Advanced drug delivery reviews
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The existence of pathogenic mutations in beta-APP and the presenilin genes provides strong support for the hypothesis that Abeta production and deposition contribute to the etiology of Alzheimer's disease (AD). The heterogeneous carboxyl termini of Abeta molecules deposited in the hippocampus, cortex and cerebrovasculature of AD patients are generated by gamma-secretase. The gamma-secretase that generates the termini in vivo is a complex of proteins containing presenilin as an integral component. ⋯ The use of potent inhibitors has aided the discovery and characterization of gamma-secretase functions and reinforced the concept that a successful drug must demonstrate selectivity for lowering Abeta without disrupting the function of gamma-secretase targets. The discovery of drugs that can selectively inhibit beta-APP cleavage is an important objective. This review focuses on studies that enhance our understanding of the effects of inhibiting gamma-secretase and provide direction for developing effective and selective gamma-secretase inhibitors as drugs to treat AD.
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Adv. Drug Deliv. Rev. · Dec 2002
ReviewBeta-secretase (BACE) as a drug target for Alzheimer's disease.
Evidence suggests that the beta-amyloid peptide (Abeta) is central to the pathophysiology of Alzheimer's Disease (AD). Amyloid plaques, primarily composed of Abeta, progressively develop in the brains of AD patients, and mutations in three genes (APP, PS1, and PS2) cause early on-set familial AD (FAD) by increasing synthesis of the toxic Abeta42 peptide. Given the strong association between Abeta and AD, therapeutic strategies to lower the concentration of Abeta in the brain should prove beneficial for the treatment of AD. ⋯ BACE1 exhibits all the properties of the beta-secretase, and as the key enzyme that initiates the formation of Abeta, BACE1 is an attractive drug target for AD. This review discusses the identification and initial characterization of BACE1 and BACE2, and summarizes our current understanding of BACE1 post-translational processing and intracellular trafficking. Finally, recent studies of BACE1 knockout mice, the BACE1 X-ray structure, and implications for BACE1 drug development will be discussed.
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Adv. Drug Deliv. Rev. · Dec 2002
ReviewAn overview of the pathogenesis of cystic fibrosis lung disease.
The pathogenesis of cystic fibrosis (CF) lung disease is reviewed, focusing on an overview of the physiologic mechanisms that regulate mucus transport. A major emphasis is placed on the active transport systems that regulate the airway surface liquid (ASL) volume and, particularly, regulate the volume of the periciliary liquid (PCL) layer. ⋯ PCL depletion leads to failure of mucus transport, which is associated with persistent mucin secretion and formation of adherent mucus plaques and plugs. These plugs become the nidus for persistent bacterial airway infections that ultimately lead to a markedly anaerobic luminal environment.
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Adv. Drug Deliv. Rev. · Dec 2002
Review Historical ArticleThe cystic fibrosis therapeutics development network (CF TDN): a paradigm of a clinical trials network for genetic and orphan diseases.
Clinical trials have become critical to the advancement of medical science and to the evolution of patient care in medicine. The science of clinical research has advanced from early studies in which treatment was assessed without controls to sophisticated multinational collaborative randomized, double-blind, placebo controlled trials of therapeutic interventions. To facilitate the advancement of clinical research, clinical trials networks have been developed to conduct multicenter studies. ⋯ In the current environment, clinical research faces significant challenges related to ensuring the safe and ethical conduct of clinical research while promoting fast and efficient clinical trials. To succeed and move forward to provide treatments and find cures for diseases, clinical trials networks must continue to evolve. The Cystic Fibrosis Therapeutics Development Network represents a network that has met this challenge and will continue to provide a venue for the safe and efficient conduct of clinical trials in Cystic Fibrosis.