Pericardiectomy and pericardium window creation to treat recurrent pericardial tamponade involving a borderline ovarian tumor.

PURPOSE OF INVESTIGATION: Pericardial effusion with cardiac tamponade is an uncommon metastatic manifestation of ovarian tumors, with only one previously reported case involving a borderline ovarian tumor (BOT). CASE: A 50-year-old woman was diagnosed and treated for a primary Stage IIc BOT. The disease recurred as an emergency pericardiocentesis eight years later, which was resected following pericardial effusion with a cardiac tamponade. This occurred two more times, and on the last occasion, drainage failed to relieve her symptoms. However, her symptoms resolved after the creation of a pericardium pleural window together with a pericardiectomy. CONCLUSION: For patients with a metastatic BOT, the creation of a pericardium pleural window and pericardiectomy is effective for recurrent pericardial tamponade, if the pericardial space is posteriorly located and/or segmented.

Successful management of complete placenta previa after intrauterine fetal death in a second-trimester pregnancy by uterine artery embolization: case report and literature review.

A 27-year-old woman with complete placenta previa was referred at 22 weeks of gestation because of vaginal bleeding and fetal growth restriction. At 24 weeks, sudden fetal death occurred, but bleeding continued and transvaginal sonography revealed abundant periplacental blood flow in the uterine wall. To avoid cesarean section, the authors performed uterine artery embolization (UAE) be- fore vaginal delivery of the fetus. Subsequently, there was little bleeding when laminaria was inserted for cervical ripening and the fetus was delivered vaginally by using vaginal gemeprost. Total blood loss was only 149 ml. The present case suggests that UAE may be an option for patients with placenta previa who desire vaginal delivery after intrauterine fetal death (IUFD) in a second-trimester pregnancy.

Clinical features of 215 stage I ovarian tumors in Japanese women.

PURPOSE: Differences of the clinical features of Stage I borderline ovarian tumors and Stage I ovarian cancer need to be clarified. METHODS: We retrospectively investigated 215 patients with Stage I ovarian tumors (67 with borderline tumors and 148 with ovarian cancer) treated between 1988 and 2001. RESULTS: Only one patient with a borderline tumor developed recurrence, while recurrence was found in 20 patients with Stage I ovarian cancer. There was a significant difference in the recurrence rate between patients with Stage Ia or Ib ovarian cancer and those with Stage Ic cancer (p = 0.007). Clear cell adenocarcinoma showed a higher recurrence rate. Among our patients with recurrence, only five in whom the recurrent tumor could be surgically resected are currently alive and disease-free. CONCLUSIONS: This study confirmed the low aggressiveness of Stage I borderline ovarian tumors and high aggressiveness of Stage Ic ovarian cancer or clear cell adenocarcinoma. In patients with recurrence, surgical resection may improve survival.

VX211, a vigorous new walnut hybrid clone with nematode tolerance and a useful resistance mechanism.

VX211 is a highly vigorous Paradox hybrid clone that outgrew other walnut seedlings in the presence of nematodes. A four-year macroplot trial involving Paradox VX211 and a standard Paradox selection, AX1, demonstrated that the damage threshold level of Pratylenchus vulnus on commercially available walnut rootstocks is < 1 nematode/250 cm³ of soil. Using 1 as the initial population level (Pi) within an inoculation zone of 80 L of soil, the P. vulnus population level increased 2,500-fold in the first year of growth. Three years after inoculation soil population levels of P. vulnus on VX211 were significantly reduced compared to that of the moderately vigorous AX1. Growth of VX211 was 35% greater than that of AX1 regardless of the Pi. Examination of stained roots revealed that feeding and reproduction by P. vulnus on VX211 was primarily ectoparasitic. This is the first report on a new walnut rootstock that can be readily cloned, has high vigor, exhibits tolerance to low population levels of P. vulnus, reduces nematode feeding and reproduction within the root terminus, and is currently available to California growers.

Modelling Trends of Climatic Variability and Malaria in Ghana Using Vector Autoregression.

Malaria is considered endemic in over hundred countries across the globe. Many cases of malaria and deaths due to malaria occur in Sub-Saharan Africa. The disease is of great public health concern since it affects people of all age groups more especially pregnant women and children because of their vulnerability. This study sought to use vector autoregression (VAR) models to model the impact of climatic variability on malaria. Monthly climatic data (rainfall, maximum temperature, and relative humidity) from 2010 to 2015 were obtained from the Ghana Meteorological Agency while data on malaria for the same period were obtained from the Ghana Health Service. Results of the Granger and instantaneous causality tests led to a conclusion that malaria is influenced by all three climatic variables. The impulse response analyses indicated that the highest positive effect of maximum temperature, relative humidity, and rainfall on malaria is observed in the months of September, March, and October, respectively. The decomposition of forecast variance indicates varying degree of malaria dependence on the climatic variables, with as high as 12.65% of the variability in the trend of malaria which has been explained by past innovations in maximum temperature alone. This is quite significant and therefore, policy-makers should not ignore temperature when formulating policies to address malaria.

Binding to the naturally occurring double p53 binding site of the Mdm2 promoter alleviates the requirement for p53 C-terminal activation.

Genotoxic stress activation of the tumor suppressor transcription factor p53 involves post-translational C-terminal modifications that increase both protein stability and DNA binding activity. We compared the requirement for p53 protein activation of p53 target sequences in two major p53-regulated genes, p21/WAF1 (encoding a cell cycle inhibitory protein) and Mdm2 (encoding a ubiquitin ligase that targets p53 for proteolytic degradation). The p53 binding site in the proximal p21/WAF1 promoter contains a single p53 binding consensus sequence, while the p53 binding site in the Mdm2 promoter contains two consensus sequences linked by a 17 bp spacer. Binding of recombinant p53 protein to the p21/WAF1 binding site required monoclonal antibody PAb421, which can mimic activating phosphorylation and/or acetylation events at the C-terminus. In contrast, recombinant p53 bound strongly to the Mdm2 binding site in the absence of PAb421 antibody. Separate binding to each consensus sequence of the Mdm2 binding site still required PAb421, indicating that p53 binding was not simply due to greater affinity to the Mdm2 consensus sequences. Linking two p21/WAF1 binding sites with the 17 bp spacer region from the Mdm2 gene eliminated the PAb421 requirement for p53 binding to the p21/WAF1 site. These results suggest a mechanism for regulation of Mdm2 gene transcription that differs from that other p53-induced genes by its lack of a requirement for C-terminal activation of p53 protein. A steady induction of Mdm2 protein would maintain p53 protein at low levels until post-translational modifications following DNA damage increased p53 activity towards other genes, mediating p53 growth inhibitory and apoptotic activities.

Wild-type and mutant forms of p53 activate human topoisomerase I: a possible mechanism for gain of function in mutants.

p53-interacting proteins from mouse epidermal cells and human myelogenous leukemia cells were isolated by affinity chromatography using glutathione S-transferase (GST)-p53 fusion proteins. One of these proteins was topoisomerase I, whose interaction with p53 was recently reported. A carboxyl-terminal fragment containing the last 92 amino acids of p53 (GST-299-390) was sufficient for binding to topoisomerase I. Nanomolar concentrations of either GST-p53 or GST-299-390 enhanced the catalytic activity of purified human topoisomerase I. Purified wild-type human p53 and point mutants Ser-239, Ser-245, and His-273 were equivalent in their enhancement of human topoisomerase I activity. Because topoisomerase I is thought to promote genetic recombination, competence to enhance topoisomerase I catalytic activity coupled with a deficiency in transcriptional activity may be a mechanism for gain of function in mutant p53 proteins.

Flavocetin-A and -B, two high molecular mass glycoprotein Ib binding proteins with high affinity purified from Trimeresurus flavoviridis venom, inhibit platelet aggregation at high shear stress.

Two high molecular mass proteins, flavocetin-A and flavocetin-B, were purified from Trimeresurus flavoviridis venom. On polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate, the apparent molecular mass of flavocetin-A and -B were 149 and 139 kDa, respectively, under nonreducing conditions. On reduction, flavocetin-A showed two distinct subunits (17 and 14 kDa), and flavocetin-B three distinct subunits (17, 15 and 14 kDa). At 1 microgram/ml, flavocetin-A and -B (flavocetins) inhibited the von Willebrand factor (vWF)-dependent aggregation of fixed human platelets. However, flavocetins (10 micrograms/ml) had no effect on ADP- and collagen-induced platelet aggregation in PRP. Flavocetins (3 micrograms/ml) also inhibited shear-induced platelet aggregation at high shear stress. Furthermore, flavocetin-A completely inhibited the aggregation of and ATP release from washed platelets stimulated with a low concentration of thrombin. Flavocetin-A specifically bound to platelet with high affinity (Kd = 0.35 +/- 0.13 nM) at 21,500 +/- 1760 binding sites per platelet. The N-terminal amino acid sequences of the subunits of flavocetin-A show a high degree of homology with those of echicetin, botrocetin, alboaggregin-B and factor IX/factor X-binding protein. These results suggest that flavocetins may be a useful tool for further investigation of the GPIb-vWF interaction.

Biochemical characterization of a new disintegrin, flavostatin, isolated from Trimeresurus flavoviridis venom.

We biochemically characterized a new disintegrin, flavostatin, isolated from Trimeresurus flavoviridis venom. Flavostatin inhibited ADP-, collagen-, and thrombin receptor agonist peptide-induced platelet aggregation in human platelet-rich plasma (IC50 range: 59 to 111 nM) and blocked the binding of biotinylated human fibrinogen to purified GPIIb/IIIa with an inhibitory potency 31,000-fold higher than that of Arg-Gly-Asp-Ser (RGDS). Flavostatin strongly inhibited high-shear-stress-induced platelet aggregation in platelet-rich plasma (PRP) with an IC50 value of 188 nM. Fluorescein isothiocyanate (FITC)-conjugated flavostatin saturably bound to unstimulated and ADP-stimulated washed platelets with high affinity (Kd values: 38 and 21 nM, respectively); the corresponding number of binding sites was 86460 and 79192 per platelet. In competition experiments with several glycoprotein IIb/IIIa antagonists, the binding of FITC-conjugated flavostatin to platelets was completely inhibited by ReoPro, triflavin, TP9201, MK383 and GR144053, but not by YM207, YM337 and B6A3.

Comparative studies on the antiplatelet effects of a humanized anti-platelet glycoprotein IIb/IIIa antibody (YM337) and ReoPro under flow conditions.

Recent clinical studies have shown that the interruption of platelet function appears to be effective for treatment of coronary occlusive diseases. For this purpose, a Fab fragment of humanized anti-platelet glycoprotein (GP) IIb/IIIa monoclonal antibody (YM 337) that exhibited an in vivo antithrombotic effect without prolongation of bleeding time in monkeys was previously characterized. In this study, the effect of YM 337 under physiological flow conditions with high or low shear rate was evaluated. The antiplatelet effects of YM 337 under varying wall shear rates were examined with the whole blood flow system. This technique allows real time visualization of the formation of fluorescence-labeled platelet thrombi on a collagen surface in a parallel plate flow chamber mounted on an epifluorescence microscope. The process of thrombus growth was also recorded in video tape and subjected to computer-assisted image analysis. We found that YM 337 displayed a high shear-preferential antiplatelet effect, while ReoPro, a control anti-GP IIb/IIIa antibody, did not show such shear dependency. The present findings therefore suggest that YM 337 might be a useful antiplatelet agent which can block pathological thrombotic events occurring under high shear, such as in coronary occlusive diseases.

Enhancement of tissue-type plasminogen activator-induced thrombolysis and prevention of reocclusion by combination with a humanized anti-glycoprotein IIb/IIIa monoclonal antibody, YM337, in a rhesus monkey model of coronary thrombosis.

We examined the effect of a humanized anti-glycoprotein IIb/IIIa monoclonal antibody, YM337, on thrombolysis with tissue-type plasminogen activator in a copper coil-induced coronary thrombosis model in rhesus monkeys. Fifty minutes after the formation of an occlusive thrombus, a test drug was administered by either i.v. bolus injection followed by continuous infusion (YM337, 0.25 mg/kg + 1.5 microg/kg/min) or i.v. bolus injection (aspirin, 17 mg/kg). Sixty minutes after induction of the occlusive thrombus, thrombolysis was initiated with tPA at a total dose of 0.5 mg/kg intravenously administered over 60 min, with 10% given as an initial bolus. The median time to reperfusion was significantly shortened by YM337 [saline, 60 min (n = 5); aspirin, 45 min (n = 5); YM337, 30 min (n = 5)]. The incidence of reocclusion was significantly decreased by YM337 (saline, 4/4; aspirin, 5/5; YM337, 1/5), and the median time to reocclusion was significantly prolonged by YM337 [saline, 30 min (n = 4); aspirin, 30 min (n = 5); YM337, 180 min (n = 5)]. YM337 significantly reduced the thrombus protein content at the end of experiment. ADP-induced platelet aggregation was completely inhibited by YM337. These results suggest that YM337 may be of clinical value as an adjunctive agent in thrombolytic therapy for patients with acute myocardial infarction.

Antiplatelet and antithrombotic effects of YM337, the Fab fragment of a humanized anti-GPIIb/IIIa monoclonal antibody in monkeys.

The antiplatelet and antithrombotic effects of the Fab fragment of the humanized antiplatelet glycoprotein (GP) IIb/IIIa monoclonal antibody C4G1 (YM337) were investigated in monkeys. First, the relationship between the inhibition of platelet aggregation and the prolongation of bleeding time was studied in rhesus monkeys. YM337 dose-dependently inhibited ex vivo platelet aggregation, with complete inhibition at doses higher than 0.25 mg/kg intravenous injection or 1.5 micrograms/kg/min infusion. At 0.25 mg/kg bolus injection followed by 1.5 micrograms/kg/min infusion, YM337 immediately and continuously inhibited platelet aggregation during the 6-h infusion period with platelet aggregation rapidly returning to over 50% of baseline within 1 h after the cessation of infusion. Template-bleeding time was significantly prolonged during the period of complete inhibition of platelet aggregation. Second, the antithrombotic effects of YM337 were investigated in a photochemically-induced thrombosis model in squirrel monkeys. YM337 at a dose of 1 mg/kg intravenous injection followed by 6 micrograms/kg/min infusion for 60 min prevented occlusive thrombus formation in all 4 monkeys. In contrast, time to occlusive thrombus formation did not change on intravenous bolus injection of aspirin 17 mg/kg (11.3 +/- 5.2 min) or sodium ozagrel (9.4 +/- 3.0 min) compared with saline (13.3 +/- 4.0 min). YM337 but not aspirin or sodium ozagrel significantly inhibited ex vivo ADP-induced platelet aggregation, while all drugs completely inhibited arachidonic acid-induced platelet aggregation. However, while aspirin and sodium ozagrel inhibited the thromboxane B2 generation accompanying arachidonic acid-induced platelet aggregation, YM337 had no effect on this variable. Platelet counts and bleeding time showed no significant change in any group in this squirrel monkey model. These results indicate that YM337, with a short half-life, may be a useful therapeutic agent in patients with thrombotic disorders.

Epitopes and biological activities of two monoclonal antibodies to platelet integrin alpha IIb beta 3.

We have developed two monoclonal antibodies (MAbs), B6A3 and C4G1. The whole molecules of the two MAbs inhibited in vitro human platelet aggregation induced by either ADP, collagen or thrombin, and their F(ab')2 fragments inhibited ex vivo platelet aggregation induced by ADP in monkey. The concentrations necessary for complete inhibition were 5 and 1 microgram/ml for B6A3 and C4G1, respectively. The Fab fragment of C4G1 but not B6A3 inhibited platelet aggregation. B6A3 and C4G1 bound to activated platelets with dissociation constants of 0.25 and 0.82 nM, respectively. B6A3 recognized an epitope on beta 3, which was sensitive to reduction and alkylation of cystine residues, and C4G1 recognized a conformational epitope on the alpha IIb beta 3 complex, which was sensitive to EDTA. The binding of fibrinogen to activated platelets was inhibited by both MAbs. However, the binding of fibrinogen to isolated alpha IIb beta 3 was inhibited by the whole molecule of C4G1 but not B6A3, although both MAbs bound to the isolated alpha IIb beta 3. The binding of these MAbs to the isolated alpha IIb beta 3 was not inhibited by either Arg Gly Asp Ser (RGDS) or fibrinogen gamma-peptide. In addition, B6A3 but not C4G1 bound to human endothelial cells. These MAbs should contribute to the elucidation of the mechanism of platelet aggregation.

Dietary gamma-linolenic acid dose-dependently modifies fatty acid composition and immune parameters in rats.

gamma-linolenic acid (GLA) has been reported to improve several inflammatory disorders through regulation of eicosanoid production. However, since GLA is a precursor of arachidonic acid, it may bring about increasing tissue arachidonic acid levels with subsequent pro-inflammatory events. To explore this possibility, we examined the effect of high-dose GLA acid on the fatty acid profile of immune cells, leukotriene B4 production by peritoneal exudate cells and immunoglobulin productivity of mesenteric lymph node lymphocytes of Sprague-Dawley rats. Male rats were fed 10% fat diets containing graded levels, 0, 20, 40 and 60% of GLA for 3 weeks. The results showed the distinction in activity of metabolizing GLA between immune cells and liver. Thus, in immune cells such as mesenteric lymph node and spleen lymphocytes and peritoneal exudate cells, more dihomo-gamma-linolenic acid was found than in the liver. Leukotriene B4 production by peritoneal exudate cells was significantly suppressed when fed the highest level of GLA suggesting a lower risk of allergic reaction. Moreover, immunoglobulin productivity in mesenteric lymph node lymphocytes was promoted by dietary GLA. The present study indicates that a high dose of GLA may exert anti-inflammatory effects through suppression of leukotriene B4 release and strengthening of gut immune system, thus ameliorating allergic reaction.

Binding of [3H]FH-510 to sigma ligand recognition sites in guinea-pig brain membranes.

We examined the characteristics of the binding of radiolabeled 5,8-dimethyl-4-(2-di-n-propylaminoethyl)carbazol monohydrochloride ([3H]FH-510), a highly potent and selective sigma ligand, to guinea-pig brain membranes. [3H]FH-510 showed saturable and reversible binding to sigma binding sites. The association rate constant (k+1) and dissociation rate constant (k-1) of [3H]FH-510 were 0.023 min-1.nM-1 and 0.081 min-1, respectively. Scatchard plot analysis showed a dissociation constant (Kd) and maximal number of binding sites (Bmax) of 6.0 +/- 0.63 nM and 1763.3 +/- 177.4 fmol/mg protein (n = 7), respectively. The rank order of potency (Ki) of several structurally dissimilar sigma ligands obtained for the displacement of [3H]FH-510 binding was highly correlated with that determined for [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H](+)-3-PPP) binding. The binding of [3H]FH-510 was not influenced by histaminergic, dopaminergic, adrenergic, serotonergic or cholinergic agents at 10(-7) M. Higher [3H]FH-510 binding to brain regions was observed in the cerebellum and pons-plus-medulla. Except for the nuclear fraction, the highest level of [3H]FH-510 and [3H](+)-3-PPP binding to subcellular fractions was observed in the microsomal fraction. From these results, it is suggested that FH-510 selectively binds with high affinity to sigma binding sites in guinea-pig membranes.

Evaluation of the disintegrin, triflavin, in a rat middle cerebral artery thrombosis model.

Platelet aggregation plays a important role in the thrombotic cerebral infarction. The final common mechanism in the formation of a platelet aggregate is the linking of adjacent platelets by fibrinogen binding to the platelet integrin alpha 11b beta 3. In this study, we evaluated the effect of the disintegrin, triflavin, in a rat middle cerebral artery thrombosis model. Thrombus at the left middle cerebral artery in rat was induced by photochemical reaction between rose bengal and green light, which caused endothelial injury at the site of irradiation. We measured the time to occlusive thrombus formation and the size of ischaemic cerebral damage. Triflavin dose dependently prolonged the time to occlusive thrombus formation in this model. Triflavin also reduced the size of ischaemic cerebral damage on examination at 24 h after photochemical reaction. Triflavin dose dependently inhibited ADP- and collagen-induced platelet aggregation and platelet retention in the collagen-coated beads method ex vivo. These effects were thought to result from the blockade of platelet integrin alpha IIb beta 3. Blockade of platelet integrin alpha IIb beta 3 may be useful in the prevention of cerebral arterial thrombosis.

Evaluation of a GPIIb/IIIa antagonist YM337 in a primate model of middle cerebral artery thrombosis.

We compared the antithrombotic effect of anti-GPIIb/IIIa antibody Fab fragment YM337 with that of a thromboxane A2 synthetase inhibitor, sodium ozagrel. With the monkeys under halothane anesthesia, the right middle cerebral artery was observed via a transorbital approach without cutting the dura mater. Photoillumination (wavelength 540 nm) was applied to the middle cerebral artery, and then rose bengal (20 mg kg(-1)) was administered intravenously. The experimental drugs were intravenously injected 15 min before rose bengal injection and followed by continuous infusion for 3 h after dye injection. The thrombotic occlusion induced by this photochemical reaction in monkey middle cerebral artery was reproducible. YM337 significantly prolonged the time to first occlusion and the total time of arterial patency during the 3-h observation period after dye injection. In contrast, sodium ozagrel had no significant effect. YM337 but not sodium ozagrel significantly inhibited ex vivo ADP-induced platelet aggregation. However, while sodium ozagrel significantly inhibited the thromboxane B2 generation accompanying arachidonic acid-induced platelet aggregation, YM337 had no effect on this variable. Neurological deficit in the YM337-treated animals was significantly milder than that in the control group. The area of infarct in the YM337 treatment animals was smaller than that in the control group. The novel selective GPIIb/IIIa antagonist YM337 was effective in ameliorating the decrease in patency of the middle cerebral artery and reducing the area of cerebral infarction in monkeys.

Antithrombotic effect of YM-75466 is separated from its effect on bleeding time and coagulation time.

The antithrombotic effects of YM-75466 ([N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-nap hthyl)methyl]sulfamoyl]acetic acid monomethane sulfonate), a novel orally-active factor Xa inhibitor, and its effects on bleeding time and coagulation time were studied in rats and compared with those of warfarin. Both agents were orally administered. In the venous thrombosis model, YM-75466 and warfarin inhibited thrombus formation dose-dependently, with ID50 values of 3.3 and 0.56 mg/kg, respectively. Ex vivo study showed that both YM-75466 and warfarin prolonged prothrombin time dose-dependently, with doses, causing a two-fold prolongation of prothrombin time in the control group, of 89 and 0.38 mg/kg, respectively. In bleeding time studies, YM-75466 and warfarin prolonged bleeding time dose-dependently, with doses, causing a two-fold prolongation of bleeding time in the control group, of > 100 and 0.43 mg/kg, respectively. These results show that the antithrombotic effects of YM-75466 are markedly separate from its effects on bleeding time and coagulation time compared with warfarin.

Antithrombotic effect of a humanized anti-GPIIb/IIIa monoclonal antibody, YM207, in a photochemically induced thrombosis model in monkeys.

We investigated the antithrombotic effects of a F(ab')2 fragment of a humanized anti-platelet glycoprotein (GP) IIb/IIIa monoclonal antibody, YM207, in a platelet-rich thrombosis model. Thrombus was induced in a mesenteric venule of squirrel monkeys by irradiation with filtered light in combination with i.v. administration of a fluorescent dye (sodium fluorescein). Time to occlusive thrombus formation was significantly prolonged by i.v. bolus injection of 0.3 mg/kg of YM207. At doses of 1 mg/kg and 3 mg/kg, complete occlusion did not occur during 60 min of the observation. Platelet aggregation in platelet-rich plasma was inhibited by YM207 at doses 0.3 mg/kg or more. A good correlation was obtained between inhibition of platelet aggregation and the percentage of GPIIb/IIIa receptors blocked by YM207. Bleeding time was significantly prolonged at a dose of 3 mg/kg. Platelet counts showed no significant change. These results suggest that YM207 is effective in preventing platelet-rich thrombus formation without inducing the prolongation of bleeding time or a significant decrease in platelet count. YM207 may be a useful therapeutic agent for the treatment of thrombotic disorders.

Comparison of the antiplatelet effect of YM337 and abciximab in rhesus monkeys.

We directly compared the effects of YM337, the Fab fragment of the humanized monoclonal antibody C4G1, on platelet aggregation and template bleeding time with those of abciximab, the Fab fragment of the human/murine chimeric monoclonal antibody 7E3, in rhesus monkeys. The duration of inhibition of platelet aggregation by abciximab after i.v. bolus injection was much longer than that by YM337. Although YM337 significantly prolonged template bleeding time at 5 min after i.v. bolus injection, this action recovered within 1 h after injection. In contrast, although abciximab also prolonged template bleeding time, the duration of this effect was sustained. In a dose-escalating continuous infusion study, we evaluated the relationship between inhibition of platelet aggregation and prolongation of template bleeding time. Platelet aggregation was inhibited by over 80% by both agents at 3 microg/kg per min, and template bleeding time was prolonged to about 30 min at 30 microg/kg per min for YM337 and 10 microg/kg per min for abciximab. Interestingly, plasma concentrations between inhibition of platelet aggregation and prolongation of template bleeding time did not overlap with YM337, but did overlap with abciximab. These results suggest that YM337 allows easier control of antiplatelet activity with less effect on bleeding time than abciximab, and has a wider therapeutic window than abciximab.