In vitro pharmacological profile of SK-896, a new human motilin analogue

SK-896 ([Leu(13)]motilin-Hse) is a new human motilin analogue synthesized by Escherichia coli using a biotechnological method. We investigated the binding of SK-896 to motilin receptors and the contractile effect of SK-896 on smooth muscle preparations isolated from the gastrointestinal tract and various regional organs in order to clarify its in vitro pharmacological profile. SK-896 inhibited the binding of (125)I-human motilin to rabbit gastroduodenal motilin receptors with the same potency as unlabeled human motilin. The IC(50) values of SK-896 and human motilin were 3.5 +/- 1.5 and 3.1 +/- 1.8 nmol/l, respectively. The K(d) of human motilin was 3.0 +/- 1.5 nmol/l, and the Ki of SK-896 was 3.4 +/- 1.5 nmol/l. SK-896 induced contraction of smooth muscle preparations isolated from rabbit duodenum in a concentration-dependent manner. However, there was no effect of SK-896 on duodenal preparations isolated from the dog and the rat. SK-896 thus exhibited species specificity in its contractile effect. We next investigated the effect of SK-896 on various smooth muscle preparations isolated from rabbit gastrointestinal tract, trachea, bladder, gallbladder, uterus, vas deferens and artery. Results showed that SK-896 induced contraction of smooth muscle preparations isolated from gastrointestinal tract, with potencies in the order duodenum > gastric pylorus = jejunum = descending colon > ascending colon >/= ileum. However, there was no effect of SK-896 on smooth muscle preparations from gastric fundus and other regional organs. SK-896 thus exhibited regional specificity in its contractile effect. Moreover, the effects of SK-896 on smooth muscle preparations from rabbit duodenum were the same as those of human motilin, and were not inhibited by pretreatment with tetrodotoxin and atropine but were inhibited by verapamil. These findings indicate that SK-896 has the same pharmacological profile as human motilin. They suggest that SK-896 acts on gastrointestinal smooth muscle isolated from rabbit directly and specifically.     

Pharmacokinetic and pharmacodynamic studies of SK-896, a new human motilin analogue,in healthy male volunteers

OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of SK-896 ([Leu(13)]motilin-Hse) after intravenous administration to healthy male volunteers. DESIGN AND SETTING: This was a non-blinded phase I study.Participants: Thirty male Japanese volunteers (mean age 30.6 years) participated in this study. The volunteers were divided into five groups receiving different doses of SK-896. METHODS: The pharmacokinetics and pharmacodynamics of SK-896 were evaluated after single intravenous infusions of doses of 10, 20, 40 and 80 micro g over 20 minutes to fasting volunteers, or after multiple intravenous infusions (twice a day for 3 days) of doses of 40 micro g over 20 minutes to volunteers in the morning (fasting) and afternoon (non-fasting). Plasma concentrations of immunoreactive SK-896 were determined by radioimmunoassay, and borborygmus was measured as an indicator of drug effect (acceleration of gastrointestinal motility) with an improved Holter electrocardiograph attached to the abdomen. RESULTS: When SK-896 was given by single intravenous infusion at each dose, the plasma concentration of immunoreactive SK-896 rapidly increased to a maximum at the end of the infusion. After the infusion was completed, plasma concentrations declined monoexponentially with an elimination half-time of 4.57-5.64 minutes. The area under the concentration-time curve and the maximum concentration (1.04-9.08 microg-equiv./L) increased in proportion to the dose, and there were no dose-related changes in plasma clearance (7.59-9.34 mL/min/kg), mean residence time (7.83-9.51 minutes) or steady-state volume of distribution (62.9-73.9 mL/kg), indicating that SK-896 plasma concentrations can be described by a linear pharmacokinetic model within the dose range of the present study. After beginning administration, an increase in borborygmus was observed. At doses of 40 and 80 micro g, the borborygmus did not continue even when the plasma concentration was maintained, suggesting that tachyphylaxis occurs at a higher dose. When SK-896 was given as multiple intravenous infusions, the pharmacokinetics did not change with repeated administration. The intensity of borborygmus was low with afternoon administration, reaching only one-third to one-half that with morning administration, suggesting that, like native motilin, SK-896 does not stimulate gastrointestinal motility in the non-fasting state. CONCLUSIONS: The appropriate dose and administration period (fasting or non-fasting) are important factors in stimulating and maintaining gastrointestinal motility when treating gastroparalysis with SK-896.     

Effects of SK-896, a new human motilin analogue ([Leu13]motilin-Hse), on postoperative ileus in dogs after laparotomy

The effects of SK-896, a new human motilin analogue ([Leu13]motilin-Hse), on digestive tract motility in postoperative ileus were evaluated in a dog model of ileus after laparotomy. SK-896 was intravenously administered at 0.17, 0.33 and 0.67 microg/kg starting soon after operation and then at 6-h intervals, for a total of 9 times. SK-896 progressively, dose-dependently and significantly increased the duodenal motility from 1 h after operation. The recovery time of the gastrointestinal-interdigestive migrating complex (GI-IMC) activity, which is an indicator of normal gastrointestinal tract activity after laparotomy, was 56.5 +/- 5.0 h in the control group. SK-896 significantly shortened this recovery time. On the other hand, the plasma SK-896 concentrations declined diexponentially after administration, and can be described by a linear pharmacokinetic model within the dose range used. In addition, the pharmacokinetics of SK-896 did not change significantly at any postoperative time. There was no correlation between the plasma SK-896 concentrations and the intensity of duodenal motility, because the activity in the duodenum decreased transiently 13 h after laparotomy and increased with time thereafter. The changes in the activity are considered to reflect the progressive changes in the state of ileus. In conclusion, SK-896 increased the duodenal motility significantly, shortening the recovery time of GI-IMC-like activity in dogs with post-laparotomy ileus. Therefore, it is expected from these results that SK-896 would be useful and effective for the treatment of gastroparalysis after abdominal surgery.     

The effect of SK-896 on post-operative ileus in dogs: gastrointestinal motility pattern and transit

The aim of this study was to investigate the effect of SK-896 (Phe-Val-Pro-Ile-Phe-Thr-Try-Gly-Glu-Leu-Gln-Arg-Leu-Gln-Glu-Lys-Glu- Arg-Asn-Lys-Gly-Gln-Hse), a new motilin analogue, on gastrointestinal motility and transit in dogs with post-operative ileus, and to compare the effects of this agent on these parameters with the effects of prostaglandin F(2alpha), a well-known gastroprokinetic agent. We used chronically implanted force transducers to measure motility and radiography of radio-opaque markers to measure transit. Infusion of SK-896 1 microgram/kg/h, for 20 min twice a day induced interdigestive migrating contractions-like motility. Infusion of prostaglandin F(2alpha), 20 microgram/kg/h, for 1 h twice a day induced continuous contractions in the distal part of the small intestine. The time of first appearance of interdigestive migrating contractions in the stomach (gastric-interdigestive migrating contractions) and the gastric emptying time of the solid marker with the administration of SK-896 were significantly less than those noted with the administration of prostaglandin F(2alpha). It appears that gastric-interdigestive migrating contractions play an important role in the transit of substances, especially solid substances, in the gastrointestinal tract. We conclude that SK-896, which induced gastric-interdigestive migrating contractions, is effective to induce early recovery from post-operative ileus.     

Pharmacokinetics of diltiazem and a new analogue, LR-A/113, in the conscious rat.

Pharmacokinetics and metabolism of diltiazem and a new analogue, LR-A/113, have been studied in the rat. Conscious rats, with the jugular vein cannulated, received the compounds by intravenous (3 mg/kg body weight) or oral (50 mg/kg body weight) route. Parent compounds and their N-demethyl and N-deacetyl metabolites were assayed at serial times in blood. Half-life of elimination of diltiazem was significantly shorter than that of LR-A/113, both after oral (37 +/- 9 vs 59 +/- 26 min) and intravenous (29 +/- 12 vs 57 +/- 16 min) administration. N-deacetyl-diltiazem concentrations after oral administration were higher than the parent compound and N-demethyldiltiazem; LR-A/113 blood concentrations were higher than those of its two metabolites. Metabolites were measurable only in traces after intravenous administration. Oral bioavailability was very low, 3.5% for diltiazem and 4.2% for LR-A/113. In conclusion, the substitution of a methyl by an isopropyl group appears to slow in vivo elimination of the analogue of diltiazem, LR-A/113.     

红霉素对狗消化间期和餐后胃肠运动的影响及机制探讨

目的观察静脉注射红霉素对狗消化间期胃肠移行性复合运动（ＭＭＣ）和餐后运动的作用并探讨可能机制。方法应用低顺应性毛细管水灌注消化道腔内测压系统记录清醒狗胃肠收缩活动。在ＭＭＣＩ相和餐后静脉注射红霉素记录胃肠运动变化并抽血测定血浆胃动素浓度。结果①血浆胃动素随ＭＭＣ不同时相呈周期性波动,血浆胃动素浓度在 ＭＭＣⅢ相时最高,ＭＭＣＩ相时最低。②在 ＭＭＣＩ相时从静脉注射红霉素可以激发胃和十二指肠ＭＭＣⅢ相收缩,但不伴有血浆胃动素升高。引起狗ＭＭＣⅢ相收缩的最适红霉素浓度为０,５ｍｇ·ｋｇ－１体重;红霉素１０ｍｇ·ｋｇ－１引起胃肠持续收缩并出现十二指肠－胃逆蠕动,导致恶心呕吐。③阿托品明显抑制红霉素所致的胃和十二指肠ＭＭＣⅢ相收缩。④红霉素增强狗餐后胃窦和十二指肠的收缩活动。结论红霉素有促进胃肠动力作用,作用机制与胃动素释放无关,可能部分通过胆碱能神经介导。     

Cardiovascular effects of the new angiotensin-converting-enzyme inhibitor, cilazapril, in anesthetized and conscious dogs

Cilazapril is a new angiotensin-converting-enzyme inhibitor. In conscious renal-hypertensive dogs, cilazapril (2 X 10 mg/kg/day p.o.) caused a long-lasting (greater than 24 h) decrease in systolic arterial blood pressure, the magnitude of which was potentiated by pretreatment with furosemide. A maximal fall in systolic blood pressure of 39 +/- 6 mm Hg (from 145 +/- 5 to 106 +/- 7 mm Hg) was recorded. The antihypertensive effect did not decline with repeated administration and was accompanied by only a slight increase in heart rate. Cilazapril also reduced systolic blood pressure in furosemide-pretreated normotensive dogs. Hemodynamic studies in anesthetized dogs revealed that cilazapril (0.03-1 mg/kg i.v.) caused a fall in mean arterial and left ventricular systolic pressures. At the highest dose of 1 mg/kg i.v., the blood-pressure-lowering effect (-27%) was due to a decrease in total peripheral resistance (-12%) and cardiac output (-16%). Intravenous administration of cilazapril to anesthetized dogs resulted in a rise in plasma renin activity and a significant fall in plasma angiotensin II levels. In conscious normotensive dogs, cilazapril (0.3-10 mg/kg p.o.) exerted diuretic and saluretic effects, which were accompanied by a significant increase in renal plasma flow (46%), but only a slight rise in the glomerular filtration rate. These results characterize cilazapril as an effective and long-lasting antihypertensive drug, with diuretic activity and, possibly, preload- as well as afterload-reducing properties.     

Effects of SK-951, a benzofuran derivative, as a prokinetic agent in rats and dogs

The gastrokinetic activity of SK-951 ((-)4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2,3-dihy dro-2-methylbenzo[b]furan-7-carboxamide hemifumarate), a benzofuran derivative with 5-hydroxytryptamine (5-HT)4-receptor agonist activity, was studied in rats and dogs. The effects of SK-951 were also investigated in a model of vagotomy-induced gastroparesis in comparison with cisapride. In rats, both SK-951 and cisapride enhanced gastric emptying of liquids (phenol red) at a dose of 1-100 mg/kg, p.o. Gastric emptying of liquid (acetaminophen) in fasted beagle dogs was enhanced significantly by SK-951 (1.0 mg/kg, i.v.), whereas the effect of cisapride (0.2-1.0 mg/kg, i.v.) was not statically significant. Similar results were found when radiopaque markers were given with standard meal to dogs with vagotomy-induced gastroparesis. The delayed gastric emptying of radiopaque markers by vagotomy was reversed by SK-951 (1.0 mg/kg, i.v.), whereas cisapride showed no effect at doses from 0.1 to 1.0 mg/kg, i.v. These results indicated that oral and intravenous administration of SK-951 accelerates gastric emptying of both liquids and solids in animal models. Thus, SK-951 may be a highly potent and useful prokinetic agent in comparison to cisapride.     

Hemodynamic, hormonal, and renal effects of the prostacyclin analogue iloprost in conscious dogs with and without heart failure.

To test the efficacy of exogenous prostaglandins for vasodilator therapy in heart failure, we studied the effects of the prostacyclin-derivative iloprost (1.5-150 ng/kg/min) in seven conscious dogs before and after induction of heart failure by right ventricular pacing (250/min. 10 days). In healthy dogs, iloprost (150 ng/kg/min) decreased mean arterial blood pressure (MAP) (-45%) by a decrease in total peripheral resistance (TPR) (-55%), and increased cardiac output (CO) (+24%) and heart rate (HR) (+20%) with no effect on right atrial and pulmonary arterial pressures (RAP, PAP). Plasma norepinephrine (NE) (+47%), renin (+351%), and aldosterone (+126%) were increased. Urine flow (-70%) and Na excretion (-53%) were decreased. Iloprost (15 ng/kg/min) increased renal blood flow (RBF) (+29%), but did not change glomerular filtration rate (GFR). In dogs with heart failure, iloprost decreased arterial BP (-31%), TPR (-42%) and pulmonary vascular resistance (-28%) and increased CO (+29%), with no change in RAP and PAP. Plasma NE (+34%), renin (+385%), and aldosterone (+146%) were increased. RBF was unchanged. GFR (-24%) and filtration fraction (FF) (-30%) were decreased, as was urine flow (-65%). In experimental heart failure, iloprost is a potent arteriolar dilator, increasing CO with no preload effect. These beneficial effects are limited, however, by further neurohumoral activation and deterioration of renal function.     

Atropine potentiates the pressor effect of arginine-vasopressin in conscious dogs

The hemodynamic effects of injections of arginine-vasopressin (AVP) at different doses were measured before and after administration of atropine (250 micrograms/kg), propranolol (2 mg/kg), or phenoxybenzamine (5 mg/kg) in conscious dogs. Measurements of arterial pressure derived from a chronic indwelling catheter, and aortic flow derived from an aortic electromagnetic flow probe, were digitized and analyzed by computer to assess mean and pulsatile arterial pressure, cardiac output, total peripheral resistance, heart rate, and other hemodynamic variables. AVP alone moderately increased arterial pressure and decreased cardiac output and heart rate. For doses between 20 and 40 ng/kg, mean arterial pressure increased by 17.4 +/- 1.5 mm Hg. After atropine, the same dose of AVP increased pressure by 51.6 +/- 3.2 mm Hg. The bradycardiac response to AVP was blunted by atropine as was the decrease in cardiac output. The effect of AVP on total peripheral resistance was not affected by atropine. Neither alpha- nor beta-adrenergic blockade enhanced the pressor effect of arginine-vasopressin. Our results indicate that the potentiation of the pressor response to AVP previously reported with total autonomic blockade is largely due to preventing a vagallymediated decrease in cardiac output in conscious dogs.     

Antihypertensive effect of CS-905, a novel dihydropyridine calcium blocker, in conscious hypertensive dogs

CS-905, (+-)-3-(1-diphenylmethylazetidin-3-yl)5-isopropyl 2-amino-1,4-dihydro-6-methyl-4-(m-nitrophenyl)-3,5-pyridine-dicarboxy lat e, is a novel dihydropyridine calcium blocker. Both CS-905 and nicardipine, when administered orally, produced a dose-dependent fall of blood pressure in conscious perinephritic hypertensive dogs. Unlike the hypotensive effect of nicardipine, that of CS-905 has a gradual onset and is long-lasting, with little increase in the heart rate and plasma renin activity (PRA). The lack of both tachycardia and increase of PRA is probably mostly due to the slow onset of antihypertensive action following CS-905.     

Mitemcinal (GM-611), an orally active motilin receptor agonist,accelerates colonic motility and bowel movement in conscious dogs

The prokinetic effects of mitemcinal, an orally active motilin receptor agonist, on the lower gastrointestinal tracts were investigated in conscious dogs. Oral administration of mitemcinal (0.1–1 mg/kg) stimulated colonic motility, which was measured by chronically implanted force-transducers, as well as gastric motility in a dose-dependent manner. The gastrointestinal contractile activities induced by mitemcinal were inhibited by the continuous intravenous infusion of GM-109, a selective motilin receptor antagonist. Oral administration of mitemcinal (0.3–3 mg/kg) also accelerated bowel movement after feeding without inducing diarrhea in dogs. The results demonstrate that mitemcinal stimulates colonic motility via motilin receptors and the effect of mitemcinal on colonic motility may reflect bowel movement after feeding. Thus, mitemcinal could be a promising agent for treatment of not only the upper but also the lower gastrointestinal motility disorders. Received 26 July 2006, accepted 21 August 2006     

Kinetics of antisecretory action of a new H2-antagonist, YM-11170, in conscious dogs

The antisecretory property of YM-11170 was compared with that of cimetidine and atropine in the Heidenhain pouch dog. YM-11170 inhibited competitively dimaprit-induced gastric acid secretion in doses of 33 and 100 nmol/kg per h and its antisecretory potency was 148 times more pronounced than that of cimetidine. The secretory action of pentagastrin and methacholine was also inhibited by YM-11170 and cimetidine with doses similar to those required for the inhibition of dimaprit action although the inhibition by the H2-antagonists was not of the surmountable type. Atropine inhibited gastric secretion stimulated by methacholine and pentagastrin more strongly than that stimulated by dimaprit. It is concluded that YM-11170 is a competitive antagonist of dimaprit-induced gastric secretion in vivo and that the activity of the H2-antagonists in blocking gastric H2-receptors may reflect their inhibitory effect on the acid response to pentagastrin and methacholine.     

Effects of mitemcinal (GM-611), an acid-resistant nonpeptide motilin receptor agonist, on the gastrointestinal contractile activity in conscious dogs

The effects of mitemcinal (GM-611) on the gastrointestinal contractile activity were investigated using chronically implanted force transducers in conscious dogs and were compared with the effects of porcine motilin (pMTL), EM-523 and EM-574. In the interdigestive state, intravenous and oral administration of mitemcinal, EM-523 and EM-574 induced the gastrointestinal contractile activity in a manner similar to pMTL. The contractile activity caused by mitemcinal was suppressed by continuous intravenous infusion of a motilin receptor antagonist. In the digestive state, intravenous and oral administration of mitemcinal, EM-523 and EM-574 also stimulated the gastrointestinal contractile activity. Mitemcinal, EM-523 and EM-574 given intravenously increased the gastric contractile activity in a similar dose range; however, mitemcinal was approximately 10 times more potent than EM-523 and EM-574 when administered orally in the digestive state. These results indicate that the mitemcinal-induced gastrointestinal contractile activity operates via motilin receptors and possesses a higher activity than EM-523 and EM-574 when administered orally in conscious dogs in the digestive state. Mitemcinal may therefore be useful in the treatment of several gastrointestinal disorders involving dysmotility, such as gastroparesis and functional dyspepsia, even when administered orally.     

Effect of dobutamine, a new cardioselective sympathomimetic drug, on myocardial oxygen balance in conscious dogs

The effects of (+/-)-4-(2-[3-(p-hydroxyphenyl)-1-methylpropyl]-amino)-ethyl-pyrocatechol hydrochloride (dobutamine) on myocardial O2 balance were investigated in healthy conscious dogs with experimental AV-block. Dobutamine, injected as a bolus of 3, 6, 10 micrograms/kg, increased myocardial contractility, coronary flow, coronary venous O2 saturation and aortic pressure, while initially decreasing SA-node rate. Following ganglionic blockade the effects of dobutamine on myocardial contractility were unchanged while those on coronary flow and coronary venous O2 saturation were reduced by 30%. Aortic pressure and heart rate showed a dose dependent, long-lasting increase. The effects of dobutamine on heart rate and myocardial contractility could be abolished by beta 1-adrenoceptor blockade with practolol (2 mg/kg) while the effects on coronary flow and myocardial O2 extraction were reduced by 40% after practolol. Following beta 1 + 2 adrenoceptor blockade with propranolol, dobutamine increased aortic pressure and coronary flow while coronary resistance and myocardial oxygen extraction were unaffected.     

An application of a new antibiotic, ceftriaxone, during the perinatal period

1. Ceftriaxone (CTRX) was not transferred well into cerebrospinal fluid in healthy individuals. 2. The transplacental passage and the transfer of CTRX into amniotic fluid were very good, and CTRX seems useful for the treatment of perinatal infections. 3. Clinically, CTRX was very effective against amniotic infections and infections of the puerperal uterus: Clinical efficacies were excellent in 1 case and good in 3 out of 4 cases (efficacy rate: 100%). 4. No side effects or laboratory abnormalities were observed.     

Gastric emptying in diabetic gastroparetic dogs: ffects of SK-951,a novel prokinetic agent

We examined whether delayed gastric emptying could be produced by diabetes in dogs. Diabetes was produced by a single injection of streptozotocin (30 mg/kg i.v.), and diabetic hyperglycemia was observed from 2 to 15 months after injection. The plasma acetaminophen concentration, which is an indirect indicator of the gastric emptying rate, was delayed in 2 of 5 diabetic dogs from 15 months after the induction of diabetes. The effects of SK-951, a benzofuran derivative, on delayed gastric emptying were also examined in diabetic gastroparetic dogs in comparison with those of cisapride. SK-951 (1 mg/kg i.v.) significantly enhanced delayed gastric emptying in diabetic dogs, but cisapride (1 mg/kg i.v.) had no effect. In addition, SK-951 increased the plasma glucose levels in a manner correlated with its effect on gastric emptying. The present study suggested that SK-951 may be useful in the treatment of diabetic gastroparesis.     

Effects of CV-3611, a new free radical scavenger, on ischemic heart failure in conscious beagle dogs

The effects of CV-3611, a new free radical scavenger, on coronary circulation failure and infarct size after ischemia/reperfusion were studied in conscious beagle dogs. The dogs underwent occlusion of the left circumflex coronary artery for 60 min and then were reperfused for 14 days. The dogs were divided into three groups: a control group, a pre-treated group that received CV-3611 or alpha-tocopherol, and a post-treated group that received CV-3611. During occlusion, varying degrees of ventricular arrhythmia were noted; after reperfusion, the arrhythmia tended to become severe. CV-3611 at a daily dose of 10 mg/kg or 30 mg/kg and alpha-tocopherol at a daily dose of 60 mg/kg reduced the incidence of overall post-occlusion arrhythmia. Coronary blood flow in the control group was reduced to 20% of the preocclusion level at 7 days after reperfusion, whereas in the CV-3611 and alpha-tocopherol treated groups, the decreased coronary flow was remarkably suppressed. The infarct size for the CV-3611- and alpha-tocopherol-treated groups, measured at 14 days after reperfusion, was reduced by 70% when compared with the control group. Based on these observations, it is proposed that CV-3611 exerts its beneficial effects on ischemic tissue by protecting against oxygen free radical-mediated damage induced by ischemia/reperfusion.     

Protective effect of beraprost sodium, a new chemically stable prostacyclin analogue, against the deterioration of baroreceptor reflex following transient global cerebral ischaemia in dogs.

1. A possible cerebroprotective effect of a chemically stable prostacyclin analogue, beraprost sodium, was investigated in a canine model of cerebral ischaemia. Cerebral ischaemia was produced by the combined occlusions of the left subclavian and the brachiocephalic arteries with preceding ligations of the intercostal arteries. 2. The decrease in baroreceptor reflex sensitivity (BRS), measured by phenylephrine-induced reflex bradycardia, following 5 min ischaemia was used to assess the cerebroprotective effect. 3. Beraprost (1 microgram kg-1 min-1 i.v., infused for 15 min just before ischaemia) completely prevented the decrease in BRS. Although the lower dose of beraprost (0.1 microgram kg-1 min-1 i.v.) failed to show such a protective effect, its inhibitory effect on ADP-induced platelet aggregation was as potent as that of the higher dose. 4. The extent of decrease in BRS was inversely correlated with the extent of the residual blood flow in the medulla oblongata during ischaemia. Since beraprost did not affect the extent of the residual blood flow during ischaemia, its cerebroprotective effect could not be ascribed to the reduction of the degree of ischaemia by increasing collateral blood flow to the brain. 5. Post-ischaemic reduction of the regional blood flow in the medulla and the cerebral cortex was completely prevented by the higher dose of beraprost. 6. The present study suggests that the cerebroprotective effect of beraprost may be independent of its anti-aggregatory and vasodilator effects. It is possible that the protection may be due to a prostacyclin-like cytoprotective effect through membrane stabilization.