Gianluigi Viganò

1-(2-Pyrimidinyl)-Piperazine as Active Metabolite of Buspirone in Man and Rat

Buspirone (BP), a newly developed antianxiety agent, forms 1-(2-pyrimidinyl)-piperazine (PmP) during its biotransformation in rats and man. After oral administration of pharmacologically effective doses of BP-hydrochloride to rats (1 and 10 mg/kg), the metabolite appears in significant amounts in body fluids and tissues; it is highly concentrated in the central nervous system, the brain-to-plasma concentration ratios being approximately 5 at the time of the maximum concentrations (Cmax). In man given the anxiolytic dose (20 mg) of BP the metabolite reaches higher plasma Cmax values than its parent drug. Its plasma elimination t1/2 is more than double that for BP. These results, together with the fact that PmP is biochemically and pharmacologically active, suggest that the metabolite may contribute significantly to the central effects of the parent drug.

Moderate doses of aspirin and risk of bleeding in renal failure

Uraemic patients have a bleeding tendency thought to be due to platelet functional abnormalities, but haemodialysis paradoxically exposes patients to the thrombotic complications of arteriovenous shunts. Possible treatments of the latter have been debated. The effect of 100 mg/m2 aspirin on haemostatic function was studied in 29 uraemic patients on chronic haemodialysis who had normal or only slightly prolonged bleeding times. Aspirin did not significantly affect bleeding time in healthy controls but prolonged it in uraemic patients. In 12 of the 29 uraemic patients, the bleeding time after aspirin was longer than 15 min. Aspirin completely abolished thromboxane A2 generation by both control and uraemic platelets, indicating that its effect in uraemic patients is not due to differential inhibition of platelet cyclo-oxygenase. Products of lipoxygenase enzyme and factor VIII von Willebrand factor did not seem to have a role. A careful risk-benefit evaluation is necessary before giving aspirin to uraemic patients on haemodialysis to prevent thrombosis of the arteriovenous shunt.

Recombinant human erythropoietin to correct uremic bleeding.

Recombinant human erythropoietin may improve hemostasis of uremic patients by correcting anemia. However, a complete correction of renal anemia carries the risk of hypertension, encephalopathy, thrombosis, and hyperkalemia. Our aim was to establish the minimum level of packed cell volume (PCV) achieved with recombinant human erythropoietin that corrects the prolonged bleeding time in uremia. Twenty patients with chronic renal failure, anemia, and very prolonged bleeding time (greater than or equal to 15 minutes) were randomly allocated to erythropoietin or no specific treatment. The initial dose of erythropoietin was 50 U/kg intravenously (IV) three times a week. Every 4 weeks, the dose was increased by 25 U/kg until a normalization of bleeding time was achieved. Erythropoietin at a dose ranging from 150 to 300 U/kg/wk induced an increase in PCV to a range of 27% to 32% in all patients but one, and normalized bleeding time in all patients. A significant negative correlation (r = 0.898, P less than 0.001) was found between PCV and bleeding time measurements. Erythropoietin also significantly (P less than 0.01) increased values for red blood cell (RBC) distribution width (basal, 11.3 +/- 0.6; 12 weeks, 13.1 +/- 1.3). Platelet count and platelet function parameters did not significantly change. In untreated patients, no changes were recorded in all the parameters considered. These results establish in a controlled fashion that erythropoietin shortens bleeding time of uremic patients and indicate that a partial correction of renal anemia is enough to normalize bleeding time.

Influence of Antacid Administrations on Aspirin Absorption in Patients With Chronic Renal Failure on Maintenance Hemodialysis

In order to investigate the possible interaction between oral aspirin and antacids in uremic patients on chronic hemodialysis, we administered to 5 uremic patients: (1) aspirin alone; (2) aluminum-magnesium hydroxide with aspirin; (3) aluminum-magnesium hydroxide followed (two hours) by aspirin; (4) calcium carbonate simultaneously with aspirin; and (5) calcium carbonate followed (two hours) by aspirin. In all the occasions, aspirin was given two hours after a standard lunch. Both antacid preparations induced comparable changes in aspirin mean peak plasma concentration (Cmax), if given simultaneously with aspirin, whereas no difference was found in other pharmacokinetic parameters. When antacids were followed (two hours) by aspirin, both Cmax and time of maximum concentration (Tmax) were significantly altered in respect to the value with aspirin alone. No changes in the time course of post aspirin serum thromboxane B2 were detected when aspirin and antacids were administered simultaneously, but the inhibition of serum thromboxane B2 was delayed when antacids were followed (two hours) by aspirin. These results indicate that the administration of antacids to uremic patients interferes with absorption of oral aspirin. This interference can be minimized if aspirin and antacids are given simultaneously.

Failure of Prostacyclin to Improve Peripheral Arterial Disease in Dialysis Patients

Giuseppe Remuzzi, MD, Istituto di Ricerche Farmacologiche Mario Negri, Via Gavazzeni 11, I-24100 Bergamo (Italy) Dear Sir, Patients with severe atherosclerosis are generally accepted for chronic treatment of end-stage renal failure by dialytic techniques [1,2]. In these patients atherosclerotic complications are the most common cause of mortality [3] and peripheral arterial disease an important cause of disability, probably exacerbated by the accelerated atherosclerosis described in dialysis patients [4]. Surgery x is usually unsuitable for these patients because of extensive arterial disease and/or general debility, and conventional medical management is often unsuccessful or contraindicated. So, the results of clinical trials suggesting that prostacyclin (PGI2), a potent vasodilator and anti-platelet agent [5], can be useful in the medical treatment of peripheral arterial disease [6–8], prompted us to assess the effectiveness of this new promising treatment in dialysis patients with peripheral arterial disease. Five male patients (table 1) with stable intermittent claudication (no changes in walking distance during the previous 3 months) were randomly allocated, in a double-blind crossover placebocontrolled trial, to receive an 8-hour intravenous infusion each day for 3 consecutive days either of PGI2 (Wellcome Foundation, Rome, Italy; 2–10 ng/kg/min) dissolved in glycine buffer or of glycine buffer alone. After a 3-month interval each patient crossed over to the other arm of the trial. The diagnosis of peripheral arterial disease was based on typical history, clinical examination and angiography. The following were evaluated both before and after each infusion: skin color, foot temperature (as mean of hallux, medial and lateral malleolar, and interdigital temperatures), hallux oscillography – basal and after 40 min of indirect warming (IW) -‚ walking distance and platelet aggregation. Platelet aggregation was studied 24 h and hallux oscillography and walking distance 1 week after the end of the infusion. Blood pressure and heart rate were monitored during the infusions. Data were analyzed by two-way analysis of variance using Tukey-Cicchetti test for multiple comparison. At the end of the study, no patient was assessed as having improved skin color after either treatment. The mean increases in foot temperatures after PGI2 and glycine infusion were not significantly different. Room temperature was constant during the entire study period. Basal hallux oscillography showed a significant increase in hallux arterial pulse after IW only in the less involved side before either PGI2 (pre IW: 3.7 ± 1.2 mm, post IW: 13.5 ± 7 mm; p < 0.05)

Thrombogenesis and Anticoagulation in Patients Undergoing Chronic Hemodialysis

A tendency toward thrombosis (particularly of the arterovenous shunt) is a frequent complication of uremic patients on hemodialysis. It is well known that uremia is associated with complex coagulation abnormalities (1, 2, 3, 4) which include both bleeding diathesis (for a review see chapter by Winchester JF) and hypercoagulability. Table 1 shows the factors involved in the latter disturbance. The results of the global coagulation screening tests in uremic patients are generally normal. Most consistent findings are an increased level of fibrinogen (5) and decreased protein C anticoagulant activity with normal amidolytic activity and antigen (6, 7). Recently, it has been documented that the reduced protein C anticoagulant activity is due to the presence of a soluble plasma inhibitor that interferes specifically with the anticoagulant activity of activated protein C (8). Given the role of fibrinogen and protein C in coagulation homeostasis, it is not surprising that these abnormalities contribute to the increased risk of thrombosis episodes in these patients. In vivo studies have also demonstrated enhanced platelet activity in this population (9, 10, 11).