Treatment of kidney diseases associated with elevated AVP
Inventors
Kishore, Bellamkonda K. • Zhang, Yue • Carlson, Noel G.
Assignees
US Department of Veterans Affairs • University of Utah • Government of the United States of America
Publication Number
US-10614684-B2
Publication Date
2020-04-07
Expiration Date
2038-01-31
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Abstract
Disclosed are methods for treating kidney disease including autosomal dominant polycystic kidney disease (ADPKD) in a subject, comprising the step of administering to the subject a composition comprising a therapeutically effective amount of ticagrelor or a derivative thereof, thereby treating ADPKD. Disclosed are methods of decreasing arginine vasopressin (AVP) production in a subject comprising the step of administering to the subject a composition comprising an effective amount of ticagrelor, thereby decreasing AVP production. Disclosed are methods for treating dilutional hyponatremia in a subject comprising the step of administering to the subject a composition comprising an effective amount of ticagrelor, thereby decreasing AVP production.
Core Innovation
The invention relates to methods for treating kidney diseases, including autosomal dominant polycystic kidney disease (ADPKD), by administering a therapeutically effective amount of ticagrelor or its derivatives to a subject. The treatment specifically targets diseases associated with elevated arginine vasopressin (AVP) levels. Administering ticagrelor results in decreased production of AVP, leading to a reduction in cyst number and/or size and preventing increase in kidney size. The inventions further cover methods to inhibit AVP production in hypothalamic cells, thereby affecting the progression of ADPKD or other AVP-related diseases.
The background identifies a significant problem: ADPKD is a common inherited kidney disease caused by mutations in PKD1 or PKD2 genes, characterized by renal cyst formation and kidney function decline, often leading to end-stage renal disease (ESRD). Existing therapies to slow cyst growth have significant side effects, and no specific long-term therapy is available. Elevated AVP levels contribute to disease progression through stimulation of cAMP production in kidney collecting duct cells. Hence, a treatment that safely reduces AVP production and limits cyst growth with fewer side effects is needed.
The invention solves this problem by using ticagrelor, previously known as an anti-clotting drug, for a new therapeutic purpose: reducing AVP production and activity in kidney diseases associated with elevated AVP, such as ADPKD and dilutional hyponatremia. The treatment provides a method for decreasing AVP production from hypothalamus, inhibiting renal cyst growth and ameliorating disease symptoms. Ticagrelor is shown to decrease urinary AVP excretion, increase urine output, and decrease urine osmolality in a dose-dependent manner, with potential for long-term administration and improved safety over existing therapies like tolvaptan.
Claims Coverage
The patent contains one identified independent claim focusing on inhibition of AVP production in hypothalamic cells by administering ticagrelor. The main inventive features describe the effective inhibition of AVP production, alone or combined with additional therapeutics.
Method of inhibiting AVP production in hypothalamic cells using ticagrelor
Administering an effective amount of ticagrelor to hypothalamic cells to inhibit production of arginine vasopressin (AVP).
Co-administration of additional therapeutics
Optionally administering one or more additional therapeutics alongside ticagrelor, including mTOR inhibitors, somatostatin analogues, vasopressin V2 receptor antagonists, or epidermal growth factor receptor inhibitors.
Determination of AVP production reduction by comparative measurement
Decreasing AVP production is assessed by comparing AVP levels in blood or urine before and after ticagrelor administration.
Effective plasma concentration range of ticagrelor
The effective amount of ticagrelor or its derivatives is within a plasma concentration range of about 1.0 to 6.0 μM for inhibiting hypothalamic AVP production.
Collectively, the claims cover methods of reducing AVP production in hypothalamic cells by ticagrelor administration, alone or combined with other therapeutics, with effectiveness measured by AVP level reduction within specified plasma concentration ranges.
Stated Advantages
Administration of ticagrelor reduces AVP production in a dose-dependent manner, resulting in decreased urinary concentrating ability which can slow cyst growth in ADPKD.
Use of ticagrelor offers a potential long-term treatment with fewer and tolerable side effects compared to existing therapies like vasopressin V2 receptor antagonists (e.g., tolvaptan).
The method avoids overstimulation of AVP’s V1a and V1b receptors by reducing circulating AVP, unlike chronic V2 receptor blockade that leads to increased AVP levels.
Ticagrelor has an established safety record for long-term use in cardiovascular patients, supporting its utility in ADPKD treatment.
The inhibitory effect of ticagrelor on hypothalamic AVP production is a novel off-target effect distinct from its anti-platelet action, making it difficult to mimic by other drugs and providing unique therapeutic potential.
Documented Applications
Treatment of autosomal dominant polycystic kidney disease (ADPKD) by administration of ticagrelor to reduce cyst size and number, decrease or prevent kidney enlargement, and ameliorate symptoms such as acute loin pain, haematuria, and hypertension.
Reduction of arginine vasopressin (AVP) production in subjects with diseases characterized by elevated AVP levels.
Treatment of dilutional hyponatremia by administering ticagrelor to decrease AVP production and ameliorate related symptoms such as fatigue, headache, and muscle cramps.
Inhibition of cyst growth in kidneys of subjects suffering from kidney diseases associated with elevated AVP.
Potential combined administration with other therapeutics including mTOR inhibitors, somatostatin analogues, vasopressin V2 receptor antagonists, and epidermal growth factor receptor inhibitors for enhanced treatment of kidney diseases.
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