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Probucol
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<h2 id="medical-uses">Medical uses</h2> <p>In Japan, it is approved for "hyperlipidemia (including <a href="/facts/Familial_hypercholesterolemia/HSB8U9XQ">familial hypercholesterolemia</a> and <a href="/facts/Xanthoma/kkdJksvS">xanthomas</a>)".<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a><a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> In China, it is approved for hypercholesterolemia.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p> <h2 id="adverse-effects">Adverse effects</h2> <p>During both clinical trials and postmarketing surveillance, most adverse effects were limited to the digestive system and the skin. Those included diarrhea, abdominal pain, nausea, loss of appetite, rash, and itching. For each of these effect, the incidence was between 0.1% and 1% ("uncommon"). QT prolongation was noted as rare (< 0.1%) in the package inserts. Elevated liver enzymes (ALT, AST, ALP, LDH), elevated BUN, reduction in red blood cells, white blood cells, and/or platelet count, elevated <a href="/facts/Creatine_kinase/kYtNQKjy">creatine kinase</a> are also possible.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a><a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> The Chinese package insert states that ALT, AST, bilirubin, uric acid, and BUN elevations are transient.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p><p>Possible serious adverse effects include ventricular arrhythmia (<a href="/facts/Torsades_de_pointes/dsdr4HPF">Torsades de pointes</a>), syncope, gastrointestinal bleeding, peripheral neuritis, and rhabdomyolysis. The frequency of these are unknown.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a><a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p> <h2 id="drug-interactions">Drug interactions</h2> <p>May reduce the blood concentration of <a href="/facts/Cyclosporin/tcIToHvK">cyclosporin</a> (unknown mechanism). There exist reports of significantly declined HDL-C with <a href="/facts/Clofibrate/5tyjpuQY">clofibrate</a> (unknown mechanism).<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> </p><p>Risk of arrhythmia is elevated when used with other drugs that can cause arrhythmia, especially <a href="/facts/Tricyclic_antidepressants/vpBLER2Q">tricyclic antidepressants</a> and <a href="/facts/Phenothiazines/SXgRQEeb">phenothiazines</a>.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> Potentiates the effect of diabetic medications and coumarin anticoagulants.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> </p> <h2 id="mechanism-of-action">Mechanism of action</h2> <p>Probucol lowers the level of <a href="/facts/Cholesterol/TnfPlYc1">cholesterol</a> in the bloodstream by increasing the rate of <a href="/facts/Low-density_lipoprotein/R5VLPxAg">LDL</a> <a href="/facts/Catabolism/CFWUdphX">catabolism</a>. Specifically, this happens by changing the structure of LDL, among other effects. The <a href="/facts/LDL_receptor/zsSjTYyb">LDL receptor</a> is not involved: it works in rabbits and humans without a working LDL receptor (homozygous <a href="/facts/Familial_hypercholesterolemia/HSB8U9XQ">familial hypercholesterolemia</a>).<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> It also enhances the excretion of cholesterol into bile. It is able to lower LDL-C by 10-20%.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> </p><p>It is also a powerful <a href="/facts/Antioxidant/4TG4MQ83">antioxidant</a>. At a low dose (insufficient to affect LDL-C or HDL-C levels), it prevents the oxidation of cholestrol in LDLs.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> This might slow the formation of <a href="/facts/Foam_cell/lALAEhU8">foam cells</a>, which form <a href="/facts/Atherosclerosis/WIS8QQ6v">atherosclerotic</a> <a href="/facts/Atheroma/cMw1I9rt">plaques</a>. It partially does this by increasing <a href="/facts/PON1/GfYFoYsm">PON1</a> activity, thus increasing the antioxidant properties of HDL.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> </p><p>Probucol also lowers HDL-C (HDL cholesterol, i.e. the amount of cholesterol found in HDLs) by about 30%. This has historically caused its discontinuation from several Western countries.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> This has several causes: </p> <ol><li>It inhibits <a href="/facts/ABCA1/zGuswmrA">ABCA1</a>-dependent cholesterol transport (but not <a href="/facts/SCARB1/6Vn92R8q">SR-BI</a>–mediated efflux), which moves cholesterol from cells such as macrophages into HDL.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a></li> <li>It increases <a href="/facts/CETP/bGadPuxw">CETP</a> activity by lowering the amount of <a href="/facts/ANGPTL3/xLtuwCGQ">ANGPTL3</a>. This also causes an increase in preβ1-HDL (lipid-poor particles) and a decrease in HDL phospholipids.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a><a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a></li> <li>It increases HDL absorption by the liver via <a href="/facts/SCARB1/6Vn92R8q">SR-BI</a>.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a></li></ol> <p>Recall that one of the functions of HDL is <a href="/facts/Reverse_cholesterol_transport/vQcyHXe7">reverse cholesterol transport</a> (moving cholesterol from peripheral tissues into the liver). Inhibition of ABCA1 would be detrimental to the process, whereas enhancing CETP and SR-BI activities is beneficial for the transport function. Overall, probucol increases the capacity for reverse cholesterol transport, so the observed HDL-C reduction does not lead to a decrease in a patient's cholesterol-removing ability.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> </p><p>The adverse effect of QT prolongation is possibly due to inhibition of <a href="/facts/HERG/26yUany0">hERG</a> trafficking.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> </p> <h2 id="pharmacokinetics">Pharmacokinetics</h2> <p>Oral absorption is limited and erratic. Food increases absorption. With a single oral dose of 250 mg, tmax is at 18 hours post-ingestion.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> If taken daily, 3 to 4 months are required to reach steady-state concentrations.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> </p><p>The tissue distribution of probucol has been studied in rats, dogs, and monkeys using a 14C-labelled version of the drug. In rats, a single 100 mg/kg dose results in liver, adrenal glands, and brown fat concentrations at 3–10× plasma concentration and central nervous system, gonad, and eye concentrations at 1/7–1/20× plasma concentration. In rats, 21 days of continuous 100 mg/kg/d feeding results in accumulation in brown fat, adrenal glands, liver, and adipose tissue at 10–46× plasma concentration and central nervous system, gonad, and eye concentrations at 1–1/2× plasma concentration.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> </p> <h2 id="research">Research</h2> <p>Probucol has been found to have antioxidant and anti-inflammatory properties via several different mechanisms.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> These properties have led to research into the drug's potential capacity to treat <a href="/facts/Sensorineural_hearing_loss/wa81Kykf">sensorineural hearing loss</a> related to oxidative stress,<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a><a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> as well as formulations to improve the delivery of the drug into the ear.<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a> </p><p>After promising test results in mouse models, probucol is under study at Weston Brain Institute of McGill University as a possible aid in delaying the onset of <a href="/facts/Alzheimer%27s_disease/w7Ad6tdg">Alzheimer's disease</a>. The protocol for a future Australian Phase II study was published in 2022.<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a> </p><p>Novel packaging methods have been tried to optimize the pharmacokinetic properties of probucol – the goal is usually to produce a more stable absorption profile and to reduce absorption by <a href="/facts/Cardiac_muscle/oMqU4Sdu">cardiac muscle</a> cells. Some show promise in lab animals, but have not yet been tested in humans.<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> </p> <h3>Analogues</h3> <p>A number of probucol analogues have been tested in animal models by researchers seeking to optimize aspects of probucol's action while reducing its side effects. Succinobucol, the succinate ester of probucol, failed to demonstrate a useful degree of efficacy in clinical trials targeting acute coronary syndrome. BO-653, another analogue, failed its phase II trial targeting atherosclerosis treatment and prevention of post-angioplasty restenosis.<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> </p> <h2 id="society-and-culture">Society and culture</h2> <p>In Japan, Probucol was available under both the Lorelco brand name, the Sinlestal brand name, and the generic "TOWA" brand. In January 2021, Towa Pharmaceutical Co., Ltd. announced that it would discontinue the sale of Probucol Tablets 250 mg "TOWA" due to various circumstances.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a> </p> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Yamamoto A (11 December 2008). "A Unique Antilipidemic Drug - Probucol". Journal of Atherosclerosis and Thrombosis. 15 (6): 304–5. doi:10.5551/jat.E621. PMID 19075491. Retrieved 2020-01-29. <a href="http://www.jstage.jst.go.jp/article/jat/15/6/15_E621/_article" target="_blank">http://www.jstage.jst.go.jp/article/jat/15/6/15_E621/_article</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Yamashita S, Masuda D, Matsuzawa Y (August 2015). "Did we abandon probucol too soon?". Current Opinion in Lipidology. 26 (4): 304–16. doi:10.1097/MOL.0000000000000199. PMID 26125504. Probucol has been used as a lipid-lowering drug for a long time especially in Japan, although Western countries quitted its use because of the reduction in serum HDL-cholesterol (HDL-C). <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Yamashita S, Matsuzawa Y (November 2009). "Where are we with probucol: a new life for an old drug?". Atherosclerosis. 207 (1): 16–23. doi:10.1016/j.atherosclerosis.2009.04.002. PMID 19457483. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Yamashita S, Matsuzawa Y (November 2009). "Where are we with probucol: a new life for an old drug?". Atherosclerosis. 207 (1): 16–23. doi:10.1016/j.atherosclerosis.2009.04.002. PMID 19457483. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Mamoshina P, Rodriguez B, Bueno-Orovio A (March 2021). "Toward a broader view of mechanisms of drug cardiotoxicity". Cell Reports. 2 (3): 100216. doi:10.1016/j.xcrm.2021.100216. PMC 7974548. PMID 33763655. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974548" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974548</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Yamashita S, Masuda D, Matsuzawa Y (February 2021). "New Horizons for Probucol, an Old, Mysterious Drug". Journal of Atherosclerosis and Thrombosis. 28 (2): 100–102. doi:10.5551/jat.ED132. PMC 7957029. PMID 32507832. Probucol was developed as an anti-oxidative compound to prevent the degradation of tire rubber and later applied to reduce serum LDL-C levels in patients with hypercholesterolemia. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957029" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957029</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>"ロレルコ錠250mg/ロレルコ細粒50% 添付文書 第15版" [Package Insert for Lorelco Tablets 250mg/Lorelco Fine Granules 50% Version 15] (in Japanese). Archived from the original on 2018-09-04. Retrieved 2018-09-04. <a href="https://web.archive.org/web/20180904084613/https://www.info.pmda.go.jp/go/pack/2189008F1287_1_01/" target="_blank">https://web.archive.org/web/20180904084613/https://www.info.pmda.go.jp/go/pack/2189008F1287_1_01/</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>"シンレスタール錠250mg/シンレスタール細粒50% 添付文書" [Package Insert for Sinlestal Tablets 250mg/Sinlestal Fine Granules 50%] (in Japanese). November 2011. Archived from the original on 2018-09-04. Retrieved 29 March 2015. <a href="https://web.archive.org/web/20180904052403/http://www.info.pmda.go.jp/go/pack/2189008C1094_3_02" target="_blank">https://web.archive.org/web/20180904052403/http://www.info.pmda.go.jp/go/pack/2189008C1094_3_02</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>"普罗布考片" [Probucol Tablet (Package Insert text on Manufacturer Website)]. cdjfk.com.cn (in Chinese). <a href="https://www.cdjfk.com.cn/product/special-detail.jsp?id=125" target="_blank">https://www.cdjfk.com.cn/product/special-detail.jsp?id=125</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>"ロレルコ錠250mg/ロレルコ細粒50% 添付文書 第15版" [Package Insert for Lorelco Tablets 250mg/Lorelco Fine Granules 50% Version 15] (in Japanese). Archived from the original on 2018-09-04. Retrieved 2018-09-04. <a href="https://web.archive.org/web/20180904084613/https://www.info.pmda.go.jp/go/pack/2189008F1287_1_01/" target="_blank">https://web.archive.org/web/20180904084613/https://www.info.pmda.go.jp/go/pack/2189008F1287_1_01/</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>"シンレスタール錠250mg/シンレスタール細粒50% 添付文書" [Package Insert for Sinlestal Tablets 250mg/Sinlestal Fine Granules 50%] (in Japanese). November 2011. Archived from the original on 2018-09-04. Retrieved 29 March 2015. <a href="https://web.archive.org/web/20180904052403/http://www.info.pmda.go.jp/go/pack/2189008C1094_3_02" target="_blank">https://web.archive.org/web/20180904052403/http://www.info.pmda.go.jp/go/pack/2189008C1094_3_02</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>"普罗布考片" [Probucol Tablet (Package Insert text on Manufacturer Website)]. cdjfk.com.cn (in Chinese). <a href="https://www.cdjfk.com.cn/product/special-detail.jsp?id=125" target="_blank">https://www.cdjfk.com.cn/product/special-detail.jsp?id=125</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>"ロレルコ錠250mg/ロレルコ細粒50% 添付文書 第15版" [Package Insert for Lorelco Tablets 250mg/Lorelco Fine Granules 50% Version 15] (in Japanese). Archived from the original on 2018-09-04. Retrieved 2018-09-04. <a href="https://web.archive.org/web/20180904084613/https://www.info.pmda.go.jp/go/pack/2189008F1287_1_01/" target="_blank">https://web.archive.org/web/20180904084613/https://www.info.pmda.go.jp/go/pack/2189008F1287_1_01/</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>"シンレスタール錠250mg/シンレスタール細粒50% 添付文書" [Package Insert for Sinlestal Tablets 250mg/Sinlestal Fine Granules 50%] (in Japanese). November 2011. Archived from the original on 2018-09-04. Retrieved 29 March 2015. <a href="https://web.archive.org/web/20180904052403/http://www.info.pmda.go.jp/go/pack/2189008C1094_3_02" target="_blank">https://web.archive.org/web/20180904052403/http://www.info.pmda.go.jp/go/pack/2189008C1094_3_02</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>"ロレルコ錠250mg/ロレルコ細粒50% 添付文書 第15版" [Package Insert for Lorelco Tablets 250mg/Lorelco Fine Granules 50% Version 15] (in Japanese). Archived from the original on 2018-09-04. Retrieved 2018-09-04. <a href="https://web.archive.org/web/20180904084613/https://www.info.pmda.go.jp/go/pack/2189008F1287_1_01/" target="_blank">https://web.archive.org/web/20180904084613/https://www.info.pmda.go.jp/go/pack/2189008F1287_1_01/</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>"普罗布考片" [Probucol Tablet (Package Insert text on Manufacturer Website)]. cdjfk.com.cn (in Chinese). <a href="https://www.cdjfk.com.cn/product/special-detail.jsp?id=125" target="_blank">https://www.cdjfk.com.cn/product/special-detail.jsp?id=125</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>"普罗布考片" [Probucol Tablet (Package Insert text on Manufacturer Website)]. cdjfk.com.cn (in Chinese). <a href="https://www.cdjfk.com.cn/product/special-detail.jsp?id=125" target="_blank">https://www.cdjfk.com.cn/product/special-detail.jsp?id=125</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> <li id="fn:18"><p>Yamashita S, Masuda D, Matsuzawa Y (August 2015). "Did we abandon probucol too soon?". Current Opinion in Lipidology. 26 (4): 304–16. doi:10.1097/MOL.0000000000000199. PMID 26125504. Probucol has been used as a lipid-lowering drug for a long time especially in Japan, although Western countries quitted its use because of the reduction in serum HDL-cholesterol (HDL-C). <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></p></li> <li id="fn:19"><p>Yamashita S, Masuda D, Matsuzawa Y (August 2015). "Did we abandon probucol too soon?". Current Opinion in Lipidology. 26 (4): 304–16. doi:10.1097/MOL.0000000000000199. PMID 26125504. Probucol has been used as a lipid-lowering drug for a long time especially in Japan, although Western countries quitted its use because of the reduction in serum HDL-cholesterol (HDL-C). <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:19" class="footnote-back-ref">↩</a></p></li> <li id="fn:20"><p>Yamashita S, Masuda D, Matsuzawa Y (August 2015). "Did we abandon probucol too soon?". Current Opinion in Lipidology. 26 (4): 304–16. doi:10.1097/MOL.0000000000000199. PMID 26125504. Probucol has been used as a lipid-lowering drug for a long time especially in Japan, although Western countries quitted its use because of the reduction in serum HDL-cholesterol (HDL-C). <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:20" class="footnote-back-ref">↩</a></p></li> <li id="fn:21"><p>Yamashita S, Masuda D, Matsuzawa Y (August 2015). "Did we abandon probucol too soon?". Current Opinion in Lipidology. 26 (4): 304–16. doi:10.1097/MOL.0000000000000199. PMID 26125504. Probucol has been used as a lipid-lowering drug for a long time especially in Japan, although Western countries quitted its use because of the reduction in serum HDL-cholesterol (HDL-C). <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:21" class="footnote-back-ref">↩</a></p></li> <li id="fn:22"><p>Inagaki M, Nakagawa-Toyama Y, Nishida M, Kawase R, Kawase M, Nakaoka H, et al. (22 November 2011). "Abstract 12669: Effect of Probucol on Antioxidant Properties of HDL in Patients with Heterozygous Familial Hypercholesterolemia". Circulation. 124 (suppl_21): A12669. doi:10.1161/circ.124.suppl_21.A12669 (inactive 7 February 2025).{{cite journal}}: CS1 maint: DOI inactive as of February 2025 (link) <a href="https://www.ahajournals.org/doi/10.1161/circ.124.suppl_21.A12669" target="_blank">https://www.ahajournals.org/doi/10.1161/circ.124.suppl_21.A12669</a> <a href="#fnref:22" class="footnote-back-ref">↩</a></p></li> <li id="fn:23"><p>Yamashita S, Masuda D, Matsuzawa Y (August 2015). "Did we abandon probucol too soon?". Current Opinion in Lipidology. 26 (4): 304–16. doi:10.1097/MOL.0000000000000199. PMID 26125504. Probucol has been used as a lipid-lowering drug for a long time especially in Japan, although Western countries quitted its use because of the reduction in serum HDL-cholesterol (HDL-C). <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:23" class="footnote-back-ref">↩</a></p></li> <li id="fn:24"><p>Favari E, Zanotti I, Zimetti F, Ronda N, Bernini F, Rothblat GH (28 October 2004). "Probucol inhibits ABCA1-mediated cellular lipid efflux". Arterioscler. Thromb. Vasc. Biol. 24 (12): 2345–50. doi:10.1161/01.ATV.0000148706.15947.8a. PMID 15514211. <a href="https://doi.org/10.1161%2F01.ATV.0000148706.15947.8a" target="_blank">https://doi.org/10.1161%2F01.ATV.0000148706.15947.8a</a> <a href="#fnref:24" class="footnote-back-ref">↩</a></p></li> <li id="fn:25"><p>Miida T, Seino U, Miyazaki O, Hanyu O, Hirayama S, Saito T, et al. (October 2008). "Probucol markedly reduces HDL phospholipids and elevated prebeta1-HDL without delayed conversion into alpha-migrating HDL: putative role of angiopoietin-like protein 3 in probucol-induced HDL remodeling". Atherosclerosis. 200 (2): 329–335. doi:10.1016/j.atherosclerosis.2007.12.031. PMID 18279878. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:25" class="footnote-back-ref">↩</a></p></li> <li id="fn:26"><p>Franceschini G, Sirtori M, Vaccarino V, Gianfranceschi G, Rezzonico L, Chiesa G, et al. (1989). "Mechanisms of HDL reduction after probucol. Changes in HDL subfractions and increased reverse cholesteryl ester transfer". Arteriosclerosis. 9 (4): 462–469. doi:10.1161/01.ATV.9.4.462. PMID 2751476. <a href="https://doi.org/10.1161%2F01.ATV.9.4.462" target="_blank">https://doi.org/10.1161%2F01.ATV.9.4.462</a> <a href="#fnref:26" class="footnote-back-ref">↩</a></p></li> <li id="fn:27"><p>Yamashita S, Masuda D, Matsuzawa Y (August 2015). "Did we abandon probucol too soon?". Current Opinion in Lipidology. 26 (4): 304–16. doi:10.1097/MOL.0000000000000199. PMID 26125504. Probucol has been used as a lipid-lowering drug for a long time especially in Japan, although Western countries quitted its use because of the reduction in serum HDL-cholesterol (HDL-C). <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:27" class="footnote-back-ref">↩</a></p></li> <li id="fn:28"><p>Yamashita S, Masuda D, Matsuzawa Y (August 2015). "Did we abandon probucol too soon?". Current Opinion in Lipidology. 26 (4): 304–16. doi:10.1097/MOL.0000000000000199. PMID 26125504. 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