Has time come for a re-assessment of spa therapy? The NAIADE survey in Italy.

Goal of this study was to investigate whether appropriately applied spa therapy in several indications could be associated with a subsequent fall in the need for costly health services and missed working days due to sick-leave. The Naiade project was a multicenter observational, longitudinal, questionnaire-based study comparing an "entry" inquiry addressed to patients before an entry thermal cycle, and a "return" inquiry after 1 year. Routine statistical methods were used for comparisons. The study was carried out in 297 of the 340 certified Italian spa centers. Inquiries were managed by the spa doctor(s), with the collaboration of family doctors, and when necessary, hospitals, other health services, labour offices and employers. After exclusion of regular customers and of patients with acute disease phases or severe health conditions, 39,943 patients divided into eight diseases subgroups (rheumatic, respiratory, dermatologic, gynaecologic, otorhynologic, urinary, vascular and gastroenteric) underwent entry inquiry and appropriate spa treatment. Patients who returned for treatment after 1 year ("index year") were 23,680 (59.2%) and received return inquiry. Outcomes considered were: frequency and duration of hospitalisation periods; missed working days; regular use of disease-specific drugs; and resort to "non-spa" rehabilitation therapies. The data collected at return inquiry were compared with those of entry inquiry. All the considered outcomes appeared to be significantly reduced in the index year in seven of the eight disease subgroups in comparison with the previous year. In conclusion, disease-appropriate spa treatments were followed by a reduction in the need of subsequent health interventions in most disease subgroups. The health promoting value of spa treatments should therefore undergo more rigorous assessment with randomised controlled studies.

Oral anticoagulation treatment in the elderly: a nested, prospective, case-control study.

BACKGROUND: Whether elderly patients are at increased risk of complications during oral anticoagulant treatment (OAT) is still a matter of debate. METHOD: Bleeding and thrombotic events occurring during OAT in 461 patients, aged 75 years or older when they started OAT, and in 461 patients younger than 70 years, matched for sex, OAT indication, and treating center, were examined in a prospective, multicenter, inception-cohort study. RESULTS: Bleeding rate was 9.9% and 6.6% patient-years in elderly and young patients, respectively (P = .07), and 2.1% and 1.1% for major bleeding (P = .19); 6 and 1 events, respectively, were fatal (all intracranial, relative risk, 6.4; P = .05). In the elderly, bleeding rate was lower (4.5%) for international normalized ratios (INRs) between 2.0 and 2.9; it was higher during the first 90 treatment days (P = .05) and when arterial vascular disease was the indication for OAT (P = .03). Thrombosis rate was 4.2% and 2.5% patient-years in elderly and young patients, respectively (P = .10); however, 13 and 5 events were fatal (relative risk, 2.8; P = .04). Thrombosis rate was lower (1.5%) for INRs between 2.0 and 2.9; it was higher during the first 90 treatment days (P<.001) and 6 of 7 venous events occurred at lower than 2.0 INRs. CONCLUSIONS: A nonsignificant trend was noted toward a higher rate of both bleeding and thrombotic complications in elderly vs matched younger patients. Intracranial bleeding and fatal thrombotic events were significantly more frequent in the elderly. Our results also indicate that lower than 2.0 INRs do not preclude bleeding in the elderly nor offer adequate protection from thrombotic events. Moderate anticoagulation (2.0-3.0 INRs) in elderly patients seems the safest and most effective.

Thrombophilia and venous thromboembolism. International consensus statement. Guidelines according to scientific evidence.

Thrombophilia is the term now used to describe predisposition to increased risk of venous and occasionally arterial thromboembolism due to hematological abnormalities. It can be a multifactorial disorder where congenital defects of anticoagulant or procoagulant factors may be combined with acquired hematological abnormalities. It should be considered in patients with a documented unexplained thrombotic episode or a positive family history. The aim of this document is to provide guidelines for investigation and management of patients with thrombophilia in the presence or absence of venous thromboembolism (VTE).

Venous thromboembolism, oral contraceptives and high prothrombin levels.

The G20210A prothrombin mutation, associated with elevated prothrombin levels, is a risk factor for venous thromboembolism (VTE) and displays a strong interaction with oral contraceptives (OC). No data are available on VTE risk of OC use in women with high prothrombin levels, either associated or not with the mutation. The aim of this study was to evaluate the risk of VTE in OC users with high prothrombin levels, either including or excluding carriers of the prothrombin mutation. Prothrombin levels were measured by a chromogenic assay in 152 women who suffered from VTE in reproductive age and in 296 healthy women. Subjects carrying thrombophilic alterations other than the G20210A prothrombin mutation were excluded. Prothrombin levels were stratified into quartiles. The OR of subjects in the upper quartile were 3.10 [95% confidence interval (CI) 1.73-5.55] and 2.07 (95% CI 1.11-3.85) in all women and in those not carrying the prothrombin mutation, respectively. Among the 152 patients, 88 had experienced VTE during OC; in the control group we considered as OC users the women who had used OC for at least 6 months in the 2 years before presentation but had stopped the treatment at least 3 months before the time of blood sampling (n = 127). For the interaction between OC and prothrombin levels only the two extreme strata of prothrombin were considered. Women with the lowest prothrombin levels and who did not use OC were used as reference category. The VTE risk of using OC in subjects with prothrombin levels in the upper quartile was increased 5.4-fold (95% CI 2.38-12.3) and 3.5-fold (95% CI 1.48-8.22) in all women and in those not carrying the prothrombin mutation, respectively. We conclude that elevated prothrombin levels, even in women without the G20210A prothrombin mutation, are associated with an increased risk for venous thromboembolism and that oral contraceptive use potentiates such association.

Protease activities, as well as plasminogen activators, contribute to the "lytic" state during orthotopic liver transplantation.

High levels of tissue plasminogen activator (t-PA) have been reported to be the main component of the high fibrinolytic activity measured in patients during orthotopic liver transplantation. However, a previous study of our group suggested that specific t-PA may not completely account for the massive fibrinolytic activities recorded. In the present study we investigated the fibrinolytic patterns in 10 consecutive liver cirrhosis patients undergoing OLT. Euglobulin fibrinolytic activity, measured either on physiologic (fibrin plates) or amidolytic substrates, increased as expected during anhepatic and reperfusion phases, but largely exceeded the specific activity of t-PA, as proved by quenching procedures using anti-t-PA antibodies. The presence of plasmin- and trypsin-like amidolytic activities was detected in native plasmas at the end of anhepatic and reperfusion phases, together with decreased levels of protease inhibitors, especially alpha 1 Antitrypsin. In conclusion, the hyperfibrinolytic pattern recorded in the central OLT phases is not only attributable to an increased t-PA concentration, and is better described as a complex "lytic" state also including the presence of free proteases (plasmin- and trypsin-like), with limited participation of u-PA. Although t-PA increase is probably the main mechanism of stimulation of the fibrinolytic system during OLT, actual and not just potential proteolytic activities can be found in this condition independent of the occurrence of major hemorrhagic complications.

Improvement of walking distance by defibrotide in patients with intermittent claudication--results of a randomized, placebo-controlled study (the DICLIS study). Defibrotide Intermittent CLaudication Italian Study.

Defibrotide is an antithrombotic drug which enhances prostacyclin production and activates fibrinolytic system. The aim of this study was to investigate the improvement of walking distance in patients with intermittent claudication treated with defibrotide. DICLIS was a double blind, placebo-controlled study which included patients with walking distance autonomy at a standardized treadmill test < or =350 > or =100 meters. A total of 310 patients were randomly allocated to placebo (n = 101), defibrotide 800 mg/day (n = 104) or defibrotide 1200 mg/day (n = 105). During a one year follow-up, the Absolute Walking Distance (AWD) was measured six times (0, 30, 60, 90, 180, 360 days). Similar improvement in walking distance was found in the three groups until the 90th day; thereafter placebo group showed no further increase, while AWD continued to increase in the defibrotide groups. Between the 180th and 360th day visits, AWD was significantly higher (P <0.01) in patients given defibrotide than in patients given placebo. No difference in efficacy was observed between the two dosages of defibrotide. No differences in side effects were observed among the three groups. The results of the present trial suggest that long-term administration of defibrotide improves walking distance in patients with intermittent claudication.

Association of reduced factor VIII with impaired platelet reactivity to adrenalin and collagen after total thyroidectomy.

Twenty-one thyroprival patients, previously submitted to total thyroidectomy for tumours, were investigated during stabilized L-thyroxine supplementation and at the end of a 20-25 day "no-therapy" period, necessary for a 131I total body scintigraphy. During supplementation therapy a lower than normal mean beta-thromboglobulin (beta-TG) release level was found, the other blood clotting and platelet function tests being normal. After substitution therapy withdrawal, platelet function tests showed reduced adrenalin aggregation, increased collagen threshold aggregating concentrations, decreased beta-TG release values and reduced aggregation to ristocetin, whereas blood clotting tests showed prolonged aPTT values and reduced levels of factor VIII:C and vWf:Ag. We conclude that in acquired hypothyroidism the lowering of factor VIII:C and vWf:Ag (acquired von Willebrand disease) is associated with impaired platelet reactivity not only to ristocetin but also to collagen and especially adrenalin. In the patients investigated these changes were almost completely corrected by substitutive therapy with L-thyroxine at clinically effective doses.

A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy.

The optimal long-term treatment of acute venous thromboembolism (VTE) in patients with malignancy remains undefined. In particular, based on current evidence, it is uncertain whether secondary prophylaxis using standard intensity oral anticoagulant therapy is associated with higher risks of bleeding and recurrent thrombosis in patients with cancer than in those without cancer. This study compared the outcome of anticoagulation courses in 95 patients with malignancy with those of 733 patients without malignancy. All patients were participants in a large, nation-wide population study and were prospectively followed from the initiation of their oral anticoagulant therapy. Based on 744 patient-years of treatment and follow-up, the rates of major (5.4% vs 0.9%), minor (16.2% vs 3.6%) and total (21.6% vs 4.5%) bleeding were statistically significantly higher in cancer patients compared with patients without cancer. Bleeding was also a more frequent cause of early anticoagulation withdrawal in patients with malignancy (4.2% vs. 0.7%; p <0.01; RR 6.2 (95% CI 1.95-19.4). There was a trend towards a higher rate of thrombotic complications in cancer patients (6.8% vs. 2.5%; p = 0.058; RR 2.5 [CI 0.96-6.5]) but this did not achieve statistical significance. In the group of patients with cancer, the bleeding rate was high across the different INR categories and was independent of the temporally associated International Normalized Ratio (INR). In contrast, the bleeding rate was increased only with INR values greater than 4.5 in the group of patients without cancer. The rate of thrombotic events was significantly higher in both cohorts when the INR was less than 2.0. In conclusion, patients with malignancy treated with oral anticoagulants have a higher rate of bleeding and possibly an increased risk of recurrent thrombosis compared with patients without malignancy. Safer and more effective anticoagulant therapy is needed for this challenging group of patients.

Activation of blood coagulation after abrupt or stepwise withdrawal of oral anticoagulants--a prospective study.

The occurrence of a "rebound hypercoagulable state" in patients after dicontinuation of oral anticoagulants is still a matter of debate and no definite recommendation can be made on the best procedure for anticoagulant withdrawal. The present study investigated the changes in the levels of markers of activated blood coagulation in 32 patients (pts) in whom warfarin treatment (for venous thromboembolic disease) was randomly withdrawn abruptly (n = 17, group A) or gradually (n = 15, group B: 2/3 of initial dose the 1st week, 1/3 the 2nd weeks and nothing from the 3rd week on). Blood was sampled at baseline, once a week for the first three weeks and after 2 months. At the 1st week group A had significantly higher F1+2 and TAT values (p < 0.001); at the 2nd week F1+2 levels remained higher (p < 0.05) though INR values were not different from those of group B. After baseline, higher than normal F1+2 levels were recorded in 32/66 (48%) controls in group A vs 15/60 (25%) in group B (p < 0.01); at the 2nd week, 10/17 (59%) patients in group A vs 1/15 (7%) in group B still had higher than normal F1+2 levels (p < 0.01). The values of areas under curve (AUC) and maximum concentrations of all variables were not statistically different in the two groups; however, very high levels were observed in a few cases of group A. Thrombotic events (one DVT recurrence and one thrombophlebitis in a varicose vein) occurred in 2 pts of group A, both with high F1+2 and TAT AUC values.(ABSTRACT TRUNCATED AT 250 WORDS)

Double-blind, randomized comparison of systemic continuous infusion of 0.25 versus 0.50 mg/kg/24 h of alteplase over 3 to 7 days for treatment of deep venous thrombosis in heparinized patients: results of the European Thrombolysis with rt-PA in Venous Thrombosis (ETTT) trial.

Thirty-two patients with acute, proximal-vein thrombosis were treated with heparin and alteplase (0.25 versus 0.5 mg/kg/24 h during 3-7 days) in a randomized, double-blind, multicenter, European (ETTT) trial. The treatment resulted in a decrease of the venographic Marder's score from 18 (6-25) to 13 (2-24) units (median, range) in Group I (0.25 mg/kg/24 h, n = 15, median decrease 3.0, p = 0.32) and from 17.5 (3-33) to 15.5 (0-27) in Group II (0.5 mg/kg/24 h, n = 16, median decrease 4.0, p = 0.23). Comparison of the sequential venograms could be performed in 14 cases of Group I and in 15 cases in Group II. A minority of patients showed substantial partial recanalization of the initially obstructed veins on the control venogram (one in each treatment group) and most of the control venograms showed either thrombus size reductions (5 in Group I, 7 in Group II) or no change or even deterioration (8 in Group I, 7 in Group II). Major bleedings were observed in 7 patients (7/32, 22%), 5 of them occurring in Group II (5/17, 29%). Thus, the results of the ETTT trial show that the used low dosages of alteplase administered intravenously over 3-7 days in heparinized patients cannot be recommended as a treatment for patients with deep venous thrombosis of lower limbs and/or pelvis. Further studies are needed to define a more suitable dosage regimen of alteplase in this indication.

Oral anticoagulant therapy control: evidence that INR expression improves the inter-laboratory comparability of results--the Bologna oral anticoagulant control exercise.

The aims of the present study were: 1) interlaboratory normalization of prothrombin time (PT) testing for anticoagulant therapy control through calibration of customary thromboplastins against international reference materials, and 2) "on field" validation of the advantages offered by expression of results as International Normalized Ratio (INR) as opposed to percentage activity. PT tests were carried out over 8 days on the same normal subjects (16) and patients on oral anticoagulants (48) in the 9 laboratories of the Bologna area. The use of customary thromboplastins and coagulometers was maintained in all labs throughout the study. The main results were: 1) the interlaboratory CV of the prothrombin ratios obtained for each sample with all customary thromboplastins (5 different brands) was 15%, but was reduced to levels of 5.8 to 8.9 when using constant thromboplastin brands and batches; 2) the International Sensitivity Index (ISI) values obtained in the different labs were only slightly influenced by the use of different coagulometers; 3) comparable ISI values were obtained through direct calibration with the international reference material and through intermediate calibration with a locally selected standard; 4) use of INR values instead of percentage activity greatly reduced interlaboratory variability and significantly improved uniformity of anticoagulation level measurements, thus reducing the possibility of erroneous prescriptions. The Bologna exercise is therefore of educational value for laboratory and community doctors of the area in understanding and accepting the INR system.

Dermatan sulphate for the prevention of postoperative venous thromboembolism in patients with cancer. DOS (Dermatan sulphate in Oncologic Surgery) Study Group.

BACKGROUND: Patients undergoing surgery for cancer are at high risk for venous thromboembolism (VTE). Agents that selectively inhibit thrombin, such as dermatan sulphate, have potential for a favourable benefit-risk ratio in the prevention of this complication. METHODS: Patients scheduled for elective abdominal, thoracic, gynecologic or urologic surgery for cancer resection, were randomised to dermatan sulphate (600 mg intramuscularly on the second day before surgery, then 300 mg once daily), or calcium heparin (5,000 IU subcutaneously t.i.d., starting 2 hours before operation). Both treatments were continued until postoperative day 7 or until adequate mobilisation was achieved. Bilateral venography was scheduled at the end of treatment. Venograms were centrally assessed in blind conditions. The study outcomes were VTE (venographically proven deep vein thrombosis IDVT] or symptomatic, objectively confirmed pulmonary embolism) and bleeding complications. RESULTS: At 27 centres, 842 patients were randomised and underwent surgery (418 dermatan sulphate, 424 heparin). Efficacy was assessed in 521 patients with adequate venography and/or confirmed pulmonary embolism. DVT was observed in a total of 96 patients; symptomatic non-fatal pulmonary embolism developed in 2 patients (one per group), who also had DVT at venography. Postoperative VTE occurred in 40 of 267 patients on dermatan sulphate, 15.0%, versus 56 of 254 patients on heparin. 22.0% (p = 0.033). Relative risk reduction was 32.7% (95% confidence interval, 3.1 to 53.2%). The rate of bleeding complications in all operated patients was 6.9% with dermatan sulphate and 7.5% with heparin (confidence interval for the absolute risk difference, -4.1 to 2.9%). The inhospital mortality rate was 1.2% and 1.4%, respectively. CONCLUSIONS: In oncologic surgery, dermatan sulphate prevents VTE more effectively than heparin without increasing bleeding complications.

A prostacyclin-sparing effect of indobufen vs. aspirin.

Indobufen ((+/-)-2-[p-(1-oxo-2-insoindolinyl)-phenyl]-butyric acid, indo) is a drug inhibiting platelet function by a reversible block of the arachidonic acid metabolism at the level of cyclooxygenase. Since tolerability profile of such drugs is mostly linked to extra-platelet cyclooxygenase inhibition, we prospectively evaluated the extent of platelet and extra-platelet cyclooxygenase inhibition by in vivo administration of indo in comparison with ASA. We assessed the effects of the two drugs on the ex vivo generation of TXB2 and 6-keto-PGF1 alpha in whole blood, as indices of the production of TXA2 and PGI2 (prostacyclin), respectively, either after spontaneous clotting at 37 degrees C for 1 h (Study 1) or after the addition of 2 micrograms/ml collagen (Study 2). Generation of 6-keto-PGF1 alpha in whole blood is a mixed index of platelet and extra-platelet cyclooxygenase activity, deriving from both platelet and white blood cell arachidonic acid metabolization. Fifteen patients with ischemic heart disease and baseline serum TXB2 levels > 300 ng/ml were allocated to receiving one single administration of either indobufen 200 mg (n = 6) or aspirin 500 mg (n = 9). Whole blood prostanoid generation was assessed at 0, 1, 2, 4, 6, 8, 12 and 24 h after drug administration (Study I). Ten healthy male volunteers were allocated to a double-blind, randomized crossover comparison of indo 200 mg b.i.d. vs. ASA 300 mg/d for 7 days (Study 2). Prostanoid generation and whole blood platelet aggregation were performed before and at the end of each study period (Day 0 and Day 7). At each time-point after single dose administration (Study 1), indobufen caused less % inhibition of whole blood 6-keto-PGF1 alpha than of TXB2. At 2 h, TXB2 was reduced to a similar extent after ASA (98 +/- 4%) and indo (97 +/- 6%) (p = N.S.), while inhibition of 6-keto-PGF1 alpha was clearly different ( > 98% after ASA, 81 +/- 2.5% after indo, p < 0.01). After one week of ASA or indo (Study 2) the maximum extent of whole blood platelet aggregation was similarly inhibited (from 17.2 +/- 1.4 ohms to 3.6 +/- 1.3 ohms with ASA; from 18.3 +/- 1.0 ohms to 1.6 +/- 0.7 ohms with indo (p ASA vs. indo = N.S.). Despite equal inhibition of whole blood TX production after collagen (from 49.0 +/- 4.3 ng/ml to 1.1 +/- 0.6 ng/ml with ASA, from 49.8 +/- 1.3 ng/ml to 1.4 +/- 0.6 ng/ml with indo), again, however, 6-keto-PGF1 alpha production was less affected by indo than by ASA (from 409 +/- 30 pg/ml to 37 +/- 13 pg/ml with ASA, inhibition = 91%; from 396 +/- 35 to 318 +/- 40 with indo, inhibition = 20%). These differential effects of indo and ASA might lead to a better platelet selectivity, tolerability and benefit/risk profile of indo vs. ASA, which are worthy of further assessment.

Thrombotic events during oral anticoagulant treatment: results of the inception-cohort, prospective, collaborative ISCOAT study: ISCOAT study group (Italian Study on Complications of Oral Anticoagulant Therapy).

The paper reports on rate and type of thrombotic events occurring during the observational, prospective, inception-cohort, multicenter ISCOAT study. 2,745 unselected, daily practice patients, consecutively referring to 34 Italian anticoagulation clinics to monitor the oral anticoagulant treatment, were included in the study from beginning of their first anticoagulant course. During a total follow-up of 2,011 patient-years of treatment 70 thrombotic events (3.5 per 100 patient years) were recorded in 67 patients: 20 fatal (1%), 39 major (1.9%) and 11 minor (0.6%). 34/70 events occurred within the first 90 days of treatment (relative risk - at multivariate analysis - of < or =90 days vs. >90 = 20.6, C.I. 12.7-33.5; p <0.0001). The risk was higher in patients aged > or =70 y (1.62, C.I. 1.0-2.61; p <0.05), and when indication for anticoagulant treatment was peripheral/cerebral arterial disease (1.84, C.I. 1.01-3.36; p <0.05). The frequency of thrombotic events was 17.5% when international normalised ratio (INR) levels were < 1.5, decreasing to 2.3% for INRs within the 2-2.99 category (relative risk of INRs <2.0 vs. > or =2 = 1.88, C.I. 1.16-3.07; p <0.05). The recorded rate of thrombotic events was lower than that reported in the few available studies. A greater risk should be expected during the first 90 days of treatment, when anticoagulation levels are <2.0 INR, in patients > 70 years and in those with cerebrovascular/peripheral arterial disease.

Interaction between vitamin B6 deficiency and low EFA dietary intake on kidney phospholipids and PGE2 in the rat.

Vitamin B6 is involved in the metabolism of long chain polyunsaturated fatty acids and phospholipids. We have studied the interaction between pyridoxine deficiency and low amounts of dietary essential fatty acids (EFA) in the rat. The fatty acid composition of kidney phospholipids of pyridoxine deficient animals shows a decrease of 20:3 n9 and an increase of 20:4 n6 in comparison with control and pair fed animals. This variation of fatty acid composition could be due to the simultaneous effect of vitamin B6 deficiency, which reduces the oxidation of linolenate, and of a low intake of EFAs which stimulates delta-6-desaturase. The dietary treatment also influences kidney Prostaglandin E2 (PGE2) levels which are higher in vitamin B6 deficient animals. This effect could be correlated with a higher response to sympathetic stimulation caused by the simultaneous presence of vitamin B6 deficiency and low EFA availability. Also the higher level of arachidonate could be involved in promoting PGE2 synthesis.

Influence of dietary fatty acids on phospholipid composition and prostaglandin E synthesis in rat kidneys.

The effects of oils with different amounts of n6 and n3 fatty acid precursors and derivatives were evaluated on phospholipid composition and PGE2 synthesis of rat kidneys. Dietary lipids were: olive oil, an olive-blackcurrant-fish oil mixture and a blackcurrant-fish oil mixture. We observed in the kidneys of rats fed the blackcurrant-fish oil mixture a significant decrease in PGE2 synthesis, while arachidonate values did not show significant variations. A decrease of PGE2 synthesis could be due to competitive and inhibitory effects of fatty acids other than arachidonate, observed in the kidney phospholipid composition in our dietary conditions.

Effect of diets containing different amounts of precursor and derivative fatty acids on serum TXB2.

Dietary precursor and derivative polyunsaturated fatty acids influence metabolic parameters, such as eicosanoid synthesis. We have studied the effect of dietary intakes of lipids containing different amounts of precursor and derivative fatty acids (olive oil, olive-blackcurrant-fish oil mixture, blackcurrant-fish oil mixture, MCT (medium chain triglycerides)-soyabean oil mixture) on serum thromboxane B2 (TXB2) in four groups of rats. Plasma fatty acid composition showed differences related to dietary intakes. TXB2 levels were similar in all conditions except in the group receiving the mixture of olive-blackcurrant-fish oils which showed lower values.

Long-term effects of ticlopidine on fibrinogen and haemorheology in patients with peripheral arterial disease.

The effects of ticlopidine treatment (250 mg b.i.d. for 21 months) on fibrinogen and other rheological variables, as compared to placebo, were studied in 44 patients with intermittent claudication due to peripheral arterial occlusive disease. Blood samples were collected every 3 months during this double-blind, randomised placebo-controlled trial which lasted 21 months. Consistently lower values of fibrinogen, haematocrit and whole blood viscosity at high and low shear rate levels were found in the ticlopidine group; the intergroup differences were statistically significant at most but not all follow-up examinations. A significant time-related variance was observed in the ticlopidine group for the measured variables, also after correction for the variability found in the placebo group. Thus, the observed changes in the ticlopidine group are mainly treatment related. These effects on fibrinogen and haemorheology may contribute, besides the known antiplatelet activity of the drug, to the clinical improvement reported in a larger group of claudicants to which the present subset of patients belong.

Effects of iloprost (ZK 36374), a prostacyclin derivative, on platelet function after ischaemic exercise in patients with stable angina pectoris.

The effect of a chemically stable prostacyclin analogue (Iloprost) on platelet function was investigated in a controlled study in patients with angiographically confirmed stable angina pectoris after ischaemic exercise. In placebo experiments, ADP platelet aggregation was increased after exercise only when measured in whole blood and not in PRP. While plasma thromboxane B2 levels were unchanged, those of 6-keto PGF1 alpha were significantly although transiently increased after exercise. Iloprost displayed a potent antiaggregating activity in PRP and also reversed platelet hyperaggregation occurring in whole blood determinations after exercise. Plasma thromboxane B2 levels were significantly reduced but occasionally a rebound increase occurred 30 min. after end of the infusion. In contrast plasma level of 6-keto PGF1 alpha did not change after Iloprost and its recorded post-exercise increase was counteracted, thus suggesting a negative feed-back mechanism between Iloprost and natural prostacyclin. The data also suggest that degradation of the analogue is probably accomplished through pathways different from those of PGI2.

Increased placental production of leukotriene B4 in gestational hypertension.

Production of some lipoxygenase and cyclooxygenase derivatives of arachidonic acid was measured in placental tissue obtained from women with gestational hypertension and with normal pregnancies. The levels of leukotriene B4 were about five times higher in placentas from hypertensive women and also raised thromboxane A2 and reduced prostaglandin E2 levels were observed. Prostacyclin production was lowered only in women with more severe hypertension, in association with the highest measured levels of leukotriene B4 and thromboxane A2. It is suggested that increased placental levels of leukotriene B4 and thromboxane A2 appear already in mild gestational hypertension, while depression of prostacyclin may occur only at more severe stages of gestational hypertensive disease.