2 research outputs found
Overview of milling techniques for improving the solubility of poorly water-soluble drugs
AbstractMilling involves the application of mechanical energy to physically break down coarse particles to finer ones and is regarded as a “top–down” approach in the production of fine particles. Fine drug particulates are especially desired in formulations designed for parenteral, respiratory and transdermal use. Most drugs after crystallization may have to be comminuted and this physical transformation is required to various extents, often to enhance processability or solubility especially for drugs with limited aqueous solubility. The mechanisms by which milling enhances drug dissolution and solubility include alterations in the size, specific surface area and shape of the drug particles as well as milling-induced amorphization and/or structural disordering of the drug crystal (mechanochemical activation). Technology advancements in milling now enable the production of drug micro- and nano-particles on a commercial scale with relative ease. This review will provide a background on milling followed by the introduction of common milling techniques employed for the micronization and nanonization of drugs. Salient information contained in the cited examples are further extracted and summarized for ease of reference by researchers keen on employing these techniques for drug solubility and bioavailability enhancement
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Pharmacological aspects of the inhibition of mammalian respiratory complex I
Mitochondrial complex I, a large respiratory enzyme located in the inner mitochondrial membrane, catalyses electron transfer from NADH to ubiquinone while concomitantly translocating protons across the membrane to sustain ATP synthesis. A crucial aspect of the pharmacology of complex I is drug-induced mitochondrial dysfunction, particularly its role in liver toxicity. Complex I inhibition causes an energy deficit and can lead to adverse changes in the status of the mitochondrial [NADH]/[NAD+] pool and increased reactive oxygen species production, causing widespread damage.
A library of molecules that are known candidates for causing complex I-driven drug- induced mitochondrial dysfunction was compiled using database and literature searches and then tested with assays on isolated mammalian complex I, mitochondrial membranes and cultured mammalian cells. The results extend the knowledge of complex I-linked drug toxicity and define a proof-of-principle methodology for the investigation of further unknown candidate molecules. Using this methodology, the Screen-Well V2 library from Enzo Life Sciences, containing 786 FDA-approved drugs, was used to investigate the role of complex I-linked drug toxicity on a wider scale. The results show that complex I is targeted by many structurally unrelated pharmacological compounds, but whether catalysis is inhibited in vivo requires drug transport into the mitochondrion, limiting the adverse physiological consequences in most cases tested.
Furthermore, three structure-activity relationship studies were carried out on specific classes of complex I inhibitors: rotenoid natural product compounds, a family of pyrazole-based compounds under investigation as anticancer drugs, and variants on the drug Mubritinib. These studies identified structural determinants of binding to complex I and improve our understanding of complex I inhibition