Are the vascular complications of diabetes mellitus preceded by an altered thromboxane/prostacyclin plasmatic ratio?

Although many data regarding the biosynthesis of thromboxane A2 and prostacyclin in diabetes mellitus have recently appeared in the literature, it is not clear whether an imbalance between the generation of the two prostaglandins might be connected to the vascular complications of diabetes. In the present review we have tried to emphasize the most significant aspects of these studies and we have focused on alterations of platelet prostacyclin receptors and on the effects of circulating immune complexes on platelets of diabetics. It is likely that studies on the release of platelet derived growth factor as well as more precise definitions of its action on vessel wall cells leading to a massive release of prostacyclin, will permit us to ascertain whether an alteration in prostaglandin ratio is linked to the genesis of the vascular complications in diabetics.

[Platelet hyperfunction in prethrombotic vascular disease]. / L'iperattività piastrinica in patologia vascolare pretrombotica.

In 3 groups of patients with high thrombotic risk (diabetes mellitus, hyperbetalipoproteinemia, hypertension) the platelet aggregation and the level of circulating platelet aggregates were found statistically higher than in normal controls. In addition, platelet aggregation in diabetic patients was found statistically higher than in the other 2 groups of patients. Therefore these 2 parameters of platelet function are useful for the screening of patients with potential risk for thrombosis allowing a more selective and defined prophylaxis, both of thrombosis and atherosclerotic complications.

[Effects of therapy with aminaftone on chronic venous and lymphatic stasis]. / Effetti della terapia con aminaftone sulla stasi venosa e linfatica cronica.

Following a short introduction on the physiopathology of the phlebo-lymphatic system, the results of a study carried out on 114 patients suffering from chronic venous insufficiency (CVI) treated at the Department of General Clinical Surgery and Surgical Therapy of the University of Ferrara are reported. These patients were subdivided into two random groups and treated with common phlebotonic drugs and aminaftone, respectively. Both groups were also subjected to those physical and medical measures that are usually adopted for the treatment of such patients. The therapeutic effects were assessed by comparing symptomatology before and after 90 days of treatment, both subjectively (patient's assessment of the symptoms by means of a scoring system) and with objective methods (measurements and echo-Doppler examinations). The differences between the two groups were statistically very significant in favour of patients who had taken aminaftone. Excellent results were obtained in the treatment of CVI as well as in lymphatic-related pathology (lymphedema).

Factor VIII-related activities after 1-deamino-8-D-arginine vasopressin in multicentric reticulohistiocytosis.

A woman with multicentric reticulohistiocytosis, having symptoms including bleeding and a borderline level of factor VIII, was given an i.v. infusion of DDAVP as a pharmacological test to evaluate the release of factor VIII-related properties from storage sites. The results show a reduced response to DDAVP in the patient in comparison with a normal control subject. This could be due either to a defect in the release of the factor VIII complex after DDAVP or to a reduced synthesis and/or storage capacity by the storage cells.

[Ultrasonics in the diagnosis of deep hematomas in hemophilia]. / Contributo ecotomografico alla diagnosi degli ematomi profondi in corso di emofilia.

The authors emphasize the clinical importance of US in evaluating the extent and the topographic relationships of haematomas. Seven haemorrhagic episodes occurred in this group of patients have been studied using US. For retrobulbar haematomas we have utilized a single water bath transducer operating at 5 and 7.5 MHz, while for soft tissue (muscle) we have utilized linear array transducer operating at 3.5 MHz. The haemorrhagic complications consisted of two deep haematomas involving the ileo-psoas muscle, with different evolution; two relapsing haematomas of the soleus muscle followed by different clinical course; two post-traumatic relapsing retrobulbar haematomas which gave rise to severe complications; two haematomas which occurred simultaneously in the right iliac fossa. Our experience suggests that US can give both accurate diagnostic information and useful clues concerning the solution and therapeutic management of haematomas. This leads to a better prognosis, mostly when the instrumental investigation is carried out early.

Guanidinophenyl derivatives of pyrazole: synthesis and inhibitory effect on serine proteinases, blood coagulation and platelet aggregation.

Guanidinophenyl derivatives of pyrazole have been synthesized. Their inhibitory effects on (i) bovine trypsin, bovine thrombin, porcine pancreatic kallikrein catalyzed hydrolysis of p-nitro anilide of N alpha -benzoyl-arginine and (ii) blood coagulation and platelet aggregation, were investigated. The kinetic behaviour of all compounds conformed to that of a reversible competitive inhibition pattern, and they were also found to act in vitro as inhibitors of platelet aggregation induced by ADP.

Platelet aggregation and evaluation of the ratio thromboxane B2/6-keto-prostaglandin F1 alpha in the plasma of patients on long term cimetidine treatment.

It has been reported that a long term treatment with cimetidine may give rise to thrombotic complications and may cause reversible damage to blood cells. In 57 patients on long term cimetidine treatment, platelet aggregates, platelet aggregation in vitro, plasma 6-keto-PGF1 alpha/thromboxane B2 ratio and platelet cyclic AMP levels were assessed. In 52% of the patients, platelet aggregate ratios were abnormal and collagen and ADP-hypersensitive platelets were observed. Such alterations began occurring after the first month of therapy and were shown to worsen progressively during the administration. Four of these patients, who developed unexpected thrombotic compliances after about 7 months of therapy, showed higher than normal plasma thromboxane B2, lower plasma 6-keto-PGF1 alpha and two of them, lower platelet cyclic AMP concentrations. It is suggested that cimetidine, through an unknown mechanism which probably involves activation of endogenous cyclic AMP phosphodiesterase, may favour the action of platelet aggregating agents.

[Ethyl esters of N-amidinobenzoyl aminoacids: inhibitory effect on thrombin, blood coagulation and platelet aggregation]. / Esteri etilici di N-amidinobenzoil aminoacidi: effetto inibitore sulla trombina sulla coagulazione del sangue e sull'aggregazione piastrinica.

In a previous paper we described the synthesis and the antiproteolytic activity of N-(3- and N-(4-amidinobenzoyl)-L-amino acids. As an extension of these studies we examined the possible inhibitory effect of these compounds on thrombin, blood coagulation and platelet aggregation. Values of Ki for the binding to thrombin are independent of the nature of the amino acids side chain and superimposable with those obtained for the formation of benzamidine-thrombin adduct. These data suggest slight effect on blood coagulation. The benzamidine derivatives are more active on platelets.

Aromatic amidines: inhibitory effect on purified plasma serine proteinases, blood coagulation and platelet aggregation.

The inhibitory effect of benzamidine as well as of 1,3-di-(p-amidinophenoxy)-2,2-bis-(p-amidinophenoxymethyl)propane (TAPP-H) and TAPP-halo derivatives (with Cl, Br or I) on (i) the catalytic properties of purified plasma serine proteinases (notably, factor Xa, factor VIIa, thrombin and plasmin), (ii) blood coagulation, and (iii) platelet aggregation was investigated in vitro. For all the enzyme/inhibitor systems examined, the inhibition patterns were strictly competitive, and titrations conformed to simple equilibria. The inhibitory effect of TAPP-H and TAPP-halo derivatives is higher, by at least 10-fold, than that of benzamidine, which binds at the primary specificity subsite (S1) of serine proteinases and is commonly taken as a molecular inhibitor model. The high inhibitory effect of aromatic tetraamidines has been interpreted taking into account an additional productive binding for a second benzamidine or halo-benzamidine moiety to the enzyme surface. As a whole, the data reported here indicate that aromatic amidines inhibit the plasma serine proteinases involved in different steps of haemostasis (coagulation and platelet aggregation) as well as clot lysis under physiological-like conditions in vitro.

Amidinosemicarbazido derivatives of pyrazole: synthesis and inhibitory effect on blood coagulation and platelet aggregation.

Amidinosemicarbazido derivatives of pyrazole having various substituents on pyrazole ring were prepared and their effect on platelet function and blood coagulation was determined in vitro. Platelet aggregation and serotonin release induced by ADP, collagen, arachidonic acid and thrombin were markedly inhibited by pyrazole derivatives at mM concentrations. Compounds with a hydrophobic nucleus at position 1 of the pyrazole ring showed the most potent antiplatelet activity. On the contrary, their effect on blood coagulation was faintly inhibitory.

Aromatic tetra-amidines: synthesis of halo-derivatives and their antiproteolytic activity.

Mono-halo derivatives of 1,3-di-(p-amidinophenoxy)-2,2-bis-(p-amidinophenoxymethyl)p ropane (TAPP-H) have been synthesized and their inhibitory effect on the bovine trypsin, bovine thrombin and porcine pancreatic kallikrein catalyzed hydrolysis of p-nitroanilides of amino acids was investigated, at pH 8.1 and 37 degrees, in parallel with that of TAPP-H and benzamidine. The addition of a halogen (Cl, Br or I) at position 2 of each benzamidine moiety of TAPP-H is accompanied by an increase of the inhibitory effect. This is especially evident in the case of porcine pancreatic kallikrein inhibition by TAPP-Cl. The structural basis of the different inhibitory effect of TAPP-H, TAPP-halo derivatives and benzamidine on the catalyzed hydrolysis of the proteinases examined are discussed and the role of Asp-189 in bovine trypsin, Asp-189 and Glu-149 or Asp-192 in bovine thrombin and Asp-189 and Asp-A148 or Glu-150 in porcine pancreatic kallikrein is focused.

Lipoprotein(a) plasma levels and apo(a) isoforms are not associated with longevity or disability in a sample of Italian octo-nonagenarians. Associazione Medica Sabin.

Cardiovascular diseases are the leading cause of disability and mortality in western countries. Lipoprotein(a) [Lp(a)] is now considered an independent risk factor for atherosclerosis, and might consequently be related to longevity and/or disability. In the context of a study on metabolic and anthropometric parameters in a sample of Italian octo-nonagenarians, Lp(a) and apo(a) isoforms were evaluated. One-hundred and fifty Italian octo-nonagenarians were classified as free-living or disabled, according to Katz's index, and compared to 91 healthy control adults. All the study subjects were recruited from a valley (Val Vibrata valley) near Teramo, in the central part of Italy. The median Lp(a) concentration of the whole group was 17 mg/dL (range 1-161 mg/dL), which is much higher than the values observed in Caucasian populations. No differences were detected between the octo-nonagenarian group (median 16 mg/dL, range 1-126 mg/dL) and the control group (median 19.5 mg/dL, range 1-161 mg/dL), nor between the free-living and the disabled groups. Apo(a) isoforms were similarly distributed among free-living, disabled and control subjects. While our findings suggest that Lp(a) plasma levels and apo(a) isoforms are not factors associated with longevity or disability, we cannot exclude that the low incidence of other major risk factors for atherosclerosis in our free-living octo-nonagenarians hampered the full expression of the lipoprotein(a) atherogenic potential, and thus allowed the achievement of a very old age in a good healthy status, even in carriers of high Lp(a) levels or small apo(a) isoforms.

Aromatic tetra-amidines: antiproteolytic and antiesterolytic activities towards serine proteinases involved in blood coagulation and clot lysis.

The inhibitory effect of 1,3-di-(p-amidinophenoxy)-2,2-bis-(p-amidinophenoxymethyl)propane (TAPP-H), TAPP-halo derivatives (with Cl, Br or I) and benzamidine on the Ancrod, bovine Factor Xa, and human plasmin catalyzed hydrolysis of esters and anilides of amino acids was investigated, at pH 8.1 and 37 degrees, and compared with that shown from these compounds on bovine thrombin and porcine pancreatic kallikrein catalysis. The inhibitory effect of TAPP-H and TAPP-halo derivatives on the proteinases considered, involved, to different extents, in blood coagulation and clot lysis, is higher by at least 10-fold, than that of benzamidine, which binds at the primary specificity subsite (S1) of serine endopeptidases and is commonly taken as a molecular inhibitor model. The high inhibitory effect of aromatic tetra-amidines has been interpreted taking into account an additional productive binding for a second benzamidine or halo-benzamidine moiety to the enzyme surface. Moreover, the data reported here allowed us to clarify the inhibition mechanism (in vitro) of TAPP-H on blood coagulation, induced by the "cancer coagulation factor" produced by the Walker carcinoma in Wistar rats and on the fibrinogen-to-fibrin conversion, and to identify some serine proteinases which act as targets for aromatic tetra-amidines.