Methods and compositions for the treatment of neuropsychiatric and addictive disorders

Abstract

The present invention relates to methods and compositions for treating neuropathic pain and neuropsychiatric disorders by administering agents that are effective in reducing the effective amount, inactivating, and / or inhibiting the activity of a Na+—K+-2Cl− (NKCC) cotransporter. In certain embodiments, the Na+—K+-2Cl− co-transporter is NKCC1.

Description

REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. patent application Ser. No. 11 / 549,274, filed Oct. 13, 2006; U.S. Patent Application No. 60 / 727,564, filed Oct. 17, 2005; U.S. Patent Application No. 60 / 727,318, filed Oct. 17, 2005; and U.S. patent application Ser. No. 11 / 251,724, filed Oct. 17, 2005, the disclosures of which are incorporated herein by reference in their entireties.TECHNICAL FIELD OF THE INVENTION[0002]The present invention relates to methods and compositions for treating selected conditions of the central and peripheral nervous systems employing non-synaptic mechanisms. More specifically, the present invention relates to methods and compositions for treating neuropsychiatric and addictive disorders by administering agents that modulate expression and / or activity of sodium-potassium-chloride co-transporters.BACKGROUND OF THE INVENTION[0003]Neuropathic pain and nociceptive pain differ in their etiology, pathophysiology, diagnosis and ...

AI Technical Summary

Benefits of technology

[0016]The treatment compositions and methods of the present invention are useful for treating conditions including addictive disorders and neuropsychiatric disorders, such as bipolar disorders, anxiety disorders (including panic disorder, social anxiety disorder, obsessive compulsive disorder, posttraumatic stress disorder, generalized anxiety disorder and specific phobia (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th edition—Text Revision, 2000)), depression and schizophrenia, that are characterized by neuronal hypersynchrony. The inventive compositions and methods may be employed to reduce neuronal hypersynchrony associated with addictive and / or neuropsychiatric disorders without suppressing neuronal excitability, thereby avoiding the unwanted side effects often associated with agents currently employed for the treatment of addictive disorders and neuropsychiatric disorders.

[0017]Addictive disorders include eating disorders (including obesity and binge eating), alcoholism, sexual addiction, addiction to narcotics and smoking, addiction to exercise and gambling. As used herein, the term “addictive disorder” is defined as a disorder characterized by an uncontrollable compulsion to repeat a behavior regardless of its consequences. The inventive compositions and methods may be employed to reduce neuronal hypersynchrony associated with such conditions without suppressing neuronal excitability, thereby avoiding unwanted side effects.

[0019]Analogs of CNS-targeted NKCC co-transporter antagonists such as furosemide, bumetanide, piretanide, azosemide and torsemide that may be usefully employed in the inventive compositions and methods include those provided below as Formulas I-VIII. The inventors believe that such analogs have increased lipophilicity and reduced diuretic effects compared to the CNS-targeted NKCC co-transporter antagonists from which they are derived and thus result in fewer undesirable side effects when employed in the inventive treatment methods.

[0038]In one embodiment, the level of diuresis that occurs following administration of an effective amount of an analog provided below as Formula I-VIII, is less than 99%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10% of that which occurs following administration of an effective amount of the parent molecule from which the analog is derived. For example, the analog may be less diuretic than the parent molecule when administered at the same mg / kg dose. Alternatively, the analog may be more potent than the parent molecule from which it is derived, so that a smaller dose of the analog is required for effective relief of symptoms, thereby eliciting less of a diuretic effect. Similarly, the analog may have a longer duration of effect in treating disorders than the parent molecule, so that the analog may be administered less frequently than the parent molecule, thus leading to a lower total diuretic effect within any given period of time.

[0045]In certain embodiments, the inventive methods for treatment of addictive disorders involve the administration of a treatment agent comprising a diuretic (for example, a loop diuretic such as furosemide, torasemide or bumetanide, or a thiazide or thiazide-like diuretic) in combination with one or more anti-diuretic components, in order to counteract unwanted diuretic effects of the primary treatment agent. Negative side effects that can be avoided by such methods include loss of body water, and depletion of electrolytes (such as potassium, magnesium, calcium and thiamine) and B vitamins. Anti-diuretic components that may be usefully employed in such methods include, for example, antidiuretic hormones, such as vasopressin, which increases water reabsorption by the kidneys; and salts and electrolytes, which act to replenish ions lost due to diuresis. In a preferred embodiment, the diuretic treatment agent and the anti-diuretic component are combined together in a composition formulated as a liquid beverage, food or food supplement.

Problems solved by technology

It is typically well localized and often has an aching or throbbing quality.

Neuropathic pain is difficult to treat.

Analgesic drugs that are effective against normal pain (e.g., opioid narcotics and non-steroidal anti-inflammatory drugs) are rarely effective against neuropathic pain.

Similarly, drugs that have activity in neuropathic pain are not usually effective against nociceptive pain.

However, only some, and not all, antiepileptic drugs are effective in treating neuropathic pain, and furthermore such antiepileptic drugs are only effective in certain subsets of patients with neuropathic pain (McCleane, Expert. Opin. Pharmacother. 5:1299-1312, 2004).

Many of the drugs currently employed in the treatment of such disorders have significant negative side effects, such as tendencies to induce dependence.

One serious drawback of these therapies is that they are nonselective and exert their actions on both normal and abnormal neuronal populations.

This leads to negative and unintended side effects, which may affect normal CNS functions, such as cognition, learning and memory, and produce adverse physiological and psychological effects in the treated patient.

Common side effects include over-sedation, dizziness, loss of memory and liver damage.

Addictive disorders, such as eating disorders (including obesity), addiction to narcotics, sexual addiction, alcoholism and smoking, are a major public health problem that impacts society on multiple levels.

It has been estimated that substance abuse costs the US more than $484 billion per year.

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