Therapy for kidney disease and/or heart failure   

Abstract: Medical systems and methods for treating kidney disease alone, heart failure alone, chronic kidney disease with concomitant heart failure, or cardiorenal syndrome are described. The systems and methods are based on delivery of a natriuretic peptide such as Vessel Dilator to a subject. Methods for increasing and maintaining peptide levels at a certain concentration include direct peptide delivery via either an external or implantable programmable pump.

This application contains a “Sequence Listing” submitted as an electronic .txt file. The information contained in the Sequence Listing is hereby incorporated by reference.

FIELD OF THE INVENTION

The invention relates to therapies involving the administration of a natriuretic peptide for the treatment of pathological conditions such as kidney disease alone, heart failure alone, or kidney disease with concomitant heart failure. The systems and methods of the invention can increase and/or control in vivo levels of natriuretic peptide in the plasma or serum of the subject to optimize the outcome of a therapeutic regimen(s). The invention further relates to the field of chronic and acute delivery of a drug through routes of administration including but not limited to subcutaneous, intravascular, intraperitoneal and direct to organ. A preferred route is subcutaneous administration. The methods of delivery contemplated by the invention include, but are not limited to, implanted and external pumps at programmed or fixed rates, implanted or percutaneous vascular access ports, depot injection, direct delivery catheter systems, and local controlled release technology.

Kidney disease (KD), also known as renal disease, is a progressive loss in renal function over a period of months or years. In particular, Kidney Disease (KD) is a major U.S. public health concern with recent estimates suggesting that more than 26 million adults in the U.S. have the disease including chronic kidney disease (CKD). The primary causes of KD are diabetes and high blood pressure, which are responsible for up to two-thirds of the cases. In recent years, the prevalence of KD has increased due to a rising incidence of diabetes mellitus, hypertension (high blood pressure) and obesity, and also due to an aging population. Because KD is co-morbid with cardiovascular disease, heart failure is a closely related health problem. In the case of Chronic Kidney Disease (CKD), patients have an increased risk of death from cardiovascular events because CKD is thought to accelerate the development of heart disease (McCullough et al., Chronic kidney diseases, prevalence of premature cardiovascular disease, and relationship to short-term mortality, Am. Heart J., 2008; 156:277-283). CKD patients generally have cardiac-specific mortality rates many times higher than age- and sex-matched non-CKD populations, and it has been suggested that the pathological heart-kidney interactions are bidirectional in nature (Ronco C. et al., Cardiorenal syndrome, J. Am. Coll. Cardiol. 2008; 52:1527-39). In a recently proposed classification system for Cardio-Renal Syndrome (CRS), Type II Cardio-Renal Syndrome (CRS) is expressly defined as constituting chronic abnormalities in cardiac function (e.g., chronic congestive heart failure) that simultaneously causes progressive and permanent kidney disease. Similarly, Type IV CRS is defined under the same classification scheme as being a type of kidney disease that contributes to decreased cardiac function, cardiac hypertrophy and/or increased risk of adverse cardiovascular events.

Heart failure (HF) is a condition in which the heart\'s ability to pump blood through the body is impaired. HF includes, but is not limited to, acute heart failure, chronic heart failure, and acute decompensated (ADHF). HF is a common condition that affects approximately 5 million people in the United States, with 550,000 new cases diagnosed each year. Symptoms of HF include swelling and fluid build-up in the legs, feet, and/or lungs; shortness of breath; coughing; elevated heart rate; change in appetite; and fatigue. If left untreated, compensated HF can deteriorate to a point where a person undergoes ADHF, which is the functional deterioration of HF. ADHF is a major clinical challenge because HF as a primary discharge diagnosis accounts for over 1 million hospital discharges and over 6.5 million hospital days (Kozak et al., National Hospital Discharge Survey: 2002 annual summary with detailed diagnosis and procedure data, Vital Health Stat. 13, 2005; 158:1-199). The financial burden due to HF is largely borne by public health resources (e.g., Medicare and Medicaid) wherein the 6 month readmission rate is 50%, the short-term mortality rate (i.e., 60-90 days) is around 10%, and the 1 year mortality risk is around 30% (Jong et al., Prognosis and determinants of survival in patients newly hospitalized for heart failure: a population based study, Arch. Intern. Med. 2002; 162:1689-94). Recently, the number of hospitalizations attributed to ADHF has risen significantly where many people are readmitted soon after discharge because of recurring symptoms or further medical complications. Current ADHF treatments focus on removing excess fluid buildup by increasing urination with diuretic medications or by draining fluid directly from the veins via ultrafiltration. ADHF can also be treated using vasodilators, inotropes, and other therapeutic regimens described herein and as known within the art. However, recent data suggests that dialysis in patients with end stage renal disease (ESRD) may precipitate ADHF (Burton et al., Hemodialysis-induced cardiac injury: determinants and outcomes, Clin. J. Am. Soc. Nephrol. 2009; 4:914-920).

One pharmaceutical approach to treat HF is the use of Nesiritide (B-type natriuretic peptide), which is an FDA approved therapeutic option that lowers elevated filing pressures and improves dyspnea. Nesiritide is the recombinant form of the 32 amino acid human B-type natriuretic peptide, which is normally produced by the ventricular myocardium. The drug facilitates cardiovascular fluid homeostasis through counter-regulation of the renin-angiotensin-aldosterone system and promotion of vasodilation, natriuresis, and diuresis. Nesiritide is administered intravenously usually by bolus injection, followed by IV infusion. Another approved atrial natriuretic type peptide is human recombinant atrial natriuretic peptide (ANP), Carperitide, which has been approved for the clinical management of ADHF in Japan since 1995, is also administered via intravenous infusion. Another peptide under study is human recombinant urodilatin (URO), Ularitide.

In the case of Nesiritide, one recent large study suggested that Nesiritide is ineffective in treating severe heart failure (Lingegowda et al., Long-term outcome of patients treated with prophylactic Nesiritide for the prevention of acute kidney injury following cardiovascular surgery, Clin. Cardiol. 2010; 33(4):217-221). The study concluded that the reno-protection provided by Nesiritide in the immediate postoperative period was not associated with improved long-term survival in patients undergoing high-risk cardiovascular surgery.

One obstacle to delivering peptides in a clinically effective manner is that peptides generally have poor delivery properties due to the presence of endogenous proteolytic enzymes, which are able to quickly metabolize many peptides at most routes of administration. In addition, peptides and proteins are generally hydrophilic do not readily penetrate lipophilic biomembranes, and have short biological half-lives due to rapid metabolism and clearance. These factors are significant deterrents to the effective and efficient use of most protein drug therapies. Although a peptide drug can be administered intravenously, this route of administration can potentially cause undesirable effects because the peptide drug is directly introduced into the bloodstream. Intramuscular (IM) administration may be considered where sustained action is preferred. However, IM administration could result in slow absorption and possible degradation of the peptide at the injection site. Subcutaneous (SQ) injection can provide a slower absorption rate compared to IM administration and might be useful for long term therapy. However, potency could be decreased via SQ administration due to degradation and poor absorption.

Hence, there is an unmet need for drug delivery systems and device-mediated methods of protein delivery that can offer significant advantages over conventional delivery systems by providing increased efficiency, improved performance, patient compliance and convenience. There is also a need for clinically effective therapies for delivering and treating KD alone or with concomitant. HF. In the field of both chronic and acute delivery of peptides, there is an unmet need for maintaining the therapeutic effect of an atrial natriuretic peptide for a desired period of time and at a specific plasma concentration. There is also need for continuous infusion of a natriuretic peptide as an effective alternative to administration by multiple injections. There is a need for developing the pharmacokinetic and pharmacodynamic profile for ANP drugs useful for treating KD and HF. There is also an unmet need for developing therapies providing for improved efficacy of the delivered peptides using parenteral dosage forms such as intravenous, intramuscular, and subcutaneous injection or infusion.

Many studies have shown that known KD and HF therapies are associated with mortality in patients with heart failure. Hence, there is an unmet need for developing new agents and methods of delivery to safely and effectively improve cardiac performance and modulate fluid load. There is also an unmet need for methods that open new pathways to improve quality of life and outcomes of patients with acute and worsening decompensated heart failure and KD.

SUMMARY

The disclosure provided herein is directed to a study of continuous subcutaneous (SQ) administration of Atrial Natriuretic Peptide (ANP) hormones such as vessel dilator (VD) kaliuretic peptide (KP), and brain natriuretic peptide, generally referred to herein as “natriuretic peptides,” to patients having Kidney Disease (KD) alone, Heart Failure (HF) alone, or KD with concomitant HF. The continuous subcutaneous administration of a natriuretic peptide can be used to maintain in vivo concentrations of the natriuretic peptide above a critical efficacy threshold for an extended period of time. Both bolus and continuous SQ delivery of natriuretic peptides are contemplated. The invention disclosed herein has a number of embodiments that relate to therapeutic regimens and systems for treatment of KD alone, HF alone or KD with concomitant HF. In certain embodiments, a medical system or method is used to treat a subject having cardiorenal syndrome (CRS).

In certain embodiments, a medical system or method is used to treat a subject having heart disease.

In certain embodiments, a medical system or method is used to treat a subject having kidney disease.

In certain embodiments, a medical system or method is used to treat a subject having cardiorenal syndrome (CRS) selected from CRS Type I, CRS Type II, CRS Type III, CRS Type IV or CRS Type V.

In certain embodiments, a medical system or method is used to treat a subject having heart disease selected from chronic heart failure, congestive heart failure, acute heart failure; decompensated heart failure, systolic heart failure, or diastolic heart failure.

In certain embodiments, a medical system or method is used to treat a subject having kidney disease selected from Stage 1 kidney disease, Stage 2 kidney disease, Stage 3 kidney disease, Stage 4 kidney disease, Stage 5 kidney disease, and end-stage renal disease.

|0≦y≦(65−n)}. In another embodiment, the volume of distribution for the natriuretic peptide is from any one of about 5 to about 65 L, about 10 to about 25 L, about 5 to about 15 L, about 30 to about 65 L and about 45 to about 65 L.

A method for administering a natriuretic peptide such as VD and KP to a subject having KD alone, HF alone, or KD with concomitant HF is provided. The method comprises administering a natriuretic peptide to a subject using a drug provisioning apparatus to maintain a plasma level of the natriuretic peptide in the subject within a specified mean steady state concentration range. This specified concentration is not greater than a plasma level reached by either a single subcutaneous bolus injection of the natriuretic peptide at 6000 ng of the natriuretic peptide per kilogram of the subject\'s body weight or a plasma level reached by a one hour intravenous infusion of the natriuretic peptide at 100 ng of the natriuretic peptide per kilogram·minute of the subject\'s body weight. The specified concentration can also not be greater than a plasma level reached by either a single subcutaneous bolus injection of the natriuretic peptide at 18,000 ng of the natriuretic peptide per kilogram of the subject\'s body weight or a plasma level reached by a one hour intravenous infusion of the natriuretic peptide at 300 ng of the natriuretic peptide per kilogram·minute of the subject\'s body weight. The method can administer the natriuretic peptide subcutaneously, intramuscularly, or intravenously. One route is subcutaneous administration. The method delivers the ANP hormones selected from any one of long-acting natriuretic peptide (LANP), kaliuretic peptide (KP), urodilatin (URO), atrial natriuretic peptide (ANP) and vessel dilator (VD), and also brain natriuretic peptide (BNP).

A therapeutic method for treatment of KD alone, HF alone, or KD with concomitant HF is provided is provided. The therapy is based on a method of treatment that effects increased levels of natriuretic peptide. The method includes increasing plasma levels of a natriuretic peptide in a subject having KD alone, HF alone, or KD with concomitant HF is provided by causing the selective release of the natriuretic peptide using a drug provisioning component. The method further includes a control unit consisting of a processor being operably connected to and in communication with the drug provisioning component, wherein the control unit contains a set of instructions that causes the drug provisioning component to administer the natriuretic peptide to the subject according to a therapeutic regimen. The therapeutic regimen is tailored so that the plasma concentration of the natriuretic peptide is maintained within a specified range by effecting controlled administration of the natriuretic peptide using the drug provisioning component. This specified concentration is not greater than a plasma level reached by either a single subcutaneous bolus injection of the natriuretic peptide at 6000 ng of the natriuretic peptide per kilogram of the subject\'s body weight or a level reached by a one hour intravenous infusion of the natriuretic peptide at 100 ng of the natriuretic peptide per kilogram·minute of the subject\'s body weight. This specified concentration can also not be greater than a plasma level reached by either a single subcutaneous bolus injection of the natriuretic peptide at 18,000 ng of the natriuretic peptide per kilogram of the subject\'s body weight or a level reached by a one hour intravenous infusion of the natriuretic peptide at 300 ng of the natriuretic peptide per kilogram·minute of the subject\'s body weight.

A second therapeutic method of treating a subject having KD alone, HF alone, or KD with concomitant HF is provided, wherein the method includes increasing plasma or serum concentration of the natriuretic peptide in the subject using the systems of the invention. The method further includes maintaining circulating levels of natriuretic peptide in the plasma or serum of the subject within a specified mean steady state concentration range. In any embodiment, the specified mean steady state concentration is not greater than a plasma level reached by either a single subcutaneous bolus injection of the natriuretic peptide at 6000 ng of the natriuretic peptide per kilogram of the subject\'s body weight or a plasma level reached by a one hour intravenous infusion of the natriuretic peptide at 100 ng of the natriuretic peptide per kilogram·minute of the subject\'s body weight. In any embodiment, the specified mean steady state concentration is not greater than a plasma level reached by either a single subcutaneous bolus injection of the natriuretic peptide at 18,000 ng of the natriuretic peptide per kilogram of the subject\'s body weight or a plasma level reached by a one hour intravenous infusion of the natriuretic peptide at 300 ng of the natriuretic peptide per kilogram·minute of the subject\'s body weight.

In any embodiment, the method may further include monitoring one or more physiologic parameters of the subject. In any embodiment, the method further includes creating a subject-specific dose-response database using data collected from the subject, evaluating the data in the database, calculating instructions for use with a drug delivery device to maintain a plasma level of the natriuretic peptide in the subject within a specified mean steady state concentration range, and further monitoring subject data and updating the database as necessary. Data collected from the subject could include subject weight, enzyme levels, biomarkers, observed drug clearance, etc.

A medical system for administering the natriuretic peptide to a subject having KD alone, HF alone, or KD with concomitant HF is provided. The medical system includes a drug provisioning component that selectively releases a pharmaceutically effective amount of natriuretic peptide to the subject and a control unit consisting of a processor operably connected to and in communication with the drug provisioning component. The control unit is programmed with a set of instructions that causes the drug provisioning component to administer the natriuretic peptide to the subject according to a therapeutic regimen comprising administering a natriuretic peptide to the subject subcutaneously, wherein the therapeutic regimen is sufficient to maintain circulating levels of the natriuretic peptide in the plasma or serum of the subject above a desired mean steady state concentration. In any embodiment, the therapeutic regime is selected to maintain serum natriuretic peptide concentrations in the subject at a value not greater than a critical concentration threshold. The critical concentration can be either the plasma level reached by either a single subcutaneous bolus injection of the natriuretic peptide at 6000 ng of the natriuretic peptide per kilogram of the subject\'s body weight or the plasma level reached by a one hour intravenous infusion of the natriuretic peptide at 100 ng of the natriuretic peptide per kilogram·minute of the subject\'s body weight. The critical concentration can also be either the plasma level reached by either a single subcutaneous bolus injection of the natriuretic peptide at 18,000 ng of the natriuretic peptide per kilogram of the subject\'s body weight or the plasma level reached by a one hour intravenous infusion of the natriuretic peptide at 300 ng of the natriuretic peptide per kilogram·minute of the subject\'s body weight.

In any embodiment of the invention, the natriuretic peptides may include any of the atrial natriuretic peptide (ANP) hormones and brain natriuretic peptide (BNP). ANP hormones include long acting natriuretic peptide (LANP), kaliuretic peptide (KP), atrial natriuretic peptide (ANP), vessel dilator (VD), and urodilatin (URO).

In any embodiment of the invention, the drug provisioning component of the medical system may administer the natriuretic peptide to the subject subcutaneously, intramuscularly, or intravenously. A preferred route is subcutaneous administration.

In any embodiment of the invention, a drug provisioning component may consist of any of the following elements: an external or implantable drug delivery pump, an implanted or percutaneous vascular access port, a direct delivery catheter system, and a local drug-release device. In any embodiment of the invention, the drug provisioning component can deliver the natriuretic peptide at a fixed, pulsed, or variable rate. The drug provisioning component may also be programmable or controllable by a patient who is a subject of the invention.

In any embodiment of the invention, sensors of the medical system of the invention may monitor one or more physiological parameters of the subject obtained by a sensor. These parameters are preferably related to blood pressure or the renal system and can include blood pressure, pulmonary artery pressure, left atrial pressure, right atrial pressure, central venous pressure, lung fluid volume, proteinuria, plasma renin, cardiac output, and glomerular filtration rate.

In any embodiment of the invention, a control unit may operate to regulate the selective release of the natriuretic peptide to maintain a mean steady state concentration using data obtained from the subject. The control unit may further contain computer memory, and the control unit, using the computer memory and processor, may further compile and store a database containing data collected from the subject and also compute a dosing schedule that makes up a part of the therapeutic regimen.

In any embodiment, a medical system is provided for administering a natriuretic peptide. The medical system has a drug provisioning component to administer a therapeutically effective amount of a natriuretic peptide to a subject suffering from kidney disease alone, heart failure alone, or kidney disease with concomitant heart failure, said drug provisioning component maintaining an effective plasma concentration of the natriuretic peptide based, at least in part, on a volume of distribution for the natriuretic peptide exhibited by the subject.

|0≦y≦(60−n)}.

In any embodiment, a method for administering a natriuretic peptide is provided. The natriuretic peptide is administered to a subject using a drug provisioning component to maintain a plasma level of the natriuretic peptide at a steady state concentration from about 0.5 to about 40 ng/mL or from about 0.5 to about 60 ng/mL, wherein the natriuretic peptide is administered through a subcutaneous route.

In any embodiment, a method for administering a natriuretic peptide is provided. The natriuretic peptide is administered to a subject suffering from kidney disease alone, heart failure alone, or with concomitant kidney disease and heart failure using a drug provisioning component based at least in part on a volume of distribution for the natriuretic peptide exhibited by the subject.

In any embodiment of the invention, a specified range of plasma concentration of the natriuretic peptide is not greater than a plasma concentration of the natriuretic peptide reached during either a subcutaneous bolus of the natriuretic peptide at 6000 ng/kg or a 1 hour intravenous infusion of the natriuretic peptide at 100 ng/kg·min in the subject.

In any embodiment of the invention, a specified range of plasma concentration of the natriuretic peptide range is not greater than a plasma concentration of the natriuretic peptide reached during either a subcutaneous bolus of the natriuretic peptide at 18,000 ng/kg or a 1 hour intravenous infusion of the natriuretic peptide at 300 ng/kg·min in the subject.

In any embodiment of the invention, a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide in a cyclic on/off pattern at a rate (ng/kg of body weight) for multiple days, wherein the rate results in a plasma concentration of natriuretic peptide not greater than a plasma concentration of the natriuretic peptide reached in the subject during either a subcutaneous bolus at 6000 ng/kg or a 1 hour intravenous infusion of the natriuretic peptide at 100 ng/kg·min.

In any embodiment of the invention, a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide in a cyclic on/off pattern at a rate (ng/kg of body weight) for multiple days, wherein the rate results in a plasma concentration of natriuretic peptide not greater than a plasma concentration of the natriuretic peptide reached in the subject during either a subcutaneous bolus at 18,000 ng/kg or a 1 hour intravenous infusion of the natriuretic peptide at 300 ng/kg·min.

In any embodiment of the invention, a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide at a rate (ng/kg of body weight) for 4 hours on and 8 hours off, then 4 hours on and 8 hours off for each of 3 days, wherein the rate results in a plasma concentration of natriuretic peptide not greater than a plasma concentration of the natriuretic peptide reached in the subject during either a subcutaneous bolus at 6000 ng/kg or a 1 hour intravenous infusion of the natriuretic peptide at 100 ng/kg·min.

In any embodiment of the invention, a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide at a rate (ng/kg of body weight) for 4 hours on and 8 hours off, then 4 hours on and 8 hours off for each of 3 days, wherein the rate results in a plasma concentration of natriuretic peptide not greater than a plasma concentration of the natriuretic peptide reached in the subject during either a subcutaneous bolus at 18,000 ng/kg or a 1 hour.

In any embodiment of the invention, a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide to maintain a plasma level of the natriuretic peptide at a steady state concentration from any one of about 0.5 to about 60 ng/mL, about 0.5 to about 40 ng/mL, about 10 to about 60 ng/mL, about 20 to about 40 ng/mL, about 30 to about 60 ng/mL, about 15 to about 55 ng/mL, about 25 to about 55 ng/mL about 35 to about 55 ng/mL about 23 to about 42 ng/mL about 19 to about 43 ng/mL about 10 to about 50 ng/mL 10 to about 20 ng/mL, about 20 to about 30 ng/mL, about 20 to about 35 ng/mL, about 25 to about 40 ng/mL, and about 30 to about 40 ng/mL.

In any embodiment of the invention, a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide to maintain a plasma level of the natriuretic peptide (ng/mL) at a steady state concentration in the range represented by n to (n+i), where n={xεR|0<x≦60} and i={yεR 0≦y≦(60−n)}.

In any embodiment of the invention, a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide to maintain a plasma level of the natriuretic peptide (ng/mL) at a steady state concentration in the range represented by n to (n+i), where n={xεR|0<x≦40} and i={yεR|0≦y≦(40−n)}.

In any embodiment of the invention, a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide at a continuous rate (ng/kg of body weight) matching the area under the curve of a subcutaneous bolus at 18,000 ng/kg of the subject.

In any embodiment of the invention, wherein a medical system contains a control unit in communication with the drug provisioning component.

In any embodiment of the invention, a drug provisioning component is selected from an external or implantable drug delivery pump, an implanted or percutaneous vascular access port, a direct delivery catheter system, and a local drug-release device.

In any embodiment of the invention, a drug provisioning component is programmable.

In any embodiment of the invention, a drug provisioning component is controlled by a patient who is the subject.

In any embodiment of the invention, a medical system has a control unit having a processor and memory wherein the processor compiles and stores a database of data collected from the subject using a sensor and computes a dosing schedule.

In any embodiment of the invention, data collected from the subject is transmitted via radio frequency by a transmitter, and the data is received by an external controller.

In any embodiment of the invention, data collected from the subject is transmitted and digital instructions returned to the control unit via the Internet.

In any embodiment of the invention, a drug provisioning component and a control unit are co-located.

In any embodiment of the invention, a drug provisioning component, or the control unit are connected or controlled wirelessly.

In any embodiment of the invention, a drug provisioning component is programmed to release a single bolus of 6000 ng of natriuretic peptide per kilogram of the subject\'s body weight wherein the single bolus is administered three times at 0 hours, 24 hours and 48 hours.

In any embodiment of the invention, a drug provisioning component is programmed to continuously deliver 18,000 ng of natriuretic peptide per kilogram of the subject\'s body weight over 72 hours.

In any embodiment of the invention, a medical system has a patch pump in communication with a control unit.

In any embodiment of the invention, a specified range of a plasma concentration of the natriuretic peptide is not greater than a plasma concentration of the natriuretic peptide reached during either a subcutaneous bolus of the natriuretic peptide at 18,000 ng/kg or a 1 hour intravenous infusion of the natriuretic peptide at 300 ng/kg·min in the subject.

In any embodiment of the invention, a drug provisioning component subcutaneously delivers a therapeutically effective amount of the natriuretic peptide at a rate (ng/kg of body weight) for 4 hours on and 8 hours off, then 4 hours on and 8 hours off for each of 3 days, wherein the rate results in a plasma concentration of natriuretic peptide not greater than a plasma concentration of the natriuretic peptide reached in the subject during either a subcutaneous bolus at 6000 ng/kg or a 1 hour intravenous infusion of the natriuretic peptide at 100 ng/kg·min.

In any embodiment, a method for administering a natriuretic peptide has the step of compiling and storing data collected from the subject using a processor and memory, and computing a dosing schedule.

In any embodiment, a method for administering a natriuretic peptide has the step of adjusting a dosing schedule to meet pharmacokinetic variables calculated from one or more subject parameters, wherein the subject parameters include any one of blood pressure, pulmonary artery pressure, left atrial pressure, right arterial pressure, central venous pressure, lung fluid volume, proteinuria, plasma renin, cardiac output, and glomerular filtration rate.

In any embodiment, a method for administering a natriuretic peptide has the step of collecting data from the subject and transmitting the data via radio frequency to an external controller.

In any embodiment, a method for administering a natriuretic peptide has the step of collecting and transmitting data from the subject and returning digital instructions to a control unit via the Internet.

In any embodiment, a method for administering a natriuretic peptide uses a drug provisioning component, and a control unit that are connected or controlled wirelessly.

In any embodiment, a method for administering a natriuretic peptide uses a drug provisioning component programmed to release a single bolus of 6000 ng of natriuretic peptide per kilogram of the subject\'s body weight.

In any embodiment, a method for administering a natriuretic peptide uses a drug provisioning component programmed to release a single bolus of 18,000 ng of natriuretic peptide per kilogram of the subject\'s body weight.

In any embodiment, a method for administering a natriuretic peptide uses a single bolus repeated three times.

In any embodiment, a method for administering a natriuretic peptide uses a drug provisioning component programmed to continuously deliver 6,000 ng of natriuretic peptide per kilogram of the subject\'s body weight.

In any embodiment, a method for administering a natriuretic peptide uses a drug provisioning component programmed to continuously deliver 18,000 ng of natriuretic peptide per kilogram of the subject\'s body weight.

In any embodiment, a method for administering a natriuretic peptide has the step of using a patch pump in communication with a control unit.

In any embodiment, a method for administering a natriuretic peptide maintains a plasma concentration of the natriuretic peptide at a steady state concentration at a specified range from about 0.5 to about 40 ng/mL.

|0≦y≦(60−n)}.

|0≦y≦(40−n)}.

In any embodiment, a method for administering a natriuretic peptide maintains a plasma concentration of the natriuretic peptide at a steady state concentration at a specified range at any one of about 10 to 60 ng/mL, about 10 to about 20 ng/mL, about 20 to about 30 ng/mL, about 20 to about 35 ng/mL, about 25 to about 40 ng/mL, and about 30 to about 40 ng/mL.

In any embodiment, a method for administering a natriuretic peptide is performed on a subject exhibiting a subcutaneous adsorption half-life for the natriuretic peptide from any one of about 0 to about 60 minutes, 0 to about 5 minutes, 15 to about 25 minutes, 0 to about 30 minutes, and 15 to about 30 minutes.

In any embodiment, a method for administering a natriuretic peptide is performed on a subject exhibiting a subcutaneous adsorption half-life for the natriuretic peptide of about 20 minutes.

In any embodiment, a method for administering a natriuretic peptide is performed, wherein the natriuretic peptide is administered to a subject at a rate from any one of about 10 to about 300 ng/kg·min, about 10 to about 150 ng/kg·min, about 25 to about 145 ng/kg·min, about 30 to about 140 ng/kg·min, about 35 to about 125 ng/kg·min, about 50 to about 120 ng/kg·min, about 65 to about 115 ng/kg·min, and about 85 to about 110 ng/kg·min of the subject\'s body weight.

In any embodiment, a method for administering a natriuretic peptide is performed wherein from about 0.6 to about 9 μg of the natriuretic peptide is administered to the subject per kg of the subject\'s body weight in an hour time period.

In any embodiment, a method for administering a natriuretic peptide is performed wherein the natriuretic peptide is administered to a subject at a rate from any one of about 1 to about 8 μg, about 2 to about 5 μg, about 3 to about 4 μg, about 1 to about 7 μg, about 3 to about 5 μg, about 2 to about 6 μg, about 7 to about 9 μg, and about 8 to about 9 μg of the natriuretic peptide is administered to the subject per kg of the subject\'s body weight in an hour time period.

In any embodiment, a method for administering a natriuretic peptide is performed wherein the natriuretic peptide is vessel dilator (VD).

In any embodiment of the invention, a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide at a continuous rate (ng/kg of body weight) matching the area under the curve of a subcutaneous bolus at 6000 ng/kg of the subject.

In any embodiment of the invention, a drug provisioning component delivers a therapeutically effective amount of the natriuretic peptide to maintain a plasma level of the natriuretic peptide at a steady state concentration from any one of about 0.5 to about 60 ng/mL, about 0.5 to about 40 ng/mL, about 10 to about 60 ng/mL, about 20 to about 40 ng/mL, about 30 to about 60 ng/mL, about 15 to about 55 ng/mL, about 25 to about 55 ng/mL about 35 to about 55 ng/mL about 23 to about 42 ng/mL about 19 to about 43 ng/mL about 10 to about 50 ng/mL 10 to about 20 ng/mL, about 20 to about 30 ng/mL, about 20 to about 35 ng/mL, about 25 to about 40 ng/mL, and about 30 to about 40 ng/mL.

In any embodiment of the invention, the drug provisioning component can deliver the natriuretic peptide at a fixed, pulsed, or variable rate.

In any embodiment of the invention, a drug provisioning component can consist of any of the following elements: an external or implantable drug delivery pump, an implanted or percutaneous vascular access port, a direct delivery catheter system, and a local drug-release device.

In any embodiment of the invention, a drug provisioning component can subcutaneously deliver a therapeutically effective amount of the natriuretic peptide at a continuous rate (ng/kg of body weight) matching the area under the curve of a subcutaneous bolus at 6000 ng/kg of the subject.

In any embodiment of the invention, any specified range is in addition to an endogenous concentration of the natriuretic peptide.

In any embodiment of the invention, the natriuretic peptide is selected from any one of long-acting natriuretic peptide (LANP), kaliuretic peptide (KP), urodilatin (URO), atrial natriuretic peptide (ANP), vessel dilator (VD), and brain natriuretic peptide (BNP).

In any embodiment, a method for administering a natriuretic peptide uses a drug provisioning component selected from an external or implantable drug delivery pump, an implanted or percutaneous vascular access port, a direct delivery catheter system, and a local drug-release device.

Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following detailed description. It is to be understood, however, that the detailed description and specific examples, while indicating some embodiments of the present invention are given by way of illustration and not limitation. Many changes and modifications within the scope of the present invention may be made without departing from the spirit thereof, and the invention includes all such modifications.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the pharmacokinetic model of the subcutaneous injection as compared to an estimated model of the equivalent intravenous (IV) dosage for Vessel Dilator (VD) peptide.

FIG. 2 shows a disposable external infusion pump.

FIG. 3 shows the pharmacokinetic model for IV infusion at two different dosages.

FIG. 4 shows the pharmacokinetic model for IV infusion with varying half-life for elimination.

FIG. 5 shows the pharmacokinetic model for single bolus subcutaneous injections with instantaneous absorption and varying half-life for elimination.

FIG. 6 shows the pharmacokinetic model for IV infusion as compared to an estimated model of the equivalent dosage by single subcutaneous bolus.

FIG. 7 shows the pharmacokinetic model for single bolus subcutaneous injections with varying half-life for elimination combined with a half-life for absorption of the administered peptide.

FIG. 8 shows the pharmacokinetic model for single bolus subcutaneous injections with varying half-life for absorption.

FIG. 9 shows the pharmacokinetic model for IV infusion as compared to an estimated model of the equivalent dosage by single subcutaneous bolus with varying half-life for absorption.

FIG. 10 shows a detailed view of the pharmacokinetic model from FIG. 9.

FIGS. 11A and 11B show the measured plasma concentration of VD in canines at a total dose of 7.2 mg/kg and 14.4 mg/kg, respectively.

FIGS. 12A and 12B show dose normalized AUCτ and dose normalized Cmax for observed plasma concentration of VD in canines.

FIGS. 13A and 13B show the dose dependence of AUCτ and Cavg for observed plasma concentration of VD observed in rats.

FIG. 14 shows the time-dependent observation of plasma concentration for VD in male rats receiving continuous subcutaneous administration of VD. The open triangle represents a suspected outlier measurement excluded from the trend line.

FIG. 15 shows the time-dependent observation of plasma concentration for VD in female rats receiving continuous subcutaneous administration of VD.

FIG. 16 shows glomerular filtration rates for a canine heart failure model treated with a natriuretic peptide.

FIG. 17 shows a change in urine flow rate for a canine heart failure model treated with a natriuretic peptide.

FIG. 18 shows a change in sodium excretion rate for a canine heart failure model treated with a natriuretic peptide.

FIG. 19 shows right atrial pressures for a canine heart failure model treated with a natriuretic peptide.

FIG. 20 shows pulmonary capillary wedge pressures for a canine heart failure model treated with a natriuretic peptide.

FIG. 21 shows Pre-proANF (56-92) plasma concentration data for a canine heart failure model treated with natriuretic peptide.

FIGS. 22 A and B show a change in blood pressure for a rat model treated with a natriuretic peptide.

FIG. 23 shows a change in albumin excretion for a rat model treated with a natriuretic peptide.

FIGS. 24 A and B show a change in protein excretion for a rat model treated with a natriuretic peptide.

FIG. 25 shows a change in renal cortical blood flow for a rat model treated with a natriuretic peptide.

FIG. 26 shows a change in creatinine clearance for a rat model treated with a natriuretic peptide

FIG. 27 shows serum urea levels for a rat model treated with a natriuretic peptide.

FIG. 28 shows urine cGMP levels for a rat model treated with a natriuretic peptide.

FIG. 29 shows serum prostaglandin E2 levels for a rat model treated with a natriuretic peptide.

FIG. 30 shows an assessment schedule for screening prior to infusion and during a 6-hour subcutaneous infusion session.

FIG. 31 shows an assessment for after a 6-hour subcutaneous infusion session.

DETAILED DESCRIPTION

The invention relates to selective delivery of a natriuretic peptide using a drug provisioning component that can include infusion pumps, implanted or percutaneous vascular access ports, direct delivery catheter systems, local drug-release devices or any other type of medical device that can be adapted to deliver a therapeutic to a subject. The drug provisioning component can administer the natriuretic peptide subcutaneously, intramuscularly, or intravenously at a fixed, pulsed, continuous or variable rate. A preferred embodiment of the invention contemplates subcutaneous delivery using an infusion pump at a continuous rate to maintain a specified plasma concentration of the natriuretic peptides. Natriuretic peptides and their sequences are disclosed in U.S. Pat. No. 5,691,310 and U.S. Patent App. Pub. Nos. 2006/0205642, 2008/0039394, 2009/0062206, and 2009/0170196, each of which is incorporated by reference herein in its entirety.

Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the relevant art. Generally, the nomenclature used herein for drug delivery, pharmacokinetics, pharmacodynamics, and peptide chemistry is well known and commonly employed in the art. Further, the techniques for the discussed procedures are generally performed according to conventional methods in the art.

The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

The terms “administering,” “administer,” “delivering,” “deliver,” “introducing,” and “introduce” can be used interchangeably to indicate the introduction a compound, agent or peptide into the body of a patient, including methods of introduction where the compound, agent or peptide will be present in the blood or plasma of a subject to whom the compound, agent or peptide is administered.

The term “comprising” includes, but is not limited to, whatever follows the word “comprising.” Thus, use of the term indicates that the listed elements are required or mandatory but that other elements are optional and may or may not be present.

The term “consisting of” includes and is limited to whatever follows the phrase the phrase “consisting of.” Thus, the phrase indicates that the limited elements are required or mandatory and that no other elements may be present.

The phrase “consisting essentially of” includes any elements listed after the phrase and is limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase indicates that the listed elements are required or mandatory but that other elements are optional and may or may not be present, depending upon whether or not they affect the activity or action of the listed elements.

“Pharmaceutically acceptable” is meant to encompass any carrier, which does not interfere with effectiveness of the biological activity of the active ingredient and that is not toxic to the host to which it is administered.

“Drug provisioning component” encompasses any and all devices that administers a therapeutic agent to a subject and includes infusion pumps, implanted or percutaneous vascular access ports, direct delivery catheter systems, local drug-release devices or any other type of medical device that can be adapted to deliver a therapeutic to a subject. The drug provisioning component and the control unit may be “co-located,” which means that these two components, in combination, may make up one larger, unified unit of a system.

As used herein, “programmable” refers to a device using computer hardware architecture and being capable of carrying out a set of commands, automatically.

“Glomerular filtration rate” describes the flow rate of filtered fluid through the kidney. The estimated glomerular filtration rate or “eGFR” is a measure of filtered fluid based on a creatinine test and calculating the eGFR based on the results of the creatinine test.

“Intravenous” delivery refers to delivery of an agent by means of a vein.

“Intramuscular” delivery refers to delivery of an agent by means of muscle tissue.

“Subcutaneous” delivery refers to delivery of an agent by means of the subcutis layer of skin directly below the dermis and epidermis.

A “patch pump” is a device that adheres to the skin, contains a medication, and can deliver the drug over a period of time, either transdermally or via an integrated subcutaneous mini-catheter.

The term “delivering,” “deliver,” “administering,” and “administers” can be used interchangeably to indicate the introduction of a therapeutic or diagnostic agent into the body of a subject in need thereof to treat a disease or condition, and can further mean the introduction of any agent into the body for any purpose.

The “field of chronic delivery” involves the following four parameters: period of treatment, scope, route of administration, and method of delivery. “Chronic delivery” means a period of treatment or drug delivery of more than 24 hours, even if the drug is not delivered continuously for that period of time. The scope of delivery involves one or more drugs, in any combination. The route of administration includes, but is not limited to, subcutaneous, intravascular, intraperitoneal and direct to organ, as described in further detail herein. The method of delivery includes, but is not limited to, implanted and external pumps, programmed or fixed rate, implanted or percutaneous vascular access ports, depot injection, direct delivery catheter systems, and local controlled release technology, as described in further detail herein.

The “field of acute delivery” involves the same four parameters as for the field of chronic delivery. The difference between the two fields is the period of treatment. “Acute delivery” means a period of treatment or drug delivery of less than or equal to 24 hours, even if the drug is delivered continuously for that period of time.

The term “therapeutically effective amount” refers to an amount of an agent (e.g., atrial natriuretic peptides) effective to treat at least one symptom of a disease or disorder in a subject. The “therapeutically effective amount” of the agent for administration may vary based upon the desired activity, the diseased state of the subject being treated, the dosage form, method of administration, subject factors such as the subject\'s sex, genotype, weight and age, the underlying causes of the condition or disease to be treated, the route of administration and bioavailability, the persistence of the administered agent in the body, evidence of natriuresis and/or diuresis, the type of formulation, and the potency of the agent.

The terms “treating” and “treatment” refer to the management and care of a patient having a pathology or condition for which administration of one or more therapeutic compounds or peptides is indicated for the purpose of combating or alleviating symptoms and complications of the condition. Treating includes administering one or more formulations or peptides of the present invention to prevent or alleviate the symptoms or complications or to eliminate the disease, condition, or disorder. As used herein, “treatment” or “therapy” refers to both therapeutic treatment and prophylactic or preventative measures. “Treating” or “treatment” does not require complete alleviation of signs or symptoms, does not require a cure, and includes protocols having only a marginal or incomplete effect on a patient.

The term “therapeutic regimen” is used according to its meaning accepted in the art and refers to, for example, a part of a treatment plan for an individual suffering from a pathological condition that specifies factors such as the agent or agents to be administered to the patient or subject, the doses of such agent(s), the schedule and duration of the treatment, etc.

An “infusion device” or “infusion pump” describes a means for delivering an infusion liquid into a patient or subject subcutaneously, intravenously, arterially, or by any other route of administration. Typically, the infusion pump has three major components: a fluid reservoir, a catheter system for transferring the fluids into the body, and a device that generates and/or regulates flow of the infusion fluid to achieve a desired concentration of a therapeutic agent in the body. One of ordinary skill will appreciate that there are many ways for regulating the flow of the infusion liquid by either mechanical or electric means. Hence, many forms for delivering the liquid are contemplated by the present invention, and such varied embodiments do not depart from the spirit of the invention. For example, the infusion fluid of the invention can be delivered and regulated using either roller pumps or electro-kinetic pumping (also known as electro-osmotic flow). Examples of infusion devices further include, but are not limited to, an external or an implantable drug delivery pumps.

The term “continuous infusion system” refers to a collection of components for continuously administering a fluid to a patient or subject for an extended period of time without having to establish a new site of administration each time the fluid is administered. As in the “infusion device” or “infusion pump,” the fluid in the continuous infusion system typically contains a therapeutic agent or agents. The system typically has one or more reservoir(s) for storing the fluid(s) before it is infused, a pump, a catheter, cannula, or other tubing for connecting the reservoir to the administration site via the pump, and control elements to regulate the pump. The device may be constructed for implantation, usually subcutaneously. In such a case, the reservoir will usually be adapted for percutaneous refilling.

The terms “continuous administration” and “continuous infusion” are used interchangeably herein and mean delivery of an agent, such as an atrial natriuretic peptide, in a manner that, for example, avoids fluctuations in the in vivo concentrations of the agent throughout the course of a treatment period. “Delivery” as used herein, can mean any type of means to effect a result either by electrical, mechanical or other physical means. This can be accomplished by constantly or repeatedly injecting substantially identical amounts of the agent, typically with a continuous infusion pump device, for a set period of time, e.g., at least every hour, 24 hours a day, seven days a week for a period such as at least 3 to 7 days, such that a steady state serum or plasma level is achieved for the duration of the treatment. This can also be described as a cyclic on/off pattern. Continuous administration of the agent may also be made by subcutaneous, intravenous, or intra-arterial injection at appropriate intervals for an appropriate period of time in a pharmaceutically effective amount.

A “deliverable amount” is defined as any amount of a measured fluid that can be delivered through a fluid delivery catheter as known by those of ordinary skill in the art. “Delivery” as used herein generally, can mean any type of means to effect a result either by electrical, mechanical or other physical means.

“Risk” relates to the possibility or probability of a particular event occurring either presently or at some point in the future.

The terms “subject” and “patient” can be used interchangeably, and describe a member of any animal species, preferably a mammalian species, optionally a human. The animal species can be a mammal or vertebrate such as a primate, rodent, lagomorph, domestic animal or game animal. Primates include chimpanzees, cynomologous monkeys, spider monkeys, and macaques, e.g., Rhesus or Pan. Rodents and lagomorphs include mice, rats, woodchucks, ferrets, rabbits and hamsters. Domestic and game animals include cows, horses, pigs, sheep, deer, bison, buffalo, mink, felines, e.g., domestic cat, canines, e.g., dog, wolf and fox, avian species, e.g., chicken, turkey, emu and ostrich, and fish, e.g., trout, catfish and salmon. The subject can be an apparently healthy individual, an individual suffering from a disease, or an individual being treated for a disease.

The term “sample” refers to a quantity of a biological substance that is to be tested for the presence or absence of one or more molecules.

“Renin,” also known as angiotensinogenase, is an enzyme that participates in the body\'s renin-angiotensin system (RAS), which regulates the body\'s mean arterial blood pressure by mediating extracellular volume (i.e., that of the blood plasma, lymph and interstitial fluid) and arterial vasoconstriction. Renin is released by the kidney when a subject has decreased sodium levels or low blood volume.

“Endogenous” substances are those that originate from within an organism, tissue, or cell.

The term “pharmacokinetics” is used according to its meaning accepted in the art and refers to the study of the action of drugs in the body. Pharmacokinetics includes, for example, the effect and duration of drug action, and the rate at which the drug is absorbed, distributed, metabolized, and eliminated by the body.

The term “pharmacodynamics” is used according to its meaning accepted in the art and refers to the study of the biochemical and physiological effects of drugs on the body, the mechanism of drug action, and the relationship between drug concentration and effect.

The phrase “area under the curve” or “AUC” refers to the area under a plasma concentration versus time curve. It indicates a measurement of drug absorption. AUC is described by the following formula:

AUC=∫0∞C(t)dt

where C(t) indicates the concentration of the drug in the plasma at time t.

“Half-life” or “half-time” as used herein in the context of administering a peptide drug to a patient is defined as the time required for the blood plasma concentration of a substance to halve (“plasma half-life”) its steady state. The knowledge of half-life is useful for the determination of the frequency of administration of a drug for obtaining a desired plasma concentration. Generally, the half-life of a particular drug is independent of the dose administered. There could also be more than one half-life associated with the peptide drug depending on multiple clearance mechanisms, redistribution, and other mechanisms known in the art. Usually, alpha and beta half-lives are defined such that the alpha phase is associated with redistribution, and the beta phase is associated with clearance. For protein drugs that are, for the most part, confined to the bloodstream, there can be at least two clearance half-lives.

“Elimination” refers to the removal or transformation of a drug in circulation, usually via the kidney and liver.

“Elimination half-life” is the time required for the amount of drug in the body to decrease by 50%.

“Absorption” refers to the transition of drug from the site of administration to the blood circulation.

The term “specified range,” as used herein contemplates both a measured value, such as the concentration value of an agent or peptide in the plasma of a patient, and a measured value that is either added or subtracted from a normal or basal level of a subject.

“Loading dose” refers to the dose(s) of drugs given at the onset of therapy to rapidly provide a therapeutic effect. Use of a loading dose prior to a maintenance dosage regimen will shorten the time required to approach a steady state.

In pharmacokinetics, “steady state” represents the equilibrium between the amount of drug given and the amount eliminated over the dosing interval. In general, it takes drug four to five half-lives to reach a steady state, however the multiple can vary depending on the route of administration. Sampling should occur when the drug has reached its steady state to judge efficacy and toxicity of the drug therapy. Steady state should not be confused with the therapeutic range.

“Mean steady state concentration,” denoted by “Css” refers to the concentration of a drug or chemical in a body fluid, usually plasma, at the time a “steady state” has been achieved and rates of drug administration and drug elimination are equal. Steady state concentrations fluctuate between a maximum (peak) (“Cmax”) and minimum (trough) (“Cmin”) concentration with each dosing interval. Css is a value approached as a limit and is achieved following the last of an infinite number of equal doses given at equal intervals.

“Plasma concentration” (Cp) refers to the amount of a drug in the blood plasma of the patient.

“Maximum plasma concentration” (Cmax) refers to the maximum amount of a drug observed in the blood of a patient or subject.

“Average plasma concentration” (Cavg) refers to the average amount of a drug observed in the blood of a patient or subject over a time course of a period of observation of the amount of the drug in the blood.

“Minimum plasma concentration” (Cmin) refers to the minimum amount of a drug observed in the blood of a patient or subject over a time course of a period of observation of the amount of the drug in the blood.

“Time to maximum concentration” (Tmax) refers to the time observed to reach maximum plasma concentration of a drug as measured from the initiation of regimen of administration of the drug.

“Percent fluctuation” (% Fluctuation) refers to the difference between Cmax and Cmin for a drug in the blood over a time course of a period of observation of the amount of the drug in the blood, where

%   Fluctuation = C max - C min C avg × 100.

The “volume of distribution” (VOD) is a hypothetical volume that is the proportionality constant which relates the concentration of drug in the blood or serum and the amount of drug in the body.

“Pharmacokinetic constraints,” as used herein, describes any factor that determines the pharmacokinetic profile of a drug such as immunogenicity, route of administration, endogenous concentrations of the natriuretic peptides, diurnal variation, and rate of drug delivery.

A “dose-response” relationship describes how the likelihood and severity of adverse health effects (i.e., the responses) are related to the amount and condition of exposure to an agent (i.e., the dose provided). Dose-response assessment is a two step process. The first step involves an assessment of all data that are available or can be gathered through experiments, in order to document the dose-response relationship(s) over the range of observed doses (i.e., the doses that are reported in the data collected). However, frequently this range of observation may not include sufficient data to identify a dose where the adverse effect is not observed (i.e., the dose that is low enough to prevent the effect) in the human population. The second step consists of extrapolation to estimate the risk, or probably of adverse effect, beyond the lower range of available observed data to make inferences about the critical region where the dose level begins to cause the adverse effect in the test population.

A “dose-response database,” as used in the invention is a computer database that stores the data collected for dose-response assessment. The database thus provides inputs for mathematical modeling for computing risk of various adverse effects that are to be associated with the drug and certain doses of the drug.

“Patient parameters,” as described herein includes parameters that may affect the efficacy of therapy or indicate a parameter that affects the efficacy of therapy, e.g., activity, activity level, posture, or a physiological parameter of the patient or subject. Other physiological patient parameters include heart rate, respiration rate, respiratory volume, core temperature, blood pressure, blood oxygen saturation, partial pressure of oxygen within blood, partial pressure of oxygen within cerebrospinal fluid, muscular activity, arterial blood flow, electromyogram (EMG), an electroencephalogram (EEG), an electrocardiogram (ECG), or galvanic skin response.

“Selective release” of an atrial natriuretic peptide as used in the invention describes the controlled delivery of a therapeutic using the drug delivery component, and can also refer to a controlled or programmed release of the atrial natriuretic peptide into the vasculature of the patient, according to a treatment protocol, through use of the drug provisioning component.

A “subcutaneous bolus injection” is the subcutaneous administration of a “bolus,” of a medication, drug or other compound that is given to a subject to raise concentration of the compound in the subject\'s blood to a desired level. Specifically, the injection is made in the subcutis, the layer of skin directly below the dermis and epidermis, collectively referred to as the cutis. The bolus injection may be delivered using a pump that may be programmable.

An “intra-arterial fluid delivery catheter,” or the phrase “catheter specially adapted for insertion in an artery” is defined as a small tube configured for insertion into an artery for the purpose of delivering a fluid into the circulatory system of the patient. Similarly, an “intravenous fluid delivery catheter” is defined as a small tube configured for insertion into a vein for the purpose of delivering a fluid into the circulatory system of the patient.

The “distal tip” of a catheter is the end that is situated farthest from a point of attachment or origin, and the end closest to the point of attachment or origin is known as the “proximal” end.

“Vascular access ports,” as described herein, are ports for infusing and/or withdrawing fluid from a patient. The vascular access or infusion ports typically incorporate mechanical valves which open during use, such as when a needle is inserted into the port, and close in between use, such as when a needle is removed from the part. In certain forms, the ports can be positioned subcutaneously underneath the skin, or percutaneously when the access part of the port is placed above the level of the skin to be accessed without skin penetration eliminating the need for using needle sticks to access the vasculature. Vascular access devices may also be implantable. These devices typically consist of a portal body and a catheter. The catheter may be either integral with the portal body or separate from the body to be attached at the time of implantation.

A “direct delivery catheter system,” as used herein is a catheter system for guiding an elongated medical device into an internal bodily target site. The system can have a distal locator for locating a target site prior to deployment of the catheter. The catheter can be introduced through a small incision into the bodily vessel, channel, canal, or chamber in question; or into a bodily vessel, channel, canal, or chamber that is otherwise connected to the site of interest (or target site), and then guided through that vessel to the target site.

The term “peptide,” as used herein, describes an oligopeptide, polypeptide, peptide, protein or glycoprotein, and includes a peptide having a sugar molecule attached thereto. As used herein, “native form” means the form of the peptide when produced by the cells and/or organisms in which it is found in nature. When the peptide is produced by a plurality of cells and/or organisms, the peptide may have a variety of native forms. “Peptide” can further refer to a polymer in which the monomers are amino acids that are joined together through amide bonds. Also included are peptides which have been modified using ordinary molecular biological techniques so as to improve their resistance to proteolytic degradation or to optimize solubility properties or to render them more suitable as a therapeutic agent. Analogs of such peptides include those containing residues other than naturally occurring L-amino acids, e.g., D-amino acids or non-naturally occurring synthetic amino acids. The present invention also embraces recombination peptides such as recombinant human ANP (hANP) obtained from bacterial cells after expression inside the cells. It will be understood by those of skill in the art that the peptides and recombinant peptides of the present invention can be made by varied methods of manufacture wherein the peptides of the invention are not limited to the products of any of the specific exemplary processes listed herein.

The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. The present invention also provides for analogs of proteins or peptides which comprise a protein as identified above.

The term “fragment,” as used herein, refers to a polypeptide that comprises at least six contiguous amino acids of a polypeptide from which the fragment is derived. In preferred embodiments, a fragment refers to a polypeptide that comprises at least 10 contiguous amino acids of a polypeptide from which the fragment is derived, more preferably at least 10 contiguous amino acids, still more preferably at least 15 contiguous amino acids, and still more preferably at least 20 contiguous amino acids of a polypeptide from which the fragment is derived.

The term “natriuretic peptide fragment” refers to a fragment of any natriuretic peptide defined and described herein.

As used herein, “cardiovascular disease” refers to various clinical diseases, disorders or conditions involving the heart, blood vessels, or circulation. Cardiovascular disease includes, but is not limited to, coronary artery disease, peripheral vascular disease, hypertension, myocardial infarction, and heart failure.

The terms “natriuretic” or “natriuresis” refer to the ability of a substance to increase sodium clearance from a subject.

The terms “renal or cardiovascular protective” and “renal or cardiovascular protective effects” refer to the ability of a substance to improve one or more functions of the kidneys or heart of a subject, including natriuresis, diuresis, cardiac output, hemodynamics, renal cortical blood flow or glomerular filtration rate, or to lower the blood pressure of the subject. Any measurable diagnostic factor that would be recognized by one having skill in the art as reducing stress on the kidneys and/or heart or as evidence of improvement in the function of the renal or cardiovascular system can be considered a renal or cardiovascular protective effect. The term “renal protective” or “renal protective effect” refers to a measurable diagnostic factor that would be recognized by one having skill in the art as particularly related to an indication of reduced stress on the kidneys or improvement in renal function. The term “cardiovascular protective” or “cardiovascular protective effect” refers to a measurable diagnostic factor that would be recognized by one having skill in the art as particularly related to an indication of reduced stress on the cardiovascular system or improvement in cardiac function.

As used herein, “heart failure” (HF) refers to a condition in which the heart cannot pump blood efficiently to the rest of the body. Heart failure may be caused by damage to the heart or narrowing of the arteries due to infarction, cardiomyopathy, hypertension, coronary artery disease, valve disease, birth defects or infection. Heart failure may also be further described as chronic, congestive, acute, decompensated, acute decompensated, systolic, or diastolic. The NYHA classification describes the severity of the disease based on functional capacity of the patient and is incorporated herein by reference. Heart failure can be with preserved ejection fraction or be with reduced ejection fraction. Further, heart failure can include left heart failure or right heart failure.

“Acute heart failure” means a sudden onset or episode of an inability of the heart to pump a sufficient amount of blood with adequate perfusion and oxygen delivery to internal organs. Acute heart failure can be accompanied by congestion of the lungs, shortness of breadth and/or edema.

Relating to heart failure, for example, “increased severity” of cardiovascular disease refers to the worsening of the disease as indicated by increased New York Heart Association (NYHA) classification, and “reduced severity” of cardiovascular disease refers to an improvement of the disease as indicated by reduced NYHA classification.

The “renal system,” as defined herein, comprises all the organs involved in the formation and release of urine including the kidneys, ureters, bladder and urethra.

“Proteinuria” is a condition in which urine contains an abnormal amount of protein. Albumin is the main protein in the blood; the condition where the urine contains abnormal levels of albumin is referred to as “albuminuria.” Healthy kidneys filter out waste products while retaining necessary proteins such as albumin. Most proteins are too large to pass through the glomeruli into the urine. However, proteins from the blood can leak into the urine when the glomeruli of the kidney are damaged. Hence, proteinuria is one indication of kidney disease (KD).

“Kidney disease” (KD) is a condition characterized by the slow loss of kidney function over time. The most common causes of KD are high blood pressure, diabetes, heart disease, and diseases that cause inflammation in the kidneys. Kidney disease can also be caused by infections or urinary blockages. If KD progresses, it can lead to end-stage renal disease (ESRD), where the kidneys fail completely. In the Cardiorenal Syndrome (CRS) classification system, CRS Type I (Acute Cardiorenal Syndrome) is defined as an abrupt worsening of cardiac function leading to acute kidney injury; CRS Type II (Chronic Cardiorenal syndrome) is defined as chronic abnormalities in cardiac function (e.g., chronic congestive heart failure) causing progressive and permanent kidney disease; CRS Type II (Acute Renocardiac Syndrome) is defined as an abrupt worsening of renal function (e.g., acute kidney ischaemia or glomerulonephritis) causing acute cardiac disorders (e.g., heart failure, arrhythmia, ischemia); CRS Type IV (Chronic Renocardiac syndrome) is defined as kidney disease (e.g., chronic glomerular disease) contributing to decreased cardiac function, cardiac hypertrophy and/or increased risk of adverse cardiovascular events; and CRS Type V (Secondary Cardiorenal Syndrome) is defined as a systemic condition (e.g., diabetes mellitus, sepsis) causing both cardiac and renal dysfunction (Ronco et al., Cardiorenal syndrome, J. Am. Coll. Cardiol. 2008; 52:1527-39). KD can be referred to by different stages indicated by Stages 1 to 5. Stage of KD can be evaluated by glomerular filtration rate of the renal system. Stage 1 KD can be indicated by a GFR greater than 90 mL/min/1.73 m2 with the presence of pathological abnormalities or markers of kidney damage. Stage 2 KD can be indicated by a GFR from 60-89 mL/min/1.73 m2, Stage 3 KD can be indicated by a GFR from 30-59 mL/min/1.73 m2 and Stage 4 KD can be indicated by a GFR from 15-29 mL/min/1.73 m2. A GFR less than 15 mL/min/1.73 m2 indicates Stage 5 KD or ESRD. It is understood that KD, as defined in the present invention, contemplates KD regardless of the direction of the pathophysiological mechanisms causing KD and includes CRS Type II and Type IV and Stage 1 through Stage 5 KD among others. Kidney disease can further include acute renal failure, acute kidney injury, and worsening of renal function.

“Hemodynamics” is the study of blood flow or circulation. The factors influencing hemodynamics are complex and extensive but include cardiac output (CO), circulating fluid volume, respiration, vascular diameter and resistance, and blood viscosity. Each of these may in turn be influenced by physiological factors. Hemodynamics depends on measuring the blood flow at different points in the circulation. Blood pressure is the most common clinical measure of circulation and provides a peak systolic pressure and a diastolic pressure. “Blood pressure” (BP) is the pressure exerted by circulating blood upon the walls of blood vessels. Invasive hemodynamic monitoring measures pressures within the heart. One of the most widely used methods of hemodynamic monitoring is the use of the Swan-Ganz Catheter. Through the use of the Swan-Ganz catheter one can measure central venous pressure (CVP) and obtain a subject\'s CO.

“Central venous pressure” (CVP) describes the pressure of blood in the thoracic vena cava, near the right atrium of the heart. CVP reflects the amount of blood returning to the heart and the ability of the heart to pump the blood into the arterial system. Another method for obtaining the cardiac output is using the Fick Method, in which a port is disposed in the pulmonary artery and measures pulmonary artery pressures. This port can also be configured to have a balloon that when inflated measures the pulmonary artery wedge pressure (PCWP).

“Mean arterial pressure” (MAP) is a term used in medicine to describe an average blood pressure in an individual. It is defined as the average arterial pressure during a single cardiac cycle.

“Left atrial pressure” (LAP) refers to the pressure in the left atrium of the heart. Pulmonary artery wedge pressure is used to provide an indirect estimate of LAP. Although left ventricular pressure can be directly measured by placing a catheter into the left ventricle by feeding it through a peripheral artery, into the aorta, and then into the ventricle, it is not feasible to advance this catheter back into the left atrium. LAP can be measured by placing a special catheter into the right atrium then punching through the interatrial septum; however, this is not usually performed because of damage to the septum and potential harm to the patient.

“Right atrial pressure” refers to the pressure in the right atrium of the heart. Central venous pressure is used to provide an indirect, noninvasive, measure of right atrial pressure.