US20060100159A1 - Preventing desensitization of receptors - Google Patents
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- US20060100159A1 US20060100159A1 US11/274,047 US27404705A US2006100159A1 US 20060100159 A1 US20060100159 A1 US 20060100159A1 US 27404705 A US27404705 A US 27404705A US 2006100159 A1 US2006100159 A1 US 2006100159A1
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Definitions
- the invention herein is directed to prevention of desensitization of receptors to activation by agonists.
- GPCRs G-protein coupled receptors
- the GPCRs include ⁇ -adrenergic receptors, ⁇ -adrenergic receptors, opioid receptors and prostaglandin receptors.
- agonists are administered to activate the receptors, the receptors become desensitized, i.e., agonist administration no longer results in therapeutic activation of receptors and the receptors regardless of agonist administration are unable to control the pathologic condition.
- GPCRs G-protein receptor kinases
- the GRKs phosphorylate agonist-occupied receptors thereby promoting binding of ⁇ -arrestin molecules which inhibit interactions between the receptors and G-proteins while also promoting internalization of the receptors. GRKs thus dampen signaling by the GPCRs.
- the typical response is decreased level of GPCRs and desensitization thereof (i.e., inability of agonist to activate the receptor and inability of the GPCRs to control the disease event).
- nitric oxide donors that donate nitric oxide or a related redox species and provide bioactivity that is identified with nitric oxide, preferably S-nitrosoglutathione (GSNO), inhibit the GRKs dramatically thereby allowing GPCRs to signal and to be recycled to the cell surface, i.e., thus preventing desensitization of the GPCRs and allowing GPCRs to be available in sufficient amount to control the disease event.
- GSNO GSNO results in growth of heart muscle (hypertrophy) in vivo (which can be both dependent and independent of expression of receptors) and prevents cardiac ⁇ -adrenergic receptor down regulation after chronic administration of a ⁇ -adrenergic agonist.
- the above discoveries support the invention herein which is directed to a method for treating a patient with a disease or pathologic condition associated with G-protein receptor kinase activity where the G-protein receptor kinase activity would otherwise cause desensitization of a receptor controlling said disease or condition, said method comprising the step of administering NO donor that donates nitric oxide or a related redox species and provides bioactivity that is identified with nitric oxide to inhibit the G-protein receptor kinase activity, thereby sensitizing or preventing desensitization of said receptor.
- disease or condition associated with G-protein receptor kinase activity is used herein to mean a disease or condition resulting from under-stimulation of a GPCR or related insufficient activation of a GPCR.
- G-protein receptor kinase activity is described in Pierce, et al cited above.
- controlling said disease or condition is used herein to mean influence the biochemical or clinical correlate of the disease or condition.
- the term “desensitization of a receptor” is used herein to mean decreased activity or decreased level of expression or decreased responsiveness.
- the term “to inhibit the G-protein receptor kinase activity” is used herein to mean to decrease its activity.
- FIG. 1 is a graph of heart weight divided by body weight versus control or agent introduced and shows results of Background Example 2.
- FIG. 2 is a graph of airway resistance versus allergen challenge at recited concentrations and shows results of Background Example 3.
- FIG. 3 is a graph showing effect of GSNO on GRK phosphorylation of a synthetic peptide and shows results of Background Example 4.
- the method of the invention herein which is directed to a method for treating a patient with a disease or pathologic condition associated with G-protein receptor kinase activity where the G-protein receptor kinase activity would otherwise cause desensitization of a receptor controlling said disease or condition, said method comprising the step of administering NO donor that donates nitric oxide or a related redox species and provide bioactivity that is identified with nitric oxide, to inhibit G-protein receptor kinase activity thereby sensitizing or preventing desensitization of said receptor.
- the receptors controlling the diseases or conditions are thiol-containing receptors and can be, for example, ⁇ -adrenergic receptors, ⁇ -adrenergic receptors, ⁇ -opioid receptors and prostaglandin receptors.
- Diseases or conditions where a receptor controlling the disease or condition is a ⁇ -adrenergic receptor include, for example, right or left heart failure, a patient on a left ventricular heart assist device awaiting heart transplant and a patient who has had heart surgery and otherwise cannot be disconnected from a heart pump without loss of heart function or a patient undergoing surgery who is at risk for a cardiac event.
- a receptor controlling the disease or condition is a ⁇ -adrenergic receptor
- Diseases or conditions where a receptor controlling the disease or condition is an ⁇ -adrenergic receptor include benign prostatic hypertrophy and urinary incontinence.
- Patients with diseases or conditions where a receptor controlling the disease or condition is the ⁇ -opioid receptor include patients being treated with an opiate because of pain or a patient addicted to an opiate.
- Patients being treated with opiates include patients with severe pain because of surgery, cancer or accidental injury.
- Opiates include, for example, morphine, oxycodone, codeine and meperidine.
- a receptor controlling the disease or condition is the prostaglandin receptor
- inflammatory conditions including rheumatoid arthritis.
- Cystic fibrosis is included in the case when the NO donor is one capable of acutely lowering FEV1 by more than 12% and the NO donor is administered in a therapeutically effective amount which is insufficient to acutely lower FEV1 by more than 12% (i.e., use of a dose which does not cause bronchodilation); treatment of a patient with cystic fibrosis with nitrolylating agent without regard to limiting dosage, is taught in WO 02/32418.
- 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, NF ⁇ B.
- a receptor protein e.g., ras protein, adrenergic receptor, NF ⁇ 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. Pat. No. 6,359,182 and in WO 02/34705.
- S-nitroso compounds including S-nitrosothiols useful herein include, for example, S-nitrosoglutathione (GSNO), 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.
- GSNO S-nitrosoglutathione
- S-nitroso-N-acetylpenicillamine S-nitroso-cysteine and ethyl ester thereof
- S-nitroso cysteinyl glycine S-nitroso-gamma-methyl-L-homocy
- 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.
- a preferred NO donor for use herein is GSNO.
- the GSNO When GSNO is administered in the treatment of a disease or pathologic condition where the receptor controlling said disease or condition is a ⁇ -adrenergic receptor, the GSNO functions to sensitize or prevent desensitization of the receptor as well as to increase heart pumping action as well as to provide the effect of an ⁇ -adrenergic agonist of maintaining or increasing blood pressure and also to activate ryanodine receptor so it releases calcium resulting in improved contractility.
- the amount of NO donor administered is an amount which causes the receptor to control the disease or pathologic condition controlled by it and sensitizes or prevents desensitization of said receptor.
- An amount that sensitizes or prevents desensitization of a receptor can be determined by pharmacological or clinical response or by receptor binding studies.
- the dosage of NO donor administered in the case of a patient with heart failure, or who is connected to a left ventricular heart assist device awaiting heart transplant or who has had heart surgery and otherwise cannot be disconnected from a heart pump without loss of heart function is a dosage that increases heart pumping function and in the case of GSNO is a dosage which also stimulates growth of heart muscle.
- the dosage of NO donor for an operative procedure is one which protects from a coronary event.
- the dosage of NO donor for a patient being treated with or who is addicted to an opiate is a dosage which stabilizes or reduces the dosage of opiate to obtain a particular level of effect.
- the dosage of NO donor for an inflammatory condition is an inflammation ameliorating effect, e.g., to ameliorate bronchoconstriction and hypoxia and prevent the long term deterioration of lung function, dyspnea, cough, chronic airway infection, bronchiectasis, atelectasis and pneumonothorax in patients with cystic fibrosis and in the case of rhematoid arthritis to reduce joint inflammation and tenderness and synovial thickening and joint stiffness.
- administering an effective amount of NO donor involves administration to achieve an amount of NO donor in the blood of 100 picomolar to 100 micromolar depending on the agent administered and the disease or condition treated.
- the NO donor is administered in a therapeutically effective amount which is insufficient to lower mean arterial blood pressure or pulmonary artery pressure by more than 10%.
- GSNO When GSNO is the treating agent, it is preferably administered at a dosage ranging from 0.01 nmol/kg/min to 1000 nmol/kg/min, very preferably from 0.1 to 10 nmol/kg/min.
- the GSNO or NO donor is preferably administered in amount which both increases the pumping action of the heart and causes growth of heart muscle and very preferably in conjunction with a ⁇ -adrenergic receptor agonist, e.g., isoproterenol, dobutamine or dopamine.
- the ⁇ -adrenergic receptor agonist is preferably administered in an amount which increases pumping action of the heart.
- this dosage ranges from 0.5 to 50 ⁇ g/min.
- NO donor treating agents have benefit in the case of patient with chronic heart failure regardless of whether ⁇ -adrenergic agonist has or is being administered. It is known that in chronic heart failure, catecholamines are highly elevated and thus the receptor may be down regulated and/or the system desensitized, and that ⁇ -adrenergic agonists and other inotropic agents can kill patients, if used chronically because of further down regulation and desensitization. Thus NO donor functioning as a GRK inhibitor, used without ⁇ -adrenergic agonist administration, provides a unique therapeutic benefit. Moreover, as indicated above, NO donor treating agent has a benefit in the case of patients with chronic heart failure, when administered conjointly with ⁇ -adrenergic agonist.
- mice were treated with 10 ng/kg/day of GSNO or PBS infused continuously for 1 week through an azlet miniosmotic pump placed subcutaneously. Another set of mice was treated for 7 days with isoproterenol (30 mg/kg/day), and the fourth and final group received for 7 days, isoproterenol (30 mg/kg/day) plus GSNO (10 ng/kg/day). The mice were sacrificed and heart tissue was removed. Saturation binding with radiolabeled I 125 -cyanopindolol was carried out in purified cardiac membrane according to the procedure of Iaccarino et al, Circulation 98, 17A3-17A9 (1998).
- mice not treated with GSNO or isoproterenol the amount of ⁇ -adrenergic receptor was determined to be 40-50 fmol per mg protein.
- the amount of ⁇ -adrenergic receptor was determined to be 20 fmol per milligram protein, demonstrating receptor down-regulation.
- mice treated with GSNO but not isoproterenol the amount of ⁇ -adrenergic receptor was determined to be 40 fmol per mg/protein or the same as for normal mice (no GSNO or isoproterenol).
- mice treated with GSNO and isoproterenol (30 mg/kg/day) the amount of ⁇ -adrenergic receptor was determined to be 90 fmol per mg protein.
- mice were treated with 10/ng/kg/day of GSNO, or with PBS (control) or with isoproterenol (at a dosage of 30 mg/kg/day) or with 10 mg/kg/day of GSNO plus 30 mg/kg/day isoproterenol, infused continuously for 1 week.
- the animals were sacrificed and the hearts were weighed and a ratio of heart weight to body weight was determined for each case.
- the results are set forth in FIG. 1 where hw:bw, i.e., the legend on the vertical axis, is the ratio of heart weight to total body weight and “ISO” means isoproterenol.
- hw:bw i.e., the legend on the vertical axis
- GSNO treatment increases the size of the heart muscle consistent with preventing desensitization of the ⁇ -adrenergic receptor.
- Treatment with isoproterenol also increased the size of the heart muscle.
- the combination of isoproterenol plus GSNO has even more effect in increasing size of heart muscle.
- the increase in size of heart (hypertrophy) is an advantage especially in the case of a patient on a left ventricular heart assist device awaiting heart transplant and in the case of a patient who has had heart surgery and cannot be disconnected from a heart pump without loss of heart function.
- the asterisks in FIG. 1 mean p>0.05 compared to control.
- mice having normal GSNO reductase (wild type or WT) and GSNO reductase knockout mice (KO), that is with GSNO reductase knocked out thereby having increased level of GSNO were tested for responsiveness to airway provocation.
- the mice were challenged with phosphate buffered saline (PBS) or ovalbumin (OVA) according to the procedure of described in Drazen, J., et al, Annual Rev. Physiology 61, 593-625 (1999). Mice were sensitized to ovalbumin (OVA) by intraperitoncal injection 2 weeks prior to airway challenge.
- PBS phosphate buffered saline
- OVA ovalbumin
- a 49-year old white male awaiting cardiac transplantation is placed a left ventricular assist device, but continues to suffer from severe shortness of breath. He is begun on IV GSNO 4 nmol per kg per minute with decrease in shortness of breath and an increase in cardiac output.
- Intravenous GSNO is begun at 2 nmol per kg per minute and after two hours the patient is successfully removed from bypass.
- a 75-year-old white male with metastatic prostate cancer is suffering from severe bone pain unresponsive to opiates. He is begun on intravenous GSNO at 10 nmol per kg per minute in conjunction with morphine which now relieves his pain.
- a 29-year-old heroine addict enters a clinic where his dose is tapered gradually.
- his dose is tapered gradually.
- ethyl nitrite is started intravenously at 2 nmol per kg per minute and symptoms of withdrawal, including sweats and shaking, are ameliorated.
- a 66-year-old white female with rheumatoid arthritis and pulmonary infiltrates complains of shortness of breath and knee pain. She is begun on intravenous ethyl nitrite at 2 nmol per kg per minute with improvement in respiratory status and a decrease in knee pain.
Abstract
Desensitization of receptors that control disease is prevented by inhibiting G-protein receptor kinases. This has applicability, e.g., for patients with heart failure or on a left ventricular heart device or a heart pump after surgery or about to undergo surgery and at high risk for a cardiac event or on an opiate or addicted to opiate or with cystic fibrosis or rheumatoid arthritis.
Description
- This is a continuation-in-part of U.S. application Ser. No. 09/986,807 filed on Nov. 13, 2001, the whole of which is incorporated herein by reference.
- The invention herein is directed to prevention of desensitization of receptors to activation by agonists.
- Many receptors which are involved in controlling pathologic conditions are coupled to G-proteins (Pierce, K. L., et al, Nature Review (Molecular Cell Biology) 3, 639-650 (2002)). These are called G-protein coupled receptors (GPCRs). The GPCRs include α-adrenergic receptors, β-adrenergic receptors, opioid receptors and prostaglandin receptors. Over time, when agonists are administered to activate the receptors, the receptors become desensitized, i.e., agonist administration no longer results in therapeutic activation of receptors and the receptors regardless of agonist administration are unable to control the pathologic condition.
- It is known that when agonist binds to a GPCR to activate it, the sequence of events is that the receptor is phosphorylated, the phosphorylated receptor moves to the interior of the cell it is associated with, i.e., it is internalized, with the internalization often involving recruitment of β-arrestin and then the receptor is recyled and moves to the surface of the cell housing it where it is available to control a disease event and to bind to agonist for activation for control of the disease event. The GPCRs have G-protein receptor kinases (GRKs) associated with them. The GRKs phosphorylate agonist-occupied receptors thereby promoting binding of β-arrestin molecules which inhibit interactions between the receptors and G-proteins while also promoting internalization of the receptors. GRKs thus dampen signaling by the GPCRs. The typical response is decreased level of GPCRs and desensitization thereof (i.e., inability of agonist to activate the receptor and inability of the GPCRs to control the disease event). It has been discovered herein that nitric oxide donors (NO donors) that donate nitric oxide or a related redox species and provide bioactivity that is identified with nitric oxide, preferably S-nitrosoglutathione (GSNO), inhibit the GRKs dramatically thereby allowing GPCRs to signal and to be recycled to the cell surface, i.e., thus preventing desensitization of the GPCRs and allowing GPCRs to be available in sufficient amount to control the disease event. It has also been discovered herein that administration of GSNO results in growth of heart muscle (hypertrophy) in vivo (which can be both dependent and independent of expression of receptors) and prevents cardiac β-adrenergic receptor down regulation after chronic administration of a β-adrenergic agonist.
- The above discoveries support the invention herein which is directed to a method for treating a patient with a disease or pathologic condition associated with G-protein receptor kinase activity where the G-protein receptor kinase activity would otherwise cause desensitization of a receptor controlling said disease or condition, said method comprising the step of administering NO donor that donates nitric oxide or a related redox species and provides bioactivity that is identified with nitric oxide to inhibit the G-protein receptor kinase activity, thereby sensitizing or preventing desensitization of said receptor.
- The term “disease or condition associated with G-protein receptor kinase activity” is used herein to mean a disease or condition resulting from under-stimulation of a GPCR or related insufficient activation of a GPCR.
- G-protein receptor kinase activity is described in Pierce, et al cited above.
- The term “controlling said disease or condition” is used herein to mean influence the biochemical or clinical correlate of the disease or condition.
- The term “desensitization of a receptor” is used herein to mean decreased activity or decreased level of expression or decreased responsiveness.
- The term “to inhibit the G-protein receptor kinase activity” is used herein to mean to decrease its activity.
-
FIG. 1 is a graph of heart weight divided by body weight versus control or agent introduced and shows results of Background Example 2. -
FIG. 2 is a graph of airway resistance versus allergen challenge at recited concentrations and shows results of Background Example 3. -
FIG. 3 is a graph showing effect of GSNO on GRK phosphorylation of a synthetic peptide and shows results of Background Example 4. - We turn now to the method of the invention herein which is directed to a method for treating a patient with a disease or pathologic condition associated with G-protein receptor kinase activity where the G-protein receptor kinase activity would otherwise cause desensitization of a receptor controlling said disease or condition, said method comprising the step of administering NO donor that donates nitric oxide or a related redox species and provide bioactivity that is identified with nitric oxide, to inhibit G-protein receptor kinase activity thereby sensitizing or preventing desensitization of said receptor.
- The receptors controlling the diseases or conditions are thiol-containing receptors and can be, for example, β-adrenergic receptors, α-adrenergic receptors, μ-opioid receptors and prostaglandin receptors.
- Diseases or conditions where a receptor controlling the disease or condition is a β-adrenergic receptor include, for example, right or left heart failure, a patient on a left ventricular heart assist device awaiting heart transplant and a patient who has had heart surgery and otherwise cannot be disconnected from a heart pump without loss of heart function or a patient undergoing surgery who is at risk for a cardiac event. Excluded from invention herein are treatment of pulmonary hypertension and treatment of systemic hypertension which are covered in the parent application hereto.
- Diseases or conditions where a receptor controlling the disease or condition is an α-adrenergic receptor include benign prostatic hypertrophy and urinary incontinence.
- Patients with diseases or conditions where a receptor controlling the disease or condition is the μ-opioid receptor include patients being treated with an opiate because of pain or a patient addicted to an opiate. Patients being treated with opiates include patients with severe pain because of surgery, cancer or accidental injury. Opiates include, for example, morphine, oxycodone, codeine and meperidine.
- Diseases or conditions wherein a receptor controlling the disease or condition is the prostaglandin receptor include inflammatory conditions including rheumatoid arthritis. Cystic fibrosis is included in the case when the NO donor is one capable of acutely lowering FEV1 by more than 12% and the NO donor is administered in a therapeutically effective amount which is insufficient to acutely lower FEV1 by more than 12% (i.e., use of a dose which does not cause bronchodilation); treatment of a patient with cystic fibrosis with nitrolylating agent without regard to limiting dosage, is taught in WO 02/32418.
- As indicated above the agents administered herein to inhibit GRK actively are NO donors. 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, NFκB. 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. Pat. No. 6,359,182 and in WO 02/34705. Examples of S-nitroso compounds including S-nitrosothiols useful herein include, for example, S-nitrosoglutathione (GSNO), 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. A preferred NO donor for use herein is GSNO. When GSNO is administered in the treatment of a disease or pathologic condition where the receptor controlling said disease or condition is a β-adrenergic receptor, the GSNO functions to sensitize or prevent desensitization of the receptor as well as to increase heart pumping action as well as to provide the effect of an α-adrenergic agonist of maintaining or increasing blood pressure and also to activate ryanodine receptor so it releases calcium resulting in improved contractility.
- The amount of NO donor administered is an amount which causes the receptor to control the disease or pathologic condition controlled by it and sensitizes or prevents desensitization of said receptor. An amount that sensitizes or prevents desensitization of a receptor can be determined by pharmacological or clinical response or by receptor binding studies. The dosage of NO donor administered in the case of a patient with heart failure, or who is connected to a left ventricular heart assist device awaiting heart transplant or who has had heart surgery and otherwise cannot be disconnected from a heart pump without loss of heart function, is a dosage that increases heart pumping function and in the case of GSNO is a dosage which also stimulates growth of heart muscle. The dosage of NO donor for an operative procedure is one which protects from a coronary event. The dosage of NO donor for a patient being treated with or who is addicted to an opiate is a dosage which stabilizes or reduces the dosage of opiate to obtain a particular level of effect. The dosage of NO donor for an inflammatory condition is an inflammation ameliorating effect, e.g., to ameliorate bronchoconstriction and hypoxia and prevent the long term deterioration of lung function, dyspnea, cough, chronic airway infection, bronchiectasis, atelectasis and pneumonothorax in patients with cystic fibrosis and in the case of rhematoid arthritis to reduce joint inflammation and tenderness and synovial thickening and joint stiffness.
- In general, administering an effective amount of NO donor involves administration to achieve an amount of NO donor in the blood of 100 picomolar to 100 micromolar depending on the agent administered and the disease or condition treated.
- Preferably the NO donor is administered in a therapeutically effective amount which is insufficient to lower mean arterial blood pressure or pulmonary artery pressure by more than 10%.
- When GSNO is the treating agent, it is preferably administered at a dosage ranging from 0.01 nmol/kg/min to 1000 nmol/kg/min, very preferably from 0.1 to 10 nmol/kg/min. For diseases or conditions where a receptor controlling the disease or condition is a β-adrenergic receptor, the GSNO or NO donor is preferably administered in amount which both increases the pumping action of the heart and causes growth of heart muscle and very preferably in conjunction with a β-adrenergic receptor agonist, e.g., isoproterenol, dobutamine or dopamine. The β-adrenergic receptor agonist is preferably administered in an amount which increases pumping action of the heart. For isoproterenol, this dosage ranges from 0.5 to 50 μg/min.
- Administration of the NO donor treating agents have benefit in the case of patient with chronic heart failure regardless of whether β-adrenergic agonist has or is being administered. It is known that in chronic heart failure, catecholamines are highly elevated and thus the receptor may be down regulated and/or the system desensitized, and that β-adrenergic agonists and other inotropic agents can kill patients, if used chronically because of further down regulation and desensitization. Thus NO donor functioning as a GRK inhibitor, used without β-adrenergic agonist administration, provides a unique therapeutic benefit. Moreover, as indicated above, NO donor treating agent has a benefit in the case of patients with chronic heart failure, when administered conjointly with β-adrenergic agonist.
- The invention is supported by the following background examples and illustrated by the following working examples:
- Mice were treated with 10 ng/kg/day of GSNO or PBS infused continuously for 1 week through an azlet miniosmotic pump placed subcutaneously. Another set of mice was treated for 7 days with isoproterenol (30 mg/kg/day), and the fourth and final group received for 7 days, isoproterenol (30 mg/kg/day) plus GSNO (10 ng/kg/day). The mice were sacrificed and heart tissue was removed. Saturation binding with radiolabeled I125-cyanopindolol was carried out in purified cardiac membrane according to the procedure of Iaccarino et al, Circulation 98, 17A3-17A9 (1998). For mice not treated with GSNO or isoproterenol the amount of β-adrenergic receptor was determined to be 40-50 fmol per mg protein. For mice not treated with GSNO but treated with isoproterenol (30 mg/kg/day), the amount of β-adrenergic receptor was determined to be 20 fmol per milligram protein, demonstrating receptor down-regulation. For mice treated with GSNO but not isoproterenol, the amount of β-adrenergic receptor was determined to be 40 fmol per mg/protein or the same as for normal mice (no GSNO or isoproterenol). For mice treated with GSNO and isoproterenol (30 mg/kg/day), the amount of β-adrenergic receptor was determined to be 90 fmol per mg protein. The experiment shows that GSNO prevents desensitization and down-regulation of β-adrenergic receptors caused by isoproterenol and stimulates expression of the β-adrenergic receptors.
- Mice were treated with 10/ng/kg/day of GSNO, or with PBS (control) or with isoproterenol (at a dosage of 30 mg/kg/day) or with 10 mg/kg/day of GSNO plus 30 mg/kg/day isoproterenol, infused continuously for 1 week. The animals were sacrificed and the hearts were weighed and a ratio of heart weight to body weight was determined for each case. The results are set forth in
FIG. 1 where hw:bw, i.e., the legend on the vertical axis, is the ratio of heart weight to total body weight and “ISO” means isoproterenol. As shown inFIG. 1 , GSNO treatment increases the size of the heart muscle consistent with preventing desensitization of the β-adrenergic receptor. Treatment with isoproterenol also increased the size of the heart muscle. The combination of isoproterenol plus GSNO has even more effect in increasing size of heart muscle. The increase in size of heart (hypertrophy) is an advantage especially in the case of a patient on a left ventricular heart assist device awaiting heart transplant and in the case of a patient who has had heart surgery and cannot be disconnected from a heart pump without loss of heart function. The asterisks inFIG. 1 mean p>0.05 compared to control. - Mice having normal GSNO reductase (wild type or WT) and GSNO reductase knockout mice (KO), that is with GSNO reductase knocked out thereby having increased level of GSNO, were tested for responsiveness to airway provocation. The mice were challenged with phosphate buffered saline (PBS) or ovalbumin (OVA) according to the procedure of described in Drazen, J., et al, Annual Rev. Physiology 61, 593-625 (1999). Mice were sensitized to ovalbumin (OVA) by
intraperitoncal injection 2 weeks prior to airway challenge. Baseline airway resistance measurements (PenH) were performed on mice after methacholine challenge (MCh) followed by airway challenge 24 hours later with aerosolized PBS or OVA. The mice challenged with aerosolized saline (PBS) served as the control group. The results are shown inFIG. 2 where PenH is airway resistance and MCh is methacholine challenge. As shown inFIG. 2 , the wild type mice showed a significant increase in airway resistance after OVA challenge at methacholine concentrations of 12 and 25 mg/ml whereas the KO mice had no change. The results suggest that GSNO administration will cause hyporesponsiveness to allergen challenge further suggesting that the GSNO causes sensitizing or prevents desensitization of the appropriate GPCRs, e.g., prostaglandin receptors. - An isolated system was provided consisting of medium, GRK, standard synthetic peptide substrate and radiolabeled 32P -adenosine triphosphate, i.e., 32P-ATP, as a source of phosphate. Runs were carried out on the system without additives, and with 500 μM glutathione (GSH) present and with GSNO (500 μM) present or with GSNO (50 μM) present or with GSNO (5 μm) present. The amount of bound 32P was measured in counts per minute (CPM). The results are shown in
FIG. 3 where, here is shown a concentration dependent reduction in incorporation of 32P when GSNO is present. The results suggest that GSNO inhibits GRK to inhibit phosphorylation of substrate (incorporated 32P). The same result of GRK inhibition and interference with substrate phosphorylation was found when S-nitroso-cysteine (L-SNC) was substituted for GSNO. - A 65-year old with class 4 congestive heart failure enters the hospital with shortness of breath and bradyacardia. He is given 10 μg per minute of intravenous isoproterenol with resolution of symptoms. The patient is subsequently switched to IV dobutamine at 10 μg per kg per minute titrated to cardiac output. Over the following three days the drug is increased to 30 μg per kg per minute to maintain cardiac output. The patient is then begun on IV GSNO at 2 nmol per kg per minute and cardiac output improved over the following 24 hours. The dose of dobutamine is subsequently decreased gradually and then stopped. The patient undergoes bypass surgery and does well even though he has been viewed as at high risk.
- A 49-year old white male awaiting cardiac transplantation is placed a left ventricular assist device, but continues to suffer from severe shortness of breath. He is begun on IV GSNO 4 nmol per kg per minute with decrease in shortness of breath and an increase in cardiac output.
- A 68-year old white female with an ejection fraction of 17% undergoes coronary artery bypass grafting. The surgeons are unable to remove the patient from bypass. Intravenous GSNO is begun at 2 nmol per kg per minute and after two hours the patient is successfully removed from bypass.
- A 75-year-old white male with metastatic prostate cancer is suffering from severe bone pain unresponsive to opiates. He is begun on intravenous GSNO at 10 nmol per kg per minute in conjunction with morphine which now relieves his pain.
- A 29-year-old heroine addict enters a clinic where his dose is tapered gradually. In order to avoid symptoms of withdrawal ethyl nitrite is started intravenously at 2 nmol per kg per minute and symptoms of withdrawal, including sweats and shaking, are ameliorated.
- A 17-year-old white female with cystic fibrosis enters the hospital complaining of shortness of breath. She is begun on inhaled beta agonists, but shows little improvement over the following six days. She is started on inhaled GSNO (3 cc of a 10 mM solution,
pH 7, 4×/day). Although her FEV1 does not change acutely and her blood pressure remains stable, symptoms of shortness of breath resolve over the following 48 hours (with corresponding improvement in FEV1). - A 66-year-old white female with rheumatoid arthritis and pulmonary infiltrates complains of shortness of breath and knee pain. She is begun on intravenous ethyl nitrite at 2 nmol per kg per minute with improvement in respiratory status and a decrease in knee pain.
- Variations
- Variations on the above will be obvious to those skilled in the art. Therefore the scope of the invention is to be determined by the claims.
Claims (16)
1. A method of treating a patient with a disease or pathologic condition associated with G-protein receptor kinase activity where the G-protein receptor kinase activity would otherwise cause desensitization of a receptor controlling said disease or condition, said method comprising the step of administering nitric oxide donor that donates nitric oxide or a related redox species and provides bioactivity that is identified with nitric oxide to inhibit the G-protein receptor kinase activity thereby sensitizing or preventing desensitization of said receptor.
2. The method of claim 1 where said NO donor is S-nitrosoglutathione.
3. The method of claim 1 where the receptor is a β-adrenergic receptor.
4. The method of claim 3 where the disease or condition is heart failure.
5. The method of claim 4 where the NO donor is S-nitrosoglutathione and the S-nitrosoglutathione administration causes increase in heart pumping and also stimulates growth of heart muscle.
6. The method of claim 5 where the S-nitrosoglutathione is administered in conjunction with administration of a therapeutically effective amount of isoproterenol.
7. The method of claim 3 where the disease or condition is where the patient is connected to a heart assist device awaiting heart transplant.
8. The method of claim 7 where the NO donor is S-nitrosoglutathione.
9. The method of claim 3 where the disease or condition is where the patient has had heart surgery and otherwise cannot be disconnected from heart pump without loss of heart function.
10. The method of claim 9 where the NO donor is S-nitrosoglutathione.
11. The method of claim 1 where the patient is about to undergo surgery and is at high risk for a cardiac event.
12. The method of claim 11 where the NO donor is S-nitrosoglutathione.
13. The method of claim 1 where the receptor is the μ-opioid receptor and the patient is being treated with or is addicted to an opiate.
14. The method of claim 1 where the disease or condition is an inflammatory condition which is not asthma, and when the inflammatory condition is cystic fibrosis and the NO donor is one capable of acutely lowering FEV1 by more than 12%, the NO donor is administered in a therapeutically effective amount which is insufficient to acutely lower FEV1 by more than 12%.
15. The method of claim 14 where the disease or condition is cystic fibrosis.
16. The method of claim 14 where the disease or condition is rheumatoid arthritis.
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110086234A1 (en) * | 2009-10-13 | 2011-04-14 | Nathan Stasko | Nitric oxide-releasing coatings |
US8282967B2 (en) | 2005-05-27 | 2012-10-09 | The University Of North Carolina At Chapel Hill | Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications |
US8591876B2 (en) | 2010-12-15 | 2013-11-26 | Novan, Inc. | Methods of decreasing sebum production in the skin |
US8981139B2 (en) | 2011-02-28 | 2015-03-17 | The University Of North Carolina At Chapel Hill | Tertiary S-nitrosothiol-modified nitric—oxide-releasing xerogels and methods of using the same |
US9526738B2 (en) | 2009-08-21 | 2016-12-27 | Novan, Inc. | Topical gels and methods of using the same |
US9919072B2 (en) | 2009-08-21 | 2018-03-20 | Novan, Inc. | Wound dressings, methods of using the same and methods of forming the same |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6627738B2 (en) * | 1995-09-15 | 2003-09-30 | Duke University | No-modified hemoglobins and uses therefor |
US6723703B2 (en) * | 2000-10-16 | 2004-04-20 | Duke University | Therapeutic use of aerosolized S-nitrosoglutathione in cystic fibrosis |
AU2002224466A1 (en) * | 2000-10-31 | 2002-05-15 | Duke University | Hypotension |
US6627602B2 (en) * | 2001-11-13 | 2003-09-30 | Duke University | Preventing desensitization of receptors |
US20040110691A1 (en) * | 2001-11-13 | 2004-06-10 | Stamler Jonathan S. | Thiol reactive agents as a therapeutic modality |
GB0326047D0 (en) * | 2003-11-07 | 2003-12-10 | Univ Sheffield | Substance |
US20080249176A1 (en) * | 2004-04-23 | 2008-10-09 | Rasmussen Helge H | Methods and Compositions for the Treatment of Myocardial Conditions |
JP2008303145A (en) * | 2005-09-22 | 2008-12-18 | Takeda Chem Ind Ltd | Cardiotonic comprising grk inhibitor |
FR2914554B1 (en) * | 2007-04-05 | 2009-07-17 | Germitec Soc Par Actions Simpl | METHOD OF MONITORING THE USE OF A MEDICAL DEVICE. |
EP3050537A1 (en) | 2008-10-06 | 2016-08-03 | Indiana University Research and Technology Corporation | Methods and apparatus for active or passive assistance in the circulatory system |
LT3463432T (en) * | 2016-05-27 | 2021-01-25 | Ipsen Biopharm Limited | Liquid neurotoxin formulation stabilized with tryptophan or tyrosine |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4476108A (en) * | 1981-01-16 | 1984-10-09 | Kessler Jack H | Bactericidal method |
US5574068A (en) * | 1991-03-29 | 1996-11-12 | Brigham And Woman's Hospital | S-nitrosothiols as smooth muscle relaxants and therapeutic uses thereof |
US5873359A (en) * | 1990-12-05 | 1999-02-23 | The General Hospital Corporation | Methods and devices for treating pulmonary vasoconstriction and asthma |
US6063407A (en) * | 1995-02-16 | 2000-05-16 | The General Hospital Corporation | Treatment of vascular thrombosis and restenosis with inhaled nitric oxide |
US6472390B1 (en) * | 2001-11-13 | 2002-10-29 | Duke University | Use of therapeutic dosages for nitric oxide donors which do not significantly lower blood pressure or pulmonary artery pressure |
US6627602B2 (en) * | 2001-11-13 | 2003-09-30 | Duke University | Preventing desensitization of receptors |
Family Cites Families (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63208525A (en) * | 1987-02-25 | 1988-08-30 | Kikkoman Corp | Remedy for cardiac insufficiency |
US5385937A (en) | 1991-04-10 | 1995-01-31 | Brigham & Women's Hospital | Nitrosation of homocysteine as a method for treating homocysteinemia |
US5891459A (en) | 1993-06-11 | 1999-04-06 | The Board Of Trustees Of The Leland Stanford Junior University | Enhancement of vascular function by modulation of endogenous nitric oxide production or activity |
US5728705A (en) * | 1993-10-04 | 1998-03-17 | The Trustees Of Columbia University In The City Of New York | Method of inducing vasorelaxation to treat pulmonary hypertension |
US5703073A (en) * | 1995-04-19 | 1997-12-30 | Nitromed, Inc. | Compositions and methods to prevent toxicity induced by nonsteroidal antiinflammatory drugs |
US5645839A (en) * | 1995-06-07 | 1997-07-08 | Trustees Of Boston University | Combined use of angiotensin inhibitors and nitric oxide stimulators to treat fibrosis |
US6197745B1 (en) * | 1995-09-15 | 2001-03-06 | Duke University | Methods for producing nitrosated hemoglobins and therapeutic uses therefor |
US6294517B1 (en) | 1996-02-02 | 2001-09-25 | Nitromed, Inc. | Compositions and kits comprising alpha-adrenergic receptor antagonists and nitric oxide donors and methods of use |
US5985862A (en) * | 1996-05-02 | 1999-11-16 | G.D. Searle & Co. | Pharmaceutical compositions having steroid nitrate ester derivatives useful as anti-inflammatory drugs |
US6057367A (en) | 1996-08-30 | 2000-05-02 | Duke University | Manipulating nitrosative stress to kill pathologic microbes, pathologic helminths and pathologically proliferating cells or to upregulate nitrosative stress defenses |
CA2278784A1 (en) * | 1997-02-06 | 1998-08-13 | Jonathan S. Stamler | No-modified hemoglobins and uses therefor |
JP4777489B2 (en) * | 1997-03-31 | 2011-09-21 | ザ チルドレンズ メディカル センター コーポレーション | Nitrosylation to inactivate apoptotic enzymes |
WO1998052580A1 (en) | 1997-05-21 | 1998-11-26 | Duke University | Treating asthma by preventing and/or accommodating for s-nitrosothiol breakdown |
US6486206B1 (en) * | 1997-09-29 | 2002-11-26 | Cprx Inc. | Mechanical and pharmacologic therapies to treat cardiac arrest |
AU9596698A (en) | 1997-10-15 | 1999-05-03 | Thomas Jefferson University | Nitric oxide donor compositions, methods, apparatus, and kits for preventing or alleviating vasoconstriction or vasospasm in a mammal |
ATE277038T1 (en) * | 1997-12-23 | 2004-10-15 | Amersham Health As | NITROGEN OXIDE RELEASING CHELATING AGENTS AND THEIR THERAPEUTIC USE |
US6007824A (en) | 1998-07-09 | 1999-12-28 | Duckett; Melvin J. | Natural composition and method for the treatment of sexual dysfunction |
AU763000B2 (en) * | 1998-10-30 | 2003-07-10 | Nicox S.A. | Nitrosated and nitrosylated nonsteroidal antiinflammatory compounds, compositions and methods of use |
US7045152B2 (en) * | 1999-09-08 | 2006-05-16 | Duke University | Treating pulmonary disorders with gaseous agent causing repletion of GSNO |
US6314956B1 (en) * | 1999-09-08 | 2001-11-13 | Duke University | Pulmonary delivery of NO group-containing compound in gas form to treat respiratory, cardiac and blood disorders |
CA2410632A1 (en) * | 2000-06-22 | 2001-12-27 | David S. Garvey | Nitrosated and nitrosylated taxanes, compositions and methods of use |
US6723703B2 (en) | 2000-10-16 | 2004-04-20 | Duke University | Therapeutic use of aerosolized S-nitrosoglutathione in cystic fibrosis |
US6359182B1 (en) | 2000-10-26 | 2002-03-19 | Duke University | C-nitroso compounds and use thereof |
US7179791B2 (en) | 2001-01-11 | 2007-02-20 | Duke University | Inhibiting GS-FDH to modulate NO bioactivity |
US6489206B2 (en) * | 2001-03-22 | 2002-12-03 | United Microelectronics Corp. | Method for forming self-aligned local-halo metal-oxide-semiconductor device |
-
2002
- 2002-10-25 US US10/280,085 patent/US6627602B2/en not_active Expired - Lifetime
-
2003
- 2003-06-30 US US10/608,120 patent/US6964984B2/en not_active Expired - Fee Related
- 2003-10-20 WO PCT/US2003/029134 patent/WO2004039313A2/en active Application Filing
- 2003-10-20 CA CA002503624A patent/CA2503624A1/en not_active Abandoned
- 2003-10-20 EP EP03777526A patent/EP1567182A4/en not_active Withdrawn
- 2003-10-20 JP JP2004548325A patent/JP4705783B2/en not_active Expired - Fee Related
- 2003-10-20 AU AU2003287006A patent/AU2003287006B2/en not_active Ceased
-
2005
- 2005-11-15 US US11/274,047 patent/US20060100159A1/en not_active Abandoned
-
2010
- 2010-04-26 JP JP2010101547A patent/JP2010159307A/en not_active Withdrawn
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4476108A (en) * | 1981-01-16 | 1984-10-09 | Kessler Jack H | Bactericidal method |
US5873359A (en) * | 1990-12-05 | 1999-02-23 | The General Hospital Corporation | Methods and devices for treating pulmonary vasoconstriction and asthma |
US5574068A (en) * | 1991-03-29 | 1996-11-12 | Brigham And Woman's Hospital | S-nitrosothiols as smooth muscle relaxants and therapeutic uses thereof |
US6063407A (en) * | 1995-02-16 | 2000-05-16 | The General Hospital Corporation | Treatment of vascular thrombosis and restenosis with inhaled nitric oxide |
US6472390B1 (en) * | 2001-11-13 | 2002-10-29 | Duke University | Use of therapeutic dosages for nitric oxide donors which do not significantly lower blood pressure or pulmonary artery pressure |
US6627602B2 (en) * | 2001-11-13 | 2003-09-30 | Duke University | Preventing desensitization of receptors |
US6964984B2 (en) * | 2001-11-13 | 2005-11-15 | Duke University | Preventing desensitization of receptors |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9403851B2 (en) | 2005-05-27 | 2016-08-02 | The University Of North Carolina At Chapel Hill | Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications |
US8282967B2 (en) | 2005-05-27 | 2012-10-09 | The University Of North Carolina At Chapel Hill | Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications |
US11691995B2 (en) | 2005-05-27 | 2023-07-04 | The University Of North Carolina At Chapel Hill | Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications |
US8956658B2 (en) | 2005-05-27 | 2015-02-17 | The University Of North Carolina At Chapel Hill | Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications |
US8962029B2 (en) | 2005-05-27 | 2015-02-24 | The University Of North Carolina At Chapel Hill | Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications |
US9403852B2 (en) | 2005-05-27 | 2016-08-02 | The University Of North Carolina At Chapel Hill | Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications |
US9526738B2 (en) | 2009-08-21 | 2016-12-27 | Novan, Inc. | Topical gels and methods of using the same |
US9737561B2 (en) | 2009-08-21 | 2017-08-22 | Novan, Inc. | Topical gels and methods of using the same |
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US10376538B2 (en) | 2009-08-21 | 2019-08-13 | Novan, Inc. | Topical gels and methods of using the same |
US11583608B2 (en) | 2009-08-21 | 2023-02-21 | Novan, Inc. | Wound dressings, methods of using the same and methods of forming the same |
US20110086234A1 (en) * | 2009-10-13 | 2011-04-14 | Nathan Stasko | Nitric oxide-releasing coatings |
US8591876B2 (en) | 2010-12-15 | 2013-11-26 | Novan, Inc. | Methods of decreasing sebum production in the skin |
US8981139B2 (en) | 2011-02-28 | 2015-03-17 | The University Of North Carolina At Chapel Hill | Tertiary S-nitrosothiol-modified nitric—oxide-releasing xerogels and methods of using the same |
US9713652B2 (en) | 2011-02-28 | 2017-07-25 | The University Of North Carolina At Chapel Hill | Nitric oxide-releasing S-nitrosothiol-modified silica particles and methods of making the same |
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EP1567182A2 (en) | 2005-08-31 |
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CA2503624A1 (en) | 2004-05-13 |
WO2004039313A3 (en) | 2004-07-22 |
AU2003287006A1 (en) | 2004-05-25 |
JP4705783B2 (en) | 2011-06-22 |
AU2003287006B2 (en) | 2010-03-18 |
WO2004039313A2 (en) | 2004-05-13 |
EP1567182A4 (en) | 2010-09-08 |
US20040053852A1 (en) | 2004-03-18 |
US20030092633A1 (en) | 2003-05-15 |
JP2006503901A (en) | 2006-02-02 |
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