TREATMENT FOR SARS-COV-2 AND OTHER CORONAVIRUSES
20220362344 · 2022-11-17
Inventors
Cpc classification
International classification
Abstract
A method of treating a corona virus infection in a human includes administering to the human an effective amount of at least one a natriuretic peptide (NP) and a neprilysin inhibitor (NI). A pharmaceutical composition for the treatment of corona virus in a human includes one of a recombinant natriuretic peptide (rNP) and a chimeric natriuretic peptide D (CD-NP) and a pharmaceutically acceptable carrier.
Claims
1. A method of mitigating the symptoms of a corona virus infection in a subject in need thereof, comprising: administering to the subject an effective amount of at least one a natriuretic peptide (NP) and a neprilysin inhibitor (NI).
2. The method of claim 1, wherein the corona virus infection is SARS-COV-2.
3. The method of claim 1, further comprising: using the at least one of the NP and the NI for initiating in the human at least one of: downregulating ACE2 receptors and altering a ratio of angiotensin-converting enzyme (ACE) protein to ACE2 protein; regulating an inflammation reaction and a cytokine storm; reducing production of proinflammatory cytokines (PICs); downregulating IL-6, iL2, IL7, GCSF, IP10, MCP1, and MIP1; inhibiting Janus Associated Kinases (JAKs), JAK1, and JAK2; inhibiting tumor necrosis factor (TNF) synthesis; inhibiting tumor necrosis factors a (TNFa) in macrophages and blood; inhibiting lipopolysaccharide (LPS) in the macrophages; reducing activation of NF-.sub.kB inhibiting a vascular endothelial growth 15 factor (VEGF); downregulating neutrophil recruitment on inflamed endothelium; restoring a reactive oxygen species (ROS) oxidative stress of tissues; controlling angiopathy; inhibiting hyper coagulopathy and resulting thromboembolism and disseminated intravascular coagulation (DIC); regulating an abnormal coagulation cascade and/or angiopathy and/or inflammation and viremia; restoring equilibrium of RAAS, sympathetic, and coagulation pathway; increasing NOS activity and endothelial function; remodeling of vasculature; preventing an increased ratio between ACE to ACE2; reducing expression of platelet P selectin; reducing platelet—leucocyte interactions; suppressing thrombin-induced platelet aggregation; reducing expression of plasminogen activator inhibitor 1 (PAI 1); and improving vasoconstriction.
4. The method of claim 1, further comprising: using the at least one of the NP and the NI for at least one of preventing and improving a condition in the subject which condition is at least one of: respiratory complication and/or failure; cardiac complication and/or failure; kidney complication and/or failure; central nervous system complication and/or failure; peripheral nervous system complication and/or failure; cutaneous disruption; skeleto-muscular disruption; hyperglycemia and metabolic complication; gastrointestinal complication; endocrine and reproductive system complication and/or failure; multisystem inflammatory syndrome; and hypoxia.
5. A pharmaceutical composition, comprising: a natriuretic peptide (NP); a neprilysin inhibitor (NI); and a pharmaceutically acceptable carrier.
6. The composition of claim 5, wherein there is only one NP.
7. The composition of claim 5, further comprising multiple NPs.
8. The composition of claim 5, wherein the NP is a recombinant natriuretic peptide (rNP).
9. The composition of claim 8, wherein the rNP is selected from the group consisting of recombinant A-type natriuretic peptide (rANP), recombinant B-type natriuretic peptide (rBNP), and recombinant C-type natriuretic peptide (rCNP).
10. The composition of claim 5, wherein the NP is a chimeric natriuretic peptide D (CD-NP).
11. The pharmaceutical composition of claim 5, wherein there is only one NI.
12. The pharmaceutical composition of claim 5, further comprising multiple NIs.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0118]
[0119]
[0120] The disclosure and its various embodiments can now be better understood by turning to the following detailed description of the preferred embodiments which are presented as illustrated examples of the embodiments defined in the claims. It is expressly understood that the embodiments as defined by the claims may be broader than the illustrated embodiments described below.
DETAILED DESCRIPTION OF THE INVENTION
[0121] The following detailed description is of the best currently contemplated modes of carrying out the invention. The description is not to be taken in a limiting sense but is made merely for the purpose of illustrating the general principles of the invention, since the scope of the invention is best defined by the appended claims.
[0122] Various inventive features are described below that can each be used independently of one another or in combination with other features. However, any single inventive feature may not address any of the problems discussed above or may only address one of the problems discussed above. Further, one or more of the problems discussed above may not be fully addressed by any of the features described below.
Components of the Treatment/Composition
[0123] The inventive treatment/composition can use a variety of combinations of medications, doses, routes of administration, and durations of treatment.
[0124] The Natriuretic Peptides (NP), whose clinical and physiological effects are a foundation of the inventive treatment/composition, and other medications that may protect the NPs and enhance the effect of endogenous, and exogenous NPs, such as inhibitors of neutral endopeptidase, (NEP), also known as metallo-endopeptidase (MME), in specific, neprilysin inhibitors, decrease the break down and complement their actions and clinical effects by other effects aside from preventing the breakdown.
Natriuretic Peptides
[0125] Introduction
[0126] Natriuretic Peptides (NP) are a family of genetically distinct peptides with similar structure/function that share common membrane receptors. NPs are expressed in nearly all organs in the body. 6 types of NPs are currently known: A-type, B-type, C-type, D-type Urodilatin and, VNP (ventricular NP). Each type of NP is associated with different organs, receptors, and affinities to the receptors.
[0127] Clinical evidence of NP general benefits and effects: [0128] The natriuretic peptides have been implicated in the protection against atherosclerosis, thrombosis, and myocardial ischemia. [0129] Identification of natriuretic peptide receptors in a broad range of tissues, including the pancreas, liver, and adipose tissues, implies biological effects beyond pressure-volume homeostasis. [0130] In population-based studies, low circulating concentrations of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are associated with obesity and metabolic dysfunction. [0131] Genetically determined increased concentrations of ANP and BNP are associated with reduced blood pressure and reduced risk of hypertension in animal models and in the general population. [0132] Dysregulation or low levels of the natriuretic peptides contribute to metabolic dysfunction and could lead to cardiovascular complications, such as atherosclerosis, thrombosis, hypertension, and myocardial ischemia, and other metabolic conditions as obesity, hypercholesteremia, glucose intolerance, type 2 diabetes mellitus. [0133] Elevated levels of NPs are observed when there are injuries to vital organs. For example, BNP is a reliable marker for damage to the heart, such as in heart failure, atrial fibrillation. [0134] ANP is increased in ARDS, Car Pulmonale and Pulmonary hypertension. [0135] NP's are increased in high altitude sickness, sleep apnea and extreme exercise. (REFERENCE 9). [0136] NPs are elevated in COVID-19 Acute Respiratory Distress Syndrome, without heart involvement, (REFERENCE 3), perhaps as a compensating process for respiratory difficulty.
[0137] Objects of the present invention include: [0138] NPs are quickly degraded by other compounds in the body: the half-life of an A-type NP is several minutes, while of B-type NP is 20 minutes. An important aspect of this inventive treatment/composition is to increase the availability of NPs in the body, by first protecting the naturally occurring NPs from degradation, and by introducing additional NPs into the body, as well as maintain their bio effectiveness and functionality. [0139] Yet more, it may have a synergistic effect with other medications, such as ARB, soluble ACE2, or Guanyl cyclase stimulator (Vergudo) and others.
Physiologic Effects of Np's
[0140] NPs and their receptors mediate a diverse array of physiologic effects ranging from the control of blood pressure to regulating the immune and coagulation systems. This broad assortment of responses is achieved from the distinct actions of individual natriuretic peptides interacting with specific guanylyl cyclase receptors.
[0141] A-type Natriuretic Peptide (ANP)
[0142] ANP is degraded from pro ANP, a 28-amino acid peptide. ANP has a half-life of approximately 10 minutes in vivo.
[0143] ANP is synthesized as an inactive preprohormone, encoded by the human NPPA gene mostly in the atrial myocytes. proANP is released following stimulation of atrial cells, and rapidly converted to the 28-amino-acid ANP on the cell surface by the cardiac transmembrane serine protease Corin also known as ANP-converting enzyme. ANPs are secreted from the cardiac atrium as a response to several stimuli.
[0144] Atrial dilatation and stretching of the wall triggering the atrial volume receptors, increased sympathetic stimulation of the b receptors, increased sodium concentration, increased Endothelin, which cause vasoconstriction.
[0145] The generic name is Carperitide™ (in Japan) and is Antaridine™ (in USA).
[0146] B-type Natriuretic Peptide (BNP)
[0147] BNP affects the same receptors as ANP, but with a lower affinity. BNPs have the same physiologic effects as ANPs, but BNPs have a longer half-life of 22 min. BNP is mostly expressed in the ventricles of the heart ventricle and the brain. BNP's cellular mediator is PKG, and it is degraded from pro-BNP, a 32-amino acid peptide also cleaved by Corin or Furin.
[0148] The generic name is Nesiritide™
[0149] C-type Natriuretic Peptide (CNP)
[0150] The main effect of CNPs is to relax the vascular endothelium in response to stimuli such as shear stress (like NO) and certain proinflammatory cytokines. CNP is a selective agonist for the B-type natriuretic receptor (NPRB). The half-life of CNP is about three minutes. The precursor pro CNP is cleaved by Furin into CNP.
[0151] D-type Natriuretic Peptide (DNP)
[0152] DNP resists breakdown by neutral endopeptidase and is 10 times more potent than ANP in stimulating cGMP production in GC-A expressing cells. It exists as ‘DNP-LI’ in human plasma and the atrial myocardium. A 38-amino acid peptide, DNP is also available from the venom of the green mamba snake Dendroaspis augusticeps. Blocking the NPR-C receptor with DNP can replace the action of CNP to promote vasodilation, inhibition of the vascular inflammation, to decrease the thrombotic phenomena, which are serious problems in COVID disease.
[0153] Urodilatin (URO)
[0154] Endogenous URO is believed to be produced by the kidney through local synthesis and/or processing of renal or circulating pro-ANP. URO plays a pivotal role in regulation of urinary sodium excretion.
[0155] The generic version is ULARITIDE™.
[0156] Ventricular NP (VNP)
[0157] Expression has only been confirmed in the hearts of primitive ray-finned bony fish, in which it is responsible for the maintenance of fluid and salt homeostasis.
[0158] Other Chimeric Variations
[0159] Chimeric natriuretic peptide (CD-NP) is also known as Cenderitide™. CD-NP is created by the fusion of the 15 amino acid C-terminus of DNP with the full CNP structure This peptide chimera is a dual activator of the natriuretic peptide receptors NPR-A and NPR-B.) (REFERENCE 20).
[0160] AC-NP that combined the 17-amino acid ring of C type natriuretic peptide (CNP) with the 6-amino acid N-terminus and 5-amino acid C-terminus of atrial natriuretic peptide
[0161] VNP (VASONATRIN) which is a chimera of CNP and ANP possessing the 22-amino acid ringed structure of CNP, along with the C-terminus of ANP. (REFERENCE 21).
[0162] ANX042 Generic name: ASBNP™
[0163] ZD100 Generic name: MANP™ (REFERENCE 17)
Receptors
[0164] NPs act on the following cell surface receptors: [0165] Guanylyl cyclase-A (GC-A) which is also known as natriuretic peptide receptor-A (NPRA/ANPA) or NPR1 [0166] Guanylyl cyclase-B (GC-B) which is also known as natriuretic peptide receptor-B (NPRB/ANPB) or NPR2 [0167] Natriuretic peptide clearance receptor (NPRC/ANPC) or NPR3 (clearance), which serves both as clearance and as inhibitory G protein.
[0168] The binding of NPs to its receptor causes the conversion of GTP to cGMP and raises intracellular cGMP. As a consequence, cGMP activates a cGMP-dependent kinase (PKG or cGK) or one or more phosphodiesterase (PDEs), which is the cell mediator for NP.
[0169] Those are important regulators of intracellular Ca2+ concentrations by mediating Ca2+ sequestration in the endoplasmic or sarcoplasmic reticulum and downregulation of the L-type Ca2+ channels located in the cell membrane.
[0170] However, it may also work directly on the target receptor such as on the medullary cells of the kidney. It may also directly modulate ion channels.
[0171] The NPR-C lacks guanylyl cyclase activity; instead, receptor activation is coupled to inhibition of Adenyl Cyclase or activation of PLC, phospholipase C; (PLC). Moreover, indirect cGMP signaling downstream from NPR-C occurs through activation of eNOS.
[0172] Whereas the NPR-A preferentially binds ANP and BNP, the NPR-B binds CNP with the highest affinity. All natriuretic peptides bind to the NPR-C, which is the most abundantly expressed throughout the body.
[0173] The broad distribution of the NPRs is indicative of the wide range of biological effects of the natriuretic peptides.
TABLE-US-00001 TABLE Biological effects of the natriuretic peptides EFFECT PEPTIDE Lipolysis ANP, BNP, CNP Increased mitochondrial respiration and fat oxidation in ANP, BNP skeletal muscle Lowering of blood glucose and insulin levels BNP Decreased gastric emptying and absorption BNP EFFECT PEPTIDE Inhibition of ghrelin (also known as appetite-regulating BNP hormone) and depression of hunger feeling Increase of capacity of thermogenic energy expenditure ANP, BNP in adipocytes Inhibition of leucocyte recruitment and platelet- CNP leucocyte aggregates Inhibition of platelet aggregation CNP Inhibition of expression of adhesion molecules on ANP, CNP endothelial cells Inhibition of smooth vascular cell proliferation and ANP, BNP, CNP migration Decreased expression of tissue factor and plasminogen ANP, BNP, CNP activator inhibitor 1 from endothelial cells and vascular smooth muscle cells Suppression of infarct size resulting from ischemia and ANP, BNP, CNP reperfusion Relaxation of coronary arteries CNP Inhibition of cardiac fibroblast proliferation ANP, BNP, CNP Inhibition of hypertrophy in cardiomyocytes ANP, CNP Inhibition of macrophage infiltration, collagen ANP synthesis, and expression of proinflammatory chemotactic factors in angiotensin II-induced myocardial remodeling Stimulation of chondrocyte proliferation, hypertrophy, CNP and cartilage matrix production Loss-of-function mutations in the genes encoding CNP CNP or NPR-B causes dwarfism Regulation of fetal bone growth CNP Modulation of spermatozoa motility, testicular germ CNP cell development, and testosterone synthesis Relaxation of smooth muscle cells in the myometrium CNP Decrease occular pressure ANP
Detailed Effects of NPs (FIGS. 2A-2E)
[0174] Cardiac effect: inhibit cardiac hypertrophy, and fibrosis, as it inhibits fibroblast proliferation and decreasing inflammation since NPRs are abandoned in cardiac tissue mostly the NRP B. In response to myocardial stretch and insults to the myocardium, such as hypoxia there is upregulated expression and release of natriuretic peptides. Antifibrotic effects have been demonstrated with in vitro and in vivo administration of CNP and the chimeric analogue CD-NP (created by fusion of CNP and D-type natriuretic peptide).
[0175] Hypoxia: damage prevention in the myocardium for example with acute myocardial infarction. A decrease of nearly 15% in infarct size was reported in patients treated with Carperitide for 3 days compared to placebo. Those cardioprotective effects are because of cGMP and subsequent cGMP-PKG signaling which balance the cellular apoptosis and cells survival through the NPR A and B, but also indirectly through NO generation through the NPR C.
[0176] Hypertension: by suppression of the renin-angiotensin-aldosterone system. Patients with primary hypertension have low level of NPs.
[0177] Atherosclerosis and thickening of the vascular wall; ANP and CNP have been shown to reduce expression of adhesion molecules such as monocyte chemoattractant protein 1 (also known as C-C motif chemokine 2) and P-selectin both of which are considered pivotal for the activation of endothelial cells and the subsequent infiltration of leucocytes as well as inhibition of intimal thickening resulting from smooth muscle cell migration.
[0178] Thrombosis: Activated platelets have a role in the atherogenic process by recruiting leucocytes through the formation of platelet-leucocyte aggregates and by secretion of proinflammatory cytokines. In concert with the coagulation and fibrinolytic systems, activated platelets are also involved in thrombosis and in the thromboembolic complications observed in atherosclerosis.
[0179] CNP reduces the expression of platelet P-selectin, reduce platelet-leucocyte interactions, and suppress thrombin-induced platelet aggregation.
[0180] CNP reduced expression of plasminogen activator inhibitor 1 (PAI-1), which is the major physiological inhibitor of fibrinolysis.
[0181] Adrenal effects: reduction of aldosterone and catecholamines from the adrenal gland.
[0182] Vascular smooth muscle: relaxation via the cGMP receptors as well as inhibiting the sympathetic system.
[0183] CNS effect: All three natriuretic peptides, particularly C-type natriuretic peptide, are produced in the brain. Pressor hormones or amines such as endothelin, vasopressin, and norepinephrine, but not angiotensin II, stimulate the release of atrial natriuretic peptide from hypothalamic neurons which will produce a negative feedback through the pituitary. In the brain stem they act to decrease the sympathetic tone by tonic regulation of cardiovascular baroreceptor signal.
[0184] Dermatological effects: The receptor of SARS-CoV-2, ACE2, was found to be expressed on skin, mainly on keratinocyte. As a result, there are skin manifestations, some are severe, such as Erythema, Chilblain-like lesions, Urticaria-like lesions, Vesicular, Livedo/necrosis, Petechiae, accompanied by pruritus. However, it was proven that ATII has a role in skin healing (REFERENCE 2) since BNP is present in injured skin, suggesting that BNP may play a role in cutaneous wound healing
[0185] Metabolic Effects: (REFERENCE 6).
[0186] Adipose tissue-increase FFA release by inducing lipolysis in a cGMP-dependent in adipocytes.
[0187] Lack of NP's contributes to development of obesity and insulin resistance diabetes.
[0188] Reduction of gastric emptying, suppression of food intake and sensation of hunger, as well as induction of adiponectin expression in adipocytes.
[0189] Treatment of human white adipocytes both with ANP and BNP, independently, has been shown to lead to the induction of functional phenotype characteristics of brown adipocytes, a so-called browning of fat, which increases the capacity for thermogenic energy expenditure.
[0190] Have the effect of glucagon-like peptide 1 (GLP-1) analogues used in the treatment of type 2 diabetes and obesity.
[0191] It has also a cytoprotective effects in the myocardial, vascular smooth, endothelial, and hepatocytes through its control of the oxidative stress.
Effects of NPs on Regulatory Pathways and Systems
[0192] NPs are known to have a wide range of effects on the regulatory pathways in the body:
[0193] Renin Angiotensin Aldosterone System (RAAS)
[0194] Natriuretic peptides (NPs) can help to restore balance in the Renin Angiotensin Aldosterone System (RAAS). NPs block Renin, the enzyme that cleaves Angiotensinogen into Angiotensin I, which reduces the amount of Angiotensin II that can be converted by ACE. This action also reduces the ratio of ACE to ACE2.
[0195] Kinin Kallikrein System (KKS)
[0196] The RAAS interacts with the KKS via ACE, ACE2, and Ang II, which means that an imbalanced RAAS can contribute to an imbalanced KKS. Therefore, the balancing effects of NPs on the RAAS can also help to balance the KKS.
[0197] Sympathetic System
[0198] NPs help to balance the sympathetic system by reducing the levels of aldosterone and catecholamines, and by inhibiting the release of the neurotransmitter norepinephrine by the sympathetic nerve terminals. NPs can also balance the RAAS, and reduce levels of Ang II, which influences the sympathetic system and raises blood pressure.
[0199] Coagulation System
[0200] The coagulation system is responsible for atherosclerosis (depositing plaques of fatty material on the inner walls of arteries) and thrombosis (formation of blood clots). NPs help to control to these effects in the following ways: [0201] Inhibiting leucocyte recruitment and platelet-leucocyte aggregates help to avoid the initial formation of the clot. [0202] Inhibiting platelet aggregation withholds a major component of the blood clot. [0203] Inhibiting the expression of adhesion molecules on endothelial cells helps to limit inflammation by reduce the permeability of the blood vessel. [0204] Inhibiting the proliferation and migration of smooth vascular cells helps to control the progression of atherosclerosis in hypertension-induced vascular remodeling. [0205] NPs also decrease the expression of tissue factor and plasminogen activator inhibitor 1 from endothelial cells and vascular smooth muscle cells by reducing levels of Ang II. This helps to block the procoagulant effects of these compounds. [0206] Because the Coagulation System and the KKS are closely related, the regulatory effects of NPs on the KKS can indirectly help to balance the Coagulation System.
[0207] Reactive Oxygen Species (ROS)
[0208] In the beginning of an infection, NPs promote the ROS reaction which is one of the cell's responses to invasion. Later in the process, NPs will counter-regulate the ROS to avoid their overexpression.
[0209] Prime the neutrophil immune cells to release Reactive Oxygen Species (ROS), which aids in clearance of the invading microbes. The NPs also help to regulate the production of the ROS and Nitric Oxide (NO) because excess levels of these compounds are harmful to the body.
Effect of NPs in COVID Disease (FIGS. 2A-2E)
[0210] As an observation, in severe COVID 19 disease the fatal patients started with very low levels of the proBNP, which accelerated as they approach death (REFERENCE 19).
[0211] Conversely, the patients who made it through recovery started with much higher levels of proBNP, which only increased slightly during hospitalization, and then fell off as they recovered REFERENCE 19).
[0212] Though the following describes possible mechanism(s) of how the present invention occurs, the following are not intended to limit the scope of the present invention.
[0213] Viral Infection, Incubation, Replication
[0214] Natriuretic peptides (NPs) serve as a counter-regulatory system for the renin angiotensin aldosterone system (RAAS). By blocking renin, the enzyme that cleaves Angiotensinogen into Angiotensin I, NPs influence the level of Angiotensin II (Ang II) which increase the levels of ACE and ACE2. This helps to restore equilibrium between the ACE/Ang II/AT1 R axis and ACE2/Ang 1-7/MAS axis.
[0215] Due to the counter-regulatory action described above, the availability of ACE2 receptors for infection by SAR-COV-2 is decreased and aborted. This occurs because the feedback cycle of ACE2 cannot be sustained, and the virulence of the virus is mitigated.
[0216] Improved immune response to pathogens such as viruses and bacteria. NPs help to control the proliferation of immune cells. NPs are expressed in lymphoid tissues such as thymus, lymph nodes spleen and in macrophages.
[0217] In the innate immune response to intracellular microbes such as viruses, NPs will induce the natural killer cells (NK) to induce the programmed death of host cells (apoptosis) that are infected by the microbes. At the beginning of this process, the stimulated NK cells will also secrete interferon (INF) which then activates the macrophages to kill the microbes that have been engulfed by the macrophages (‘phagocytosed’).
[0218] NPs prime the neutrophil immune cells to induce leukotriene B4 and ROS, to upregulate the marker CD11B, and induce the phagocytic activity of the macrophages. The NPs closely regulate the production of the ROS and Nitric Oxide (NO) because excess levels of these compounds are harmful to the body.
[0219] In the ‘delayed’ immune response, the NPs encourage the T cells to mature into CD4+ and CDS+ cells. This counteracts the virus-induced loss of lymphocyte immune cells (lymphopenia) that occurs in COVID-19.
[0220] NPs promote the hormone thymopoietin and T cell maturation by promoting the dendritic cells.
[0221] ANP regulates the balance between Th1-type cytokines and Th2-type cytokines responses.
[0222] NPs may also inhibit TMPRSS2, the serine protease which must be present for the virus to enter the cell. TMPRSS2 is highly expressed in cancer disease. NPs have a regulatory effect on various types of cancer through its cGMP receptor. (REFERENCE: 8).
Effect of NPs on Immune Response, Cytokine Storm, and Runaway Inflammation and HIH
[0223] NPs reduce the production of proinflammatory mediators by inhibiting inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX-2) as well as TNF synthesis. (ANP also affects the action of TNF: it interferes with the inflammatory effects of TNF on the endothelium. The NP counteracts TNF-induced endothelial permeability and adhesion and the attraction of inflammatory cells.)
[0224] NPs reduce the production of proinflammatory mediators by inhibiting iNOS.
[0225] NPs regulate the production of inflammatory mediators in macrophages.
[0226] NPs inhibit the lipopolysaccharide (LPS) induced expression of iNOS in macrophages, and significantly reduce the activation of NF-KB as well as the secretion of tumor necrosis factor a (TNFa) in macrophages and blood.
[0227] NPs will attenuate the production of IL1 13, IL1RA, IL6, IL?, IL8, IL9, IL10, basic FGF2, GCSF, GMCSF, IFNy, IP10, MCP1, MIP1a, MIP113, PDGFB, TNFa, and VEGFA, as well as proinflammatory cytokines (PIC), including IL2, IL?, IL10, GCSF, IP10, MCP1, MIP1a, and TNFa.
[0228] NPs are Janus Kinase Inhibitors, and downregulate the JAK 1 and JAK 2 protein, which decreases the inflammatory response. (REFERENCE 18).
Effect of NPs on Chronic Inflammation and Autoimmune Response
[0229] NPS may counteract an exacerbated TH1 response as seen in chronic delayed type hypersensitivity reactions which lead to fibrosis and necrosis of the surrounding tissue.
Dysregulation of the RAAS System and Other ‘Cross Talk Axes’
[0230] Because they counter-regulate the RAAS, the other cross talk axes (KKS, immune, sympathetic) can be affected indirectly through the RAAS, as well as through direct actions.
[0231] ACE, ACE2, and Ang II, regulate the KKS. Therefore, the effects of NPs on these proteins will also affect the KKS.
[0232] NPs affect the sympathetic system, which is over expressed in Covid disease, in several ways: [0233] By affecting the adrenal gland or the CNS and inhibiting the release of norepinephrine by the sympathetic nerve terminals. [0234] Indirectly, by counter regulating the RAAS system, which is also negative controlled by the sympathetic system.
[0235] In the coagulation system, which is closely related with the KKS, NPs have atherosclerotic and thrombotic control in the following ways: [0236] By inhibiting leucocyte recruitment and platelet-leucocyte aggregates [0237] By inhibiting platelet aggregation [0238] By inhibiting the expression of adhesion molecules on endothelial cells [0239] By inhibiting the proliferation and migration of smooth vascular cells
[0240] NPs decrease the expression of tissue factor and plasminogen activator inhibitor 1 from endothelial cells and vascular smooth muscle cells, which are induced by Ang II.
[0241] ROS System (Reactive Oxygen Species)
[0242] In the beginning of the infection, NPs promote the ROS reaction which is one of the cell's responses to invasion. Later in the process, NPs will counter-regulate the ROS to avoid their overexpression.
[0243] Pulmonary Involvement by Several Mechanisms
[0244] NPs will reduce venous pressure which reduces pulmonary capillary wedge pressure, which in turn reduces pulmonary hypertension and improves ARDS and right-side cardiac failure.
[0245] Controlling the Viral Infection in the Lungs
[0246] By rebalancing the RAAS in the lungs, NPs will decrease the number of ACE2 receptors in the lungs that are available for infection by the virus. This will reduce the rate and severity of the viral infection of cells in the lungs and reduce the number of new viruses that can infect other cells.
[0247] Limiting the Runaway Immune Response and the Cytokine Storm
[0248] Lowering the rate of the viral infection will also decrease the shedding of ACE2 receptors from infected cells that contributes to the runaway immune response and damage to lung tissue.
[0249] Improving the immune response to protect against secondary infections may also reduce the hypoxia.
[0250] Improving the Inefficient Respiratory Shunt
[0251] Improving the ARDS and the Inefficient Shunt that is created by severe vasoconstriction in the leftover aerated lungs. The NP will induce vasodilatation and so improve the shunt.
[0252] Controlling Hypercoagulation & Pulmonary Emboli
[0253] By Controlling Hypercoagulation & Emboli they will prevent the Pulmonary emboli, commonly seen in Covid patients.
[0254] Rebalancing the Reactive Oxygen Species
[0255] NPs also help to rebalance the Reactive Oxygen Species (ROS) system, which helps to increase oxygenation and reduce radical products. By reducing oxidative stress, NPs help to improve the toxic condition on the alveoli in the lungs, which can also contribute to the hypoxia.
[0256] Improving the Function of the Central Nervous System
[0257] NPs can help to improve the function of the Central Nervous System and respiratory regulatory centers which may be affected by COVID-19 and contribute to the hypoxia.
[0258] Improving the Performance of the Heart
[0259] NPs improve the performance of the myocardium in the heart, which experiences a higher ‘workload’ when there is vasoconstriction and hypoxia.
[0260] Compensating Mechanism for Injuries and Extreme Conditions
[0261] NPs may be a mechanism for compensating for extreme environments and healing injuries to organs. For example, researchers have observed elevated NPs in healthy people at high altitudes, and in patients with high altitude sickness and sleep apnea. In stress tests researchers have observed elevated levels of B-type NPs (REFERENCE 9, 10).
[0262] Coagulation
[0263] NPs mitigate hyper coagulopathy and micro thromboembolism through direct effects on the RAAS and the Coagulation Cascade, as described previously.
[0264] Cardiac Involvement
[0265] NPs provide the following benefits for cardiac involvement in the disease: [0266] Suppress the infarct size that results from ischemia and reperfusion [0267] Relax the coronary arteries [0268] Inhibit proliferation of cardiac fibroblasts [0269] Inhibit hypertrophy in cardiomyocytes [0270] Inhibit infiltration of macrophages [0271] Promote the synthesis of collagen and expression of proinflammatory chemotactic factors in Ang II-induced myocardial remodeling
[0272] Kidney Involvement
[0273] Controlling Natriuresis [0274] Inducing the cGMP receptor mainly affects the medullary collecting duct of the kidney on the Natrium potassium Atpase pump to increase natriuresis. [0275] Increasing the glomerular filtration rate (GFR) and filtration fraction, which produces natriuresis (increased sodium excretion) and diuresis (increased fluid excretion). [0276] Unlike most diuretic drugs, the renal effects of NPs are potassium sparing. [0277] ANP will also increase the filtration rate by direct effect to dilate the afferent arteriole. [0278] Decreasing circulating levels of Renin, Ang II, and aldosterone, which relaxes the mesangial cells which results in further natriuresis and diuresis.
[0279] Vasoconstriction [0280] Counteracting the vasoconstriction that is induced by Norepinephrine [0281] Counteracting vasoconstriction by balancing the RAAS and reducing levels of Ang II [0282] Decreased angiotensin II contributes to systemic vasodilation and decreased systemic vascular resistance
[0283] ANP inhibits the renal sympathetic system that cause vasoconstriction.
[0284] Hypertension
[0285] NPs help to control hypertension by balancing the RAAS which reduces Ang II, which in turn reduces vasoconstriction and increases vasodilation. The mechanism of systemic vasodilation also involves NP receptor-mediated elevations in vascular smooth muscle.
[0286] General Vasoconstriction (Due to Imbalance of the RAAS)
[0287] NPs dilate veins. This increase ‘venous compliance’ which decreases the central venous pressure, which reduces cardiac output by decreasing ventricular preload. NPs dilate arteries, which decreases systemic vascular resistance and systemic arterial pressure. The mechanism of systemic vasodilation involves NP receptor mediated elevations in vascular smooth muscle.
[0288] Hyperglycemia and Metabolic Complications
[0289] NPs induce the following: [0290] Lipolysis increased mitochondrial respiration and fat oxidation in skeletal muscle, [0291] Lower blood glucose and insulin levels, [0292] Decreased gastric emptying and absorption, [0293] Inhibition of ghrelin (also known as appetite regulating hormone) [0294] Depression of feelings of hunger, [0295] Increase of capacity of thermogenic energy expenditure in adipocytes. [0296] Improving the involvement of the gastrointestinal system, leading to decreased fecal virus load. (REFERENCE12) [0297] Improving the involvement of the endocrine system. [0298] Improving the involvement of reproductive systems.
[0299] Testicular Complications and Other Reproductive Systems
[0300] NPs have the following effects: [0301] Modulation of spermatozoa motility, testicular germ cell development, and testosterone synthesis, [0302] Relaxation of smooth muscle cells in the myometrium
[0303] Psychiatric Effects
[0304] As a result of their impact on the brain and regulatory effect on the hippocampus and hypothalamus, NPs may also have the effect of reducing anxiety. (REFERENCE 11)
Neprilysin Inhibitors
[0305] Though the following describes possible mechanism(s) of how the present invention occurs, the following are not intended to limit the scope of the present invention
[0306] Neprilysin catalyzes the degradation of NPs. This action contributes to the short half-lives of NPs (typically 2 to 20 minutes).
[0307] Neprilysin
[0308] Neprilysin is a cell membrane-bound neutral endopeptidase (NEP), a metallo-endopeptidase (MME) that is expressed throughout the body, including the central nervous system, the kidneys, and vascular system, and the neutrophils, lymphocytes, and lymphoid progenitors in the immune system. Neprilysin is a member in metallopeptidases (MME), which include, NEP2, ECE1, ECE2 (endothelin converting enzyme) and phosphate regulated neutral endopeptidase (PHEx).
[0309] Neprilysin has been observed generating and degrading many bioactive peptides in vitro, but the mechanism and the effect of metabolizing those peptides with similar and counteracting activity, is not well understood. Because neprilysin is just one of many peptidases that degrade peptides, the net effect of neprilysin should only be considered in vivo and not in isolation.
[0310] Neprilysin degrades many peptides including the following: [0311] Ang I, Ang II, and Ang 1-7 (the most important of the three) [0312] Bradykinin and kallidin (causing vasodilatation, vascular permeability, pain, inflammation), Note: This effect only occurs with artificially-high doses and combined with Angiotensin-Converting Enzyme Inhibitors (ACEI). (REFERENCE 13). [0313] Glucagon (anti-inflammatory, lungs protector, stimulate hepatic glucose and ketone production) [0314] Oxytocin (protective effect in Acute Lung Injury) [0315] Enkephalins L, M enkephalins (anti-inflammatory and analgesia), oxytocin), glucagon, enkephalins, substance P, neurotensin, [0316] Adrenomedullin (causing vasodilatation) [0317] Dynorphin (causing analgesia) [0318] B endorphin (causing analgesia) [0319] ACTH (stimulate adrenal corticosteroids secretion) [0320] CGRP (causing vasodilatation pain inflammation, migraine) [0321] Bombesin like peptide (a mitogen as well as stimulate gastrin and Cholecystokinin), [0322] Chemotactic peptide formyl Met-Leu Phe (causing inflammation), [0323] Cholecystokinin cck8 (stimulates gall bladder, pancreas, and intestinal motility, create sense of satiety) [0324] Endothelin 1 and 2 (causing vasoconstriction, mitogenesis, vascular hypertrophy) [0325] FGF 2, fibroblast growth factor 2, (causing angiogenesis) [0326] Galanin (inhibits neurotransmitter release) [0327] Bastrin releasing peptide (a mitogen, stimulation of gastrin, somatostatin and CCK and gastric acid)
[0328] Another important aspect of this invention is that Neprilysin could be used as a biomarker to indicate the effectiveness of the proposed treatment on lymphopenia in COVID and other diseases. Neprilysin also exists in soluble form in the blood and cerebral spinal fluid and so can be used as a biomarker. (REFERENCE 15). Because Neprilysin is abandoned in lymphoid progenitors in the immune system such as early B, pro-B and pre-B, Neprilysin is used as a marker known as the common acute lymphoblastic leukemia antigen (CALLA). Neprilysin/CALLA is highly positive in acute lymphatic leukemia and hematological diseases, and it could be used as a biomarker to indicate the effectiveness of the proposed treatment on lymphopenia in COVID and other diseases.
[0329] Neprilysin Inhibitors
[0330] By blocking the action of Neprilysin, Neprilysin Inhibitors limit the degradation of NPs. This can extend the availability of naturally occurring NPs and enhance their beneficial effects. (REFERENCE 5). Neprilysin Inhibitors also have a negligible inhibitory effect on other metallopeptidase such as NEP2, ECE1, ECE2.
[0331] Beside blocking the NPs degradation, Neprilysin inhibitors have a variety of other effects that are relevant to the treatment of coronavirus infections, as follows: [0332] Blocking or downregulating the expression of ACE2 receptors, which reduces the ports of entry for the virus to infect a cell [0333] Improving the balance between ACE and ACE2, which helps to mitigate the dysregulation of the RAAS and related cross talk systems (KKS, immune, sympathetic) [0334] May block or downregulating the collaborator protein TMPRSS2, which is required for the virus to enter and infect the cell [0335] Downregulating interleukin IL-6, which helps to mitigate the cytokine storm by discouraging the secretion of proteins and factors that contribute to vascular permeability and leakage that are part of the hypotension and pulmonary dysfunction in ARDS
[0336] Neprilysin inhibitors have a number of secondary benefits that help to mitigate the effects of the runaway immune response and cytokine storm: [0337] Reducing inflammation and hyperreactivity in the airway by increasing glucagon [0338] Mitigating the cytokine storm by downregulating interleukin IL-6, which discourages the secretion of proteins and factors that contribute to the vascular permeability and leakage that are part of the hypotension and pulmonary dysfunction in ARDS [0339] Protecting the lungs from acute lung injury by increasing oxytocin [0340] Inhibiting influenza, a virus infection by increasing methionine enkephalin which upregulates the antiviral state in RAW264.7 cells [0341] Neprilysin promotes the expression of bradykinin receptors. Inhibiting neprilysin with sacubitril will decrease the expression of the bradykinin receptors. and the overall effect of bradykinin. [0342] Neprilysin plays an alternate role in balancing the Angiotensin's and rebalancing the RAAS, independent on other pathways.
[0343] Possible Side Effects from Neprilysin Inhibitors
[0344] The following side effects were observed in extreme situations in vitro: [0345] At artificially high doses and in the presence of Angiotensin-Converting Enzyme Inhibitors (ACEI), Neprilysin Inhibitors may inhibit the degradation of bradykinins and other inflammatory peptides, resulting in angioedema, bronchoconstriction, and inflammation (REFERENCE 13) [0346] Inhibiting the degradation of amyloid b peptides, which may predispose the patient to Alzheimer's, age-related macular degeneration, and cerebral amyloid angiopathy. (Observed in vitro) [0347] Inhibiting the degradation of Bombesin-like peptide, a mitogen, may promote cancer. (Observed in vitro) [0348] May lead to sensorimotor axonal polyneuropathy
[0349] Existing or Expired Medications That Can Be Used [0350] Sacubitril combined with valsartan (LCZ696. Manufactured and trademarked by Novartis as Entresto™) [0351] Sacubitril (AHU-377), a prodrug which is a component of sacubitril/valsartan. Sacubitril is a prodrug that is activated to Sacubitrilat (LBQ657) by demethylation via esterase Sacubitrilat is the compound that inhibits the enzyme neprilysin [0352] Sacubitrilat (LBQ657), the active metabolite of sacubitril. [0353] RB-101, an enkephalinase inhibitor, used in scientific research. [0354] UK-414,495 [0355] Omapatrilat (dual inhibitor of Neprilysin and angiotensin-converting enzyme) developed by BMS did not receive FDA approval due to angioedema safety concerns. [0356] Ecadotril. [0357] Candoxatril
Other Components of the Treatment
[0358] Routes of Administration
[0359] The routes of administration of the treatment will depend on the patient's condition, preferences, and state of health. The routes that may be used include the following: [0360] Oral route (PO) in the form of pills, capsules, or tablets, or as a solution or liquid. [0361] Injection route Intravenous (IV), intramuscular (IM), or subcutaneous (SC) [0362] Intrathecal [0363] Transrectal Suppository [0364] Inhalational route/pulmonary route-Bronchial, Inhalation, or nasal spray [0365] Sublingual/Buccal route. Sublabial [0366] Topical route Creams, ointments, [0367] Transdermal patch, [0368] Eyedrops [0369] In the form of long acting, short acting, immediate release, or delayed release.
[0370] Tailoring the Treatment
[0371] The treatment can be tailored to reflect the specific symptoms and complications that each patient experiences.
[0372] For example, the particular affinities of the A-type NP may be included or emphasized in the treatment when the following conditions are present: [0373] Acute Respiratory Distress Syndrome and Pulmonary hypertension [0374] Cytokine Storm and significant involvement of the immune system [0375] Renal hypertension [0376] Electrolyte imbalance [0377] Overstimulated sympathetic nervous system (in excess) [0378] Overweight patients
[0379] The B-type NPs may be included or emphasized in the treatment when there is cardiac failure or involvement of the central nervous system and its essential regulatory centers. (and regulatory systems). The C-type NPs may be included or emphasized in the treatment to prevent or mitigate (hypercoagulation and) thromboembolic phenomena.
[0380] Periods and Timing of the Treatment
[0381] The timing of the treatment may also be tailored to reflect the specifics of each patient's condition and situation. For example, if the treatment is intended to be a preventative measure for a patient who was exposed to a known carrier of SARS-COV-2, the recommended treatment would be from 14 to 21 days, or at the incubation period of the virus. For this it may be applicable to use a rectal suppository, to prevent GI shedding and spreading, buccal, or sublingual, nasal spray, inhalation, or to prevent and mitigate the respiratory spreading and the following lung injury and ARDS or as preventing in exposed individual and community.
[0382] For a mild form of the disease, where only cough, fever, myalgia, and fatigue are experienced, treatment for a period of one week, or until the symptoms subsided, would be appropriate.
[0383] In patients with moderate to severe condition, the treatment might continue until a significant improvement is seen and continued until the patient is discharged.
[0384] In critical patients, IV, intrabrachial treatments of 3 to 4 days with high doses may be indicated.
[0385] When there are neurological complications, such as encephalitis and neurological deficits, it may be advisable to use intrathecal route.
Clinical Evidence of the Invention
[0386] NP's are increased in the early stage of cardiac failure in Covid 19 disease and favor a recovery, while high NPs in severe patients with late increase correlate with increased death (REFERENCE 19) [0387] NP's are elevated in early stage of sepsis favor for recovery, compared to a late increase in late stages of the sepsis when there is a high mortality rate. [0388] NPs are elevated in COVID disease with no explanation elevate among patients with severe respiratory illnesses even in the absence of elevated filling pressures or clinical heart failure.
Prophetic Examples of Administration
[0389] The following are examples of how the treatment could be implemented with different combinations of medications, routes of administration, and timing.
[0390] All the following encounter regimes may be extended to lower doses as long as there is a clinical improvement and may extend to higher doses as long as there are no serious side effects and still there is increase in benefit.
[0391] Single NP, Administered Via IV
[0392] In one implementation, the treatment is administered in the form of recombinant BNP (such as Natrecor™ which is manufactured by Janssen) with an initial IV bolus of 2 mcg/kg, followed by a continuous infusion of flow rate of 0.01 mcg/kg/min for up to 96 hours. This may be indicated for patients with heart failure and/or involvement of the Central Nervous System. The dose-limiting side effect of Natrecor™ is severe hypotension. Do not initiate the treatment if systolic blood pressure is less than 110.
[0393] Single NP, Administered Via IV
[0394] In another instance, the treatment is administered in the form of ANP human recombinant, such as Carperitide™ (manufactured by Daiichi Sankyo, Japan) in a low dose such as intravenous 0.02 mcg/kg/min for up to 72 hours.
[0395] Combination of NPs, Administered Via IV
[0396] In yet another implementation, the treatment is a combination of recombinant ANP, BNP, and CNP, administered by IV, with the following doses: ANP with a continuous infusion of 0.02 mcg/kg/min; and BNP with a continuous infusion of flow rate of 0.01 mcg/kg/hr; and CNP with a continuous infusion of 0.001 mcg/kg/min. The medications are administered for up to 96 hours or until the desired clinical effects are achieved. This may be indicated for heart failure and/or thrombosis or microangiopathy.
[0397] Neprilysin Inhibitor (Sacubitril) and ARB (Valsartan), commercially available as Entresto™, Administered Via Tablet
[0398] Another example of the treatment is a combination of sacubitril and valsartan, administered as a tablet twice daily, with increasing doses as tolerated, beginning at 50 mg (24 mg sacubitril/26 mg valsartan) and increasing to 100 mg (49/51 mg) and then to 200 mg (97/103) mg. The treatment is continued until the clinical effects are achieved.
[0399] Even though this invention does not include synergistic drug combinations of different classes, since Entresto™ is the only available drug for NI, we still use it.
[0400] Sacubitril, PO, BID, Administered Via Tablet
[0401] In this example, the treatment is sacubitril administered orally, twice daily, with a dose of 100 mg BID The treatment is continued until the clinical effects are achieved.
[0402] NPs and Sacubitril, Administered Via IV
[0403] In this instance of the invention, the treatment is a combination of NPs (ANP, BNP, CNP) and sacubitril administered as a continuous infusion in a clinically appropriate dose such as a total of 0.01 mcg/kg/min for the NPs and 100 mg BID for the sacubitril.
[0404] ANP, BNP, Sacubitril, Administered Via Intrathecal Injection
[0405] In this instance of the invention, the treatment consists of ANP, BNP, and sacubitril, administered via a single injection into the spinal column (intrathecal). The doses are the lowest doses of to avoid neurotoxicity. This may be indicated for involvement of the Central Nervous System.
[0406] Nasal Spray
[0407] In this instance one can use a saline solution of 0.68-0.9% 9 cc adding Carperitidern 1 cc of 0.01 mcg/cc concentration which will make it a concentration of 0.001 mcg/cc apply at least 3 times a day.
[0408] Inhalation Route
[0409] Inhalation route might be very important in preventing lung injury and further ARDS; by preventing the endothelial permeability as well as shedding virus infected ace2.
[0410] For example, one could use a soluble ANP (Carperitide™) In this instance one can use a saline solution of 0.68-0.9% 9 cc adding Carperitidern 1 cc of 0.01 mcg /cc concentration which will make it a concentration of 0.001 mcg/cc in propellant HFA˜134a (1,1,′1,2 tetrafluoroethane) and ethanol. apply at about 3 times a day.
[0411] Rectal Route Suppository
[0412] This route may prevent and mitigated gastrointestinal symptoms complication and long-time virus spreading. For example, using cocoa butter or a similar substitute, polyethylene glycol, hydrogels, and glycerinated gelatin as a base and add ANP in the form of Carperitide .sub.,M or powder.
Prophetic Examples of Compositions
[0413] Single NP
[0414] Natrecor™ (Nesiritide)
[0415] As described in https://www.rxlistcmn/natrecor-drug.htm
[0416] The recommended dose of NATRECOR™ is an IV bolus of 2 mcg/kg followed by a continuous infusion of 0.01 mcg/kg/min up to 96 hours. Do not initiate NATRECOR™ at a dose that is above the recommended dose. The loading dose may not be appropriate for those with low systolic blood pressure (SBP)<110 mm Hg or for patient.
[0417] Carperitide™
[0418] Manufactured by Daiichi Sankyo, Japan also known as Anaritide
[0419] In a low dose such as slow rate of Intravenous 0.01-0.02 mcg/kg/min for up to 72 hours. Carperitide™ or A anaritide (Auriculin™, or human atrial natriuretic peptide, amino acid residues 102 to 126; Scios, Mountain View, Calif.) compares favorably to Nesiritide™ in several ways; it has a shorter half-life (2 minutes), does not mandate bolus infusion, and is used mostly as a single.
[0420] Glyco-Modified Atrial Natriuretic Peptide Derivatives
[0421] Synthesized Using Chemo-enzymatic Synthesis Approaches
[0422] This version of ANP has an extended the half-life of 14.9 d but not available as yet. (REFERENCE 17)
[0423] CDuNP Cenderitide Subcutaneous
[0424] Daily subcutaneous infusion of CD-NP at 10-30 ng/kg/day over period of 5 to 30 days (REFERENCE 17)
[0425] CD-NP Cenderitide Patch
[0426] (REFERENCE 17) sustained release 12-84 mg/ml (for 0-6 hours) or 1-6 mg/ml (for 1-30 days). film (1 cm 61 cm 60.004 cm) with a release of 1-6 ng/kg/day (between 1 to 30 days)
[0427] Ularitide
[0428] 15 ng/kg body weight continuous infusion for 3 days, which will address mostly kidney and heart failure
[0429] VNP
[0430] Single bolus of 50 μg/kg
[0431] ANX 042
[0432] IV—(still investigational)
[0433] Subcutaneous (SQ) MANP (ZD100)
[0434] which is highly resistant to degradation by NEP, as well as it seems the best-in-class pGC-A activator, once a day subcutaneous administration for 3 days
[0435] Combination of NPs
[0436] A combination of Nesiritidern but half the dose a single administration re a bolus of an IV bolus of 1 mcg/kg (to omit if blood pressure is <“110) followed by a continuous infusion of 0.005 mcg/kg/min up to 96 hours, and Carperitide™ (manufactured by Daiichi Sankyo, Japan) (Anaritide) in a low dose such as slow rate of Intravenous 0.005-0.01 mcg/kg/min tor up to 72 hours,
[0437] Neprilysin Inhibitor (Sacubitril) and ARB (Valsartan)
[0438] Sacubitril/Valsartan (LCZ696); available as Entresto by Novartis. Sacubitril (24 mg, 49 mg, or 97 mg) and valsartan (26 mg, 51 mg, or 103 mg). The valsartan component in this combination has a higher bioavailability as compared to regular valsartan tablets; therefore, valsartan 26 mg, 51 mg, and 103 mg in the brand-name combination are equivalent to valsartan 40 mg, 80 mg, and 160 mg in other formulations, respectively. To be given from the exposure for at least a month.
[0439] NPs and Sacubitril
[0440] NP as described in single NP above such as 3 days of the above one of the NP with the doses and preparation as described for a single dose. Carperitide™ 0.01-0.02 mcg/kg/min for up to 72 hours or Nesiritide™ continuous infusion of 0.01 mcg/f . . . ; g/min up to 96 hours it may with halt the dose of the first bolus, re IV bolus of 1 mcg/kg) and Sacubitril (24 mg, 49 mg, or 97 mg). It may be useful to start Sacubitril before or together with the NP.
[0441] ANP, BNP, Sacubitril
[0442] In this combination, will use both ANP and BNP as a combination of Nesiritide™ but half the dose a single administration re a bolus of an IV bolus of 1 mcg/kg (to omit if blood pressure is <110) followed by a continuous infusion of 0.005 mcg/kg/min up to 96 hours and Carperitide™ (manufactured by Daiichi Sankyo, Japan) (Anaritide) in a low dose such as slow rate of Intravenous 0.005-0.0i mcg/kg/min for up to 72 hours and Sacubitril (24 mg, 49 mg, or 97 mg). It may be useful to start Sacubitril before or together with the NP.
[0443] Many alterations and modifications may be made by those having ordinary skill in the art without departing from the spirit and scope of the embodiments. Therefore, it must be understood that the illustrated embodiments have been set forth only for the purposes of example and that it should not be taken as limiting the embodiments as defined by the following embodiments and its various embodiments.
[0444] Therefore, it must be understood that the illustrated embodiments have been set forth only for the purposes of example and that it should not be taken as limiting the embodiments as defined by the following claims. For example, notwithstanding the fact that the elements of a claim are set forth below in a certain combination, it must be expressly understood that the embodiments include other combinations of fewer, more or different elements, which are illustrated embodiments of the above even when not initially claimed in such combinations. A teaching that two elements are combined in a claimed combination is further to be understood as also allowing for a claimed combination in which the two elements are not combined with each other, but may be used alone or combined in other combinations. The excision of any illustrated embodiment of the element of the embodiments is explicitly contemplated as within the scope of the embodiments.
[0445] The words used in this specification to describe the various embodiments are to be understood not only in the sense of their commonly defined meanings, but to include by special definition in this specification structure, material or acts beyond the scope of the commonly defined meanings. Thus, if an element can be understood in the context of this specification as including more than one meaning, then its use in a claim must be understood as being generic to all possible meanings supported by the specification and by the word itself.
[0446] The definitions of the words or elements of the following claims are, therefore, defined in this specification to include not only the combination of elements which are literally set forth, but all equivalent structure, material or acts for performing substantially the same function in substantially the same way to obtain substantially the same result. In this sense, it is therefore contemplated that an equivalent substitution of two or more elements may be made for any one of the elements in the claims below or that a single element may be substituted for two or more elements in a claim. Although elements may be described above as acting in certain combinations and even initially claimed as such, it is to be expressly understood that one or more elements from a claimed combination can in some cases be excised from the combination and that the claimed combination may be directed to a sub-combination or variation of a sub-combination.
[0447] Insubstantial changes from the claimed subject matter as viewed by a person with ordinary skill in the art, now known or later devised, are expressly contemplated as being equivalent within the scope of the claims. Therefore, obvious substitutions now or later known to one with ordinary skill in the art are defined to be within the scope of the defined elements.
[0448] The claims are thus to be understood to include what is specifically illustrated and described above, what is conceptually equivalent, what can be obviously substituted and also what essentially incorporates the essential idea of the embodiment.
REFERENCES
(All of Which Are Incorporated Herein by Reference)
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