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February 2002

Effect of policosanol on platelet aggregation and serum levels of arachidonic acid metabolites in healthy volunteers.

Policosanol is a cholesterol-lowering drug with hypocholesterolemic effects demonstrated in experimental models, healthy volunteers and patients with type II hypercholesterolemia. In addition, antiplatelet effects of policosanol have been shown in experimental models and healthy volunteers. This study reports the results of a 2-week, randomized, double-blind, placebo-controlled trial investigating the effects of policosanol on platelet aggregation and thromboxane B2 and prostacyclin (6 keto PGF1alpha) production after stimulation with collagen in healthy volunteers. The volunteers were on a placebo-baseline period for 7 days and thereafter they received randomly, under double-blind conditions, placebo or policosanol (10 mg/day) for 15 days. Platelet aggregation was determined at baseline and after 15 days of treatment. Significant reductions of arachidonic acid and collagen-induced platelet aggregation were observed. Thromboxane, but not prostacyclin, generation induced by collagen was also inhibited by policosanol.

Prostaglandins Leukot Essent Fatty Acids 1998 Jan;58(1):61-4

Comparative study of policosanol, aspirin and the combination therapy policosanol-aspirin on platelet aggregation in healthy volunteers.

A randomized, double-blind, placebo-controlled study was conducted in 43 healthy volunteers to compare the effects of policosanol (20 mg day-1), aspirin (ASA) (100 mg day-1) and combination therapy (policosanol 20 mg day-1 plus ASA 100 mg day-1) on platelet aggregation. The healthy volunteers were randomly treated for 7 days. Both, platelet aggregation and coagulation time were measured at baseline and after therapy. When policosanol was administered platelet aggregation induced by ADP (37.3%), epinephrine (32.6%) and collagen (40.5%) were significantly reduced. Meanwhile, aspirin significantly reduced platelet aggregation induced by collagen (61.4%) and epinephrine (21.9%) but not ADP-induced aggregation. Combined therapy significantly inhibited aggregation induced by all the agonists reaching the highest reductions of platelet aggregation induced by collagen (71.3%) and epinephrine (57.5%). Coagulation time did not change significantly in any group. No subject withdrew from the trial. Four volunteers reported mild adverse experiences during the study: three ASA-treated cases referred headache, epigastralgia and nose bleeding, meanwhile one patient receiving combination therapy reported gum bleeding. The present results demonstrate that policosanol (20 mg day-1) is as effective as ASA (100 mg day-1). Moreover, combination therapy shows some advantages compared with the respective monotherapies.

Pharmacol Res 1997 Oct;36(4):293-7

Safety of HMG-CoA reductase inhibitors: focus on atorvastatin.

Statins effectively lower LDL-cholesterol and some members of this class have been shown to reduce the risk of major cardiovascular events and total mortality in patients with or at risk for coronary heart disease. Statins are in general well tolerated. Withdrawal rates related to adverse events are low (< or =3%). The most common adverse events are mild gastrointestinal symptoms. Elevated serum transaminase levels occur infrequently (< or = 1.5%). These are generally asymptomatic, reversible and rarely require drug withdrawal. Statins do not cause adverse endocrine effects, do not alter glycemic control in diabetic patients, and do not increase cancer risk. Dose-related myopathy and/or rhabdomyolysis also occurs very rarely, although the risk is increased by concomitant administration of cyclosporine, niacin, fibrates, or by CYP3A4 isoenzyme inhibitors (e.g. erythromycin, systemic azole antifungal agents etc.) with statins metabolized by this isoenzyme. The pharmacokinetics of the individual statin should be considered in patients receiving polypharmacological treatments, to minimize the risk of unfavorable drug interactions. Atorvastatin is well tolerated in long-term treatment of dyslipidemia and is characterized by a safety profile similar to the other available statins.

Cardiovasc Drugs Ther 2001;15(3):211-8

Eye health

Oxidative damage and age-related macular degeneration.

This article provides current information on the potential role of oxidation in relation to age-related macular degeneration (AMD). The emphasis is placed on the generation of oxidants and free radicals and the protective effects of antioxidants in the outer retina, with specific emphasis on the photoreceptor cells, the retinal pigment epithelium and the choriocapillaris. The starting points include a discussion and a definition of what radicals are, their endogenous sources, how they react, and what damage they may cause. The photoreceptor/pigment epithelium complex is exposed to sunlight, is bathed in a near-arterial level of oxygen, and membranes in this complex contain high concentrations of polyunsaturated fatty acids, all considered to be potential factors leading to oxidative damage. Actions of antioxidants such as glutathione, vitamin C, superoxide dismutase, catalase, vitamin E and the carotenoids are discussed in terms of their mechanisms of preventing oxidative damage. The phototoxicity of lipofuscin, a group of complex autofluorescent lipid/protein aggregates that accumulate in the retinal pigment epithelium, is described and evidence is presented suggesting that intracellular lipofuscin is toxic to these cells, thus supporting a role for lipofuscin in aging and AMD. The theory that AMD is primarily due to a photosensitizing injury to the choriocapillaris is evaluated. Results are presented showing that when protoporphyric mice are exposed to blue light there is an induction in the synthesis of Type IV collagen synthesis by the choriocapillary endothelium, which leads to a thickened Bruch’s membrane and to the appearance of sub-retinal pigment epithelial fibrillogranular deposits, which are similar to basal laminar deposits. The hypothesis that AMD may result from oxidative injury to the retinal pigment epithelium is further evaluated in experiments designed to test the protective effects of glutathione in preventing damage to cultured human pigment epithelial cells exposed to an oxidant. Experiments designed to increase the concentration of glutathione in pigment epithelial cells using dimethylfumarate, a monofunctional inducer, are described in relation to the ability of these cells to survive an oxidative challenge. While all these models provide undisputed evidence of oxidative damage to the retinal pigment epithelium and the choriocapillaris that is both light- and oxygen-dependent, it nevertheless is still unclear at this time what the precise linkage is between oxidation-induced events and the onset and progression of AMD.

Mol Vis 1999 Nov 3;5:32

Oxidative damage and protection of the RPE.

This review provides a model for the role of oxidative stress in the etiology of age-related macular degeneration (AMD). Epidemiological studies of diet, environmental and behavioral risk factors suggest that oxidative stress is a contributing factor of AMD. Pathological studies indicate that damage to the retinal pigment epithelium (RPE) is an early event in AMD. In vitro studies show that oxidant treated RPE cells undergo apoptosis, a possible mechanism by which RPE cells are lost during early phase of AMD. The main target of oxidative injury seems to be mitochondria, an organelle known to accumulate genomic damages in other postmitotic tissues during aging. The thiol antioxidant GSH and its amino acid precursors protect RPE cells from oxidant-induced apoptosis. Similar protection occurs with dietary enzyme inducers which increase GSH synthesis. These results indicate that therapeutic or nutritional intervention to enhance the GSH antioxidant capacity of RPE may provide an effective way to prevent or treat AMD.

Prog Retin Eye Res 2000 Mar;19(2):205-21

Vitamin supplement use and incident cataracts in a population-based study.

OBJECTIVE: To determine the relationship between vitamin supplement use and the 5-year incidence of nuclear, cortical, and posterior subcapsular cataract in the Beaver Dam Eye Study cohort. DESIGN: The 5-year incidence of cataract, determined from slitlamp (nuclear cataract) and retroillumination (cortical and posterior subcapsular cataract) photographs, was assessed in a population-based cohort of persons participating in baseline (1988-1990) and follow-up (1993-1995) examinations. Detailed data regarding the type, dosage, and duration of supplement use were obtained by in-person interviews at follow-up. PARTICIPANTS: Residents of Beaver Dam, Wis, aged 43 to 86 years, were identified by private census. Of the 3684 participants in both baseline and follow-up examinations, 3089 were eligible for incident cataract analysis in the present study. RESULTS: Compared with nonusers, the 5-year risk for any cataract was 60% lower among persons who, at follow-up, reported the use of multivitamins or any supplement containing vitamin C or E for more than 10 years. Taking multivitamins for this duration lowered the risk for nuclear and cortical cataracts but not for posterior subcapsular cataracts (odds ratios [95% confidence intervals] = 0.6 [0.4-0.9], 0.4 [0.2-0.8], and 0.9 [0.5-1.9], respectively). Use of supplements for shorter periods was not associated with reduced risk for cataract. Measured differences in lifestyle between supplement users and nonusers did not influence these associations, nor did variations in diet as measured in a random subsample. CONCLUSIONS: These data add to a body of evidence suggesting lower risk for cataract among users of vitamin supplements and stronger associations with long-term use. However, the specific nutrients that are responsible cannot be ascertained at this time, and unmeasured lifestyle differences between supplement users and nonusers may explain these results.

Arch Ophthalmol 2000 Nov;118(11):1556-63

Aging affects the retrobulbar circulation differently in women and men.

BACKGROUND: While aging clearly has protean biological effects on every organ system, the differential effects of aging in women and men in the retrobulbar vasculature, to our knowledge, have never been investigated. Because glaucoma and age-related macular degeneration are closely linked to advanced age, we performed a cross-sectional study using color Doppler imaging of 4 retrobulbar vessels in both healthy women and men. OBJECTIVE: To define the influence of aging per se on ocular hemodynamics. METHODS: Women (n = 73) and men (n = 55), aged from 20 to 90 years, free of ocular and systemic disease, and with normal intraocular pressure, were recruited for this study. Postmenopausal women who were not receiving estrogen replacement therapy were also recruited. Studies involved color Doppler imaging analysis of the ophthalmic, central retinal, and nasal and temporal posterior ciliary arteries. Ophthalmic arterial peak systolic and end-diastolic velocities and a Pourcelot resistance index were determined for each vessel. RESULTS: In both sexes, ophthalmic arterial end-diastolic velocity decreased and the Pourcelot resistance index rose with advancing age (each P<. 001); peak systolic velocity in the ophthalmic vessel was age-independent. In contrast, central retinal arterial flow velocities were unaffected by age in both sexes. In the posterior ciliary arteries, in men, flow velocities and the Pourcelot resistance index were independent of age. However, in women, end-diastolic velocity decreased with age in both the nasal and temporal posterior ciliary vessel (each P<.05); peak systolic velocity was constant; the Pourcelot resistance index in each ciliary artery rose with advancing age (each P<.05). CONCLUSION: In healthy women and men, aging-induced changes in retrobulbar hemodynamics are comparable to alterations seen in patients with glaucoma or age-related macular degeneration, suggesting that vascular changes with senescence may contribute to increased risk for these diseases in older age.

Arch Ophthalmol 2000 Aug;118(8):1076-80

A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene and zinc for age-related macular degeneration and vision loss: AREDS report no. 8.

BACKGROUND: Observational and experimental data suggest that antioxidant and/or zinc supplements may delay progression of age-related macular degeneration (AMD) and vision loss. OBJECTIVE: To evaluate the effect of high-dose vitamins C and E, beta carotene and zinc supplements on AMD progression and visual acuity. DESIGN: The Age-Related Eye Disease Study, an 11-center double-masked clinical trial, enrolled participants in an AMD trial if they had extensive small drusen, intermediate drusen, large drusen, noncentral geographic atrophy, or pigment abnormalities in 1 or both eyes, or advanced AMD or vision loss due to AMD in 1 eye. At least 1 eye had best-corrected visual acuity of 20/32 or better. Participants were randomly assigned to receive daily oral tablets containing: (1) antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; and beta carotene, 15 mg); (2) zinc, 80 mg, as zinc oxide and copper, 2 mg, as cupric oxide; (3) antioxidants plus zinc; or (4) placebo. MAIN OUTCOME MEASURES: (1) Photographic assessment of progression to or treatment for advanced AMD and (2) at least moderate visual acuity loss from baseline (> or =15 letters). Primary analyses used repeated-measures logistic regression with a significance level of.01, unadjusted for covariates. Serum level measurements, medical histories, and mortality rates were used for safety monitoring. RESULTS: Average follow-up of the 3640 enrolled study participants, aged 55-80 years, was 6.3 years, with 2.4% lost to follow-up. Comparison with placebo demonstrated a statistically significant odds reduction for the development of advanced AMD with antioxidants plus zinc (odds ratio [OR], 0.72; 99% confidence interval [CI], 0.52-0.98). The ORs for zinc alone and antioxidants alone are 0.75 (99% CI, 0.55-1.03) and 0.80 (99% CI, 0.59-1.09), respectively. Participants with extensive small drusen, nonextensive intermediate size drusen, or pigment abnormalities had only a 1.3% 5-year probability of progression to advanced AMD. Odds reduction estimates increased when these 1063 participants were excluded (antioxidants plus zinc: OR, 0.66; 99% CI, 0.47-0.91; zinc: OR, 0.71; 99% CI, 0.52-0.99; antioxidants: OR, 0.76; 99% CI, 0.55-1.05). Both zinc and antioxidants plus zinc significantly reduced the odds of developing advanced AMD in this higher-risk group. The only statistically significant reduction in rates of at least moderate visual acuity loss occurred in persons assigned to receive antioxidants plus zinc (OR, 0.73; 99% CI, 0.54-0.99). No statistically significant serious adverse effect was associated with any of the formulations. CONCLUSIONS: Persons older than 55 years should have dilated eye examinations to determine their risk of developing advanced AMD. Those with extensive intermediate size drusen, at least 1 large druse, noncentral geographic atrophy in 1 or both eyes, or advanced AMD or vision loss due to AMD in 1 eye, and without contraindications such as smoking, should consider taking a supplement of antioxidants plus zinc such as that used in this study.

Arch Ophthalmol 2001 Oct;119(10):1417-36

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