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Title:  Use of therapeutic dosages for nitric oxide donors which do not significantly lower blood pressure or pulmonary artery pressure

United States Patent:  6,472,390

Issued:  October 29, 2002

Inventors:  Stamler; Jonathan S. (Chapel Hill, NC); Piantadosi; Claude A. (Durham, NC); Dewhirst; Mark W. (Durham, NC)

Assignee:  Duke University (Durham, NC)

Appl. No.:  986807

Filed:  November 13, 2001

Abstract

Patients with pathologic conditions involving constriction or proliferation of smooth muscle or disease associated with cysteine containing proteins, or who are at risk for such, are administered a therapeutically effective amount of a nitric oxide (NO) donor which is insufficient to acutely lower mean arterial blood pressure or pulmonary artery pressure by more than 10%. In one subgenus, NO donor is administered to modify red blood cell membrane receptors to prevent red blood cells from causing vasoconstriction. A related method which allows increased dosage of NO donor without acutely lowering mean arterial blood pressure comprises administering the NO donor into an artery of the patient. In another method, patients having a cardiovascular syndrome, or who are at risk for such, are administered a therapeutically effective amount of thiol which does not acutely affect blood pressure to a significant degree.

DETAILED DESCRIPTION OF THE INVENTION

We turn now to the method of the first embodiment of the invention herein, that is to the method for prophylaxis or treatment of a patient with a pathologic condition involving constriction or proliferation of smooth muscle or who is at risk for such, except for a patient having acute thrombotic complications of restenosis or platelet embolism or other thromboembolic event, said method comprising administering an NO donor which is capable of acutely lowering mean arterial blood pressure or pulmonary artery pressure by more than 10% to said patient in a therapeutically effective amount which is insufficient to acutely lower mean arterial blood pressure or pulmonary artery pressure by more than 10%, e.g., by more than 5%.

The treatment is directed to patients with a pathological condition involving constriction or proliferation of smooth muscle.

The prophylaxis is directed to patients who are at risk for a pathological condition involving constriction or proliferation of smooth muscle.

Pathological conditions involving constriction or proliferation of smooth muscle are, for example, acute coronary spasm (e.g., from angina, myocardial infarction and all ischemic syndromes), pulmonary hypertension (e.g., from heart failure, primary pulmonary hypertension and chronic obstructive pulmonary disease, i.e., COPD), systemic hypertension, asthma, rectal spasm, esophageal spasm, pyloric stenosis, and stroke. Of these, coronary spasm, pulmonary hypertension, systemic hypertension, and heart failure are diseases of vascular smooth muscle. Asthma involves airway smooth muscle. Rectal spasm and esophageal spasm and pyloric stenosis involve gastrointestinal smooth muscle. All these pathological conditions involve constriction of smooth muscle except for heart failure. Pulmonary hypertension, pyloric stenosis and asthma involve proliferation of smooth muscle. In respect to systemic hypertension, the invention causes no acute drop in mean arterial blood pressure but reduction over time (analogous to treatment of depression), e.g., over 2 weeks; this is an important effect in the vast majority of cases of hypertension, where the risk accumulates over many years and acute effects are not relevant.

We turn now to the NO donor which is administered. An NO donor donates nitric oxide or a related redox species and more generally provides nitric oxide bioactivity, that is activity which is identified with nitric oxide, e.g., vasorelaxation or stimulation or inhibition of a receptor protein, e.g., ras protein, adrenergic receptor, NFK.kappa.B. NO donors including S-nitroso, O-nitroso, C-nitroso and N-nitroso compounds and nitro derivatives thereof and metal NO complexes, but not excluding other NO bioactivity generating compounds, useful herein are described in "Methods in Nitric Oxide Research," edited by Feelisch, M., and Stamler, J. S., John Wiley & Sons, New York, 1996, pages 71-115 which is incorporated herein by reference. NO donors which are C-nitroso compounds where nitroso is attached to a tertiary carbon which are useful herein include those described in U.S. patent application Ser. No. 09/695,934. Examples of S-nitroso compounds including S-nitrosothiols useful herein include, for example, S-nitrosoglutathione, S-nitroso-N-acetylpenicillamine, S-nitroso-cysteine and ethyl ester thereof S-nitroso cysteinyl glycine, S-nitroso-gamma-methyl-L-homocysteine, S-nitroso-L-homocysteine, S-nitroso-gamma-thio-L-leucine, S-nitroso-delta-thio-L-leucine, and S-nitrosoalbumin. Examples of other NO donors useful herein are sodium nitroprusside (nipride), ethyl nitrite, nitroglycerin, SIN1 which is molsidomine, furoxamines, N-hydroxy (N-nitrosamine) and perfluorocarbons that have been saturated with NO or a hydrophobic NO donor. The NO donors herein are ones that acutely lower blood pressure or pulmonary artery pressure if the dose administered is high enough. A discovery herein is that these same NO donors can still block constriction and thus ameliorate (and prophylax against) pathological constriction of smooth muscle and can desensitize receptors at lower dosages which do not acutely lower blood pressure or pulmonary artery pressure. The term NO donors capable of lowering mean arterial blood pressure or pulmonary artery pressure by more than 10% is used herein to mean NO donor, the administration of which, will lower mean arterial blood pressure or pulmonary artery pressure by more than 10% if the dose administered is high enough, and is used herein to distinguish NO donors, the administration of which will not cause acute lowering of mean arterial blood pressure or pulmonary artery pressure by more than 10% regardless of dosage. It appears that an NO donor which will not acutely lower mean arterial blood pressure by more than 10% regardless of dosage is described in Bing, R. J., et al., Biochem. Biophys. Res. Com. 275, 350-353 (2000) and is referred to therein as 2-hydroxybenzoic acid 3-nitrooxymethylphenyl ester and also as B-NOD; regardless of whether or not B-NOD will acutely lower mean arterial blood pressure or pulmonary artery pressure by more than 10% at some dosage, it is meant to exclude B-NOD from the NO donors herein.

As indicated above, administration is of the NO donor is in a therapeutically effective amount which is insufficient to acutely lower mean arterial blood pressure or pulmonary artery pressure more than 10%, e.g., by more than 5% (and thus previously deemed ineffective). Additionally, the dosage is insufficient to raise FEVI by 10% or more (and thus previously viewed as ineffective) for the treatment or prophylaxis of asthma as measured by standard medical approaches, e.g., spirometry, insufficient to lower gastrointestinal muscle tone by more than 10% in the treatment or prophylaxis of rectal spasm by as measured by standard medical approaches, e.g., manometry, insufficient to lower esophageal smooth muscle tone by more than 10% in the treatment or prophylaxis of esophageal spasm as measured by standard medical approaches, e.g., manometry, and insufficient to dilate the pyloris by more than 10% in the treatment or prophylaxis of pyloric stenosis as measured by standard medical approaches, e.g., manometry.

The therapeutically effective amount is an amount that ameliorates a symptom or symptoms of the condition being treated or in the case of prophylaxis an amount that prevents symptom(s) from occurring or causes the symptom(s) which occur to be less in intensity than those that would occur without the administration of the invention. For acute coronary spasm, symptom(s) that are ameliorated include chest pain, hypoxemia and myocardial infarction or size of infarction is decreased. For pulmonary hypertension, symptom(s) that are ameliorated include heart failure, shortness of breath and cough. For systemic hypertension, symptom(s), signs, that are ameliorated include headache, but need not be present. For asthma, symptom(s) which are ameliorated include shortness of breath, cough and wheezing. For rectal spasm, symptoms that are ameliorated include pain. For esophageal spasm, symptoms that are ameliorated include pain. For pyloric stenosis, symptom(s) which are ameliorated include pain and insufficient food intake. For stroke, symptoms which are ameliorated include cognitive, sensory, and motor symptoms. In all these cases, prophylaxis involves administration to those at risk to prevent the symptoms from occurring or causes the symptom(s) which do occur to be less in intensity than those which would otherwise occur and treatment involves administration to those having the disease or condition even if asymptomatic.

In general, administering a therapeutically effective amount for the first embodiment involves administration in an amount to achieve a concentration of NO donor in the blood of 100 picomolar to 100 micromolar (depending on the drug administered and the disease treated or at risk for) which is less than the amount which acutely lowers mean arterial blood pressure more than 10%, e.g., by more than 5%, for example, less than amounts causing at least 50% smooth muscle relaxation, ie., micromolar amounts, or to achieve concentration less than that which lowers pulmonary artery pressure more than 10%, e.g., by more than 5%. Amounts of drug will vary depending on NO donor as well as disease state.

Routes of administration for the first embodiment for NO donor include, for example, intravenous, nebulized, aerosolized, topical, sublingual, and subcutaneous but not intraarterial. Ethyl nitrite may be administered, for example, as a gas or in an infusion.

We turn now to the method of the second embodiment of the invention herein, that is to the method for prophylaxis or treatment of a patient with a disease associated with a receptor having a cysteine residue or other cysteine containing protein that is modified by NO donor to inhibit or stimulate its function or at risk therefor, comprising administering an NO donor which is capable of acutely lowering mean arterial blood pressure or pulmonary artery pressure by more than 10% to said patient in a therapeutically effective amount which is insufficient to acutely lower mean arterial blood pressure or pulmonary artery pressure by more than 10%, e.g., by more than 5%.

Receptors having cysteine residues include serotonin receptors, adrenergic receptors, NMDA receptors, ryanodine receptors, muscarinic receptors, and kinin receptors. In one subgenus of the second embodiment, the receptors having a cysteine residue also include membrane receptors. In a different subgenus of the second embodiment, the receptors having a cysteine residue do not also include membrane receptors.

Other cysteine containing protein that is modified by NO donor to inhibit its function includes NF.kappa.B, AP1, ras, Na+ channels, Ca2+ channels, K+ channels, and prion protein. (See Stamler, J. S., Cell, 2001.)

Diseases associated with serotonin receptors treatable in the second embodiment herein include, for example, depression, stress, anxiety and atherosclerosis.

Diseases associated with adrenergic receptors include, for example, systemic hypertension, pulmonary hypertension and coronary artery disease.

Diseases associated with NMDA receptors include, for example, atherosclerosis, neurodegeneration, Alzieimer's disease, dementia, Parkinson's disease, stress and anxiety.

We turn now to the membrane receptors. In one subgenus of the second embodiment, the NO donor is administered to modify membrane receptors, such as those in red blood cells, e.g., AEI protein; this prevents the causing of vasoconstriction by red blood cells and decreases the associated risk of heart attack, stroke, pulmonary hypertension and systemic hypertension and thus mitigates the cardiovascular toxicity associated with red blood cells. The method of this subgenus includes infusing NO donor in an amount which is insufficient to acutely lower mean arterial blood pressure and pulmonary artery pressure more than 10%, e.g., more than 5%, but which is a therapeutic amount to load red blood cells to prevent vasoconstricting effect of red blood cells and prophylax against or treat ischemic disorders, sickle cell disease, and thalassemias.

We turn now to the cysteine containing proteins that are not receptors.

Diseases that are associated with NF.kappa.B, Ca2+ and K+ channels include stroke and heart failure.

Diseases that are associated with other cysteine containing protein that is not receptor include prion related diseases, e.g., Creutzfeldt-Jacob disease, kuru and mad cow disease, and malignant hyperthermia.

We turn now to the method of the second embodiment generally.

The treatment involves administration to those having the disease.

The prophylaxis involves administration to those at risk for the disease.

The NO donors administered are the same as in the case of the first embodiment.

We turn now to the amount of NO donor administered in the second embodiment. As indicated above, this is a therapeutically effective amount of NO donor which is insufficient to acutely lower mean arterial blood pressure or pulmonary artery pressure more than 10%, e.g., by more than 5%, and which changes blood vessel diameter less than 10%.

The therapeutically effective amount for the second embodiment is an amount that ameliorates a symptom or symptoms of the disease being treated or in the case of prophylaxis an amount that prevents symptoms from occurring or causes the symptom(s) which occur to be less in intensity than those which would occur without the administration of the invention. For treatment or prophylaxis of depression, the amount is an amount effective to ameliorate the presence or occurrence of symptoms of depression, e.g., morbid mood, sleep disorder and inability to experience grief, joy or pleasure. For treatment or prophylaxis of stress, the amount is an amount effective to ameliorate the presence or occurrence of fear and anxiety. For treatment or prophylaxis of anxiety, the amount is an amount effective to ameliorate the presence or occurrence of symptoms of restlessness, unusual fatigability, difficulty in concentration, irritability, muscle tension and disturbed sleep. For treatment or prophylaxis of atherosclerosis, the amount is an amount effective to ameliorate the presence or occurrence of symptoms of vasospasm, ischemia, myocardial infarction, progression of atherosclerotic lesions and heart failure. For prophylaxis of systemic hypertension, the amount is an amount effective to control blood pressure to improve symptoms, e.g., headache, and to prevent stroke or other complication. In the treatment or prophylaxis of pulmonary hypertension, the amount is an amount effective to ameliorate the presence or occurrence of symptoms as described above. In the treatment or prophylaxis of heart failure, the amount is an amount effective to ameliorate the presence or occurrence of symptoms of shortness of breath, fatigue, exercise intolerance, and swelling of the legs. In the treatment or prophylaxis of asthma or COPD, the amount is an amount effective to ameliorate the presence of symptoms as described above. In the treatment or prophylaxis of neurodegeneration, the amount is an amount effective to ameliorate the presence or occurrence of symptoms of cognitive, motor, sensory, and vestibular impairment. In the treatment or prophylaxis of Alzheimer's disease, the amount is an amount effective to ameliorate the presence or occurrence of symptoms of memory loss or other impairments as recited in standard textbooks. In the treatment or prophylaxis of dementia, the amount is an amount effective to ameliorate the presence or occurrence of cognitive symptoms or other related impairments as defined in standard textbooks. In the treatment or prophylaxis of a prion-related disease, the amount is an amount effective to ameliorate the presence or occurrence of cognitive symptoms or psychological impairment. In the treatment or prophylaxis of coronary artery disease, the amount is an amount effective to ameliorate the presence or occurrence of symptoms of pain or myocardial infarction or to decrease its size. In a treatment or prophylaxis involving red blood cells, the amount is an amount effective to prevent vasoconstricting effect of red blood cells.

Benefit is obtained because the doses used herein are sufficient to desensitize receptors and alter other proteins involved in disease where hyposensitivity mediates or potentiates the occurrence and intensity of symptoms. For example, for prophylaxis or treatment of atherosclerosis, the administration of the second embodiment negates sensitivity to vasospasm, ischemic and myocardial infarction. Benefit is obtained because dosages functional to desensitize receptors and other disease involved proteins include dosages which have no effect on vascular tone. The goal here is to mitigate hyposensitivity without affecting vascular tone or blood pressure. The dosages used for the second embodiment are those that mitigate hyposensitivity without affecting vascular tone.

In general, administering a therapeutically effective amount for the second embodiment involves administration to provide in blood a concentration of NO donor of 100 picomolar to 100 micromolar (depending on the drug administered and the disease treated or at risk for) which is less than the amount which acutely lowers the mean arterial blood pressure or pulmonary artery pressure more than 10%, for example, more than 5%, for example, less than micromolar amounts, or equivalent amount of NO bioactivity.

Routes of administration for the second embodiment herein, include, for example, intravenous, oral, subcutaneous, nebulized, bur not intraarterial.

We turn now to the third embodiment herein, i.e., the method herein for treating a patient in need of an NO donor and of increased blood pressure, comprising administering a therapeutically effective amount of NO donor directly into an artery of the patient.

The patients for this method include, for example, those having the disorders of sepsis or orthostatic hypotension or hypotention of any cause with mean arterial blood pressures less than 90 mm Hg or systolic blood pressure less than 90 mm Hg.

The NO donors are those described above and include, for example, S-nitrosohemoglobin and S-nitrosoglutathione.

The therapeutically effective amount is an amount which relieves symptoms of the disorder being treated and raises mean arterial blood pressure by at least about 10%, e.g., from 90 to 100 mm Hg. The amounts depend on the drug being administered but generally provide nanomolar to micromolar concentrations of drug in the blood.

This method is related to the first and second embodiments described above in allowing increased dosage compared to what is described for the first and second embodiments without acutely lowering mean arterial blood pressure.

We turn now to the fourth embodiment herein, i.e., the method herein for the prophylaxis or treatment of a patient with a cardiovascular syndrome, or at risk therefor, comprising administering a therapeutically effective amount of a thiol which is insufficient to acutely lower mean arterial blood pressure or pulmonary artery pressure by more than 10%, e.g., by more than 5%.

The term "cardiovascular syndrome" is used herein to mean heart disease, stroke, transient ischemic attack, ischemic coronary syndrome, peripheral vascular disease, claudication, impotence, and mesenteric or other organ ischemia.

The treatment is directed to patients with a cardiovascular syndrome.

The prophylaxis is directed to patients at risk for a cardiovascular syndrome.

The thiols useful in the fourth embodiment are those that, when added to blood, promote S-nitrosothiol formation in blood, i.e., cause increase in levels of circulating endogenous S-nitrosothiols. The term "circulating" is used to mean circulating in blood. Addition of thiol to blood to raise circulating endogenous S-nitrosothiol levels is described in Lipton, Nature, 2001.

Suitable thiols for use in the fourth embodiment include, for example, glutathione and N-acetylcysteine.

The therapeutically effective for the fourth embodiment is an amount that causes increase in level of circulating S-nitrosothiols and thereby ameliorates a symptom or symptoms of the pathological condition being treated, or in the case of prophylaxis prevents symptoms from occurring or causes the symptom(s) which occur to be less in intensity than those that would occur without the administration of the invention. For the treatment of angina, for example, the therapeutically effective amount is an angina ameliorating amount. Increase in level of circulating S-nitrosothiols can be measured as described in Feelisch, M. and Stamler, J. S., "Methods in Nitric Oxide Research," John Wiley & Sons, New York, 1996.

In general, administering a therapeutically effective amount for the fourth embodiment involves administration to provide in the blood a concentration of administered thiol of 1 nanomolar to 10 millimolar (depending on the drug administered and the disease treated, or at risk for) which is less than the amount which acutely lowers the mean arterial blood pressure and pulmonary artery pressure by more than 10%, e.g., by more than 5%.

Routes of administration for the second embodiment, include, for example, oral and intravenous administration.

Thus, in the fourth embodiment herein, thiol, e.g., glutathione or N-acetylcysteine, is given to a patient, e.g., by oral or intravenous administration, at concentrations that do not acutely change blood pressure or pulmonary artery pressure, in order to raise the circulating levels of endogenous S-nitrosothiols. Lipton (Nature, 2001) has shown that thiol added to blood promotes S-nitrosothiol formation. The fourth embodiment herein differs from Lipton in administering amounts of thiol that do not acutely affected mean arterial blood pressure or pulmonary artery pressure in a significant degree.

Claim 1 of 27 Claims

What is claimed is:

1. A method for prophylaxis or treatment of a patient with a disease of the vasculature involving constriction or proliferation of smooth muscle or other pathologic condition involving constriction or proliferation of smooth muscle, or at risk for such, except for acute thrombotic complications of restenosis or platelet embolism or other thromboembolic events, said method comprising administering to said patient an NO donor that donates nitric oxide or a related redox species and provides bioactivity that is identified with nitric oxide and which is capable of acutely lowering mean arterial blood pressure or pulmonary artery pressure by more than 10% in a therapeutically effective amount which is insufficient to acutely lower mean arterial blood pressure or pulmonary artery pressure by more than 10%, with the proviso that when the NO donor is ethyl nitrite, it is administered in a liquid, orally or by infusion.
 


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