Advanced drug delivery reviews
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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.
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Adv. Drug Deliv. Rev. · Nov 2002
ReviewGenetic contribution to variable human CYP3A-mediated metabolism.
The human CYP3A subfamily plays a dominant role in the metabolic elimination of more drugs than any other biotransformation enzyme. CYP3A enzyme is localized in the liver and small intestine and thus contributes to first-pass and systemic metabolism. CYP3A expression varies as much as 40-fold in liver and small intestine donor tissues. ⋯ Moreover, the substrate specificity and product regioselectivity of these isoforms can differ from that of CYP3A4, such that the impact of CYP3A5 and CYP3A7 polymorphic expression on drug disposition will be drug dependent. In addition to genetic variation, other factors that may also affect CYher factors that may also affect CYP3A expression include: tissue-specific splicing (as reported for prostate CYP3A5), variable control of gene transcription by endogenous molecules (circulating hormones) and exogenous molecules (diet or environment), and genetic variations in proteins that may regulate constitutive and inducible CYP3A expression (nuclear hormone receptors). Thus, the complex regulatory pathways, environmentally susceptible milieu of the CYP3A enzymes, and as yet undetermined genetic haplotypes, may confound evaluation of the effect of individual CYP3A genetic variations on drug disposition, efficacy and safety.
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The introduction of in vivo microdialysis (MD) to clinical pharmacological studies has opened the opportunity to obtain previously inaccessible information about the drug distribution process to the clinically relevant target site. The aim of this review is to provide a comprehensive overview of the current literature about MD in drug delivery studies from a clinical perspective. In particular the application of MD in clinical--antimicrobial, oncological and transdermal--and neurological research will be described and the scope of MD in pharmacokinetic-pharmacodynamic (PK-PD) studies will be discussed. It is concluded that MD has a great potential for both academic and industrial research, and may become the method of choice for drug distribution studies in humans.