Abstract

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Peptidomimetic RGD (Arg-Gly-Asp) analogs, which bind to glycoprotein (GP) IIb/IIIa on the surface of activated platelets, have been shown to inhibit platelet aggregation. Consequently, such RGD analogs can be used for the treatment of unstable angina pectoris and myocardial infarction. However, the low oral bioavailability for this class of compounds has been hindering their clinical development. Although many factors affect the oral activity of a drug, the limited membrane permeability of RGD analogs due to charge and high polarity is thought to be a major factor leading to the low oral activity of such compounds. Another factor is the metabolic lability of some such RGD analogs in the presence of proteases and peptidases. During the last 5 years, major progress has been made in the development of orally active RGD analogs. To improve the metabolic stability of RGD analogs, N-alkylation and C-terminal modification methods have been used successfully. To improve the membrane permeability of RGD analogs, two major strategies have been used. The first one is the strategy of prodrug. Along this line, simple ester prodrugs, double prodrugs, triple prodrugs, and cyclic prodrugs have been prepared with improved membrane permeability and oral activity. The second approach used is the de novo design of centrally constrained RGD analogs with improved oral bioavailability while maintaining the desired potency against GP IIb/IIIa. The lessons learned from the modification of RGD analogs could also help the future design of other peptidomimetic drugs with improved oral bioavailability.

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In this paper, we address the problem of quantifying the impact of backoff misbehaving nodes in IEEE 802.11 networks. We propose two performance metrics, throughput gain ratio and throughput degradation ratio to quantify the performance gain of misbehaving nodes over legitimate nodes and the performance loss of legitimate nodes due to backoff misbehavior, respectively. We use asymptotic analysis to derive both throughput gain ratio and throughput degradation ratio in an IEEE 802.11 network in the presence of multiple misbehaving nodes. We show that, in general, the throughput gain ratio increases linearly with the number of legitimate nodes, and the throughput degradation ratio increases linearly with the number of misbehaving nodes. Finally, we use ns-2 simulations to validate our analytical results.

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