In vitro characterization of SynthoPlate™ (synthetic platelet) technology and its in vivo evaluation in severely thrombocytopenic mice.

Essentials Platelet transfusion suffers from availability, portability, contamination, and short shelf-life. SynthoPlate™ (synthetic platelet technology) can resolve platelet transfusion limitations. SynthoPlate™ does not activate resting platelets or stimulate coagulation systemically. SynthoPlate™ significantly improves hemostasis in thrombocytopenic mice dose-dependently. SUMMARY: Background Platelet transfusion applications face severe challenges, owing to the limited availability and portability, high risk of contamination and short shelf-life of platelets. Therefore, there is significant interest in synthetic platelet substitutes that can provide hemostasis while avoiding these issues. Platelets promote hemostasis by injury site-selective adhesion and aggregation, and propagation of coagulation reactions on their membranes. On the basis of these mechanisms, we have developed a synthetic platelet technology (SynthoPlate™) that integrates platelet-mimetic site-selective 'adhesion' and 'aggregation' functionalities via heteromultivalent surface decoration of lipid vesicles with von Willebrand factor-binding, collagen-binding and active platelet integrin glycoprotein (GP) IIb-IIIa-binding peptides. Objective To evaluate SynthoPlate for its effects on platelets and plasma in vitro, and for systemic safety and hemostatic efficacy in severely thrombocytopenic mice in vivo. Methods In vitro, SynthoPlate was evaluated with aggregometry, fluorescence microscopy, microfluidics, and thrombin and fibrin generation assays. In vivo, SynthoPlate was evaluated for systemic safety with prothrombin and fibrin assays on plasma, and for hemostatic effects on tail-transection bleeding time in severely thrombocytopenic (TCP) mice. Results SynthoPlate did not aggregate resting platelets or spontaneously promote coagulation in plasma, but could amplify the recruitment and aggregation of active platelets at the bleeding site, and thereby site-selectively enhance fibrin generation. SynthoPlate dose-dependently reduced bleeding time in TCP mice, to levels comparable to those in normal mice. SynthoPlate has a reasonable circulation residence time, and is cleared mostly by the liver and spleen. Conclusion The results demonstrate the promise of SynthoPlate as a synthetic platelet substitute in transfusion treatment of platelet-related bleeding complications.

Double-blind study comparing the long-term efficacy of the COX-2 inhibitor nimesulide and naproxen in patients with osteoarthritis.

This double-blind one-year study compares the long-term efficacy and safety of nimesulide with naproxen in patients with osteoarthritis (OA) of the knee or hip. Patients were randomised to nimesulide 100 mg twice daily (n = 183) or naproxen 250 mg morning, 500 mg evening (n = 187). The primary efficacy variable was change in pain intensity (WOMAC A scale) at 6 months. Nimesulide tablets showed at least equivalent efficacy to naproxen tablets in reducing pain intensity at 6 and 12 months (nimesulide -22.5% at 6 and 12 months; naproxen -22.4% at 6 months, -19.9% at 12 months; non-inferiority proven). At 6 months the investigator assessed efficacy as 'good' or 'excellent' in 59.3% of nimesulide and 56.4% of naproxen-treated patients, with corresponding values for patient assessment of 57% and 52.7%. Both treatments were well tolerated, with fewer related gastrointestinal adverse events reported with nimesulide (77 cases, 47.5%) than with naproxen (96 cases, 54.5%). This study shows nimesulide to be as effective as naproxen in the long-term treatment of OA and to be associated with fewer gastrointestinal side-effects.

A hierarchical approach to the sustainable management of Controlled Ecological Life Support Systems: part 1, an ecological and engineering synthesis.

In this article we present, in an expository manner, an approach to the sustainable management of a Controlled Ecological Life Support System (CELSS) based on concepts from both engineering and ecology. Our perspective leads us to express the sustainability of CELSS in terms of constraints imposed on its subsystems. These constraints are of two types: static and operational. Static constraints capture the basic sustainability requirements of the individual subsystem components--they represent the absolute limits (bounds) on the operating range of these subsystems. Operational constraints, on the other hand, represent a response to global changes in the availability of system resources. They are imposed as the system evolves dynamically to avert shortages or surpluses in resources in various subsystems. As well as having implications on design, our perspective, termed the constraint perspective, leads naturally to a management hierarchy. The second article (this issue) in this series will explore the feasibility of this approach and demonstrate some of its consequences based on a simple CELSS model.

A hierarchical approach to the sustainable management of controlled ecological life support systems: part 2, systems realization and analysis.

The second in a series of two articles exploring the sustainable management of a controlled ecological life support system (CELSS), this article examines the feasibility of the approach outlined in Part 1 using a simple, abstract CELSS representation comprising buffers and pumps. We develop a two-level management hierarchy in which the top level imposes constraints on the operation of the lower level. The compartments can operate freely within these constraints. This freedom can be used to enhance system performance and robustness. Additionally, the higher level does not require detailed subsystem representations. Our approach to sustainable management of CELSS allows for the active distribution of system mass, taking into account component constraints and system dynamics.

System issues for Controlled Ecological Life Support Systems.

There are several characteristics of a Controlled Ecological Life Support System that are distinct from commonly engineered systems. These are: 1) the uncertainty, due to limited data availability, and variability due to the heterogeneity of biological subsystems; 2) the closed, ecological nature of the system; and 3) the primary criterion of maximizing the probability of survival. Consequences of these features include: complex dynamics characterized by time scales ranging from milliseconds to months, posing difficult problems with respect to mathematical modeling and predictability; and the necessity for a unique controller design that can translate the high level requirement of survivability to low-level actuator tasks. Future research in the systems and control area should include an ecological perspective focusing on the unique dynamical characteristics of a Controlled Ecological Life Support System.

Double-blind, randomised, multi-centre clinical study evaluating the efficacy and tolerability of nimesulide in comparison with etodalac in patients suffering from osteoarthritis of the knee.

In a double-blind study, the efficacy and tolerability of nimesulide 200mg/day, administered orally, was compared with etodolac 600mg/day in the treatment, for 3 months, of 200 patients suffering from osteoarthritis of the knee. Although spontaneous pain showed a significant improvement during the course of the study, there was no difference in the efficacy of either compound. Similarly, there was a progressive and significant reduction in the Lequesne functional index although no statistical difference was found between nimesulide and etodolac. The physician's overall assessment of efficacy was significantly in favour of nimesulide but the same assessment for patients who completed all 12 weeks showed no such bias. Adverse events (AEs) were generally mild or moderate and were commonly gastrointestinal in origin. There was no difference in the rate of incidence of AEs and, with the exception of week 8 where etodolac was apparently better tolerated, there were no statistical differences in tolerability between the two therapies.