Biomedical subjects
Publications and source records attributed to M Basista.
Prostacyclin (PGI2) connects all the pharmacologic properties of drugs being used till now in sudden deafness. 30 patients with sensori-neural sudden deafness were treated by prostacyclin and placebo in the double-blind test situation. In therapeutic group of 15 patients were 87% of complete recovery, but in placebo only 6%.
In a pilot study the therapeutic effect of 2 x 500 mg etofibrate (Lipo Merz retard) on lipids and lipoproteins, fibrinolytic activity and clinical parameters was studied for four weeks in hyperlipidemic patients suffering from arteriosclerosis obliterans (Fontaine stage II/III). The study parameters were evaluated prior to and after the four weeks of treatment. Administration of etofibrate resulted in a significant decrease in serum cholesterol and triglyceride levels, the decrease in LDL-/HDL-cholesterol-ratio due mainly to an elevation of the HDL-cholesterol fraction, an increase in plasma fibrinolytic activity, an increased peripheral blood flow in the ischemic leg, and an increase in the pain-free walking distance. Thus, etofibrate applied twice daily might be recommended for the treatment of hyperlipidemic patients with signs of arteriosclerosis obliterans, Fontaine stage II/III.
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Nitrendipine (Bayotensin) is a dihydropyridine derivative that appears to preferentially dilate peripheral vessels by a cellular mechanism similar to those found with other calcium blocking agents. In this study nitrendipine when infused (0.2-0.3 mg/kg i.v.) into anaesthetized cats caused a release of a substance disaggregating platelet clumps which had adhered to blood superfused collagen strip. The appearance of this unstable disaggregating substance was prevented by the pretreatment of cats with acetylsalicylic acid (50 mg/kg i.v.). In atherosclerotic rabbits nitrendipine stimulated release of prostacyclin-like substance without effect on proaggregatory concentrations of arachidonic acid and adenosine diphosphate. In rats nitrendipine inhibited the development of atherosclerotic changes in the aorta evoked by the atherogenic diet with ergocalciferol (vitamin D2). It is suggested that nitrendipine may promote formation of prostacyclin in arteries and inhibit the development of atherosclerosis.
Molsidomine and its active metabolite SIN-1 were examined in humans and animals for their fibrinolytic and antithrombotic activity. In humans six and eight hours after ingestion of molsidomine retard (8 mg) a marked shortening of euglobulin clot lysis time was observed. Neither molsidomine nor SIN-1 activated fibrinolysis in vitro. In rabbits SIN-1 decreased the size of arterial and venous thrombus. Similar results were obtained with urokinase.
A double-blind study on prostacyclin (5 ng/kg/min infused i.v. for 5 hrs per day during 6 consecutive days) for the treatment of peptic gastric ulcers was carried out in thirty patients (15 prostacyclin, 15 placebo). Gastroscopy and its scoring was performed 1-2 days before the treatment, as well as a day and a week after the course of treatment was completed. Basal acid output (BAO) and pentagastrin stimulated release of gastric acid (maximum acid output MAO; peak acid output PAO) were measured before the treatment, during the third infusion, and one day after all the infusions had been completed. At the same time the basal release of bicarbonate into gastric juice was determined. Prostacyclin significantly accelerated healing of the ulcers at the end point of the study. Simultaneously, in the prostacyclin-treated patients an increase in bicarbonate release into gastric juice was noted, although the acidity of gastric juice was not changed. Our study shows a cytoprotective action of prostacyclin on a damaged human gastric mucosa.
We have studied generation of eicosanoids in blood vessels and platelets of rabbits in relation to platelet aggregation and plasma fibrinolytic activity at early stages of experimental atherosclerosis. A level of lipid peroxides in plasma augmented progressively from the 2-nd to 12-th week of atherogenic diet. In parallel, platelets generated more TXA2 and 12-HETE while in blood vessels a gradual reduction of prostacyclin formation was observed. Reduction in generation of PGI2 was accompanied by steady formation of PGE2. In the second week of the diet a slight decrease appeared of aggregatory response while later aggregability of platelets was increased. At first, plasma fibrinolytic activity was decreased, but it significantly augmented after 12 weeks of the diet. The above data indicate that changes of arachidonic acid metabolism in platelets and blood vessels appear at a very early stage of atherosclerosis and they influence platelet function and plasma fibrinolytic activity.
The distribution of the mucosal PGE2-generating capacity was bioassayed in the duodenum of 17 patients with duodenal ulcer (age range 20-58 years), and in 17 subjects (age range 21-57 years) who did not suffer from this disease. The age of the subjects within both groups was precisely matched in pairs. In contrast to the "young" controls or the "young" patients (under 37) or the "old" patients (over 37) the "old" control group of subjects showed an age-dependent increase in the mucosal PGE2 generation. It is concluded that with increasing age the mucosal PGE2 plays an increasingly important role in the protection against duodenal ulcers.
Molsidomine and its active metabolite SIN-1 were examined in humans and animals for platelet suppressant and fibrinolytic activities. Following oral administration of molsidomine at doses of 6 or 15 mg/kg to rabbits, their blood platelets in PRP ex vivo required higher threshold concentrations of ADP, AA and thrombin to be aggregated. Unlike molsidomine, SIN-1 when infused (10 and 20 micrograms/kg i.v.) into anaesthetized cats caused a release of a substance disaggregating platelet clumps which had adhered to blood superfused collagen strip. The appearance of this unstable disaggregating substance was prevented by the pretreatment of cats with aspirin (50 mg/kg i.v.). It is suggested that SIN-1 may promote formation of a PGI2-like substance. In humans shortening of euglobulin clot lysis time was observed 60 min after a single ingestion of 2 mg of molsidomine. This fibrinolytic effect of molsidomine was not abolished by the pretreatment of patients with aspirin. Neither molsidomine nor SIN-1 activated fibrinolysis in preformed euglobulin clots in vitro.
In a placebo-controlled trial healthy volunteers and patients with hyperlipoproteinemias types II and IV received orally vitamin E at doses of 300 mg and 600 mg daily for 2 weeks. Serum tocopherol levels increased two-fold, but serum concentrations of total lipids, cholesterol, triglycerides, ceruloplasmin and transferrin remained unchanged. Dietary supplementation with vitamin E suppressed elevated concentrations of plasma lipid peroxides and this effect was correlated with an increase in serum antioxidant activity. In patients a mild platelet suppressant effect of vitamin E (600 mg daily) was observed. Feeding an atherogenic diet to rabbits for a week resulted in elevation of plasma lipid peroxides and a 90% decrease in arterial generation of prostacyclin. Enrichment of the atherogenic diet with 100 mg vitamin E daily prevented the increase in plasma lipid peroxides and protected the prostacyclin generating system in arteries. Thus, in hyperlipoproteinemias vitamin E corrects certain abnormalities of lipid metabolism which might predispose to atherosclerosis.
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Twenty-one patients with arteriosclerosis obliterans of lower extremities were treated with beta-pyridylcarbinol (Ronicol) for five weeks. The long-term therapy with beta-pyridylcarbinol did not influence platelet aggregability. Activation of the fibrinolytic system was observed. This fibrinolytic effect of Ronicol was abolished in patients treated with aspirin. In most cases a slight clinical improvement was seen, manifested by elongation of pain-free walking distance and increased blood flow in affected limbs. It is concluded that the therapeutic effect of Ronicol in humans may be partly mediated by the release of endogenous prostacyclin.
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Infusion of PGI2 at a dose of 5 or 10 ng/kg/min during 72 hours into patients with peripheral vascular disease was followed by increased susceptibility of platelets to proaggregatory action of ADP and collagen but not that of arachidonate. The above effects were observed 24 hours after termination of infusion of PGI2. A tendency to an increased formation of TXA2 in PRP aggregated by arachidonate was also noticed. Infusion of PGI2 at a dose of 2 mg/kg/min during 72 hours into the patients caused the decreased platelet aggregability to ADP and arachidonate but not to collagen, and a decreased tendency to production of TXA2 in PRP aggregated by arachidonate. The existence of a "rebound effect" in platelets after a long term PGI2 therapy is suggested.
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Ten patients with ischaemic stroke were treated with prostacyclin (2.5-5.0 ng/kg/min i.v. in 6 h courses 4-10 times during 1-2.5 days). In all patients a dramatic regression of hemiplegia, or hemiparesis, or aphasia occurred in the first few hours of prostacyclin infusion. Four to eight weeks later 6 patients left the clinic without neurological deficit; 3 patients had minor residual hemiparesis in upper limbs. In one patient, the occlusion of the contralateral carotid artery led to his death. It is considered that an antagonism may exist between endogenous cerebral prostanoids and prostacyclin and may have been responsible for the beneficial effects of prostacyclin therapy.