Giuseppe Pennisi

High circulating levels of cytokines (IL-6 and TNFa), adhesion molecules (VCAM-1 and ICAM-1) and selectins in patients with peripheral arterial disease at rest and after a treadmill test:

Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis that is associated with systemic inflammation. The aim of our study was to assess whether plasma markers of inflammation increased after exercise in patients with PAD. The study was conducted on two groups of 20 subjects each: one group (mean age 68.4 6 5.09 years) was affected by PAD with claudication, while the other group consisted of healthy controls (66.9 6 6.1 years). Concentrations of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFa) were determined in plasma, in supernatants and in cells stimulated with 1 mg lipopolysaccharide in all patients. E-selectin (ES), L-selectin (LS) and P-selectin (PS) concentrations and plasma concentrations of VCAM-1 and ICAM-I were also determined. All determinations were performed in patients at rest and after the treadmill exercise. Resting values of soluble mediators were greater in PAD patients than in controls. They increased in both groups after the treadmill test, even if post-treadmill concentrations were signifi cantly higher in PAD patients (PAD p < 0.001 or 0.0001, controls p < 0.05 or 0.001). These results confi rm that white blood cell activation is characteristic of systemic atherosclerosis and that these inflammation markers increase in conditions of hemodynamic stress.

Plasma levels and zymographic activities of matrix metalloproteinases 2 and 9 in type II diabetics with peripheral arterial disease

Deregulation of matrix metalloproteinases (MMPs) is an important factor contributing to the development of vascular lesions. Plasma levels and zymographic activities of MMP-2 and MMP-9 were investigated in type II diabetics with (n = 51) or without (n = 42) peripheral artery disease (PAD) and in normal volunteers (n = 23). Plasma MMP-2 levels were higher in type II diabetics with (p < 0.01) or without (p < 0.05) PAD in comparison with normal volunteers. Similarly, type II diabetics with (p < 0.0001) or without (p > 0.05) PAD had higher plasma MMP-9 levels than normal volunteers. Plasma zymographic activities of both MMP-2 and MMP-9 were positively correlated with their plasma levels. Plasma MMP-2 zymographic activity was higher in type II diabetics with PAD than type II diabetics without PAD (p > 0.05). Plasma MMP-9 zymographic activity was higher in type II diabetics with (p < 0.0001) or without (p < 0.0001) PAD in comparision with normal volunteers. Together, these results indicate that increased plasma levels and zymographic activities of MMP-2 and MMP-9 may contribute to PAD in type II diabetics. In particular, plasma MMP-9 may be a useful marker for the development of vascular disease in type II diabetics.

Duration of menopause and behavior of malondialdehyde, lipids, lipoproteins and carotid wall artery intima-media thickness

AIM our study assessed whether minor or major hormonal deficiency influenced oxidative status and vascular wall structure in menopausal women. METHODS the study series was made up of 62 non hypertensive non diabetic menopausal women (mean age 52.3+/-4.7 years) divided into two groups depending on duration of menopause (group 1 duration 0-5 years; group 2 duration over 5 years). Total cholesterol (TC), LDL cholesterol (LDL-C), HDL-cholesterol (HDL-C), triglycerides (TG), malondialdehyde (MDA) and common carotid artery wall intima-media thickness (IMT) were determined in the entire series. RESULTS mean TC, LDL-C, TG, MDA and IMT values were higher in group 2 than group 1. The intergroup difference between MDA (P<0.007) and IMT values (P<0.006) values was statistically significant. CONCLUSIONS the study revealed a close temporal correlation between plasma oxidative stress and carotid wall IMT, jeopardizes vascular wall status as menopause proceeds.

A randomised, controlled clinical trial evaluating changes in therapeutic efficacy and oxidative parameters after treatment with propionyl L-carnitine in patients with peripheral arterial disease requiring haemodialysis.

ObjectiveWe explored the efficacy of intravenous therapy with propionyl L-carnitine in patients with both peripheral arterial disease (PAD) and chronic renal insufficiency requiring haemodialysis.MethodsThe trial was a randomised, double-blind, placebo-controlled trial. Sixty-four patients on haemodialysis (32 per treatment arm) with chronic renal insufficiency and PAD were assigned to receive either intravenous propionyl L-carnitine 600mg or placebo 3 times weekly for 12 months. The main outcome measures were the ankle/brachial index (ABI), plasma malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) concentrations, and the plasma nitrite/nitrate ratio (NO2/NO3); these were measured at baseline and at 6 and 12 months.ResultsSignificant increases in ABI were observed in the propionyl L-carnitine group, whereas in the placebo group the reverse trend was seen. In patients treated with propionyl L-carnitine, significant progressive decreases were seen in plasma MDA, 4-HNE and the NO2/NO3 ratio from baseline. In the placebo-treated group, only weakly significant or no differences were seen.ConclusionIntravenous administration of propionyl L-carnitine to haemodialysis patients with PAD improves both haemodynamic flow and the oxidative profile.

Gastroprotective effect of aqueous extract of Cistus incanus L. in rats

The antiulcer activity of a short-boiled aqueous extract from aerial parts of Cistus incanus was studied in rats against gastric lesions induced by necrotizing agents (1N HCl and absolute ethanol), indomethacin, serotonin and reserpine. The extract, containing bioflavonoids, was orally administered in the range from 0.25 to 0.50 g kg-1. It was found to have significant dose-related protective effects in all these experimental models, and was more effective against reserpine- and serotonin-induced mucosal congestion and haemorrhagic ulcers. These data suggest that the active constituents of the crude extract could be responsible for its protective effect by maintaining an efficient gastric mucosal microvascular supply.

Propionyl-L-Carnitine Therapy: Effects on Endothelin-1 and Homocysteine Levels in Patients with Peripheral Arterial Disease and End-Stage Renal Disease

Background/Aims: Recent data have addressed the issue of higher levels of homocysteine (Hcy) and endothelin-1 (ET-1) in end-stage renal disease (ESRD) that may be considered an independent predictor for cardiovascular disease. The prevalence of peripheral arterial disease (PAD) in patients with ESRD has been reported to be relevant, highlighting its clinical importance. We aimed to explore the therapeutic role of propionyl-L-carnitine (PLC) in hemodialysis patients with PAD by measuring ankle/brachial index (ABI), ET-1 and Hcy. Design: Randomized, double-blind, placebo-controlled trial. Methods: Sixty-four patients on hemodialysis with chronic renal insufficiency and PAD were assigned to receive either intravenous PLC (600 mg) or placebo 3 times weekly for 12 months. The ABI and plasma levels of ET-1 and Hcy were measured at baseline, 6 and 12 months. Results: In the PLC-treated group, progressive increases in ABI were observed, while in the placebo group the reverse trend was seen. Highly significant and progressive reductions in plasma levels of ET-1 and Hcy, compared to baseline, were also seen in the PLC-treated group. Conclusions: Hemodynamic flow, endothelial profile and Hcy levels were ameliorated by the administration of PLC in hemodialysis patients with ESRD and PAD.

Oxidative stress and endothelial damage in patients with asymptomatic carotid atherosclerosis.

Abstract It is know that oxidative stress can be able to induce cytotoxicity of blood cells, stimulate release of inflammatory cytokines, and induce the production of growth factors. The aim of this study was to investigate oxidative stress and endothelial dysfunction in patients with asymptomatic carotid artery disease and healthy controls. Native low-density lipoproteins, oxidised low-density lipoproteins, malondialdehyde, nitrates, glutathione peroxidase activity and endothelin-1 were determined in patients without severe (range between 30% and 50%) carotid artery stenosis. Native low-density lipoproteins, oxidized low-density lipoproteins, malondialdehyde, glutathione peroxydase, and endothelin-1 concentrations were higher in patients than in health controls (P<0.001). No difference was observed in nitrate values (P<0.8). Our results revealed oxidative stress in patients without severe carotid artery stenosis and clinical symptoms. This was shown by the elevated malondialdehyde and oxidized low-density lipoprotein levels.

Transcutaneous PCO2 Level as an Index of Tissue Resistance to Ischemia

The authors performed a retrospective study on a data base of 525 patients with periph eral arterial disease, to analyze the pathophysiologic meaning of resting transcutaneous pressure of carbon dioxide (PCO2) and of CO2 production during three minutes of local ischemia. The resting and postischemic PCO2 and its maximum increase related to rest (PCO2 production) were measured with Kontron 7640 equipment. The results show a significant increase of PCO2 production in the Fontaine stage 2A (183 patients, 4.61 mmHg, P < 0.0001), in stage 2B (194 patients, 5.22 mmHg, P < 0.0001), in the third stage (83 patients, 6.10 mmHg, P < 0.0001), and in the fourth stage (53 patients, 8.66 mmHg, P < 0.0001). Only the patients at the first stage showed an insignificant increase, perhaps because of the small number (12) in this group. The authors feel that the measurement of tcPCO2 production during local ischemic stress can be a very important parameter for evaluating peripheral arterial disease as an expression of metabolic tissue performance and, overall, of the tissue resistance to ischemia.

Efficacy of L-Propionyl Carnitine in the Treatment of Chronic Critical Limb Ischaemia

ObjectiveTo compare the therapeutic benefits of L-propionyl carnitine (LPC) with those of pentoxifylline in the clinical treatment of patients with chronic critical limb ischaemia.DesignRandomised, single-blind study.Patients188 patients, 85 with a recent (within the previous 15 days) reduction in pain-free walking distance (PWD), 59 with rest pain lasting for ≥2 weeks, and 44 patients with skin ulcers that had appeared during the previous 15 days.InterventionsIntravenous infusion with LPC 1.2 g/day or pentoxifylline 1.2 g/day In both groups, patients also received calcium heparin 25 000 U/day (12 500U twice daily) subcutaneously. Treatment duration was 2 weeks.Main Outcome Measures and ResultsWith both treatments, an increase in the PWD, a reduction in the use of analgesics for pain relief and a reduction in the diameter (in cm) of skin ulcers were observed; all changes were significant versus baseline for both groups. However, a statistically significant difference was observed between the results obtained with LPC and those obtained with pentoxifylline, which was in favour of LPC. Mean PWD increased by 78% in the LPC group vs 30% in the pentoxifylline group (p < 0.001), mean pain score decreased by 83 vs 46% (p < 0.001), and mean ulcer size decreased by 48 vs 25% (p < 0.001).ConclusionsLPC, which has already been shown to produce beneficial effects in the treatment of the chronic phase of peripheral vascular disease, was also found in this study to have greater effects in delaying disease progression than pentoxifylline, a drug that has been extensively tested for this indication. LPC, therefore, appears to be a promising treatment option in patients with peripheral arterial disease and should be further explored in large randomised, long-term controlled trials.

Effects of long-term hormone replacement therapy on arterial wall thickness ,lipids and lipoproteins ,fibrinogen and antithrombin III

We aimed to study the effects of hormone replacement therapy (HRT) in menopausal women on lipoproteins ,blood coagulation ,arterial blood pressure and markers of atherosclerosis. A total of 186 postmenopausal women were studied; 98 used HRT (0.625 mg 17 β-estradiol plus 10 mg progestin) and were followed for 48 months ,and were matched with 98 women without therapy. Low-density lipoproteins ,high-density lipoproteins ,triglycerides ,antithrombin III ,systolic and diastolic arterial pressure and intima–media thickness were measured at 6 ,12 ,24 ,38 and 48 months. In users of HRT ,we found a significant reduction of the lipoproteins ,triglycerides ,systolic and diastolic pressures and intima–media thickness; however ,we found an increase in high-density lipoproteins and anthitrombin III in comparison with non-users. This study has shown a protective effect of HRT on such risk factors and on certain markers of atherosclerosis.