cardiovascular-agents and taprostene

Atherosclerotic peripheral arterial disease is a major health problem in the western world, often manifested as intermittent claudication, affecting 10-20% males above 60 years. Ischemic complications can lead to rest pain, ulceration and gangrene. The treatment of choice for critical limb ischemia (CLI) is vascular reconstruction or endovascular interventions. Medical management with vasodilator antiplatelet prostaglandins, could be considered in patients unsuitable for surgery. Long term follow-up on previous prostaglandin studies has been insufficient to evaluate amputation rates. Hence this study evaluated safety and longer term efficacy of taprostene sodium, a prostacyclin (PGI2) analogue in CLI. The aim of this study was to determine whether Taprostene sodium, a PGI2 analogue, was a safe and effective treatment for CLI.. This paper reports the data from the Scottish-Finnish-Swedish PARTNER Study Group which consisted of a double-blind placebo controlled multi-centre study evaluating Taprostene compared to placebo. The primary endpoints were pain relief and early ulcer healing response at the end of the four week infusion phase and amputation at six months follow-up. The patients were randomly allocated to receive taprostene or placebo in a two to one randomization of active versus placebo. A total of 111 patients with CLI were recruited. Taprostene was given twice a day over two 2 hour periods for four weeks. The early response was evaluated at the end of the four week infusion phase. In patients with rest pain without ulceration, a positive response was complete pain relief without any requirement for analgesic therapy. However in patients with ulceration, a positive response was defined as a decrease in the ulcer size by >30%. Amputation scores were compared at the end of the 6 months follow-up period for all participants.. Seventy-four patients received taprostene and 37 placebo. Overall, 61 male patients were enrolled in the study along with 50 females with 11% more women in the taprostene (active) group. For both patients with and without ulcers there was no statistically significant difference noted in the early response between those receiving taprostene and those receiving placebo infusion. The percentage of patients without any amputations was 43% in the taprostene group compared to 38% in the control group at the end of six months; however, these results were not statistically significant.. Although a reasonable number of patients enrolled in the study it has not been possible to demonstrate any statistically significant benefit of taprostene over placebo. This may be due to more patients with risk factors for peripheral artery disease (PAD) such as hypertension, diabetes mellitus and cigarette smoking in the actively treated group and also due the increased number of women in the active group who are known to generally respond less favourably to antiplatelet agents.

Topics: Aged; Aged, 80 and over; Amputation, Surgical; Analgesics; Cardiovascular Agents; Chi-Square Distribution; Critical Illness; Double-Blind Method; Drug Administration Schedule; Epoprostenol; Europe; Female; Humans; Infusions, Parenteral; Ischemia; Limb Salvage; Lower Extremity; Male; Pain; Pain Measurement; Placebo Effect; Time Factors; Treatment Outcome; Wound Healing

The white blood cell count (WCC) is known to be predictive of cardiac and cerebral vascular events. No one has yet investigated this in critical limb ischaemia (CLI).. Baseline WCC was examined in relation to lower limb amputation 6 months after a 4 week treatment period with i.v. placebo or i.v. taprostene in 366 patients with CLI.. The WCC was related to a significant increase in amputation, relative risk 1.6 (p=0.001, 95% CI: 1.2-2.0) in CLI patients with WCC > or =9x10(9)/l vs patients with WCC <9x10(9)/l. Its association with disabling amputation persisted on logistic regression analyses which included cigarette smoking as a variable and also treatment group (p<0.001). The WCC is therefore an easily measurable prognostic variable in CLI.. The white blood cell may promote intractable tissue ischaemia by capillary plugging and/or release of toxic chemicals and may have distinct effects on tissue viability.

Topics: Amputation, Surgical; Cardiovascular Agents; Double-Blind Method; Epoprostenol; Female; Humans; Ischemia; Leg; Leukocyte Count; Logistic Models; Male; Neutrophils; Placebos; Single-Blind Method; Smoking

In a double blind pilot study, we examined the effects of the stable prostacyclin derivate taprostene compared to a combination of aspirin and dipyridamole on platelet uptake and clinical outcome after peripheral percutaneous angioplasty. Taprostene was administered to 19 patients as a continuous intravenous infusion from 2 hours before until 8 (n = 6) or 24 (n = 6) hours after angioplasty; 7 control patients were given a combination of 330 mg aspirin and 75 mg dipyridamole. Uptake of 111-indium labelled platelets at the site of the PTA was measured 3 hours before and 4 and 24 hours after angioplasty. Clinical parameters were obtained one day before PTA, on the following day and 3 months after the procedure. There was a tendency for slightly higher platelet uptake ratios in the taprostene groups as compared to the control group especially in patients requiring technically difficult procedures. There were no differences between the 3 groups with regard to primary success or periinterventional complications. In the taprostene patients, 3 early reocclusions were found up to 72 hours after the procedure and 1 late reocclusion within 3 months. In the control group, no reocclusion was apparent in the observation time. No advantages were found when taprostene was administered during angioplasty as compared to conventional treatment with aspirine and dipyridamole.

Topics: Administration, Oral; Adult; Aged; Angioplasty, Balloon; Arterial Occlusive Diseases; Aspirin; Cardiovascular Agents; Dipyridamole; Drug Therapy, Combination; Epoprostenol; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Pilot Projects; Platelet Activation; Recurrence; Treatment Outcome

Critical limb ischaemia (CLI) is a serious clinical condition that often immediately precedes limb loss. The Consensus Documents of 1989 and 1991 attempted to define CLI and give direction to its investigation and management. Whilst the need for such a consensus was clear and should be supported we believe the definition of CLI as documented in the Consensus Documents I and II recommendation number I is wrong. We present evidence from 140 patients with severe limb ischaemia taken from the PARTNER Group studies to support our request for an amendment to the ankle pressure recommendation from < or = 50 mmHg to >50 mmHg and big toe pressure from < or = 30 mmHg to >30 mmHg for the purpose of conducting clinical trials and to include Doppler index and tcPO2 as additional parameters. We also believe that the current document may be actually excluding the only group of patients likely to benefit from drug treatment or other interventions and that the above amendment should be prioritized.

Topics: Amputation, Surgical; Blood Pressure; Cardiovascular Agents; Combined Modality Therapy; Consensus Development Conferences as Topic; Epoprostenol; Europe; Follow-Up Studies; Humans; Ischemia; Leg; Peripheral Vascular Diseases; Prostaglandins, Synthetic; Retrospective Studies; Survival Rate; Treatment Outcome; Vascular Surgical Procedures

Prostaglandins and prostacyclin are potent vasodilators with marked hemodynamic effects, i.e., both improve cardiac function and possibly cause myocardial ischemia. In order to assess the stable prostacyclin analogon taprostene (T) we first performed an open preliminary study with increasing T-doses (6.5-50 ng/kg/min) and, secondly a double-blind crossover study versus placebo to investigate its influence on ischemic ST-segment depression during exercise stress testing under continuous T-infusions of 25 ng/kg/min (in one case 12.5 ng/kg/min). Eleven of 12 normotensive male patients (age 40 to 60, mean 52.8 +/- 8.4 years) suffering from angiographically proven coronary heart disease and stable angina pectoris completed the study. T was well tolerated, even under increasing doses, and blood pressure and the ECG parameters did not change. The double-blind study revealed no variation in the extent of ischemic ST-segment depression when compared to placebo, and all other ECG parameters as well as the blood pressure remained unaffected. Thus, myocardial ischemia cannot be ruled out completely under T, but earlier clinical findings may be confirmed characterizing T as a marked cytoprotective agent and, to a less degree, as a potent vasodilator.

Topics: Adult; Aged; Cardiovascular Agents; Coronary Circulation; Coronary Disease; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Epoprostenol; Exercise Test; Hemodynamics; Humans; Male; Middle Aged; Myocardial Ischemia

Taprostene is a prostacyclin analogue that inhibits platelet aggregation and thus might be a useful adjuvant to thrombolytic agents in acute myocardial infarction. In a placebo-controlled dose rising study, taprostene or placebo was intravenously infused in 80 patients treated with the thrombolytic agent saruplase (rscu-PA) for acute myocardial infarction. Three doses of taprostene were used: 6.25; 12.5; or 25.0 ng.kg-1 x min-1. Taprostene or placebo was infused for 48 h, followed by a 24 h tapering period. All 80 patients had short symptom-to-treatment delay and marked ST segment elevation. Patency at 90 min was documented in 58/78 patients (two patients had no angiography). Success rate varied from 67-82% in the four treatment arms (P = 0.33). Patency after rescue PTCA was seen in 10 out of 13 patients. Of the 58 patients having a patent artery at 90 min, none of the 43 taprostene patients and one of the 15 placebo patients had a re-occluded artery at the second angiography at 32-48 h (5/58 patients had no recatheterization). Conversely, of nine patients who had successful rescue PTCA, three of four placebo patients had a re-occluded artery at the second angiography compared to one of five taprostene patients (one placebo patient had no recatheterization) (P = 0.33). Safety evaluation revealed no major difference between the placebo plus saruplase and the taprostene plus saruplase groups. Taprostene was well tolerated up to 25 ng.kg-1 x min-1. Although taprostene did not affect 90 min patency, there was a trend to better maintenance of patency after rescue PTCA.

Topics: Angioplasty, Balloon, Coronary; Cardiovascular Agents; Coronary Angiography; Double-Blind Method; Drug Therapy, Combination; Epoprostenol; Hemodynamics; Humans; Infusions, Intravenous; Myocardial Infarction; Pilot Projects; Recombinant Proteins; Survival Rate; Thrombolytic Therapy; Urokinase-Type Plasminogen Activator

Topics: Arterial Occlusive Diseases; Blood Pressure; Cardiovascular Agents; Clinical Trials as Topic; Epoprostenol; Female; Flushing; Humans; Infusions, Intravenous; Male; Platelet Aggregation; Prostaglandins, Synthetic

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

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

We examined the effects of taprostene (2.5 x 10(-8) M to 1 x 10(-7) M), a stable prostacyclin analog, on PMN-endothelial interaction (i.e., adherence) and subsequent vasocontraction and endothelial dysfunction. Taprostene effectively inhibited the adherence of leukotriene B4-stimulated autologous cat polymorphonuclear (PMN) leukocytes to isolated cat coronary artery endothelium. Taprostene also inhibited coronary artery vasocontraction to leukotriene B4-stimulated PMNs (p < 0.01). In isolated coronary artery rings stimulated with either 2 U/ml of thrombin or 100 microM hydrogen peroxide (H2O2), adherence of unstimulated PMNs to coronary endothelium was significantly increased, resulting in vasocontraction and subsequent endothelial dysfunction. However, taprostene (1 x 10(-7) M) significantly attenuated unstimulated PMN adherence to stimulated coronary endothelium. This antiadherence action effectively attenuated PMN-induced coronary artery vasocontraction (p < 0.01) and significantly blunted the subsequent PMN-induced endothelial dysfunction (p < 0.01) characterized by a loss of endothelium-derived nitric oxide (NO). Thus, taprostene exerts a profound inhibitory effect on PMN-endothelium interaction and subsequent PMN-mediated coronary endothelial dysfunction, which may be beneficial in ischemia-reperfusion and other inflammatory states.

Topics: Analysis of Variance; Animals; Binding Sites; Cardiovascular Agents; Cats; Cell Adhesion; Coronary Vessels; Endothelium, Vascular; Epoprostenol; Hydrogen Peroxide; In Vitro Techniques; Leukotriene B4; Male; Neutrophils; Nitric Oxide; Prostaglandins, Synthetic; Superoxide Dismutase; Thrombin; Vasoconstriction

Murine resident peritoneal macrophages were stimulated with lipopolysaccharide and treated with phosphodiesterase (PDE) inhibitors zardaverine, rolipram and motapizone. The PDE inhibitors suppressed the formation of tumor necrosis factor (TNF) by macrophages. The mono-selective PDE IV inhibitor rolipram and the dual-selective PDE III/IV inhibitor zardaverine had equal inhibitory potency, whereas the PDE III inhibitor motapizone was of lower inhibitory potency. All PDE inhibitors acted in synergy with the adenylate cyclase activators prostaglandin E2 and CG 4203, a prostacyclin analog, and super-additive effects of combinations were observed. The PDE inhibitors also blocked the formation of leukotriene C4 (LTC4); however, substantially higher doses were needed than for blockade of TNF synthesis. Furthermore, no additive or synergistic effects were observed upon combined treatment with adenylate cyclase activators. It is suggested that the suppression of TNF formation by PDE inhibitors is mediated mainly by a PDE isoenzyme of type IV. The effect of PDE inhibitors on LTC4 synthesis appears to be mediated by a different mechanism.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cardiovascular Agents; Cells, Cultured; Cyclic Nucleotide Phosphodiesterases, Type 4; Epoprostenol; Isoenzymes; Lipopolysaccharides; Macrophages; Male; Mice; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Platelet Aggregation Inhibitors; Pyridazines; Pyrrolidinones; Rolipram; SRS-A; Tumor Necrosis Factor-alpha

The effects of low dose human superoxide dismutase and low dose taprostene, a stable analogue of prostacyclin, were investigated separately and together in a model of myocardial ischemia (1.5 h) with reperfusion (4.5 h) in open chest, anesthetized cats. Taprostene (60 ng/kg per min), human superoxide dismutase (0.25 mg/kg per h), both agents together, or their vehicle, were infused intravenously in cats starting 0.5 h after occlusion of the left anterior descending coronary artery. Neither low dose taprostene nor low dose human superoxide dismutase exerted any endothelial or myocardial protection in this model. However, the two agents together showed a significant endothelial and myocardial protection in cats with myocardial ischemia and reperfusion. Compared with cats that were untreated or received only taprostene or human superoxide dismutase, cats receiving both agents exhibited a lower plasma creatine kinase activity at every time point observed after reperfusion, a reduced area of cardiac necrosis (7 +/- 2% vs. 21 +/- 5% area at risk, p less than 0.001), lower myeloperoxidase activity in the ischemic region (p less than 0.01) and a significant preservation of vasorelaxant responses of left anterior descending coronary rings to endothelium-dependent vasodilators, acetylcholine (p less than 0.001) and A-23187 (p less than 0.001). Taprostene appears to act additively with human superoxide dismutase to inhibit neutrophil adherence and activation and to inactivate superoxide radicals, and thus reduce cellular injury 4.5 h after reperfusion of the ischemic heart. Use of this agent may allow low doses of superoxide dismutase to be used more effectively in early myocardial ischemia.

Topics: Animals; Cardiovascular Agents; Cats; Coronary Disease; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Epoprostenol; Humans; Male; Myocardial Reperfusion Injury; Myocardium; Prostaglandins, Synthetic; Superoxide Dismutase

The prostacyclin analogue taprostene protects against lethal endotoxemia in rats. In the present study, the effects of taprostene on endotoxin-induced cardiovascular, pulmonary and renal alterations have been investigated. In anesthetized rabbits, infusion of 0.5 mg/kg Escherichia coli lipopolysaccharide i.v. over 30 min produced systemic hypotension, pulmonary hypertension, and decreases in cardiac output, peripheral oxygen delivery and renal glomerular filtration rate. In endotoxemic rabbits treated with taprostene (0.2 micrograms.kg-1.min-1 i.v. over 180 min), the blood pressure tended to be lower than in untreated endotoxemic controls. Taprostene reduced the total peripheral resistance and abolished the endotoxin-induced increases in pulmonary artery pressure and resistance. Taprostene prevented the decreases in cardiac output and peripheral oxygen supply. At the end of the experiment the glomerular filtration rate was higher in taprostene-treated than in untreated endotoxemic rabbits and did not differ significantly from that in non-endotoxemic controls. The results show that taprostene prevents the pulmonary hypertension, preserves cardiac output and peripheral oxygen delivery, and substantially maintains the glomerular filtration rate in endotoxin-shocked rabbits.

Topics: Animals; Blood Pressure; Cardiovascular Agents; Endotoxins; Epoprostenol; Heart; Heart Rate; Kidney; Lung; Male; Rabbits

Like the native epoprostenol (prostacyclin, PGI2), the oxacyclic epoprostenol analogue taprostene affects platelet functions. In the rat taprostene inhibited in vivo induced ADP aggregation after i.v. bolus injection, i.v. infusion, s.c. and p.o. application with ED50 values of 4.6 micrograms/kg, 0.36 microgram/kg/min, 190 micrograms/kg and approximately 760 micrograms/kg, respectively. In vivo induced collagen aggregation was inhibited with an ED50 value of 17.1 micrograms/kg i.v. Referring to both bolus injection and i.v. infusion, taprostene was about 3 times less active than the native prostacyclin, but the antiaggregatory effect of taprostene was longer lasting. 5,6-Dihydroepoprostenol inhibited ADP-induced aggregation with an ED50 value of 3 micrograms/kg/min, being 10 fold less active than taprostene. Whereas epoprostenol induced a rebound effect by increasing in vivo aggregation after the end of infusion, no such effect could be seen after taprostene. In the mouse s.c. and p.o. application of taprostene inhibited aggregation with the same efficacy as in the rat. Intra-arterial infusion of taprostene into the rabbit inhibited ADP-induced aggregation ex vivo with an ED50 value of 0.49 micrograms/kg/min. An increased bleeding time was observed in rats in doses of 2.15 micrograms/kg i.v. and higher, corresponding to the antiaggregatory dose range of taprostene. Administered alone, taprostene did not prolong the clotting time in rats. However, in heparinized rats, the heparin-induced prolongation of clotting time was further increased by taprostene with a threshold dose of 21.5 micrograms/kg (= heparin sparing effect).

Topics: Adenosine Diphosphate; Animals; Bleeding Time; Blood Coagulation; Blood Platelets; Cardiovascular Agents; Dose-Response Relationship, Drug; Epoprostenol; In Vitro Techniques; Injections, Intravenous; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Rabbits; Rats; Rats, Inbred Strains

[(5Z,13E,9 alpha,11 alpha,15S)-2,3,4-Trinor - 1,5 - inter-m - phenylene - 6,9 - epoxy - 11,5 - dihydroxy - 15 - cyclohexyl - 16,17,18,19,20-pentanor]- prosta-5,13-dienoic acid (sodium salt) (CG 4203) is a new stable epoprostenol (prostacyclin) analogue with a relative platelet antiaggregatory potency of 0.46 (ADP aggregation in vitro) and a hypotensive potency of 0.14 (anaesthetized rat i.v.) as compared to epoprostenol. In isolated perfused rat hearts, CG 4203 (4.64 X 10(-9) mol/l) significantly attenuated arrhythmias and loss of left ventricular creatine kinase (CK) activity observed in control hearts after 30 min perfusion with hypoxic and 30 min reperfusion with oxygenated Krebs-Ringer solution. In anaesthetized rats, CG 4203 (1.0 microgram X kg-1 X min-1 i.v.) significantly reduced incidence of ventricular fibrillation and increase in plasma CK activity after ligation of the left coronary artery. Infusion of 1.0 and 2.15 micrograms X kg-1 X min-1 CG 4203 i.v. in anaesthetized rats dose-dependently inhibited electrocardiographic changes, i.e. ST depression observed after i.v. injection of 1.0 IU X kg-1 vasopressin. In rat models of sustained myocardial hypoxia, myocardial infarction, and transient cardiac ischemia, CG 4203 thus exerts cardioprotective effects which, depending on the model considered, may be ascribed to either its vasodilatory, coronary dilatory, antiaggregatory or epoprostenol-like cytoprotective activity.

Topics: Animals; Cardiovascular Agents; Coronary Disease; Creatine Kinase; Epoprostenol; In Vitro Techniques; Male; Myocardial Contraction; Nitroglycerin; Oxygen; Perfusion; Rats; Rats, Inbred Strains; Vasopressins