Controlled evaluation of pantethine, a natural hypolipidemic compound, in patients with different forms of hyperlipoproteinemia.

Pantethine (P), the stable disulphate form of pantetheine, major component and precursor of coenzyme A, was evaluated within a double-blind protocol (8 weeks for P or for a corresponding placebo) in 29 patients, 11 with type IIB hyperlipoproteinemia, 15 with type IV, and 3 with an isolated reduction of high density lipoprotein cholesterol (HDL-C) levels. In type IIB patients, P (300 mg t.i.d.) determined a highly significant lowering of plasma total and low density lipoprotein (LDL) associated cholesterol (-13.5% for both parameters). In the same patients, HDL-C levels increased about 10% at the end of treatment. Switching from P to placebo was associated with a rapid return to the baseline cholesterolemia. Both in type IIB and type IV patients, plasma triglyceride levels were reduced around 30%, when P was given as the first treatment; when it was preceded by placebo, reductions were less striking (respectively, -17.8% for type IIB and -13.0% for type IV, at the end of P treatment). HDL-C levels were not increased by P, either in type IV, and in the patients with low HDL cholesterolemia. In type IV, LDL cholesterol levels showed a variable response to P: they tended to increase when below 132 mg/dl, prior to treatment, and to be reduced when above this level. This study provides evidence for a significant hypocholesterolemic effect of P, a natural compound free of overt side effects. It also indicates that P may raise HDL-C levels in type IIB patients, while moderately reducing triglyceridemia.

Plasma homocysteine and folate are related to arterial blood pressure in type 2 diabetes mellitus.

The aim of this study was to assess the relationship between homocysteine (tHcy), folate and vitamin B12 levels, urinary albumin excretion, and arterial blood pressure in patients with non-insulin-dependent diabetes mellitus (NIDDM). Our study was carried out in 33 NIDDM patients (16 men, 17 women) and 16 healthy volunteers as controls (seven men, nine women). Fasting and postmethionine load plasma tHcy levels were assessed, together with folate, vitamin B12, and urinary albumin excretion levels. In NIDDM patients, there were correlations between folate and mean arterial pressure (r = -0.352, P = .046), folate and systolic blood pressure (r = -0.437, P = .013), folate and vitamin B12 (r = 0.499, P = .004), tHcy and vitamin B12 (r = -0.348, P = .04), ln tHcy and ln folate (r = -0.404, P = .01), and, lastly, between tHcy, either fasting or postload, and urinary albumin excretion. Patients with elevated tHcy levels had significantly higher diastolic blood pressure (P = .04) and mean arterial pressure (P = .03). Otherwise, higher folate values were associated with lower systolic blood pressure (P = .004) and mean arterial pressure (P = .02). In addition, NIDDM patients with complications presented higher tHcy basal values than the group without complications (P = .003). A particular propensity of such patients towards endothelial dysfunction could explain the presence of correlations between these metabolic parameters and arterial blood pressure.

Fasting and post-methionine load homocyst(e)ine values are correlated with microalbuminuria and could contribute to worsening vascular damage in non-insulin-dependent diabetes mellitus patients.

The study aim was to assess the relationship between homocyst(e)inemia and microalbuminuria in non-insulin-dependent diabetes mellitus (NIDDM) patients. The study was performed on 33 NIDDM patients (16 males and 17 females), and 16 healthy control subjects (seven males and nine females). Plasma fasting and post-methionine load homocyst(e)ine (tHcy), together with other parameters that could modify tHcy levels, were assessed. There were no significant differences between NIDDM patients and controls for fasting tHcy (8.12 +/- 3.17 v 7.19 +/- 2.40 micromol/L) and post-methionine load tHcy (26.51 +/- 11.50 v 25.06 +/- 10.76 micromol/L). Moreover, there was a significant correlation between urinary albumin excretion (UAE) and fasting tHcy (r = .340, P = .05) and post-methionine load tHcy (r = .502, P = .004) in NIDDM patients. Fasting tHcy was correlated both with post-methionine load tHcy (r = .429, P = .01) and with vitamin B12 (r = -.349, P = .04) in NIDDM patients. Microalbuminuric NIDDM patients had higher fasting tHcy (9.05 +/- 3.83 micromol/L) than normoalbuminurics (7.12 +/- 1.95 micromol/L). In addition, NIDDM patients with complications presented higher fasting tHcy values than the group without complications (9.61 +/- 3.34 v 6.53 +/- 2.09 micromol/L, Kolmogorov-Smirnov two-sample test for nonparametric data [KS] = 1.794, P = .003), without any other significant differences in the parameters considered. tHcy could be an important risk factor worsening the prognosis in NIDDM patients, especially microalbuminuric patients. Microalbuminuric NIDDM patients could be particularly prone to hyperhomocyst(e)inemia, probably due to endothelial or renal dysfunction with a reduction in the scavenging of tHcy.

Effects of defibrotide after oral and parenteral administration in patients with peripheral obliterative arterial disease (POAD).

Defibrotide (D) a polidesoxyribonucleotidic derivative provided with fibrinolytic and antithrombotic activity has already proven effective when administered by parenteral route in patients with peripheral obliterative arterial disease (POAD). Bioavailability studies gave evidence that the drug is absorbed by 50-70% when administered orally. Thus, aim of this trial was to evaluate whether the drug might exert similar clinical and biological effects after oral/parenteral dosing in a 2:1 ratio. This was a randomized cross-over study including 17 out patients with POAD (Leriche stage II). D was administered by oral (400 mg b.i.d.) and intramuscular route (200 mg b.i.d.), both treatments lasting 15 days. In basal conditions and at the end of both treatments the following evaluations were made: (1) absolute walking distance (tread mill); (2) Doppler ultrasonographic examination (Winsor index); (3) strain-gauge plethysmography (rest flow and peak flow). In addition in the same occasions plasma samples were collected for the assessment of plasminogen (chromogenic assay) and fibrinolytic activity (fibrin plates). Defibrotide administration was followed by a significant increase in walking distance both after oral and parenteral administration [basal conditions (IRL): 232.7 +/- 23.0 meters; oral: 273.1 +/- 28.1 m; i.m.: 277.9 +/- 26.8 m, p less than 0.01 - (IRA) basal conditions: 380.1 +/- 25.6; oral: 437.1 +/- 31.5 m; i.m.: 442.5 +/- 34.0 m, p less than 0.01] and by a significant increase in peak flow (basal conditions: 9.66 +/- 1.04; oral: 10.90 +/- 0.90; i.m.: 11.12 +/- 0.98, p less than 0.05), while Winsor index and rest flow were unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of indobufen on whole blood platelet aggregation recorded in the morning in patients with ischaemic heart disease.

Platelets are involved in the progression of coronary atherosclerosis as well as in the development of the acute precipitating event. Recently, it has been shown that normal subjects present increased platelet aggregation between 6.00 a.m. and 9.00 a.m.; epidemiological studies have shown a higher incidence of myocardial infarction between these times. This study evaluated, by an impedence method using whole blood, platelet aggregation induced by ADP (3 microM) and collagen (2 microM/ml). Measurements were made at 6.00 a.m., 9.00 a.m. and 12.00 noon, the day before and the day after evening administration of 200 mg indobufen, a platelet aggregation inhibitor, in 12 patients with ischaemic heart disease. Patients showed a significant increase of platelet aggregation between 6.00 a.m. and 9.00 a.m. which was inhibited by the prior evening administration of indobufen.

[Platelet aggregation in whole blood with the impedance method in subjects with non-complicated essential arterial hypertension]. / L'aggregazione piastrinica su sangue intero con metodo impedenzometrico nei soggetti portatori di ipertensione arteriosa essenziale non complicata.

Arterial hypertension is considered a major risk factor in atherosclerosis in the pathogenesis of which platelet activity plays a fundamental role. However the data in the literature on platelet function in arterial hypertension do not always agree. The present study was conducted on whole blood, using the impedance metering technique to assess platelet aggregation induced by ADP (10 pg) and collagen (2 mg/ml) in 15 patients with uncomplicated essential hypertension and 25 healthy controls. Analysis of the data shows a statistically significant difference between the aggregation curves of the hypertensive and the healthy subjects with excessive platelet aggregation in those suffering from uncomplicated arterial hypertension.

[Platelet aggregation in whole blood and thromboxane B2 in type II and IV hyperlipidemia]. / Aggregazione piastrinica su sangue intero e trombossano B2 nelle iperlipemie di tipo II e IV.

Platelets play an essential role in the pathogenesis of atherosclerosis; by impedance method we valued in whole blood platelet aggregation induced by collagen in 40 healthy subjects and in 40 type II and type IV hyperlipemic subjects. Meanwhile by radioimmunoassay we dosed thromboxane B2, a stable product of thromboxane A2, released by platelets during activation, in 7 healthy subjects and 25 hyperlipemic subjects. The statistical investigation put in evidence that at higher plasmatic levels of cholesterol, triglycerides and LDL correspond a greater platelet sensitivity to the aggregating agent, while the opposite happens to higher levels of HDL. The dosage of thromboxane B2 put in evidence a moderate increase in hyperlipemic as to healthy subjects, probably pointing to a state of platelet activity.

[Increase in erythrocyte and plasma viscosity in patients with atherosclerotic vasculopathy of different sites]. / Aumento della viscosità eritrocitaria e plasmatica in pazienti affetti da vasculopatia aterosclerotica a diversa localizzazione.

Peripheral atherosclerotic arteriopathies are characterised by increased blood viscosity and, according to some, by a reduction in red blood cell deformability. Red blood cell viscosity was studied in 40 atherosclerosic patients (14 carotid and 26 aortoiliacofemoral lesions). All patients were subjected to the standard diagnostic examination (Doppler velocimetry, etc.). Fifty healthy non-smokers of the same sex and 20 heavy smokers were studied as controls. The viscosity of the whole blood, and plasma and blood fibrinogen were assayed. In studying erythrocyte viscosity, cells poor in leucocytes and platelets suspended in a saline phosphate buffer were employed. The atherosclerotic patients presented significantly higher mean levels of erythrocyte viscosity (p less than 0.01) and the increase in plasma viscosity and blood fibrinogen was also statistically significant. The viscosity of the whole blood was also increased in these patients (p less than 0.001). The increase in blood viscosity in subjects with peripheral arteriopathies therefore appears to be attributable to the plasma and to rheological alterations in the red blood cells.

[Blood, plasma, erythrocyte viscosity and index of erythrocyte filtration in subjects with hyperlipemia]. / La viscosità ematica, plasmatica, eritrocitaria e l'indice di filtrazione eritrocitario in soggetti affetti da iperlipemia.

40 hyperlipidaemic patients (26 type II a and b, 14 type IV) and 50 healthy controls were studied. The patients were not suffering from any other pathology of note and were under no drug treatment. Blood viscosity at natural Ht and at Ht 45% and plasma viscosity were measured. Red blood cell viscosity and deformability was studied on washed red cells, poor in leucocytes and platelets and suspended in a saline phosphate buffer. The patients with hyperlipidaemia had blood viscosity higher than healthy people. Red blood cell and plasma viscosity were higher in subjects with hyperlipidaemia. There was no difference in the filtration index between the people under study. The increased blood viscosity found in people with hyperlipidaemia appears to be attributable to changes in both the plasma and the erythrocytes.

[Hemorrheologic disorders of red cells in subjects at risk for atherosclerosis]. / Le alterazioni emoreologiche del globulo rosso in soggetti a rischio per aterosclerosi.

Cigarette smoking, hypercholesterolaemia, hypertriglyceridaemia, are all known risk factors for atherosclerotic vascular lesions. Often they are associated with alterations mainly due to increased haematocrit (smoking) or to the influence of triglycerides and cholesterol on the erythrocyte membrane or plasma viscosity. In order to eliminate these factors, washed red blood cells, poor in leucocytes and platelets, in a suspension with phosphate saline buffer were studied. 20 heavy smokers, 40 patients with hyperlipidaemia (26 II a or b; 14 IV) and 50 healthy people were considered. Red blood cell viscosity was calculated at 4 shear rate between 0.37 and 69.5 sec-1. Red blood cell deformability, as an indicator of cell filtration through Nucleopore membranes was also studied. There was no difference in the filtration index among the subjects under study. Red blood cell viscosity increased in smokers and in patients with hyperlipidaemia.

[Hemorrheologic disorders in obese patients. Study of the viscosity of the blood, erythrocytes, plasma, fibrinogen and the erythrocyte filtration index]. / Le alterazioni emoreologiche negli obesi. Studio della viscosità ematica, eritrocitaria, plasmatica, del fibrinogeno e dell'indice di filtrazione eritrocitaria.

Risk factors for atherosclerosis are often associated with haemorheological changes. On this point, obesity (recently advocated as an independent risk factor) was not much studied and with not univocal results. We have studied 70 obese patients (BMI greater than 30) and 50 healthy subjects (BMI less than 25). Among obese 26 had no more pathologies, 29 had hypertension, 3 suffered from ischemic heart disease, 3 suffered from occlusive arteriopathy, 9 were hyperlipidemic, 10 were smokers. We determined plasma viscosity and whole blood viscosity (at haematocrit corrected to 45% too). Washed erythrocytes, poor in leucocytes and platelets and resuspended in phosphate-buffered saline, were used for study of erythrocyte viscosity and deformability. Obese patients showed raised mean blood viscosity values when compared to healthy controls (p less than 0.01); an even more significant increase (p less than 0.001) was found concerning plasma viscosity and fibrinogen. Erythrocyte viscosity and red blood cell filterability index did not show any significant difference. We found no significant correlation between viscosity values and presence of hypertension, hyperlipidemia and smoking habit among obese. In conclusion, the higher vasculopathy incidence might be caused by an increase in blood viscosity, mostly due to plasmatic component. This fact appears to be independent from the presence of atherosclerosis complications or other risk factors.

[Platelet aggregation in whole blood and prostacyclin in hyperlipemia types II and IV]. / Aggregazione piastrinica su sangue intero e prostaciclina nelle iperlipemie di tipo II e IV.

Platelets play an essential role in the pathogenesis of atherosclerosis. Prostacyclin is a strong physiological inhibitor of platelets aggregation; prostacyclin indeed is involved in the regulation of platelet interactions with vessel walls and is considered to play a major role in the homeostatic balance. The impedance aggregometry allows the evaluation of platelet aggregation in whole blood. We valued platelet aggregation in whole blood induced by ADP (10 microM) in 40 healthy subjects and in 40 type II and type IV hyperlipemic subjects. Meanwhile by radioimmunoassay we dosed 6-keto PGF1 alpha, a stable product of prostacyclin, in 7 healthy subjects and in 33 hyperlipemic subjects. The statistical investigation put in evidence that at higher plasmatic levels of cholesterol, triglycerides and LDL correspond a greater platelet sensitivity to the aggregating agent, while the opposite happens to higher levels of HDL. The dosage of 6-keto PGF1 alpha put in evidence an increase of this substance in hyperlipemic as to healthy subjects, probably as an answer to augmented platelet aggregation.

[Changes in lipid status during pravastatin treatment]. / Modificazioni del quadro lipidico durante trattamento con pravastatina.

Reduced cholesterolemia lowers the risk of ischemic cardiopathy, especially if LDL cholesterol levels are reduced. Today this effect can be achieved using drugs following the discovery of a new class of molecules: statins are specific inhibitors of HMG-CoA-reductase, a key enzyme in cholesterol biosynthesis. These molecules act by modifying the intracellular quota of cholesterol, especially at a hepatocytic level, thus enabling an enhanced expression of those genes responsible for forming receptors for membrane LDL with an increased number of receptors. This leads to a modulation of receptor activity which interferes with LDL uptake, promoting more rapid clearance. The aim of this study was to confirm the efficacy and tolerability of pravastatin when used for long periods in patients with high cholesterol levels, and to compare its activity to that of gemfibrozil.

[Relations between overweight, thrombophilia and cardiovascular risk]. / Relazione tra sovrappeso corporeo, trombofilia e rischio cardiovascolare.

Seventy-one healthy subjects, aged 20 to 60, 19 males and 52 females, body mass index (BMI) 19 to 40, were enrolled in the study. None of them were smokers, or affected by hyperlipidemia, arterial hypertension or impaired glucose tolerance. We measured plasminogen activators inhibitor (PAI) activity, C-peptide levels, plasma fibrinolytic activity. We found a correlation between BMI and plasma fibrinolytic activity (r = -0.382, p less than 0.005), between BMI and PAI (r = 0.353, p less than 0.005), between BMI and C-peptide (r = 0.694, p less than 0.001) and between PAI and C-peptide (r = 0.404, p less than 0.02). Our data show a correlation between obesity and low fibrinolytic activity, probably due to high PAI levels. In obesity impaired fibrinolytic activity, maybe linked to hyperinsulinemia, could induce thrombophilic state.

[Factor VII and cardiovascular risk in obese subjects]. / Fattore VII e rischio cardiovascolare negli obesi.

We investigated whether or not obesity is related to increased factor VII activity. We studied 70 obese subjects (aged 25 to 50 years, 25 males and 45 females, body mass index (BMI): mean +/- SD = 32.44 +/- 5.44) and 33 non-obese subjects (aged 25 to 50 years, 12 males and 21 females, BMI: mean +/- SD = 21.80 +/- 1.70). None of them were smokers or affected by hyperlipidemia, diabetes mellitus, impaired glucose tolerance or arterial hypertension. Factor VII activity was measured by the coagulometric method. We found higher factor VII activity in obese subjects (115.74 +/- 26.10%) than in healthy subjects (98.55 +/- 23.49%, p less than 0.005). Increased factor VII levels could determine a thrombophilic state involved in the genesis of cardiovascular accidents in obesity.

[Changes in morning platelet aggregation in patients with peripheral obliterating arteriopathy after evening administration of picotamide]. / Modificazioni dell'aggregazione piastrinica mattutina in soggetti affetti da arteriopatia obliterante periferica dopo somministrazione serale di picotamide.

Platelets are involved in the progressive pathogenesis of atherosclerosis. It has been shown that there is usually an increase in platelet aggregation between 6 and 9 a.m.; in the present study. in 10 patients suffering from chronic occlusive arterial disease, the impedancemetric method was used to evaluate, in whole blood, platelet aggregation induced by ADP and collagen the day prior to and the day following the evening administration of 300 mg picotamide. Analysis of the data obtained shows, in accordance with the findings of other authors, in increase of platelet aggregation from 6 a.m. to 9 a.m. This increase is suppressed by the evening administration of the anti-aggregant.

[Evaluation of the efficacy and safety of pravastatin in primary hypercholesterolemia]. / Valutazione dell'efficacia e della sicurezza della pravastatina nelle ipercolesterolemie primitive.

Hypercholesterolemia can be a risk factor which engenders coronary heart disease. Today, it seems certain that lowering the cholesterolemia reduces this risk, especially if this reduction is referred to the cholesterol which is linked to the low density lipoprotein, called LDL. It has been demonstrated that the principle way to remove the LDL is by getting it into the hepatocyte through a specific membrane receptor, the research, therefore, has been developed with the aim of pharmacologically modifying the quota of intercellular cholesterol and consequently, in the modulation of the receptivity function by the interference of the LDL uptake, assisting a faster clearance. We can identify a new class of pharmacological drugs, that are the specific inhibitors of the HMGCoA reductase, fundamental enzime in the biosynthesis of cholesterol. This group of inhibitors has recently been enriched by the addition of a new molecule pravastatin. Our task has been to confirm the effectiveness and tolerability of pravastatin, administered for a prolonged period to patients with high levels of cholesterolemia; we have compared it with gemfibrozil, a well-known medicine which has hypocholesterolemic effects. In conclusion, our work, whilst emphasising the expediency of ipolipidic treatment, has undoubtedly proved, that 40 mg of pravastatin in a single evening dose, shows a high degree of efficiency, without side effects. Due to these factors, we can also say that pravastatin prevents, or really induces the regression, of atheroscherotic disease.