AbstractConventional treatment of hemophilia A (HA) requires repetitive IV injection of coagulation factor VIII (FVIII). Subcutaneous administration of FVIII is inefficient because of binding to the extravascular matrix, in particular to phospholipids (PLs), and subsequent proteolysis. To overcome this, recombinant dimeric fragments of von Willebrand factor (VWF) containing the FVIII-stabilizing D3 domain were engineered. Two fragments, called VWF-12 and VWF-13, demonstrated high binding affinity to recombinant human FVIII (rhFVIII) and suppressed PL binding in a dose-dependent manner. High concentrations of VWF fragments did not interfere with the functional properties of full-length VWF in vitro. The HA mouse model was used to study the effects of VWF-12 or VWF-13 on the in vivo pharmacokinetics of rhFVIII, demonstrating (1) no significant impact on rhFVIII recovery or half-life after a single IV administration; (2) enhanced bioavailability (up to 18.5%) of rhFVIII after subcutaneous administration; and (3) slow absorption (peak concentration, 6 hours) and prolonged half-life (up to 2.5-fold) of rhFVIII after subcutaneous administration. Formation of anti-FVIII antibodies was not increased after administration of rhFVIII/VWF-12 subcutaneously compared with rhFVIII IV. A single subcutaneous dose of rhFVIII/VWF-12 provided protection in the HA tail-bleeding model for up to 24 hours. In summary, recombinant VWF fragments support FVIII delivery through the subcutaneous space into vascular circulation without interfering with VWF or FVIII function. Slow resorption and excretion of FVIII after subcutaneous administration highlight the potential application of VWF fragments for subcutaneous FVIII prophylaxis in HA.

2005-08-01·DNA and Cell Biology4区 · 生物学

Elicitation of Immunity in Mice After Immunization with the S2 Subunit of the Severe Acute Respiratory Syndrome Coronavirus

4区 · 生物学

Article

作者: Zhu, Weijia ; Zhang, Shu ; Sun, Shuhan ; Wang, Kaiyu ; Guo, Yingjun ; Chen, Ze

The S2 domain of the severe acute respiratory syndrome coronavirus (SARS-CoV) spike (S) protein is responsible for fusion between virus and target cell membranes, and is expected to be immungenic. In this study, we investigated the immune responses against the S2 subunit in BALB/c mice, which were vaccinated either with plasmid DNA encoding the S2 domain (residues 681-1120), the recombinant S2 fragment (residues 681-980) in incomplete Freund's adjuvant, or with inactivated SARS-CoV. The increased number of specific cytotoxic cells (CTLs) and the high titer of specific antibody showed stimulation of both arms of the immune system in these groups. The shift in cytokines suggested that Th1-polarized immune response was induced by plasmid pCoVS2, meanwhile the Th2-dominant response was induced by recombinant S2 fragment and inactivated vaccine. However, the titer of neutralizing antibodies was only detectable in mice immunized with inactivated virus, but not with pCoVS2 plasmid. Taken together, the S2 domain could induce specific cellular immune response and a high level of total IgG but little neutralizing antibodies against infection by SARSCoV.

2004-10-01·Journal of Urology1区 · 医学

THE NEW ECONOMICS OF RADICAL PROSTATECTOMY: COST COMPARISON OF OPEN, LAPAROSCOPIC AND ROBOT ASSISTED TECHNIQUES

1区 · 医学

Article

作者: GETTMAN, MATTHEW T. ; LOTAN, YAIR ; CADEDDU, JEFFREY A.

PURPOSEWe evaluated the costs components of laparoscopic (LRP) and robot assisted prostatectomy (RAP), and compared their costs to those of open radical retropubic prostatectomy (RRP).MATERIALS AND METHODSA model was created using commercially available software to compare the costs of treatment with LRP, RAP or RRP. Hospital costs were obtained from a large county hospital. A literature search was performed to determine typical (average) robot costs, length of stay and operative time for RRP, LRP and RAP. We limited our analysis to mature series and included only the most recent efforts. The cost of the robot was estimated at 1,200,000 dollars with a 100,000 dollars yearly maintenance contract. It was assumed that the robot would be used across specialities for a total of 300 cases yearly in a 7-year period. We performed a series of 1 and 2-way sensitivity analyses to evaluate the costs of LRP, RAP and RRP, while varying robot costs, the number of robotic cases, hospital length of stay, operative time and cost of laparoscopic/robotic equipment.RESULTSRRP was the most cost-effective approach with a cost advantage of 487 dollars and 1,726 dollars over LRP and RAP, respectively. If we excluded the initial cost of purchasing a robot, the cost difference between RRP and RAP was 1,155 dollars. This large difference in RRP and RAP costs resulted from a cost of 857 dollars per case to pay for robot purchase and maintenance, and the high cost of 1,705 dollars for equipment per case. An even shorter RAP operative time (140 vs 160 minutes) and length of stay (1.2 vs 2.5 days) did not compensate for the added expenditure. LRP cost more than RRP primarily due to equipment costs (533 dollars) since the shorter hospital stay (1.3 vs 2.5 days) was compensated for by longer operative time (200 vs 160 minutes).CONCLUSIONSThe costs of new technology are typically borne out in the first years of use and RAP is no exception with high robot costs for purchase, maintenance and operative equipment overshadowing savings gained by shorter length of stay. While RRP is currently the least costly approach, LRP has proved to be almost as cost competitive as RRP, whereas RAP will require a significant decrease in the cost of the device and maintenance fees.

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适应症	最高研发状态	国家/地区	公司	日期
阿尔茨海默症	临床1期	美国	Socratech LLC	-
阿尔茨海默症	药物发现	美国	ZZ Biotech LLC	-
阿尔茨海默症	药物发现	美国	ZZ Biotech LLC	-
阿尔茨海默症	药物发现	美国	Socratech LLC	-