KR-102958627-B1 - Composition for improving or treating cystic kidney disease and use thereof

KR102958627B1KR 102958627 B1KR102958627 B1KR 102958627B1KR-102958627-B1

Abstract

The present invention relates to the therapeutic effect of combining an antihistamine and a selective serotonin reuptake inhibitor on kidney disease. By screening FDA-approved drugs for new uses using a kidney organoid mimicking polycystic kidney disease, drugs for new uses were selected. When the selected antihistamine, desloratadine, and the serotonin reuptake inhibitor, duloxetine, were combined, the formation and growth of kidney cysts were inhibited. In an ADPKD animal model, the formation and growth of cysts were inhibited, kidney function was maintained at normal levels, and liver cysts and liver fibrosis caused by ADPKD were treated. Furthermore, in in vitro and animal models of kidney fibrosis, the combination of desloratadine and duloxetine significantly treated kidney fibrosis. In particular, the above effects were synergistically enhanced, and it was confirmed that this synergistic effect was superior compared to combinations of other drugs. Therefore, this can be usefully applied for the prevention or treatment of kidney disease and for the treatment of liver cysts and liver fibrosis.

Inventors

김용균
남선아
김진원
김수아

Assignees

가톨릭대학교 산학협력단
주식회사알젠오가노바이오테크놀로지

Dates

Publication Date: 20260511
Application Date: 20250618
Priority Date: 20240618

Claims (19)

A pharmaceutical composition for the prevention or treatment of kidney disease, comprising one or more selected from the group consisting of desloratadine, stereoisomers thereof, pharmaceutically acceptable salts or solvates; and duloxetine, stereoisomers thereof, pharmaceutically acceptable salts and solvates, wherein A pharmaceutical composition for the prevention or treatment of kidney disease, wherein the kidney disease is one or more selected from the group consisting of cyst formation or kidney disease associated with cyst formation, polycystic kidney disease (PKD), renal fibrosis, acute renal injury, and end-stage renal disease (ESKD).
A pharmaceutical composition for the prevention or treatment of kidney disease according to claim 1, wherein the desloratadine, its stereoisomer, a pharmaceutically acceptable salt or solvate and the duloxetine, its stereoisomer, a pharmaceutically acceptable salt or solvate are mixed in a weight ratio of 1:1 to 20.
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A pharmaceutical composition for the prevention or treatment of kidney disease according to claim 1, wherein the polycystic kidney disease (PKD) is autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD).
A pharmaceutical composition for the prevention or treatment of kidney disease, wherein the composition inhibits cystogenesis or growth.
A pharmaceutical composition for the prevention or treatment of kidney disease, wherein the composition maintains kidney function, in accordance with claim 1.
A pharmaceutical composition for the prevention or treatment of kidney disease, wherein the composition increases the phosphorylation of Akt in claim 1.
A pharmaceutical composition for the prevention or treatment of kidney disease, wherein the composition reduces the phosphorylation of p38 MAPK, ERK(1/2), GSK3β, β-catenin, or mTOR.
A pharmaceutical composition for the prevention or treatment of kidney disease, wherein the composition reduces the expression of B-Raf or c-Myc in claim 1.
A pharmaceutical composition for the prevention or treatment of one or more selected from the group consisting of liver cysts and liver fibrosis, comprising one or more selected from the group consisting of desloratadine, stereoisomers thereof, pharmaceutically acceptable salts or solvates; and duloxetine, stereoisomers thereof, pharmaceutically acceptable salts and solvates.
A pharmaceutical composition for the prevention or treatment of one or more selected from the group consisting of liver cysts and liver fibrosis, wherein the desloratadine, its stereoisomer, pharmaceutically acceptable salt or solvate and the duloxetine, its stereoisomer, pharmaceutically acceptable salt or solvate are mixed in a weight ratio of 1:1 to 20.
A pharmaceutical composition for the prevention or treatment of one or more selected from the group consisting of liver cysts and liver fibrosis, wherein at least one selected from the group consisting of liver cysts and liver fibrosis is caused by polycystic kidney disease (PKD).
A pharmaceutical composition for the prevention or treatment of any one or more selected from the group consisting of liver cysts and liver fibrosis, wherein the polycystic kidney disease (PKD) is autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD).
A quasi-drug composition for the prevention or improvement of kidney disease, comprising one or more selected from the group consisting of desloratadine, stereoisomers thereof, pharmaceutically acceptable salts or solvates; and duloxetine, stereoisomers thereof, pharmaceutically acceptable salts and solvates, wherein A quasi-drug composition for the prevention or improvement of kidney disease, wherein the kidney disease is one or more selected from the group consisting of cyst formation or kidney disease associated with cyst formation, polycystic kidney disease (PKD), renal fibrosis, acute renal injury, and end-stage renal disease (ESKD).
A quasi-drug composition for the prevention or improvement of one or more selected from the group consisting of liver cysts and liver fibrosis, comprising one or more selected from the group consisting of desloratadine, stereoisomers thereof, pharmaceutically acceptable salts or solvates; and duloxetine, stereoisomers thereof, pharmaceutically acceptable salts and solvates.
A food composition for the prevention or improvement of kidney disease comprising one or more selected from the group consisting of desloratadine, stereoisomers thereof, food-grade acceptable salts or solvates; and duloxetine, stereoisomers thereof, food-grade acceptable salts and solvates, wherein A food composition for the prevention or improvement of kidney disease, wherein the kidney disease is one or more selected from the group consisting of cyst formation or kidney disease associated with cyst formation, polycystic kidney disease (PKD), renal fibrosis, acute renal injury, and end-stage renal disease (ESKD).
A food composition for the prevention or improvement of one or more selected from the group consisting of liver cysts and liver fibrosis, comprising one or more selected from the group consisting of desloratadine, stereoisomers thereof, food-grade acceptable salts or solvates; and duloxetine, stereoisomers thereof, food-grade acceptable salts and solvates.
A health functional food composition for the prevention or improvement of kidney disease, comprising one or more selected from the group consisting of desloratadine, stereoisomers thereof, food-grade acceptable salts or solvates; and duloxetine, stereoisomers thereof, food-grade acceptable salts and solvates, wherein A health functional food composition for the prevention or improvement of kidney disease, wherein the kidney disease is one or more selected from the group consisting of cyst formation or kidney disease associated with cyst formation, polycystic kidney disease (PKD), renal fibrosis, acute renal injury, and end-stage renal disease (ESKD).
A health functional food composition for the prevention or improvement of one or more selected from the group consisting of liver cysts and liver fibrosis, comprising one or more selected from the group consisting of desloratadine, stereoisomers thereof, food-grade acceptable salts or solvates; and duloxetine, stereoisomers thereof, food-grade acceptable salts and solvates.

Description

Composition for improving or treating cystic kidney disease and use thereof The present invention relates to the therapeutic effect of kidney disease resulting from the combined administration of an antihistamine and a selective serotonin reuptake inhibitor. The kidneys are vital organs responsible for maintaining homeostasis in the body. They regulate body fluid volume, blood ion concentration, and pH, excrete metabolic waste products, toxins, and drugs, and perform blood pressure regulation as well as other metabolic and endocrine functions. Additionally, they activate Vitamin D to facilitate calcium absorption in the small intestine and participate in the synthesis of various hormones. Kidney disease refers to a condition in which the kidneys fail to perform their excretory, regulatory, metabolic, and endocrine functions normally, resulting in an overall decline in function or abnormalities. Functional decline caused by kidney damage leads to enlargement of the kidneys and related structures, renal atrophy, changes in fluid volume, electrolyte imbalance, metabolic acidosis, impaired gas exchange, reduced anti-infectious function, and the accumulation of uremic toxins. Chronic kidney disease (CKD) is recognized as a serious disease worldwide. The main causes are diabetes and hypertension, while other causes include urinary tract obstruction, specific kidney abnormalities (such as polycystic kidney disease and glomerulonephritis), and autoimmune diseases (such as systemic lupus erythematosus) in which antibodies damage the small blood vessels (glomeruli) and tubules (renal tubules) of the kidneys. Acute kidney injury becomes chronic kidney disease when irreversible kidney damage caused by these various diseases or when kidney function does not recover and persists for more than three months following treatment for an injury. Symptoms of chronic kidney disease include nocturia, fatigue, nausea, itching, muscle cramps and spasms, loss of appetite, confusion, shortness of breath, and body edema (most commonly in the legs). The condition of patients suffering from chronic kidney disease requiring renal replacement therapy, such as dialysis or transplantation, is referred to as end-stage renal disease (ESRD). Currently, there are no effective treatments available other than renin-angiotensin-aldosterone system (RAS) inhibitors, such as angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors, used alone or in combination. However, even these treatments are only effective in delaying the onset of ESRD or inhibiting the decline in glomerular filtration rate (GFR) in some CKD patients; their effects are minimal for the majority of CKD patients. The persistence of various chronic kidney diseases ultimately leads to end-stage renal failure. Chronic renal failure is caused by chronic glomerulonephritis, diabetes, hypertension, urinary tract obstruction, renal tuberculosis, and hereditary kidney disease; even if the underlying cause is treated, kidney function does not recover, and while the progression to renal failure can be slowed, it cannot be prevented. Polycystic kidney disease (PKD), one of the causes of chronic kidney disease, is caused by genetic defects. There are several genetic defects that lead to PKD; some types are caused by dominant genes, while one rare type is caused by a recessive gene. When caused by a dominant gene, it is called autosomal dominant polycystic kidney disease (ADPKD). This is the most common human genetic disease of the kidney and is primarily caused by germline mutations in the PKD1 or PKD2 genes, which encode the ciliary cyst proteins polycystin 1 and 2 (PC1 and PC2) (W. E. Sweeney, Jr., E. D. Avner, Pathophysiology of childhood polycystic kidney diseases: new insights into disease-specific therapy. Pediatr Res 75, 148-157(2014); E. Cornec-Le Gall, A. Alam, R. D. Perrone, Autosomal dominant polycystic kidney disease. Lancet 393, 919-935(2019); and J. Hughes et al., The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nat Genet 10, 151-160(1995)). It is known that defects in the PKD1 gene are the cause in 85% of patients diagnosed with ADPKD, and defects in the PKD2 gene are the cause in 15%. PC1 and PC2 proteins coexist across the cell membranes of renal epithelial cells, the extracellular matrix, and primary cilia, and a deficiency of the PC1-PC2 complex in the cilia is known to play a role in cyst formation. Patients with ADPKD develop multiple cysts in both kidneys; as the size and number of cysts increase, renal function eventually ceases, leading to death in their 50s or 60s. Cyst progression occurs as cystic epithelial cells proliferate, followed by the accumulation of fluid within the cyst, causing it to enlarge. ADPKD accounts for approximately 2% of the causes among dialysis patients in Korea and is the fourth most common condition after diabetes, hypertension, and glomerulonephritis. ADP