The Effect of the Extra Virgin Olive Oil Minor Phenolic Compound 3',4'-Dihydroxyphenylglycol in Experimental Diabetic Kidney Disease.

The aim of this study was to analyze the possible nephroprotective effect of 3',4'-dihydroxyphenylglycol (DHPG), a polyphenolic compound of extra virgin olive oil (EVOO), on renal lesions in an experimental model of type 1 diabetes. Rats were distributed as follows: healthy normoglycemic rats (NDR), diabetic rats treated with saline (DR), and DR treated with 0.5 mg/kg/day or 1 mg/kg/day of DHPG. DR showed a significantly higher serum and renal oxidative and nitrosative stress profile than NDR, as well as reduced prostacyclin production and renal damage (defined as urinary protein excretion, reduced creatinine clearance, increased glomerular volume, and increased glomerulosclerosis index). DHPG reduced the oxidative and nitrosative stress and increased prostacyclin production (a 59.2% reduction in DR and 34.7-7.8% reduction in DHPG-treated rats), as well as 38-56% reduction in urinary protein excretion and 22-46% reduction in glomerular morphological parameters (after the treatment with 0.5 or 1 mg/kg/day, respectively). Conclusions: DHPG administration to type 1-like diabetic rats exerts a nephroprotective effect probably due to the sum of its antioxidant (Pearson's coefficient 0.68-0.74), antinitrosative (Pearson's coefficient 0.83), and prostacyclin production regulator (Pearson's coefficient 0.75) effects.

Neuroprotective Effect of 3',4'-Dihydroxyphenylglycol in Type-1-like Diabetic Rats-Influence of the Hydroxytyrosol/3',4'-dihydroxyphenylglycol Ratio.

The aim of this study was to assess the possible neuroprotective effect of 3',4'-dihydroxyphenylglycol (DHPG), a polyphenol from extra virgin olive oil (EVOO), in an experimental model of diabetes and whether this effect is modified by the presence of another EVOO polyphenol, hydroxytyrosol (HT). The neuroprotective effect was assessed in a hypoxia-reoxygenation model in brain slices and by quantifying retinal nerve cells. The animals were distributed as follows: (1) normoglycemic rats (NDR), (2) diabetic rats (DR), (3) DR treated with HT (5 mg/kg/day p.o.), (4) DR treated with DHPG (0.5 mg/kg/day), or (5) with 1 mg/kg/day, (6) DR treated with HT plus DHPG 0.5 mg/kg/day, or (7) HT plus 1 mg/kg/day p.o. DHPG. Diabetic animals presented higher levels of oxidative stress variables and lower numbers of neuronal cells in retinal tissue. The administration of DHPG or HT reduced most of the oxidative stress variables and brain lactate dehydrogenase efflux (LDH) as an indirect index of cellular death and also reduced the loss of retinal cells. The association of DHPG+HT in the same proportions, as found in EVOO, improved the neuroprotective and antioxidant effects of both polyphenols.

Nephroprotective Effect of the Virgin Olive Oil Polyphenol Hydroxytyrosol in Type 1-like Experimental Diabetes Mellitus: Relationships with Its Antioxidant Effect.

The aim of this study was to determine whether hydroxytyrosol administration prevented kidney damage in an experimental model of type 1 diabetes mellitus in rats. Hydroxytyrosol was administered to streptozotocin-diabetic rats: 1 and 5 mg/kg/day p.o. for two months. After hydroxytyrosol administration, proteinuria was significantly reduced (67-73%), calculated creatinine clearance was significantly increased (26-38%), and the glomerular volume and glomerulosclerosis index were decreased (20-30%). Hydroxytyrosol reduced oxidative and nitrosative stress variables and thromboxane metabolite production. Statistical correlations were found between biochemical and kidney function variables. Oral administration of 1 and 5 mg/kg/day of hydroxytyrosol produced an antioxidant and nephroprotective effect in an experimental model of type 1-like diabetes mellitus. The nephroprotective effect was significantly associated with the systemic and renal antioxidant action of hydroxytyrosol, which also influenced eicosanoid production.

Neuroprotective Effect of Hydroxytyrosol in Experimental Diabetic Retinopathy: Relationship with Cardiovascular Biomarkers.

The aim of the study was to test the neuroprotective effect of hydroxytyrosol (HT) on experimental diabetic retinopathy. Animals were divided in four groups: (1) control nondiabetic rats, (2) streptozotocin-diabetic rats (DR), (3) DR treated with 1 mg/kg/day p.o. HT, and (4) DR treated with 5 mg/kg/day p.o. HT. Treatment with HT was started 7 days before inducing diabetes and was maintained for 2 months. In the DR group, total area occupied by extracellular matrix was increased, area occupied by retinal cells was decreased; both returned to near-control values in DR rats treated with HT. The number of retinal ganglion cells in DR was significantly lower (44%) than in the control group, and this decrease was smaller after HT treatment (34% and 9.1%). Linear regression analysis showed that prostacyclin, platelet aggregation, peroxynitrites, and the dose of 5 mg/kg/day HT significantly influenced retinal ganglion cell count. In conclusion, HT exerted a neuroprotective effect on diabetic retinopathy, and this effect correlated significantly with changes in some cardiovascular biomarkers.

Neuroprotective Effect of Hydroxytyrosol in Experimental Diabetes Mellitus.

The aim of the study was to analyze the possible neuroprotective effect of hydroxytyrosol (HT) in diabetic animals in a model of hypoxia-reoxygenation. Rats (10 animals/group) were distributed in five groups: nondiabetic rats, control diabetic rats (DR), and DR rats treated for 2 months with 1, 5, or 10 mg/kg/day po HT. At the end of follow-up, an experimental model of hypoxia-reoxygenation in brain slices was tested. The DR group showed increased cell death, oxidative and nitrosative stress, and an increase in brain inflammatory mediators. These alterations were significantly greater in DR than in normoglycemic animals. HT significantly reduced oxidative (38.5-52.4% lipid peroxidation) and nitrosative stress (48.0-51.0% nitric oxide and 43.9-75.2% peroxynitrite concentration) and brain inflammatory mediators (18.6-40.6% prostaglandin E2 and 17.0-65.0% interleukin 1ß concentration). Cell death was reduced by 25.9, 37.5, and 41.0% after the administration of 1, 5, or 10 mg/kg/day. The administration of HT in rats with experimental diabetes thus had a neuroprotective effect.

Effects of hydroxytyrosol on cardiovascular biomarkers in experimental diabetes mellitus.

The aim of this study was to assess the influence of hydroxytyrosol (HT) on cardiovascular biomarkers and morphometric parameters of the arterial wall in streptozotocin-diabetic rats. Seven groups of rats (N=10 per group) were studied for 2 months: nondiabetic rats (NDR), diabetic rats treated with saline (DR) and DR treated with HT (0.5, 1, 2.5, 5 and 10 mg kg-1 day-1 p.o.). DR had higher platelet aggregation values, higher thromboxane B2, plasma lipid peroxidation, 3-nitrotyrosine, oxidized LDL (oxLDL), myeloperoxidase, vascular cell adhesion molecule 1 (VCAM-1) and interleukin-1ß (IL-1ß) concentrations, and lower aortic 6-keto-prostaglandin F1α and nitric oxide production than NDR. Aortic wall area and smooth muscle cell count were also higher in DR than in NDR. HT significantly reduced both oxidative and nitrosative stress, oxLDL concentration, VCAM-1 and inflammatory mediators, platelet aggregation and thromboxane B2 production. Morphometric values in the aortic wall were reduced to values near those in NDR. In conclusion, HT influenced the major biochemical processes leading to diabetic vasculopathy, and reduced cell proliferation in the vascular wall in this experimental model.

Differences in the Neuroprotective Effect of Orally Administered Virgin Olive Oil (Olea europaea) Polyphenols Tyrosol and Hydroxytyrosol in Rats.

The neuroprotective effect of virgin olive oil (VOO) polyphenols has been related to their antioxidant effect. The main objective was to analyze how tyrosol and hydroxytyrosol contribute to the antioxidant and neuroprotective effects of VOO in a model of hypoxia-reoxygenation in rat brain slices. Rats were treated per os (po) (10 or 20 mg/kg/day) with hydroxytyrosol ethyl ether (HTEE), tyrosol ethyl ether (TEE), or 3,4-di-o-methylidene-hydroxytyrosol ethyl ether (MHTEE), used as a negative control for antioxidant effects. Lipid peroxidation was inhibited with HTEE, TEE, and MHTEE (from 5.0 ± 1.5 to 2.6 ± 1.5, 4.5 ± 1.5, and 4.8 ± 1.5 nmol/mg protein, respectively). However, all three compounds had similar neuroprotective effects: from 2.8 ± 0.07 to 1.8 ± 0.02 arbitrary units for HTEE, 1.4 ± 0.09 arbitrary units for TEE, and 1.3 ± 0.2 arbitrary units for MHTEE. All three compounds inhibited 3-nitrotyrosine production (from 3.7 ± 0.3 to 1.2 ± 0.03 nmol/0.1 g tissue for HTEE, 1.0 ± 0.2 nmol/0.1 g tissue for TEE, and 1.3 ± 0.1 nmol/0.1 g tissue for MHTEE), prostaglandin E2 production (from 55.7 ± 2.2 to 46.4 ± 1.9 pg/0.1 g tissue for HTEE, 24.7 ± 1.3 pg/0.1 g tissue for TEE, and 27.6 ± 2.6 pg/0.1 g tissue for MHTEE), whereas only HTEE inhibited IL1ß production (from 35.7 ± 1.5 to 21.6 ± 0.8 pg/0.1 g tissue). Pearson correlation coefficients related neuroprotective effect with an antioxidant effect for HTEE (R = 0.72, p < 0.001), and inhibition of nitrosative stress (R = 0.78, 0.67, and 0.66 for HTEE, TEE, and MHTEE, respectively, p < 0.001) and inflammatory mediators (R = 0.72, 0.79, and 0.64 for HTEE, TEE, and MHTEE, respectively, p < 0.001) with all three compounds.

Role of the inhibition of oxidative stress and inflammatory mediators in the neuroprotective effects of hydroxytyrosol in rat brain slices subjected to hypoxia reoxygenation.

The aim of this study was to analyze the mechanism of the neuroprotective effect of hydroxytyrosol (HT) in an experimental model of hypoxia-reoxygenation in rat brain slices. After reoxygenation the increase in lactate dehydrogenase efflux was inhibited by HT in a concentration-dependent manner and dose-dependent inhibition after oral administration to rats for 7 days (1, 5 and 10 mg/kg per day). Maximum inhibition was 57.4% in vitro and 38.7% ex vivo. Hydroxytyrosol reduced oxidative stress parameters: it inhibited lipid peroxidation and increased enzymatic activities related with the glutathione system both in vitro and after oral administration to rats. The increase in prostaglandin E2 and interleukin 1ß after reoxygenation were inhibited after incubation of brain slices with HT and after oral administration. The accumulation of nitric oxide in brain slices was reduced in a concentration-dependent manner. In conclusion, HT exerts a neuroprotective effect in a model of hypoxia-reoxygenation in rat brain slices, both in vitro and after 7 days of oral administration to rats. HT exerts an antioxidant activity and lowered some inflammatory markers in this model.

Hydroxytyrosyl alkyl ether derivatives inhibit platelet activation after oral administration to rats.

The low lipophilicity of hydroxytyrosol (HT) has motivated efforts to synthesize homologous series with better lipid solubility, such as the ethers, which are more lipophilic than HT. Because HT inhibits platelet aggregation, the aim of the study was to assess the possible anti-platelet effect of five HT ether derivatives (ethyl, butyl, hexyl, octyl and dodecyl) after oral administration to rats. Whole blood collagen-induced platelet aggregation and calcium-induced thromboxane B2 (TxB2), aortic 6-keto-prostaglandin F1α (6-keto-PGF1α) and nitrites+nitrates, plasma concentration of lipid peroxides (TBARS) and red blood cell content of reduced glutathione (GSH) were measured. The administration of 20 mg/kg/day inhibited platelet aggregation, TxB2 and TBARS in a non-linear manner related to the length of the carbon chain, with a cut-off effect in the hexyl derivative. Aortic nitrite and red blood cell GSH production were also increased. The aortic production of 6-keto-PGF1α was unaltered except in the group treated with the dodecyl derivative. The administration of 50 mg/kg/day showed a similar pharmacodynamic profile but without the non-linear effect. In conclusion, HT ethers, especially the hexyl derivative, are a potential alternative to hydroxytyrosol, and their effect merits additional research to determine their role in the prophylaxis of vascular disease.

Cytoprotective effect of hydroxytyrosyl alkyl ether derivatives after oral administration to rats in a model of glucose-oxygen deprivation in brain slices.

This study was designed to determine whether the oral administration of hydroxytyrosol (HT) alkyl ether derivatives has a neuroprotective effect in rats. The animals were treated for 7 days with HT or ethyl, butyl, hexyl, octyl, and dodecyl HT ether. A method of in vitro hypoxia-reoxygenation in brain slices was used. Hexyl, octyl, and dodecyl HT derivatives reduced brain cell death (LDH efflux). Lipid peroxidation and nitrite concentrations were inhibited most by hexyl, octyl, and dodecyl derivatives. Concentrations of 3-nitrotyrosine were reduced by HT butyl, hexyl, octyl, and dodecyl ether derivatives. Interleukin-1ß was significantly reduced in brain slices from rats treated with all HT ether derivatives. LDH efflux showed a linear correlation with brain concentrations of lipid peroxides, nitrites plus nitrates, and interleukin 1ß. The reduction in oxidative and nitrosative stress and decreased production of pro-inflammatory interleukins may be the basis for the observed neuroprotective effects.

Cytoprotective effect of nonsteroidal antiinflammatory drugs in rat brain slices subjected to reoxygenation after oxygen-glucose deprivation.

The aim of this study was to assess the possible neuroprotective effect of the main nonsteroidal antiinflammatory drugs (NSAIDs) in an experimental model of hypoxia-reoxygenation in rat brain slices. After reoxygenation the increase in lactate dehydrogenase (LDH) efflux was inhibited by nimesulide, celecoxib and meloxicam with an IC(50) in the 10(-6)M range, by flurbiprofen, ibuprofen and diclofenac in the 10(-5)M range, and by salicylic acid, indomethacin, acetylsalicylic acid and mefenamic acid the 10(-4)M range. The effect of other NSAIDs was seen with an IC(50) greater than 10(-3)M. A statistically significant linear correlation between the values of LDH efflux and prostaglandin E(2) was found for NSAIDs whose IC(50) of cytoprotection (LDH efflux) was below 10(-4)M. The concentration of interleukin 10 was increased with nimesulide, celecoxib, meloxicam, flurbiprofen, ibuprofen and diclofenac. Flurbiprofen and diclofenac significantly inhibited the production of lipid peroxides. The increase in brain nitrite levels was significantly reduced with celecoxib, flurbiprofen, diclofenac and salicylic acid. Concentrations of 3-nitrotyrosine were significantly reduced with celecoxib, flurbiprofen, ibuprofen, salicylic acid and ketorolac. In conclusion, NSAIDs with the greatest cytoprotective effect (nimesulide, celecoxib and meloxicam) may exert their effect mainly through the blockade of cyclooxygenase-2 (COX-2) activity. Other compounds with neuroprotective activity may complement their lower anti-COX-2 effect with a slight increase in interleukin 10 and reduced oxidative and nitrosative stress in our model of hypoxia-reoxygenation in rat brain slices.

Virgin olive oil administration improves the effect of aspirin on retinal vascular pattern in experimental diabetes mellitus.

The aim of the present study is to evaluate the possible influence of virgin olive oil (VOO) on the effect of acetylsalicylic acid (ASA) in platelet aggregation, prostanoid and NO production and retinal vascular pattern in rats with experimental type 1-like diabetes. We used 100 male Wistar rats that were distributed into five groups: (1) non-diabetic rats (NDR); (2) untreated diabetic rats (DR); (3) DR treated with ASA (2 mg/kg per d per os (p.o.)); (4) DR treated with VOO (0.5 ml/kg per d p.o.); (5) DR treated with ASA plus VOO. The duration of diabetes was 3 months, and each treatment was administered from the first day of diabetes. Variables that were quantified were platelet aggregation (I(max)), thromboxane B(2) (TxB(2)), aortic prostacyclin (6-keto-PGF(1alpha)) and NO, and the percentage of retina with horseradish peroxidase-permeable vessels (HRP-PV). Diabetic rats showed a higher I(max) (35 %) and TxB(2) (63 %) than NDR, and a lower 6-keto-PGF(1alpha), NO and HRP-PV than NDR ( - 74.6 %). ASA and VOO administration reduced these differences and prevented the percentage of HRP-PV ( - 59.7 % with ASA and - 46.7 % with VOO). The administration of ASA plus VOO showed a strong platelet inhibition (80.2 v. 23.4 % for VOO and 50.6 % for ASA+VOO, P < 0.0001), and reduced HRP-PV differences to - 31.6 % (P < 0.001 with respect to DR and P < 0.0001 with respect to DR treated with ASA). In conclusion, the administration of VOO to rats with type 1-like diabetes mellitus improves the pharmacodynamic profile of ASA, and increases its retinal anti-ischaemic effect.

Effect of virgin olive oil plus acetylsalicylic acid on brain slices damage after hypoxia-reoxygenation in rats with type 1-like diabetes mellitus.

Aspirin is the most widely used drug for the secondary prevention of ischemic stroke in patients suffering from diabetes mellitus. Moreover virgin olive oil (VOO) administration exerts a neuroprotective effect in healthy rat brain slices. The aim of the present study was to determine the possible influence of VOO administration to streptozotocin-diabetic rats (DR) on the neuroprotective effect of aspirin in rat brain. DR were treated during 3 months with saline, aspirin (2mg/kg/day p.o.), VOO (0.5 mL/kg/day p.o.) or its association; a control normoglycemic group was treated with saline. Brain slices were subjected to oxygen-glucose deprivation before a reoxygenation period. All the treatments significantly reduced lactate dehydrogenase LDH efflux after reoxygenation (-54.1% for aspirin, -51.3% for VOO and -72.9% for aspirin plus VOO). Lipid peroxides in brain slices were also reduced after the treatment with aspirin (-17.90%), VOO (-37.3%) and aspirin plus VOO (-49.2%). Production of nitric oxide after reoxygenation was inhibited by all the treatments (-46.5% for ASA, -48.2% for VOO and -75.8% for ASA plus VOO). The activity of the inducible isoform (iNOS) was inhibited by the three types of treatment (-31.8% for ASA, -29.1% for VOO and -56.0% for ASA plus VOO). The main conclusion of our study is that daily oral administration of VOO to diabetic rats may be a natural way to increase the neuroprotective effect of aspirin in diabetic animals.

Virgin olive oil polyphenol hydroxytyrosol acetate inhibits in vitro platelet aggregation in human whole blood: comparison with hydroxytyrosol and acetylsalicylic acid.

Hydroxytyrosol acetate (HT-AC) is a polyphenol present in virgin olive oil (VOO) at a proportion similar to hydroxytyrosol (HT) (160-479 micromol/kg oil). The present study was designed to measure the in vitro platelet antiaggregating activity of HT-AC in human whole blood, and compare this effect with that of HT and acetylsalicylic acid (ASA). The experiments were designed according to the standard procedure to investigate the activity of ASA. HT-AC and HT inhibited platelet aggregation induced by ADP, collagen or arachidonic acid in both whole blood and platelet-rich plasma (PRP). ASA and HT-AC had a greater effect in whole blood than in PRP when ADP or collagen was used as inducer. ASA and HT-AC had a greater effect in PRP+leucocytes than in PRP alone. All three compounds inhibited platelet thromboxane B2 and leucocyte 6-keto-prostaglandin F1alpha (6-keto-PF1 alpha) production. The thromboxane/6-keto-PGF1alpha inhibition ratio (as an indirect index of the prostanoid equilibrium) was 10.8 (SE 1) for HT-AC, 1.0 (SE 0.1) for HT and 3.3 (SE 0.2) for ASA. All three compounds stimulated nitric oxide production, although HT was a weaker effect. In our experiments only concentrations higher than 500 microm (HT) or 1 mm (HT-AC and ASA) inhibited 3-nitrotyrosine production. All three compounds inhibited the production of TNFalpha by leucocytes, with no significant differences between them. In quantitative terms HT-AC showed a greater antiplatelet aggregating activity than HT and a similar activity to that of ASA. This effect involved a decrease in platelet thromboxane synthesis and an increase in leucocyte nitric oxide production.

Neuroprotective effect of hydroxytyrosol and hydroxytyrosol acetate in rat brain slices subjected to hypoxia-reoxygenation.

Hydroxytyrosol (HT) and hydroxytyrosol acetate (HT-AC) are two well-known phenolic compounds with antioxidant properties that are present in virgin olive oil (VOO). Because VOO has shown neuroprotective effects in rats, the purpose of the present study was to investigate the possible neuroprotective effect of HT and HT-AC in a model of hypoxia-reoxygenation in rat brain slices after in vitro incubation of these compounds or after 7 days of oral treatment with 5 or 10 mg/kg per day. Lactate dehydrogenase (LDH) efflux to the incubation medium was measured as a marker of brain cell death. HT and HT-AC inhibited LDH efflux in a concentration-dependent manner, with 50% inhibitory concentrations of 77.78 and 28.18 microM, respectively. Other well-known antioxidants such as vitamin E and N-acetyl-cysteine had no neuroprotective effect in this experimental model. After 1 week of treatment, HT (5 and 10 mg/kg per day p.o.) reduced LDH efflux by 37.8% and 52.7%, respectively, and HT-AC reduced LDH efflux by 45.4% and 67.8%. These data are additional evidence of the cytoprotective effect of VOO administration, and provide a preliminary basis for further study of these polyphenols as potential neuroprotective compounds.

Effects of hydroxytyrosol and hydroxytyrosol acetate administration to rats on platelet function compared to acetylsalicylic acid.

Virgin olive oil (VOO) contains the polyphenols hydroxytyrosol (HT) and hydroxytyrosol acetate (HT-AC). This study investigated the antiplatelet effect of HT and HT-AC in healthy rats and compared their effects to acetylsalicylic acid (ASA). All compounds were administered orally for 7 days. HT and HT-AC inhibited platelet aggregation in whole blood, with a 50% inhibitory dose (ID50) of 48.25 mg/kg per day for HT, 16.05 mg/kg per day for HT-AC, and 2.42 mg/kg per day for ASA. Platelet synthesis of thromboxane B2 was inhibited by up to 30% by HT and 37% by HT-AC; the ID50 of this effect for ASA was 1.09 mg/kg per day. Vascular prostacyclin production was inhibited by up to 27.5% by HT and 32% by HT-AC; the ID50 of this effect for ASA was 6.75 mg/kg per day. Vascular nitric oxide production was increased by up to 34.2% by HT, 66% by HT-AC, and 64% by ASA. We conclude that HT and HT-AC administered orally inhibited platelet aggregation in rats and that a decrease in thromboxane synthesis along with an increase in nitric oxide production contributed to this effect.

Effects of dexibuprofen on platelet function in humans: comparison with low-dose aspirin.

BACKGROUND: The aim of the current study is to evaluate the antiplatelet effect of dexibuprofen in healthy volunteers in comparison with low-dose aspirin. METHODS: Healthy volunteers (n = 12) were treated in a crossover manner with 100 mg daily aspirin or with 800 mg daily dexibuprofen. Blood samples were obtained within 24 h; 3, 7, and 14 days after repeated doses; and 24 h after the last dose. In each sample, the authors measured platelet aggregation, thromboxane B2, 6-keto-prostaglandin F1alpha, and nitric oxide. RESULTS: The antiplatelet effect of dexibuprofen (maximal inhibition of aggregation was 48-55% for adenosine diphosphate and 90-95% for collagen and arachidonic acid) was equal to the effect of aspirin. The main difference between the two drugs was in the degree of recovery of platelet function. The effect of aspirin persisted for 24 h after the last dose (remaining inhibition 50%, respect to the pretreatment value), whereas platelet aggregation had returned to baseline pretreatment values within 24 h after dexibuprofen was stopped. CONCLUSIONS: Both aspirin and dexibuprofen inhibited platelet function with a similar intensity, but dexibuprofen exerted a reversible effect for 24 h after the last dose.

Triflusal: an antiplatelet drug with a neuroprotective effect?

Triflusal is a derivative of salicylic acid with a well-established platelet aggregation inhibitory profile. Its pharmacokinetic and pharmacodynamic properties differ, however, somewhat from those of acetylsalicylic acid. A number of recent experimental and clinical studies have shown that triflusal is a potentially useful choice in the treatment and prophylaxis of brain ischemia because of its antithrombogenic as well as neuroprotective effects. Its antithrombogenic effect has been demonstrated at the clinical as well as at the experimental level, while its neuroprotective effect has been shown only in experimental models. The drug interferes with thrombogenesis by inhibiting thromboxane synthesis and increasing the levels of cAMP and nitric oxide. Its neuroprotective action is the result of its antioxidant and antiinflammatory effects in brain tissue. From a clinical standpoint triflusal is similar in efficacy to acetylsalicylic acid in preventing stroke, but has less adverse effects, especially it is less likely to cause bleeding. Because of its pharmacodynamic properties and lower rate of adverse reactions, triflusal may be a useful alternative to acetylsalicylic acid in the prevention of stroke.

Pharmacological approach to diabetic retinopathy.

Diabetic retinopathy is the most frequent cause of legal blindness in the population of 30-to-70-year olds. Whether retinopathy appears or not depends mainly on the duration of the disease and the degree of metabolic control the patient maintains. High blood glucose values lead to important changes in cellular metabolism and the main effects of these alterations are endothelial dysfunction that sets in motion the morphological process of diabetic retinopathy. The biochemical lesions caused by prolonged hyperglycemia can be positively influenced, but usually not normalized, pharmacologically with some groups of drugs, which are now under development. This makes tight control of glycemia a key measure in preventing the onset or progression of diabetic retinopathy, together with an effective program of ophthalmologic detection and follow-up in patients with diabetes. Regarding the role of endothelial dysfunction, antiplatelet drugs have been shown to slow some aspects of the evolution of diabetic retinopathy in its initial stages, mainly a lower degree of microaneurysms. However, a new approach to controlling endothelial dysfunction shows promise, mainly through the vascular endothelial growth factor (VEGF) inhibitors. These agents may prove to be especially useful in the treatment of proliferative diabetic retinopathy. Other encouraging results have been obtained in studies of antioxidant drugs and inhibitors of the formation of advanced glycation end products. Once retinal lesions appear, preventive measures need to be redoubled, with special attention to controlling glycemia; however, it is also necessary to resort to laser photocoagulation. This intervention aims to eliminate areas of ischemia and to diminish the formation of retinal exudates. If this measure fails or if vitreous hemorrhage appears, the only remaining therapeutic measure is vitrectomy.

Influence of glucose concentration on the effects of aspirin, ticlopidine and clopidogrel on platelet function and platelet-subendothelium interaction.

Clinical studies have shown that the ability of aspirin to prevent cerebrovascular accidents is weaker in patients with diabetes. The aim of this study was to determine whether high concentrations of glucose modified the effect of aspirin, ticlopidine and clopigodrel on platelet function and platelet-subendothelium interactions. This in vitro study tested three different concentrations of glucose. The effects were analyzed by comparing platelet aggregometry in whole blood, nitric oxide and prostacyclin production in cultures of human endothelial cells, and by quantitative analysis of morphological features of the platelet-subendothelium interaction under flow conditions. High concentrations of glucose increased platelet aggregation (13.9 Omega with 5 mM glucose vs. 21.6 Omega with 16.6 mM) and platelet-subendothelium interactions (28.9% with 5 mM glucose vs.35.2% with 16.6 mM), and decreased nitric oxide and prostacyclin production. In the presence of high concentrations of glucose, the antiaggregant effect of aspirin and its influence on nitric oxide production were diminished (IC50 54 microM with 5 mM glucose vs.556 microM with 16.6 mM glucose), and its effect on the platelet-subendothelium interaction was reduced (10.5% platelet occupancy with 5 mM glucose vs.23% with 16.6 mM glucose). The effects of ticlopidine and clopidogrel were not significantly modified.