Biomedical subjects

T Uematsu

Publications and source records attributed to T Uematsu.

At least 145 records · Page 8Linked to original sources

PubMed1997

Antiplatelet effect of FK633, a platelet glycoprotein IIb/IIIa antagonist, on thrombus formation and vascular patency after thrombolysis in the injured hamster carotid artery.

The antithrombotic and restenosis-preventing effects of FK633, an inhibitor of platelet aggregation via binding to the glycoprotein (GP) IIb/IIIa receptor, were studied, IC50 value of FK633 against platelet aggregation ex vivo induced by 2.5 microM adenosine diphosphate (ADP) was 5.4 x 10(-7) M as determined using hamster platelet rich plasma. The inhibitory effect was also investigated in vivo on thrombus formation at the carotid arterial wall injured by a modified catheter. As a control, the left carotid artery was injured and the time required to develop a thrombotic occlusion (3.9 +/- 1.1 min, mean +/- S.E.M., n = 18) was determined. Then, the right carotid artery of the same animal was injured while a continuous intravenous (i.v.) infusion of FK633 was administered at doses of 0 (saline), 0.1, 0.3 or 1.0 mg/kg/h. The time to occlusion was dose-dependently prolonged. In a separate experiment, 10% of the total tPA dose (0.52 mg/kg) was injected into the injured artery as a bolus and the remaining was infused i.v. at a constant rate for 30 min. When FK633 (0.3 or 1.0 mg/kg/h) was infused together with tPA, late patency of the reperfused artery was much improved as compared with that of treatment with tPA alone. Bleeding time, measured at the end of the tPA infusion, was markedly prolonged when the higher dose of FK633 (1.0 mg/kg/h) was coadministered, however coadministration of the lower dose of FK633 (0.3 mg/kg/h) was almost without prolongation on the bleeding time, despite a significant effect on the vascular patency after thrombolysis. Next, neointima formation was evaluated 2 weeks after the vascular injury. When FK633 (0.3 mg/kg/h) was continuously infused i.v. by an implanted osmotic pump for 3, 7 or 14 days after the vascular injury, the neointimal area formation was significantly suppressed in the treatment groups for 7 or 14 days. These findings suggest that FK633 inhibits platelet activation in the injured artery and improves vascular patency after thrombolysis with tPA with a concomitant suppression of neointima formation.

Animals↗

PubMed1997

[Helical CT of the breast: detection of intraductal spread and multicentricity of breast cancer].

PURPOSE: This study was performed to evaluate the clinical utility of postcontrast helical CT (HCT) scan for the detection of intraductal spread (DS) and multicentricity of breast cancer. MATERIALS AND METHODS: DS and multicentricity in 84 patients with invasive ductal carcinoma were evaluated by preoperative postcontrast HCT. The HCT protocol of 3-mm section width and 3 mm/sec table speed was used with the patients in a supine position. Scanning started 70sec after beginning the intravenous injection of 90 ml (27 gI) of contrast material at the rate of 1.5 ml/sec. The three-dimensional images were displayed. RESULTS: Eighty-four of 84 main tumors (100%) were shown as enhanced masses by postcontrast HCT. The sensitivity and specificity of HCT for the detection of DS and multicentricity were 60.0% (18/30) and 88.9% (48/54), and 88.9% (16/18) and 90.9% (60/66), respectively. When DS and multicentric lesions were combined, the sensitivity and the specificity were 76.3% (29/38) and 89.1% (41/46), respectively. CONCLUSION: HCT of the breast is effective in detecting DS and multicentric lesions of breast cancer and might be useful in helping surgeons to successfully perform breast-conserving surgery.

Adult↗

PubMed1997

Deletion of serum lectin-reactive alpha-fetoprotein by acyclic retinoid: a potent biomarker in the chemoprevention of second primary hepatoma.

A goal of cancer chemoprevention is the deletion of latent premalignant or malignant clones before they expand to a clinically detectable tumor. However, such clonal deletion has not been demonstrated in clinical studies. We have evaluated serum levels of lectin-reactive alpha-fetoprotein (AFP-L3), which suggests the presence of latent hepatoma cells, in a randomized controlled trial that used acyclic retinoid to prevent second primary hepatomas in patients who had received treatments that cured initial hepatomas. The trial involved 21 patients in each acyclic retinoid (600 mg daily) and placebo group and consisted of a 12-month period of drug administration and a subsequent follow-up period. Serum AFP-L3 was determined at entry and at the end of the 12-month treatment period using lectin-affinity electrophoresis and antibody-affinity blotting. Although neither treatment affected serum levels of total AFP, acyclic retinoid significantly reduced AFP-L3 levels after a 12-month administration (P < 0.01). Acyclic retinoid not only deleted AFP-L3 from patients who had been positive for AFP-L3 at entry but also prevented the appearance of AFP-L3 in patients who had been negative at entry (P < 0.01). In contrast, placebo significantly raised the incidence of AFP-L3-positive patients after a 12-month administration from that at entry (P < 0.05). Patients positive for AFP-L3 after a 12-month treatment had a significantly higher risk of second primary hepatomas in the subsequent follow-up period (P = 0.03). Acyclic retinoid may have deleted a clone of latent hepatoma cells producing AFP-L3 and thereby inhibited second primary hepatomas. Serum AFP-L3 may be a useful intermediate biomarker in the chemoprevention of second primary hepatomas by acyclic retinoid.

Antineoplastic Agents↗

PubMed1996

The loss of recombinant human granulocyte colony-stimulating factor and recombinant human TNF-alpha priming effects on the superoxide-generating response in exudated neutrophils is associated with a decrease in their receptor affinities.

Several cytokines are known to enhance FMLP-stimulated superoxide generation in human circulating blood neutrophils through binding to their specific receptors, a process referred to as the priming effect. The priming effects produced by recombinant human granulocyte CSF (rhGCSF) and TNF-alpha (rhTNF-alpha) on FMLP-stimulated superoxide production in human and rabbit blood neutrophils were compared with their effects in their respective tissue neutrophils, i.e., human salivary and rabbit peritoneal neutrophils. The receptor binding characteristics of rhGCSF and rhTNF-alpha were also compared between the two types of neutrophils. Both rhGCSF and rhTNF-alpha produced dose-dependent priming effects on FMLP-stimulated superoxide production in human blood neutrophils, whereas they failed to produce any priming effects in human salivary neutrophils. Similar results were obtained for the priming effects by rhGCSF in rabbit blood and peritoneal neutrophils. A decrease in receptor binding affinity, but not in receptor density, in tissue neutrophils was demonstrated by analyzing the binding of [125I]rhGCSF and [125I]rhTNF-alpha. These findings suggest that tissue neutrophils are less responsive to rhGCSF and rhTNF-alpha in the modulation of FMLP-stimulated superoxide generation. This is due at least in part to the lower affinities of GCSF and TNF-alpha to their receptors in tissue neutrophils. This marked difference in priming effects by cytokines between blood and tissue neutrophils may represent an early step in the defensive responses against invading microorganisms or Ags.

Animals↗

PubMed1996

Treatment of roentogenographically occult endobronchial carcinoma with external beam radiotherapy and intraluminal low dose rate brachytherapy.

PURPOSE: A prospective Phase II study was done to investigate the treatment results of combined external beam and intraluminal radiotherapy in roentogenographically occult inoperable endobronchial carcinoma. METHODS AND MATERIALS: In 41 patients (all male) with roentogenographically occult endobronchial carcinoma, a combination of external beam radiotherapy using linac x-ray and intraluminal low dose rate brachytherapy via 192Ir thin wire (1.48 GBq) was performed. External beam radiotherapy comprised of 40 Gy in 20 fractions over 4 weeks was carried out, whereas intraluminal brachytherapy consisted of 25 Gy in five fractions over 2.5-5 weeks. The dose reference point for brachytherapy varied (3-9 mm) according to a diameter of the bronchus. RESULTS: Excluding two cases in which bronchoscopy was refused (1) and was still being treatment (1), 39 patients were treated according to plan. By the last intraluminal brachytherapy, no tumor was endoscopically identifiable in all cases. The follow-up period ranged from 1-41 months, with a median of 24.5 months. Recurrence occurred in two cases, with subsequent surgery: one is alive without cancer and the other died of uncontrolled lung cancer at 35 months. Radiation pneumonitis was observed in two cases for whom glucocorticoid and antibiotics were administered. Both recovered and resumed work. Other recurrences or severe complications from irradiation have not been observed so far. Two or more separate primary cancers were observed in 19 (lung, 10; other organs, 10) of the 41 patients. CONCLUSIONS: The combination treatment of external beam radiotherapy and intraluminal brachytherapy is effective for roentogenographically occult endobronchial carcinoma with acceptable complications.

Aged↗

PubMed1996

Immunohistochemical detection of Bax and Bcl-2 proteins in gerbil hippocampus following transient forebrain ischemia.

Time-course expression of Bax and Bcl-2 proteins, identified as apoptosis-regulating molecules, was assessed in gerbil hippocampus following transient forebrain ischemia. Brain sections from animals sacrificed at 48, 72, 96 h and 7 days following 5 min ischemia were immunohistochemically evaluated using polyclonal antibodies specific for Bax and Bcl-2 proteins, respectively. The intensity of Bax expression in CA1 neurons increased with time and peaked at 72 h, and immediately disappeared at 96 h following 5 min ischemia. No expression of Bcl-2 in the CA1 neurons was recognized in all the time evaluated.

Animals↗

PubMed1996

Serum dehydroepiandrosterone and DHEA-sulfate in patients with adult T-cell leukemia and human T-lymphotropic virus type I carriers.

The serum levels of dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) were determined by radioimmunoassay in 38 patients with adult T-cell leukemia (ATL). Levels of serum DHEA and DHEA-S were also measured in 60 human T-lymphotropic virus type I (HTLV-I) carriers, and did not differ from those in 60 healthy control subjects. Serum levels in patients with ATL were lower than those in the age- and sex-matched healthy controls and in HTLV-I carriers with statistical significance. Serum DHEA and DHEA-S in male patients with acute and lymphoma-type ATL were 1.06 +/- 0.77 ng/ml and 245.8 +/- 192.9 ng/ml, respectively. Levels in male patients with chronic and smoldering-type ATL were 1.69 +/- 0.68 ng/ml and 477.6 +/- 251.5 ng/ml, respectively. Serum levels of DHEA and DHEA-S in patients with acute and lymphoma-type ATL were significantly lower than those in patients with chronic and smoldering-type ATL (P < 0.05). These data suggest that a decrease in serum levels of DHEA and DHEA-S may be associated with patients who have some clinical subtypes of ATL. Moreover, androgens may have a therapeutic role in patients with ATL, as administered in patients with hairy-cell leukemia. Because there is at present no curative chemotherapy for ATL, a trial combination of androgens and standard chemotherapy may be a reasonable therapeutic option in such patients.

Adrenal Cortex↗

PubMed1996

Pharmacokinetics and safety of a novel, long-acting, prodrug-type potassium channel opener, Y-27152, in healthy volunteers.

The pharmacokinetics and safety of a novel, long-acting, prodrug-type K(+)-channel opener, Y-27152, were investigated in healthy male volunteers. In the first phase, single oral doses of 0.1, 0.25, 0.5, 0.75, and 1.0 mg of Y-27152 (n = 3-6 per dose) were given after overnight fasts in a dose-escalating manner. The 0.75-mg dose was given both after an overnight fast or after food to examine the effects of food intake. In the second phase, multiple doses of Y-27152 were taken after meals once daily for 7 consecutive days. In part A of this phase, either placebo (n = 3) or 0.5 mg of Y-27152 (n = 6) was taken for 7 days, and in part B of this phase 0.5-, 0.75-, and 1.0-mg doses were taken in a dose-escalating manner for 1,3, and 3 days, respectively (n = 9). In the single-dose study, peak concentration (Cmax) and area under the plasma concentration-time curve (AUC) of main active metabolite (Y-26763; M1) increased in parallel with dosage. This dose-linearity was less obvious with Y-27152, which had an AUC approximately 6 to 10 times less than that of M1. Administration with food at 0.75 mg resulted in a small but significant decrease (approximately 10%) in the Cmax and AUC of M1. At doses of 0.5 mg or higher, participants experienced headaches and palpitations, which were probably due to the vasodilatory effects and did not require treatment. Mean diastolic blood pressure significantly decreased and pulse rate increased at doses of 0.5 mg or higher compared with predose values. Plasma renin activity was significantly elevated 4 hours after the administration of the 0.75- and 1.0-mg doses, but showed no significant change at 0.5 mg. In the multiple-dose study, the time profile of the plasma concentration of M1 approximately coincided with the simulation curves worked out using the pharmacokinetic parameters obtained in the singledose study. The incidence of headaches tended to increase with dose in part B, but drug administration was not discontinued in any case. Plasma renin activity again increased 4 hours after administration. In phase B of the multiple-dose study, diastolic blood pressure decreased and pulse rate increased compared with predose values. Y-27152 was metabolized to M1 and well tolerated in healthy volunteers, and its pharmacologic effects were likely caused by vasodilation, which could make it an effective antihypertensive agent.

Administration, Oral↗

PubMed1996

Design of a suitable formulation of FK613, a novel antiallergic agent, based on its pharmacokinetic and pharmacodynamic properties in healthy subjects.

The pharmacokinetic and pharmacodynamic properties of FK613, a novel indolyl piperidine derivative, were investigated after oral administrations of 5, 10 and 20 mg in hard gelatin capsules to healthy male volunteers. FK613 was rapidly and almost completely absorbed, and >89% was recovered in the urine as the unchanged form. The urinary excretion of FK613 was linearly correlated with plasma concentration and its low water solubility was the main concern regarding the safety. In another experiment using a double-blind crossover design, in which 0 (placebo), 5 and 20 mg FK613 were administered to determine the plasma concentration-effect relationship, suppression of the intradermal histamine-induced skin reaction by FK613 was observed. Thus, the maintenance of a plasma concentration of FK613 in the range of 80-250 ng center dot ml-1 was recommended to ensure the suppression of histamine-induced wheal by >50% and not to exceed the solubility in urine. To achieve this, a new hydrogel-type formulation of FK613 was developed, with the aim both of delaying its absorption, so as to suppress the sharp rise in plasma concentration, and of maintaining the effective concentration for a longer period of time. This formulation was administered after meals at the doses of 20, 30, 40, 50 and 60 mg, and at repeated doses of 40 mg twice daily for 6.5 days to evaluate the pharmacokinetics and safety in healthy subjects. The area under the plasma concentration curve increased linearly with dose, whereas maximum plasma concentration (Cmax) tended to peak as dose increased, indicating the desirable properties of this formulation. Although Cmax exceeded 250 ng/ml at doses of 30 mg or more, no urinary crystal formation was observed on careful inspection of urine.

Adult↗

PubMed1996

Resection of the inferior head of the pancreas: report of a case.

We developed a new technique for partial resection of the head of the pancreas with an end-to-side pancreaticoduodenostomy, while preserving the duodenum, the common bile duct, and the upper part of the head of the pancreas around the duct of Santorini. A resection of the inferior head of the pancreas was performed in a patient with an intraductal mucin-producing tumor of the pancreas. This procedure is considered to be appropriate for treating both benign disease and noninvasive malignant disease involving either the uncinate process or the duct of Wirsung, because it removes both the uncinate process and the pancreatic tissue around the duct of Wirsung. We thus believe that a resection of the inferior head of the pancreas with an end-to-side pancreaticoduodenostomy can help play a significant role in the management of patients with benign diseases and localized malignant tumors of the pancreas.

Adenocarcinoma, Papillary↗

PubMed1996

The effects of intravenously infused catecholamines on hepatic blood flow in conscious dogs with experimental obstructive jaundice.

This study was conducted to examine how the effects of dopamine and dobutamine on hepatic blood flow were influenced by obstructive jaundice in a conscious canine model. Prior to biliary obstruction, portal venous blood flow (PVF) increased in response to the infusion of either dopamine or dobutamine: dopamine infused at 8 micrograms/kg per min produced an increase of 19 +/- 0% in PVF, while dobutamine infused at 16 micrograms/kg per min produced an increase of 30 +/- 2%. Although hepatic arterial blood flow (HAF) decreased dose-dependently in response to the infusion of dopamine, no significant change was observed in HAF in response to any dose of dobutamine. Obstructive jaundice attenuated or completely abolished the PVF-increasing effect of dopamine, whereas it did not significantly alter the effect of dobutamine on hepatic blood flow. In dogs with obstructive jaundice, dopamine at 16 micrograms/kg per min produced a decrease of 17 +/- 3% in PVF. These findings suggest that dobutamine is more effective than dopamine for increasing hepatic blood flow in patients with obstructive jaundice.

Animals↗

PubMed1996

Granulocyte-colony stimulating factor produced by pancreatic carcinoma.

CONCLUSION: A rare case of granulocyte-colony stimulating factor (G-CSF) produced by carcinoma of the pancreas has been reported. BACKGROUND: This is the first case showing high G-CSF concentration in the aspirated tumor fluid (mucin) at its early stage without leukocytosis. METHODS: The tumor, detected incidentally in a 64-yr-old male, was removed by a distal pancreatectomy. The mass was 7.0 x 6.5 x 4.5 cm, and was histologically diagnosed as cystadenocarcinoma with prominent sarcomatous transformation. It was classified as anaplastic carcinoma. RESULTS: After 4 wk of resection, progressive leukocytosis was observed. Seven weeks after the operations, the peripheral leukocyte count increased to 126,000/mL. After 8 wk of resection, the patient died of recurrence. The serum G-CSF concentration was elevated after recurrence. The preserved mucin contained in the cystic components of the resected specimen had a G-CSF concentration higher than 2400 pg/mL. G-CSF is a known cytokine and an etiologic agent in paraneoplastic syndromes. An early diagnosis can, therefore, be made prior to the manifestation of clinical symptoms by the evaluation of the aspirated tumor fluid. This can lead to the prevention of the paraneoplastic syndrome with inhibitory cytokines in future.

Cystadenocarcinoma↗

PubMed1996

Measurement of 5-fluorouracil in scalp hair: a possible index of patient compliance with oral adjuvant chemotherapy.

OBJECTIVE: Little is known about patient compliance with oral adjuvant chemotherapy. It is estimated to be poor especially in Japan, where it is still unusual for patients to be directly informed of their diagnosis of malignancy. 5-Fluorouracil (5-FU) was measured in hair samples to assess patient exposure to 5-FU, and its potential usefulness is discussed as an index of compliance with postoperative adjuvant chemotherapy. METHODS: Hair samples obtained from 55 patients, who had received oral 5-FU (total dose 27-41 g) as postoperative adjuvant chemotherapy over a 6-month period, were used for the analysis of 5-FU. The drug was extracted from the hair using ethyl acetate, and its fluorescence derivatization was employed for measurement with HPLC. The detection limit of 5-FU in hair was 0.01 ppm. RESULTS: In 22 out of 55 samples 5-FU content was under the detection limit, whereas in the remaining 33 samples the drug was detected in a range of 0.006-2.125 ng per hair strand; in addition, drug content showed a lognormal distribution. 5-FU was detected in the hair collected from those patients who were possibly compliant with the postoperative oral adjuvant chemotherapy. CONCLUSION: As many as 40% of the patients analysed were supposed to be much less compliant. Even in the possibly compliant patients, the degree of compliance with the therapy varied according to a log-normal distribution.

Animals↗

PubMed1996

Effect of dietary fat content on oral bioavailability of menatetrenone in humans.

The purpose of this investigation was to determine the effects of fat content and frequency of meals on the oral bioavailability of menatetrenone (2-methyl-3-all-trans-tetraprenyl-1,4-naphthoquinone), a vitamin K2 with four isoprene units. In the first series of studies, menatetrenone (15 mg) was administered at breakfast time to 18 healthy male volunteers after meals with three different fat contents (meals A, B, and C) on three occasions in a crossover design. The three types of meals had almost the same calorie content (721-746 kcal) with varied fat contents (A, 8.8 g; B, 20.0 g; C, 34.9 g). The area under the plasma menatetrenone concentration-time curve within the first 24 h (AUC0-24) increased with increase of fat content: 371 +/- 194, 485 +/- 150, and 1024 +/- 341 ng.h/mL (mean +/- SD, n = 18) after meals A, B, and C, respectively. On the fourth occasion, the same dose of menatetrenone was administered to all volunteers after taking meal B, but in this case the lunch 5 h after drug administration was omitted from the protocol. The time profile of plasma menatetrenone showed a single peak when lunch was not taken, whereas it showed two peaks with lunch. On the fifth occasion, 12 out of 18 volunteers took the same dose of menatetrenone after a meal with the highest fat content (53.8 g of fat and 789 kcal; meal D), showing that AUC0-24 was almost the same as that for meal C, 1027 +/- 389 and 991 +/- 392 ng.h/mL (n = 12) for meals C and D, respectively. The oral bioavailability of lipid-soluble vitamin K was influenced by the fat content of a meal, although the increase in bioavailability seemed to reach a peak when the lipid content of the meal was > 35 g.

Administration, Oral↗

PubMed1996

Structure-activity relationships for substrates and inhibitors of mammalian liver microsomal carboxylesterases.

PURPOSE: Carboxylesterases are important in the detoxification of drugs, pesticides and other xenobiotics. This study was to evaluate a series of substrates and inhibitors for characterizing these enzymes. METHODS: A series of novel aliphatic esters and thioesters were used in spectral assays to monitor human, murine and porcine esterases. A series of transition state mimics were evaluated as selective esterase inhibitors. RESULTS: Several alpha-alkyl thioacetothioates were found to be approximately 2 to 11-fold superior to commonly used substrates for monitoring carboxylesterase activity. Insertion of a heteroatom in the acid portion of these esters in the beta or gamma position relative to the carbonyl had a dramatic effect on enzyme activity with S or O substituents often improving the kCAT/K(M) ratio of the substrate and N decreasing it. Several alpha,alpha'-bis (2-oxo-3,3,3-trifluoropropylthio)alkanes proved to be potent selective transition state mimics of the esterase activity with IC50's from 10(-5) to 10(-9)M. CONCLUSIONS: This library of substrates and inhibitors are useful research tools for characterizing the numerous isozymes of carboxylesterases present in mammalian tissues.

Animals↗

PubMed1996

Reduced expression of dipeptidyl peptidase (DPP) IV in peripheral blood T lymphocytes of oral cancer patients.

To investigate the mechanism of decrease of serum DPP IV activity in oral cancer patients, we analyzed the expression of DPP IV in peripheral blood T lymphocytes of oral cancer patients and healthy subjects. Consequently, serum DPP IV activity was found to correlate significantly with the number of peripheral blood lymphocytes (PBL), T lymphocytes and CD26 (identified as DPP IV)+ T lymphocytes in healthy subjects, and the number of PBL and CD26+ T lymphocytes in cancer patients. However, the numbers of PBL and T lymphocytes were significantly less in cancer patients than in healthy subjects. Although the number of CD26+ T lymphocytes was somewhat greater in cancer patients than in healthy subjects, serum DPP IV activity was significantly lower in cancer patients. DPP IV activity and amount of CD26 in T lymphocyte plasma membranes were much less in cancer patients than in healthy subjects. These findings suggest that a decrease in the number of T lymphocytes and the small amount of DPP IV in their plasma membrane may contribute to the decrease of serum DPP IV activity in cancer patients.

Adult↗

PubMed1996

Completely impacted teeth in dentate and edentulous jaws.

Panoramic radiographs from 1026 patients were examined for the presence of completely impacted teeth. The prevalence of completely impacted teeth in the edentulous jaw was lower than that in the dentate jaw in both the upper and lower jaws. The prevalence of completely impacted third molars in the edentulous jaw was also lower than that in the dentate jaw. However, there was no difference in the prevalence of completely impacted canine teeth and completely impacted anterior maxillary supernumerary teeth (mesiodens) in the edentulous jaw. These findings may indicate that completely impacted canine teeth and impacted anterior maxillary supernumerary teeth (mesiodens) are not influenced by the loss of erupted teeth.

Adult↗

PubMed1996

Pharmacokinetic and pharmacodynamic properties of FK070 (KDI-792), a novel thromboxane receptor antagonist/thromboxane synthetase inhibitor, after single and multiple oral administrations to healthy volunteers.

FK070, a thromboxane A2 (TXA2) receptor antagonist/TXA2 synthetase inhibitor, was given orally to healthy male volunteers in a single- and multiple-dose study. In the single-dose study (200, 300, 400 mg), the area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (Cmax) increased non-linearly with dose, while the mean elimination half-life (V0) was essentially unchanged (3.9-7.3h). Recovery of the unchanged drug in the urine was 12-25%. Cmax and AUC as determined with 200 mg of drug after a meal decreased by about 60 and 30%, respectively. Ex-vivo platelet aggregation in the plasma by a TXA2 analogue, U46619, was almost completely inhibited within 1 h, after all doses of drug, with a significant dose-dependent inhibition maintained for 8 h or more, which was much longer than was expected from drug plasma concentration. The aggregation by adenosine diphosphate (ADP) was inhibited to a lesser extent. FK070 also inhibited TXA2 synthetase as evidenced by decreased production of TXB2 and reciprocally increased production of 6-keto-prostaglandin F1 alpha in the serum during ex-vivo whole blood coagulation. These effects peaked 1 h after drug and lasted until 4 h with the higher doses. In the multiple-dose study (300 mg, twice a day, after meals for 6.5 days), drug concentrations in the plasma were well fitted to a three-compartment open model with first-order absorption. FK070 afforded extensive inhibition of platelet aggregation by U46619 throughout the administration period, with a significant inhibition lasting as long as 48 h after conclusion of administration. No clearly drug-related changes were found in routine laboratory tests, subjective and objective findings, or vital signs. FK070 was concluded to be well tolerated and to provide long-lasting blockade of TXA2 receptors, and plasma concentration-dependent inhibition of TXA2 synthetase in the platelets.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗