Differences in Fatty Acid Oxidation between Nab-Paclitaxel- and Solvent-Based Paclitaxel-Treated A549 Cells Based on Metabolomics.

The pharmacokinetics, safety, and anticancer efficacy profiles of nanoparticle albumin-bound (nab)-paclitaxel formulations are superior to those of solvent-based paclitaxel formulations. The aims of the present study were to study the effects of nab-paclitaxel and solvent-based paclitaxel formulations on the metabolic profiles of the model cell line (A549) and attempt to elucidate the associated metabolic pathways. A mass spectrometry-based cell metabolomics approach and viability evaluation were used to explore the potential difference. Western blotting was utilized to measure the levels of relevant proteins, and carnitine palmitoyltransferase 1 (CPT1) activities were quantified. Fold changes normalized to controls in levels of carnitine and several acylcarnitines were significantly different (p < 0.05) between A549 cells treated with nab-paclitaxel and those treated with solvent-based paclitaxel. Relative to the controls, there were also significant fold change differences in palmitic and linoleic acid levels in the cell lysates, mitochondrial CPT1 activities, and mitochondrial medium-chain acyl-CoA dehydrogenase (MCAD) protein levels in the A549 cells subjected to the nab-paclitaxel and solvent-based paclitaxel formulations. Results suggested that the two formulations differentially modulated fatty acid oxidation in the A549 cells. While cell viability results did not reveal significant differences, the findings implied that a mass spectrometry-based cell metabolomics approach could be a sensitive tool to explore the differences caused by formulation changes without using animals. Since uncertainties of products containing nanomaterials warrant holistic screening to address safety concerns, the aforementioned approach may be of regulatory importance and is worth further investigation.

Cell metabolomics analyses revealed a role of altered fatty acid oxidation in neurotoxicity pattern difference between nab-paclitaxel and solvent-based paclitaxel.

Peripheral neuropathy (PN) is a dose-limiting, painful adverse reaction associated with the use of paclitaxel. This common side effect was often partially attributed to the solvent used for solubilization of the highly hydrophobic drug substance. Therefore, the development of alternative formulations thrived, which included that of Abraxane® containing nanoparticle albumin-bound paclitaxel (nab-paclitaxel). However, studies demonstrated inconsistent conclusions regarding the mitigation of PN in comparison with the traditional formulation. The mass spectrometry-based cell metabolomics approach was used in the present study to explore the potentially associated mechanisms. Although no significant difference in the effects on cell viability was observed, fold changes in carnitine, several acylcarnitines and long-chain fatty acid(s) were significantly different between treatment groups in differentiated and undifferentiated SH-SY5Y cells. The most prominent difference observed was the significant increase of octanoylcarnitine in cells treated with solvent-based paclitaxel, which was found to be associated with significant decrease of medium-chain acyl-CoA dehydrogenase (MCAD). The findings suggested the potential role of altered fatty acid oxidation in the different neurotoxicity patterns observed, which may be a possible target for therapeutic interventions worth further investigation.

The impact of the rare disease and Orphan Drug Act in Taiwan.

The Rare Disease and Orphan Drug Act (the Act) was enacted in 2000 in Taiwan for the facilitation of the research, development, and accessibility of orphan drugs and special nutritional foods; for the prevention and early diagnosis of rare diseases; and for providing intensive care for patients with rare diseases. The aim was to investigate the impact of the Act on the availability and use of orphan drugs in Taiwan in the hope of identifying the remaining challenges and possible solutions to assist future policy making, which may be applicable in other countries as well. The information and statistics for rare diseases and orphan drugs retrieved from the official annual reports and documents were analyzed. There were 225 diseases recognized as rare diseases, and one-third (75/225) of them were congenital metabolic disorders. Among the 110 designated orphan drugs that could apply for listing in the National Health Insurance (NHI) Pharmaceutical Benefits and Reimbursement Scheme, approximately half (62/110) of them were granted marketing authorization. While the NHI program compulsory for all citizens increased patient accessibility to orphan drugs, the rapidly increasing economic burden became an urgent issue for the government. Emerging gene therapies may be the solution to unmet medical needs and also a financial obstacle to tackle. The Act increased the availability of orphan drugs while the NHI system facilitated patient access, which benefited many patients with rare diseases in Taiwan. However, the soaring economic burden was noticed and was anticipated to aggravate. More communication and cooperation between stakeholders is critical in finding solutions for the long-term sustainability of the NHI system.