Villiam Zamboni

Pharmacology of Desmin (low molecular weight Dermatan sulphate) in healthy volunteers following intravenous bolus administration of different dosages (200, 400, 800 mg)

Eight healthy volunteers (6 males, 2 females, mean age 31.6 yrs), were administered--on three separate days--200, 400 and 800 mg of a new low molecular weight Dermatan sulphate (Desmin), given as a single i.v. bolus (2 min.) injection. Before each administration and 10, 20, 30 min., 1, 2, 4, 8, 12, 24 hours after, blood samples were drawn and the following coagulative assays performed: aPTT (activated Partial Thromboplastin Time), TT (Thrombin Time), anti Xa (Xa Factor inhibition), Heptest, Stachrom D.S.. Furthermore, a kinetic analysis was performed on the activity curves calculated on the Heptest and Stachrom data. Plasma peak values and half lives of the parameters checked showed a clear dose-effect relationship. aPTT and TT showed very short-lasting variations and the inhibition of Factor Xa was moderate, but significant. The most evident and specific effects of Desmin were those on Heptest and Stachrom D.S.: both tests were influenced in a clear-cut and dose-dependent way, mainly as a consequence of the action of Desmin on HCII, with partially different kinetic patterns. A series of in vitro experiments proved an anti Xa effect of Desmin, mediated by antithrombin III, well above the possible interference of the small (< 1%) heparin contaminants in Desmin. An even more marked anti Xa activity was seen in the in vivo study, an observation so far unrecognized for this type of drug: some possible interpretations of this fact are discussed.

THE TREATMENT OF DEEP VEIN THROMBOSIS WITH CONTINUOUS INTRAVENOUS LOW-MOLECULAR-WEIGHT DERMATAN SULPHATE (DESMIN). A PILOT STUDY

Eight patients with femoro-popliteal or sural DVT, confirmed by phlebography, were treated with intravenous Desmin (LMW-dermatan sulphate): on the first day, after an initial i.v. injection of 400 mg, all patients received an infusion of 800 mg in 500 ml of saline, during 24 hours; this infusion was repeated in each of the subsequent 9 days (global treatment period: 10 days). To monitor efficacy of the antithrombotic treatment a phlebography, with calculation of Marder score, was repeated at the end of treatment. Laboratory tests monitoring blood coagulation were carried out: aPTT, TT, PT. Factor Xa inhibition (by chronometric and chromogenic method), Stachrom DS, fibrinogen, prothrombin fragments F1 + 2 and TAT. Seven patients completed the ten-day treatment: 6 patients evidenced good improvement of the phlebographic patterns, 1 remained stationary and 1 patient was withdrawn due to adverse events. During the ten days treatment we did not observe any variation of blood coagulation tests. Desmin tolerability was good and no haemorrhagic episodes were registered. The collected results point to a good antithrombotic activity of the new LMW-dermatan sulphate, that deserves to be further evaluated with controlled investigations on larger number of patients.

Tolerability and Clinical Efficacy of Desmin in the Treatment of Superficial Thrombovaricophlebitis

Fifty-six patients with superficial thrombovaricophlebitis of the lower limbs were enrolled in an open and multicenter (4 centers) trial for a period of thirty days. Patients were randomly allocated to three treatment groups to receive a new low-molecular-weight dermatan sulfate (Desmin) at the dose, respectively, of 100 mg once daily by subcuta neous (SC) route, 100 mg twice a day SC, and 200 mg once daily by intramuscular (IM) route. The general and local tolerability and the clinical efficacy of the drug were evaluated by means of clinical, instrumental, and laboratory parameters. Desmin proved capable of effectively improving the symptoms of patients affected by thrombovari cophlebitis, inducing rapid regression by the tenth day of treatment. The daily dose of 200 mg (either SC or IM) was more effective than the 100 mg dose. The systemic toler ability of the drug, administered for the first time for one month, was extremely good, without significant variations in the relevant laboratory tests. Local tolerance (at the site of injection) of the drug was also good.

Pharmacodynamics of a new low-molecular-weight dermatan sulfate after a single subcutaneous injection in elderly patients with chronic venous disorders: A phase I trial

Abstract Fourteen patients, aged older than 65 years, with chronic venous disorders, underwent a Phase I pharmacodynamic study of the single subcutaneous (SC) administration of a new low-molecular-weight dermatan sulfate. Immediately before and 1, 2, 4, 6, 8, 12, and 24 hours after the SC injection of 100 mg of the drug, the following coagulation and fibrinolysis variables were checked: activated partial thromboplastin time, thrombin time, activated factor X (Xa) inhibition, global anticoagulant activity, as measured by Heptest, selected anti-IIa activity, as measured by Stachrom DS, functional and antigenic plasminogen-activator inhibitor, and functional tissue plasminogen activator. Routine laboratory blood and urine tests to monitor systemic tolerability of the drug were performed. The local tolerability and the occurrence of adverse events were also monitored. Results show anti-Xa and anti-IIa activity, as measured by Heptest and Stachrom DS, increased significantly after administration of the drug, thus suggesting an antithrombotic action. Functional and antigenic PAI concentrations were unchanged. Both systemic and local tolerability of a single SC dose of low-molecular-weight dermatan sulfate were very good.

Pharmacokinetics of low molecular weight dermatan sulphate (desmin) in different cohorts of patients.

BRIEF COMMUNICATION Pharmacokinetics of Low Molecular Weight Dermatan Sulphate (Desmin) in Different Cohorts of Patients Sylvie Saivin, Didier Carrie, Jean Escourrou, Patrick Duchene, Villiam Zamboni5, Miriam Barbanti5, Ernesto Palazzini5 and Georges Houin1 1Laboratoire de Pharmacocinetique et Toxicologie Clinique, Hopital Rangueil, Toulouse, France; Service de Cardiologie, Hopital Purpan, Toulouse, France; Service de Gastro-Enterologie et Nutrition, Hopital Rangueil, Toulouse, France; 4ADME Bioanalyses, Mougins, France; 5Alfa Wassermann, Bologna, Italy.

Preliminary comparison of the clinical efficacy and tolerability of low-molecular-weight dermatan sulfate and calcium heparin in postthrombotic syndrome

Abstract Fifty-three patients with postthrombotic syndrome (36 women and 17 men; mean age, 52.9 years; age range, 26 to 80 years) took part in this open-label, observer-masked, treatment-controlled, multicenter study comparing low—molecular-weight dermatan sulfate (desmin) and calcium heparin. Patients were distributed among three treatment groups: (1) group A—desmin 200 mg once daily intramuscularly (IM); (2) group B—desmin 200 mg twice daily IM; and (3) group C—calcium heparin 5000 IU twice daily subcutaneously. Treatments lasted 2 months for all three groups. The primary efficacy end point of the study was the reduction of limb edema, assessed by measuring changes in the circumference of the more affected limb. Limb venous pressure, healing of stasis ulcers, and improvement of signs and symptoms of venous stasis were also monitored. Treatment tolerability was monitored throughout the study. After 2 months of therapy, desmin and calcium heparin were found to be similarly effective in relieving the signs and symptoms of venous stasis, particularly limb edema and pain. Statistically significant reductions in venous pressure in the affected limbs were achieved with both drugs; however, no statistically significant between-group difference was seen in the reduction of limb circumference, perhaps because of the small number of patients in the study. Although both drugs were effective in promoting healing of cutaneous ulcers, the difference in the prevalence of ulcers (1 patient in the calcium heparin group vs 12 patients in the desmin groups) in the treatment groups precluded a valid comparison of treatments. The tolerability of desmin therapy was found to be superior to that of calcium heparin both systemically (calcium heparin was associated with statistically and clinically significant alterations in serum transaminases) and locally (hemorrhagic suffusion occurred in several patients after the injection of calcium heparin).