Antioxidant properties of indapamide, 5-OH indapamide and hydrochlorothiazide evaluated by oxygen-radical absorbing capacity and electron paramagnetic resonance.

The aim of these experiments was to investigate the radical scavenging properties of three diuretics: indapamide (IND) and its major metabolite, 5-OH indapamide (5-OH IND), compared to a reference diuretic, hydrochlorothiazide (HTZ). Electron Paramagnetic Resonance (EPR) was used to determine the scavenging abilities of these compounds on enzymatically produced superoxide radical anion, with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) used as a spin-trap. These experiments revealed that IND and specially 5-OH IND were effective superoxide radical anion scavengers at 0.2 mg/ml. In the second part of these studies, allophycocyanin was used as an indicator of free radical mediated protein damage. In the assay, 2,2'-azobis(2-amidinopropane) hydrochloride (AAPH) was used as a peroxyl radical generator, Trolox (a water-soluble analogue of vitamin E) as a control standard, and the loss of allophycocyanin fluorescence was monitored. The antioxidant effects of the diuretics were expressed in oxygen-radical absorbing capacity (ORAC), where one ORAC unit equals the net protection produced by 1 microM Trolox. HTZ showed no protection up to 100 microM final concentration, whereas IND and 5-OH IND showed linear correlation with respect to concentration when expressed in ORAC units: 5-OH IND induced the highest protection against peroxyl radical. The above observations suggested that IND and 5-OH IND are potent radical scavengers, with the metabolite 5-OH IND having a superior antioxidant potency than IND. By contrast, HTZ had no effect. These radical scavenging properties of 5-OH IND may be of clinical interest for vascular protection and may help to protect the heart from oxidative injury.

The beneficial effect of a beta-D-xyloside, Iliparcil, in the prevention of postthrombolytic rethrombosis in the rat.

The effect of Iliparcil, a new orally active beta-D-xyloside venous antithrombotic, was studied on the rethrombosis following thrombolytic therapy in rats, using a modified Umetsu model. The drug was administered by oral route prior to thrombolytic therapy, which consisted of administering a combination of heparin and urokinase (H/U) at 37.5 and 70,000 IU/kg, respectively. Time to reocclusion increased from 3.9 min with saline to 10.5 min following H/U injection. When Iliparcil (30 mg/kg, oral route) was administered 4 h before H/U injection, the time to reocclusion was increased by 250% compared with H/U alone (p < 0.001). Similarly, dermatan sulfate (DS), administered intravenously (3 mg/kg) 5 min before thrombus induction, also increased the time to reocclusion (300% compared with H/U alone; p < 0.001). It was also shown that times to reocclusion following Iliparcil or DS treatments were still increased even when heparin dosage was decreased. These results suggest that an antithrombotic product derived from the beta-D-xyloside family could be advantageously used in combination with thrombolytic treatment instead of heparin, which causes complications and side effects.