绞股蓝总皂甙对家兔血小板聚集释放及cAMP水平的影响

本文研究了绞股蓝总皂甙对家兔血小板聚集、5—羟色胺释放及血小板内cAMP含量的影响.结果发现绞股蓝总皂甙在体内和体外均明显抑制二磷酸腺苷,花生四烯酸和胶原诱导的血小聚集;抑制血小板5—羟色胺的释放;升高血小板内cAMP的水平.效应与剂量间呈现依赖关系.提示绞股蓝总皂甙为一血小板功能抑制剂,作用机理可能与其升高血小板内cAMP的水平,抑制血小板释放活性物质有关.     

Clinical study on imipenem/cilastatin sodium in the field of pediatrics

Imipenem/cilastatin sodium (MK-0787/MK-0791) was administered to pediatric patients with infections, and the following results were obtained. Pharmacokinetic study Two children, 11 years of age (38 kg body weight) and 3 years of age (15.5 kg body weight), were administered by 30 minutes intravenous drip infusion a single dose of 500 mg/500 mg (13.2 mg/13.2 mg per kg) and 250 mg/250 mg (16.1 mg/16.1 mg per kg) of MK-0787/MK-0791, respectively. Serum concentrations of MK-0787 reached their peaks at the end of drip infusion at a value of 56.33 micrograms/ml and 55.98 micrograms/ml, respectively. Concentrations of the drug decreased as the time after the administration increased, and they reached 0.14 microgram/ml and 0.12 microgram/ml, respectively in the older and the younger children at 6 hours after the administration. Half-lives (T 1/2) of the drug in serum were calculated to be 1.21 hours and 1.04 hours, respectively. The concentration of the drug in cerebrospinal fluid for the 11 years old was 0.52 microgram/ml 2 hours after the drip infusion and the serum concentration at the time was 4.02 micrograms/ml. Peak serum concentrations of MK-0791 in the 2 children were 53.73 micrograms/ml and 22.99 micrograms/ml, respectively, at the end of drip infusion. After 1 hour, the serum concentration of the drug decreased to 10.54 micrograms/ml in 1 case and not detectable in the other case. Urinary recovery rates of MK-0787 in 6 hours after the drip infusion was 82.9% and 63.6% in the 2 children and those of MK-0791 were 57.9% and 74.6%. Clinical study Clinical studies on MK-0787/MK-0791 were carried out in 6 pediatric patients; 1 each with femoral cellulitis, sepsis suspected, salmonellosis, acute tonsillitis, bronchopneumonia and streptococcosis. Lengths of treatment were 2 2/3-4 days for 5 cases and 6 days for 1 case. The patients were treated by 30-60 minutes intravenous drip infusions twice a day for 1 case, and 3 times a day for 5 cases at daily doses of 54.5-66.7 mg/kg. The treatment was effective in all cases, with 3 cases judged excellent and 3 cases good. The safety of the drug was studied in 7 patients. No side effects nor clinically abnormal values were observed in any cases.     

Non-peptide GPIIb/IIIa inhibitors. 20. Centrally constrained thienothiophene alpha-sulfonamides are potent, long acting in vivo inhibitors of platelet aggregation.

The synthesis and pharmacology of 4, a potent thienothiophene non-peptide fibrinogen receptor antagonist, are reported. Compound 4 inhibited the aggregation of human gel-filtered platelets with an IC50 of 8 nM and demonstrated an 8-fold improvement in affinity for isolated GPIIb/IIIa receptors over analogues possessing an isoindolinone backbone. Flow cytometry studies revealed that the binding of 4 to resting platelets is a diffusion-controlled process (kon = 3.3 x 10(6) M-1 s-1) and that 4 binds to dog and human platelets with comparable affinity (Kd = 0.04 and 0.07 nM, respectively). Ex vivo platelet aggregation in dogs was completely inhibited by an iv dose of 5 microg/kg [corrected], and an oral dose of 50-90 microg/kg [corrected] followed by low daily doses of 10 microg/kg [corrected] was sufficient to maintain approximately 80% inhibition of ex vivo platelet aggregation over several days. Inhibition of ADP-induced platelet aggregation in anesthetized dogs at 77 +/- 7% resulted in a moderate 2.5-fold increase in bleeding time, while complete inhibition (100%) resulted in an approximately 10-min bleeding time. Additional doses were required to increase the bleeding time to the maximum time allowed in the protocol (15 min), thus indicating a potentially useful and safe separation of efficacy and bleeding time.     

Endothelin-1 inhibits platelet aggregation in vivo: a study with 111indium-labelled platelets.

1. A non-invasive technique for the scintigraphic determination of 111indium-labelled platelet aggregation stimulated with submaximal doses of adenosine diphosphate (ADP, 56 micrograms kg-1 i.v.), collagen (100 micrograms kg-1 i.v.), platelet-activating factor (PAF, 0.1 microgram kg-1 i.v.) or thrombin (18 iu kg-1 i.v.) was used to investigate the platelet-inhibitory effects of endothelin 1 (ET-1) in anaesthetized rabbits in vivo. 2. ET-1 (1 nmol kg-1 i.v.) inhibited ADP-stimulated platelet aggregation in vivo; a maximum inhibition of 78% of the control value was reached at 3 min, with 45% inhibition at 15 min, and a return to control values at 30 min after injection of the peptide. 3. ET-1 (1 nmol kg-1 i.v.) inhibited in vivo platelet aggregation in response to collagen or PAF by 86% and 52%, respectively, but had no effect on thrombin-induced platelet aggregation. 4. Indomethacin (5 mg kg-1 i.v.) abolished the ET-1-induced inhibition of ADP-stimulated platelet aggregation and significantly potentiated and prolonged the pressor response brought about by ET-1. 5. In conclusion, the data demonstrate that ET-1 potently inhibits platelet aggregation in the anaesthetized rabbit in vivo by releasing a hypotensive and anti-aggregatory cyclo-oxygenase product, presumably prostacyclin, into the circulation.     

Beneficial effect of OKY-046, a selective thromboxane A2 synthetase inhibitor, on experimental cerebral vasospasm

Effects of OKY-046, a selective inhibitor of thromboxane (TX)A2 synthetase and a platelet aggregation inhibitor, on in vitro and in vivo models of cerebral vasospasm were studied. The contraction of the isolated rabbit basilar artery by an exposure to 1.0 ml of whole rabbit blood plus 0.05 or 0.1 units/ml of thrombin was diminished by the treatment with 10(-4) M of OKY-046 and/or 10(-6) M of cinanserin. When the whole blood of rabbits treated intravenously with 1 mg/kg/min of OKY-046 was used, the contraction of the basilar artery was decreased to about half of the control contraction. Angiographically recognized cerebral vasospasm in vivo, by a transorbital injection of 5.0 to 7.0 ml of autologous arterial blood into the cisterna magna of dogs, was suppressed by 0.05 and 0.5 microgram of OKY-046. Moreover, the decrease in the regional cerebral blood flow in autologous blood infused-dogs was inhibited by 0.5 microgram of OKY-046. The increase in TXB2 in the cerebrospinal fluid of dogs was significantly inhibited, and the level of 6-keto-PGF1 alpha was slightly increased by the treatment of OKY-046. The ratio of 6-keto-PGF1 alpha/TXB2 was increased from 1.5 to 5.2 in OKY-046-treated dogs. No effect on the basal tone and response to vasoactive agonists such as norepinephrine, KCl and PGE1 was observed in the isolated spiral thoracic aorta of guinea pigs or rabbits. Taken together with our previous findings, we conclude that the inhibition of cerebral vasospasm in the in vitro and in vivo models by the treatment of OKY-046 might be due to an inhibition of platelet aggregation, an inhibition of TXA2 generation and an increase in the ratio of PGl2/TXA2.     

Antithrombotic activity of the phosphodiesterase III inhibitor pelrinone in a canine model of coronary artery thrombosis: enhancement of efficacy with concurrent alpha 2-adrenergic antagonism.

The purpose of this study was to determine if idazoxan, an alpha 2-adrenergic antagonist, could enhance the antithrombotic activity of pelrinone, a PDE III inhibitor, in a canine model of coronary thrombosis that uses electrical current to injure the coronary endothelium. Thrombus mass in vehicle-treated animals was 37.9 +/- 8 mg. Pelrinone, 0.625 and 2.5 mg/kg decreased thrombus size by 46 and 21%, respectively, while idazoxan, 0.75 mg/kg decreased thrombus mass by 43%. When this dose of idazoxan was combined with pelrinone, 0.625 and 2.5 mg/kg, thrombus mass was decreased by 71 and 91%, respectively. Antithrombotic efficacy correlated with the ability of these treatments to inhibit epinephrine-sensitized, collagen-induced platelet aggregation. Sixty minutes following drug administration, idazoxan, 0.50 mg/kg inhibited aggregation by 50%, while pelrinone, 0.625 and 2.5 mg/kg inhibited aggregation by 55 and 68%, respectively. Combined administration of idazoxan with pelrinone, 0.625 and 2.5 mg/kg resulted in 80 and 95% inhibition of aggregation, respectively. Similar trends in inhibiting platelet aggregation to epinephrine-sensitized ADP and arachidonic acid were also observed. Experimental treatments did not affect hematocrit or circulating platelet count, although pelrinone was observed to prolong prothrombin time slightly. To examine the effect of drug-induced increases in coronary blood flow on thrombus formation, the potassium channel activator drug cromakalim was studied at a dose (0.1 mg/kg) that increased coronary blood flow by 25-35 ml/min above baseline in sham control animals. Animals treated with cromakalim showed a shorter time to coronary occlusion (103 +/- 11 min) vs. vehicle (173 +/- 24 min) and developed larger thrombi (53.7 +/- 19 mg). These results demonstrate that coronary vasodilation does not contribute to antithrombotic activity in this model. Results from the study also show that alpha-adrenergic inhibition of platelet function can potentiate phosphodiesterase inhibitor antiaggregatory and antithrombotic activity.     

Antithrombotic effect of TRK-100, a novel, stable PGI2 analogue

TRK-100, a stable PGI2 analogue structurally different from carbacyclines, was compared with other antiplatelet drugs for its effect on platelet functions using animal models. TRK-100 (10-300 nM) inhibited rat platelet aggregation induced by ADP (3 microM), collagen (12.5 micrograms/ml) and A23187 (10 microM), and its potency was about 1/3-1/7 that of PGI2. TRK-100 (0.3-3 mg/kg, p.o.) dose-dependently inhibited rabbit platelet adhesion (ED50: 2.2 mg/kg), and its effect lasted over at least 5 hr. In contrast, aspirin and ticlopidine (both at 300 mg/kg, p.o.) showed only a slight inhibition (4-7%). In the thrombocytopenia induced by collagen injection in rats, TRK-100 (3-300 micrograms/kg, i.v.; 0.1-3 mg/kg, p.o.) dose-dependently inhibited a decrease in platelet number, and its ED50 was 0.48-0.62 mg/kg orally and 13.7-16.4 micrograms/kg intravenously, while the inhibition by aspirin and ticlopidine (both at 1000 mg/kg, p.o.) was 40 and 37%, respectively. In the experimental thread thrombosis in rats. TRK-100 (0.03-3 mg/kg, p.o.) dose-dependently inhibited thrombus formation, and its ED50 was 0.46 mg/kg, being 21 and 87 times as potent as aspirin and ticlopidine, respectively. These results reveal that TRK-100 has a potent antiplatelet activity and is orally and intravenously effective for a variety of thrombosis models, suggesting that it may have a therapeutic value as an antithrombotic drug.     

Studies on imipenem/cilastatin sodium in the field of pediatrics

Pharmacokinetic and clinical studies on imipenem (MK-0787)/cilastatin sodium (MK-0791), a combined drug of carbapenem antibiotics (MK-0787) and renal depeptidase inhibitor (MK-0791) in a 1:1 ratio, were performed in the field of pediatrics. Absorption and excretion Serum levels and urinary excretion of MK-0787/MK-0791 were determined in 7 children aged 4 to 11 years. Four cases were administered with a single dose of MK-0787/MK-0791 at 10 mg/10 mg/kg by intravenous drip infusion and the other 3 cases were given a single dose of 20 mg/20 mg/kg. Serum concentrations of MK-0787 reached their peaks at the end of drip infusion where the mean level was 17.5 +/- 1.0 micrograms/ml for the group given 10 mg/10 mg/kg, and 43.6 +/- 2.1 micrograms/ml for the group given 20 mg/20 mg/kg. Concentrations decreased with half-lives of 0.82 +/- 0.10 hour and 0.74 +/- 0.04 hour for the low and high doses, respectively, and serum levels at 6 hours after administration were 0.3 +/- 0.1 microgram/ml and 0.4 +/- 0.1 microgram/ml, respectively. Peak concentrations of MK-0791 were 22.6 +/- 4.8 micrograms/ml in the 10 mg/10 mg/kg group and 52.9 +/- 4.7 micrograms/ml in the 20 mg/20 mg/kg group at the end of the drip infusion. Half-lives were 0.56 +/- 0.17 hour and 0.46 +/- 0.11 hour for the 2 doses, respectively while MK-0791 levels were below detection limit at 6 hours after administration. Mean urinary recovery rates in 6 hours after administration were 54.0 +/- 15.3% and 49.3 +/- 7.8% for MK-0787 and MK-0791, respectively, in the group of 10 mg/10 mg/kg, and 62.0 +/- 7.4% and 65.3 +/- 9.2%, respectively, in the group of 20 mg/20 mg/kg. These results showed that pharmacokinetics of MK-0787 and MK-0791 in children were similar to that in adults. Clinical study MK-0787/MK-0791 was used for treatment in a total of 22 pediatric patients to evaluate clinical effectiveness, bacteriological efficacy and adverse reactions. Each of patients was treated 3 or 4 times per day at a single dose of 11.4-22.8 mg/kg (of MK-0787). Duration of treatment ranged from 2.5 to 18 days and total doses ranged from 1.36 to 19.92 g. Clinical efficacy in cases including 2 with acute purulent tonsillitis, 1 with acute purulent otitis media, 9 with acute pneumonia, 1 with pythorax, 3 with acute purulent lymphadenitis, and 6 with acute pyelonephritis were judged excellent in 20 cases and good in 2 cases; an efficacy rate of 100%.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparison of the effects of drugs on the aggregation of hamster platelets in vivo and in vitro

1. A method is described for measuring the inhibitory effectiveness of drugs on the aggregation by ADP of hamster platelets in vivo.2. The method was used to compare the effects of several drugs, viz. adenosine, imipramine, desmethylimipramine and aspirin, on platelet aggregation in vivo with their in vitro effects measured photometrically.3. The concentrations of adenosine and imipramine present in the cheek pouch after 10 min infusions were measured using radioactively labelled drugs.4. The results show that adenosine (0.4 muM) inhibited platelet aggregation in vivo by 43%, whereas several times this concentration was required to produce the same inhibition in vitro.5. Imipramine and desmethylimipramine (0.4 muM) did not inhibit platelet aggregation in vivo; in vitro, however, desmethylimipramine caused up to 34% inhibition at concentrations as low at 0.25 muM.6. Aspirin (estimated 0.2 mM) inhibited platelet aggregation in vivo by 37% whereas similar inhibition in vitro required about 1 mM aspirin. Sodium salicylate was several times less potent than aspirin in vivo.     

Fundamental and clinical evaluation of imipenem/cilastatin sodium in the field of pediatrics

A combination drug of imipenem (MK-0787), a new carbapenem antibiotic, and cilastatin sodium (MK-0791) at a ratio of 1:1 was used to treat infections in 8 children, and the concentrations of MK-0787 were determined in plasma, urine and pus of 1 patient and in cerebrospinal fluid of another patient. Eight patients, aged 2 months to 12 years (males: 3, females: 5), were treated with MK-0787/MK-0791. They consisted of 3 with urinary tract infections (causative organisms: E. coli, K. oxytoca plus E. faecalis, and unknown), and 1 patient each with pneumonia (H. influenzae), enteritis (Salmonella C1), cellulitis (S. aureus), purulent lymphadenitis (unknown) and purulent meningitis (E. coli). The dose, ranging from 7.4 mg/7.4 mg/kg to 11.8 mg/11.8 mg/kg, 3 or 4 times daily, was administered by a 30-minute or 60-minute intravenous drip infusion for 5 to 11 days. To the patient with purulent meningitis, however, 25.85 mg/25.85 mg/kg on the 1st day and 12.9 mg/12.9 mg/kg from the 2nd day were administered 4 times daily. Clinical responses in urinary tract infections were excellent in 2 and good in 1, and responses in pneumonia, enteritis, cellulitis, purulent lymphadenitis and purulent meningitis were excellent, good, good, excellent and poor, respectively. The efficacy rate in a total of 8 patients was 87.5%. As adverse reactions, a rash was observed in one patient and a convulsion in another. The rash disappeared after discontinuation of the administration of the drug and the convulsion stopped after a reduction of the dosage. As abnormal laboratory findings, slight prolongation of the prothrombin time was observed in 1 patient, but no bleeding tendency was noted. When MK-0787/MK-0791 (500 mg/500 mg, or 8.7 mg/8.7 mg/kg) was given by a 60-minute intravenous drip infusion to a 12-year-old boy with cellulitis, the peak plasma concentration of MK-0787 was 31.4 micrograms/ml occurring at the end of the infusion, and then the concentration decreased to 13.9 micrograms/ml in 0.5 hour, 8.9 micrograms/ml in 1 hour, 2.8 micrograms/ml in 2 hours, 0.63 microgram/ml in 4 hours and 0.14 microgram/ml in 6 hours. The half-life was 0.83 hour. These plasma levels provided concentrations exceeding MIC90's against major infective bacteria for 2 hours. The urinary recovery in the first 7 hours was 75.0%, and the urinary concentration was greater than 100 micrograms/ml for 5 to 7 hours.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of the new antimigraine drug serotonin receptor antagonist tropoxin on platelet aggregation

The effect of the new antimigraine drug tropoxin - the serotonin receptor (5-HT2) antagonist - on the human platelet aggregation in vitro induced by ADP (1 x 10(-5) M) and epinephrine (2.5 x 10(-6) M) was studied. Tropoxin reliably inhibited the ADP-induced platelet aggregation in a concentration range of 0.01 - 7 mg/ml. A significant inhibition effect with respect to the epinephrine-induced platelet aggregation was observed in a drug concentration range of 2 - 7 mg/ml, although a reliable antiaggregant activity was also observed below 2 mg/ml. A bolus administration of tropoxin (10 mg/kg) in rabbits decreased the ADP-induced platelet aggregation ex vivo by a factor of 1.2 - 1.4. The effect appeared 45 min after treatment and was observed during subsequent 30 min.     

The in vitro and ex vivo antiplatelet effect of TRK-100, a stable prostacyclin analog, in several species

Effect of TRK-100, a stable PGI2 analog, on platelet function was tested in vitro and ex vivo. TRK-100 at the dose range of 0.5-300 nM inhibited platelet aggregation induced by arachidonic acid, adenosine 5'-diphosphate and collagen in several species including human platelets. The potency of TRK-100 was 1/2 to 1/5 that of PGI2. The effect was strong in human and cat platelets. In conscious rabbits and rats, oral TRK-100 at the dose range of 0.1-1 mg/kg inhibited ex vivo platelet aggregation up to 80% in the rat and 70% in the rabbit, and the effect lasted over 5 hr. However, in both species, the effect on blood pressure was minimal. In anesthetized rabbits, inhibition of platelet aggregation was the same level as in the conscious animal, but blood pressure depression was observed. Cyclic AMP levels of human platelets, 2 min after incubation, was elevated up to 2.4 microM/10(9) platelets by 100 ng/ml of PGI2 and 1.5 microM by 100 ng/ml of TRK-100. It was shown that TRK-100 has a potent antiplatelet effect both in vitro and ex vivo in many species through elevation of platelet cAMP. These results suggest that TRK-100 may be a potential oral antithrombotic drug.     

Pharmacokinetics of prednisone and prednisolone at steady state in the rabbit

A range (approximately 0.2-2.0 micrograms/min/kg) of constant rate iv infusions of prednisolone (as the phosphate ester) was administered to five rabbits either singly or as two consecutive infusions, and then again at about the same rates of infusion as part of multiple infusion studies. Prednisone (as the succinate) was also infused at three different infusion rates (range, 1.5-15 micrograms/min/kg) to four of the five rabbits. Plasma concentrations of prednisolone and prednisone at steady state were measured by HPLC. The binding of prednisone and prednisolone in plasma was measured by equilibrium dialysis. The multiple infusion studies demonstrated that the nonlinearity in plasma clearance of prednisolone could not be attributed to any time-dependent effect. The average plasma clearance of prednisolone increased by 250% when its rate of infusion was increased 10-fold. The ranges of clearance values at low and high rates of infusion were 2.51-4.08 and 6.08-10.98 ml/min/kg, respectively. The binding of prednisolone in plasma was found to be concentration dependent. At the lower rates of infusions, the clearance of unbound prednisolone appeared to increase on increasing its rate of infusion but remained relatively constant thereafter (greater than 1.0 microgram/min/kg). The ranges of unbound plasma prednisolone clearance at low and high rates of infusions were 30.3-67.7 and 50.6-110.2 ml/min/kg, respectively. The percentage of unbound prednisone increased on increasing the total plasma prednisone concentration (ranges at low and high concentrations of prednisone were 15.5-33.7 and 32.3-47.6%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and pharmacodynamics of the prostacyclin analogue iloprost in man

Summary Plasma levels of the prostacyclin analogue, iloprost, were measured by antibody/GC/MS in healthy male volunteers given 1 and 3 ng/kg per min i.v. for 45 min, and 1 µg/kg p.o. Following i.v. infusion, the steady-state plasma levels of iloprost were strictly dose-dependent (46±8 pg/ml and 135±24 pg/ml). The disposition was biphasic with half-lives of 3–4 min and 0.5 h. After oral administration, absorption of the drug was extremely rapid, the maximum plasma level of 251±32 pg/ml being achieved after 10±6 min. The bioavailability was 16±4%. Platelet aggregation induced by 2 µM ADP was reduced by 53% and 68% at the end of the two different infusions, and by 68% 15 min after p.o. administration. The ex-vivo inhibition of platelet aggregation by iloprost was not affected by preceding drug treatment. The cAMP content of platelets was increased by a factor of 2.5 at the end of the infusions and to a lesser extent 15 min after oral dosing. A slight increase in heart rate occurred during the infusion and within 30 min after oral administration; blood pressure was virtually unaffected. Except for transient side-effects (facial flush and headache) no adverse reactions were observed.     

Correlation between the in vivo efficacy of GPIIb/IIIa receptor antagonists (m7E3, MK-383 and DMP-728) and ex vivo platelet inhibition

In vivo antithrombotic efficacy of GPIIb/IIIa receptor antagonists (m7E3, MK-383 and DMP-728) was studied with respect to their ex vivo platelet inhibition in heparinized platelet-rich plasma (hPRP) and citrated platelet-rich plasma (cPRP) using a canine model of carotid artery thrombosis. For each drug group (n = 6), the right carotid artery was used as control vessel and resulting occlusive thrombus was kept in situ to examine the direct thrombolytic efficacy of the antagonists. Thirty minutes after occlusion of control vessel, a low or high dose of each antagonist was administered and the left carotid artery was used as test vessel. All control vessels occluded within 86-96 min in response to electrolytic injury. The incidence of occlusion with lower doses of m7E3, DMP-728, and MK-383 was 100, 33 and 100%, respectively; corresponding times to occlusion were 174, 220 and 118 min. Lower doses inhibited ADP- or AA-induced platelet aggregation in cPRP (>80%). Incidence of occlusion with high doses of m7E3, DMP-728 and MK-383 was 33, 0 and 0%, respectively; corresponding times to occlusion were 209, >240 and >240 min. Higher doses inhibited aggregation in cPRP (>80%), but only partially in hPRP (45-66%). Dose-dependent prolongation of bleeding time occurred with all antagonists. None of the antagonists lyzed preformed thrombi in control vessels. The results indicate that ex vivo platelet aggregation conducted in hPRP, as opposed to conventional cPRP, provides a better assessment of the in vivo efficacy of GPIIb/IIIa receptor antagonists.     

Pharmacological activities of a novel thienodiazepine derivative as a platelet-activating factor antagonist

(S)-(+)-6-(2-Chlorophenyl)-3-cyclopropanecarbonyl-8,11- dimethyl - 2,3,4,5 - tetrahydro - 8H - pyrido[4',3':4,5] thieno[3,2-fl-[1,2,4]triazolo]4,3-a][1,4]diazepine (E-6123) is a newly synthesized platelet-activating factor (PAF) antagonist. The effects of E-6123 on in vitro and in vivo PAF-induced responses were investigated. The IC50 values of E-6123 on 3H-PAF binding to human and guinea pig platelets were 2.7 and 3.0 nmol/l, respectively, and those on PAF-induced platelet aggregation in platelet-rich plasma of human, guinea pig and beagle dog were 10.1, 14.7 and 16 nmol/l, respectively. Oral administration of E-6123 at 3 and 10 micrograms/kg to dogs inhibited ex vivo PAF-induced platelet aggregation in a dose-dependent manner. In guinea pigs, E-6123 at 3 micrograms/kg completely inhibited ex vivo PAF-induced platelet aggregation up to 8 h and the inhibition was still significant at 24 h after administration. Occupancy of the platelet PAF receptor by E-6123 at 3 h and 24 h after administration amounted to 80% and 56%, respectively. Bronchoconstriction induced by PAF injection in guinea pigs was inhibited dose-dependently by oral or intravenous administration of E-6123 at similar doses. The IC50 value of E-6123 at 3 h after oral administration was 1 microgram/kg. Oral administration of E-6123 at 3 micrograms/kg inhibited the bronchoconstriction by more than 90% up to 8 h. Hemato-concentration induced by PAF injection in guinea pigs was inhibited by oral administration of E-6123 at 10 micrograms/kg. E-6123 also protected mice from PAF injection-induced death in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of a new thromboxane A2 antagonist, S-145, on platelet aggregation

The newly synthesized compound S-145, (+/-)-5(Z)-7-(3-endo-phenylsulfonylamino [2.2.1] bicyclohept-2-exo-yl)heptenoic acid, inhibited arachidonic acid (AA)-, 9,11-methanoepoxy-PGH2 (U46619)-, collagen- and ADP-induced human platelet aggregation in vitro with IC50 values of 0.25, 0.34, 0.22, and 0.08 microM, respectively. The inhibiting potency of this compound to AA- or U46619-induced platelet aggregation was about twice that of ONO-3708 and 1/7-1/14 that of SQ29,548 in human platelets, about 7 times that of ONO-3708 and 1/3-1/7 that of SQ29,548 in guinea pig platelets, and 250-800 times that of ONO-3708 and 1-7 times that of SQ29,548 in rabbit platelets. When S-145 was administered orally to guinea pigs at the dose of 0.1 mg/kg, AA-induced platelet aggregation was completely inhibited at 30 and 60 min after the administration, but not at 3 and 6 hr. The minimum effective doses of S-145 (p.o.) to AA- and collagen-induced platelet aggregation at 60 min after the administration were 0.01 mg/kg and 0.03 mg/kg, respectively. The potency of S-145 (p.o.) to inhibit AA- and collagen-induced guinea pig platelet aggregation was 30-300 times that of ONO-3708 or SQ29,548 and 300-1000 times that of aspirin. These results suggest that S-145 is a thromboxane A2 antagonist showing a potent inhibiting effect on platelet aggregation by oral administration.     

Genistein,an isoflavone included in soy,inhibits thrombotic vessel occlusion in the mouse femoral artery and in vitro platelet aggregation

Diet can be the most important factor that influences risks for cardiovascular diseases. Genistein included in soy is one candidate that may benefit the cardiovascular system. Here, we investigated the inhibitory effects of genistein on thrombotic vessel occlusion in the mouse femoral artery using a photochemical reaction, and in vitro platelet aggregation in whole blood measured by single platelet counting. Genistein (10 mg/kg), intravenously administered 10 min before the rose bengal injection, significantly prolonged the thrombotic occlusion time from 6.1+/-0.4 to 8.4+/-0.8 min (P<0.05). Genistein at doses higher than 30 microM significantly (P<0.01) inhibited in vitro platelet aggregation induced by collagen (1 and 3 microg/ml). When 10 mg/kg genistein was intravenously administered, ex vivo platelet aggregation induced by collagen (1 and 3 microg/ml) was significantly suppressed (P<0.01). In conclusion, genistein prevented in vivo thrombogenesis and suppressed in vitro platelet aggregation. These results suggest that dietary supplementation of soy may prevent the progression of thrombosis and atherosclerosis.     

Basic and clinical studies on imipenem/cilastatin sodium in the pediatric field

Basic and clinical studies have been performed on imipenem/cilastatin sodium (MK-0787/MK-0791) in the pediatric field. Antibacterial activities of MK-0787 against 14 clinical isolates of S. aureus and 67 isolates of E. coli were determined. The MIC of MK-0787 was 0.10 microgram/ml or less against all 14 strains of S. aureus. The MIC of MK-0787 was 0.39 microgram/ml or less against all 67 strains of E. coli. The pharmacokinetics of MK-0787/MK-0791 was studied at dose levels of 10 mg/10 mg/kg and 20 mg/20 mg/kg. The peak serum levels of MK-0787 achieved approximately 1 hour after the administration of 10 mg/10 mg/kg and 20 mg/20 mg/kg doses were 38.6 micrograms/ml and 36.2 micrograms/ml, respectively. The serum half-lives were 0.8 hour and 0.9 hour, respectively. The total 6-hour urinary excretions were 82.1% and 66.7%, respectively. The MK-0787/MK-0791 was administered to 13 children with bacterial infections. The clinical results were excellent or good in all cases. The overall efficacy rate was 100%. As a side effect, diarrhea was observed in 1 patient. Abnormalities in laboratory findings observed were elevation of direct bilirubin in 1 patient, thrombocytosis in 2, and a prolonged prothrombin time in 1 patient. Based on the above results, it can be concluded that MK-0787/MK-0791 is a safe and effective drug to use for the treatment of pediatric infections.     

人参皂甙对血小板聚集性、cAMP和cGMP含量的影响

本文报告了人参皂甙对家兔血小板聚集性,cAMP和cGMP含量的影响。结果表明,人参皂甙在体内外均抑制由花生四烯酸、ADP和凝血酶诱导的血小板聚集。同时,人参皂甙明显升高血小板中cAMP含量,但是不影响血小板中cGMP含量。提示人参皂甙对血小板聚集的抑制作用与其升高血小板中cAMP含量有关。