18.Nardini M, et al. Effect of caffeic acid dietary supplementation on the antioxidant defense system in rat: an in vivo study. Arch Biochem Biophys 1997; 342: 157-160.

19.Stadler RH, Turesky RJ, Müller O, et al. The inhibitory effects of coffee on radical-mediated oxidation and mutagenicity. Mutat Res 1994; 308: 177-190.

20.Heiss C, Dejam A, Kleinbongard P, et al. Vascular effects of cocoa rich in flavan-3-ols. JAMA 2003; 290: 1030-1031.

21.Miller KB, Stuart DA, Smith NL, et al. Antioxidant activity and polyphenol and procyanidin contents of selected commercially available cocoa-containing and chocolate products in the United States. J Agric Food Chem 2006; 54: 4062-4068.

22.Lee KW, Kim YJ, Lee HJ, et al. Cocoa has more phenolic phytochemicals and a higher antioxidant capacity than teas and red wine. J Agric Food Chem 2003; 51: 7292-7295.

23.Engler MB, Engler MM, Chen CY, et al. Flavonoid-rich Dark chocolate improves endothelial function and increases plasma epichtechin concentrations in healthy adults. J Am Coll Nutr 2004; 23: 197-204.

24.Heiss C, Schroeter H, Balzer J, et al. Endothelial function, nitric oxide, and cocoa flavonols. J Cardiovasc Pharmacol 2006; 47(Suppl 2): S128-135.

25.Karim M, McCormick K, Kappagoda CT. Effects of cocoa extracts on endothelium-dependent relaxation. J Nutr 2000; 130: 2105S-2108S.

26.Grassi D, Necozione S, Lippi C, et al. Cocoa reduces blood pressure and insulin resistance and improves endothelium dependent vasodilation in hypertensives. Hypertension 2005; 46: 398-405.

27.Taubert D, Berkels R, Roesen R, et al. Chocolate and blood pressure in elderly individuals with isolated systolic hypertension. JAMA 2003; 290: 1029-1030.

28.Innes AJ, Kennedy G, McLaren M, et al. Dark chocolate inhibits platelet aggregation in healthy volunteers. Platelets 2003; 14: 325-327.

29.Hermann F, Spieker LE, Ruschitzka F, et al. Dark chocolate improves endothelial and platelet function. Heart 2006; 92: 199-120.

30.Wan Y, Vinson JA, Etherton TD, et al. Effects of cocoa powder and dark chocolate on LDL oxidative susceptibility and prostaglandin concentrations in humans. Am J Clin Nutr 2001; 74: 596-602.

31.Grässel E. Effect of Ginkgo biloba extract on mental performance. Double-blind study using computerized measurement conditions in patients with cerebral insufficiency. Fortschr der Medizin 1992; 110: 73-76.

N-acetyl cysteine

Robert Nussenblatt

N-acetylcysteine (NAC) is an acetylated variant of L-cysteine and has several medical indications. Its use is based on its proposed mechanism of influencing both anti-oxidant and nitric oxide systems, which can be very active during infections and stress. Glutathione is one of the body’s major anti-oxidants1 and helps to detoxify substances that harmful during inflammatory and infectious processes. Glutathione is composed of glutamate, glycine and cysteine. Cysteine is present in cells in the lowest concentration of the three.2 Since glutathione production is dependent on the presence of these three substrates, a low concentration of cysteine may inhibit rapid production of gluthathione when needed. Therefore, exogenously administered NAC could help in meeting this anti-oxidant need. A second mechanism of action is as a vasodilator by its effect on nitric oxide.3

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Perhaps its best known indication is as an antidote for acetaminophen overdose. NAPQI is the toxic metabolite of acetaminophen. NAC replenishes glutathione, which then binds directly to the toxic metabolite. This enhances a nontoxic sulfate conjugation in the liver cell.4 NAC has also been evaluated in another clinical adverse event, contrast induced nephropathy, which occurs in about 2% of cases with normal serum creatinines. However, patients with serum creatinine levels above 2.0 mg/dL or with diabetes are at high risk to develop this complication.5 An initial prophylactic trial using NAC showed a positive result.6 A large number of controlled studies ensued with varied findings, the majority either showing an effect or the result being inconclusive.7 NAC is not used standardly as prophylaxis.

Several studies have evaluated NAC in treating chronic obstructive pulmonary disease (COPD). In an open label study of almost 1400 patients, NAC resulted in clear clinical improvement.8 There was a decrease in the viscosity of phlegm and decreased coughing shortness of breath. Another trial showed a decrease in the deterioration of the FEV1 in older patients treated with NAC.9 In addition, there have been several randomized trials with the majority showing a clinical benefit to NAC therapy.7

In another pulmonary disorder, pulmonary fibrosis, a study randomizing patients to either NAC (600mg TID) and placebo also showed that the deterioration of lung function was slowed in those patients receiving the active therapy.10 In one randomized controlled trial, NAC was useful in attenuating and preventing the signs and symptoms of influenza in a frail population.11

Side effects at doses 1200 mg BID or lower have been minimal with mostly gastrointestinal problems along with skin rashes. At the higher doses used to treat acetaminophen toxicity, there can more severe adverse events including tinnitus, headache, rash, chills, fever, and an allergic reaction.

The potential use of NAC in ocular disorders has been suggested in several studies, both of the retina and the trabecular meshwork. One study emphasized the importance of neuroprotection in glutamate induced cytotoxicity.12 In this study using rat RGC-5 cells, glutamate treatment resulted in RGC-5 cell death. Pretreatment of these cells with NAC resulted in a reversal of the cytotoxic effects. A second model evaluated the glaucoma associated mutant optineurin in the induced death of RGC.13 Plasmids expressing either the wild type or various optineurin mutants were inserted into a variety of cells lines. In the E50K mutation of optineurin-induced RGC death, reactive oxygen species were produced with the expression of E50K. The addition of NAC inhibited the cell death. Finally, a recent study evaluated the potential role of antioxidants in defects potentially leading to POAG. He et al. suggested that a mitochondrial complex 1 defect is associated with trabecular cell degeneration.14 Cultured trabecular cells from POAG patients had significantly higher reactive oxygen species levels compared to controls. Anti-oxidants, including NAC, protected against cell death by inhibiting ROS generation and cytochrome-C release.

References

1.Dekhuijzen PN. Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease. Eur Respir J 2004; 23: 629-636.

2.Dickinson DA, Moellering DR, Iles KE, et al. Cytoprotection against oxidative stress and the regulation of glutathione synthesis. Biol Chem 2003; 384: 527-537.

3.Ardissino D, Merlini PA, Savonitto S, et al. Effect of transdermal nitroglycerin or N-acetyl- cysteine, or both, in the long-term treatment of unstable angina pectoris. J Am Coll Cardiol 1997; 29: 941-947.

4.Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med 1988; 319: 1557-1562.

5.Rihal CS, Textor SC, Grill DE, Berger PB, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002; 105: 22592264.

6.Tepel M, van der Giet M, Schwarzfeld C, et al. Prevention of radiographic-contrast-agent- induced reductions in renal function by acetylcysteine. N Engl J Med 2000; 343: 180-184.

7.Millea PJ. N-acetylcysteine: multiple clinical applications. Am Fam Physician 2009; 80: 265-269.

8.Tattersall AB, Bridgman KM, Huitson A. Acetylcysteine (Fabrol) in chronic bronchitis – a study in general practice. J Int Med Res 1983; 11: 279-284.

9.Lundback B, Lindstrom M, Andersson S, et al. Possible effect of acetylcysteine on lung function. Eur Respir J 1992; 5(Suppl 15): S289.

10.Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005; 353: 2229-2242.

11.De Flora S, Grassi C, Carati L. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J 1997; 10: 1535-1541.

12.Aoun P, Simpkins JW, Agarwal N. Role of PPAR-gamma ligands in neuroprotection against glutamate-induced cytotoxicity in retinal ganglion cells. Invest Ophthalmol Vis Sci 2003; 44: 2999-3004.

13.Chalasani ML, Radha V, Gupta V, et al. A glaucoma-associated mutant of optineurin selectively induces death of retinal ganglion cells which is inhibited by antioxidants. Invest Ophthalmol Vis Sci 2007; 48: 1607-1614.

14.He Y, Leung KW, Zhang YH, et al. Mitochondrial complex I defect induces ROS release and degeneration in trabecular meshwork cells of POAG patients: protection by antioxidants. Invest Ophthalmol Vis Sci 2008; 49: 1447-1458

Taurine

Robert Nussenblatt

Taurine (2-aminoethanesulfonic acid) is the decarboxylation product of cysteine, and is mainly obtained from diet. It is a free sulfur ß-amino acid found in animal tissue and is one of the most abundant low molecular weight compounds, present in the micromolar range per gram wet weight. While the body can make taurine from sulfur precursers, it is produced endogenously in the liver from methionine and cysteine. Enzymes that are needed for taurine production include cysteine sulfinic acid decarboxylase, which is the rate limiting step in the cascade leading to taurine.1 However, the amount produced is insufficient

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and dietary sources are needed. Taurine is found freely in the cytosol and is found particularly in the heart, retina, brain and blood.

Taurine has been associated with many different physiologic activities, including calcium transport, antioxidation, neurotransmission, and regulation of protein phosphorylation.2 It should be added that the dominant role of taurine still needs to be determined. Significant changes in plasma and tissue levels occur in aging rats.3 These decreases are noted in the eye as well4 and may be due to a decrease in liver biosynthetic enzymes. Of interest is that withdrawing taurine from the diet of animals does not enhance the decrease; yet augmenting the exogenous amount of taurine helps to resolve the deficit. However these observations are in the rat. In the human, the data is less robust. What has been shown is that taurine concentrations increase in the cerebrospinal fluid of aging humans,5 and by upwards of 30%.

As with other tissues, taurine is found in high concentrations in phagocytic cells. It is believed to provide protection against inflammatory cytotoxicity, anti-oxidant activity, and membrane stabilization. Taurine appears to mediate these effects by eliminating highly toxic HOCL and generating non-toxic TauCl. TauCl appears to suppress the production of many inflammatory mediators, including NO, TNF-alpha, IL-1, Il-2, and IL-6. It appears to suppress production of IL-10 as well, which is a downregulatory cytokine.6,7 It would appear that taurine in phagocytes prevents chronic inflammatory processes. The underlying mechanisms in macrophages appears to be the inhibition of NO by the suppression of the activation of several factors, including Ras, ERK1/2, and NF-kB. In neutrophils, taurine appears to exert an inhibitory effect by inhibiting p47phox and the assembly of the NADPH-oxidase complex.7

Taurine appears to play an important in ocular development. It appears structurally similar to the neurotransmitters GABA and glycine. Taurine plays a role aslo in the formation and maintenance of neural tissue. Kittens given taurinedeficient diets exhibited retinal degeneration and CNS defects.8 Interestingly, taurine increased the numbers of rod photoreceptors in retinal culture.9 It appears to act in retinal progenitors via the GlyRa2 subunit containing glycine receptors.10 As noted above, levels in animals decrease with aging, and specific ERG changes in rats can be associated with these decreased tissue levels, reflecting the fact that the retina has a decreased ability to deal with oxidative stress.1 Exogenous taurine administration may be helpful in preventing age related changes in the retina.1 Taurine concentrations seem to be markedly decreased in injured photoreceptors of dogs with glaucoma.11 Taurine transformed rat retinal ganglia are protected from hypoxia-induced apoptosis, probably through the prevention of mitochondrial dysfunction.12 One report in a small number of rabbits suggested that when topically applied 0.5% timolol was mixed with several amino acids, including taurine, the IOP decrease in the rabbit eye was greater than with timolol alone.13