Effects of gemfibrozil on insulin sensitivity and on haemostatic variables in hypertriglyceridemic patients.

In order to assess the efficacy of gemfibrozil on lipid and haemostatic parameters in patients with plurimetabolic syndrome, a multicenter double-blind placebo controlled, parallel study was carried out in 56 patients with primary hypertriglyceridemia and glucose intolerance. These patients had elevated PAI activity and antigen and t-PA antigen levels at rest and after venous occlusion. Gemfibrozil reduced plasma triglyceride levels (P<0.001), whereas it increased free fatty acids (P<0.05) and high density lipoprotein cholesterol levels (P<0.05). In those patients reaching normalization of plasma triglyceride levels (triglyceride reduction > or =50%) (n=15), insulin levels (P<0.05) as well as the insulin resistance index were reduced by gemfibrozil treatment, suggesting an improvement of the insulin resistance index in this patient subgroup. Gemfibrozil treatment did not affect plasma fibrinolysis or fibrinogen levels, despite marked reduction of plasma triglycerides and improvement of the insulin sensitivity associated with triglyceride normalization.

TAT, F1 + 2, and D-dimer levels in patients after coronary angiography with nonionic or ionic contrast media or after cardiac catheterization.

The prothrombotic effects of nonionic contrast media (NICM) have been evaluated in both biological and clinical studies. The question of whether there is a higher risk of thromboembolism during angiography with NICM than with ionic contrast media (ICM) has not yet been answered, nor has the precise role of the angiographic procedure per se in such complications been determined. The present study was performed to compare in vivo the potential prothrombotic effects during cardiac angiography of an NICM with those of an ICM, to estimate the effects of the procedure per se, and to assess how long these effects might be maintained. We measured blood levels of three markers of activation of blood coagulation: thrombin-antithrombin III (TAT) complexes, prothrombin fragment 1 + 2 (F1 + 2), and the split product of fibrin, D-dimer, before and after coronary angiography in three groups of patients. In group 1, 14 patients underwent coronary angiography with the NICM iopamidol 370. In group 2, 10 patients underwent coronary angiography with the ICM ioxaglate. In group 3, 10 patients were evaluated immediately after cardiac catheterization, before the injection of contrast material, as controls. No statistically significant differences between the three groups were found in TAT, F1 + 2, or D-dimer levels at different times before and after coronary angiography. There was a trend toward a transient increase in TAT levels after coronary angiography with iopamidol, which at first suggested a possible brief activation of hemostasis with this NICM, but a similar trend was also seen in the control group. We hypothesize that not only the type of contrast material, but also the angiographic procedure per se and patient-related factors all play roles in determining a prothrombotic state during coronary angiography.

Effects of two different HMG-CoA reductase inhibitors on thromboxane production in type IIA hypercholesterolemia.

Many studies have found that familial hypercholesterolemia, a hyperlipoproteinemia associated with premature atherosclerosis, is characterized by enhanced platelet aggregation. This study was undertaken to measure the urinary excretion of the two main urinary thromboxane B2 (TXB2) metabolites (2, 3-dinor-TXB2 and 11-dehydro-TXB2) in 20 patients affected by familial hypercholesterolemia treated for one month with 40 mg/day of pravastatin (10 patients) in comparison to 10 normocholesterolemic subjects. After a run-in period, the type II A patients showed total cholesterol levels (296 +/- 32 mg/dL) significantly higher (P < 0.001) than those of control subjects (155 +/- 46 mg/dL). The urinary concentrations of 11-dehydro-TXB2 and 2,3-dinor-TXB2 also significantly differed (P < 0.001) between control group (1,463 +/- 1,440 and 386 +/- 447 pg/mg urinary creatinine) and treated patients (3,536 +/- 2,112 and 914 +/- 572 pg/mg urinary creatinine). At baseline there was a positive correlation between total cholesterol (TC) levels and urinary TXB2 metabolite concentrations (2,3-dinor-TXB2 r = 0.61, P < 0.02; 11-dehydro-TXB2, r = 48, P < 0.05), but not between low-density-lipoprotein cholesterol (LDL-C) and the urinary compounds. At the end of a four-week treatment. TC and LDL-C had decreased significantly from the baseline levels, by 27% and 30% in the fluvastatin group (P < 0.01) and by 23% and 31% in the pravastatin group (P < 0.01), with no significant difference between the two groups. After the two treatments with HMG-CoA reductase inhibitors, there was no statistically significant reduction of the urinary metabolite levels. In addition, the positive correlation seen at baseline between TC and TXB2 metabolites was no longer present. In accord with previous studies, we found a significant correlation between TC levels and TXB2 metabolites concentrations in type II A hypercholesterolemic patients. Although, short-term treatment with two statins reduced TC levels, it did not change the thromboxane metabolite excretion.

Effects of fluvastatin and pravastatin on lipid profiles and thromboxane production in type IIa hypercholesterolemia.

The aim of this study was to assess the effects of fluvastatin and pravastatin on lipid profiles and urinary thromboxane (TX) A2 metabolites (11-dehydro TXB2 and 2,3-dinor TXB2) in patients with type IIa hypercholesterolemia. A total of 20 patients (13 men, 7 women; mean age 53 +/- 9 years) with primary type IIa hypercholesterolemia (Fredrickson's classification) in a 4-week, double-blind, parallel-group study were randomized to fluvastatin or pravastatin, both at 40 mg once daily (at bedtime), after a single-blind, 4-week, placebo run-in period. Total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides were measured after placebo (baseline) and after 4 weeks of double-blind treatment. Thromboxane metabolites were measured at the same time points, using an enzyme immunoassay kit, in 12 hr urine samples. At baseline, the mean +/- SD levels of total cholesterol, LDL-C, triglycerides, and HDL-C were: 292 +/- 23, 213 +/- 47, 186 +/- 119 and 41 +/- 17 mg/dL with fluvastatin; and 301 +/- 40, 212 +/- 40, 150 +/- 124 and 43 +/- 10 mg/dL with pravastatin, respectively. Baseline thromboxane-metabolite levels were positively and significantly (p < 0.04) correlated with levels of total cholesterol, but not LDL-C. Compared with baseline, total cholesterol and LDL-C were significantly (p < 0.01) decreased by 27% and 30% with fluvastatin, and by 23% and 31% with pravastatin, respectively. HDL-C increased from 41 +/- 17 to 59 +/- 25 mg/dL with fluvastatin, and from 43 +/- 10 to 46 +/- 12 mg/dL with pravastatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipoprotein (a) and fibrinolytic system in liver cirrhosis. Coagulation Abnormalities in Liver Cirrhosis (CALC) Study Group.

Several observations have suggested that lipoprotein (a) (Lp(a)) is a risk factor for coronary artery disease because of potential interference with fibrinolysis secondary to its activation of plasminogen. However, there are few data on the possible role of Lp(a) in liver cirrhosis. The present study was carried out, to better elucidate its relationship to the fibrinolytic system in liver cirrhosis. We studied the plasma levels of Lp(a) and the fibrinolytic parameters of 95 patients with liver cirrhosis (57 men, 38 women, aged 26-81). Patients in Child-Pugh class C (n = 32) had significantly lower levels of Lp(a) than those in class B (n = 45), and the class B had lower Lp(a) values than class A (n = 18) (1.4 (0.0-3.7) vs 2.9 (0.0-6.1) vs 3.4 (1.8-5.5); the data are log-transformed). Alpha-2-antiplasmin and plasminogen, had patterns similar to those of Lp(a), tissue plasminogen activator (t-PA) was significantly increased only in class C (class A: 7.5 +/- 5.8 ng/ml; class B: 10.8 +/- 7.7 ng/ml; class C: 19.1 +/- 11.3 ng/ml). Patients with systemic hyperfibrinolysis (cross-linked fibrin degradation products, XDP > 200 ng/ml) also had lower levels of Lp(a) than those without 1.6 (0.0-4.4) vs (0.0-6.1); p = 0.0002. There was a significant correlation between Lp(a) and plasminogen (r = 0.43; p = 0.001). Lipoprotein (a) progressively decreases as liver cirrhosis worsens but it appears unlikely to be involved in causing the hyperfibrinolytic state often observed in advanced liver cirrhosis, in which there are marked abnormalities of several other fibrinolytic parameters, also including increased t-PA and decreased inhibitors.

Plasma levels of tumor necrosis factor and endothelial response in patients with chronic arterial obstructive disease or Raynaud's phenomenon.

Tumor necrosis factor alpha (TNF-alpha) is a cytokine that affects endothelial cells' function by changing their antithrombotic potential to a net procoagulant effect. Only a few data have so far been reported for the pathophysiologic role of TNF in vascular diseases in the involvement of microvessels and/or macrovessels and a prothrombotic state. In the present study the authors evaluated plasma TNF (and interleukin-1) levels in 20 patients with chronic arterial obstructive disease (CAOD) with intermittent claudication and 10 CAOD patients with more severe disease (pain at rest/skin ulcers). In addition, they studied 10 patients with Raynaud's phenomenon (RP), suspected to be secondary to a collagen disease. The control group consisted of 20 subjects matched for sex and age with the three groups of patients. TNF levels were assayed by enzyme-linked immunosorbent assay. The antigen levels of von Willebrand factor (vWF), tissue plasminogen activator (t-PA), and its inhibitor (PAI) were also determined as markers of release from the endothelium, while the fragment 1 + 2 of prothrombin (F1 + 2) and thrombin-antithrombin III (TAT) complexes were assessed as indexes of systemic thrombin generation. TNF levels were significantly higher in both groups of CAOD patients than in controls or RP patients, and the same was true for vWF. t-PA was significantly higher only in the CAOD subjects with more severe disease. No differences among groups were seen in PAI antigen/activity or thrombin generation. When data were corrected for age, TNF no longer differentiated CAOD patients from controls and RP subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet and endothelial response with trapidil in patients with peripheral obliterative arteriopathy.

The activity of trapidil, an antiaggregating agent with PDGF antagonist properties, was investigated in order to verify its possible modulating effect in the endothelial and platelet activation. PDGF, t-PA, PAI-1 and ET-1 plasma levels were measured before and after a 2 month treatment period with trapidil 200 mg tablets bid or placebo in 30 patients affected by POA in Fontaine stage II. PDGF and PAI-1 significantly (p < 0.05) increased in the placebo group, and PDGF also in the comparison between treatments (p < 0.05). Aggregation data demonstrate an absence of Ca++ antagonist action of trapidil. The results of this study suggest that trapidil can interfere with the combined vascular and platelet response in atherogenesis.

Platelet-derived growth factor (PDGF) in patients with different degrees of chronic arterial obstructive disease.

Platelet activation and platelet-derived growth factor (PDGF) play a pivotal role in the pathogenesis of atherosclerosis. Evidence has been accumulating that in the evolution of chronic arterial obstructive disease (CAOD) platelets are also crucially important. The aim of the present study was, therefore, to assess plasma levels of PDGF in patients with different degrees of CAOD according to Fontaine. Twenty patients (17 men, 3 women, mean age sixty-eight +/- seven years) with intermittent claudication (Fontaine stage II) entered the study and their PDGF levels were assessed by radioimmunoassay. Ten additional patients (7 men, 3 women, mean age seventy-three +/- seven years) with more severe CAOD (leg pain at rest/skin ulcers) were also studied. Ten healthy subjects (6 men, 4 women, mean age fifty-four +/- six years) comprised the control group. Patients in stage II were reinvestigated after sixty days of a "training" procedure. Patients with both intermittent claudication and more severe disease had higher levels of PDGF than controls (controls 165.9 +/- 119.1 pg/mL; Fontaine stage II 403.5 +/- 218.4; Fontaine stage III/IV 578.1 +/- 637.2: ANOVA P = 0.04) with no difference between the two groups of patients. After the training period, PDGF levels were significantly higher than at baseline (863.7 +/- 819.6 pg/mL vs 403.5 +/- 218.4) but without significant improvement of physical performance. The elevation of PDGF levels in blood from CAOD patients could be the result of marked platelet activation due to interaction with a widely damaged peripheral vasculature. The same was not true for coronary heart disease, in which normal values of PDGF in venous blood were found.(ABSTRACT TRUNCATED AT 250 WORDS)

Need to expand microvascular investigation of patients with Raynaud's phenomenon of different etiology: clinical patterns of 106 consecutive patients.

The differential diagnosis of Raynaud's Phenomenon (RP) is still problematic because of the wide variety of underlying etiological possibilities. Therefore, the diagnostic screening of patients requires easily reproducible, rapid and reliable tests to find those cases of RP secondary to a connective tissue disorder. The present study of 106 consecutive RP patients was carried out by using a combination of clinical examination, biomicroscopy of fingernail folds and bulbar conjunctiva (with scoring of vascular damage), plus the assessment of antinuclear antibodies on HEP2 cells. On the basis of the reported findings, it can be concluded that patients with RP secondary to collagen disease or so suspected also show abnormalities of the conjunctival microcirculatory bed. Patients with both primary and suspected secondary RP are significantly younger at the time of first diagnosis than patients with collagen disease-associated RP.

t-PA, PAI, and protein C before and after vascular occlusion of the upper limb in patients with Raynaud's phenomenon.

Tissue plasminogen activator (t-PA) and its inhibitor (PAI) were assessed in venous blood drawn before and after venous occlusion (bvo, avo) for 33 patients with Raynaud's phenomenon (RP), 14 with primary RP (PRP), 9 with suspected secondary RP (SSRP), and 10 with definite collagen disease and secondary RP (SRP). There were significant differences in PAI values avo between PRP (and controls), SSRP, and SRP. PAI activity decreased significantly avo only in controls and in PRP, and there was significant t-PA antigen elevation avo in the same groups. In addition, since PAI is neutralized by activated protein C (PC), both PC antigen and PC activity were assessed avo and bvo. PC Ag remained unchanged in all groups, with PC activity significantly lower than controls in SRP and SSRP. Finally the authors looked for interference of anticardiolipin antibodies (ACA) and lupus-like anticoagulant (LAC) with the PC system in collagen disease-associated RP. Specific IgG ACA were found in only 1 patient with SRP. In conclusion, there is an endothelial derangement, involving t-PA release and PAI, in SSRP and SRP patients. The reduced PC activity in these latter groups appears to be due to increased PAI influence rather than to ACA/LAC.

Deficient fibrinolytic response in patients with Raynaud's phenomenon and its correction with defibrotide.

Twenty outpatients presenting with Raynaud's phenomenon secondary to clinical or preclinical inflammation of connective tissue were treated orally with defibrotide 400 mg three times daily or a matching placebo in a randomized double-blind study. The test product defibrotide (a polydeoxyribonucleic acid compound of animal origin with demonstrated profibrinolytic activity when administered parenterally) was administered orally for 3 weeks in order to explore its effects on the parameters of extrinsic fibrinolysis before and after venous stasis. The antigen of t-PA and its inhibitor PAI, free and total, and the biologic activity of PAI were assayed in basal conditions and after treatment. Although a marked increase of t-PA was seen with the active treatment, PAI activity was significantly reduced by defibrotide. Immunoreactive PAI was not significantly modified by treatment, even though it dropped considerably after venous stasis in the defibrotide group. Thus, the disturbance of endothelial function that seems to occur in vasculitis and in Raynaud's phenomenon secondary to inflammation of connective tissue (or so suspected to be) would constitute the basis of a disturbance of fibrinolysis, which oral defibrotide seems able to correct. Further studies are warranted to define the clinical effectiveness of this treatment in patients with Raynaud's phenomenon.

Effects of ticlopidine and indobufen on platelet aggregation induced by A23187 and adrenaline in the presence of different anticoagulants.

As Ca2+ is known to play a fundamental role in platelet function, the effect of combining two platelet aggregating agents (adrenaline and the ionophore A23187) with different effects on Ca2+ was studied at levels subthreshold for aggregation using platelet-rich plasma from eight atherosclerotic patients. Adrenaline lowered the A23187 threshold required to induce aggregation. The effects of treating patients with the antiplatelet agents, indobufen and ticlopidine, on A23187 and adrenaline induced aggregation of platelets prepared in hirudin or sodium citrate was also evaluated. Aggregation was also studied using platelets resuspended in Ca2(+)-free and Ca2(+)-enriched Tyrode solution. Before treatment hirudin treated platelet-rich plasma, which has physiological extraplatelet Ca2+ levels, was more sensitive to A23187 and adrenaline than was citrated platelet-rich plasma, which has suppressed Ca2+ levels. Ticlopidine significantly raised the concentration of A23187 required to induce aggregation in citrated but not hirudin treated platelet-rich plasma. Indobufen did not significantly affect A23187 induced aggregation. Ticlopidine acts by inhibiting the glycoprotein IIb-IIIa complex on the platelet membranes. Low levels of extracellular Ca2+ and ticlopdine may act synergistically to reduce the aggregatory response of stimulated platelets.

Comparative dose study of a theophylline sustained-release tablet formulation after repeated administrations.

Two different doses of a sustained-release tablet formulation of theophylline were administered to two groups of patients affected by chronic obstructive pulmonary disease. Pharmacokinetic parameters were determined after a single administration of the drug. In this experiment, the theophylline plasma levels were determined 1, 2, 4, 8, 12 and 24 h after the drug administration. In another experiment, the patients received the drug "once-daily", in the morning, for nine consecutive days. Plasma theophylline levels were monitored 24 h after the first administration and twice daily on days 3, 6 and 9. Patients receiving 700 mg/day showed theophylline levels ranging from 8.49 +/- 1.04 micrograms/ml to 20.99 +/- 2.09 micrograms/ml. In this group theophylline concentrations were found to be greater than 10 micrograms/ml also 24 h after the tablets' administration. These data show that in case of single daily theophylline administration an high dosage is necessary to maintain the drug concentration within the range of therapeutic levels.

Increased monocyte procoagulant activity (tissue factor) in patients with essential mixed cryoglobulinemia.

Procoagulant activity (PCA) of peripheral blood mononuclear cells was studied in vitro in 14 consecutive patients with essential mixed cryoglobulinemia (EMC). Mononuclear cells tested immediately after isolation expressed significantly higher PCA than cells from a matched control group (P less than 0.01). PCA generated by patients' cells after incubation at 37 degrees C for four hours without any stimulant was significantly higher than that produced by control cells (P less than 0.001). Lower mononuclear cell PCA was observed in the subgroup of patients treated with low doses of prednisone than in untreated patients. In two patients given high-dosage prednisone, cell PCA was markedly reduced. These findings suggest that mononuclear cells may be activated for PCA production in vivo by cryoglobulins or other unknown stimuli. Mononuclear phagocytes, by producing PCA in vivo, might be directly implicated in the local fibrin deposition in tissue lesions of EMC.