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AIDS 08/2000; 14(11):1664-7. · 6.24 Impact Factor
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ABSTRACT: The mechanism for the efficacy of once- or twice-daily subcutaneous injections of low-molecular-weight heparins (LMWHs) for the treatment of venous thromboembolism has been difficult to explain. The confusion exists because the observation from experimental studies that the antithrombin activity of LMWHs is necessary for their antithrombotic effect is inconsistent with the reported short half-life of the antithrombin activity of LMWHs. Previous pharmacokinetic studies were performed with lower doses of LMWHs than have been used in contemporary trials, and antithrombin activity was assessed with the barely sensitive chromogenic assay.
We performed a pharmacokinetic study to compare the relative half-lives of prophylactic and therapeutic doses of LMWHs assessing antithrombin activity with both the chromogenic and a more sensitive assay (plasma thrombin neutralization assay). An eight-way cross-over randomized study in healthy volunteers was performed. Enoxaparin (20 and 40 mg and 1 and 2 mg/kg) and nadroparin (7500 and 10,000 ICU and 225 and 450 ICU/kg) were administered subcutaneously. The maximal peak activity for aPTT ratio was 1.7. A dose-dependent peak activity was found for both antifactor Xa and antithrombin activities. Disappearance time of these activities after the highest dose of both LMWHs was longer than 16 hours. Overall mean antifactor Xa activity half-life was 4.6 hours. Overall mean antithrombin activity half-life was longer than 4 hours.
Our results provide an explanation for the effectiveness of LMWHs administered either once or twice daily. High and sustained plasma antithrombin activity is achieved when LMWHs are administered in therapeutic doses used in contemporary trials with only a moderate prolongation of the aPTT.
Circulation 12/1995; 92(10):2819-24. · 14.74 Impact Factor
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M Marroni,
P Gresele,
G Landonio,
A Lazzarin,
M Coen,
R Vezza,
M S Sinnone, E Boschetti,
A M Nosari,
G Stagni,
G G Nenci,
S Pauluzzi
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ABSTRACT: To determine the effect of interferon-alpha for severe, zidovudine-resistant, HIV-1-related thrombocytopenia.
Prospective, randomized, double-blind, placebo-controlled, multicenter, crossover trial.
Outpatient clinics in Central Northern Italy.
15 sequential patients positive for HIV-1 with platelet counts less than 25 x 10(9)/L who were refractory to 1 month of full-dose (1000 mg/d) zidovudine.
Interferon-alpha (3 million units) or placebo (1 mL saline) three times a week subcutaneously for 4 weeks, followed by a 4-week washout period. Patients were then switched to the alternative treatment for the next 4 weeks, followed by another 4 weeks of washout, and they were randomly assigned to either sequence of treatment. Patients received zidovudine (200 mg three times daily) throughout the study.
The primary end point was the platelet count (measured weekly). Secondary end points were qualitative assessment of the platelet response; bleeding time; p24 antigen in serum; CD4/CD8 counts; beta 2-microglobulin in serum; and platelet-associated IgG.
Interferon-alpha significantly increased platelet counts in the 12 patients who completed the study (baseline level, 15.6 +/- 7.1 x 10(9)/L; after 4 weeks of interferon-alpha therapy, 82.2 +/- 52.2 x 10(9)/L). The estimated increase in the platelet count after interferon-alpha compared with placebo was 60.0 x 10(9)/L (95% CI, 23.2 to 96.8 x 10(9)/L). The increase was already statistically significant after 3 weeks (66.6 +/- 49.7 x 10(9)/L) and remained significantly increased 1 week after discontinuing interferon-alpha therapy (58.2 +/- 45.0 x 10(9)/L). Placebo did not modify the platelet count. The bleeding time was significantly shortened by interferon-alpha. Four of 12 patients who had more serious alterations of some measures reflecting disease severity did not respond to interferon-alpha. No relevant side effects were observed.
Interferon-alpha is a safe and effective treatment for zidovudine-resistant, HIV-related thrombocytopenia.
Annals of internal medicine 10/1994; 121(6):423-9. · 16.73 Impact Factor
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ABSTRACT: Impedance plethysmography (IPG) has high sensitivity and specificity in patients with symptomatic deep vein thrombosis (DVT) while it fails to detect asymptomatic DVT. The aim of this study was to determine whether the features of thrombi such as location, size and occlusiveness could explain the different accuracy of IPG in symptomatic and asymptomatic DVT patients. One-hundred and seventeen consecutive outpatients with a clinical suspicion of DVT and 246 consecutive patients undergoing hip surgery were admitted to the study. In symptomatic patients IPG was performed on the day of referral, followed by venography, while in asymptomatic patients IPG was performed as a surveillance programme, followed by bilateral venography. A venography proved DVT was observed in 37% of the symptomatic patients and 34% of the asymptomatic limbs. A significantly higher proportion of proximal DVTs was found in symptomatic patients than in asymptomatic patients (78% vs 46%; p = 0.001). The mean Marder score, taken as an index of thrombus size, was significantly higher in symptomatic patients than in asymptomatic patients (19.0 vs 9.6; p = 0.0001). A significantly higher proportion of occlusive DVTs was observed in symptomatic than in asymptomatic patients (69% vs 36%; p = 0.001). We conclude that the unsatisfactory diagnostic accuracy of IPG in asymptomatic DVT is due to the high prevalence of distal, small and non occlusive thrombi. Such thrombi are unlikely to cause a critical obstruction of the venous outflow and therefore to produce a positive IPG.
Thrombosis and Haemostasis 09/1993; 70(2):266-9. · 5.04 Impact Factor
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Thrombosis Research 06/1992; 66(2-3):259-64. · 2.44 Impact Factor
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ABSTRACT: Patients admitted for surgical removal of varicose veins were treated in a blinded manner for 48 hours prior to surgery with either placebo, low-dose aspirin (25 mg twice daily), dipyridamole (150 mg twice daily) or both. Segments of vein excised at surgery were incubated with or without sodium arachidonate and subsequent prostacyclin (PGI2) production was measured without knowledge of treatment given. During the first 5 minute period of incubation in the presence of arachidonate, veins from dipyridamole-treated patients demonstrated increased (by 75%) arachidonate-stimulated PGI2 production compared to placebo-treated patients. By contrast, PGI2 production was reduced by 64% by aspirin treatment and 67% by aspirin plus dipyridamole compared to placebo-treated patients (p = less than 0.05). In unstimulated vein segments incubated in the absence of arachidonate, spontaneous PGI2 production during the first 5 minute incubation period was increased 32% following dipyridamole treatment but was unchanged following aspirin treatment. By contrast, unstimulated (spontaneous) PGI2 production in patients treated with aspirin plus dipyridamole was reduced by 57% (p = less than 0.05), compared to both placebo- and aspirin-treated patients, and by 71% (p = less than 0.05) compared to dipyridamole-treated patients. With repeated change of incubation medium, the ability of vein walls to produce PGI2 declined. This exhaustion was not prevented by drug treatment. However, drug effects between patient treatment groups were consistent over successive incubation periods. These results suggest that certain therapeutic benefits that might be achieved by enhancement of PGI2 production from vascular endothelium following dipyridamole treatment may be reduced by simultaneous aspirin treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Thrombosis Research 05/1990; 58(2):109-17. · 2.44 Impact Factor
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ABSTRACT: Twenty-three patients with mild heart failure (I-II NYHA classes) on digitalis and diuretics were assigned to the following treatment in a random and double-blind fashion: ibopamine-captopril, ibopamine-placebo, captopril-placebo, and placebo-placebo. The doses of captopril and ibopamine were respectively 25 mg t.i.d. and 100 mg t.i.d. The incremental exercise time (until exhaustion) and the peak VO2 (oxygen consumption), the indexes of left ventricular function (by echo and nuclear stethoscope) and ventricular arrhythmias (evaluated by prolonged Holter monitoring) were assessed before randomization, at 45 days and at 3 months. Ejection fraction, exercise time, peak VO2, ventricular arrhythmias and heart rate (at rest and during exercise) appeared to be equally unaffected by each treatment. Our results show that ibopamine exerts no significant effects on either heart rate or ventricular arrhythmias and that indexes of left ventricular function are not modified by any treatment in mild congestive heart failure.
Cardiology 02/1990; 77 Suppl 5:36-42. · 1.71 Impact Factor
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ABSTRACT: The effect of dipyridamole on prostacyclin (PGI2) production in the presence or in the absence of sodium arachidonate was examined in human veins collected from otherwise normal subjects undergoing saphenous vein removal. Vein segments, maintained in ex vivo culture, that were removed from subjects treated with dipyridamole for two days prior to surgery synthesized 2.5 times more PGI2 (p less than 0.05) than veins that were removed from placebo-treated subjects when incubated in the presence of arachidonate. This difference decreased progressively when vein segments were washed repeatedly and then re-incubated in the presence of arachidonate. Direct addition of dipyridamole to vein segments incubated in vitro resulted in a dose-dependent increase in PGI2 production when the incubation was carried out in the presence of arachidonic acid. No effect of dipyridamole was observed in experiments performed in the absence of arachidonic acid. A mathematical analysis based on both ex vivo and in vitro experiments of the rate of decline of endothelial cell PGI2 biosynthesis suggested that the elevation of PGI2 with dipyridamole treatment resulted from increased PGI2 synthesis rather than decreased PGI2 catabolism. These data support the hypothesis that dipyridamole both ex vivo and in vitro enhances and prolongs PGI2 production by human vessels.
Biomedica biochimica acta 02/1990; 49(4):263-71.
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ABSTRACT: Beta 2-agonists and theophylline compounds are first line drugs and are extensively used in the treatment of acute bronchial asthma. Beta 2-agonists are continuously expanding as a class of drugs. Recent research has increased the available knowledge of their cardiovascular and metabolic effects. Cardiovascular effects might be due to direct stimulation of beta 2-receptors sited in the atrial muscle. Metabolic effects (i.e. increase in blood glucose, insulin and non-esterified fatty acid (NEFA), decrease in plasma potassium) are, at least partly, a consequence of direct or reflex stimulation. Despite recent progress, slow-release theophylline compounds remain a basic approach to asthma management. Future progress in this field will probably be concerned with a more complete knowledge of 'ultra-slow' theophylline compounds (level of the plasma concentration fluctuation and patient compliance) and more complete results regarding the influence exerted by food (and gastric pH) on the rate and extent of absorption.
The European respiratory journal. Supplement 07/1989; 6:551s-555s.
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ABSTRACT: Ten patients with congestive heart failure (CHF) (NYHA II-IV) on adjusted doses of digitalis and diuretics underwent a careful clinical assessment including an evaluation of exertion dyspnoea and the usual echocardiographic indices of cardiac performance. A cardiopulmonary exercise test with an increment of 20W every 3 minutes was prolonged until exhaustion. Systemic arterial pressure, ECG, VO2, VCO2 and VE were monitored throughout. Gas tensions, plasma catecholamines and lactate were measured in blood samples taken at the first and third minute of each exercise stage. The above measurements were carried out before and after 3 months of treatment with Captopril, 50 mg b.i.d. or t.i.d. A highly significant correlation between arterial lactate and plasma norepinephrine (NE) was observed in each patient during both exercise tests (r = 0.77 to 0.99; p less than 0.05 at least). Left ventricular end-diastolic dimensions were reduced by Captopril (from 69.9 +/- 1.7 to 65.2 +/- 1.4 mm, p less than 0.01) along with a concomitant increase in percent fractional shortening. Most of the patients were reclassified at a lower NYHA class and a significant decrease in dyspnoea score was observed. The exercise time was significantly increased (from 11.2 +/- 1.8 to 12.9 +/- 1.9 min; p less than 0.05), but the peak values of NE, arterial lactate and VO2 were not affected by the treatment. The predicted value of VE at a VCO2 of 1 L/min, regarded as an index of dyspnoea, was significantly decreased by Captopril (from 41.4 +/- 2.9 to 38.9 +/- 2.7 L/min; p less than 0.05). The positive effects of long-term treatment with Captopril on cardiac performance in CHF are confirmed. Sympathetic activity is linked to anaerobic muscular metabolism during exercise and seems to be independent of pharmacological ACE inhibition. The discrepancy between the exercise tolerance and the peak VO2 might be explained by a better utilization of the available energy.
Acta cardiologica 02/1988; 43(5):569-82. · 0.61 Impact Factor
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Chest 11/1987; 92(4):768-9. · 5.25 Impact Factor
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Recenti progressi in medicina 01/1987; 77(12):587-92.
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ABSTRACT: We have undertaken the present study to evaluate the acute effects of propranolol and verapamil on the diastolic function in patients with hypertrophic cardiomyopathy. We used a non imaging isotope device, the nuclear stethoscope, that has been so far mainly employed for assessment of systolic function, although fitted for detecting diastolic filling rates and times as well. Relative cardiac output, ejection fraction, rapid and slow filling times and rates were measured in five patients suffering from hypertrophic cardiomyopathy in basal conditions and 10.20 and 30 minutes after i.v. administration for either propranolol or verapamil, with a time interval of at least 24 hours between the two acute drug studies. With respect to the baseline values only verapamil showed a significant improvement in rapid and maximum filling rates, suggesting that diastolic function is more beneficially affected by Ca-entry blockers rather than beta-blockers in hypertrophic cardiomyopathy.
Giornale italiano di cardiologia 04/1985; 15(3):307-9.
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ABSTRACT: The present study was carried out to test the hypothesis of a possible effectiveness of captopril--an enzymatic inhibitor of both angiotensin II formation and bradykinin degradation--on hypoxic pulmonary hypertension. In 6 patients with this clinical condition, captopril-induced changes in pulmonary hemodynamics were observed after the acute administration of the drug with and without a short period of oxygen therapy at a flow rate sufficient to keep the PaO2 over 60 mm Hg. In our patients, captopril significantly lowered pulmonary arterial pressure and vascular resistance only when combined with oxygen, suggesting that an increase in bradykinin availability and/or a decrease in angiotensin II synthesis might be important factors in reversing pulmonary arterial hypertension only after blunting of the hypoxic stimulus on pulmonary circulation. Moreover, the authors suggest that the employment of vasodilators in the setting of hypoxic pulmonary hypertension should be considered not only as a means of relieving vasoconstriction but also as a possible tool for maintaining cardiac output and, in turn, peripheral oxygen delivery.
Respiration 02/1985; 48(4):296-302. · 2.26 Impact Factor
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ABSTRACT: 1. Nifedipine, a calcium antagonist drug, was given sublingually (10 mg) to seven normal subjects and 19 patients with essential hypertension. In addition, 12 of the hypertensive subjects then received nifedipine (10 mg thrice daily) for 3 weeks. 2. Sublingual administration of nifedipine in hypertensive patients induced a prompt and sustained reduction of blood pressure, without a significant increase of heart rate; in normotensive subjects blood pressure did not change, and heart rate was significantly increased. After chronic treatment, blood pressure remained reduced and heart rate did not rise. 3. Plasma catecholamines and plasma renin activity increased significantly in normotensive subjects after acute administration. 4. After both acute and chronic administration, only plasma noradrenaline was significantly increased in hypertensive patients; in long-term treatment, it was increased in both the lying and standing positions. 5. Nifedipine is an active antihypertensive drug, which may induce some degree of sympathetic activation.
Clinical Science 01/1980; 57 Suppl 5:115s-117s. · 4.61 Impact Factor
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La Clinica terapeutica 04/1977; 80(6):530-6. · 0.27 Impact Factor
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Minerva medica 04/1976; 67(16):1079-83. · 0.90 Impact Factor
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Bollettino della Società italiana di cardiologia 02/1976; 21(9):1525-31.
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ABSTRACT: The present study was carried out to test the hypothesis of a possible effectiveness of captopril – an enzymatic inhibitor of both angiotensin II formation and bradykinin degradation – on hypoxic pulmonary hypertension. In 6 patients with this clinical condition, captopril-induced changes in pulmonary hemodynamics were observed after the acute administration of the drug with and without a short period of oxygen therapy at a flow rate sufficient to keep the PaO2 over 60 mm Hg. In our patients, captopril significantly lowered pulmonary arterial pressure and vascular resistance only when combined with oxygen, suggesting that an increase in bradykinin availability and/or a decrease in angiotensin II synthesis might be important factors in reversing pulmonary arterial hypertension only after blunting of the hypoxic stimulus on pulmonary circulation. Moreover, the authors suggest that the employment of vasodilators in the setting of hypoxic pulmonary hypertension should be considered not only as a means of relieving vasoconstriction but also as a possible tool for maintaining cardiac output and, in turn, peripheral oxygen delivery.
Respiration 08/1970; 48(4):296-302. · 2.26 Impact Factor
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ABSTRACT: Patients admitted for surgical removal of varicose veins were treated in a blinded manner for 48 hours prior to surgery with either placebo, low-dose aspirin (25 mg twice daily), dipyridamole (150 mg twice daily) or both. Segments of vein excised at surgery were incubated with or without sodium arachidonate and subsequent prostacyclin (PGI2) production was measured without knowledge of treatment given. During the first 5 minute period of incubation in the presence of arachidonate, veins from dipyridamole-treated patients demonstrated increased (by 75%) arachidonate-stimulated PGI2 production compared to placebo-treated patients. By contrast, PGI2 production was reduced by 64% by aspirin treatment and 67% by aspirin plus dipyridamole compared to placebotreated patients (p=<0.05). In unstimulated vein segments incubated in the absence of arachidonate, spontaneous PGI2 production during the first 5 minute incubation period was increased 32% following dipyridamole treatment but was unchanged following aspirin treatment. By contrast, unstimulated (spontaneous) PGI2 production in patients treated with aspirin plus dipyridamole was reduced by 57% (p=<0.05), compared to both placeboand aspirin-treated patients, and by 71% (p=<0.05) compared to dipyridamole-treated patients. With repeated change of incubation medium, the ability of vein walls to produce PGI2 declined. This exhaustion was not prevented by drug treatment. However, drug effects between patient treatment groups were consistent over successive incubation periods. These results suggest that certain therapeutic benefits that might be achieved by enhancement of PGI2 production from vascular endothelium following dipyridamole treatment may be reduced by simultaneous aspirin treatment.
Thrombosis Research.
