FIELD OF THE INVENTION

The present invention is related to compositions and methods of treatment for various neuropsychiatric disorders. For example, a composition comprising a combination of metabolic pathway substances and co-factors that regulate the nitric oxide pathway may be useful in treating such neuropsychiatric disorders. In some cases a combination of L-arginine and tetrahydrobiopterin (BH4) may be useful as these compounds both cross the blood brain barrier and interact with the NMDA-NO-cGMP pathway but bypass an impaired NMDA receptor. Such combination compositions are expected to maximize NO's neuroprotection and neuroplasticity effects and minimize NO's neurotoxic effects.

BACKGROUND

Currently available antineuropsychiatric medications all fall into the “me too” category which are directed to regulation of a dopamine D2 receptor. Consequently, no significant progress has been made for new drug development to improve impaired NMDA receptor function in schizophrenia. Such D2 receptor oriented therapy has significant adverse effects, such as extrapyramidal symptoms and cardiometabolic side effects, which require safety monitoring.

What is needed in the art is a compound or compound combination that has a benign safety profile (e.g., for example, nutrient supplements), no need for intensive safety monitoring, no significant cardiometabolic side effects that are associated with currently available antineuropsychiatric medications.

SUMMARY OF THE INVENTION

The present invention is related to compositions and methods of treatment for various neuropsychiatric disorders. For example, a composition comprising a combination of metabolic pathway substrates and co-factors that regulate the nitric oxide pathway may be useful in treating such neuropsychiatric disorders. In some cases a combination of L-arginine and tetrahydrobiopterin (BH4) may be useful as these compounds both cross the blood brain barrier and interact with the NMDA-NO-cGMP pathway but bypass an impaired NMDA receptor. Such combination compositions are expected to maximize NO's neuroprotection and neuroplasticity effects and minimize NO's neurotoxic effects.

In one embodiment, the present invention contemplates a method, comprising: a) providing: i) a patient comprising an uncoupled nitric oxide synthase pathway and exhibiting at least one symptom of a neuropsychiatric disorder: and ii) a pharmaceutical composition comprising L-arginine and tetrahydrobiopterin; b) administering said pharmaceutical composition to said patient under conditions such that said uncoupled nitric oxide synthase pathway converts to a coupled nitric oxide synthase pathway and said at least one symptom of a neuropsychiatric disorder is reduced. In one embodiment, said uncoupled nitric oxide synthase pathway underproduces nitric oxide. In one embodiment, said uncoupled nitric oxide synthase pathway overproduces superoxide, hydrogen peroxide and peroxynitrite. In one embodiment, aid superoxide, hydrogen peroxide and peroxynitrite confers neurotoxicity and induces said at least one symptom of a neuropsychiatric disorder. In one embodiment, said coupled nitric oxide synthase pathway produces a homeostatic level of nitric oxide. In one embodiment, said homeostatic level of nitric oxide confers neuroprotection. In one embodiment, said coupled nitric oxide synthase pathway produces minimal levels of superoxide, hydrogen peroxide and peroxynitrite. In one embodiment, said homeostatic level of nitric oxide confers neuroplasticity. In one embodiment, said neuropsychiatric disorder is schizophrenia. In one embodiment, said neuropsychiatric disorder is depression. In one embodiment, said neuropsychiatric disorder is bipolar disorder. In one embodiment, said neuropsychiatric disorder is delusion. In one embodiment, said neuropsychiatric disorder is selected from the group consisting of schizotypal personality disorder, delusional disorder, brief neuropsychiatric disorder, schizophreniform disorder, schizoaffective disorder, substance/medication-induced neuropsychiatric disorder, neuropsychiatric disorder due to another medical condition, catatonia, depressive disorders and bipolar and related disorders. In one embodiment, said uncoupled nitric acid synthase pathway is an uncoupled endothelial nitric acid synthase pathway. In one embodiment, said administering occurs over a twenty-one-day period.

In one embodiment, the present invention contemplates a pharmaceutical composition comprising L-arginine and tetrahydrobiopterin. In one embodiment, the pharmaceutical composition comprises 6 grams of said L-arginine. In one embodiment, the pharmaceutical composition comprises 500 mg of said tetrahydrobiopterin. In one embodiment, the pharmaceutical composition comprises a liquid. In one embodiment, the pharmaceutical composition comprises a powder. In one embodiment, the pharmaceutical composition comprises a tablet. In one embodiment, the pharmaceutical composition comprises a capsule.

Definitions

To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as “a”, “an” and “the” are not intended to refer to only a singular entity but also plural entities and also includes the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.

The term “about” or “approximately” as used herein, in the context of any assay measurements refers to +/−5% of a given measurement.

The term “uncoupled” as used herein refers to a dysregulation of an enzymatic pathway involving electron transport. For example, electrons in an uncoupled pathway undergo incomplete reactions thereby resulting in the production of oxidized byproducts. In particular, an uncoupled nitric oxide pathway produces oxidized byproducts including but not limited to superoxide, hydrogen peroxide and/or peroxynitrite.

The term “coupled” as used herein refers to a properly regulated enzymatic pathway involving electron transport. For example, electrons in a coupled pathway undergo complete reactions thereby resulting in the production of physiologically compatible products. In particular, a coupled nitric oxide pathway produces nitric oxide at homeostatic levels.

The term “neuropsychiatric disorder” as used herein refers to mental psychosis including but not limited to neuropsychiatric illnesses, psychosis due to general medical conditions, and/or substance-induced psychosis. In particular, a neuropsychiatric disorder may include but is not limited to schizophrenia, depression, bipolar disorder and/or delusions, schizotypal personality disorder, delusional disorder, brief neuropsychiatric disorder, schizophreniform disorder, schizophrenia, schizoaffective disorder, substance/medication-induced neuropsychiatric disorder, neuropsychiatric disorder due to another medical condition, and catatonia. Should we include all these conditions? In addition, should we include “depressive disorders” and “bipolar and related disorders”

The term “converts” as used herein refers to an interaction of a compound with an uncoupled electron transport pathway, where the compound undergoes a chemical transformation that shifts the pathway equilibrium into a coupled electron transport pathway. For example, the addition of tetrahydrobiopterin converts an uncoupled nitric oxide synthase pathway into a coupled nitric oxide synthase pathway by re-establishing the homeostatic tetrahydrobiopterin/dihydrobiopterin ratio within the pathway.

The term “confers” as used herein refers to an interaction of a compound with a neuronal tissue, where the compound undergoes a chemical transformation that either results in neuroprotection or neurotoxicity.

The term “neurotoxicity” as used herein refers to neuronal tissue damage caused by, for example, inflammation or oxidation.

The term “neuroprotection” as used herein refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (e.g., oxidative stress) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time. Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing the loss of neurons.

The term “homeostatic” as used herein refers to the maintenance of relatively stable internal physiological conditions. Consequently, “a homeostatic level” of a compound would be considered to be within an expected normal range within a specified population of healthy individuals.

The term “underproduces” as used herein refers to the generation of a compound by a biochemical pathway that is sufficiently below homeostatic levels that the lack of the compound results in a symptom of a neuropsychiatric disorder.

The term “overproduces” as used herein refers to the generation of a compound by a biochemical pathway that is sufficiently above homeostatic levels that the excess of the compound results in a symptom of a neuropsychiatric disorder.

The term “effective amount” as used herein, refers to a particular amount of a pharmaceutical composition comprising a therapeutic agent that achieves a clinically beneficial result (i.e., for example, a reduction of symptoms). Toxicity and therapeutic efficacy of such compositions can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD50/ED50. Compounds that exhibit large therapeutic indices are preferred. The data obtained from these cell culture assays and additional animal studies can be used in formulating a range of dosage for human use. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

The term “symptom”, as used herein, refers to any subjective or objective evidence of disease or physical disturbance observed by the patient. For example, subjective evidence is usually based upon patient self-reporting and may include, but is not limited to, pain, headache, visual or auditory disturbances, disorganized thoughts, mood fluctuation, nausea and/or vomiting. Alternatively, objective evidence is usually a result of medical testing including, but not limited to, body temperature, complete blood count, lipid panels, thyroid panels, blood pressure, heart rate, electrocardiogram, tissue and/or body imaging scans.

The term “disease” or “medical condition”, as used herein, refers to any impairment of the normal state of the living animal or plant body or one of its parts that interrupts or modifies the performance of the vital functions. Typically manifested by distinguishing signs and symptoms, it is usually a response to: i) environmental factors (as malnutrition, industrial hazards, climate, or psychosocial stress); ii) specific infective agents (as worms, bacteria, or viruses), iii) inherent defects of the organism (as genetic anomalies); and/or iv) combinations of these factors.

The terms “reduce,” “inhibit,” “diminish,” “suppress,” “decrease,” “prevent” and grammatical equivalents (including “lower,” “smaller,” etc.) when in reference to the expression of any symptom in an untreated subject relative to a treated subject, mean that the quantity and/or magnitude of the symptoms in the treated subject is lower than in the untreated subject by any amount that is recognized as clinically relevant by any medically trained personnel. In one embodiment, the quantity and/or magnitude of the symptoms in the treated subject is at least 10% lower than, at least 25% lower than, at least 50% lower than, at least 75% lower than, and/or at least 90% lower than the quantity and/or magnitude of the symptoms in the untreated subject.

The term “drug” or “compound” as used herein, refers to any pharmacologically active substance capable of being administered which achieves a desired effect. Drugs or compounds can be synthetic or naturally occurring, non-peptide, proteins or peptides, oligonucleotides or nucleotides, polysaccharides or sugars.

The term “administered” or “administering”, as used herein, refers to any method of providing a composition to a patient such that the composition has its intended effect on the patient. An exemplary method of administering is by a direct mechanism such as, local tissue administration (i.e., for example, extravascular placement), oral ingestion, transdermal patch, topical, inhalation, suppository etc.

The term “patient” or “subject”, as used herein, is a human or animal and need not be hospitalized. For example, out-patients, persons in nursing homes are “patients.” A patient may comprise any age of a human or non-human animal and therefore includes both adult and juveniles (i.e., children). It is not intended that the term “patient” connote a need for medical treatment, therefore, a patient may voluntarily or involuntarily be part of experimentation whether clinical or in support of basic science studies.

The term “pharmaceutically” or “pharmacologically acceptable”, as used herein, refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human.

The term, “pharmaceutically acceptable carrier”, as used herein, includes any and all solvents, or a dispersion medium including, but not limited to, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils, coatings, isotonic and absorption delaying agents, liposome, commercially available cleansers, and the like. Supplementary bioactive ingredients also can be incorporated into such carriers.

