BR-112020008714-B1 - Use of serotonergic medications to treat virus-induced thrombocytopenia.

Abstract

The present invention relates to the use of serotonergic compounds for the treatment of virus-induced thrombocytopenia. More particularly, the invention relates to methods of treating thrombocytopenia by blocking serotonin activity. For example, 5HT2A receptor and/or 5HT1A receptor inhibitors and/or mast cell degranulation inhibitors and/or serotonin reuptake inhibitors may be used. Preferably, the thrombocytopenia is induced by dengue or Japanese Encephalitis virus, and the inhibitors are preferably ketanserin, WAY-100135, sarpogrelate, or fluoxetine.

Inventors

• ASHLEY LAUREN ST. JOHN
• MOHAMAD FADHLI BIN MASRI
• Abhay RATHORE

Assignees

• NATIONAL UNIVERSITY OF SINGAPORE

Dates

Publication Date

20260310

Application Date

20181031

Priority Date

20171101

Claims (3)

1. 1. Use of at least one serotonergic compound selected from the group consisting of ketanserin [3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-1H-quinazoline-2,4-dione], sarpogrelate [4-[1-(dimethylamino)-3-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]propan-2-yl]oxy-4-oxobutanoic acid], fluoxetine, and WAY 100135 [(S)-N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide] or a pharmaceutically acceptable salt or solvate thereof, characterized in that it is for the manufacture of a medicament for treating flavivirus-induced thrombocytopenia.
2. 2. Use according to claim 1, characterized in that the virus is either the dengue virus or the Japanese encephalitis virus.
3. 3. Use, according to any one of claims 1 to 2, characterized in that the medicament is formulated to be administered orally, sublingually, intravenously, or intraperitoneally.

Description

FIELD OF INVENTION [001] The present invention relates to the treatment of virus-induced thrombocytopenia. More particularly, the invention relates to methods of treating thrombocytopenia by blocking serotonin activity. For example, 5HT2A receptor inhibitors and/or 5HT1A receptor inhibitors and/or mast cell degranulation inhibitors and/or serotonin reuptake inhibitors may be used. BACKGROUND [002] Dengue is caused by infection with the dengue virus, of which there are four serotypes. There are no targeted therapies available to treat dengue infection or its characteristic symptoms, such as thrombocytopenia or hemorrhage. Current measures involve symptomatic treatment as well as vaccination. Some communities, such as Singapore, engage in vector control to prevent further spread of disease [Guzman, M.G. & Harris, E. Dengue. The Lancet 385, 453-465 (2015)], but the results of vector control have been limited. Although dengue usually resolves on its own, there is the possibility of serious complications such as dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). Patients with DHF/DSS frequently present with substantially decreased platelet counts, abdominal pain, and plasma leakage that can lead to organ damage and/or shock [St John, A.L., et al., Nature reviews. Microbiology 11, 420-426 (2013)]. Due to this possibility, patients may be admitted to hospitals for monitoring. A reduced platelet count, or thrombocytopenia, is one of the most consistent symptoms of dengue disease and this frequently occurs in patients diagnosed with both mild and severe forms of dengue infection [St John, A.L., et al., Nature reviews. Microbiology 11, 420-426 (2013); Halstead, S.B. Lancet 370, 1644-1652 (2007)]. This can predispose the patient to severe bleeding, which can be fatal. In addition to dengue, many viruses induce thrombocytopenia, including human immunodeficiency virus, hepatitis C, bunyavirus, rotavirus, hantavirus, adenovirus, Epstein-Barr virus, cytomegalovirus, and others [Assinger, A. Frontiers in immunology 5, 649 (2014)]. [003] Current estimates suggest that 390 million people are infected with the dengue virus each year [de Clerck, F., et al., Agents Actions 43, 225-234 (1994)]. There is a high clinical and economic burden due to the need for hospitalizations during severe infections. Therefore, any treatment for dengue would represent a significant benefit for patients and healthcare professionals. [004] Previous studies have demonstrated that the production of inflammatory mediators (including those produced by mast cells) and platelet activation are important features of dengue pathogenesis. It is necessary to provide treatments that alleviate virus-induced thrombocytopenia. SUMMARY OF THE INVENTION [005] Surprisingly, it was found that mast cell activation by viral infection leads to the release of serotonin into the circulation, leading to platelet activation and aggregation and thrombocytopenia. Administration of serotonergic drugs prevented or improved the development of thrombocytopenia in vivo. [006] Drugs targeting serotonin or preventing its release can be used to treat virus-induced thrombocytopenia. Targeting the 5HT2A and/or 5HT1A serotonin receptor using receptor antagonists or preventing serotonin uptake in platelets prevents virus-induced thrombocytopenia and blocks platelet aggregation. Serotonin inhibitors represent a novel treatment strategy for dengue virus (DENV), Japanese encephalitis virus (JEV), and perhaps other viruses that induce thrombocytopenia and downstream complications, such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), bunyavirus, rotavirus, hantavirus, adenovirus (ADV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV). Many serotonergic drugs, particularly ketanserin, have been approved for use. Therefore, expensive and time-consuming safety trials can be bypassed, allowing for faster clinical use. By preventing thrombocytopenia, the severity of the infection can be reduced, leading to fewer medical complications and fewer hospitalizations [St John, A.L., et al., Nature reviews Microbiology 11, 420-426 (2013)]. This represents a significant medical and economic benefit. [007] According to a first aspect, the present invention provides a composition comprising at least one serotonergic compound for the treatment of virus-induced thrombocytopenia. [008] In preferred embodiments, at least one serotonergic compound inhibits serotonin release from mast cells and/or serotonin uptake by platelets and/or inhibits serotonin activity. Serotonin release from mast cells can be inhibited by 5HT1A receptor antagonists or by mast cell stabilizers that inhibit degranulation. Mast cell stabilizers may have the benefit of preventing serotonin release, but would not be able to block the effects of already released serotonin. Serotonin uptake by platelets can be inhibited by selective serotonin reuptake inhibitors (SSRIs) or serotonin reuptake antagonist and inhibit