iloprost and taprostene

Topics: Alprostadil; Clinical Trials as Topic; Epoprostenol; Humans; Iloprost; Prostaglandins; Prostaglandins, Synthetic; Vascular Diseases

Topics: Alprostadil; Clinical Trials as Topic; Epoprostenol; Humans; Iloprost; Prostaglandins; Prostaglandins, Synthetic; Vascular Diseases

The influence of intravenous infusions of various prostaglandins on in vivo platelet function was studied after labelling of autologous platelets with 100 mu ci 111 indium-oxinesulfate in patients with peripheral vascular disease stage II according to FONTAINE. PGI2 (5 ng/kg/min) provoked a significant decrease of platelet deposition and a prolongation in platelet half-life time (74 +/- 6 vs 68 +/- 5 hours). PGE1 (25 ng/kg/min) failed to influence platelet deposition, but prolonged significantly platelet half-life time (82 +/- 6 vs 76 +/- 8 hours). CG 4203 (25 ng/kg/min) decreased significantly platelet deposition and prolonged significantly platelet half-life time (73 +/- 10 vs 67 +/- 11 hours). Iloprost (1 and 2 ng/kg/min) reduced significantly platelet deposition without dose relation. Half-life time was increased significantly after therapy compared to placebo (1 ng: 76 +/- 7 vs 69 +/- 7; 2 ng: 73 +/- 9 vs 67 +/- 9 hours).

Topics: Aged; Alprostadil; Arteriosclerosis; Cardiovascular Agents; Epoprostenol; Humans; Iloprost; Male; Middle Aged; Platelet Aggregation Inhibitors

Herein we provide evidence for the coexpression of two distinct prostacyclin (PGI(2)) receptors (IP) on BEAS-2B human airway epithelial cells. IP receptor heterogeneity initially was suggested by the finding that the rank orders of potency of PGI(2) and three structurally similar analogs [taprostene, iloprost, 15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC)] for the inhibition of chemokine (CXCL9 and CXCL10) release and for transcriptional activation/augmentation of cAMP response element and glucocorticoid response element luciferase reporters were distinct. Indeed, PGI(2), taprostene, and iloprost activated both reporters whereas 15-deoxy-TIC was inert. Conversely, 15-deoxy-TIC, PGI(2), and taprostene (but not iloprost) suppressed chemokine release. Further experiments established that iloprost did not antagonize the inhibitory effect taprostene or 15-deoxy-TIC on chemokine output. Likewise, 15-deoxy-TIC failed to antagonize taprostene- and iloprost-induced reporter transactivation. Thus, iloprost- and 15-deoxy-TIC-induced responses were apparently mediated via pharmacologically distinct receptors. In human embryonic kidney 293 cells overexpressing the human recombinant IP receptor receptor, 15-deoxy-TIC was considerably less potent (>10,000-fold) than iloprost and taprostene in promoting cAMP accumulation, yet in BEAS-2B cells, these analogs were equipotent. IP receptor heterogeneity was also supported by the finding that the affinity of the IP receptor antagonist R-3-(4-fluorophenyl)-2-[5-(4-fluorophenyl)-benzofuran-2-yl-methoxycarbonyl-amino] propionic acid (RO3244794) for the receptor mediating inhibition of chemokine release was approximately 10-fold lower than for the receptor mediating both transcriptional outputs. Finally, small interfering RNAs directed against the IP receptor gene, PTGIR, failed to block the suppression of chemokine output induced by taprostene and 15-deoxy-TIC, whereas taprostene- and iloprost-induced transcriptional responses were markedly attenuated. Collectively, these results indicate that PGI(2), taprostene and 15-deoxy-TIC suppress chemokine release from BEAS-2B cells by interacting with a novel IP receptor that we denote here as the "IP(2)" subtype.

Topics: Benzofurans; Cells, Cultured; Chemokine CXCL10; Chemokine CXCL9; Cyclic AMP; Dose-Response Relationship, Drug; Epoprostenol; HEK293 Cells; Humans; Iloprost; Propionates; Receptors, Epoprostenol; Receptors, Prostaglandin; Recombinant Proteins; Respiratory Mucosa

The ability of prostacyclin analogues to stimulate adenylyl cyclase (AC) and phospholipase C (PLC) in Chinese hamster ovary (CHO) cells expressing cloned human (hIP) or cloned mouse (mIP) prostacyclin receptors has been compared. For hIP, the order of potency (pEC(50)) for stimulating AC and PLC pathways was similar: AFP-07 (9.3, 8.4)>cicaprost (8.3, 6.9), iloprost (7.9, 6.8)>taprostene (7.4, 6.8)>carbacyclin (6.9, 6.6), PGE(1) (6.6, 5.1). Although the standard IP agonists cicaprost and iloprost behaved similarly in both hIP and mIP receptor-expressing cells, carbacyclin and PGE(1) showed significantly higher potency at the mIP receptor, suggesting that the agonist recognition sites on hIP and mIP receptors are not identical. A further distinction between hIP and mIP receptors was found with taprostene, which had greater efficacy at hIP receptors (AC 94%, PLC 14%) than at mIP receptors (AC 77%, PLC 0%) (cicaprost=100% in each assay).

Topics: Adenylyl Cyclases; Animals; Cloning, Molecular; COS Cells; Cricetinae; Enzyme Activation; Epoprostenol; Gene Expression; Humans; Iloprost; Mice; Prostaglandins, Synthetic; Rats; Receptors, Epoprostenol; Receptors, Prostaglandin; Recombinant Proteins; Signal Transduction; Species Specificity; Type C Phospholipases

Oxidation and glycation of low-density lipoprotein (LDL) has been claimed to play a central role in the pathogenesis of atherosclerosis. Therefore, the inhibition of this processes is of major therapeutic importance. In the present paper the influence of prostaglandin (PG)I2, and its stable analogues taprostene and iloprost on copper-induced oxidation of native, glycated and glycoxidated LDL was investigated. The results show, that the most pronounced effect on inhibition of native LDL-oxidation was obtained by taprostene in the whole concentration range tested (0.2 microg-10 microg/ml) reaching a maximal inhibition of 95% at 10 microg/ml. Examining glycoxidated LDL the inhibitory effect on oxidation was less pronounced reaching only about 10%. In case of glycated LDL, however, no significant inhibitory effect on oxidation was seen. Iloprost was effective as inhibitory agent against oxidation of native LDL at concentrations of 10 and 20 microg/ml, showing a maximal inhibition of 86% at a concentration of 20 microg/ml. Iloprost was ineffective on oxidation of glycated and glycoxidated LDL. Examining the extremely short-lived PGI2 itself, no significant inhibitory effect on oxidation of native, glycated or glycoxidated LDL, however, was seen. This finding might be of relevance for patients with diabetes mellitus, showing a decreased endogenous PGI2-production in particular those with bad metabolic control and high concentrations of circulating advanced glycosylation end products (AGEs).

Topics: Adult; Aged; Diabetes Mellitus; Dose-Response Relationship, Drug; Epoprostenol; Female; Glycation End Products, Advanced; Humans; Iloprost; Lipoproteins, LDL; Male; Middle Aged; Oxidation-Reduction

The specific prostacyclin (IP) receptor agonist cicaprost relaxed human pulmonary artery preparations precontracted with phenylephrine [50% inhibitory concentration (IC50) approximately 0.6 nM], U-46619 (IC50 approximately 0.9 nM), and K+ (approximately 40% maximal relaxation); endothelium removal had little effect on relaxant activity. Ranking of relaxant potencies for prostacyclin and five of its analogs was 17 alpha, 20-dimethyl-delta 6,6a-6a-carba PGI1 (TEI-9063) > or = cicaprost > iloprost > prostacyclin > taprostene > benzodioxane prostacyclin > 15-deoxy-16 alpha-hydroxy-16 beta,20-dimethyl-delta 6,6a-6a-carba PGI1 (TEI-3356). The potency of the isocarbacyclin TEI-3356 may have been under-estimated because of its contractile (EP3 receptor agonist) activity. The potency ranking of four nonprostanoid prostacyclin mimetics was 3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy] acetic acid (BMY 45778; IC50 approximately 2.5 nM) > > 2-[3-[2-(4, 5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid (BMY 42393) > octimibate > CU 23 (a novel diphenylindole). From IP receptor binding affinities obtained on human platelet membranes, it is suggested that the slightly shallower log concentration-response curves for BMY 45778, BMY 42393, and CU 23 may reflect the near-maximal receptor occupancy required for complete relaxation. A fifth nonprostanoid, CU 602, had much shallower log concentration-response curves than cicaprost against phenylephrine tone but not against U-46619 tone; this may indicate IP receptor partial agonism coupled with TP receptor antagonism. The relaxant actions of the nonprostanoid mimetics were more persistent than those of the prostacyclin analogs on washout of the organ bath; by the inhalation route, this type of compound may be retained within pulmonary tissue and thus afford greater pulmonary/systemic selectivity than currently used pulmonary vasodilators.

Topics: Acetates; Aged; Cardiovascular Agents; Child; Child, Preschool; Dose-Response Relationship, Drug; Enzyme Inhibitors; Epoprostenol; Fatty Acids; Humans; Iloprost; Imidazoles; Indoles; Middle Aged; Muscle, Smooth, Vascular; Oxazoles; Phenoxyacetates; Platelet Aggregation Inhibitors; Prostaglandins, Synthetic; Pulmonary Artery; Receptors, Epoprostenol; Receptors, Prostaglandin; Structure-Activity Relationship; Vasoconstrictor Agents; Vasodilator Agents