Drug Development Articles

as a Prodrug Using Heparin/Protamine-Based Drug Delivery System

Jun F. Liang, Yong T. Li, Maureen E. Connell, Victor C. Yang
AAPS PharmSci . 2000 ; 2 (1 ):
Keywords: Drug Delivery
Abstract : Positively charged peptides [(Arg)7Cys] were successfully linked to tissue-specific plasminogen activator (tPA) using cross-linking agent N-succinimidyl 3-(2-pyridyldithio) propionate. Specific amidolytic activity of this tPA/(Arg)7Cys (termed modified tPA, mtPA) was 3900 IU/µg as compared to 5800 IU/µg of the parent tPA. Both activation of plasminogen with mtPA (Km = 2.7 mM-1) and tPA (Km = 1.1 mM-1) in a purified system followed Michaelis-Menten kinetics. In addition, (Arg)7Cys modification did not result in significant changes in the fibrin-binding ability of tPA, and mtPA still retained a response to fibrinogen similar to that of the parent tPA.

Abstract In the search for a radioligand capable of imaging cannabinoid CB1 receptors in the living human brain by SPECT (single photon emission computed tomography), N-(morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM281) was synthesized. This compound is an analog of the potent, CB1 receptor selective antagonist SR141716A [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide]. AM281 bound to brain and spleen membrane preparations (CB1 and CB2 receptors, respectively) with Ki values of 12 nM and 4200 nM, respectively. AM281 also inhibited the response of guinea-pig small intestine preparation to a cannabinoid receptor agonist. Thus, AM281 behaves as a CB1 receptor selective antagonist. Methods for the rapid, high-yield synthesis and purification of [123I]AM281 were developed, and transaxially reconstructed brain SPECT images obtained after continuous infusion of [123I]AM281 in baboons.

Developing and Using Analytical Methods to Achieve Quality by Design and Efficiency in Drug Development Analytical method development is a critical part of the drug development process. Analytical methods are used to check the quality of materials that will be used in clinical trials. As drug development progresses toward registration, these and other methods are used to generate information that will enable quality to be designed into the manufacturing processes of drug substances and formulated drug products. This practice can lead to a detailed understanding of production processes and the development of control mechanisms that will ensure product quality.


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