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At least 127 records · Page 7Linked to original sources
PubMed1979

Azaprostanoic acid derivatives. Inhibitors of arachidonic acid induced platelet aggregation.

A series of 13-azaprostanoic acids (4a-h) and a 15-azaprostanoic acid (11a) have been prepared. Synthesis of the 15-aza derivative is based on a novel transformation of a ketone to an N-substituted ethylenamine using a formylmethylimino phosphate derivative. Several of the azaprostanoic acid derivatives were found to be potent inhibitors of platelet aggregation induced by arachidonic acid, whereas no effect was observed on ADP-induced primary aggregation, indicating blockade of the platelet arachidonic acid cascade. The compounds do not inhibit bovine cyclooxygenase activity and are postulated as acting beyond the synthesis of the prostaglandin endoperoxides. The inhibitory effect of the 13-aza series is highly sensitive to both stereochemistry and length of the amino side chain. Any deviation from the natural prostaglandin skeletal arrangement results in decreased biological activity.

Adenosine Diphosphate↗
PubMed1977

Prostaglandin isosteres. 1. (8-Aza-, 8,10-diaza-, and 8-aza-11-thia)-9-oxoprostanoic acids and their derivatives.

A series of novel (8-aza-, 8,10-diaza-, and 8-aza-11-thia)-9-oxoprostanoic acids has been synthesized and evaluated for their ability to mimic the E series prostaglandins in stimulating cAMP formation in the mouse ovary and in binding to the rat kidney plasma prostaglandin receptor. 7-[2-(3-Hydroxyoctyl)-1,1,4-trioxo-3-thiazolidinyl]heptanoic acid markedly stimulates cAMP formation at reasonable pharmacological concentrations and avidly binds to the rat kidney prostaglandin receptor.

Animals↗
PubMed1987

[Treatment of duodenal ulcer with rosaprostol in patients resistant to treatment with anti-H2].

The results obtained with the combined treatment Rosaprostol + anti-H2 in 10 patients with duodenal ulcer previously treated with insufficient results with anti-H2 drugs are described (in comparison with other 10 patients under the same conditions treated with anti-H2 alone). The results are clearly favourable (statistical significance) for Rosaprostol. The drug was well tolerated.

Adult↗
PubMed1988

Prostaglandin cytoprotection in man: effectiveness of rosaprostol.

We studied the effect of a new prostaglandin analogue, 9-hydroxy-19,20-bis-norprostanoic acid (rosaprostol), on the duodenal mucosa of humans after administration of 40% ethanol. Eighteen healthy volunteers entered the study, which followed a blind cross-over design. At time 0 all the volunteers received rosaprostol or placebo; 5 minutes later, 40% ethanol (50 ml dose) was given. The mucosa was examined for lesions 3, 60 and 180 min later under endoscopy, light and scanning microscopy. It was found that: (i) 40% ethanol damaged the duodenum, with blood extravasation, inflammation and necrosis of the mucosa, (ii) rosaprostol significantly protected the mucosa 3 min after 40% ethanol, and (iii) the damage became worse after 3 h when placebo was given, whereas it was reduced after 1 h when PG was administered. The results suggest that PGs not only protect the mucosa against ethanol damage, but also stimulate its recovery.

Adolescent↗
PubMed1984

Modulation of vascular thrombosis by products of arachidonic acid metabolism.

It has been postulated that metabolites of the arachidonic acid pathway exert an important influence on hemostasis and thrombosis. This notion is based on in vitro experiments. We have utilized two experimental models to elucidate the physiologic roles of thromboxane A2 (TxA2) and prostacyclin (PGI2) in the modulation of thrombus formation. The role of TxA2 in promoting thrombus formation was evaluated in a rabbit model where the aorta was deendothelialized by a balloon catheter technique and indium-111-labeled platelets were used as a marker for quantifying platelet deposition. Both 1-benzylimidazole, a thromboxane synthase inhibitor, and 13-azaprostanoic acid, an antagonist of thromboxane/endoperoxide receptors significantly reduced the platelet deposition onto the damaged vessel wall. The data indicate the TxA2 plays an important role in thrombosis and hemostasis. The influence of PGI2 insufficiency due to accelerated PGI2 degradation on microvascular thrombosis was evaluated in a unique clinical disease, i.e. thrombotic thrombocytopenic purpura (TTP). Accelerated PGI2 degradation was observed in several patients with chronic TTP. The degradation abnormalities were corrected by plasma infusion in vivo or serum supplement in vitro. To test the hypothesis that PGI2 must be bound to serum macromolecules to prevent rapid hydrolysis, serum binding capacity for PGI2 was measured by Sephadex G-25 gel filtration. The binding capacity was significantly reduced in the patients and was corrected by serum supplement. Abnormalities of PGI2 binding were also noted in a group of patients with ischemic stroke. Our findings suggest that there exist in the serum certain constituents which bind and stabilize PGI2.(ABSTRACT TRUNCATED AT 250 WORDS)

Arachidonic Acid↗
PubMed1988

Boreal freshwater fish diet modifies the plasma lipids and prostanoids and membrane fatty acids in man.

The effect of fish diet on 43 healthy male students was studied. They ate a fish-containing meal for 15 weeks on an average of 3.7 times per week. Twenty-one of them voluntarily restricted their lipid intake while the rest ate normally. Controls continued their usual eating habits (19 students). The meals consisted of Finnish freshwater fish (87%) (vendace, pike, perch and rainbow trout) and brackish water fish (13%) (Baltic herring) that provided about 1 g of omega-3 polyunsaturated fatty acids per day (0.25 g eicosapentaenoic acid and 0.55 g docosahexaenoic acid). During the diet, omega-3 fatty acids increased in erythrocyte ghosts and platelets at the expense of omega-6 fatty acids. The concentration of serum cholesterol diminished in those fish consumers who lowered their lipid intake. Apolipoprotein A1 and B were lowered in both fish-consuming groups. Triglyceride levels also showed a tendency to decrease. The formation of thromboxane B2 during incubation of whole blood decreased in both fish-consuming groups. The decrease of plasma 6-keto-PGF1 alpha was not statistically significant, if compared with the controls. The results obtained indicate that a moderate intake of fish-containing meals has some beneficial effects on the plasma lipid and prostanoid metabolism, when coronary heart disease risk factors are considered.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

The thromboxane antagonist, 13-azaprostanoic acid, inhibits arachidonic acid-induced Ca2+ release from isolated platelet membrane vesicles.

In the present study we investigated the ability of the arachidonic acid metabolites, prostaglandin H2 and thromboxane A2, to release Ca2+ from isolated platelet vesicles. The vesicles were prepared through modification of previously described procedures. 45Ca uptake and release were determined by Millipore filtration and isotope counting of the filter paper. Incubation of the vesicles (25 degrees C) with 50 microM CaCl2 (plus 45Ca) resulted in the accumulation of 13 nmol Ca2+ per mg of protein under steady-state conditions. Addition of arachidonic acid (25 microM) resulted in a 42% release of the accumulated Ca2+ and the production of 150 ng thromboxane B2/mg protein. Pretreatment of the vesicles with indomethacin (4 microM) completely inhibited arachidonic acid-induced Ca2+ release and reduced thromboxane B2 synthesis by 82%. Pretreatment of the vesicles with the specific thromboxane A2/prostaglandin H2 antagonist, 13-azaprostanoic acid (20 microM), also resulted in complete inhibition of Ca2+ release but no inhibition of thromboxane B2 production. Addition of prostaglandin H2 (0.3 microM) to the platelet vesicles produced a significant release of Ca2+ only in the presence of the adenylate cyclase inhibitor, 2',5'-dideoxyadenosine (100 microM). This Ca2+ release was totally blocked by 13-azaprostanoic acid (20 microM). The thromboxane synthetase inhibitor 9,11-azoprosta-5,13-dienoic acid (azo analog I, 3.6 microM), in the presence of 2',5'-dideoxyadenosine, only slightly inhibited Ca2+ release in response to added prostaglandin H2, even though thromboxane B2 production was blocked by 95%.

Adenosine Triphosphate↗
PubMed1983

2-(6-carboxyhexyl)cyclopentanone hexylhydrazone. A potent and time-dependent inhibitor of platelet aggregation.

Two new azaprostanoids, a hydrazone (3) and hydrazide (4), have been prepared by the condensation of 2-(6-carboxyhexyl)cyclopentanone with n-hexylhydrazine and caproic acid hydrazide. Preliminary results with the stable hydrazide 4 indicate that it inhibits arachidonic acid (AA) induced human platelet aggregation and that, unlike 13-azaprostanoic acid (1), its site of action is at the cyclooxygenase level. Results with the unstable hydrazone derivative 3 indicate it to be a potent and time-dependent inhibitor of AA-induced human platelet aggregation, with its site of action also at the cyclooxygenase level.

Arachidonic Acid↗
PubMed1989

Eicosanoid release as laboratory indicator of biocompatibility.

Biocompatibility evaluation of extracorporeal devices requires the establishment of sensitive indicators of blood cells/surface interactions. Among others, arachidonic acid derivatives, such as prostaglandins and thromboxanes, play an important role in the cell control systems. Hence, the release of eicosanoids during blood exposure to dialyzer membranes was investigated. Experiments included in vitro incubation of human blood with flat membranes (FM), as well as ex vivo perfusion of hollow fiber membranes (HFM) with blood from healthy volunteers in single-pass fashion. In both models, a significant release of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) was detected. In addition, the amount of eicosanoid release depended on the type of membrane tested. After a 10-min FM incubation with fresh blood, plasma concentrations of TXB2 and PGE2 were pronounced by polycarbonate when compared to Cuprophan and polyacrylonitrile. During 10 min of open loop perfusion of HFM, polymethylmethacrylate was the most active biomaterial, whereas the reactivity of Cuprophan was significantly lower. Among HFM, Hemophan was by far the less active. These results indicate that the release of eicosanoids represents a sensitive parameter of blood cells/membrane reactivity. Thus, the question arises as to whether or not the extracorporeal process of cyclooxygenase activity could contribute to the clinical side effects of chronical hemodialysis.

Biocompatible Materials↗
PubMed1986

Coronary vascular occlusion mediated via thromboxane A2-prostaglandin endoperoxide receptor activation in vivo.

The use of enzyme inhibitors to clarify the role of thromboxane A2 in vasoocclusive disease has been complicated by their non-specific action. To address this problem we have examined the effects of thromboxane A2/prostaglandin endoperoxide receptor antagonism in a canine model of platelet-dependent coronary occlusion. Two structurally distinct thromboxane A2/prostaglandin endoperoxide receptor antagonists, 3-carboxyl-dibenzo (b, f) thiepin-5,5-dioxide (L636,499) and (IS-(1 alpha,2 beta(5Z),3 beta,4 alpha))-7-(3-((2-((phenylamino)-carbonyl)hydrazino)methyl)-7- oxabicy-clo(2.2.1)-hept-2-yl)-5-heptenoic acid (SQ 29,548), were studied to ensure that the effects seen in vivo were mediated by receptor antagonism and did not reflect a nonspecific drug effect. Both compounds specifically inhibited platelet aggregation induced by arachidonic acid and by the prostaglandin endoperoxide analogue, U46619, in vitro and ex vivo, and increased the time to thrombotic vascular occlusion in vivo. When an antagonist (L636,499) was administered at the time of occlusion in vehicle-treated dogs, coronary blood flow was restored. In vitro L636,499 and a third antagonist, 13-azaprostanoic acid, specifically reversed endoperoxide-induced platelet aggregation and vascular smooth muscle contraction. Neither compound altered cyclic AMP in platelet-rich plasma before or during disaggregation. Therefore, reversal of coronary occlusion may reflect disaggregation of platelets and/or relaxation of vascular smooth muscle at the site of thrombus formation through specific antagonism of the thromboxane A2/prostaglandin endoperoxide receptor. Thromboxane A2/prostaglandin endoperoxide receptor antagonists are compounds with therapeutic potential which represent a novel approach to defining the importance of thromboxane A2 and/or endoperoxide formation in vivo.

Animals↗
PubMed1981

Increased platelet arachidonic acid metabolism in diabetes mellitus.

Platelets obtained from some diabetic patients show enhanced in vitro platelet aggregation. This study sought to determine if platelet obtained from insulin-dependent diabetic subjects synthesize increased quantities of the labile aggregating substance, thromboxane A2 (TXA2), and if it may play a role in the enhanced platelet aggregation. Arachidonic acid (1 mM)-stimulated TXA2 synthesis, as determined via radioimmunoassay of its stable metabolite TXB2, was significantly greater (P less than 0.01, N = 12) in platelet-rich plasma obtained from diabetics compared with matched controls. Arachidonic acid-stimulated TXB2 synthesis in the diabetic platelet-rich plasma was positively correlated with the ambient fasting plasma glucose (r = 0.61, P less than 0.02, N = 15). Platelet aggregation induced by arachidonic acid (0.4-0.8 mM) was inhibited significantly less by 13-azaprostanoic acid (P less than 0.04, N = 14), a competitive antagonist of the actions of prostaglandin H2 or TXA2 on platelets, compared with matched controls. The results support the notion that platelets obtained from some insulin-dependent diabetic subjects manifest increased synthesis of TXA2, which may contribute to the enhanced platelet aggregation.

Arachidonic Acid↗
PubMed1988

Effects of a synthetic prostanoid, rosaprostol, on the changes of gastric acidity and digestive disorders induced by NSAID.

In 24 subjects without upper gastrointestinal lesions, gastric pH was measured from 30 min before until 90 min after the administration of diclofenac sodium (50 mg), piroxicam (20 mg), or 500 mg acetylsalicylic acid. In all these cases a drop of gastric pH was recorded, which started with all the drugs 15 min after their administration and lasted throughout the recording. Pre-treatment with rosaprostol (2 g given 30 min before the start of the trial) prevented the drop in pH. Twenty subjects with chronic joint diseases were divided into two groups in a cross-over double-blind randomized experimental design. One group received piroxicam (20 mg) + rosaprostol (2 g) daily; the other group was treated with piroxicam 20 mg + placebo. The patients were clinically reviewed every week in a month and questioned about their symptoms. Statistical analysis demonstrated that patients with articular diseases treated with NSAIDs + rosaprostol exhibited a frequency and severity of symptoms lower than those recorded in subjects receiving NSAIDs + placebo. Rosaprostol was found to be capable of antagonizing the variations of gastric acid output induced by the oral administration of NSAIDs, and to prevent and treat the occurrence of digestive disorders when given in combination with NSAIDs. These effects result from the action of rosaprostol on the mucosal barrier, and this cytoprotective action is confirmed by the present study with continuous measurements of gastric pH.

Adult↗
PubMed1988

Thrombosis associated with antiphospholipid antibodies cannot be explained by effects on endothelial and platelet prostanoid synthesis.

The effect of 23 antiphospholipid antibody positive SLE sera, 4 antiphospholipid antibody negative SLE sera and 17 control sera on endothelial prostacyclin and platelet thromboxane A2 production was studied. Endothelial cells and platelets were stimulated with different agonists. Depending on the stimulus used, 4-19% of the SLE sera inhibited the prostacyclin release, whereas 4-28% enhanced prostacyclin production. Our data suggest that the pathophysiological mechanisms underlying decreased prostacyclin production are heterogeneous. Follow-up of two patients showed that prostacyclin inhibitory activity was variable in time. Platelet thromboxane production was normal or increased, but never decreased in the presence of the SLE sera. An imbalance in thromboxane A2/prostacyclin ratio was present in some patients, but did not correlate with a history of thrombosis. We conclude that, in general, interference of antiphospholipid antibodies with endothelial or platelet prostanoid synthesis does not explain the occurrence of thromboembolic manifestations in antiphospholipid antibody positive SLE patients.

Adult↗
PubMed1988

Serum and urine kinetics of rosaprostol in volunteers.

The kinetics of rosaprostol (9-hydroxy-19,20-bis-norprostanoic acid, Rosal) and of its metabolite (3-(2-n-hexyl-5-hydroxy-cyclopentyl)propionic acid) has been determined in plasma and in urine of 10 healthy volunteers after oral administration of 500 mg of rosaprostol. The peak of rosaprostol (of 524 ng/ml) appears at 4 h, whereas that of the metabolite (of 503 ng/ml) appears earlier (2 h); therefore the relationship between the two substances does not follow the precursor-successor relationship in plasma and a compartmental model has been used to fit the data. In this model the biotransformation process occurs before entering the central compartment (first-pass effect). The mean half-life of rosaprostol is equal to about 5 h and that of the metabolite is equal to 3 h. All of rosaprostol is biotransformed and only the metabolite is partially eliminated by the urine. The urinary excretion of the metabolite represents only a small fraction of the administered dose. The urinary clearance of the metabolite is equal to 5.3 l/h. The volume of distribution of both substances is equal to 21.2 l.

Anti-Ulcer Agents↗
PubMed1984

Essential fatty acids in perspective.

There are two families of essential fatty acids, the linoleic and linolenic. Linoleic acid (C18:2n-6), found mainly in vegetable seed oils, is desaturated and elongated in the body, forming arachidonic acid (C20:4n-6). Linolenic acid (C18:3n-3), the main dietary source of which is leaves, is desaturated and elongated, forming two fatty acids that are prevalent in fish oils: timnodonic (C20:5n-3) and clupanodonic (C22:6n-3). EFA are very easily peroxidized in air, but vitamin E protects against this. There are three functions of EFA. The most important is as part of phospholipids in all animal cellular membranes: in deficiency of EFA faulty membranes are formed. A second is in the transport and oxidation of cholesterol: EFA tend to lower plasma cholesterol. A third function is as precursors of prostanoids which are only formed from EFA. Deficiency of EFA in experimental animals causes lesions mainly attributable to faulty cellular membranes: sudden failure of growth, lesions of skin and kidney and connective tissue, erythrocyte fragility, impaired fertility, uncoupling of oxidation and phosphorylation. In man pure deficiency of EFA has been studied particularly in persons fed intravenously. A relative deficiency (that is, a low ratio in the body of EFA to long-chain saturated fatty acids and isomers of EFA) is common on Western diets and plays an important part in the causation of atherosclerosis, coronary thrombosis, multiple sclerosis, the triopathy of diabetes mellitus, hypertension and certain forms of malignant disease. Various factors affect the dietary requirement of EFA.

Arteriosclerosis↗
PubMed1982

Uterine prostaglandin F metabolite production in relation to glucose availability in late pregnancy and a possible influence of diet on time of delivery in the mare.

The production of uterine PGFM during different dietary states has been investigated in pregnant mares in late gestation. Arterial and uterine venous plasma concentrations of PGFM rose when food was withdrawn for 12-30 h and the V-A difference widened significantly. There was an inverse correlation between the rise in PGFM and the fall in plasma glucose during a fast, and a significant decrease in the A-V plasma glucose differences across the uterus. Plasma PGFM and free fatty acid concentrations before and during food withdrawal were also correlated but no uterine A-V difference in free fatty acids could be detected. An immediate fall in uterine PGFM levels occurred upon refeeding or infusion of glucose, which was more closely correlated with the rise in plasma glucose than the fall in free fatty acids, both of which occurred after restoration of nutrient. No detectable alterations in uterine blood flow occurred during a fast/feed cycle and hence A-V or V-A differences across the uterus gave an indication of uptake or output. PGFM production increased 5 times during a fast and glucose uptake decreased by about 70%. Basal levels were restored by 1-3 h after feeding or glucose infusion. Daily fluctuations in plasma PGFM concentrations were closely associated with the time of the morning feed of concentrates. The overnight rise in PGFM was greatest in late gestation. Five of the 8 mares delivered prematurely within 1 week of the last period of food withdrawal. Attention is drawn to the consequences of inadequate or intermittent feeding on premature delivery.

Animals↗