WO2021202286A1 - Compositions and methods for treating autonomic dysreflexia - Google Patents

Abstract

Compositions and methods are provided to treat, prevent and/or reduce the frequency of autonomic dysreflexia (AD) and/or episodic hypertensive events. The compositions include NK1 receptor antagonists for parenteral or enteral administration to a subject, or pharmaceutically acceptable salts, esters, amides, prodrugs, or derivatives thereof. The NK1 receptor antagonists can selectively block activation of NK1 receptors in the peripheral and central nervous system that give rise to AD. Methods are provided for treating an acute episode of AD in a subject by parenterally administering a therapeutically effective amount of a NK1 receptor antagonist to reduce the severity and/or duration of the AD. In addition, methods are provided for preventing or reducing the frequency and/or severity of AD by administering either parenterally or enterally a therapeutically effective amount of a NK1 receptor antagonist to a subject on a continuous basis, such as twice daily, once daily, or once weekly.

Description

COMPOSITIONS AND METHODS FOR TREATING AUTONOMIC

DYSREFLEXIA

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63/001,863, filed March 30, 2020, the entire contents of which are incorporated by reference herein.

TECHNICAL FIELD

The presently disclosed subject matter relates to methods of using neurokinin 1 (NK1) receptor antagonists to treat or prevent episodic hypertensive crises and autonomic dysreflexia.

BACKGROUND

Autonomic dysreflexia (AD; also known as autonomic hyperreflexia) is a syndrome in which there is a sudden onset of excessively high blood pressure. AD is a potentially life- threatening condition for which no specific therapy currently exits. AD is most common in individuals with a spinal cord injury (SCI) above the mid-thoracic level (specifically the sixth thoracic vertebra, T6; Kumick, 1956) in whom rates of AD range from 48 to 90% and correlate with the severity of impairment (Lindan et ak, 1980; Curt et ak, 1997; Rabadi and Aston, 2016; Stillman et ak, 2017). AD may also occur in individuals with Guillain-Barre syndrome, multiple sclerosis, head trauma, stroke, using prescription medication, or using illicit substances. AD can be a medical emergency that presents with a sudden onset of headache, sweating, flushing, nasal congestion, nausea, and exceedingly high blood pressure (hypertension). An elevation of 20 mmHg over baseline systolic blood pressure meets the current definition of AD (Krassioukov et al, 2012). Elevations in arterial pressure reflexively produce bradycardia, which is a hallmark of AD. Uncontrolled, severe, hypertension may cause serious complications, including seizures, stroke, coma, and death (Lee et al, 1994).

In individuals with an intact spinal cord, sensory stimuli such as rectal or bladder fullness are relayed to the brain for integration so that behavior can be initiated to remove the stimulus (empty the bowel or bladder) or maintain physiological homeostasis until defecation or urination is convenient (including suppression of spinal reflexes that would otherwise increase blood pressure). After a high spinal cord injury, the brain is disconnected from such sensory stimuli so that behavior to remove the stimulus is not initiated, and spinal reflexes that are normally modulated by the brain are not restrained. As a result, any sensory stimulus arising below the level of the spinal injury can trigger a reflex increase in blood pressure (Blackmer, 2003).

In individuals with SCI, attacks of AD are triggered primarily by sensory stimuli arising from visceral organs below the level of spinal injury, especially the bladder and bowel. Following SCI, people may be unable to perceive the sensations of the bladder and bowel filling and lose their ability to control urination and defecation voluntarily. Distension of the bladder or bowel is estimated to cause 75-85 % of cases of AD (Lindan et al, 1980; Inskip et ak, 2017). Sensory stimuli arising from other parts of the body may also trigger severe, episodic hypertension and AD, for example pressure sores, childbirth, and sexual activity. AD is particularly problematic in the management and care of people with SCI since attacks are also associated with catheterization and bowel evacuation procedures that are necessary to manage bladder and bowel emptying (Furusawa et al, 2011; Faaborg et al,

2014).

Currently no pharmaceutical agents are approved for the prevention of AD or severe, episodic hypertension. The Consortium for Spinal Cord Medicine guidelines (2002) recommends that non-pharmacological measures (i.e., upright positioning of the subject) be employed initially (Teasell et ak, 2000), reserving use of antihypertensive agents only for severe hypertension because of concerns that they might produce hypotension, which is commonly experienced by people with SCI (Lee et ak, 1995; Krassioukov et ak, 2009). Rather than attempting to titrate blood pressure within safe limits during crisis management with antihypertensive agents, it would be beneficial to develop a therapy that instead prevents or reverses a hypertensive crisis and AD by inhibiting the sensory inputs arising from the bladder, bowel and other parts of the body that give rise to AD.

There is an unmet need for effective therapies to treat and prevent AD and severe, episodic hypertension. The present invention provides such compositions and methods.

SUMMARY

In a first aspect of the invention, a method for preventing or reducing the frequency and/or severity of autonomic dysreflexia (AD) comprises administering to a subject a therapeutically effective amount of an active agent, wherein the active agent is a NK1 receptor antagonist or a pharmaceutically acceptable salt, ester, amide, prodrug, or derivative thereof. In a feature of this aspect, the NK1 receptor antagonist can comprises one or more compounds selected from Table 1 or Table 2. In embodiments, the NK1 receptor antagonist comprises CP-99,994, aprepitant, netupitant, rolapitant, vofopitant, orvepitant, serlopitant, vestipitant, or combinations thereof.

In a second aspect of the invention, a method of reducing one or both of severity and duration of an acute episode of autonomic dysreflexia (AD) comprising administering to a subject experiencing AD, a therapeutically effective amount of an active agent, wherein the active agent is a NK1 receptor antagonist or a pharmaceutically acceptable salt, ester, amide, prodrug, or derivative thereof, wherein administration of the active agent reduces one or both of severity and duration of the acute episode of AD. In a feature of this aspect, the NK1 receptor antagonist comprises one or more compounds selected from Table 1 or Table 2. In embodiments, the NK1 receptor antagonist comprises CP-99,994, aprepitant, netupitant, rolapitant, vofopitant, orvepitant, serlopitant, vestipitant, or combinations thereof.

In a third aspect of the invention, a pharmaceutical formulation to treat, prevent and/or reduce the frequency of autonomic dysreflexia (AD) comprises a therapeutically effective amount of a NK1 receptor antagonist, or a pharmaceutically acceptable salt, ester, amide, prodrug, or derivative thereof, and a carrier for enteral or parenteral delivery. In a feature of this aspect, the NK1 receptor antagonist comprises one or more compounds selected from Table 1 or Table 2. In embodiments, the NK1 receptor antagonist comprises CP-99,994, aprepitant, netupitant, rolapitant, vofopitant, orvepitant, serlopitant, vestipitant, or combinations thereof.

In a fourth aspect of the invention, a method of identifying one or more NK1 receptor antagonists to prevent or reduce the frequency, duration and/or severity of AD comprises measuring hypertensive responses to colorectal or bladder distension in an animal model after administration to the animal of a test NK1 receptor antagonist relative to the baseline increase in blood pressure, wherein the test NK1 receptor antagonist that reduces the hypertensive response is indicated as a NK1 receptor antagonist useful for preventing or reducing the frequency, duration and/or severity of AD in a human subject.

In a fifth aspect of the invention, a method of inhibiting an increase in blood pressure caused by colorectal or bladder distension relative to a baseline increase in blood pressure caused by colorectal or bladder distension comprises administering to the subject a therapeutically effective amount of an active agent, wherein the active agent is a NK1 receptor antagonist or a pharmaceutically acceptable salt, ester, amide, prodrug, or derivative thereof. In a feature of this aspect, the NK1 receptor antagonist comprises one or more compounds selected from Table 1 or Table 2. In embodiments, the NK1 receptor antagonist comprises CP-99,994, aprepitant, netupitant, rolapitant, vofopitant, orvepitant, serlopitant, vestipitant, or combinations thereof.

BRIEF DESCRIPTION OF THE FIGURES

The foregoing aspects and other features of the invention are explained in the following description, taken in connection with the accompanying drawings.

FIG. 1 is a schematic representation of compound structure showing common molecular features for binding to a NK1 receptor characterized using CP-99,994, aprepitant and netupitant.

FIG. 2 is a schematic representation of compound structure showing common molecular features for binding to a NK1 receptor in vofopitant, orvepitant, serlopitant, rolapitant, and vestipitant.

FIG. 3 is a physiograph chart showing inhibition of mean arterial pressure (MAP) response to colorectal distension by vofopitant (GR205171) in SCI rats.

DET AIFED DESCRIPTION

The presently disclosed subject matter can be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that the disclosure will satisfy applicable legal requirements. Indeed, many modifications and other embodiments of the presently disclosed subject matter will come to mind to one skilled in the art to which the presently disclosed subject matter pertains. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims.

Bradycardia often accompanies episodes of severe hypertension and both are included in most definitions of AD. Throughout this specification and the claims, the term AD refers to any episodic hypertensive event, with or without bradycardia. Furthermore, the phrase “severe hypertensive episode” may or may not include bradycardia and can thus be considered equivalent to the term AD. This term and this phrase may be used interchangeably. Hypertension as used herein is an increase in blood pressure in response to rectal or bladder distension, or other stimuli known to elicit AD. In rat models, hypertension can be defined as an increase in mean arterial blood pressure (MAP) in response to rectal or bladder distension or other stimuli known to elicit AD. The ability of an NK1 receptor antagonist to inhibit an increase in MAP induced by colorectal or bladder distension demonstrates its utility to prevent or treat episodes of AD in humans. In embodiments, an increase in systolic blood pressure of about 20 mmHg in a human with SCI, or an increase in mean arterial pressure (MAP) of about 40 mmHg to about 50 mmHg in a rat with SCI, is a hypertensive episode that results from AD. Regarding these embodiments, inhibiting or reducing the increase in systolic blood pressure to maintain systolic blood pressure below 150 mmHg in a person with SCI, or the increase in MAP to less than 40 mmHg in a rat with SCI, can prevent or reduce the severity or frequency of the hypertensive episode and thus prevent or reduce the severity or frequency of AD triggered by a hypertensive episode.

The physiological mechanisms that trigger AD in response to stimuli arising in the rectum, bladder, and other parts of the body are the same (Blackmer, 2003). Accordingly, the ability of an NK1 receptor antagonist to inhibit hypertension induced by colorectal distension reflects its ability to inhibit AD whether the stimulus originates in the rectum, bladder, or another part of the body.

Following long-standing patent law convention, the terms “a,” “an,” and “the” refer to “one or more” when used in the subject application, including the claims. Thus, for example, reference to “an antagonist” includes a plurality of antagonists, unless the context clearly is to the contrary (e.g., a plurality of antagonists), and so forth.

Throughout this specification and the claims, the terms “comprise”, “comprises” and “comprising” are used in a non-exclusive sense, except where the context requires otherwise. Likewise, the term “include” and its grammatical variants are intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that can be substituted or added to the listed items.

For the purposes of this specification and appended claims, the term “about”, “approximately”

when used in connection with one or more numbers or numerical ranges, should be understood to refer to all such numbers, including all numbers in a range and modifies that range by extending the boundaries above and below the numerical values set forth. The recitation of numerical ranges by endpoints includes all numbers, e.g., whole integers, including fractions thereof, subsumed within that range (for example, the recitation of 1 to 5 includes 1, 2, 3, 4, and 5, as well as fractions thereof, e.g., 1.5, 2.25, 3.75, 4.1, and the like) and any range within that range. Further, the term “about” refers to a range of +/- 0.1 , 1 , 2, 5, 10, 15, or 20% of a stated value. For example, the phrase “about four hours or less” can include 3-5 hours or any time in between. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5- fold, and more preferably within 2-fold, of a value. Where values are described in the application and claims, unless otherwise stated, it should be assumed that the term “about” means within an acceptable error range for the particular value.

The term “antagonist” as used herein refers to a pharmaceutical or pharmacological agent that does not activate the human NK1 receptor, but binds to it with high affinity, whereby it inhibits the activation of NK1 receptors by the endogenous neuropeptides, substance P and neurokinin A or any other NK1 receptor agonist.

The terms “active agent,” “agent,” “drug,” “pharmaceutical agent,” “pharmacological agent,” and “pharmacologically active agent” are used herein interchangeably for the purposes of the specification and claims.

The term “active agent” as used herein refers to a “NK1 receptor antagonist” or “antagonist”. The active agent selectively blocks activation of NK1 receptors in the peripheral and central nervous system (CNS) that give rise to AD, including but not limited to, the autonomic ganglia, sensory nerves, spinal cord, and brain.

The crystal structure of the human NK1 receptor complexed with NK1 receptor antagonists has been published (Schoppe et al, 2019). Using X-ray diffraction to resolve the receptor- ligand complex, a common pharmacophore was identified with the following components: a 6-membered ring at the “core” to which two or three substituents are attached, designated “arms 1-3.” Arm 1 comprises a linker-attached aromatic group. In some embodiments, arm 1 is di-trifluoromethoxyphenyl. Arm 2 comprises a directly attached phenyl, fluorophenyl or methoxyphenyl aromatic group. The arm 1 and arm 2 substituents determine the interaction of antagonist with the orthosteric NK1 receptor binding pocket.

Arm 3, present in some molecules, is a variable cyclic substituent that reduces the conformational flexibility of the receptor, resulting in insurmountable antagonism.

Exemplary structures are illustrated in Figure 2 d-f of Schoppe et al (2019), which is provided herewith as FIG. 1. FIG. 1 provides a schematic representation of the common molecular features for binding to the NK1 receptor for CP-99,994, aprepitant, and netupitant. In FIG. 1, schematic representations for the chemical structures of CP-99,994 (d), aprepitant (e), and netupitant (f) are provided with structural topology highlighted by labeled circles (core, arm 1, arm 2, and arm 3). From Figure 2, Schoppe et al (2019).

The same substituent groups are present in all known NK1 receptor antagonists, as illustrated with five additional exemplary embodiments in FIG. 2. FIG. 2 provides a schematic representation of the molecular features for binding to the NK1 receptor for exemplary embodiments vofopitant, orvepitant, serlopitant, rolapitant, and vestipitant. In FIG. 2, schematic representation of chemical structures of vofopitant, orvepitant, serlopitant, rolapitant, and vestipitant are provided with structural topology highlighted by labeled circles (core, arm 1, arm 2, and arm 3).

Based on resolution of the crystal structure of the NK1 receptor when bound to chemically distinct molecules, Schoppe et al (2019) state that molecular modeling can be used to design NK1 receptor antagonists for a range of therapeutic indications. As used herein, the term “NK1 receptor antagonist” refers to any molecule having a 6 membered ring core with arm 1 and arm 2 substituents that optimize their interaction with the NK1 receptor binding pocket as defined by Schoppe et al (2019). Exemplary embodiments of compounds may have a 6-membered ring core with arm 1 and arm 2 substituents, and potentially an arm 3 substituent that induces a beneficial conformational change in the receptor. Since all known NK1 receptor antagonists possess a 6-membered ring core with arm 1 and arm 2 substituents and share a common pharmacophore, a person having ordinary skill in the art would consider the ability of any NK1 receptor antagonist compound having a 6-membered ring core with arm 1 and arm 2 substituents (and potentially an arm 3 substituent) to prevent or treat AD to be representative of the class of NK1 receptor antagonist compounds having a 6-membered ring core with arm 1 and arm 2 substituents (and potentially an arm 3 substituent) as a whole.

The term “affinity” refers to the concentration of the antagonist that displaces 50% of specific ligand binding to native or recombinant human NK1 receptors (this concentration is the IC50). In a first embodiment, antagonists with “high affinity” for the human NK1 receptor possess an IC50 value of <100 nM. In a second embodiment they possess an IC50 value of <10 nM. In a third embodiment they possess an IC50 value of <1 nM. Alternatively, affinity may be expressed as the inhibition constant (Ki), or the negative logarithm of the inhibition constant (pKi), which is the concentration of the antagonist that would occupy 50% of the receptors if there were no ligand present. In a first embodiment, antagonists with “high affinity” for the human NK1 receptor possess Ki values <100 nM. In a second embodiment they possess a Ki value of <10 nM. In a third embodiment they possess a Ki value of <1 nM, corresponding to pKi values >7, >8 and >9, respectively. Compounds with high affinity for the human NK1 receptor share the common pharmacophore described above. Exemplary embodiments of NK1 receptor antagonists having high affinity for the human NK1 receptor include CP-99,994, aprepitant, netupitant, rolapitant, vofopitant, orvepitant, serlopitant, and vestipitant, which are listed in Table 1 below. Table 1. Compounds with High Affinity for Human NK1 Receptor

In Table 1, superscripts refer to data obtained from the following publications: McLean et al, 1993; ²Hale et al, 1998; ³Rizzi et al 2012; ⁴Duffy et al, 2012; ⁵di Fabio et al, 2013; ⁶Jiang et al, 2009; ⁷Brocco et al, 2008.

High affinity NK1 receptor antagonists which share the common pharmacophore described above are also highly CNS penetrant compounds, making them effective compounds for treatment and prevention of AD. The term “brain penetrant” refers to the ability of NK1 receptor antagonists to occupy NK1 receptors in the brain of a mammal. A method to measure brain NK1 receptor occupancy is by inhibition of NK1 receptor agonist- induced foot drumming in gerbils (Rupniak & Williams, 1994). In a first embodiment, the term “highly brain penetrant” refers to NK1 receptor antagonists that can inhibit foot drumming in gerbils at a dose <30 mg/kg. In a second embodiment, the dose is <10 mg/kg. In a third embodiment, the dose is <3 mg/kg. An alternative method to assess brain penetration of NK1 receptor antagonists is by inhibition of emesis (Rupniak et al, 1997). In a first embodiment, the term “highly brain penetrant” refers to antagonists that can inhibit emesis in ferrets or pigs at a dose <30 mg/kg. In a second embodiment, the dose is <10 mg/kg. In a third embodiment, the dose is <3 mg/kg. Additionally, NK1 receptor occupancy in the living human brain at therapeutic doses can be determined, e.g., using Positron Emission Tomography (PET) imagining technology. The term “highly brain penetrant” further refers to antagonists that can occupy >50%, >60%, >70%, >80, >90%, and 100% of NK1 receptors in the human brain at therapeutic doses. Table 2 includes a listing of exemplary embodiments of highly brain penetrant NK1 receptor antagonists. Table 2. Highly Brain Penetrant NK1 Receptor Antagonists

In Table 2, superscripts refer to data obtained from the following publications:

¹ Rupniak & Williams, 1994; ²Watson et al, 1995; ³Tattersall et al, 2000; ⁴Bergstrom et al, 2004; ⁵Rudd et al, 2016; ⁶Rizzi et al, 2012; ⁷Rossi et al, 2012; ⁸Duffy et al, 2012; ⁹Wang et al,

2017; ¹⁰Rupniak et al, 2003; ⁿGrelot et al, 1998; ¹²Zamuner et al, 2012; ¹³di Fabio et al,

2013; ¹⁴Ratti et al, 2013; ¹⁵Jiang et al, 2009; ¹⁶Brocco et al, 2008.

Table 1 and Table 2 provide a listing of NK1 receptor antagonists for preventing or treating AD. Exemplary NK1 receptor antagonists for preventing or treating AD include, but are not limited to, aprepitant, netupitant, rolapitant, vofopitant, vestipitant, orvepitant, and serlopitant. Because these compounds share a common pharmacophore, have high affinity for the human NK1 receptor, and are highly brain penetrant compounds, it follows that the ability of any one of these compounds to prevent or treat AD is a property shared by all compounds in the group. The term “effective amount” or “therapeutically effective amount” of a drug or pharmacological agent as used herein refers to a sufficient amount of the drug or agent to provide the desired effect, i.e., treating or preventing AD. It is recognized that the effective amount of a drug or pharmacologically active agent will vary depending on the route of administration, the selected compound, and/or the species to which the drug or pharmacological agent is administered. It is also recognized that one of skill in the art will determine appropriate effective amounts by considering such factors as metabolism, bioavailability, and other factors that affect levels of a drug or pharmacologically active agent following administration within the unit dose ranges disclosed further herein for different routes of administration·

The term “oral drug delivery” as used herein refers to a drug formulation (e.g., tablet, capsule, liquid) that is conveniently swallowed for oral administration. As used herein, the term “enteral drug delivery” refers to delivery of a drug by passage through the alimentary canal or digestive tract.

As used herein, the term “parenteral drug delivery” refers to delivery of a drug by passage into the bloodstream without first having to pass through the alimentary canal or digestive tract. In some embodiments, parenteral drug delivery can be subcutaneous, intramuscular, sublingual, transmucosal, transdermal, intranasal, inhalation, intrathecal, implantable delivery device, or intravenous.

The term “patient” or “subject” as used herein refers to both human and animal subjects. The term “pharmaceutically acceptable” as used herein refers to a material that is not biologically or otherwise undesirable (i.e., the material can be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition). As used herein, the term “pharmacologically active” refers to a derivative or metabolite of the active agent having the same type of pharmacological activity as the parent active agent. When the term “pharmaceutically acceptable” is used to refer to a derivative (e.g., a salt or an analog) of an active agent, it is to be understood that the compound is pharmacologically active as well, i.e., therapeutically effective to treat or prevent AD.

The presently disclosed subject matter relates to methods for treating or preventing AD or episodic hypertensive events in a subject, by administering a therapeutically effective amount of an active agent to the subject, wherein the active agent is a NK1 receptor antagonist or a pharmaceutically acceptable salt, ester, amide, prodrug, or derivative thereof.

In some embodiments, the method comprises administration of a NK1 receptor antagonist, or a pharmaceutically acceptable salt, ester, amide, prodrug, or derivative thereof, to prevent AD continuously. Suitable NK1 receptor antagonists are highly brain penetrant and can achieve a high level of NK1 receptor occupancy in the human brain throughout the day and night with, for example, twice daily administration, once daily administration, or once weekly administration. In some embodiments, the active agents can include (but are not limited to) orvepitant, vestipitant, vofopitant, serlopitant, rolapitant, netupitant, fosapritant and aprepitant.

The method comprises parenteral administration of a therapeutically effective amount of an active agent to a subject in urgent need thereof (i.e., a subject experiencing an acute attack of AD). Specifically, the active agent comprises a NK1 receptor antagonist or a pharmaceutically acceptable salt, ester, amide, prodrug, or derivative thereof. Thus, the disclosed methods provide for the treatment of AD through the enteral or parenteral administration of one or more NK1 receptor antagonists.

In some embodiments, the parenteral administration can include intravenous, intramuscular, sublingual, transmucosal, transdermal, intranasal, inhalation, intrathecal, implantable device, and subcutaneous administration·

In some embodiments, the presently disclosed subject matter is directed to a pharmaceutical formulation for treating AD. Specifically, the formulation comprises a therapeutically effective amount of a NK1 receptor antagonist, or a pharmaceutically acceptable salt, ester, amide, prodrug, or derivative thereof. The formulation may further comprise a carrier for enteral or parenteral delivery. The formulation may contain active agent that has been lyophilized or micronized.

In some embodiments, the active agent can be a pharmaceutical formulation selected from the group consisting of tablets, capsules, caplets, solutions, suspensions, syrups, granules, beads, powders, pellets, gels, wafers, polymers, or adhesive patches.

In some embodiments, the presently disclosed subject matter includes a method of identifying one or more NK1 receptor antagonists for treating or preventing AD, the method including, but not limited to, measuring the inhibition of hypertension elicited by colorectal distension in an animal model that includes, but is not limited to, SCI, following administration of a candidate NK1 receptor antagonist, wherein the candidate NK1 receptor antagonist that reduces such hypertension is indicated as a NK1 receptor antagonist that is useful for treating, preventing or reducing the frequency of AD in a human or animal subject. The animal can be a rat.

EXAMPLE

The following Example has been included to provide guidance to one of ordinary skill in the art for practicing representative embodiments of the presently disclosed subject matter. Considering the present disclosure and the general level of skill in the art, those of skill can appreciate that the following Example is intended to be exemplary only and that numerous changes, modifications, and alterations can be employed without departing from the scope of the presently disclosed subject matter.

Evaluation of Ability of Vofopitant to Inhibit AD Induced by Colorectal Distension

Testing was performed to evaluate whether NK1 receptor antagonists are capable of inhibiting AD elicited by colorectal or bladder distension in human subjects or in animals. Vofopitant (GR205171; available from ABX Advanced Biochemical Compounds) is a representative compound from the NK1 receptor antagonists described above, which share a common pharmacophore, have high affinity, and are highly brain penetrant compounds. A person having ordinary skill in the art would expect other NK1 receptor antagonist compounds to behave similarly to and have similar results to vofopitant. For example, the skilled artisan would expect the compounds in Table 1 and Table 2 to provide similar results to vofopitant. In particular, the skilled artisan would expect orvepitant and serlopitant to provide similar results.

The literature describes methods to produce hypertension in rats with SCI by colorectal distension (Krassioukov & Weaver, 1995). These methods represent an experimental model of human AD. Hypertension in rats is measured as an increase in mean arterial blood pressure (MAP) in response to colorectal distension. In humans, hypertension is measured as an increase in systolic blood pressure.

To determine the ability of a high affinity, highly brain penetrant NK1 receptor antagonist to treat and/or prevent AD in humans, the effect of vofopitant on colorectal distension-induced hypertension in rats with SCI was examined as described below.

Materials: Vofopitant was purchased from ABX Advanced Biochemical Compounds.

Surgical preparation of rats: Methods of producing spinal cord injury (SCI) and implantation of telemetry catheters are well described in the literature (West et al, 2015; Rabchevsky et al, 2011). Briefly, in the method, animals are anesthetized with, for example, isoflurane (1-4% in O2) or a mixture of ketamine/xylazine (50-100 mg/kg and 5-10 mg/kg, respectively) for all surgical procedures. The spinal cord is transected between the T3/4 levels. A telemetry catheter is inserted into the carotid or femoral artery and positioned near the ascending or descending aorta for measurement of blood pressure. The body of the transducer is placed in the subcutaneous space between the scapulae and the incision site closed. The animals are monitored until recovery from anesthesia. After recovery from surgical procedures, animals are habituated to handling, restraint, and colorectal manipulations on at least 2 separate occasions, in order to reduce stress reactions during experimental procedures. Nutritional supplements, fluids, analgesics, and antibiotics are administered post-operatively as needed to maintain hydration, comfort and to control infection.

Colorectal distension was performed via a balloon catheter that was placed ~2 cm into the rectum in awake freely moving or lightly restrained animals. The catheter was secured to the tail. The animals were then placed into a cage or onto a platform, and the blood pressure responses to colorectal distension were monitored as described by Krassioukov et al (2002) and Rabchevsky et al (2011).

Colorectal Distension Evoked Hypertension and AD: After spinalization (for example, 1 day or 3 weeks or more), animals underwent colorectal distension (2 ml infused in 10 sec and maintained for 50 sec). The balloon was immediately emptied, and 10 min after arterial pressure had returned to normal levels, colorectal distension was repeated once or twice more. If the arterial pressure response was consistent through this “Baseline” period, rats received a dose of test compound or vehicle. Rats were pretreated with vehicle or vofopitant (GR205171) administered subcutaneously 30 minutes prior to colorectal distension and mean arterial blood pressure was monitored continuously using standard telemetry techniques in conscious animals.

The increase in mean arterial pressure (MAP) during colorectal distension was recorded. Each dose of vofopitant or vehicle was compared (with Bonferroni adjustment) with pretreatment Baseline values to determine whether statistically significant inhibition of the increase in MAP occurred after colorectal distension.

Statistical analysis: Blood pressure values from 6 rats were averaged for each treatment group and compared with baseline (pretreatment values). A two-way ANOVA comparing the vehicle and drug response over the multiple trials was conducted followed by Tukeys’ multiple comparison test. Additional statistical analysis was performed using paired t-test; p<0.05 was considered statistically significant.

Results: In SCI rats, colorectal distension reliably increased mean arterial blood pressure (MAP) by 40-50 mmHg (“Baseline” values, Figure 1). Repeated injection of vehicle every 30 minutes had no effect on the MAP response to colorectal distension. Successive injections of 3, 10 and 30 mg/kg vofopitant (GR205171) caused a dose-related inhibition of the MAP response to colorectal distension (FIG. 3). For purposes of this application, the term “inhibition” means restraining of an action of an organ or cell, or reduction of a reflex or other activity, as a result of a NK1 receptor antagonist. The terms “inhibit” or “inhibiting” may also be used. FIG. 3 is a physiograph chart showing the increase in mean arterial pressure (MAP) in response to colorectal distension (CRD) after vehicle or varying dosages of drug. Each point is the average obtained for 6 rats in each group. Error bars are standard deviations. Baseline values refer to MAP responses obtained prior to administration of drug or vehicle. The same rats received three successive injections of vehicle or GR205171 on different test days. Open circles are data obtained after subcutaneous (SC) administration of vehicle. Filled circles are data obtained after administration of GR205171 (3, 10 or 30 mg/kg SC). Asterisks indicate a statistical difference from baseline after 10 and 30 mg/kg of vofopitant, 2-way ANOVA followed by paired t-test (p<0.05).

The findings demonstrated the ability of vofopitant to inhibit the MAP response to colorectal distension in SCI rats. The results demonstrate that the increase in mean arterial pressure in rats caused by colorectal or bladder distension can be inhibited by about 10% to about 60% relative to a baseline increase by administration of a NK1 receptor antagonist - in this example vofopitant. Using the rat model described herein, the results for inhibition of the increase in mean arterial pressure in rats translates to an inhibition of about 10% to 100% of the increase in systolic blood pressure in humans. For example, the increase in systolic blood pressure caused by colorectal or bladder distension in humans can be inhibited by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%.

The active agent, here vofopitant, may be administered in varying dosages, including from about 3 mg/kg to about 30 mg/kg. Dosages useful in rats translate to dosages of about 1 to about 60 mg in humans. Thus, exemplary dosages in humans may include about 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14, mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg, 36 mg, 38 mg, 40 mg, 42 mg, 44 mg, 46 mg, 48 mg, 50 mg, 52 mg, 54 mg, 56 mg, 58 mg, and 60 mg.

A person having ordinary skill in the art would expect other NK1 receptor antagonist compounds to behave similarly to and provide similar results to vofopitant. For example, the skilled artisan would expect the compounds in Table 1 and Table 2 to provide similar results to vofopitant. In particular, the skilled artisan would expect orvepitant and serlopitant to provide similar results to vofopitant and be effective at similar dosages to vofopitant. Other compounds listed in Table 1 and Table 2 may be less potent and require higher dosages in humans, for example 60 mg to 300 mg. REFERENCES

All publications, patent applications, patents, and other references mentioned in the specification are indicative of the level of those skilled in the art to which the presently disclosed subject matter pertains. All publications, patent applications, patents, and other references are herein incorporated by reference to the same extent as if each individual publication, patent application, patent, and other reference was specifically and individually indicated to be incorporated by reference. It will be understood that, although a number of patent applications, patents, and other references are referred to herein, such reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art.

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Claims

CLAIMS What is claimed is:

1. A method for preventing or reducing the frequency and/or severity of autonomic dysreflexia (AD), the method comprising administering to a subject a therapeutically effective amount of an active agent, wherein the active agent is a NK1 receptor antagonist or a pharmaceutically acceptable salt, ester, amide, prodrug, or derivative thereof.

2. The method of claim 1, wherein the NK1 receptor antagonist comprises one or more compounds selected from Table 1 or Table 2.

3. The method of claim 1, wherein the NK1 receptor antagonist comprises CP- 99,994, aprepitant, netupitant, rolapitant, vofopitant, orvepitant, serlopitant, vestipitant, or combinations thereof.

4. The method of claim 1, wherein the NK1 receptor antagonist comprises vofopitant, orvepitant, serlopitant, or combinations thereof.

5. The method of claim 1, wherein the active agent is a pharmaceutical formulation selected from the group consisting of tablets, capsules, caplets, solutions, suspensions, syrups, granules, beads, powders, and pellets, gels, wafers, polymers, or adhesive patches.

6. The method of claim 5, wherein the pharmaceutical formulation is administered to the subject through a parenteral or an enteral mode of delivery.

7. The method of claim 6, wherein the parenteral or enteral mode of delivery is selected from the group consisting of: oral, rectal, intravenous, intramuscular, sublingual, transmucosal, subcutaneous, transdermal, inhalation, intranasal, intrathecal, or implantable delivery device.

8. The method of claim 6, wherein the pharmaceutical formulation is administered enterally to the subject twice daily, once daily, or once weekly.

9. The method of claim 6, wherein the pharmaceutical formulation is administered enterally and wherein the active agent is one or a combination of orvepitant, vestipitant, vofopitant, serlopitant, rolapitant, netupitant, fosapritant and aprepitant.

10. The method of claim 1, wherein the subject is a human.

11. The method of claim 1, wherein the subject is at risk for AD as a result of spinal cord injury, Guillain-Barre syndrome, multiple sclerosis, head trauma, stroke, prescription medication, or illicit substance abuse.

12. A method of reducing one or both of severity and duration of an acute episode of autonomic dysreflexia (AD), comprising administering to a subject experiencing AD, a therapeutically effective amount of an active agent, wherein the active agent is a NK1 receptor antagonist or a pharmaceutically acceptable salt, ester, amide, prodrug, or derivative thereof, wherein administration of the active agent reduces one or both of severity and duration of the acute episode of AD.

13. The method of claim 12, wherein the active agent is administered through a parenteral mode of delivery.

14. The method of claim 12, wherein the subject is a human.

15. The method of claim 12, wherein the active agent is a pharmaceutical formulation in the form of a liquid, gel, wafer, polymer, or adhesive patch, and the parenteral mode of delivery is intravenous, intramuscular, intranasal, intrathecal, implantable delivery device, sublingual, transdermal, subcutaneous, inhalation, or transmucosal delivery.

16. The method of claim 15, wherein the NK1 receptor antagonist comprises one or more compounds selected from Table 1 or Table 2.

17. The method of claim 16, wherein the NK1 receptor antagonist comprises CP- 99,994, aprepitant, netupitant, rolapitant, vofopitant, orvepitant, serlopitant, vestipitant, or combinations thereof.

18. The method of claim 16, wherein the NK1 receptor antagonist comprises vofopitant, orvepitant, serlopitant, or combinations thereof.

19. The method of claim 12, wherein the acute episode of AD is triggered in the subject by a bladder catheterization, a manual bowel program, or other intermittent procedures.

20. A pharmaceutical formulation to treat, prevent and/or reduce the frequency of autonomic dysreflexia (AD), comprising: a therapeutically effective amount of a NK1 receptor antagonist, or a pharmaceutically acceptable salt, ester, amide, prodrug, or derivative thereof, and a carrier for enteral or parenteral delivery.

21. The formulation of claim 20, wherein the NK1 receptor antagonist comprises one or more compounds selected from Table 1 or Table 2.

22. The method of claim 21, wherein the NK1 receptor antagonist comprises CP- 99,994, aprepitant, netupitant, rolapitant, vofopitant, orvepitant, serlopitant, vestipitant, or combinations thereof.

23. The method of claim 21, wherein the NK1 receptor antagonist comprises vofopitant, orvepitant, serlopitant, or combinations thereof.

24. The pharmaceutical formulation of claim 20, in the form of tablets, capsules, caplets, solutions, suspensions, syrups, granules, beads, powders, pellets, gels, wafers, polymers, or adhesive patches.

25. The pharmaceutical formulation of claim 20, wherein the active agent has been lyophilized or micronized.

26. A method of identifying one or more NK1 receptor antagonist to prevent or reduce the frequency, duration and/or severity of AD, comprising: measuring hypertensive responses to colorectal or bladder distension in an animal model after administration to the animal of a test NK1 receptor antagonist relative to the baseline increase in blood pressure, wherein the test NK1 receptor antagonist that reduces the hypertensive response is indicated as a NK1 receptor antagonist useful for preventing or reducing the frequency, duration and/or severity of AD in a human subject.

27. The method of claim 26, wherein the animal is a rat.

28. A method of inhibiting an increase in blood pressure caused by colorectal or bladder distension relative to a baseline increase in blood pressure caused by colorectal or bladder distension, comprising administering to the subject a therapeutically effective amount of an active agent, wherein the active agent is a NK1 receptor antagonist or a pharmaceutically acceptable salt, ester, amide, prodrug, or derivative thereof.

29. The method of claim 28, wherein the NK1 receptor antagonist comprises one or more compounds selected from Table 1 or Table 2.

30. The method of claim 28, wherein the NK1 receptor antagonist comprises CP- 99,994, aprepitant, netupitant, rolapitant, vofopitant, orvepitant, serlopitant, vestipitant, or combinations thereof.

31. The method of claim 28, wherein the NK1 receptor antagonist comprises vofopitant, orvepitant, serlopitant, or combinations thereof.

32. The method of claim 28, wherein the increase in blood pressure due to colorectal or bladder distension is inhibited about 10% to about 100% relative to the baseline increase.

33. The method of claim 32, wherein the increase in blood pressure due to colorectal or bladder distension is inhibited by about 30% to about 100% relative to the baseline increase.

34. The method of claim 32, wherein the baseline increase in blood pressure due to colorectal or bladder distension is about 20 mmHg to about 60 mmHg.

35. The method of claim 32, wherein the inhibition of the increase in blood pressure is about 20 mmHg to about 35 mmHg.

36. The method of claim 35, wherein the inhibition of the increase in blood pressure maintains systolic blood pressure below 150 mmHg in a human subject.

37. The method of claim 28, wherein the therapeutically effective amount of an active agent comprises about 1 to 300 mg.

38. The method of claim 37, wherein the therapeutically effective amount of an active agent comprises about 1 to 60 mg

39. The method of claim 28, wherein blood pressure comprises systolic blood pressure.