The Management of Parkinson's Disease: An Overview of the Current Advancements in Drug Delivery Systems.

Parkinson's disease (PD) has significantly affected a large proportion of the elderly population worldwide. According to the World Health Organization, approximately 8.5 million people worldwide are living with PD. In the United States, an estimated one million people are living with PD, with approximately 60,000 new cases diagnosed every year. Conventional therapies available for Parkinson's disease are associated with limitations such as the wearing-off effect, on-off period, episodes of motor freezing, and dyskinesia. In this review, a comprehensive overview of the latest advances in DDSs used to reduce the limitations of current therapies will be presented, and both their promising features and drawbacks will be discussed. We are also particularly interested in the technical properties, mechanism, and release patterns of incorporated drugs, as well as nanoscale delivery strategies to overcome the blood-brain barrier.

Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that serves as an important regulator of a broad range of cellular functions. It has been linked to Alzheimer's disease as well as various other diseases, including mood disorders, type 2 diabetes, and cancer. There is considerable evidence indicating that GSK-3ß in the central nervous system plays a role in the production of abnormal, hyperphosphorylated, microtubule-associated tau protein found in neurofibrillary tangles associated with Alzheimer's disease. A series of analogues containing a pyrimidine-based hinge-binding heterocycle was synthesized and evaluated, leading to the identification of highly potent GSK-3 inhibitors with excellent kinase selectivity. Further evaluation of 34 and 40 in vivo demonstrated that these compounds are orally bioavailable, brain-penetrant GSK-3 inhibitors that lowered levels of phosphorylated tau in a triple-transgenic mouse Alzheimer's disease model.

Design, Structure-Activity Relationships, and In Vivo Evaluation of Potent and Brain-Penetrant Imidazo[1,2-b]pyridazines as Glycogen Synthase Kinase-3ß (GSK-3ß) Inhibitors.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates numerous cellular processes, including metabolism, proliferation, and cell survival. Due to its multifaceted role, GSK-3 has been implicated in a variety of diseases, including Alzheimer's disease, type 2 diabetes, cancer, and mood disorders. GSK-3ß has been linked to the formation of the neurofibrillary tangles associated with Alzheimer's disease that arise from the hyperphosphorylation of tau protein. The design and synthesis of a series of imidazo[1,2-b]pyridazine derivatives that were evaluated as GSK-3ß inhibitors are described herein. Structure-activity relationship studies led to the identification of potent GSK-3ß inhibitors. In vivo studies with 47 in a triple-transgenic mouse Alzheimer's disease model showed that this compound is a brain-penetrant, orally bioavailable GSK-3ß inhibitor that significantly lowered levels of phosphorylated tau.

Fundamental Aspects of Lipid-Based Excipients in Lipid-Based Product Development.

Poor aqueous solubility of drugs is still a foremost challenge in pharmaceutical product development. The use of lipids in designing formulations provides an opportunity to enhance the aqueous solubility and consequently bioavailability of drugs. Pre-dissolution of drugs in lipids, surfactants, or mixtures of lipid excipients and surfactants eliminate the dissolution/dissolving step, which is likely to be the rate-limiting factor for oral absorption of poorly water-soluble drugs. In this review, we exhaustively summarize the lipids excipients in relation to their classification, absorption mechanisms, and lipid-based product development. Methodologies utilized for the preparation of solid and semi-solid lipid formulations, applications, phase behaviour, and regulatory perspective of lipid excipients are discussed.