Chronic metal contamination shapes the size structure of Gammarus fossarum populations in French headwater rivers.

Assessing the effects of multigenerational exposure of aquatic animal populations to chemical contamination is essential for ecological risk assessment. However, beyond rare examples reporting the sporadic emergence of a toxicological tolerance within populations that persist in contaminated environments, conclusive results are even more limited from field studies when it comes to the alteration of life-history traits. Here, we investigated whether long-term exposure to cadmium (Cd) influences size-related life-history traits (i.e., size at puberty, median adult size, maximum size) in Gammarus fossarum, a keystone species of European stream ecosystems. We studied 13 field populations of G. fossarum (cryptic lineage B) living in headwater rivers located in natural areas scattered at a large geographical scale and exposed to contrasted bioavailable Cd contamination levels due to different local geochemical backgrounds. We achieved a detailed description of the physical and physicochemical conditions of the river reaches investigated. Land-use parameters, hydrological characteristics (flow, slope, river width, flow structure, mosaic of substrates), and physicochemical conditions (temperature, conductivity, dissolved oxygen) were measured. Metallic bioavailable contamination was assessed using a standardized active biomonitoring procedure (Gammarus caging). Based on the field demographic census of the 13 populations, our results demonstrated that chronic Cd contamination significantly influences life-history in the G. fossarum species, with a significant reduction in all size traits of populations (size at puberty, median adult size, maximum size). In addition, we confirmed Cd-tolerance in contaminated populations during exposure tests in the laboratory. Various hypotheses can be then put forward to explain the modification of size-related life-history traits: a direct toxic effect of Cd, a cost of Cd-tolerance, or an adaptive evolution of life-history exposed to toxic pressure.

Identification, expression, and endocrine-disruption of three ecdysone-responsive genes in the sentinel species Gammarus fossarum.

Taking advantage of a large transcriptomic dataset recently obtained in the sentinel crustacean amphipod Gammarus fossarum, we developed an approach based on sequence similarity and phylogenetic reconstruction to identify key players involved in the endocrine regulation of G. fossarum. Our work identified three genes of interest: the nuclear receptors RXR and E75, and the regulator broad-complex (BR). Their involvement in the regulation of molting and reproduction, along with their sensitivity to chemical contamination were experimentally assessed by studying gene expression during the female reproductive cycle, and after laboratory exposure to model endocrine disrupting compounds (EDCs): pyriproxyfen, tebufenozide and piperonyl butoxide. RXR expression suggested a role of this gene in ecdysis and post-molting processes. E75 presented two expression peaks that suggested a role in vitellogenesis, and molting. BR expression showed no variation during molting/reproductive cycle. After exposure to the three EDCs, a strong inhibition of the inter-molt E75 peak was observed with tebufenozide, and an induction of RXR after exposure to pyriproxyfen and piperonyl butoxide. These results confirm the implication of RXR and E75 in hormonal regulation of female reproductive cycles in G. fossarum and their sensitivity towards EDCs opens the possibility of using them as specific endocrine disruption biomarkers.

The VO(2)-on kinetics in constant load exercise sub-anaerobic threshold reflects endothelial function and dysfunction in muscle microcirculation.

To propose a test to evaluate endothelial function, based on VO(2) on-transition kinetics in sub-anaerobic threshold (AT) constant load exercise, we tested healthy subjects and patients with ischemic-hypertensive cardiopathy by two cardiopulmonary tests on a cycle ergometer endowed with an electric motor to overcome initial inertia: a pre-test and, after at least 24 h, one 6 min constant load exercise at 90 % AT. We measured net phase 3 VO(2)-on kinetics and, by phase 2 time constant (tau), valued endothelial dysfunction. We found shorter tau in repeated tests, shorter time between first and second test, by persisting endothelium-dependent arteriolar vasodilatation and/or several other mechanisms. Reducing load to 80 % and 90 % AT did not produce significant changes in tau of healthy volunteers, while in heart patients an AT load of 70 %, compared to 80 % AT, shortened tau (delta=4.38+/-1.65 s, p=0.013). In heart patients, no correlation was found between NYHA class, ejection fraction (EF), and the two variables derived from incremental cycle cardio-pulmonary exercise, as well as between EF and tau; while NYHA class groups were well correlated with tau duration (r=0.92, p=0.0001). Doxazosin and tadalafil also significantly reduced tau. In conclusion, the O(2) consumption kinetics during the on-transition of constant load exercise below the anaerobic threshold are highly sensitive to endothelial function in muscular microcirculation, and constitute a marker for the evaluation of endothelial dysfunction.

Factors associated with the development of stable hypertension in young borderline hypertensives.

OBJECTIVES: To identify factors predisposing subjects to the development of stable hypertension and to estimate their relative importance in 70 young patients with borderline hypertension monitored for 10 years. DESIGN: Longitudinal evaluation of the incidence of stable hypertension [diastolic blood pressure (DBP) > 95 mmHg]. METHODS: Patients were examined at baseline by determination of resting blood pressure, intracellular sodium level and individual pressor response to mental arithmetic and to intravenous saline loading. They were re-examined after 10 years to assess the prevalence of established hypertension and the importance of some prognostic variables identified prospectively (age, sex, intracellular sodium level, baseline blood pressure, pressor response to stress and acute salt-sensitivity). RESULTS: The prevalence of sustained hypertension (DBP > 95 mmHg) was 35.8% after 10 years of follow-up study. Subjects developing hypertension were older (26.9 +/- 1.3 versus 21.0 +/- 1.8 years) and showed a higher percentage of family history of hypertension (92 versus 64%) and of acute salt-sensitivity (72 versus 53%). The pressor response to mental arithmetic was greater in patients who developed hypertension (systolic blood pressure 26.9 +/- 1 versus 22.7 +/- 0.9 mmHg, P = 0.005 DBP = 16.6 +/- 0.8 versus 13.1 +/- 0.7 mmHg, P = 0.005), who also showed higher levels of intracellular sodium (30.7 +/- 0.6 versus 27.3 +/- 0.5 mmol/kg, P = 0.001). The same variables were found to be related to the development of hypertension in a multivariate analysis and the concomitant presence of 4-5 risk factors was associated with a reasonable predictive power for the identification of patients at high risk (sensitivity 72%, specificity 67%, predictive accuracy 76%). CONCLUSIONS: The present study demonstrates that borderline hypertensives at high risk of stable hypertension can be identified by the concomitant evaluation of some clinical and cellular characteristics directly related to long-term development of high blood pressure.

1-(2-Alkanamidoethyl)-6-methoxyindole derivatives: a new class of potent indole melatonin analogues.

A new series of indole melatonin analogues, bearing the amido ethyl side chain attached at the N-1 position of the indole nucleus, were synthesized and tested for their affinity for the melatonin receptor isolated from quail optic tecta in a series of in vitro ligand-binding experiments using 2-[125I]iodomelatonin as the labeled ligand. The biological activity was evaluated using two models: effects on the forskolin-stimulated cAMP accumulation in explants from quail optic tecta and evaluation of the GTP gamma S index derived from competition experiments performed in the absence or presence of GTP gamma S. Compounds 2a and 2k-n, obtained by shifting the methoxy group and the ethylamido side chain from the C-5 and C-3 positions of melatonin to the C-6 and N-1 positions of the indole nucleus, exhibited an affinity similar to that of melatonin itself, as well as full agonist activity. Optimization of the C-2 substituent by introducing Br, phenyl, or COOCH3 (2b-d) resulted in a significantly enhanced affinity (in the picomolar range) and improved agonist biological activity. Compounds lacking the methoxy group and bearing an N-alicyclic group (2h-j) behaved as partial agonists or antagonists.

Early and late angiotensin-converting enzyme inhibition in acute myocardial infarction.

Studies in animals and humans have shown that angiotensin-converting enzyme (ACE) inhibitors can prevent or at least attenuate ventricular dilation and remodeling following acute myocardial infarction (MI) and can improve subsequent left ventricular dysfunction, a strong predictor of survival. The question as to which patients will benefit most from ACE inhibitor therapy and the optimal timing of administration of such intervention after the onset of symptoms is still matter of debate, even if it is hypothesized that a greater benefit in terms of remodeling prevention may occur after early administration. However, while it is currently accepted that patients with asymptomatic postinfarctual left ventricular dysfunction can benefit from long-term administration of an ACE inhibitor when therapy is started late, the usefulness of an early administration is still to be clarified. In this setting, the question of early versus late ACE inhibitor treatment has to be related to the different evolving pattern of myocardial infarction with regard to the different degrees of postinfarction ventricular dysfunction and neurohormonal activation, whose extent could influence the effect of ACE inhibition. For example, not all patients with acute MI show progressive ventricular dilation. Early dilation is frequent in patients with anterior localization of necrosis, whereas it is usually not relevant in patients with acute inferior MI. Thus, different postinfarction patterns may differently influence the clinical success of therapeutic interventions, which can be instituted at various stages following acute MI.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo and in vitro studies on modulation of the pineal endocrine function by L-acetyl-carnitine in the rat.

Male Sprague-Dawley rats injected (i.p.) at 1500h with L-acetyl-carnitine in doses of 10, 30 or 90 mg/kg exhibited a notable increase in their pineal and serum melatonin content 1 hr later. Likewise, L-acetyl-carnitine administered in the same dose range induced a significant increase of pineal and serum melatonin content in rats treated at 0100h, following exposure of 30 min to bright white light to suppress endogenous melatonin. Under in vitro experimental conditions, however, 60 min of coincubation of isolated rat pineal glands with L-acetyl-carnitine (10(-5) M) did not result in an elevation in melatonin accumulated in the incubation medium. These results demonstrate that, in vivo, L-acetyl-carnitine can exert a modulatory action on synthesis and release of melatonin, possibly by modifying noradrenergic transmission and signal transduction in the pineal gland.

Effects of the administration of an angiotensin-converting enzyme inhibitor during the acute phase of myocardial infarction in patients with arterial hypertension. SMILE Study Investigators. Survival of Myocardial Infarction Long-term Evaluation.

A positive history of arterial hypertension (HBP) is present in as many as 30% of patients with acute myocardial infarction (AMI) and their clinical outcome could be greatly improved by drugs enhancing blood pressure control and preserving ventricular function. The aim of the present study was to evaluate the importance of a history of HBP on the clinical efficacy of early treatment with the angiotensin-converting enzyme (ACE) inhibitor zofenopril in patients with anterior AMI. We summarize the results of a post-hoc analysis of data from the Survival of Myocardial Infarction Long-term Evaluation (SMILE) study, which randomly evaluated the efficacy of zofenopril given within 24 h of symptom onset to patients with anterior AMI not undergoing thrombolysis. Of 1441 patients who entered the study, 565 (39.2%) had a history of HBP. The mean follow-up time was 12 months and the main outcome measures were 6-week combined occurrence of death and severe congestive heart failure (CHF) and 1-year mortality. After 6-week of treatment with zofenopril the relative risk of death or severe CHF was 0.60 (95% confidence interval [CI]: 0.45-0.81; 2P < .05) in the hypertensive group and 0.89 (0.74-1.08; 2P = .62) for normotensive patients, whereas the 1-year risk of death was 0.61 (95% CI: 0.23,0.89; 2P < .05) and 0.77 (95% CI: 0.52-1.17; 2P = .22), respectively. The 6-week prevalence of mild-to-moderate CHF was also significantly reduced by zofenopril in the hypertensive population (14.1% v 9.4%; 2P < .05). The present data suggest that treatment with zofenopril started within 24 h of the onset of anterior AMI could be highly beneficial in patients with a history of HBP.

Relation between lymphocyte subpopulations and pineal function in patients with early or metastatic cancer.

It has been demonstrated that melatonin and other pineal hormones play a role in the neuroendocrine control of immunity. Anomalies of both pineal and immune functions have been reported in cancer. Pineal and lymphocyte functions, however, have never been simultaneously evaluated in oncologic patients. This preliminary study was carried out in order to analyze the melatonin-lymphocyte relationship in human neoplasms. In a first investigation, we evaluated melatonin serum levels and lymphocyte subpopulations on venous blood samples collected during the morning from 46 healthy controls and from 27 cancer patients, 13 of whom had metastases, while the other 14 were without metastases. Moreover, melatonin levels were high in 10 oncological patients and within the normal range in the other 17 cases. B lymphocyte (B), total T lymphocyte (T3), T helper/inducer (T4) and T suppressor/cytotoxic (T8) mean percentages and T4/T8 mean ratios did not significantly differ, either between patients with high and normal melatonin levels, or between metastatic and nonmetastatic cancer patients. In a second study, we evaluated the effects of a prolonged treatment with melatonin (20 mg/daily intramuscularly at 3:00 p.m. for 2 months) on 8 patients with advanced cancer, in whom conventional antitumor therapies had failed. Mean percentages of B, T3, T4, T8 lymphocytes and T4/T8 mean ratios were not significantly different before or after melatonin treatment. In only one patient did the T4/T8 ratio decrease after therapy; in this case only, a stabilization of the disease was obtained, while in all 7 other patients the neoplastic disease progressed also during melatonin treatment, even if an evident improvement of the performance status was seen as it was in most cases. These results seem to exclude that melatonin may influence lymphocyte functions in cancer. Longitudinal studies and further data, however, will be needed to clarify this question.

A randomized study of tamoxifen alone versus tamoxifen plus melatonin in estrogen receptor-negative heavily pretreated metastatic breast-cancer patients.

Recent experiments suggest the possibility of modulating the efficacy of cancer endocrine therapy by the pineal hormone melatonin (MLT). In particular, it has been demonstrated that MLT may stimulate estrogen receptor (ER) expression and enhance tamoxifen (TMX) effects other than the antiestrogenic action. Therefore, MLT could amplify the efficacy of TMX also in patients with negative ER. On this basis, a randomized study was performed with TMX versus TMX plus MLT in ER-negative metastatic breast cancer patients, who were unable to tolerate further chemotherapy, because of age, low performance status and/or heavy chemotherapeutic pretreatment. The study included 40 ER-negative post-menopausal, metastatic breast cancer patients, who were randomized to receive TMX alone (20 mg/day orally) or TMX plus MLT (20 mg/day orally in the evening). No complete response was seen. Partial response rate was significantly higher in patients treated with TMX and MLT than in those, who received TMX alone (7/19 vs 2/21, p<0.05). Moreover, the percent of survival at 1 year was significantly higher in patients treated with TMX plus MLT than in those treated with TMX alone (12/19 vs 5/21, p<0.01). No MLT-related toxicity was observed; on the contrary, most patients receiving MLT experienced a relief of anxiety and of depression. This preliminary study suggests that the association of the pineal hormone MLT may make TMX effective also in ER-negative metastatic breast cancer patients.

Effect of multiple doses of clarithromycin and amoxicillin on IL-6, IFNgamma and IL-10 plasma levels in patients with community acquired pneumonia.

Inflammation is crucial for the pathogenesis of both infectious and chronic obstructive pulmonary diseases. It is therefore important to modulate pulmonary inflammation in patients with these lung disorders. Macrolide antibiotics modulate inflammation in vitro and in in vivo by inhibiting the production of proinflammatory cytokines and prostaglandin E2, neutrophil chemotactic activity and elastase activity. This study evaluates the effect of clarithromycin (500 mg b.i.d. x 7 days) in comparison to amoxicillin (1 g t.i.d. x 7 days) in patients with community acquired pneumonia by testing plasma levels of IL-6, IFNgamma and IL-10 before starting therapy and at the 3rd and 7th days of therapy. Clarithromycin significantly decreased plasma levels of IL-6 and significantly increased those of IFNgamma and IL-10 at the 3rd and 7th day in comparison to basal levels. In patients treated with amoxicillin a significant decrease in IL-6 plasma levels was observed at the 7th day of therapy, probably in relation to the resolution of inflammatory symptoms. In the same patients IFNgamma plasma levels decreased during treatment while IL-10 plasma levels were unaffected.

Differentiated distribution of norfloxacin in the medullary-cortical part of the kidney in man.

Norfloxacin administered orally in a single dose of 400 mg, rapidly reaches high levels in the renal tissues, and provides an effective therapeutic action against sensitive pathogen germs. Twelve hours after administration, the drug is still detectable in the renal tissue; particularly, it was evidenced a positive tropism in the medullary part of renal parenchyma, where they were found norfloxacin levels far higher than those of cortical parts.

Correlation between changes in prolactin and melatonin serum levels after radical mastectomy.

Both prolactin (PRL) and melatonin (MLT) (the most important pineal hormone) have been shown to play a role in regulating breast cancer growth. The present study was carried out to investigate the relationship between PRL and MLT secretions in human breast cancer. Twenty-four women with breast cancer, at clinical stage T1-2 N0-2 M0, were evaluated before and after radical mastectomy. As controls, 14 women who underwent surgery for reasons other than neoplastic disease were included in the study. PRL and MLT serum levels were measured by RIA before and 15 days after surgery. There were no significant differences in mean PRL serum levels between patients and controls; mean MLT serum values were significantly higher in patients than in controls. In no control subject was PRL affected by surgery. In contrast, 13/24 breast cancer women showed high PRL levels after mastectomy; the PRL rise induced by surgery was significantly higher in patients without axillary node involvement. MLT was not affected by mastectomy in 13 patients, whereas it was enhanced in 5 women and decreased in the last 6 cases. No significant correlation was seen between PRL and MLT changes induced by mastectomy. The present study shows that radical mastectomy influences PRL and MLT secretions, however, its clinical significance remains to be established.

Clinical study of melatonin in untreatable advanced cancer patients.

It is known that the pineal gland has some antitumor activity. Melatonin, its most important hormone, has been shown to inhibit tumor growth in vivo and in vitro. Moreover, some investigations have demonstrated an altered melatonin secretion in cancer patients. Despite these interesting data, clinical trials have never been carried out to evaluate the effects of melatonin on human neoplasms. The aim of this study was to draw some preliminary conclusions on melatonin therapy in advanced human neoplasms. Nineteen patients suffering from advanced solid tumors, which did not respond to standard therapies, entered the study. Performance status (PS) was 20 or less in 9 cases, and more than 20 in the other 10. Melatonin was given intramuscularly at a daily dose of 20 mg at 3.00 p.m., followed by a maintenance period with lower doses in patients who had a remission, a stabilization of disease or an improvement in PS. Among patients with a PS higher than 20, a partial response was achieved in one case with cancer of the pancreas; moreover, 5 of 10 had stable disease, but the other 4 cases had a progression; an evident improvement of PS was obtained in 6 of the 10 cases. In contrast, among patients with a very poor PS, 7 of 9 died within the first 2 months of therapy. This preliminary study would suggest that melatonin may be of some value in treating cancer patients in whom standard antitumor therapies have failed, particularly in improving their PS and quality of life.

Alteration of opioid peptide circadian rhythm in cancer patients.

Endogenous opioid peptides have been seen to play a role in regulating immunity and tumor growth. This study was carried out to investigate opioid activity in human cancer. We evaluated by radioimmunoassay beta-endorphin plasma levels on blood samples collected at 9.00 a.m. from 121 cancer patients and 42 healthy subjects. In 22 cancer patients and in 12 controls, beta-endorphin circadian rhythm was also investigated. Finally, in 14 cancer patients and in 10 controls GH, PRL, FSH, LH and cortisol serum levels were measured after the administration of a metenkephalin analogue, FK 33-824 (0.3 mg i.v.). No significant differences were seen in beta-endorphin mean levels between cancer patients and normal subjects. Moreover, no differences were found between patients with or without metastases, nor between those with or without chronic pain. beta-Endorphin circadian rhythm appeared to be altered in 16/22 cancer patients, and anomalous hormonal responses to FK 33-824 were seen in 13/14 patients. This study shows an altered opioid activity in human neoplasms, whose clinical significance remains to be determined.

Acute effects of various chemotherapeutic combinations on hypophyseal and pineal hormone secretions in cancer patients.

It is known that prolonged therapy with cytotoxic drugs may affect the endocrine system. The present study was carried out to establish whether administration of chemotherapeutic drugs acutely influences hypophyseal and pineal activities. Nineteen patients affected by solid tumors were included in the study, 5 of whom were treated with CMF, 4 with FEC, 4 with CEV, and 6 with CDDP. Cytotoxic drugs were intravenously administered. Venous blood samples were collected at zero time and at 30, 60, 120 and 180 min after drug administration. On a separate occasion, venous blood samples were drawn during a saline infusion only. In each sample FSH, LH, GH, PRL, TSH, cortisol, melatonin and beta-endorphin were determined by the RIA method. The only significant changes observed in this study were a rise in PRL and a decrease in beta-endorphin after CDDP administration. Melatonin was enhanced after CDDP and CMF, and cortisol decreased after CMF and FEC, but their variations were not statistically significant with respect to those seen during saline infusion.

Hemodynamic effects of nifedipine in patients with asymptomatic aortic regurgitation: evaluation by Doppler echocardiography.

Nineteen asymptomatic patients affected by isolated chronic aortic regurgitation received 20 mg of nifedipine sublingually: the acute hemodynamic effects of nifedipine were evaluated by combined cross-sectional and Doppler echocardiography. To assess variations in the regurgitant flow volume, the flow volume across the mitral and aortic valves was calculated as the product of velocity-time integral multiplied by the orifice valve area. Flow volume across these valves represented the total stroke volume, and forward stroke volume, respectively: the regurgitant volume was obtained by calculating the difference between total and forward stroke volume. Nifedipine induced a redistribution of the two components of the total left ventricular stroke volume: regurgitant stroke volume decreased from 57 +/- 22 ml/beat to 46 +/- 21 ml/beat (P < 0.002), while forward stroke volume increased from 83 +/- 12 to 93 +/- 15 ml/beat (P < 0.0005), as a consequence of the reduction in systemic vascular resistance from 1513 +/- 378 to 1092 +/- 307 dynes.sec.cm-5 (P < 0.0001). The reduction of regurgitant volume was due to either a 24.8% decrease of the aortic-left ventricular mean pressure gradient during diastole (P < 0.008) or a 6% decrease of the diastolic time interval (P < 0.04). The effect of these acute changes on left ventricular loading was to induce a reduction in oxygen consumption which was expressed by a decrease in the double product (from 10176 +/- 1767 to 9444 +/- 1559 mmHg.beats/min; P < 0.002), in spite of a significant increase in heart rate. This study, therefore, shows the beneficial acute hemodynamic effect induced by nifedipine in asymptomatic patients affected by chronic aortic regurgitation and shows that Doppler-echocardiography is a useful instrument for the evaluation of hemodynamic changes immediately after the administration of drugs.

Fixed combinations of delapril plus indapamide vs fosinopril plus hydrochlorothiazide in mild to moderate essential hypertension.

This 12-week randomized, parallel-group, multicenter study compared fixed combinations of delapril (D) 30 mg plus indapamide (I) 2.5 mg and fosinopril (F) 20 mg plus hydrochlorothiazide (H) 12.5 mg in 171 adult patients with mild to moderate essential hypertension. After a 2-week placebo run-in, sitting and standing systolic (SBP) and diastolic blood pressure (DBP) was measured by conventional sphygmomanometry. The primary efficacy endpoint was the percentage of normalized (sitting DBP < or =90 mm Hg) and responder (sitting DBP reduction of 10 mm Hg or DBP < or =90 mm Hg) patients. Treatment effects were analyzed in the intention-to-treat (ITT; n = 171) and the per-protocol (PP; n = 167) populations. The percentage of normalized and responder patients did not differ significantly between the D + I (87.4% and 92%) and the F + H (81% and 86.9%) ITT groups. Similar results were seen in the PP population. In ITT and PP patients, sitting and standing SBP and DBP values were comparable at baseline in the two groups and were significantly (P<.01) and similarly reduced at weeks 4, 8, and 12. Neither treatment induced reflex tachycardia, and both regimens were well tolerated. Four patients in the F + H group dropped out because of adverse events. In this study, the efficacy and safety of D + I were comparable to those of F + H in patients with mild to moderate essential hypertension.

An uncommon cause of pericardial actinomycosis.

Cardiac actinomycosis is rare; the pericardium is the most frequently involved site, but myocardial, endocardial and valvular involvement have all been documented. Most cases originate from a thoracopulmonary site of actinomycosis and spread directly to the pericardium. Widespread dissemination from extrathoracic organs is uncommon; in fact actinomycosis is prevented by anatomical barriers and hematogenous diffusion is rare. We describe an uncommon case of pericardial actinomycosis due to a draining fistula from the liver to the pericardial space across the diaphragm. The massive dissemination through the fistula could explain the peculiar echocardiographic images of macroscopic, echo-reflective, irregular masses, floating in the pericardial space, probably consistent with aggregates of sulfur granules.

[The pharmacology and clinical aspects of the prostanoids]. / Farmacologia e clinica dei prostanoidi.

Prostanoids are derivative of arachidonic acid and arising from a common endoperoxide and they possess multiple and even opposing effects. Their main function is to control haemostasis and to maintain vascular homeostasis. Among these compounds thromboxane, generated by platelets, is a powerful vasoconstrictor and an inducer of platelet aggregation; prostaglandin E1 (PGE1) and prostacyclin (PGI2) are potent vasodilator and inhibitor of platelet aggregation. For these properties PGE1 and PGE2 are object of interest for the potential therapeutical use in treatment of atherosclerotic diseases, where mechanisms of vascular defense are altered and amplified. Pharmacokinetic and pharmacodynamic characteristics of these compound have been per se a good rationale for plenty of experimental studies which generated enthusiasm and hope of new therapeutic means in patients with surgically unreconstructible peripheral arterial disease. Nevertheless clinical trials have to face many difficulties deriving from their properties themselves. PGE1 and PGI2 are unstable hormones with local action and it is difficult to employ them in clinical practice. Moreover their protean action is often implicated in not unusual adverse effects. The development of compounds with a prostacyclin-type of action, but long lasting and therefore easier to handle, undoubtedly facilitated clinical research. But we still lack firm indications for a correct therapeutic use. Limb ischemia is the condition in which prostanoids were mostly studied. Although anecdotal reports or uncontrolled studies provided encouraging results, several controlled trials failed to demonstrate a consistent efficacy of either PGE1 or PGI2, whilst metanalytic review of controlled trials on iloprost demonstrated an efficacy on critical and less severe limb ischemia, thromboangiitis obliterans and Raynaud's phenomenon.(ABSTRACT TRUNCATED AT 250 WORDS)