# US 2025/0085273 A1 · Novel rapid drug discovery for sepsis and agents for use as sepsis therapy

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- Number: US 2025/0085273 A1
- Document ID: US20250085273A1
- Status: Published application
- Kind: A1
- Application number: 18/800,672
- Filed: 2024-08-12
- Published: 2025-03-13
- Earliest claimed: 2023-08-11
- Applicants: The Government of the United States, AS Represented By the Secretary of the Army
- Inventors: Mark W. WIDDER; Chance M. CARBAUGH; William H. VAN DER SCHALIE; Charlotte A. LANTERI; Kevin S. AKERS
- Web page: https://patentgrep.com/patent/US20250085273A1

## CPC

- G01N 33/5088: {of vertebrates}
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

In this disclosure, a zebrafish model is established for rapid screening of potential drug candidates for prevention and treatment of sepsis. To this end, three endpoints (mortality, tail-fin edema, and reactive oxygen species detection) screening method is established to identify drugs of potential use among approved drugs and/or novel small molecules, and 16 drugs were identified, which target serotonin receptors, receptor tyrosine kinases, dietary supplements, antihistamine drugs, serotonin uptake inhibitors, monoamine oxidase inhibitors, and other antipsychotic drugs.

## Claims

### Claim 1

A method of preventing or treating severe inflammation, sepsis, and/or septic shock; comprising a step of administering an effective amount of:
a. a drug that suppresses the activity of 5-hydroxytryptamine (5-HT, serotonin) receptors, to a subject in need of such treatment, wherein the drug optionally comprises one or more of an antagonist, a partial agonist, or an inverse agonist of 5-HT receptors;
b. a drug that inhibits the activity of receptor tyrosine kinases (RTKs), to a subject in need of such treatment, wherein the drug optionally comprises one or more of an inhibitor of platelet-derived growth factor receptors (PDGFRa and PDGFRb), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and/or the glial cell-line derived neurotrophic factor receptor (RET);
c. a dietary supplement comprising a folic acid supplement and/or iron supplement
d. a drug that suppresses the activity of histamine receptors, wherein the drug optionally comprises an antagonist, a partial agonist, or an inverse agonist of histamine receptors, wherein the histamine receptor is H1, H2, H3, or H4; and/or
e. a drug that increases the level of 5-hydroxytryptamine (5-HT, serotonin) in blood, wherein the drug optionally comprises a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), or monoamine oxidase inhibitor (MAOI).

### Claim 2 (depends on 1)

The method of claim 1, wherein the 5-HT receptor is 5-HT2A, 5-HT2B, or 5-HT2C, and optionally 5-HT2A.

### Claim 3 (depends on 1)

The method of claim 1, wherein the drug that suppresses the activity of 5-HT receptors is at least one selected from ketanserin, tegaserod, paliperidone, paliperidone palmitate, quetiapine, ziprasidone, brexpiprazole, ritanserin, phenoxybenzamine, cyproheptadine, aripiprazole, chlorpromazine, clozapine, olanzapine, risperidone, nefazodone.

### Claim 4

(canceled)

### Claim 5 (depends on 1)

The method of claim 1, wherein the inhibitor of RTK is sunitinib or sunitinib malate.

### Claim 6

(canceled)

### Claim 7 (depends on 1)

The method of claim 1, wherein the folic acid supplement is levomefolic acid.

### Claim 8 (depends on 1)

The method of claim 1, wherein the iron supplement is ferric citrate.

### Claim 9

(canceled)

### Claim 10

(canceled)

### Claim 11

(canceled)

### Claim 12

(canceled)

### Claim 13

(canceled)

### Claim 14

(canceled)

### Claim 15 (depends on 1)

The method of claim 1, wherein the drug that suppresses the activity of histamine receptors is at least one selected from mepyramine, triprolidine, cetirizine, cimetidine, ranitidine, tiotidine, thioperamide, iodophenpropit, clobenpropit, tiprolisant, proxyfan, promethazine, and pitolisant, and optionally pitolisant.

### Claim 16

(canceled)

### Claim 17 (depends on 1)

The method of claim 1, wherein the drug that suppresses the activity of histamine receptors is pitolisant.

### Claim 18

(canceled)

### Claim 19

(canceled)

### Claim 20

(canceled)

### Claim 21

A method of preventing or treating severe inflammation, sepsis, and/or septic shock; comprising a step of administering an effective amount of a composition comprising fenspiride hydrochloride, levomepromazine, folic acid supplement, iron supplement, and/or RTK inhibitors to a subject in need of such treatment.

### Claim 22

(canceled)

### Claim 23

(canceled)

### Claim 24

(canceled)

### Claim 25

(canceled)

### Claim 26

(canceled)

### Claim 27

(canceled)

### Claim 28

(canceled)

### Claim 29 (depends on 1)

The method of claim 1, wherein the SSRI is selected from citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine, sertraline, and vortioxetine.

### Claim 30 (depends on 1)

The method of claim 1, wherein the MAOI is selected from isocarboxazid, phenelzine, selegiline, and tranylcypromine, rasagiline, moclobemide, and iproniazid.

### Claim 31 (depends on 1)

The method of claim 1, further comprising co-administering an effective amount of at least one antibiotic,
wherein the severe inflammation, sepsis or septic shock is caused by bacterial infection, and
wherein the drug is one or more selected from ketanserin, tegaserod, brexpiprazole, paliperidone palmitate, and sunitinib.

### Claim 32 (depends on 1)

The method of claim 1, further comprising co-administering an effective amount of at least one anti-viral drug,
wherein the severe inflammation is caused by mutation-prone RNA virus infection, and
wherein the drug is one or more selected from ketanserin, tegaserod, brexpiprazole, paliperidone palmitate, and sunitinib.

### Claim 33

A method of treating severe edema, comprising a step of administering an effective amount a drug,
wherein the severe edema is caused by cardiogenic shock, neurogenic shock, or anaphylactic shock, and
wherein the drug is one or more selected from ketanserin, tegaserod, brexpiprazole, paliperidone palmitate, and sunitinib.

### Claim 34

(canceled)

### Claim 35

(canceled)

### Claim 36

(canceled)

### Claim 37

(canceled)

### Claim 38

(canceled)

### Claim 39

A method of screening for an agent to prevent or treat inflammation, sepsis or circulatory shock using a zebrafish sepsis model, the method comprising subjecting a test agent to zebrafish embryos 3 days post-fertilization (dpf) zebrafish embryos and/or 5-dpf fully developed zebrafish exposed to 20-80 μg/mL or about 60 μg/mL P. aeruginosa LPS in the presence for a predetermined time period 15-30 hours, or about 24 hours, and
detecting vascular leakage (tail fin edema), reactive oxygen species (ROS) production and/or mortality rate of the zebrafish embryos and/or fully developed zebrafish after administering;
identifying an agent as an agent to treat or prevent inflammation, sepsis or circulatory shock if it reduces vascular leakage, ROS and/or mortality compared to untreated zebrafish embryos and/or fully developed zebrafish.

### Claim 39

(canceled)