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      Probucol will become a new model for treating cerebral infarction with a high risk of hemorrhage: A narrative review

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          Abstract

          Lipid-lowering agents are relevant in stroke prevention. Probucol (PU) is an antioxidative and lipid-lowering drug that has been used to treat atherosclerotic cardiovascular diseases and xanthomas. The drug penetrates the core of low-density lipoprotein cholesterol (LDL-C) particles, enhancing the activity of plasma cholesterol l ester transfer protein (CETP) and strengthening the liver scavenger receptor type I, resulting in reducing LDL-C; by increasing the activity of paraoxonase 1, upregulating the antioxidant function of high-density lipoprotein (HDL), and it decreases the serum HDL-cholesterol (HDL-C) level. This drug has been retired from the Western markets for lowering HDL-C levels and Q-interval prolongation. The latter side effect has been rarely reported and may be transient. Recent clinical evidence supports the effectiveness of PU in preventing cardiovascular events and in reducing mortality, irrespective of the reduction of HDL-C. Based on basic research and clinical studies, it appears that PU might be a valuable alternative when statins are ineffective or contraindicated, in patients at high risk of recurrence of cerebral ischemia and hemorrhage.

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          Where are we with probucol: a new life for an old drug?

          Probucol has a long history of clinical application with established efficacy and safety profiles. Probucol is a potent anti-oxidant drug that has been in clinical use during the past few decades for the treatment and prevention of cardiovascular diseases. Here we review the current status of knowledge on the pharmacology, clinical benefits, and the mechanism of actions of this unique drug. Probucol has diverse pharmacological properties with therapeutic effects on the cardiovascular systems. Its mechanism of pharmacologic actions at the molecular level has recently been elucidated with the new concept of HDL metabolism associated with cholesteryl ester transfer protein (CETP) or scavenger receptor class B type I (SR-BI). HDL-C reduction may not be a "side effect" but it most likely might reflect a mechanism of action of probucol. Probucol could be reconsidered as an option at least in case statins, which are known to be effective in lowering low-density lipoproteins (LDL) and coronary artery disease (CAD) risk, are not effective. In particular, a marked CAD risk reduction has been recently reported in long-term probucol treatment of patients with heterozygous familial hypercholesterolemia (FH) in Japan. Therefore, probucol could be a more common therapeutic drug for the treatment of patients with FH as well. There is more than enough reason to believe that this old drug has much more to offer than hitherto known.
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            Prevention of cardiovascular events in Asian patients with ischaemic stroke at high risk of cerebral haemorrhage (PICASSO): a multicentre, randomised controlled trial

            The optimal treatment for patients with ischaemic stroke with a high risk of cerebral haemorrhage is unclear. We assessed the efficacy and safety of cilostazol versus aspirin, with and without probucol, in these patients.
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              Lipid-Lowering Therapy and Hemorrhagic Stroke Risk: Comparative Meta-Analysis of Statins and PCSK9 Inhibitors

              Background and Purpose: Statins were shown to increase hemorrhagic stroke (HS) in patients with a first cerebrovascular event in 2006 (SPARCL), likely due to off-target antithrombotic effects, but continued to sometimes be used in patients with elevated HS risk due to absence of alternative medications. Recently, the PCSK9Is (proprotein convertase subtilisin kexin 9 inhibitors) have become available as a potent lipid-lowering class with potentially less hemorrhagic propensity. Methods: We performed a systematic comparative meta-analysis assessing HS rates across all completed statin and PCSK9I randomized clinical trials with treatment >3 months, following PRISMA guidelines. In addition to HS rates across all trials, causal relation was probed by evaluating for dose-response relationships by medication (low versus high medication dose/potency) and by presence and type of preceding brain vascular events at inception (none versus ischemic stroke/transient ischemic attack versus HS). Results: The systematic review identified 36 statin randomized clinical trials (204 918 patients) and 5 PCSK9I randomized clinical trials (76 140 patients). Across all patient types and all medication doses/potencies, statins were associated with increased HS: relative risk 1.15, P =0.04; PCSK9Is were not ( P =0.77). In the medication dose/potency analysis, higher dose/potency statins (7 trials, 62 204 patients) were associated with magnified HS risk: relative risk, 1.53; P =0.002; higher dose/potency PCSK9Is (1 trial, 27 564 patients) were not ( P =0.99). In the type of index brain vascular injury analysis for statins (5 trials, 9772 patients), prior ischemic stroke/transient ischemic attack was associated with a magnified risk of HS: relative risk, 1.43; P =0.04; and index intracerebral hemorrhage was associated with an extremely high effect estimate of risk of recurrent HS: hazard ratio, 4.06. For PCSK9Is, prior ischemic stroke/transient ischemic attack (1 trial, 5337 patients) was not associated with increased HS risk ( P =0.97). Conclusions: Statins increase the risk of HS in a medication dose- and type of index brain vascular injury-dependent manner; PCSK9Is do not increase HS risk. PCSK9Is may be a preferred lipid-lowering medication class in patients with elevated HS risk, including patients with prior HS.
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                Author and article information

                Journal
                Brain Circ
                Brain Circ
                BC
                Brain Circ
                Brain Circulation
                Wolters Kluwer - Medknow (India )
                2394-8108
                2455-4626
                Oct-Dec 2023
                30 November 2023
                : 9
                : 4
                : 222-227
                Affiliations
                [1 ] Department of Neurology, The Affiliated Hospital of Qingdao Binhai University, Qingdao, China
                [2 ] Department of Cardiology, The People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China
                [3 ] Department of Oncology Radiotherapy, The People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China
                Author notes
                Address for correspondence: Dr. Huanmin Gao, Department of Neurology, The Affiliated Hospital of Qingdao Binhai University, 689 Haiya Road, Qingdao 266404, China. E-mail: gaohuanmin@ 123456126.com
                Article
                BC-9-222
                10.4103/bc.bc_44_23
                10821687
                38284116
                373f53e7-b358-4ed7-afb3-c2999a31d2f5
                Copyright: © 2023 Brain Circulation

                This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

                History
                : 26 May 2023
                : 07 September 2023
                : 13 September 2023
                Categories
                Review Article

                bioavailability,cardiovascular,hemorrhage,probucol,risk,secondary prevention

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