Sphingosine 1-phosphate (S1P) induces shape change in rat C6 glioma cells through the S1P2 receptor: development of an agonist for S1P receptors

Treatment with isoprenaline led to a change in the cell morphology of rat C6 glioma cells. This morphological change was reverted by the addition of sphingosine 1-phosphate (S1P). Using this morphological change as a response marker we determined that DS-SG-44 ((2S,3R)-2-amino-3-hydroxy-4-(4-octylphenyl)butyl phosphoric acid) was an agonist of S1P receptors. The DS-SG-44-induced morphological reversion was not observed with such structurally related molecules as DS-SG-45 ((2S,3R)-2-amino-3-hydroxy-4-(3-octylphenyl)butyl phosphoric acid) and DS-SG-12 ((2S,3R)-2-amino-4-(4-octylphenyl)butane-1,3-diol). The S1P- and DS-SG-44-induced shape changes were neither reproduced with the S1P1/S1P3 receptor agonist VPC24191 nor inhibited by the S1P1/S1P3 receptor antagonist, VPC23019. Transfection with small interfering RNA (siRNA) for the S1P2 receptor greatly inhibited the DS-SG-44-induced shape change, and in part an S1P-induced response. In the presence of VPC23019, siRNA transfection for the S1P2 receptor almost completely blocked the S1P- and DS-SG-44-induced shape changes. Our results suggested that DS-SG-44, a newly-synthesized S1P analogue, acted as an S1P receptor agonist and that the S1P-induced shape change in rat C6 glioma cells was mediated mainly through the S1P2 receptor, and cooperatively through the S1P1/S1P3 receptors.     

<Emphasis Type="Italic">In vivo</Emphasis> kinetics and biodistribution of HB-110, a novel HBV DNA vaccine,after administration in Mice

This study investigated the pharmacokinetic profile and biodistribution of HB-110, a novel HBV therapeutic vaccine candidate, in mice. HB-110 was rapidly degraded in the blood after i.v. injection with a half-life of 1.9+/-0.083 min, and was no longer detected at 60 min except in one individual near the detection limit. In the i.m. injection, plasmid DNA was detectable at the injection site until 11 days after administration, but the amounts were just above the detection limit. The blood concentration of HB-110 showed a maximum of 604 pg/mL at 15 min after i.m. injection, which was followed by degradation to undetectable levels at 90 min. The plasmid DNA in tissues peaked at 90 min after administration. The highest concentration of plasmid DNA was detected in the liver (24.172 pg/mg tissue), and considerable amounts were also observed in the lung (9.467 pg/mg tissue) and spleen (7.688 pg/mg tissue). The amount of plasmid DNA in tissues was 2 to 3 orders of magnitude lower than in the injection site at the same time points. The HB-110 concentration in tissues, including gonads, decreased rapidly and was undetectable 24 h after administration.     

Pharmacokinetics and tissue distribution of a novel PDE5 inhibitor, SK-3530, in rats

Aim： To investigate the pharmacokinetic profile and tissue distribution of a novel phosphodiesterase type 5 inhibitor, 5-ethyl-2-{5-[4-（2-hydroxy-ethyl）-piperazine- 1-sulfonyl]-2-propoxy-phenyl }-7-propyl-3,5-dihydro-pyrrolo（3,2-d）pyrimidin-4- one （SK-3530）, in rats after administration of the ^14C-labeled compound. Methods： The pharmacokinetic parameters of SK-3530 were measured based on the total radioactivity and parent SK-3530 concentration in rat plasma after intravenous and oral administration. The tissue distribution of total radioactivity after a single oral administration of [^14C]SK-3530 at a dose of 40 mg/kg was assayed. The plasma protein binding rates of SK-3530 were assessed by in vitro and ex vivo assay. Results： The total radioactivity profiles showed linear pharmacokinetics. The maximum plasma concentration and area under the curve of the parent SK3530 were 10%-20% compared to those of the total radioactivity. After the oral administration of [^14C]SK-3530, the radioactivity was widely distributed in all tissues, and the tissue/plasma ratio of the radioactivity 1 h after administration was calculated as 0.5-2.6 with the exception of excretory organs. A relatively high penetration was shown in the adrenal glands, liver, and lung. In vitro and ex vivo plasma protein binding assay by ultrafiltration showed a considerably high binding rate of more than 97%. Condusion： SK-3530 was relatively well absorbed in the gastrointestinal tract and showed linear pharmacokinetics over the investigated dose range. SK-3530 had low oral bioavailability due to a high, first-pass metabolism.     

Antithrombotic and antiplatelet activities of Korean red ginseng extract

The antithrombotic and antiplatelet activities of Korean red ginseng extract (KRGE) were examined on rat carotid artery thrombosis in vivo and platelet aggregation in vitro and ex vivo. The KRGE significantly prevented rat carotid arterial thrombosis in vivo in a dose-dependent manner. Administration of the KRGE to rats significantly inhibited adenosine diphosphate (ADP)- and collagen-induced platelet aggregation ex vivo, although it failed to prolong coagulation times such as activated partial thromboplastin and prothrombin time indicating that the antithrombotic effect of the red ginseng may be due to its antiplatelet aggregation rather than anticoagulation effect. In line with the above observations, the red ginseng inhibited the U46619-, arachidonic acid-, collagen- and thrombin-induced rabbit platelet aggregations in vitro in a concentration-dependent manner, with IC(50) values of 390 +/- 15, 485 +/- 19, 387 +/- 11 and 335 +/- 15 microg/ml, respectively. Consistently, serotonin secretion was also inhibited by ginseng in the same pattern. These results suggest that the red ginseng has a potent antithrombotic effect in vivo, which may be due to the antiplatelet rather than the anticoagulation activity, and the red ginseng intake may be beneficial for individuals with high risks of thrombotic and cardiovascular diseases.     

A predictive model of Health Related Quality of life of parents of chronically ill children: the importance of care-dependency of their child and their support system

Background  

We assessed preferences for current health using the visual analogue scale (VAS), standard gamble (SG), time trade-off (TTO), and willingness to pay (WTP) in patients with cerebral aneurysms, a population vulnerable to cognitive deficits related to aneurysm bleeding or treatment.     

Farnesyl protein transferase inhibitory components of Polygonum multiflorum

The methanolic extract of the roots of Polygonum multiflorum (Polygonaceae) was found to show inhibitory activity towards farnesyl protein transferase (FPTase). Bioassay-guided fractionation of the methanolic extract resulted in the isolation of two anthraquinone glycosides, as inhibitors of FPTase. These compounds inhibited the FPTase activity in a dose-dependent manner.     

26例甲型H1N1流感确诊病例临床特征及治疗情况分析

目的：探讨甲型H1N1流行性感冒（流感）病例临床特点及处置方法。方法：回顾性分析我院2009年5月15日～6月8日收治住院的26例甲型H1N1流感确诊病例临床资料,明确诊断后隔离,积极给予中医个体化治疗及磷酸奥司他韦胶囊等抗病毒治疗,并与同期26例上呼吸道感染病例作对比分析。结果：治疗组13～49岁发病率显著高于对照组（P〈0.01）,50岁以上年龄发病率显著低于对照组（P〈0.01）。治疗组临床症状中乏力发生率显著高于对照组（P〈0.01）,体温升高发生率明显高于对照组（P〈0.05）。治疗组肝功能异常1例,心肌酶异常1例。治疗组痊愈出院25例,住院时间2～7 d,平均5.6 d。治疗后H1N1流感病毒阴转时间3～7 d,平均4.5 d。1例53岁重症患者持续高热合并肺气肿和既往肺结核病史,呼吸衰竭,转院后死亡。对照组26例全部治愈,无死亡病例。两组患者家属及医护人员均无接触感染。结论：甲型H1N1流感是一种传染性强的急性传染病,青年人容易受感染,有一定的并发症,中西医结合治疗是降低病死率的有效方法。     

Prophylactic low-dose heparin or prostaglandin E1 may prevent severe veno-occlusive disease of the liver after allogeneic hematopoietic stem cell transplantation in Korean children

Studies investigating the effect of prophylactic drugs on hepatic veno-occlusive disease (VOD) development are rare in children that have undergone allogeneic hematopoietic stem cell transplantation (HSCT). This study examined risk factors for VOD, the effect of prophylactic low-dose heparin or lipo-prostaglandin E1 (lipo-PGE1) and the survival rate at day +100 in children undergoing allogeneic HSCT. Eighty five children underwent HSCT between June 1997 and September 2004. Patients were diagnosed and classified as having mild, moderate or severe VOD according to Seattle clinical criteria. Among 85 patients, 25 (29%) developed VOD. VOD occurred more frequently in patients receiving busulfan-based conditioning (24/65, 37%) than in those receiving TBI-based (1/10, 10%) or other (0/10, 0%) regimens (p<0.05). The incidence of VOD was lower in patients with non-malignant disease compared to those with malignant disease (p<0.05). Survival at day +100 for non-VOD patients was better than that for VOD patients (92% vs. 76%, p<0.05). No patients receiving prophylactic heparin or lipo-PGE1 were found to develop severe VOD, whereas 5 of 35 patients not receiving such prophylaxis developed severe VOD. Given severe VOD is associated with a high mortality rate, this study indicates that prophylactic heparin or lipo-PGE1 may decrease mortality in children undergoing HSCT.