Cardiac End Points: The Need for More Research Higgins was asked about his interpretation of Baum and Weiss (2001), that is, that an increase in stroke volume was more work for the heart. The commenterâs understanding was that an increased stroke vol- ume for the same amount of work would actually lead to a decrease in the afterload and would, thus, be beneficial. Higgins explained that stroke volume, heart rate, and blood pressure all increased in the group who consumed the energy drink with taurine and that those individuals were doing more work for the same amount of exercise. Myocardial ox- ygen consumption is determined by maximal heart rate and blood pres- sure (or rate pressure product). Thus, the energy drink with taurine re- sulted in higher cardiac work, higher oxygen consumption, for the same amount of exercise done by both groups. He concluded that this was ex- cess or unnecessary work in the group who had the energy drink with taurine. He compared it to âflogging a dead horse.â Consumption of the energy drink appeared to be causing excessive stimulation, more than was needed for the amount of exercise being done. When asked whether an increased stroke volume would be advantageous for someone partici- pating in a bike time trial or very competitive race, Higgins replied that more studies would need to be done to answer that question. Schaffer commented on the fact that, according to Higgins, the only difference between the two treatment groups was taurine (i.e., individuals who consumed the energy drink with taurine were exposed to taurine, whereas individuals who consumed pure caffeine were not). According to Schaffer, taurine enhances mitochondrial function, which means it enhanc- es respiratory chain function. During exercise, the heart is somewhat hy-
140 CAFFEINE IN FOOD AND DIETARY SUPPLEMENTS poxic. If what oxygen is available could be used in a better way to produce adenosine triphosphate, the heart would benefit. Again, Higgins said that he could not comment because, as far as he was aware, the researchers did not measure that actual effect. Are the Concentrations of Other Ingredients in Energy Drinks Great Enough to Have Physiological Effects? A member of the audience asked whether some of the other ingredi- ents in caffeinated energy drinks, such as taurine, are added primarily as a way to include their name on the label and give consumers the impres- sion that there is something special about a product. Are their concentra- tions great enough to affect taste or to have physiological effects? He also questioned whether it is legal to add ingredients that are being added for their druglike effects. Schaffer replied that, for ginseng, extracts con- tain different mixes of steroids depending on how the ginseng is extract- ed. In the study he mentioned on ginseng and seizures (Lian et al., 2005), the researchers administered 20 mg of extract per kg, which he said is within the range of what is added to energy drinks. He did not know which type of ginseng extract is used in energy drinks. What About Sugar? An audience member commented on the reinforcing properties of caffeine, with young males reporting that they preferred sodas with greater caffeine content and with what she referred to as sugarâs ânatural reward system.â She suggested that the interaction between caffeine and sugar could have important implications for obesity and diabetes, with caffeine reinforcing the natural reward system of sugar. Higgins men- tioned that the topic has been covered in the literature. He noted that sug- ar contents vary among different concoctions. For example, sports drinks often have 6 to 8 percent carbohydrate concentration, which appears to be optimal for absorption during exercise, and energy drinks tend to have about 11 to 12 percent. He mentioned one study showing that the ergo- genic benefits of caffeine during exercise appear to be reduced when combined with carbohydrates, although they may improve in exercise of longer duration. Another study showed that caffeine absorption into cir- culation may be slowed and removal from circulation accelerated when
OTHER COMPOUNDS IMPACTING CAFFEINE EFFECTS 141 caffeine is consumed with large amounts of glucose. So, there does ap- pear to be some interaction between caffeine and glucose. The Value of In Vitro Versus In Vivo Studies In response to the several calls for more clinical studies, an audience member emphasized that in vivo studies would not be possible without in vitro studies. The same is true of preclinical animal studies. Phase I clini- cal trials are safety studies that can only be conducted after preclinical animal data have been collected. Higgins replied that most two-compound studies have been conduct- ed only in vitroâfor example, studies on the effects of combining caf- feine and taurineâand it is likely that there may be other interactions in vivo that may result in different effects. Goldberger pointed to sudden cardiac death as a very complex condi- tion affected by multiple factors. Even though long QT syndrome is a risk factor for sudden cardiac death, a person can live with long QT syndrome for years until suddenly, seemingly out of nowhere, sudden cardiac death appears. Many factors must converge at a particular time in order to create that environment. Even if sudden cardiac death is related to caffeine inges- tion, it probably emerges in people who have been ingesting caffeine for years. The complexity of the problem and the challenge of ferreting out these factors need to be part of the analysis and consideration. Criticism of Energy Drinks An audience member commented on the âcherry pickingâ of refer- ences that is sometimes done to make a point and the âdemonizingâ of certain groups of products, namely, energy drinks. That approach is not helpful. There are many different types of caffeinated foods and bever- ages, and an assessment of the science of the safety of caffeine exposure should consider all these different sources. REFERENCES Abebe, W. 2008. Effects of taurine on the reactivity of aortas from diabetic rats. Life Sciences 82:279â289.
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