Selective Thromboxane Synthetase Inhibitor Research Articles

The Pharmacokinetics and Pharmacodynamics of a New Thromboxane Synthetase Inhibitor, 6-(1-Imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (DP-1904) in Man after Repeated Oral Doses

The pharmacokinetics of DP-1904, a new potent and selective thromboxane synthetase inhibitor, and its effects on ex-vivo prostanoid formation have been studied in groups of Japanese normal male volunteers, who received repeated oral doses of 200 mg every 12 h for 4 doses, or 400 mg every 24 h for 2 doses, or 200 mg every 12 h for 14 doses. The drug was well tolerated by all subjects without evidence of adverse reactions. Repeated administration showed no significant changes in half-lives, tmax values, cmax values and AUC values. DP-1904 did not exhibit time-dependent kinetics. Its plasma levels were lower than the quantifiable level (50 ng mL-1) at 12 h after each dose. These data suggest no significant accumulation of DP-1904 in normal volunteers. DP-1904 reduced the serum thromboxane B2 by about 80% during the medication, the serum concentrations returning to about 44, 75 and 20% of the predrug control values at 36 h after the last 200 mg doses and 48 h after the last 400 mg dose.

The pharmacokinetics and pharmacodynamics of a new thromboxane synthetase inhibitor, 6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (DP-1904), in man after single oral administration.

The pharmacokinetics of DP-1904, a new potent and selective thromboxane synthetase inhibitor and its effects on ex-vivo prostanoid formation were studied in Japanese normal male volunteers, who received orally a single 10, 20, 50, 100, 200, 400 or 800 mg dose. The drug was well tolerated by all subjects without evidence of any adverse reactions. The absorption of DP-1904 from gastro-intestinal tract was rapid. After oral doses of 10-800 mg of the drug given to volunteers in the fasted state, the mean maximum drug concentrations in plasma (Cmax) (mean +/- s.e., n = 5) of 0.215 (+/- 0.041), 0.399 (+/- 0.037), 1.47 (+/- 0.22), 2.86 (+/- 0.22), 4.66 (+/- 0.58), 7.28 (+/- 0.72) and 16.9 (+/- 2.6) micrograms mL-1 were reached within 1 h. DP-1904 concentrations declined monophasically after Cmax with half lives of 30-40 min. These half lives were independent of the administered doses. The mean area under the concentration-time curves (AUCs) increased from 0.398 (+/- 0.038) to 30.0 (+/- 2.7) micrograms h mL-1 as the dose increased from 10 to 800 mg. Linear relations between the doses and Cmax and AUCs were observed. The correlation coefficients for Cmax and AUC were 0.930 and 0.960, respectively. The apparent oral clearance (CL/F) and renal clearance (CLR) did not change significantly as dose increased from 10 to 800 mg. The kinetics of DP-1904 proved to be linear in the dose range studied.(ABSTRACT TRUNCATED AT 250 WORDS)

UP-REGULATED THROMBOXANE PRODUCTION IN THE RAT LIVER WITH BILIARY OBSTRUCTION DOES NOT CONTRIBUTE TO PROMOTE HEPATIC INJURY

This study sought to determine whether in vivo inhibition of thromboxane A2 (TXA2) action contribute to attenuate hepatic damage after bile duct ligation (BDL). Male Wistar rats were assigned to sham operation or BDL. At the time of operation, infusion pump with saline, ozagrel natrium (TXA2 synthase inhibitor), or SQ29548 (TXA2 receptor antagonists) was implanted in the abdominal cavity. Plasma alanine aminotransferase, aspartate aminotransferase, hyaluronic acid, and total bilirubin levels were measured at 4 days after the operation. The levels of plasma TXB2, a stable metabolite of TXA2, were significantly increased after BDL. Gene expression of TXA2 synthase was also significantly upregulated in the liver. Nonetheless, either an inhibition of TXA2 synthesis by ozagrel natrium or a blockade of TXA2 receptor by SQ29548 has no effect in every measured parameter related to hepatic function. These results indicated that despite a highly increased production in the liver, TXA2 is not directly related to the hepatic injury in BDL rats.

In vitro skin penetration of dazmegrel delivered with a bioelastic matrix

The penetration of dazmegrel, a selective thromboxane synthetase inhibitor, through excised human and greyhound skin was measured. A bioelastic matrix was used for topical delivery. Results demonstrated that dazmegrel readily penetrated the skin. Penetration through greyhound skin was significantly greater than penetration through human skin. Penetration through greyhound skin was not significantly different between 4, 24, and 48 h of exposure for the low and intermediate doses studied.

Effect of DP-1904, a thromboxane synthetase inhibitor, on antigen- and spasmogen-induced bronchoconstriction in rodents

The effect of DP-1904 [6-(1-imidazolylmethyl)-5, 6, 7, 8-tetra-hydronaphthalene-2-carboxylic acid hydrochloride], a selective thromboxane synthetase inhibitor, was examined on antigen- and spasmogen-induced bronchoconstriction in rodents. Oral administration of DP-1904 (1, 3, 10 mg/kg) as well as OKY-046 (sodium ( E)-3[4-(1-imidazolylmethyl)-phenyl]-2-propanoate, 100 mg/kg), significantly inhibited immunoglobulin G-mediated bronchoconstriction in actively sensitized guinea pigs. Immunoglobulin E-mediated bronchoconstriction in actively sensitized rats was also inhibited by both DP-1904 (1, 10 mg/kg) and OKY-046 (100 mg/kg). DP-1904 (3–30 mg/kg) and OKY-046 (30 mg/kg) suppressed leukotriene D 4-induced bronchoconstriction in guinea pigs. In these models, the endogenous levels of thromboxanes significantly increased following the stimulus (antigen and leukotriene D 4). DP-1904 (10 mg/kg) inhibited the increase in thromboxane level in both plasma and bronchial alveolar lavage fluid. These actions of DP-1904 persisted for more than 12 h, indicating a long-lasting effect of DP-1904 on bronchoconstriction. The results showed that the biological activity of DP-1904 in our rodents models is more potent than that of OKY-046 (Ozagrel), which is available as an anti-asthma agent in Japan.

Pharmacokinetics of Camonagrel in experimental animal: rat, rabbit and dog.

Camonagrel is a novel selective thromboxane synthetase inhibitor. The aim of this study was to determine its main pharmacokinetic parameters in rats, rabbits and dogs after intravenous and oral administration at doses of 10 mg kg(-1). Plasma and urine concentrations of camonagrel were analyzed by HPLC with UV detection. Pharmacokinetics of camonagrel was generally fitted to a two-compartmental model and the values which defined the absorption process were: Cmax = 15.96 microg.ml(-1), Tmax approximately 0.33 h, AUC(0-infinity) (oral) approximately 12.45 microg x h x ml(-1) (rat, n=3 per pont); Cmax approximately 2.04 mg x ml(-1), Tmax approximately 1.50 h, AUC(0-infinity) (oral) approximately 4.85 microg x h x ml(-1) (rabbit, n=3); Cmax approximately 18.60 microg x ml(-1), Tmax approximately 0.44 h, AUC(0-infinity) (oral) approximately 13.40 microg x h x ml(-1) (dog, n=4). The more representative values in the distribution and elimination phase were: protein binding rate approximately 80% in the three species ("in vitro" experiment); t(1/2beta) approximately 0.22 h (rat, i.v.), = 0.28 h (rabbit i.v.) and approximately 0.45 h (dog i.v.); CI approximately 635.73 ml x h(-1) (rat i.v.), approximately 448.26 ml x h(-1) (rabbit i.v.) and approximately 463.8 ml x h(-1) (dog i.v.). The absolute bioavailability of camonagrel was approximately 79.1% in rat, approximately 21.7% in rabbit and approximately 59.3% in dog. Available elimination data in rat indicated that Camonagrel was mainly excreted in urine (approximately 80%) as unchanged drug. An unknown minor metabolite (approximately 10%) was observed only after oral dosing. Finally, the main pharmacokinetic parameters of camonagrel in rats, rabbits and dogs are presented, which allow to define its absorption, distribution and elimination processes in these species.

Evaluation of the thromboxane A2 synthetase inhibitor OKY-046 in a warm ischemia-reperfusion rat model.

The pathophysiology of ischemia-reperfusion renal injury is mediated, in part, by the generation of the vasoconstricting prostanoid thromboxane A2 (TXA2). This study was undertaken to evaluate the renoprotective effects, as well as the optimal timing and dosage, of a selective thromboxane synthetase inhibitor, OKY-046, in a unilateral nephrectomized, 60 min ischemia, 72 hr reperfusion, rodent model. Forty-one rats were subjected to right nephrectomy only (group A), or right nephrectomy with 60 min of left renal ischemia and treatment with inactive vehicle only (group B), or 2 mg/kg or 4 mg/kg of OKY-046 administered intravenously before (groups C and D) or after (groups E and F) pedicle clamping. Outcome variables included animal survival; change in kidney weight; 0, 24, and 72 hr plasma creatinine (CR); urea nitrogen (BUN); thromboxane B2 (TXB2) and 6-keto prostaglandin F(1alpha) (6 kPGF(2alpha)) levels; creatinine clearance (CRCL); and histologic evidence of renal injury. Animal survival and postperfusion kidney weight were not significantly different among the groups. However, renal functional parameters were significantly improved with the 2 mg/kg dose of OKY-046 administered after renal ischemia. (group B 72 hr Cr= 8.01 +/- 1.1 mg% vs. group E=3.99 +/- 1.5 mg%, and group B 72 hr BUN=241.3 +/- 32.8 mg% vs. group E=52.6 +/- 22.5 mg%). The CRCL was also improved in group E vs. group B, although these results did not reach statistical significance (group B=0.069 ml/min vs. group E=0.194 ml/ min). The 24 hr TXB2 levels were significantly increased in group B (0 hr=754.1 +/- 219.4 pg/ml vs. 24 hr=2055.9 +/- 550.0 pg/ml), and pre- or posttreatment with OKY-046 abrogated this increase (group C 0 hr=517.1 +/- 80.9 pg/ml vs. 24 hr=384.7 +/- 251.5 pg/ml, and group E 0 hr=781.6 +/- 390.4 pg/ml vs. 24 hr=183.0 +/- 81.4 pg/ml). The 24 hr 6 kPGF(1alpha) levels decreased in all groups, whereas 72 hr 6 kPGF(1alpha) levels increased above baseline in groups A, C, and E, but not in group B. These data demonstrate the beneficial effects of thromboxane A2 synthesis inhibition in the setting of ischemia-reperfusion injury and suggest that this renoprotection correlates with late vasodilatory prostanoid synthesis.

Ketoconazole to prevent acute respiratory distress syndrome in critically ill patients.

Ketoconazole appears to be an effective prophylactic measure in surgical patients at risk of developing ARDS. The beneficial effects may be caused by thromboxane synthetase inhibition because thromboxane B2 concentrations were decreased by ketoconazole in both studies. Two studies were unable to demonstrate a beneficial effect with the selective thromboxane synthetase inhibitor dazoxiben. Both studies consisted of a small number of subjects with already established ARDS, not prophylaxis in patients at risk of ARDS. Although the effects of ketoconazole on mortality in patients at risk of ARDS are conflicting, there may be reduced mortality in patients with sepsis. Several issues must be considered before ketoconazole is used in this setting. First, the studies to date have excluded patients at risk of hepatotoxicity, which is probably wise considering the potential hepatotoxicity with ketoconazole and the unknown benefit/risk ratio in these patients. Also, therapies that reduce gastric acidity should be avoided to ensure bioavailability. If ketoconazole is administered through a jejunostomy tube, it probably should be given with a dilute acid to enhance absorption. Furthermore, ketoconazole is a known inhibitor of the cytochrome P450 system, which results in a number of drug interactions. If ketoconazole is used, the patient's current drug therapy should be reviewed for potential interacting drugs. In light of the current studies, ketoconazole may be considered for surgical patients at risk of developing ARDS (especially patients with sepsis) with the previously noted considerations. Future research should seek to confirm ketoconazole's role for the prevention of ARDS in all critically ill patients. Additional studies also should clarify the role of various inflammatory mediators in the pathophysiology and therapy of ARDS.

Possible role of thromboxane A2 in hyperresponsiveness of isolated rat lung tissue in a Sephadex-induced eosinophilia model.

Antigen-stimulated contraction and release of chemical mediators were examined in saline- or Sephadex-treated rat lung parenchymal strips. Sephadex treatment caused eosinophilia in the blood and the lung tissue. Antigen challenge of the isolated parenchymal strips in Sephadex-treated rat was followed by passive sensitization, resulted in an augmented contraction and elevated releases of thromboxane (TX) B2 and peptide-leukotrienes (p-LTs) in bath fluid compared with those of saline-treated control. Although 5-hydroxytryptamine (5-HT) and histamine were significantly released after antigen challenge, the levels were not different between saline- and Sephadex-treated groups. DP-1904, a selective thromboxane synthetase inhibitor, and methysergide but not atropine significantly reduced the augmented contraction and inhibited the elevated TXB2 release in the Sephadex-treated group. Similar increased contraction and the elevated TXB2 release above were observed when Sephadex-treated rat lung strips were stimulated by exogenous 5-HT and LTD4. These augmented contractions were closely correlated with the increase in TXB2 level (r = 0.83; p < 0.01). In addition, contraction to U-46619, a thromboxane mimetic, was significantly greater in Sephadex-treated rat lung strips. Our results indicate that the ability of Sephadex-treated rat lung tissue to synthesize newly generated mediators such as TXA2 and p-LTs is increased, and the spasmogenic susceptibility of the lung tissue to TXA2 itself is modified by Sephadex treatment, suggesting these are due to the augmented contraction in an established hyperresponsiveness state induced by Sephadex.

Inhibitory Effect of a Selective Thromboxane Synthetase Inhibitor, OKY-046, on Acetaldehyde-Induced Bronchoconstriction in Asthmatic Patients

We recently reported that inhaled acetaldehyde causes bronchoconstriction indirectly via histamine release in patients with asthma. The purpose of this study was to investigate a role of thromboxane A2 in acetaldehyde-induced bronchoconstriction in asthmatic airways. We investigated the bronchial response to inhalation of ascending doses (5, 10, 20, and 40 mg/ml) of acetaldehyde in nine asthmatic subjects who were treated with placebo or OKY-046, a selective thromboxane A2 synthetase inhibitor, of 200 mg twice a day for 3 days, and 200 mg on the fourth day (test day) in a double-blind, randomized, placebo-controlled, crossover fashion. Percentage decreases in FEV1 caused by 20 and 40 mg/ml of acetaldehyde inhalation were significantly (p < 0.05 and p < 0.01, respectively) prevented by the pretreatment with OKY-046. Geometric mean value (geometric standard error of the mean) of acetaldehyde concentration producing a 20 percent fall in FEV1 (PC20-Ac-CHO) was significantly (p < 0.01) greater with the OKY-046 pretreatment (72.2 [1.1] mg/ml) than with the placebo pretreatment (19.8 [1.2] mg/ml). We conclude that thromboxane A2 is one of contributors to acetaldehyde-induced bronchoconstriction in asthmatic subjects. It suggests that thromboxane A2 may play an important role in endogenous histamine-induced bronchoconstriction caused by acetaldehyde in asthmatic airways. We believe that this is a first report on the interaction between endogenous histamine and thromboxane A2 in asthmatic subjects.

Effects of thromboxane synthetase inhibitor (OKY-046) on urinary prostaglandin excretion and renal function in streptozotocin-induced diabetic rat

The present study was undertaken to evaluate the effects of a selective thromboxane synthetase inhibitor (OKY-046) on urinary prostaglandins (PGs) excretion and renal parameters such as endogenous creatinine clearance rate (Ccr) and urinary protein excretion in streptozotocin (STZ)-induced diabetic rats. STZ-diabetic rats were divided into two groups; one fed standard chow (DM1) and the other, standard chow mixed with 0.1% OKY-046 (DM2) for 24 weeks. Male Wistar rats were fed standard chow for 24 weeks as control (C). Urinary thromboxane B 2 (TXB 2) and 6-keto-PGF 1α excretions significantly increased in STZ-induced diabetic rats (DM1 and DM2) compared with C after 24 weeks. The increased urinary TXB 2 excretion in DM2 was significantly reduced ( p < 0.05) compared with that in DM1 (261.1 ± 18.6 ng/gCr versus 380.0 ± 48.4 ng/gCr, mean ± SEM). No significant difference could be found in urinary protein excretion between DM1 and DM2, which was significantly higher in both diabetic groups than C after 12 and 24 weeks. Ccr in both DM1 and DM2 significantly increased ( p < 0.05) compared with C after 12 weeks. In contrast, after 24 weeks, Ccr in DM1 fell down to 0.18 ± 0.02 mL/min 100 g body weight (BW), thus being significantly lower ( p < 0.05) than that in C (0.27 ± 0.03 mL/min 100 g BW) and DM2 (0.25 ± 0.02 mL/min 100 g BW). Electron microscopic findings in diabetic rats after 24 weeks were the typical change of early diabetic nephropathy, whereas there were no obvious differences between DM1 and DM2. From these results, increased thromboxane A 2 from renal origin (partly platelet origin) in STZ-induced diabetic rats appears quite likely to be involved in the pathogenesis of diabetic nephropathy, and the inhibition of TXA 2 synthesis by OKY-046 was shown capable of preventing deterioration of renal function.

Leukotriene D4- and prostaglandin F2 alpha-induced airflow obstruction and airway plasma exudation in guinea-pig: role of thromboxane and its receptor.

1. We studied the effects of a thromboxane A2 receptor (TP receptor) antagonist, ICI-192,605 (0.5 mg kg-1, i.v.) and a selective thromboxane (Tx) synthetase inhibitor, OKY-046 (30 mg kg-1, i.v.), on airway responses induced by leukotriene D4 (LTD4; 0.2 nmol) or prostaglandin F2 alpha (PGF2 alpha; 20 nmol) instilled via the airways route to anaesthetized guinea-pigs. For a comparison, airway responses to a TxA2-mimetic, U-46619 (0.02 nmol) were also studied. We measured both lung resistance (RL) to monitor airflow obstruction, and extravasation of Evans Blue dye to quantify airway plasma exudation. 2. Instilled LTD4 into the tracheal lumen induced an immediate peak and subsequently persistent increase in RL and produced a large amount of extravasation of Evans Blue dye at all airway levels. Both ICI-192,605 and OKY-046 significantly attenuated the persistent increase in RL following the immediate response and reduced LTD4-induced extravasation of Evans Blue dye in the trachea and proximal intrapulmonary airway. Instilled LTD4 produced significant increases in immunoreactive TxB2 in bronchoalveolar lavage fluid obtained 1.5 min after instillation of LTD4. 3. Instilled PGF2 alpha into the tracheal lumen induced an immediate increase in RL which peaked at approximately 15 s. We also observed a delayed sustained increase in RL, reaching a second peak at approximately 4 min. PGF2 alpha produced small but significant increases in the amount of Evans Blue dye at all airway levels. As with PGF2 alpha, instillation of U-46619 produced a biphasic increase in RL and extravasation of Evans Blue dye. The potency of PGF2a, in inducing these airway responses was about 1000 times less than U-46619. ICI-192,605 abolished both the immediate and the delayed increase in RL after PGF2a, and also blocked PGF2a,-induced extravasation of Evans Blue dye. However, OKY-046 had no inhibitory effects on these responses.4. We conclude that airflow obstruction and airway plasma exudation induced by instilled LTD4 is, in part, mediated via TxA2 generation and subsequent activation of TP-receptors. On the other hand,instilled PGF2a, while inducing similar responses, does so primarily by direct activation of TP receptors,rather than via TxA2 generation.

Lack of short-term effect of the thromboxane synthetase inhibitor UK-38,485 on airway reactivity to methacholine in asthmatic subjects

Previous open studies have suggested that thromboxane receptor antagonists or synthesis inhibitors lower airway hyperresponsiveness in human subjects. This would indicate a role of thromboxane A2 in the development or maintenance of hyperresponsiveness in asthma. Ten nonsmoking asthmatics (aged 23-64 yrs, 9 male) were included in a randomized, double-blind, placebo-controlled, cross-over study of the effect of one week of treatment with a potent selective thromboxane synthetase inhibitor (UK-38,485, 600 mg daily) on airway responsiveness. The study was preceded by a two week run-in period, and two weeks were used for wash-out between the two trial periods. Adequacy of dosage and patient compliance was confirmed by a reduction in the ex vivo formation of thromboxane B2 (median concentration 3.22 micrograms.ml-1 after placebo, 0.10 microgram.ml-1 after UK-38,485, p < 0.05). The mean forced expiratory volume in one second (FEV1) after UK-38,485 was 2.55 l, compared to 2.56 l after treatment with placebo (p = 0.74). The geometric mean provocative dose of methacholine producing a 20% fall in FEV1 (PD20) before and after UK-38,485 was 23.9 and 32.2 micrograms, respectively, compared to 25.1 and 26.3 micrograms respectively, before and after placebo (p = 0.31). The results of this study suggest that thromboxane A2 does not play an important role in the maintenance of increased airway responsiveness in moderately severe asthmatics treated with low doses of inhaled steroids.

Bradykinin-induced airway responses in guinea pig: effects of inhibition of cyclooxygenase and thromboxane synthetase

We studied the effects of indomethacin (10 mg/kg i.v.), a cyclooxygenase inhibitor, and OKY-046 (1, 10 and 30 mg/kg i.v.), a selective thromboxane synthetase inhibitor, on airflow obstruction and airway plasma exudation induced by bradykinin (150 nmol) instilled by the airway route to anesthetized guinea pigs. To do this, we studied changes in lung resistance (R L) and extravasation of Evans Blue dye respectively. Instilled bradykinin produced an immediate and marked increase in R L which peaked at approximately 30 s. We also observed a delayed increase in R L, reaching a second peak at approximately 3 min. Bradykinin produced airway plasma exudation at all airway levels, measured as extravasation of Evans Blue dye. Indomethacin significantly inhibited both the immediate and the delayed increase in R L after bradykinin. OKY-046 had a similar significant and dose-dependent inhibitory effect on these responses. In addition, both drugs inhibited bradykinin-induced Evans blue dye extravasation in intrapulmonary airways. Bradykinin instilled by the airway route significantly decreased systemic blood pressure but this effect was not altered in animals pretreated with either indomethacin or OKY-046. We conclude that the bronchoconstrictor response and airway plasma exudation induced by instilled-bradykinin may be mediated in part via thromboxane A 2 generation.

Effects of a 48 hour continuous intravenous infusion of CGS 13080-primagrel, a selective thromboxane synthetase inhibitor, on the perinatal and early postnatal period in the guinea pig.

CGS 13080, imidazo[1,5-a]pyridine-5-hexanoic acid, was evaluated for perinatal and postnatal effects in third trimester pregnant guinea pigs and their offspring. The compound was administered via 48 hour continuous intravenous infusion to a group of pregnant guinea pigs (n = 16) at a dose of 3 mg/kg/hr starting on gestational day 52 (via chronically implanted indwelling jugular venous cannulas). A saline control group (n = 12) received equivalent volumes of normal saline 0.5 ml/kg/hr throughout the dosing period. A third group (surgery-sham, n = 16) was subjected to cannulation but not infused. A gross examination of each dam and piglets was conducted at necropsy on day 5 of lactation. The neonatal brains and all gross lesions (maternal and neonatal) were removed and fixed for histopathological examination. Compound-related clinical signs were noted in dams during the dosing phase of gestation. Six guinea pigs developed cephalic lymphatic swelling during the infusion. This observation may be correlated to the reported redistribution of fluid volume to the thorax of guinea pigs given intravenous injections of CGS 13080. There were no compound-induced effects on labor, delivery, or any of the examined reproductive parameters. There were no compound-related clinical signs, or effects on survival, body weight and developmental parameters in the F1 generation. Histopathological examination of the brains and other organs did not reveal any compound-related abnormalities. Based on these results, it was concluded that CGS 13080 did not elicit adverse perinatal and postnatal effects in guinea pigs.

Irreversible inhibition of thromboxane (TX) A 2 synthesis by Y-20811, a selective TX synthetase inhibitor

As Y-20811, sodium (±)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid, has been reported to inhibit serum thromboxane (TX) A 2 production with a long duration of action, its mechanism of action was investigated. When ( 3H]Y-20811 (3 mg/kg) was administered orally to rats, the peak platelet concentration of Y-20811 was obtained 1 hr after the administration, and the T 1 2 was 43 hr. The peak plasma concentration of Y-20811 was also obtained 1 hr after administration, but the elimination of Y-20811 from plasma was faster ( T 1 2 α = 1.5 hr, T 1 2 β = 15 hr) than that observed in platelets. Serum TXA 2 (estimated as TXB 2) production was inhibited significantly from 1 to 72 hr after the oral administration of unlabeled Y-20811 (3 mg/kg), which temporally resembled the change of the platelet Y-20811 concentration. In platelet-rich plasma, [ 3H]Y-20811 completely inhibited TXA 2 production at about 1500 pg/10 9 platelets, and the IC 50 level was about 600 pg/10 9 platelets, which was similar to values obtained in ex vivo studies. In addition, inhibition of TXA 2 production by Y-20811 still remained after washing the drug-pretreated microsomes, whereas that of dazoxiben completely disappeared. A similar irreversible inhibition of TXA 2 production was observed with aspirin. These results suggest that Y-20811 may firmly combine with platelet TX synthetase and may irreversibly inhibit TXA 2 production.

A selective thromboxane synthetase inhibitor, OKY-046, fails to improve blood rheology in endotoxin-shocked rabbits.

Effects of a selective thromboxane synthetase inhibitor, (E)-3-[4-(1-imidazolylmethyl)phenyl]-2-propenoic acid hydrochloride monohydrate (OKY-046), were studied hemorheologically in endotoxin shocked-rabbits. The animals were intravenously administrated with 0.1 mg of endotoxin 3 times at intervals of 3 days. At 7 days after the last endotoxin injection, endotoxin (0.2 mg.kg(-1)) was intravenously administrated to induce a shock. OKY-046 (30 mg.kg(-1)) was administrated after hypotension was developed by the endotoxin treatment and, then, it was continuously injected at 0.03 mg.kg(-1).min(-1). Blood pressure remained unchanged and hypotensive was maintained during the treatment with OKY-046. Blood was sampled from the femoral artery 15 (before the administration of OKY-046), 45, and 120 minutes after the final administration of endotoxin. Pa(O)(2) increased, and Pa(CO)(2), arterial pH, and base excess (BE) decreased during the endotoxin shock. The decrease of pH and BE was prevented by the administration of OKY-046. In the endotoxin-shocked animals, hematocrit, whole blood viscosity, erythrocyte deformability, plasma fluidity, and the ratio of hematocrit to whole blood viscosity showed no significant differences between the OKY-046 treated animals and non-treated ones. These data show that a selective thromboxane synthetase inhibitor (OKY-046) does not improve the blood rheology during endotoxin shock, although it seems to prevent the acidosis in some extent.

選択的Ｔｈｒｏｍｂｏｘａｎｅ合成酵素阻害薬ＯＫＹ‐０４６のモルモットインフルエンザウイルス感染後の気道反応こう進に対する抑制効果について

選択的Ｔｈｒｏｍｂｏｘａｎｅ合成酵素阻害薬ＯＫＹ‐０４６のモルモットインフルエンザウイルス感染後の気道反応こう進に対する抑制効果について

Fetal and maternal response to intravenous infusion of a thromboxane synthetase inhibitor

Pharmacologic inhibition of thromboxane synthetase activity has reversed the clinical manifestations of toxemia in the ovine model. To investigate placental transfer and fetal effects of a selective thromboxane synthetase inhibitor, CGS13080 (Ciba-Geigy, Summit, N.J.) was intravenously infused into eight singleton- or twin-bearing ewes near term. During CGS 13080 infusion (0.1 mg/kg/hr), maternal steady-state CGS 13080 levels of 102 +/- 18 ng/ml were achieved within 30 minutes and maternal serum thromboxane generation decreased significantly (13 +/- 3 to 4 +/- 1 ng/ml). However, fetal serum levels of CGS 13080 were only 4% of peak maternal concentrations and fetal serum thromboxane generation did not change. There was no evidence of change in uterine blood flow, maternal or fetal blood pressure, heart rate, blood gas values, or fetal or maternal metabolites of prostacyclin or prostaglandin E2 during the study. We speculate that CGS 13080 may be efficacious in the treatment of human pregnancy-induced hypertension.

Attenuating Effect of a Thromboxane Synthetase Inhibitor (OKY-046) on Bronchial Responsiveness to Methacholine Is Specific to Bronchial Asthma

To determine whether the involvement of thromboxane A2 in bronchial hyperresponsiveness (BHR) is specific to asthma, we examined the effects of a selective inhibitor of thromboxane synthetase (OKY-046) and a cyclooxygenase inhibitor (indomethacin) on bronchial responsiveness to methacholine in normal subjects and patients with chronic bronchitis, diffuse bronchiectasis, and intrinsic bronchial asthma. The provocative concentration of methacholine producing a 20 percent fall in forced expiratory volume in 1 s (PC20-FEV1) was measured before and after oral administration of OKY-046 (2,600 mg over four days) and indomethacin (450 mg over three days) in ten normal, ten bronchitic, nine bronchiectatic, and eight asthmatic subjects, respectively. Baseline values of FEV1 and forced vital capacity (FVC) were not altered by OKY-046 or indomethacin. The geometric mean value of PC20-FEV1 increased significantly (p less than 0.005) from 1.78 to 4.27 mg/ml after OKY-046 in asthmatic subjects, but not in normal, bronchitic, or bronchiectatic subjects. On the other hand, PC20-FEV1 increased significantly (p less than 0.005) from 2.19 to 8.13 mg/ml after indomethacin in bronchiectatic subjects, but not in normal, bronchitic, or asthmatic subjects. We conclude that the involvement of thromboxane A2 in BHR may be specific to asthma, and bronchial responsiveness of bronchiectasis may be potentiated by inflammatory release of bronchoconstrictor prostaglandins except for thromboxane A2. Further studies using thromboxane A2 receptor antagonists are needed to confirm the conclusion.