Methods and compositions for treating nephrogenic diabetes insipidus
Inventors
Kishore, Bellamkonda K. • Carlson, Noel G. • Zhang, Yue
Assignees
US Department of Veterans Affairs • University of Utah Research Foundation Inc
Publication Number
US-9539246-B2
Publication Date
2017-01-10
Expiration Date
2032-08-29
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Abstract
Disclosed is a treatment of diabetes insipidus. Methods of treating diabetes insipidus disorders associated with P2Y receptors using the compounds and compositions are also disclosed.
Core Innovation
The invention relates to methods and compositions for treating nephrogenic diabetes insipidus (NDI) by administering ADP-(P2Y12)-like receptor modulators. It specifically addresses the treatment and prevention of acquired nephrogenic diabetes insipidus associated with dysfunction of P2Y receptors, especially those induced by lithium salt administration.
Acquired NDI is characterized by the kidney's resistance to the antidiuretic hormone (ADH or arginine vasopressin, AVP), leading to symptoms such as polydipsia, polyuria, decreased urine osmolality, and a marked reduction in ADH-regulated aquaporin 2 (AQP2) water channels in the kidney medulla. Current therapies like cyclooxygenase inhibitors, thiazides, or amiloride have limitations due to variable success and adverse effects, especially in elderly and critically ill patients.
The invention provides compounds that modulate ADP-(P2Y12)-like receptor activity to treat NDI by increasing AQP2 levels in the kidney and decreasing PGE2 levels in the urine, thereby ameliorating polyuria. Lithium, a common therapeutic agent for bipolar disorder and other conditions, often induces acquired NDI as a side effect, and the invention also covers co-therapies involving ADP-(P2Y12)-like receptor modulators to prevent or treat lithium-induced NDI.
Claims Coverage
The patent includes 20 claims covering methods of treating nephrogenic diabetes insipidus, alone or co-treated with neurological or psychiatric disorders, using ADP-(P2Y12)-like receptor modulators and lithium salts. There are several inventive features relating to receptor modulation, disease treatment, and combination therapies.
Method for treating nephrogenic diabetes insipidus using ADP-(P2Y12)-like receptor modulators
Administering an effective amount of an ADP-(P2Y12)-like receptor modulator to a subject to ameliorate symptoms of nephrogenic diabetes insipidus.
Combination therapy with lithium salt
Administering a lithium salt alongside the ADP-(P2Y12)-like receptor modulator to treat conditions including acquired nephrogenic diabetes insipidus and neurological or psychiatric disorders.
Use of specific ADP-(P2Y12)-like receptor modulators
Utilizing specific modulators including clopidogrel, ticlopidine, prasugrel, ticagrelor, cangrelor, and elinogrel as therapeutics for nephrogenic diabetes insipidus.
Modulation of ADP-(P2Y12)-like receptor group members
Targeting receptor proteins within the ADP-(P2Y12)-like receptor group, such as P2Y12, P2Y13, P2Y14, GPR34, GPR34-like, GPR82, GPR87, and GPR171, to achieve therapeutic effects.
Amelioration of nephrogenic diabetes symptoms
Decreasing natriuresis, increasing AQP2 expression in kidneys, reducing water intake, and decreasing polyuria in treated subjects.
Co-administration timing flexibility
Allowing administration of the ADP-(P2Y12)-like receptor modulator and lithium salt either simultaneously or sequentially.
The claims cover inventive methods involving administration of ADP-(P2Y12)-like receptor modulators alone or with lithium salts to treat nephrogenic diabetes insipidus, including acquired forms, and co-treatment with neurological or psychiatric disorders, emphasizing specific compounds and receptor targets.
Stated Advantages
Provides new therapies for acquired nephrogenic diabetes insipidus with fewer side effects and improved tolerability, especially for critical and elderly patients.
Ameliorates lithium-induced polyuria without reducing lithium levels, potentially allowing lower clinical lithium dosing and reducing toxicity.
Increases AQP2 protein levels in the kidney, improving water reabsorption and urinary concentration.
Reduces urinary PGE2 levels, which antagonize AVP-stimulated water permeability, thereby improving kidney response.
Potential to treat age-related defects in urinary concentration by enhancing AVP release and/or sensitizing kidney response.
Documented Applications
Treatment of acquired nephrogenic diabetes insipidus, including lithium-induced NDI.
Co-treatment of nephrogenic diabetes insipidus and neurological or psychiatric disorders such as bipolar disorder via combination of lithium salts and ADP-(P2Y12)-like receptor modulators.
Use of ADP-(P2Y12)-like receptor modulators to enhance urinary concentration in age-related urinary concentration defects.
Screening methods to identify P2Y12 receptor antagonists by measuring PGE2 metabolites and AQP2 levels in kidney cells.
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