Neuroprotection: is it already applicable to glaucoma therapy?
Many categories of both natural and synthetic compounds have been reported to have neuroprotective activity. These include not only antioxidants, N-methyl-D-aspartate receptor antagonists, inhibitors of glutamate release, calcium channel blockers, polyamine antagonists, and nitric oxide synthase inhibitors, but cannabinoids, aspirin, melatonin and vitamin B12. The lack of availability of specific neuroprotectant compounds in the United States and the lack of clinical trials examining the benefits of neuroprotective agents for glaucoma currently limit the use of these agents. This article provides a short overview of the concept of neuroprotection as it applies to glaucoma and suggests the possibility of neuroprotective activity that might be provided by compounds that are presently easily available.
Curr Opin Ophthalmol 2000 Apr;11(2):78-84
N-Acetylcarnosine, a natural histidine-containing dipeptide, as a potent ophthalmic drug in treatment of human cataracts.
A study was designed to document and quantify the changes in lens clarity over 6 and 24 months in 2 groups of 49 volunteers (76 eyes) with an average age of 65.3 +/- 7.0 enrolled at the time of diagnosis of senile cataracts of minimal to advanced opacification.The patients received N-acetylcarnosine, 1% sol (NAC) (26 patients, 41 eyes = Group II), placebo composition (13 patients, 21 eyes) topically (two drops, twice daily) to the conjunctival sac, or were untreated (10 patients, 14 eyes); the placebo and untreated groups were combined into the control (reference) Group I. Patients were evaluated upon entry, at 2-month (Trial 1) and 6-month (Trial 2)-intervals for best corrected visual acuity (b/c VA), by ophthalmoscopy and the original techniques of glare test (for Trial 1), stereocinematographic slit-image and retro-illumination photography with subsequent scanning of the lens. The computerized interactive digital analysis of obtained images displayed the light scattering/absorbing centers of the lens into 2-D and 3-D scales.The intra-reader reproducibility of measuring techniques for cataractous changes was good, with the overall average of correlation coefficients for the image analytical data 0.830 and the glare test readings 0.998. Compared with the baseline examination, over 6 months 41.5% of the eyes treated with NAC presented a significant improvement of the gross transmissivity degree of lenses computed from the images, 90.0% of the eyes showed a gradual improvement in b/c VA to 7-100% and 88.9% of the eyes ranged a 27-100% improvement in glare sensitivity. Topographic studies demonstrated less density and corresponding areas of opacification in posterior subcapsular and cortical morphological regions of the lens consistent with VA up to 0.3. The total study period over 24 months revealed that the beneficial effect of NAC is sustainable. No cases resulted in a worsening of VA and image analytical readings of lenses in the NAC-treated group of patients. In most of the patients drug tolerance was good. Group I of patients demonstrated the variability in the densitometric readings of the lens cloudings, negative advance in glare sensitivity over 6 months and gradual deterioration of VA and gross transmissivity of lenses over 24 months compared with the baseline and 6-month follow-up examinations. Statistical analysis revealed the significant differences over 6 and 24 months in cumulative positive changes of overall characteristics of cataracts in the NAC-treated Group II from the control Group I.The N-acetylated form of natural dipeptide L-carnosine appears to be suitable and physiologically acceptable for nonsurgical treatment for senile cataracts.
Peptides 2001 Jun;22(6):979-94
Fruits and vegetables that are sources for lutein and zeaxanthin: the macular pigment in human eyes.
BACKGROUND: It has been suggested that eating green leafy vegetables, which are rich in lutein and zeaxanthin, may decrease the risk for age related macular degeneration. The goal of this study was to analyse various fruits and vegetables to establish which ones contain lutein and/or zeaxanthin and can serve as possible dietary supplements for these carotenoids. METHODS: Homogenates of 33 fruits and vegetables, two fruit juices and egg yolk were used for extraction of the carotenoids with hexane. Measurement of the different carotenoids and their isomers was carried out by high performance liquid chromatography using a single column with an isocratic run, and a diode array detector. RESULTS: Egg yolk and maize (corn) contained the highest mole percentage (% of total) of lutein and zeaxanthin (more than 85% of the total carotenoids). Maize was the vegetable with the highest quantity of lutein (60% of total) and orange pepper was the vegetable with the highest amount of zeaxanthin (37% of total). Substantial amounts of lutein and zeaxanthin (30-50%) were also present in kiwi fruit, grapes, spinach, orange juice, zucchini (or vegetable marrow) and different kinds of squash. The results show that there are fruits and vegetables of various colours with a relatively high content of lutein and zeaxanthin. CONCLUSIONS: Most of the dark green leafy vegetables, previously recommended for a higher intake of lutein and zeaxanthin, have 15-47% of lutein, but a very low content (0-3%) of zeaxanthin. Our study shows that fruits and vegetables of various colours can be consumed to increase dietary intake of lutein and zeaxanthin.
Br J Ophthalmol 1998 Aug;82(8):907-10
Glutathione: a vital lens antioxidant.
The reducing compound glutathione (GSH) exists in an unusually high concentration in the lens where it functions as an essential antioxidant vital for maintenance of the tissue's transparency. In conjunction with an active glutathione redox cycle located in the lens epithelium and superficial cortex, GSH detoxifies potentially damaging oxidants such as H2O2 and dehydroascorbic acid. Recent studies have indicated an important hydroxyl radical-scavenging function for GSH in lens epithelial cells, independent of the cells' ability to detoxify H2O2. Depletion of GSH or inhibition of the redox cycle allows low levels of oxidant to damage lens epithelial targets such as Na/K-ATPase, certain cytoskeletal proteins and proteins associated with normal membrane permeability. The level of GSH in the nucleus of the lens is relatively low, particularly in the aging lens, and exactly how the compound travels from the epithelium to the central region of the organ is not known. Recently, a cortical/nuclear barrier to GSH migration in older human lenses was demonstrated by Sweeney et al. The relatively low ratio of GSH to protein -SH in the nucleus of the lens, combined with low activity of the glutathione redox cycle in this region, makes the nucleus especially vulnerable to oxidative stress, as has been demonstrated with use of in vivo experimental animal models such as hyperbaric oxygen, UVA light and the glutathione peroxidase knockout mouse. Effects observed in these models, which are currently being utilized to investigate the mechanism of formation of human senile nuclear cataract, include an increase in lens nuclear disulfide, damage to nuclear membranes and an increase in nuclear light scattering. A need exists for development of therapeutic agents to slow age-related loss of antioxidant activity in the nucleus of the human lens to delay the onset of cataract.
J Ocul Pharmacol Ther 2000 Apr;16(2):121-35
Effect of photooxidation on the eye lens and role of nutrients in delaying cataract.
The function of the eye lens is to collect and focus light on the retina. To do so, it must remain clear during the decades of life. Upon aging, lens constituents are damaged and precipitate in opacities called senile cataracts. Laboratory and epidemiologic data indicate that the damage is due in part to light and active forms of oxygen. Antioxidant nutrients—ascorbate, carotenoids, and tocopherol—appear to offer protection against cataract. Fifty million persons worldwide are blind due to cataract, and, in the U.S., there are 1.2 million cataract surgeries performed at an annual cost (including physician visits) of over $3.2 billion. It has been estimated that a 10-year delay in the development of cataract would eliminate the need for half the surgeries. Since it will not be possible to replace most of the damaged lenses, it is essential to determine the efficacy of supplying adequate levels of antioxidant nutrients early in life to preserve lens function.
Carotenoids in the retina—a review of their possible role in preventing or limiting damage caused by light and oxygen.
Two of the circa 600 naturally occurring carotenoids, zeaxanthin and lutein, the major carotenoids of maize and melon respectively, are the constituents of the macula lutea, the yellow spot in the macula, the central part of the retina in primates and humans. Of the circa ten carotenoids found in the blood these two are specifically concentrated in this area, which is responsible for sharp and detailed vision. This paper reviews the ideas that this concentration of dietary carotenoids in the macula is not accidental, but that their presence may prevent or limit damage due to their physicochemical properties and their capability to quench oxygen free radicals and singlet oxygen, which are generated in the retina as a consequence of the simultaneous presence of light and oxygen. Additionally, in vitro and in vivo animal experiments are reviewed as well as observational and epidemiological data in humans. These show that there is enough circumstantial evidence for a protective role of carotenoids in the retina to justify further research. Some emphasis will be put on age-related macular degeneration (AMD), a multifactorial degenerative retinal disease for which the exposure to light and thus photochemical damage has been suggested as one of the etiological factors. Recent attempts at nutritional intervention in this condition will also be reviewed.
Effects of policosanol 20 versus 40 mg/day in the treatment of patients with type II hypercholesterolemia: a 6-month double-blind study.
Policosanol is a well defined mixture of higher aliphatic primary alcohols isolated from sugar cane wax with cholesterol-lowering effects proven for a dose range from 5-20 mg/day in patients with type II hypercholesterolemia and dyslipidemia associated with noninsulin dependent diabetes mellitus. This randomized, double-blind study investigated the cholesterol-lowering efficacy and tolerability of policosanol 20 mg/day compared with 40 mg/day. Changes in low-density lipoprotein (LDL)-cholesterol levels were predefined as the primary efficacy endpoint. Patients with type II hypercholesterolemia were enrolled in the study and instructed to continue a step I cholesterol-lowering diet for 6 weeks and those eligible to be included (89) were randomly allocated to receive under double-blind conditions placebo (n = 30), policosanol 20 mg/day (n = 29) or 40 mg/day (n = 30). After 24 weeks, policosanol at 20 and 40 mg/day significantly (p < 0.00001) lowered LDL-cholesterol by 27.4% and 28.1%, total cholesterol (p < 0.00001) by 15.6% and 17.3%, and the LDL-cholesterol/high-density lipoprotein (HDL)-cholesterol ratio by 37.2% and 36.5%, respectively. The ratio of total cholesterol/HDL-cholesterol was lowered by 27.1% and 27.5%, while HDL-cholesterol levels increased (p < 0.001) by 17.6% and 17.0%, respectively. Compared with baseline, policosanol 20 mg/day lowered triglycerides (p < 0.05) by 12.7%, while they were lowered (p < 0.01) by 15.6% at a dose of policosanol 40 mg/day. All the above-mentioned significant differences were also different from placebo and no significant changes occurred in any lipid profile parameters in the placebo group. Based on the mean values of LDL-cholesterol levels at study completion, the mean percent reductions from baseline were 27.4% and 28.1% for the 20 and 40 mg/day groups, respectively. Thus, the effects of both policosanol doses on the main efficacy variable were practically identical. Consistent with the data obtained for LDL-cholesterol, both doses were similarly effective in changing all the other lipid profile parameters. No unexpected adverse effects were observed and there were no significant between-group differences regarding safety indicator values or reported adverse effects. In conclusion, although the tolerability profile remains excellent, according to the present results policosanol at a dose of 40 mg/day does not offer significant additional cholesterol-lowering efficacy over the 20 mg/day dose.
Int J Clin Pharmacol Res 2001;21(1):43-57