US20160008394A1 - Inorganic nitrite to improve cardiopulmonary hemodynamics - Google Patents

Inorganic nitrite to improve cardiopulmonary hemodynamics Download PDF

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US20160008394A1
US20160008394A1 US14/768,198 US201414768198A US2016008394A1 US 20160008394 A1 US20160008394 A1 US 20160008394A1 US 201414768198 A US201414768198 A US 201414768198A US 2016008394 A1 US2016008394 A1 US 2016008394A1
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nitrite
canceled
pulmonary
dose
inhaled
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Mark Thomas Gladwin
Hunter Clay Champion
Edwin Parsley
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University of Pittsburgh
Aires Pharmaceuticals Inc
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University of Pittsburgh
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Assigned to UNIVERSITY OF PITTSURGH-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION reassignment UNIVERSITY OF PITTSURGH-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHAMPION, HUNTER, DR.
Assigned to UNIVERSITY OF PITTSURGH-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION reassignment UNIVERSITY OF PITTSURGH-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GLADWIN, MARK T, DR.
Publication of US20160008394A1 publication Critical patent/US20160008394A1/en
Assigned to AIRES PHARMACEUTICALS, INC. reassignment AIRES PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PARSLEY, Edwin
Assigned to NATIONAL INSTITUTES OF HEALTH (DEITR) reassignment NATIONAL INSTITUTES OF HEALTH (DEITR) CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: UNIVERSITY OF PITTSBURGH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/04—Nitro compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention is in the field of therapeutics. Specifically the treatment of cardiopulmonary diseases using inorganic nitrite.
  • Sodium nitrite is a naturally occurring compound that is commonly used as a preservative in meats. Due to its vasodilative properties and involvement in the nitric oxide pathway, drug development companies and researchers are also investigating sodium nitrite as a therapeutic agent.
  • Clinical studies using inorganic nitrite are being conducted to determine the efficacy and safety of inorganic nitrite in the treatment of pulmonary arterial hypertension, acute myocardial infarction, in transplant patients to prevent graft dysfunction, as a topical agent for chronic leg ulcers, in sickle cell disease, prevention of cerebral vasospasm, peripheral arterial disease, as an agent for cardio-protection during coronary artery bypass surgery, for use in resuscitated cardiac arrest patients, and treatment of metabolic syndrome and hypertension.
  • Preclinical studies also indicate that sodium nitrite may be useful as an agent to kill bacteria, including bacteria associated with infections in humans.
  • Heart failure is major health problem in the United States (U.S.) and elsewhere. In the U.S., HF affects over 5 million people with approximately half a million new cases occurring each year. HF is the leading cause of hospitalizations in people over 65 years in age. HF has many potential causes and diverse clinical features. Symptoms of heart failure can include dyspnea during activity or at rest, cough with white sputum, rapid weight gain, swelling in ankles, legs and abdomen, dizziness, fatigue and weakness, rapid or irregular heartbeats, nausea, palpitations, and chest pains.
  • DHF diastolic heart failure
  • SHF systolic heart failure
  • HfpEF heart failure with preserved ejection fraction
  • HFrEF heart failure with reduced ejection fraction
  • inorganic nitrite is thought to act through generation of nitric oxide (NO), its mode of action appears to differ from nitric oxide.
  • NO nitric oxide
  • Ingram et al. Am J. Phsiol. 298:H331-H339 (2010) disclose that sodium nitrite causes arterial and pulmonary vasodilation in hypoxic but not normoxic subjects, and this vasodilation was not directly associated with an elevation in plasma nitrite concentration.
  • PCWP pulmonary capillary wedge pressure
  • inhaled nitric oxide can worsen the condition and cause pulmonary edema.
  • PCWP pulmonary capillary wedge pressure
  • the inorganic nitrite is sodium nitrite.
  • the nitrite is administered by inhalation as a liquid or dry powder. As a liquid, the nitrite formulation may be nebulized for inhalation.
  • the heart failure is associated with pulmonary hypertension and/or pulmonary arterial hypertension.
  • the subject is non-responsive to inhaled nitric oxide.
  • inorganic nitrite such as inhaled inorganic nitrite
  • the administration of inorganic nitrite results in improved cardiac index and/or exercise capacity.
  • inorganic nitrite is not accompanied by a significant drop in blood pressure and increase in heart rate after administration of the inorganic nitrite.
  • the nitrite is administered by inhalation as a dry powder or liquid.
  • the liquid formulation is nebulized.
  • the subject is non-responsive to inhaled nitric oxide.
  • Conditions that can treated using the methods disclosed herein are, without limitation, acute or chronic heart failure, including diastolic dysfunction, diastolic heart failure, or systolic heart failure, pulmonary hypertension associated with diastolic heart failure, pulmonary hypertension associated with systolic heart failure, interstitial lung disease, associated pulmonary arterial hypertension, idiopathic pulmonary arterial hypertension; and sleep-disordered breathing-related pulmonary hypertension.
  • the subject is non-responsive to inhaled nitric oxide.
  • the associated pulmonary arterial hypertension is associated with a connective tissue disease, such as without limitation, scleroderma.
  • a condition amenable to treatment with inorganic nitrite in a subject in need of treatment by administering a therapeutically effective amount of inorganic nitrite to a subject with tolerance to organic nitrates.
  • the conditions amenable to treatment can include, without limitation, acute or chronic heart failure, such as diastolic dysfunction, diastolic heart failure, and/or systolic heart failure.
  • methods for treating heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF) comprising administering to a subject in need of treatment a therapeutically effective amount of inorganic nitrite.
  • the nitrite is administered by inhalation as a dry powder or liquid.
  • the liquid formulation is nebulized.
  • the subject is non-responsive to inhaled nitric oxide.
  • the amount of inorganic nitrite administered via inhalation is an emitted dose of about 90 mg or less, or about 45 mg-90 mg, or about 25 mg-80 mg nitrite, or about 25 mg-75 mg.
  • the dose can be one or more doses.
  • the dose or doses can be an escalated dose to reach the final highest dose concentration, such as about 90 mg, or about 80 mg, or about 75 mg.
  • the inhaled inorganic nitrite can be a liquid or dry powdered formulation. The liquid formulation can be nebulized for administration.
  • the inorganic nitrite is administered at a dose of nitrite that results in a plasma concentration of nitrite of about 4 micromolar to about 15 micromolar nitrite.
  • Modes of administration can include, without limitation, enteral, sublingual, parenteral, inhalation, such as oral, nasal, topical, transdermal, and rectal.
  • PH pulmonary hypertension
  • PAH pulmonary arterial hypertension
  • the nitrite is administered by inhalation as a dry powder or liquid.
  • the liquid formulation is nebulized.
  • the subject has associated acute of chronic heart failure, such as diastolic dysfunction, diastolic heart failure, or systolic heart failure, for example HFrEF or HFpEF.
  • nitrite is administered by inhalation as a dry powder or liquid.
  • the liquid formulation is nebulized.
  • the subject being treated with inorganic nitrite is non-responsive to inhaled nitric oxide and has pulmonary hypertension associated with systolic heart failure, interstitial lung disease, pulmonary arterial hypertension including associated pulmonary arterial hypertension, idiopathic pulmonary arterial hypertension; and sleep-disordered breathing-related pulmonary hypertension.
  • the PAH is associated with a connective tissue disease, such as, without limitation, scleroderma.
  • the subjects being treated with inorganic nitrite are non-responders to intravenous epoprostenol and intravenous adenosine.
  • FIG. 1 shows the effect of inhaled nitrite on pulmonary vascular resistance and systemic vascular resistance in the patients described in Table 1.
  • FIG. 2 shows that inhaled nitrite produced a dose-dependent improvement in cardiac index of patients described in Table 1.
  • FIG. 3 shows that inhaled nitrite produced a dose-dependent reduction in right atrial pressure in the patients describe in Table 1.
  • FIG. 4 shows that inhaled nitrite produced a dose-dependent reduction in pulmonary capillary wedge pressure in the patients described in Table 1.
  • FIG. 5 shows PK data for four subjects described in Table 1 at doses of 45 mg and 90 mg inhaled sodium nitrite.
  • Described herein are methods to treat acute or chronic heart failure in a subject in need of treatment using a therapeutically effective dose of inorganic nitrite, such as sodium nitrite.
  • Terms such as “treating” or “treatment” or “to treat” or “alleviating” or “to alleviate” or to “ameliorate” refer to both 1) therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder and 2) prophylactic or preventative measures that prevent and/or slow the development of a targeted pathologic condition or disorder.
  • those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented. Treatment need not result in a complete cure of the condition; partial inhibition or reduction of the condition being treated is encompassed by this term.
  • “Therapeutically effective amount,” or “therapeutic effect,” as used herein, refers to a minimal amount or concentration of inorganic nitrite that, when administered alone or in combination, is sufficient to provide a therapeutic benefit in the treatment of the condition, or to delay or minimize one or more symptoms associated with the condition.
  • therapeutically effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • the term “subject” refers to an animal, typically a human (i.e., a male or female of any age group, e.g., a pediatric patient (e.g., infant, child, adolescent) or adult patient (e.g., young adult, middle-aged adult or senior adult).
  • a human i.e., a male or female of any age group, e.g., a pediatric patient (e.g., infant, child, adolescent) or adult patient (e.g., young adult, middle-aged adult or senior adult).
  • a method for treating subjects in need of treatment who have conditions associated with high right atrial and/or pulmonary capillary wedge pressure (PCWP) using inorganic nitrite wherein the inorganic nitrite reduces one or both of either right atrial pressure or PCWP.
  • PCWP right atrial and/or pulmonary capillary wedge pressure
  • Another embodiment disclosed herein are methods for treating subjects in need of treatment who have conditions associated with high pulmonary vascular resistance (PVR) using inorganic nitrite, wherein the inorganic nitrite reduces the PVR without significantly altering the systemic vascular resistance.
  • PVR pulmonary vascular resistance
  • ILD interstitial lung disease
  • IPAH is idiopathic pulmonary arterial hypertension
  • APAH is associated pulmonary arterial hypertension
  • SSc is systemic scleroderma
  • sil is sildenafil
  • tad is tadalafil
  • amb is ambrisentan
  • bos is bosentan
  • tre is treprostinil
  • iv is intravenous; inh is inhaled
  • PH pulmonary hypertension
  • inhaled nitrite in doses of 45 mg and 90 mg
  • PVR pulmonary vascular resistance
  • SVR systemic vascular resistance
  • inhaled nitrite in doses of 45 mg and 90 mg placed into the nebulizer chamber
  • Individual response in each patient black
  • the average for the group larger squares.
  • inhaled nitrite in doses of 45 mg and 90 mg placed into the nebulizer chamber
  • Individual response in each patient black
  • the average for the group larger squares.
  • inhaled nitrite in doses of 45 mg and 90 mg
  • PCWP dose-dependent reduction in PCWP.
  • inhaled inorganic nitrite would be useful for treating conditions which result in one or more of increased right atrial pressure, increased pulmonary capillary wedge pressure, increased pulmonary arterial pressure, increased pulmonary vascular resistance, decreased cardiac index, and decreased exercise capacity.
  • Such conditions include, without limitation, acute or chronic heart failure, such as diastolic dysfunction, diastolic heart failure, systolic heart failure, pulmonary arterial hypertension associated with diastolic heart failure, pulmonary hypertension associated with systolic heart failure, interstitial lung disease, associated pulmonary arterial hypertension, idiopathic pulmonary arterial hypertension; and sleep-disordered breathing-related pulmonary hypertension.
  • the data also indicate that at the doses tested inhaled nitrite does not significantly affect heart rate, systemic blood pressure, methemoglobin, and systemic vascular resistance.
  • disclosed herein are methods for treating patients with inorganic nitrite who are tolerant to treatment with organic nitrates, and who have conditions that result in one or more of increased right atrial pressure, increased pulmonary capillary wedge pressure, increased pulmonary arterial pressure, increased pulmonary vascular resistance, decreased cardiac index, and decreased exercise capacity.
  • improvement in exercise capacity by inhaled inorganic nitrite can be determined using tests such as the six-minute walk where the distance walked in six minutes before treatment, by a subject in need of treatment, can be compared to the distance walked in six minutes by the subject after treatment with inorganic nitrite.
  • the administration of inhaled inorganic nitrite can be achieved using either a liquid formulation or a dry powder formulation.
  • the nitrite is administered via a nebulizer.
  • the nitrite is administered in a dry powder formulation, e.g., using a crushed powder delivery system. Since different devices, such as different nebulizers, deliver varying amounts of product, the doses disclosed herein are the delivered amounts, i.e., the amounts that reach the lung and are indicated as the “emitted dose”.
  • the emitted dose can be about 90 mg or less of inorganic nitrite, or about 80 mg or less of nitrite, or about 70 mg or less of nitrite or about 25 mg to about 90 mg of nitrite, or about 25 mg to about 80 g of nitrite, or about 30 mg to about 90 mg nitrite, or about 40 mg to about 90 mg of nitrite, or about 45 mg to about 90 mg of sodium nitrite, or about 45 mg to about 80 mg of nitrite.
  • Dosing can also be done using a dose titration which escalates to the highest dose.
  • Dosing can also be based on a target plasma nitrite concentration after inhalation of nitrite.
  • FIG. 5 shows plasma nitrite concentrations after inhalation of nitrite, and were found to be similar to normal volunteers at equivalent doses of inhaled nitrite: for the 45 mg dose 5-7 micromolar nitrite; and for the 90 mg dose 8-10 micromolar.
  • a target plasma concentration of nitrite can be, for example, less than or equal to about 15 micromolar plasma nitrite, or less than or equal to about 12 micromolar plasma nitrite, or less than or equal to about 8 micromolar plasma nitrite, or about 5-8 micromolar plasma nitrite, or about 7-10 micromolar plasma nitrite.
  • the targeted plasma nitrite concentration will be greater than baseline and lower than 15 micromolar nitrite to about 5 micromolar plasma nitrite.
  • a single-center, open label phase II study evaluated the effect of inhaled nitrite delivered in a dose escalation manner on the change in pulmonary vascular resistance (PVR) in subjects with pulmonary hypertension undergoing right heart catheterization.
  • PVR pulmonary vascular resistance
  • Each subject received a starting dose of 45 mg inhaled nitrite (nebulized nitrite), with subsequent planned dose escalation of 90 mg inhaled nitrite, based on pulmonary vascular resistance response and tolerability.
  • Subjects were evaluated for additional medical history. Physical examination and baseline laboratory testing were performed to verify eligibility criteria. Baseline pulmonary artery hemodynamic assessment, echocardiogram with documentation of TRV for estimation of right ventricular systolic pressure and assessment of LV systolic and diastolic function, and micromanometry measured simultaneous pressure and flow velocity signals were performed prior to inhaled nitrite treatment. Responses to 40 ppm inhaled NO were measured before nitrite nebulization via a non-rebreather face mask to assess vasodilator responsiveness.
  • the dose of inhaled nitrite was delivered via electronic nebulizer over 10 to 15 minutes.
  • right heart/pulmonary artery hemodynamics were measured as well as noninvasive systemic blood pressure monitoring and simultaneous RV echocardiography.
  • Subjects were tested for the changes in pulmonary vascular resistance (PVR) measured by right heart catheterization and using thermodilution cardiac output measurement at time zero, at times 15, 30 and 45 minutes after completion of each nebulization dose.
  • PVR pulmonary vascular resistance
  • Subjects were monitored closely for changes in blood pressure during the study. The presence of systemic hypotension defined by MAP ⁇ 50 mm Hg or 20% below baseline if initial MAP ⁇ 50 mm Hg would lead to a discontinuation of the study treatment, and the next higher dose of inhaled nitrite would not be administered. Subjects were continued to be monitored closely every 10 minutes for 2 hours.
  • nitrite samples were obtained after each dose of nitrite: pre-dose time zero, 15 minutes, 30 minutes, and 45 minutes; after the last dose, blood was collected at 60 and 120 minutes for nitrite PK analysis.
  • a single blood sample was collected for Cyclic Guanosine Monophosphate (cGMP) concentration determination at the end of the peak dose of nitrite. Measurement was made on mixed venous blood using PCW pullback samples at baseline (pre-dose) and at the maximally tolerated dose.
  • cGMP Cyclic Guanosine Monophosphate
  • sildenafil After stopping inhaled NO gas, a single dose of sildenafil was given if patients were on background sildenafil therapy at previously prescribed doses. 45-minutes after sildenafil dose baseline hemodynamics were performed. Then inhaled nitrite delivered as follows.
  • each subject received a starting dose of inhaled nitrite, with subsequent planned dose escalation of inhaled nitrite, based on pulmonary vascular resistance response and tolerability. Subjects were monitored carefully during and after the study treatment.
  • nebulized nitrite 45 mg
  • the dose of nebulized nitrite was delivered by an electronic nebulizer system that is portable, highly efficient utilizing continuously vibrating mesh aerosol generation technology that allows a high percentage respirable dose delivery, minimal loss of drug to the environment between inhalations, and a reproducible droplet size distribution for optimal delivery of drugs to the distal pulmonary tree over 10-15 minutes.
  • Subjects were instructed to breathe as calmly, and deeply as possible until no more mist was formed in the nebulizer chamber.
  • Subjects were also instructed to hold their breath for approximately 10 seconds after inhalation to allow the study drug to reach deep into the lungs.
  • the primary outcome measures for this study is change in pulmonary vascular resistance measured by right heart catheterization from time zero compared with peak effect 15 minutes post completion of nebulized dose of nitrite.
  • the secondary endpoints measure:

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WO2005007173A1 (en) 2003-07-09 2005-01-27 The Government Of The United States Of America As Represented By The Secretary, Department Of Health Use of nitrite salts for the treatment of cardiovascular conditions
CN105101977A (zh) * 2013-02-07 2015-11-25 宾夕法尼亚大学理事会 治疗心力衰竭的方法
JP6531990B2 (ja) * 2013-02-28 2019-06-19 ユニバーシティ オブ ピッツバーグ − オブ ザ コモンウェルス システム オブ ハイヤー エデュケイション 心肺血行動態を改善するための無機亜硝酸塩
KR20190103281A (ko) * 2017-01-03 2019-09-04 카르디옥실 파마슈티칼스 인코포레이티드 니트록실 공여 화합물의 투여 방법

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