tcv-309 and Shock--Septic

Sepsis and organ failure remain the main cause of death on the ICU. Sepsis is characterized by a severe inflammatory response, in which platelet-activating factor (PAF) is considered to play an important role. This study investigated whether treatment with the PAF-antagonist TCV-309 reduces morbidity and mortality in patients with septic shock. The study was conducted as a double-blind, randomized, placebo controlled multicenter study. The included patients had to fulfill the SIRS criteria with a clinical suspicion of infection, an admission APACHE II score greater than 15, and shock, defined as a mean arterial pressure <70 mmHg and/or a decrease > or =40 mmHg despite adequate fluid resuscitation. Patients received 1.0 mg/kg TCV-309 or placebo, twice daily, intravenously during 14 days. The prospectively set goals were MOF score, recovery from shock, mortality, and assessment of the safety of the medication. A total of 98 patients were included of which 97 were analyzed on an intention-to-treat basis. The overall survival at day 56 of TCV-309 treated patients was similar compared to placebo treated patients (51.0% vs. 41.7%, P = 0.47). In contrast, the mean percentage of failed organs per patient present after 14 days in the TCV-309 treated patients was significantly lower compared to the placebo treated patients (11.9% vs. 25.1%, P = 0.04), leading to a reduced need for vasopressors, dialysis, and ventilatory support. Furthermore, the mean APACHE-II score during treatment with TCV-309 was significantly lower and the number of patients recovered from shock after day 14 was significantly higher in the TCV-309 treated patient group (2/32 vs. 9/29, P = 0.01). The number of adverse events was not significantly different between the TCV-309 and placebo treated patients. TCV-309 did not change overall mortality of septic shock, however a substantial reduction in organ dysfunction and morbidity, frequently associated with septic shock was achieved, without significant adverse events.

Topics: Adult; Aged; APACHE; Double-Blind Method; Female; Humans; Inflammation Mediators; Isoquinolines; Male; Middle Aged; Multiple Organ Failure; Platelet Activating Factor; Platelet Aggregation Inhibitors; Prospective Studies; Pyridinium Compounds; Shock, Septic; Systemic Inflammatory Response Syndrome; Tetrahydroisoquinolines

The present experiments were conducted to elucidate the role of platelet-activating factor (PAF) and cyclooxygenase products in the cardiovascular responses to endotoxin in anesthetized rats. Endotoxin (10 mg/kg, i.v.) induced hypotension that was accompanied by a decrease in cardiac output and an increase in calculated total peripheral resistance, suggesting that this hypotension mainly resulted from the reduced cardiac output. The endotoxin-induced decrease in cardiac output and hemoconcentration was significantly attenuated by TCV-309 (a PAF receptor antagonist), ibuprofen (a cyclooxygenase inhibitor) or S-1452 (a thromboxane A2/prostaglandin H2-receptor antagonist). During the 3-hr observation period following endotoxin administration, ibuprofen and S-1452 showed only early protection and TCV-309 showed late attenuation of the endotoxin-induced hypotension. Tachycardiac responses to endotoxin were only blocked by ibuprofen but not by TCV-309 or S-1452. These results suggest that both PAF and cyclooxygenase product(s), including thromboxane A2, mediate the decrease in cardiac output and hypotension in rat experimental endotoxic shock. Cyclooxygenase product(s) other than thromboxane A2 or prostaglandin endoperoxide may be involved in the endotoxin-induced increase in heart rate.

Topics: Animals; Bridged Bicyclo Compounds; Fatty Acids, Monounsaturated; Hemodynamics; Ibuprofen; Isoquinolines; Male; Platelet Activating Factor; Prostaglandins; Pyridinium Compounds; Rats; Rats, Sprague-Dawley; Shock, Septic; Tetrahydroisoquinolines

The therapeutic effects of TCV-309, a novel platelet activating factor antagonist, on hemodynamics in endotoxin-induced shock were evaluated. Ten Beagle dogs were used under general anesthesia and artificial ventilation. After intravenous injection of endotoxin (3 mg/kg), TCV-309 (1 mg/kg) was administered intravenously to the dogs. The results showed that the depression of mean aortic pressure, cardiac output, left ventricular stroke work index and urine volume which occurred in endotoxin shock was significantly improved by administration of TCV-309. These results suggested that TCV-309 was a useful therapeutic for the circulatory disturbance in endotoxin shock.

Topics: Animals; Blood Pressure; Cardiac Output; Dogs; Endotoxins; Escherichia coli; Heart Rate; Hemodynamics; Isoquinolines; Platelet Activating Factor; Pyridinium Compounds; Shock, Septic; Stroke Volume; Tetrahydroisoquinolines; Vascular Resistance

The effect of TCV-309, a newly developed platelet activating factor (PAF) antagonist, on the wet/dry weight ratio of the lung (index of pulmonary edema) and the pulmonary surface activity (index of pulmonary compliance) was evaluated in comparison with that of CV-3988 (PAF-antagonist). Administration of TCV-309 (1 mg/kg) or CV-3988 (10 mg/kg) significantly reduced the wet/dry weight ratio which was increased by endotoxin administration (3 mg/kg). It also augmented the pulmonary surface activity. Administration of either TCV-309 or CV-3988 alleviated the histologic lesions caused by endotoxic shock. These results suggest that lung injury during endotoxic shock can be controlled by TCV-309 as by CV-3988.

Topics: Animals; Dogs; Escherichia coli; Isoquinolines; Lipopolysaccharides; Lung; Phospholipid Ethers; Platelet Activating Factor; Platelet Aggregation Inhibitors; Pulmonary Edema; Pulmonary Surfactants; Pyridinium Compounds; Shock, Septic; Tetrahydroisoquinolines

We investigated the effects of TCV-309, a novel platelet activating factor (PAF) antagonist, on circulatory dysfunction and hematological abnormalities in experimental canine endotoxin (ET) shock. ET caused biphasic hypotension with a decrease in cardiac output (CO), left ventricular systolic pressure (LVP) and its dp/dt(max). The first hypotensive phase occurred within 15 min, and the second phase between 90 and 180 min following the injection of ET. Pulmonary vascular resistance (PVR) abruptly increased at 15 min with a partial recovery, and was then sustained at twice the basal value throughout the experiment. TCV-309 attenuated the hypotension, the decrease in CO, LVP and its dp/dt(max), and the increase in PVR. TCV-309 had no significant effect on the increase in TPR. The decrease in plasma fibrinogen and the increase in hematocrit and plasma lactate were significantly attenuated by TCV-309. These data suggest that PAF may be a key mediator leading to shock in sepsis.

Topics: Animals; Blood Circulation; Blood Pressure; Disease Models, Animal; Dogs; Heart; Hematologic Diseases; Hemodynamics; Isoquinolines; Male; Platelet Activating Factor; Platelet Count; Pyridinium Compounds; Shock, Septic; Tetrahydroisoquinolines; Time Factors

1. The present study was conducted in order to examine the effects of the platelet-activating factor (PAF) antagonist, TCV-309, and the cyclo-oxygenase inhibitor, ibuprofen, on the acute haemodynamic responses to endotoxin in anaesthetized dogs. 2. Endotoxin (2 mg kg-1, i.v.) induced a severe hypotension by decreasing both total peripheral resistance (TPR) and cardiac output. Endotoxin also decreased central venous pressure and increased effective vascular compliance (EVC), indicating a blood pooling in the capacitance vessels. 3. The endotoxin-induced hypotension but not the fall in cardiac output, was markedly attenuated by ibuprofen. Ibuprofen abolished the decrease in TPR and even caused a systemic vasoconstriction. Ibuprofen abolished the increase in EVC. 4. The hypotension caused by endotoxin was attenuated by TCV-309 to a lesser extent than ibuprofen. However, the reduction in cardiac output produced by endotoxin was markedly attenuated by the PAF antagonist. TCV-309 also abolished the increase in EVC. In contrast to ibuprofen, TCV-309 did not affect the decrease in TPR caused by endotoxin. 5. Combined treatment with ibuprofen and TCV-309 markedly attenuated the endotoxin-induced hypotension, but not the fall in cardiac output. Nevertheless, when compared with animals treated with ibuprofen alone, treatment with ibuprofen and TCV-309 partly attenuated the endotoxin-induced reduction in cardiac output and systemic vasoconstriction. 6. These data indicate that dilatation of both resistance vessels and capacitance vessels contributes to the endotoxin-induced hypotension. It is suggested that (i) both prostanoids and PAF are involved in dilatation of capacitance vessels, (ii) prostanoids, but not PAF cause dilatation of resistance vessels and(iii) PAF may partly contribute to prostanoid-independent reduction in cardiac output in acute canine experimental endotoxin shock.

Topics: Animals; Dogs; Endotoxins; Female; Hemodynamics; Ibuprofen; Isoquinolines; Male; Nitric Oxide; Platelet Activating Factor; Pyridinium Compounds; Shock, Septic; Tetrahydroisoquinolines

We found that carrageenan (CAR), that is, sulfated polygalactose, can enhance both lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) production and the rate of lethality in mice (M. Ogata, S. Yoshida, M. Kamochi, A. Shigematsu, and Y. Mizuguchi, Infect. Immun. 59:679-683, 1991). It has been reported that platelet-activating factor (PAF) antagonists reduce the rate of mortality from endotoxin shock. However, there are few reports regarding the effect of PAF antagonists on TNF production. The aim of the present study is to examine the effect of TCV-309, a new PAF antagonist, on LPS-induced TNF production and mortality in mice pretreated with CAR. ddY mice (6 to 7 weeks old) were injected intraperitoneally with CAR (5 mg per mouse) and were then divided into two groups: mice treated with a PAF antagonist (TCV-309; Takeda Pharmaceutical Co.) and control mice. The mice treated with PAF antagonist received indicated doses of TCV-309 subcutaneously (s.c.) at 30 min before LPS injection, while the control mice received 1 ml of saline s.c. at the same time. All mice were stimulated by intravenous injection of LPS (50 micrograms per mouse) at 24 h after pretreatment with CAR. At intervals after injection of LPS, serum samples were obtained for a TNF assay in which cytotoxicity to L929 cells was measured. TCV-309 both significantly suppressed LPS-induced TNF production and reduced mortality in a dose-dependent manner. When TCV-309 was administered at 30 min before injection of LPS, the effect of TCV-309 on the suppression of TNF activity was at its peak. Treatment with TCV-309 (990 micrograms per mouse) s.c. significantly improved the survival rate after challenge with LPS compared with the survival rate of control mice. Although the 50% lethal dose of LPS was 15 micrograms per mouse for control mice, it increased to 102 micrograms per mouse for mice that were treated s.c. with TCV-309 (990 micrograms per mouse). Even in vitro, TCV-309 also inhibited LPS-induced TNF production in thioglycolate-elicited macrophages. It was concluded that PAF plays an important role in endotoxin-induced TNF production and mortality.

Topics: Animals; Carrageenan; Dose-Response Relationship, Drug; Isoquinolines; Leukotrienes; Lipopolysaccharides; Male; Mice; Platelet Activating Factor; Pyridinium Compounds; Shock, Septic; Tetrahydroisoquinolines; Tumor Necrosis Factor-alpha

Pharmacological profiles of a novel specific platelet activating factor (PAF) antagonist, TCV-309 (3-bromo-5-[N-phenyl-N-[2-[2- (1,2,3,4-tetrahydro-2-isoquinolycarbonyloxy)ethyl] carbamoyl]ethyl] carbamoyl]-1-propylpyridinium nitrate] and its beneficial effects in shock were examined. TCV-309 specifically inhibited PAF-induced aggregation of rabbit and human platelets, and [3H]PAF binding to rabbit platelet microsomes with IC50 values of 33, 58 and 27 nM, respectively. It was as potent as WEB 2086 and more potent than CV-6209 and CV-3988. TCV-309 did not cause hemolysis in human or rat blood due to a detergent-like action. In rats, TCV-309 selectively inhibited the PAF-induced hypotension, hemoconcentration and death with ED50 values of 2.7, 6.4 and 1.7 micrograms/kg (i.v.), respectively. TCV-309 most potently protected mice from death induced by PAF and due to anaphylactic shock with ED50 values of 2.1 and 2.6 micrograms/kg (i.v.), respectively, when compared with CV-3988, CV-6209, WEB 2086 (i.v.) and L-652731 (p.o.). TCV-309 also reversed PAF-induced hypotension and endotoxin-induced hypotension in rats with ED50 values of 3.3 and 1.2 micrograms/kg (i.v.), respectively. There was a significant linear relationship between the ability (ED50 value) of these PAF antagonists to prevent death induced by PAF and death due to anaphylactic shock in mice, and between their reversing ability (ED50 value) for the hypotension induced by PAF and endotoxin in rats. TCV-309 (100 micrograms/kg i.v.) protected rats from death induced by endotoxin. Thus, PAF may be a lethal mediator in anaphylactic shock and a hypotensive mediator in endotoxin shock in rodents.

Topics: Anaphylaxis; Animals; Azepines; Furans; Hemolysis; Humans; Hypotension; Isoquinolines; Male; Microsomes; Phospholipid Ethers; Platelet Activating Factor; Platelet Aggregation; Platelet Aggregation Inhibitors; Pyridinium Compounds; Rabbits; Rats; Rats, Inbred Strains; Shock, Septic; Tetrahydroisoquinolines; Triazoles