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The current FDA\u2010approved disease\u2010modifying therapeutics (DMTs) cannot cure the disease, but only alleviate the disease progression. While the majority of patients respond well to treatment, some of them are suffering from rapid progression. Current drug delivery strategies include the oral, intravenous, subdermal, and intramuscular routes, so these drugs are delivered systemically, which is appropriate when the therapeutic targets are peripheral. However, the potential benefits may be diminished when these targets sequester behind the barriers of the central nervous system. Moreover, systemic drug administration is plagued with adverse effects, sometimes severe. In this context, it is prudent to consider other drug delivery strategies improving their accumulation in the brain, thus providing better prospects for patients with rapidly progressing disease course. These targeted drug delivery strategies may also reduce the severity of systemic adverse effects. Here, we discuss the possibilities and indications for reconsideration of drug delivery routes (especially for those \u201cnon\u2010responding\u201d patients) and the search for alternative drug delivery strategies. More targeted drug delivery strategies sometimes require quite invasive procedures, but the potential therapeutic benefits and reduction of adverse effects could outweigh the risks. We characterized the major FDA\u2010approved DMTs focusing on their therapeutic mechanism and the potential benefits of improving the accumulation of these drugs in the brain.<\/jats:p>","DOI":"10.1002\/med.21973","type":"journal-article","created":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T06:21:30Z","timestamp":1684477290000},"page":"2237-2259","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Reconsidering the route of drug delivery in refractory multiple sclerosis: Toward a more effective drug accumulation in the central nervous system"],"prefix":"10.1002","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2445-9030","authenticated-orcid":false,"given":"Lukasz","family":"Kalkowski","sequence":"first","affiliation":[{"name":"Department of Diagnostic Radiology and Nuclear Medicine, Center for Advanced Imaging Research University of Maryland School of Medicine Baltimore Maryland 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