News Column

Patent Application Titled "Treatment of Pulmonary Disease" Published Online

June 20, 2014



By a News Reporter-Staff News Editor at Drug Week -- According to news reporting originating from Washington, D.C., by NewsRx journalists, a patent application by the inventors Pruzanski, Mark (New York, NY); Adorini, Luciano (Milano, IT), filed on November 26, 2013, was made available online on June 5, 2014 (see also Patents).

No assignee for this patent application has been made.

Reporters obtained the following quote from the background information supplied by the inventors: "Pulmonary diseases, commonly known as lung diseases, represent the third leading cause of death in the US. The most frequently diagnosed pulmonary diseases include emphysema, asthma, pneumonia, tuberculosis, pulmonary hypertension, and lung cancer. Pulmonary hypertension is a chronic and progressive disease. The key pathologic change in pulmonary hypertension is the remodeling of small pulmonary arteries, characterized by thickening of the intima, media, and adventitia. The progressive narrowing of the pulmonary microvascular bed, and the subsequent increase in vascular resistance, reduce their capacity to carry blood and causes an increase in pressure. Over time, the increased pressure induces an adaptive hypertrophy in the right ventricle (RV) and eventually causes heart failure and leads to patient death.

"Pulmonary hypertension may be caused by a combination of factors including autoimmune diseases such as scleroderma and rheumatoid arthritis, birth defects of the heart, blood clots in the lungs (pulmonary embolism), congestive heart failure, heart valve disease, HIV infection, extended periods of low oxygen levels in the blood, lung disease such as COPD and pulmonary fibrosis, various medications and substances of abuse, and/or obstructive sleep apnea. Although the exact pathophysiology of pulmonary hypertension remains unknown, there is increasing evidence for a crucial role of inflammation and activation of the innate and adaptive immunities in the development and progression of pulmonary hypertension (Price et al., Chest 2012, 141:210-221).

"Several therapeutic agents have been developed for the medical management of pulmonary hypertension, including prostanoids, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, and two PDE5 inhibitors, tadalafil and sildenafil. Nitric oxide (NO) is a potent relaxant agent for smooth muscle cells in the pulmonary arteries, exerting its activity through cyclic GMP (cGMP). Intracellular cGMP level depends on the activation of a number of phosphodiesterase (PDEs), among which PDE5 is the most abundantly expressed isoform in the pulmonary circulation.

"Acute Lung Injury (ALI) and its more severe form, Acute Respiratory Distress Syndrome (ARDS), are characterized by an acute inflammatory response localized to the air spaces and lung parenchyma of the lungs. ALI and ARDS are major causes of acute respiratory failure, and are associated with high morbidity and mortality in critically ill patients. ARDS may account for 36,000 deaths per year in a country the size of the US. Despite advances in ALI and ARDS patient management, such as lung-protective ventilation, there still exists a need for effective treatments.

"The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is highly expressed in different organs, including adipose tissue, liver, kidney, adrenals, intestine and vascular bed (Lefebvre, Physiol. Rev. 2009). FXR signaling modulates several metabolic pathways, regulating triglyceride, cholesterol, glucose and energy homeostasis, and potentially affects the pathogenesis of atherosclerosis by increasing NO production and reducing neointima proliferation and vascular inflammation (Lefebvre, Physiol. Rev. 2009). FXR is also expressed in rat pulmonary artery endothelial cells (ECs) (He, F., et al., Circulation Research 2006, 98: 192-199). Activation of FXR in ECs leads to downregulation of endothelin (ET)-1 expression, a potent vasoconstrictive substance. Manipulation of ET-1 expression in vascular ECs may be useful in controlling pulmonary hypertension. Also, FXR activation suppresses inflammation in the lungs and promotes lung repair after injury. FXR knock-out mice showed increased inflammation in the lungs and defective lung regeneration after acute lung injury induced by lipopoly-saccharide treatment. In vitro, FXR activation was shown to suppress the expression of P-selectin and induce Foxm 1b expression. Together these effects serve to decrease the permeability of the lung, suppress the movement of leukocytes out of circulation and into inflamed tissues, and promote lung repair in an inflammatory mouse model (Zhang, L., Mol. Endocrinol. 2012, 26(1): 27-36). Similar results were observed in the pulmonary fibrosis mouse model (Zhou et al., 2013, 761-65). These findings support the potential ability of FXR or its agonist to suppress lung injury and promote lung repair for treating inflammation-induced lung injury.

"Because current treatments are inefficient to improve survival of patients suffering from pulmonary disease, such as pulmonary hypertension, alternative therapies are urgently needed. The present invention addresses such needs.

BRIEF DESCRIPTION OF THE DRAWINGS

"FIG. 1 is a chart showing the study outline and the schedule to perform blood pressure, urine, and blood analyses on the Dahl salt-sensitive (DSS) rats. The DSS rats include four groups (see Example 4, herein referred to as 'DSS study rats').

"FIG. 2 is a graph indicating the body weight (gram) of the DSS study rats versus time (week).

"FIG. 3 is a graph indicating the survival rate (%) of DSS study rats versus time (week).

"FIG. 4 is a graph indicating the heart rate (bpm) of DSS study rats versus time (week).

"FIG. 5 is a graph indicating the systolic blood pressure (SBP; mmHg) of DSS study rats versus time (week).

"FIG. 6A is a graph indicating the heart mass % of body weight (BW) of DSS study rats.

"FIG. 6B is a graph indicating the lung mass % of BW of DSS study rats.

"FIG. 6C is a graph indicating the kidney mass % of BW of DSS study rats.

"FIG. 7 is a graph indicating the fasting blood glucose concentration (mg/dL) over time (min) during glucose tolerance test (GTT) in DSS study rats.

"FIG. 8 is a graph indicating the fasting plasma insulin concentration (ng/mL) over time (min) during GTT in DSS study rats.

"FIG. 9 is a histogram indicating the insulin sensitivity using insulin resistance (IR) index in DSS study rats.

"FIG. 10A is a graph indicating the urinary albumin (mg/day) of DSS study rats.

"FIG. 10B is a graph indicating the urinary albumin to creatinine ratio (UACR) of DSS study rats.

"FIG. 11A is a graph indicating the serum ADMA levels (.mu.mol/L) of DSS study rats over time (week).

"FIG. 11B is a graph indicating the urinary ADMA levels (nmol/body) of DSS study rats over time (week).

"FIG. 11C is a graph indicating the serum NO levels (union) of DSS study rats over time (week).

"FIG. 11D is a graph indicating the urinary NO levels (nmol/body) of DSS study rats over time (week).

"FIG. 12 is a plot indicating the degree of right ventricular hypertrophy (RVH) for each treatment group of DSS study rats following animal sacrifice.

"FIGS. 13A-D are 20.times. magnified images of hematoxylin-eosin stained lung sections taken from rats in the control group (A), monocrotaline treated group (B), monocrotaline plus obeticholic acid (OCA) treated group (C), and monocrotaline plus tadalafil treated group (D) on day 7. The long arrows indicate vessel lumen, and the short arrows indicate vessel wall.

"FIG. 13E is a histogram indicating the pulmonary artery wall thickness on day 7 in the treated rats as compared to that for the control group rats. * p

"FIGS. 14A-D are 20.times. magnified images of hematoxylin-eosin stained lung sections taken from rats in the control group (A), monocrotaline treated group (B), monocrotaline plus OCA treated group (C), and monocrotaline plus tadalafil treated group (D) on day 28. The long arrows indicate vessel lumen, and the short arrows indicate vessel wall.

"FIG. 14E is a histogram indicating the pulmonary artery wall thickness on day 28 in the treated rats as compared to that for the control group rats. * p

"FIG. 15 is a plot indicating the effect of OCA on mRNA expression of MCP-1 in the control and test groups on days 7 and 28.

"FIG. 16 is a plot indicating the effect of OCA on mRNA expression of IL-6 in the control and test groups on days 7 and 28.

"FIG. 17 is a plot indicating the effect of OCA on mRNA expression of VEGF in the control and test groups on days 7 and 28.

"FIG. 18 is a plot indicating the effect of OCA on mRNA expression of ACE2 in the control and test groups on days 7 and 28.

"FIG. 19 is a plot indicating the effect of OCA on mRNA expression of PKG1 in the control and test groups on days 7 and 28.

"FIG. 20 is a plot indicating the effect of OCA on mRNA expression of GC1a3 in the control and test groups on days 7 and 28.

"FIG. 21 is a plot indicating the effect of OCA on mRNA expression of PDE5 in the control and test groups on days 7 and 28.

"FIG. 22 is a graph depicting univariate analysis of survival in untreated or treated rats over time (days)."

In addition to obtaining background information on this patent application, NewsRx editors also obtained the inventors' summary information for this patent application: "The invention relates to a method of treating, reducing the risk of preventing, or alleviating a symptom of a pulmonary disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula A:

"##STR00002##

"or a pharmaceutically acceptable salt thereof, wherein R.sub.1, R.sub.2, R.sub.4, R.sub.7, and X are as defined herein.

"The invention also relates to use of a compound of formula A or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment, reducing the risk of, prevention, or alleviation of a symptom of a pulmonary disease or condition in a subject, wherein R.sub.1, R.sub.2, R.sub.4, R.sub.7, and X are as defined herein.

"The invention also relates to a compound of formula A or a pharmaceutically acceptable salt thereof, for the treatment, reducing the risk of, prevention, or alleviation of a symptom of a pulmonary disease or condition in a subject, wherein R.sub.1, R.sub.2, R.sub.4, R.sub.7, and X are as defined herein.

"The invention further relates to a method of reducing or suppressing inflammation in the lung in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula A:

"##STR00003##

"or a pharmaceutically acceptable salt thereof, wherein R.sub.1, R.sub.2, R.sub.4, R.sub.7, and X are as defined herein.

"The invention also relates to use of a compound of formula A or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reducing or suppressing inflammation in the lung in a subject, wherein R.sub.1, R.sub.2, R.sub.4, R.sub.7, and X are as defined herein.

"The invention also relates to a compound of formula A or a pharmaceutically acceptable salt thereof, for reducing or suppressing inflammation in the lung in a subject, wherein R.sub.1, R.sub.2, R.sub.4, R.sub.7, and X are as defined herein.

"The invention further relates to a method of promoting lung repair in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula A:

"##STR00004##

"or a pharmaceutically acceptable salt thereof, wherein R.sub.1, R.sub.2, R.sub.4, R.sub.7, and X are as defined herein.

"The invention also relates to use of a compound of formula A or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for promoting lung repair in a subject, wherein R.sub.1, R.sub.2, R.sub.4, R.sub.7, and X are as defined herein.

"The invention also relates to a compound of formula A or a pharmaceutically acceptable salt thereof, for promoting lung repair in a subject, wherein R.sub.1, R.sub.2, R.sub.4, R.sub.7, and X are as defined herein.

"The invention further relates to a pharmaceutical composition comprising a compound of formula A or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient for the for treating, reducing the risk of, preventing, or alleviating a symptom of a pulmonary disease or condition, or for reducing or suppressing inflammation in the lung, or for promoting lung repair in a subject, wherein R.sub.1, R.sub.2, R.sub.4, R.sub.7, and X are as defined herein.

"The invention further relates to a kit comprising a compound of the invention for use in a method of treating, reducing the risk of, preventing, or alleviating a symptom of a pulmonary disease or condition, or of reducing or suppressing inflammation in the lung, or of promoting lung repair in a subject, wherein R.sub.1, R.sub.2, R.sub.4, R.sub.7, and X are as defined herein.

"Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the case of conflict, the present specification, including definitions, will control. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

"Other features and advantages of the invention will be apparent from the following detailed description and claims."

For more information, see this patent application: Pruzanski, Mark; Adorini, Luciano. Treatment of Pulmonary Disease. Filed November 26, 2013 and posted June 5, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1726&p=35&f=G&l=50&d=PG01&S1=20140529.PD.&OS=PD/20140529&RS=PD/20140529

Keywords for this news article include: Drugs, Patents, Therapy, Tadalafil, Proinsulin, Legal Issues, Nitric Oxide, Impotence Agents, Peptide Hormones, Cardiovascular Agents, Genitourinary Tract Agents, Agents For Pulmonary Hypertension.

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Source: Drug Week


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