Carbacyclin Derivative Research Articles

抗凝固剤としてのカルバサイクリン誘導体(CS-570)の血液透析への臨床応用

抗凝固剤としてのカルバサイクリン誘導体(CS-570)の血液透析への臨床応用

Inhaled alternatives to nitric oxide.

should decrease pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), without affecting systemic arterial pressure (SAP), and potentially improve oxygenation by redistributing pulmonary blood flow to ventilated areas of lung. INO (INO Therapeutics Inc., Clinton NJ) possesses these properties and has gained approval from the Food and Drug Administration (FDA) for the care of neonates with acute lung injury and pulmonary hypertension (PH), and widespread clinical acceptance (but not FDA approval) for adults with PH with or without lung injury. Delivered as a gas, INO is preferentially distributed to the ventilated areas of the lung, where it produces relaxation of pulmonary vascular smooth muscle via activation of guanylate cyclase and the conversion of guanosine-5-triphosphate to cyclic guanosine monophosphate. 1 Absorbed INO is rapidly inactivated by hemoglobin, thereby preventing systemic effects and confining its vasodilator properties to the pulmonary circulation. 1 The search for inhaled selective pulmonary vasodilators was an active area of research, particularly in Europe and Australia, before the widespread publicity and testing of INO in the early 1990s. However, research on this subject appears to have declined inversely with the growing acceptance and use of INO. Until FDA approval had been granted, INO had been supplied free of charge in the United States on an investigational-drug basis. However, after FDA approval, the cost of treatment with INO became very expensive. This prompted a search at our institution for alternative agents to INO. The purpose of this article is to review the published experience concerning alternative inhaled vasodilators and, when possible, compare their reported efficacy with that of INO.

A new strategy for the enantioselective synthesis of carba-prostacyclin analogues based on organocopper conjugate addition to a bicyclic azoene and its application to the synthesis of 13,14-dinor-inter-p-phenylene carbacyclin.

An enantioselective synthesis of E/Z-13,14-dinor-inter-p-phenylene carbacyclin (E/Z-2d) by a new strategy has been realized that holds the prospect of serving as a general route for carba-prostacyclin analogues. The key intermediate in this synthesis is the bicyclic azoene Ts-9, and the key step is the regio- and stereoselective conjugate addition of the chiral arylcopper compound Cu-8d/P-n-Bu3 to the azoene with formation of hydrazone 7d. Enantioselective synthesis of azoene Ts-9 of 95% ee from ketone 4 was accomplished in four and five steps, respectively. Thus, enantioselective deprotonation of bicyclic ketone 4 with chiral base Li-10 and trapping of lithium enolate 11 with ClSiMe3 gave enol ether 12, which was chlorinated with N-chlorosuccinimide (NCS) to afford chloro ketone 13. Alternatively, chloro ketone 13 was also prepared upon chlorination of 11 with NCS. Chloro ketone 13 was converted to chloro hydrazone 14, which upon treatment with a mild base furnished azoene Ts-9. Arylcopper compound 8d of 98% ee was obtained in two steps from alcohol 16, which was prepared by enantioselective reduction of ketone 17 with (-)-diisopinocampheylchloroborane. Carbacyclin derivative E/Z-2d was found to be essentially inactive as an inhibitor of ADP induced human platelet aggregation, having an IC50 of >10 micromol/L.

Disposition of a new anti-platelet agent, CS-570 (carbacyclin derivative), in dog.

A GC/MS method for the determination of CS-570, a chemically stable prostacyclin analogue, was developed. This assay method was applied to study a disposition of CS-570 in dogs after a single or continuous intravenous administration. An acidified plasma, obtained from dogs, was spiked with 2H6-CS-570 as an internal standard and extracted with reversed-phase (ODS) cartridges. After methylation with diazomethane, further purification was carried out using normal-phase (Si) cartridges. The methyl-dimethyl-iso-propylsilyl derivative of CS-570 exhibits some suitable properties in GC/MS analysis showing the intense peak at m/z (M-43) by electron ionization. At the concentration of 8 and 80 ng/ml in plasma, CV% were 2.8 and 1.7 respectively. The limit of determination is 1 ng/ml when 1 ml sample is available. Dogs were received i. v. injection of CS-570 at a single dose of 100 μg/kg or i. v. infusion at the rate of 256 and 512 ng/kg/min for 60 min. A steep and biphasic decline of CS-570 concentration in plasma was observed both after rapid injection and after the end of the infusion with half-life of approximately 10 min at β-phase. During the continuous infusion, a rapid increace of CS-570 concentration in plasma was observed and it reached 95 % of the steady-state level within 15 min. Linear relationship was obtained between doses and AUC. A metabolite, β-oxidation product, was also found in dog plasma.

Development of a selective clean‐up method using immobilized antibody and its application to HPLC and GC/MS determination of a carbacyclin derivative, CS‐570, in plasma

Methods for the determination of CS-570, a chemically stable prostacyclin analogue, in plasma were developed by using an immobilized antibody column followed by fluorescence HPLC and GC/MS. The CS-570 antibody, obtained from rabbit plasma by giving CS-570-BSA for a few months, was coupled to Sepharose 4B and used as extraction phase for sample clean-up and extraction of the drug. A plasma sample was applied to this column, washed with water and the drug was eluted with 90% acetonitrile. 0.02% (w/v) 9-anthryldiazomethane (ADAM) was added to the extract to form a fluorescent derivative. The CS-570-ADAM adduct exhibited high sensitivity when applied to HPLC with fluorescence detection and column switching. The detection limit was 1 ng/mL when 1 mL of plasma was available. Additionally, a pentafluorobenzyltrimethylsilyl derivative of CS-570 showed excellent sensitivity when determined by capillary GC interfaced to negative ion chemical ionization MS using a stable isotope labelled analogue as an internal standard.

Anti shock psiof the prostacyclin analog, iloprost, in traumatic shock

The effects of iloprost, a synthetic carbacyclin derivative of prostacyclin (PGI 2) was studied in a standardized model of traumatic shock. Pentobarlitai anesthetized rats (33 mg/kg) subjected to Noble Collip drum trauma were characterized' by a 84 ± 10 minute survival time, a 16-fold increase in plasma cathepsin D activity, and a 5-fold increase in plasma myocardial depressant factor (MDF) activity. Iloprost significantly attenuated the accumulation of MDF activity in the plasma (69 ± 14 vs. 20 ± 6 U/ml) vehicle vs. drug (p<0.01), respectively, and significantly prolonged survival time to 243 ± 36 minutes (p<0.01). Plasma cathepsin D activity was also significantly attenuated (12 ± 1.8 vs. 6.2 ± 2.1 U/ml , vehicle vs. drug, respectively (p<0.02). Iloprost exhibited significant anti-proteolytic activity in pancreatic homogenates. Iloprost appears to exert a membrane stabilizing effect decreasing plasma cathepsin D activity and attentiating MDF production, probably secondarily to its anti-proteolytic effect and its maintenance of the splanchnic circulation. Iloprost may therefore prove to be a useful therapeutic agent in acute ischemic disorders including traumatic shock.

Studies on the pharmacokinetics of ZK 96 480, a novel PGI 2-mimetic, in rat and cynomolgus monkey

The pharmacokinetics and biodegration of the new drug were studied in rat and cynomolgus monkey after i.v. and i.g. administration of 3H-labelled ZK 96 480. In a rat liver perfusion experiment ZK 96 480 remained unchanged over 90 min. Following i.v. and i.g. dosing, the metabolic pattern in the urine and the methanolic extracts of homogenized, freeze-dried feces samples revealed almost exclusively unchanged compound in both animal species. After i.v. treatment, drug disposition in the plasma exhibited half-lives of 0.14 h and 4.3 h in rat and 0.07 h, 0.4 h and 2.5 in m monkey. Total clearance was 14 ml/min/kg in the latter species. Excretion of 3H-label was mainly fecal in rat, but exhibited no preferred route in monkey. On the basis of the urinary excretion of 3H-label and unchanged drug both gastro-intestinal absorption and bioavailability were complete. Whole body autoradiographs in rat demonstrated that there was no specific enrichment of radiolabel in any tissue or organ. The present results demonstrate that ZK 96 480 is an orally available and metabolically stable carbacyclin derivative in female rats and monkeys

Pharmacological profile of a novel carbacyclin derivative with high metabolic stability and oral activity in the rat

A novel carbacyclin derivative (16S)-13,14-dehydro-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I 2 (3-oxa-analogue) has been synthesized in order to find chemically and metabolically stable prostacyclin-memetics with a potency equal or even superior to PGI 2. The 3-oxa-analogue was found to be stabilized against β-oxidation, a main metabolic degradation step also for chemically stable PGI 2-analogues. The compound is orally available and displays a long duration of 4,5 – 48 h of antiaggregatory and hypotensive action. The 3-oxa-analogue inhibits ADP-induced platelet aggregation with an IC 50 of 3.0 nM. Following intravenous application the 3-oxa-analogue lowers diastolic blood pressure in a dose dependent manner, the ED 20 being 0.1 – 0.2 μg/kg after injection and ≤ 0.05 μg/kg/min after infusion respectively. In vivo platelet aggregation is inhibited after i.v. infusion of the 3-oxa-analogue with an IC 50 of 0.037 μg/kg/min. As compared to Iloprost, the 3-oxa-analogue is 5 – 12 fold more potent with respect to in vivo hypotensive and anti-aggregatory effects. The results of the present studies indicate that the 3-oxa-analogue has a pharmacological profile comparable to prostacyclin (PGI 2) and Iloprost. Due to the fact that the 3-oxa-analogue is chemically and metabolically stable, long term oral treatment can be achieved in clinical conditions in which PGI 2 and Iloprost have already been shown to be therapeutically useful principles.

P4H0108) - Stabilization of platelets by CS-570, a carbacyclin derivative

P4H0108) - Stabilization of platelets by CS-570, a carbacyclin derivative

The effect of the stable prostacyclin analogue ZK 36374 on experimental coronary thrombosis in the pig

The hemodynamic and antithrombotic action of ZK 36374,a stable carbacyclin derivative of prostacyclin, was studied during electrically-induced coronary artery thrombosis in the open chest anesthetized pig. Infusion of ZK 36374 (100 ng/kg/min, n=6) had no effect on heart rate and cardiac output, but caused a 20% reduction in mean arterial blood pressure by peripheral vasodilation. In animals receiving solvent or no drug prior to thrombosis induction, the time to occlusive coronary artery thrombosis (TOT) was 30 ± 2 minutes (mean ± SEM, n=17). Pretreatment with an i.v. infusion of ZK 36374 (100 ng/kg/min) prolonged TOT by 50% to 47 ± 7 minutes (p< 0.005, n=6). This prolongation of TOT was not due to the lower blood pressure in the ZK 36374 group, as dihydralazine in a dose that lowered arterial blood pressure to the same extent had no effect on TOT (32 ± 4 minutes, n=4). The results indicate that ZK 36374 may be useful in delaying (or preventing) occlusive coronary artery thrombi.

Chemical stability and anti-platelet effects of CS-570, a carbacyclin derivative

Chemical stability and anti-platelet effects of CS-570, a carbacyclin derivative

P-163) - Effects of CS-570, a carbacyclin derivative, on the ischemia-induced increase in blood viscosity and shape change of erythrocytes

P-163) - Effects of CS-570, a carbacyclin derivative, on the ischemia-induced increase in blood viscosity and shape change of erythrocytes

P-162) - Effects of OS-570, a carbacyclin derivative, on the ischemic lesion of rat hind limb

P-162) - Effects of OS-570, a carbacyclin derivative, on the ischemic lesion of rat hind limb

Effects of a carbacyclin derivative, CS-570 on various isolated blood vessels.

Effects of CS-570, 17-(R)-methyl-20-isopropylidene carbacyclin Na salt, on helical strips of isolated rabbit basilar, coronary, renal and femoral arteries were examined in comparison with those of prostaglandin(PG) I2. CS-570 and PGI2 had no effects on the resting tension, but caused dose-dependent relaxation in the arteries contracted with PGF2α, norepinephrine(NE) or 5-hydroxytriptamine(5-HT). The relaxant effect of CS-570 was long-lasting, but that of PGI2 was transient. Treatment with CS-570 attenuated contractile response of the femoral artery to NE. CS-570 but not PGI-relaxed all four arteries contracted with 30mM KCl, and this relaxation was not reversed by increasing calcium(Ca) or glucose concentration in the bathing solution. In the femoral artery contracted with PGF2α, aspirin(10−4 M) potentiated CS-570-induced relaxation, but PGI2-induced relaxation was unaffected. From these results, it appears that CS-570 caused dose-dependent relaxation in isolated rabbit basilar, coronary, renal and femoral arteries contracted with PGF2α, NE, 5-HT or KCl, and it seems that this action of CS-570 is not from specific antagonism to PGF2α, NE, 5-HT, Ca-antagonism, or inhibition of the aerobic energy metabolism.

Dissociation of Antiplatelet Effects from Myocardial Cytoprotective Activity During Acute Myocardial Ischemia in Cats by a New Carbacyclin Derivative (ZK 36 375)

We studied the potential therapeutic value of the chemically stable carbacyclin analogue ZK 36 375 during acute myocardial ischemia and compared the cardiovascular and anti- and disaggregatory effects of the compound in vitro and ex vivo. In anesthetized cats the left anterior descending coronary artery was ligated, and 30 min later an intravenous infusion of ZK 36 375 (3.6 micrograms/kg X min) or vehicle was initiated and continued for 4.5 h. ZK 36 375 reduced the ST-segment elevation at 2-5 h (p less than 0.01) when compared to vehicle-treated cats. ZK 36 375 significantly inhibited both the loss of creatine phosphokinase--specific activity and the decrease in the percentage of bound cathepsin D in the infarcted area of the myocardium (p less than 0.05). ZK 36 375 did not reverse ischemia-induced formation of platelet aggregates in vivo and was found ex vivo to be two to three orders of magnitude less active in preventing platelet aggregation, redispersing platelet aggregates, and relaxing bovine coronary arteries than prostacyclin (PGI2) or its (5E) stereoisomer ZK 36 374. It is concluded that ZK 36 375 has a significant cardioprotective activity in acute myocardial ischemia of the cat that can be dissociated from antiplatelet effects in vivo.

The antiplatelet and cardiovascular actions of a new carbacyclin derivative (ZK 36 374)--equipotent to PGI2 in vitro.

The vascular and antiplatelet activities of a new, chemically stable carbacyclin derivative (ZK 36 374) were investigated and compared to PGI2. ZK 36 374 dose-dependently relaxed bovine coronary artery strips in vitro but was without direct effects on strips of bovine coronary veins which were contracted by PGI2. ZK 36 374 dose-dependently inhibited the ADP-, thrombin- and collagen-induced platelet aggregation in human platelet-rich plasma and disperded preformed platelet aggregates in whole blood of cats ex vivo. The IC50 was 0.2–1.1 (antigaggregation) and 13 (disaggregation) nM, respectively, and in the same range as PGI2. The maximum antiplatelet dose of ZK 36 374 (resolution of platelet aggregates) in anaesthetized cats in vivo was 0.45 nmoles/kg x min, and could be increased up to 3 nmoles/kg x min, i.e. 6–7-fold without significant changes in arterial blood pressure and heart rate. This indicates an appreciable dissociation between antiplatelet and blood pressure-lowering activities of this compound, at least in this model. It is concluded that ZK 36 374 is the first, chemically stable prostacyclin-mimetic agent that is equipotent to PGI2 in vitro and might be superior to PGI2 in vivo because of a reduced blood pressure-lowering activity.