Systems, devices and methods for delivering therapeutic agents for neurostimulation

Abstract

Devices, systems, and methods for delivering therapeutic agents for neurostimulation are used to administer the therapeutic agent to a patient, modulate one or more nerves of the patient, and optionally monitor physiological parameters of the patient. The monitoring can inform neuromodulation and / or administration of the therapeutic agent. The systems, devices, and methods deliver therapeutic agents for neurostimulation. The devices administer the therapeutic agent, modulate one or more nerves of the patient, and observe and track physiological parameters of the patient. Modulation can occur during and / or after administration of the therapeutic agent to the patient. The target compounds activate peripheral nerves via agonists of chemoreceptors or somatosensory receptors, resulting in signaling in the cervical vagus nerve. These compounds exhibit chemical neuroactivation of the vagus nerve, but also via effects such as chemical agents engaging neural sensors and electrical stimulation of the vagus nerve, which has therapeutic effects in multiple disease states.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 330,352, filed April 13, 2022, the entire contents of which are incorporated by reference.

[0002] The present invention relates to novel and improved methods of therapeutic treatment and related systems and devices. More particularly, the present invention relates to the delivery of therapeutic agents in conjunction with the application of neuromodulation, optionally with monitoring of one or more physiological parameters of the patient undergoing the treatment. [Background technology]

[0003] Stimulation of certain aspects of the body with implantable electrical generators has been performed for a variety of benefits, including, for example, cardiac pacemakers, cardiac defibrillation, muscle tremor treatment, depression treatment, and modulation of the effects of drug-resistant arthritis. Other approaches have used implantable electrical stimulation to address other conditions, such as pain management and opioid addiction. These efforts have focused on stimulating neural pathways, given the ability of nerves to affect movement as well as physiological function through their own transmission of electrical signals.

[0004] Mammals, including the human body, have a complex, multi-dimensional nervous system that regulates and controls many different functions important for movement, sensing, stimuli and responses to various inputs, management of organ function, and other activities related to overall health and well-being. When studied, the nervous system is generally segmented into the central nervous system, which includes the brain and spinal cord, and the peripheral nervous system, which is further segmented into the somatic nervous system, which is involved in signal transduction and controls skeletal muscle movement, and the autonomic nervous system, which is involved in what are sometimes described as "automatic" regulatory functions.

[0005] The autonomic nervous system (ANS) has two subcategories: the sympathetic nervous system and the parasympathetic nervous system. When in balance, these two aspects of the autonomic nervous system work in concert with other aspects of the human body to regulate many activities in ways related to maintaining overall health, including, among others, breathing, cardiovascular function, blood pressure regulation, digestion and absorption of nutrients, immune system response, inflammatory response, fight or flight response to perceived and / or actual threats, resetting to points of relaxation and rest, and response and regulation to external stimuli such as light and temperature. The balance of the sympathetic and parasympathetic nervous systems greatly contributes to optimal health.

[0006] The nervous system serves as a vital communication pathway that initiates and regulates important physiological responses to various events that may affect health. It is recursively involved in efferent and afferent behavior in response to various conditions. These responses assist the body's physical functions in temporary situations, such as a defensive fight-or-flight response. However, in other situations, they shift the sympathetic and parasympathetic nervous systems to a point of imbalance. These shifts may be due to chronic advanced diseases (such as arteriosclerosis and cardiovascular disease, autoimmune disorders), long-term stress, traumatic neurological and / or physiological events, and the effects of aging over time. Remaining at these points of imbalance, if not addressed, results in certain immediate and chronic health problems.

[0007] In the context of these responses, the body utilizes elevated levels of inflammation. This inflammatory response is the body's way of trying to deal with situations that the body perceives as threatening, including conditions involving disease, illness, injury, and invasion of the body, such as by surgery or delivery of medical implants into the body. The body also utilizes inflammation in the short term to fight certain pathogens and other threat elements, such as viruses and bacteria. Inflammation is also a common response to temporary or limited injuries, such as muscle strain or bruising from activity. A short-term, temporary increase in inflammation can be beneficial as part of a coordinated, elevated immune system response to a situation that the body works to heal / deal with. However, a long-term increase in inflammation levels can be both a response to a progressive disease state and a cause of ongoing disease progression, such as progressive cardiovascular disease or autoimmune conditions.

[0008] The body's inflammatory response also needs to be balanced: when functioning properly, the immune system sends signals to and receives information from the nervous system through pathways sometimes called the inflammatory reflex, and the efferent and afferent elements of the nervous system react to potentially harmful elements that return the immune system to a previous point of equilibrium in healthy individuals with properly functioning immune systems.

[0009] Both pro-inflammatory and anti-inflammatory activity arise from communication between the body's nervous system and its immune system. This activity occurs in part through activation of the body's immune cells by the nervous system, which causes the release of cytokines. Cytokines are small proteins that act as cellular messengers that direct the body's immune system response to a threat. When this response is appropriately proportionate to the threat to the body, the immune system action and associated inflammation levels and associated cytokine response will adequately address the threat without significant risk over a short period of time. However, there are times when the immune system exceeds the necessary response, resulting in extreme / excessive release of harmful and dangerous cytokines, including high levels that can lead to organ damage, organ failure, and even death.

[0010] Recent advances in therapeutic agents for treating certain life-threatening diseases introduce new external stressors to the body that can trigger inflammatory responses. These therapeutic agents are designed to modify or otherwise alter the body's immune system response to fight certain potentially fatal forms of disease, including cancer and forms of infectious diseases, including HIV. They can include immunotherapeutics, cellular therapies, therapeutic agents for autoimmune conditions, gene therapies, MRNA-based therapies, all of which are specifically designed to modify and potentially enhance the body's ability to use the immune system to fight or prevent disease. However, a frequent, if not ubiquitous, side effect is the elevation of immune system responses that affect other aspects of the body's function in potentially harmful ways, especially with regard to the production of excessive and potentially harmful levels of cytokines. Furthermore, certain of these therapies have as their target the elevation of certain cytokines for their immune-protective activity, but lack a precise way to manage the inherent risks associated with the intentional elevation of cytokine production and its associated cytokine release syndrome (CRS) deleterious side effects.

[0011] In certain circumstances, these therapeutics involve removing biological elements from a patient or donor, typically in the form of a blood sample or other extraction means, to obtain a component of the blood sample, which is then modified or otherwise added to. The purpose of this combination is to create and reintroduce into the patient a therapeutic agent that modifies aspects of the immune system's disease-fighting arsenal by utilizing or complementing the patient's immune system's attempts to fight a particular disease. Experience has shown that a promising approach to attacking various serious diseases, such as various forms of cancer, is that modifying the immune system can result in a significant inflammatory response that can be more dangerous to the patient than the underlying disease being treated by the therapeutic agent.

[0012] Other forms of therapy do not use specific blood draws, but instead attempt to engineer cell-based responses using engineered therapeutics, such as laboratory-grown stem cells, gene therapy, mRNA-based approaches, or as a further example, bispecific antibodies, which are then introduced into the patient to create an immune system response.

[0013] As a further example, an emerging form of immuno-oncology therapy known as chimeric antigen receptor therapy, or CAR-T, involves removing blood from a cancer patient or from an otherwise cancer-free donor. This blood is treated to separate the T cells from the remaining blood, and then tagged with one or more modifications so that the T cells are essentially "programmed" to target specific antigens on tumor cells when reintroduced into the patient. This treatment and the programmed new therapeutic are then introduced into the cancer patient via infusion or other such means, whereby the patient receives this CAR-T therapy using the extracted T cells with modifications to target the form of cancer in the patient. This infusion significantly increases the number of circulating T cells in the patient's bloodstream by introducing the modified CAR-T T cells into the patient. The intended effect of this immuno-oncology therapeutic is an increase in the number of circulating CAR-T T cells that are programmed to target, bind to, and attack the identified antigen or antigens on the surface of one or more cancerous tumors. The CAR-T cells mount a localized therapeutic attack against specific cancer cells and use cytokines to recruit additional immune cells to attack the target tumor. These recruited immune cells continue to release additional cytokines, which can spill over into a systemic response with recruitment of even more immune cells and increased production of cytokines that are not tumor-specific, creating a dangerous systemic cytokine response syndrome (CRS) that continues to build up on itself unless checked.

[0014] Short-term clinical results of CAR-T therapy have shown promise; however, these results have also revealed that this therapy, and other therapies that attempt to harness and / or modify the immune system, have significant and dangerous side effects. A very significant number of patients experience a response described as putting the immune system into excessive overdrive, resulting in a cytokine storm or CRS developing as an extreme inflammatory response to CAR-T therapy. Unless the cytokine storm / CRS situation is effectively addressed, this extreme inflammatory response can be more lethal and result in more immediate death than the cancer the patient is fighting. In certain CAR-T clinical studies, over 97% of treated patients experienced a CRS inflammatory response to CAR-T therapy. In addition, these patients also commonly experience neurological / neurocognitive problems as an additional associated side effect. Other immunotherapy approaches to treat disease, including checkpoint inhibitors, bispecific therapeutics, immune-enhancing therapies, dendritic cell vaccinations, certain gene therapies, cytokine-based protein therapeutics, and other forms of cellular therapies, have all demonstrated immune system responses expressed in dangerously elevated inflammation in the form of elevated cytokine release.

[0015] To manage the cytokine storm / cytokine release syndrome response in the context of treatment with these therapeutic agents, physicians frequently administer one or more anti-inflammatory drugs, such as a nonsteroidal anti-inflammatory drug or another cyclooxygenase-2 inhibitor, a cytokine inhibitor (e.g., IL-6 inhibitor IL-10 or other interleukin inhibitor, or TNF inhibitor), an anti-inflammatory steroid (corticosteroid), a cytostatic drug such as methotrexate, or other anti-inflammatory and / or steroid drugs. These anti-inflammatory and / or steroid drugs have had varying success, and when administered, all of these drugs reduce the effectiveness of immunotherapy, as they reduce the immune system's pro-inflammatory response to address the cytokine storm / cytokine release syndrome (CRS) condition. Addressing CRS concerns with current drugs involves suppressing the immune system's pro-inflammatory response. There is a connection between the introduction of CAR-T T cells into the body and the immune system's pro-inflammatory response, which is triggered by CAR-T T cells and is important to the mechanism of action underlying the effectiveness of these therapeutic agents.

[0016] In addition to the issues associated with responding to and treating CRS conditions with current drugs, there is no clear early warning system / detection approach that provides physicians with advanced, accurate, real-time alert of an impending cytokine storm / CRS situation, especially in the context of administering immunotherapeutic agents to patients. Physicians are aware of a generalized risk period (e.g., ranging from 3-14 days for certain therapeutic agents) that does not support accurate assessment and timely response. To obtain more specific information, periodic patient monitoring of selected parameters (e.g., pulse rate and oxygen levels, etc.) is performed, but typically a patient's blood draw must be performed to specifically look for the presence of elevated inflammatory markers indicative of a cytokine storm / CRS, allowing the physician to confirm this condition. This approach has the disadvantage of being essentially a snapshot in time, which creates a double-edged set of circumstances for the patient. On the one hand, a blood draw can provide a lot of specific information. However, it takes time to obtain this information, and because this information is derived from a specific point in time (i.e., the time of blood draw) rather than over time, long-term inflammatory trends are not part of the information obtained and provided to the physician. Additionally, hours may pass before blood-based data is fully compiled and presented to the attending physician, creating a potentially dangerous delay between the time of blood draw and delivery of the information to the physician to determine whether a dangerous cytokine storm / CRS condition is occurring in the patient. During this period, the cytokine response may grow to a point potentially dangerous to the patient, while the physician waits for the information to determine whether clinical steps are necessary to address the patient's condition with a dose of anti-inflammatory medication. Alternatively, the cytokine storm may be in the process of initiating and growing at a point after the time of blood draw but prior to obtaining specific information from the blood draw, so the blood draw information may indicate that the cytokine storm has not begun, potentially creating a false comfort point.

[0017] When a physician seeks to treat a cytokine storm / CRS condition, a series of additional problems exist. The physician is faced with several decisions, all of which involve notable trade-offs under the capabilities of current approaches, treatment therapies, and devices. The physician must select a drug and dose that has the potential to suppress the cytokine storm / CRS condition before serious damage or death occurs to the patient, while attempting to balance the impact of this step on the primary focus of attempting to treat the patient's underlying condition, such as cancer in the case of CAR-T cases. The challenge for the physician is that all of the anti-inflammatory drugs the physician may choose to administer have immunosuppressive effects, resulting in the physician having a difficult dilemma. The goal of the therapeutic agent delivered to the patient is to treat the underlying severe condition, and the therapeutic agent is dosed at a specific level intended to provide a therapeutic effect via a pro-inflammatory response, and the dose and associated pro-inflammatory response is the amount determined to be necessary to treat the specific condition, e.g., a targeted cancer tumor, an infectious disease such as AIDS / HIV, an autoimmune condition including rheumatoid arthritis and inflammatory bowel disease, or other fatal or critical conditions. Therapies rely, in part, on the signaling of pro-inflammatory cytokines and other related immune system responses to ramp up the immune system and help address a particular patient's condition. Now, for cytokine storm / CRS situations, physicians must shift from focusing on the primary therapeutic treatment and instead shift their focus to treating the potentially dangerous cytokine storm / CRS side effects using anti-inflammatory drugs that are known to reduce the performance of therapeutic treatments targeting the primary condition, such as cancer, by suppressing the immune system response. Current anti-inflammatory treatments to address cytokine storm / CRS side effects use pharmacological agents that suppress the immune system via a non-specific anti-inflammatory effect, including the inhibition of signaling via pro-inflammatory cytokines. This means that physicians must intentionally lower the benefits of the primary therapeutic treatment below the target effect associated with the specified dosage level in order to effectively treat the primary condition.If the physician does not administer sufficient anti-inflammatory drugs to treat the cytokine storm / CRS condition, the patient may be harmed or even die from the cytokine storm / CRS condition. Furthermore, the anti-inflammatory medication may not have an immediate effect because it must be absorbed into the patient's circulatory system with sufficient bioavailability to affect the cytokine storm, which takes time, so the level of anti-inflammatory medication, the timing of the medication, and the patient's responsiveness to the drug all affect the effectiveness of this step.

[0018] If medication is successful against a cytokine storm / CRS condition, the efficacy of the first-line treatment may have declined to the point where the patient remains at risk from that condition, for example, an aggressive cancer that may not be as responsive to treatment at a lower dose. The physician must find his or her way by balancing these two points with difficult outcomes in either direction if the medication is off against the CRS condition, the timing of the medication, the treatment of the patient's underlying condition that prompted the first-line treatment, and the patient's physiology and responsiveness to all drugs and other factors. All this occurs with a very limited and inconsistent flow of information to the physician regarding the patient's evolving dynamic condition. As previously stated, blood draws / samples provide limited time-delayed information, plus further non-invasive monitoring capabilities are not sufficiently refined and targeted for application to cytokine storm / cytokine release syndrome situations.

[0019] An additional complication with this situation concerns the timing of presentation of the cytokine storm / CRS situation, which may vary from patient to patient. For example, with certain forms of CAR-T therapy, the cytokine storm / CRS situation may manifest itself 3-14 days after the infused CAR-T dose. This means that the patient may not be in the hospital and / or not be closely monitored when this fatal side effect occurs, or the patient may be closely monitored in the hospital but still receive a delayed response due to timing issues to confirm the status of blood draws and the resulting blood panel reports to the treating physician. During this variable and delayed window, the patient may not be evaluated for CRS until significant symptomatology is noted and the storm / CRS is ongoing, as confirmed by the delayed blood draw approach described above.

[0020] Clearly, a different approach is needed that maintains the therapeutic benefits of the drug while limiting, if not eliminating, the harmful and unproductive side effects of the patient's associated cytokine storm / cytokine release syndrome events. Furthermore, a better approach is needed to monitor the patient and inform both the patient and the corresponding medical personnel, including the treating physician, including an early warning system and additional continuous real-time dynamic information about the patient's condition, including the patient's adaptive changes as therapeutic agents and other forms of treatment are administered. The current approach, which uses intermittent information and information that is not specific to the treatment, needs to be addressed in the context of providing a better alternative than immunosuppressive anti-inflammatory drugs to treat CRS. Summary of the Invention

[0021] The present invention provides novel devices, systems, and methods for delivering a therapeutic agent for neurostimulation. In one example embodiment, the therapeutic method includes modulating one or more nerves of a patient, administering the therapeutic agent to a patient in need of administration of the therapeutic agent, and optionally monitoring one or more physiological parameters of the patient. The method of the present invention includes a monitoring step to inform the neuromodulation and / or administration of the therapeutic agent. The present invention also provides an apparatus comprising a device for modulating one or more nerves of a patient before, during, or after administration of a therapeutic agent to a patient in need of administration of the therapeutic agent, and a device for monitoring one or more physiological parameters of the patient. The present invention also provides a related apparatus comprising a device for administering a therapeutic agent to a patient in need of administration of the therapeutic agent. Furthermore, the present invention also includes a system for delivering a therapeutic agent for neurostimulation, including a device for administering a therapeutic agent, a device for modulating one or more nerves of a patient, and a monitoring device for monitoring a physiological parameter of the patient. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 shows a schematic diagram of an exemplary embodiment of the present invention, including a block diagram of a method for delivery of a therapeutic agent in association with the application of neuromodulation, optionally with monitoring of one or more physiological parameters of a patient undergoing treatment.

[0023] [Diagram 2] FIG. 2 shows a block diagram of an exemplary embodiment of the present invention including a neuromodulatory component of a method according to the present invention.

[0024] [Figure 3A] FIG. 3A shows an example of an autonomic nervous system (ANS) nerve branch in the human body. [Figure 3B] FIG. 3B shows an example of an autonomic nervous system (ANS) nerve branch in the human body.

[0025] [Figure 4]FIG. 4 shows a block diagram of an exemplary embodiment of the present invention, including an exemplary therapeutic agent for use with methods and systems according to the present invention.

[0026] [Diagram 5] FIG. 5 illustrates a block diagram of an exemplary embodiment of the present invention, including an exemplary delivery confirmation evidence point.

[0027] [Figure 6] 6A-6D show cervical vagus nerve recordings obtained at baseline, after low and high concentrations of capsaicin on the neck, and after intradermal application, respectively, and cervical vagus nerve activity obtained at baseline, after low and high concentrations of capsaicin on the neck, and after intradermal application of capsaicin on the forehead near the trigeminal nerve endings.

[0028] [Figure 7] Figures 7A-7C show cervical vagus nerve recordings obtained after cervical application of low and high concentrations of GSK1016790A, as well as cervical vagus nerve activity obtained after application of low and high concentrations of GSK1016790A to the cervical vagus nerve at the forehead near the trigeminal nerve endings, respectively, at baseline and after application of low and high concentrations of GSK1016790A to the cervical vagus nerve at the forehead near the trigeminal nerve endings.

[0029] [Figure 8] 8A-8D show cervical vagus nerve recordings obtained at baseline, after low and high concentrations of WS-12 on the neck, and after intradermal application, respectively, and cervical vagus nerve activity obtained at baseline, after low and high concentrations of WS-12 on the neck, and after intradermal application of WS-12 on the forehead near the trigeminal nerve endings. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] The present invention provides a novel method of treatment, comprising modulating one or more nerves of a patient, administering a therapeutic agent to a patient in need of the therapeutic agent, and optionally monitoring one or more physiological parameters of the patient. In the method of the present invention, a monitoring step is included to inform the neuromodulation and / or administration of the therapeutic agent. The steps of modulating one or more nerves of a patient and administering a therapeutic agent to a patient in need of the therapeutic agent represent the therapeutic dosing aspect of the method of treatment according to the present invention. The present invention also provides an apparatus comprising a device for modulating one or more nerves of a patient before, during or after administration of a therapeutic agent to a patient in need of the therapeutic agent, and a device for monitoring one or more physiological parameters of the patient. The present invention also provides a related apparatus comprising a device for administering a therapeutic agent to a patient in need of the therapeutic agent. The device may be part of a system for delivering a therapeutic agent for neurostimulation according to the present invention. For example, in one example embodiment, the present invention also includes a system for delivering a therapeutic agent for neurostimulation, comprising a device for administering a therapeutic agent, a device for modulating one or more nerves of a patient, and a monitoring device for monitoring a physiological parameter of the patient. FIG. 1 shows the elements of a treatment method and apparatus according to the present invention and identifies some features and advantages.

[0031] Modulating one or more nerves of a patient results in beneficial physiological responses for the patient undergoing treatment. These beneficial physiological responses include, but are not limited to, inhibition of the propagation of pro-inflammatory cytokines, increased heart rate variability, and alterations in brainwave activity and / or pupillary responses detected by electroencephalography (EEG) consistent with improved autonomic tone, as well as reduced pain. The method of the present invention combines neuromodulation with administration of one or more therapeutic agents to treat a patient in need of treatment. The step of modulating one or more nerves of a patient may occur before, during, or after administration of one or more therapeutic agents to the patient. The therapeutic method according to the present invention has a higher therapeutic efficacy than administration of a therapeutic agent without neuromodulation. Due to this increased therapeutic efficacy, in some embodiments, the therapeutic method according to the present invention allows treatment with a lower dose of one or more therapeutic agents. Furthermore, administration of anti-inflammatory drugs to suppress cytokine response syndromes that may spill over into the systemic circulation also diffuses into the tumor microenvironment and inhibits the activity of injected engineered (e.g., CART-T, CAR-M (macrophages), CAR-N (Nutrifiles), autoimmune enhancing therapy and cell-based vaccines or other) cells. Neuromodulation therapies, including vagus nerve stimulation (VNS) or trigeminal nerve stimulation (TNS), have the distinct advantage of acting on circulating immune cells that migrate through the bloodstream to the spleen, where they receive vagus nerve signals induced by VNS / TNS or via direct stimulation of the spleen, liver, or other organs. Injected therapeutically engineered cells, once administered, migrate to and remain in the state they are programmed to treat, e.g., the tumor they are programmed to attack. As a result, they do not receive VNS / TNS signals and do not shift to an anti-inflammatory state, thus retaining their anti-cancer properties and associated pro-inflammatory signaling at the target point. This is in contrast to administered anti-inflammatory pharmacological agents, which spread non-selectively systemically, including to the target treatment area, such as a tumor, reducing the ability of CAR-T cells or other therapeutics to fight the tumor.

[0032] Neuromodulation via implantable devices using electrical stimulation has also been shown to improve incontinence when applied to a patient's sacral nerve, and sometimes to the patient's tibial nerve. However, this approach currently requires surgical implantation of a device that contacts permanent electrodes with the sacral nerve and sometimes with the tibial nerve. This invasive approach has the attendant risks and side effects of invasive surgery, including pain, swelling and inflammation, infection, tissue and nerve injury, as well as subsequent reoperation required to replace the device when its useful life is over.

[0033] In addition to its use in controlling pelvic pain transmission and bladder function, (percutaneous) tibial nerve stimulation (PTNS) and other peripheral modulations can be used to modulate neuronal circuits to reduce local chemokine expression and inhibit the invasion of pathogenic cells. Tibial nerve stimulation affects the inflammatory reflex, where afferent vagal signaling activated by inflammatory mediators, such as cytokines or pathogen-derived molecular signals, functionally leads to efferent vagal activation that attenuates proinflammatory cytokine production. As outlined above, to achieve this, motor (efferent) signals in the vagus nerve activate the splenic nerve, which leads to the release of acetylcholine (ACh) by a subset of T lymphocytes expressing choline acetyltransferase (ChAT). ACh interacts with the α7 nicotinic ACh receptor (α7nAChR) expressed by macrophages to inhibit cytokine production.

[0034] Monitoring of one or more physiological parameters may be used to determine when to initiate treatment, confirm one or more neuromodulations by changes in the specifically measured physiological parameters (or direct measurements of changes in neural activity or neural impedance), and confirm when to repeat treatment, in addition to other patient treatment decisions that benefit from real-time dynamic monitoring. Real-time and dynamic monitoring of one or more physiological parameters may also be advantageously used to confirm both the success and direct delivery of neural stimulation and the associated ongoing beneficial physiological outcomes of treatment according to the present invention. By monitoring one or more physiological parameters, biomarkers can be measured in real time (a major advantage over the current reliance on sampling, testing, and returning laboratory results, which can take hours for each sample), and repeatedly measured over time to establish trends for each monitored biomarker. As discussed above, successful neural stimulation involves activating a nerve to generate a signal from the nerve that can affect an aspect of the inflammatory reflex and / or reduce pain. The use of moving average statistical calculations and other interrelated statistical calculations based on monitoring of one or more physiological parameters allows for real-time dynamic adjustments in the modulation of one or more nerves of a patient during treatment, administration of a therapeutic agent, or both. Real-time dynamic adjustments can be achieved by tracking and integrating measurements of one or more physiological parameters over time using artificial intelligence, neural networks, or other algorithm-based analysis. The therapeutic method according to the present invention has the distinct advantage of combining real-time monitoring and adaptive calculations based on machine learning and other artificial intelligence (AI) to identify and guide administration of a therapeutic agent along with a neuromodulatory component to address a condition more precisely than current approaches. Using artificial intelligence, experience and data from multiple patients can be used to optimize the therapeutic method according to the present invention and establish a monitoring baseline that can then be used to demonstrate the success of neuromodulation across a specific similar patient population.

[0035] Neuromodulation

[0036] As shown in Figures 1-5, the method of treatment according to the invention includes modulating one or more nerves of the patient as part of its treatment medication 200. To modulate one or more nerves of the patent, as shown in block 205, a neuromodulatory element is applied to stimulate one or more nerves of the nervous system to transmit a response through the nervous system that results in an anti-inflammatory effect or other nerve-related response. As further shown in block 300, the modulatory element or source delivers a signal to one or more nerves, such as for the vagus nerve, trigeminal nerve, splenic nerve, cervical nerve, tibial nerve, alternative peripheral or central nerves, or combinations thereof (including, in embodiments, one or more branches of these nerves). As outlined above, (percutaneous) tibial nerve stimulation (PTNS) and / or sacral nerve stimulation can be used to modulate neural circuits to address incontinence issues, as well as to reduce local chemokine expression and inhibit pathogenic cell invasion. Neuromodulation in the methods of the invention may be singular or may have multiple purposes and / or beneficial effects. Figure 2 summarizes the elements of neuromodulation 200 according to the present invention. Figures 3A and 3B show the ANS nerve branches in the human body.

[0037] As indicated in block 210, neuromodulation may be performed by one or more of several modalities including, by way of example and not limitation, delivery of electrical stimulation to the nerve, chemical stimulation (immediate or time-released), electromechanical stimulation, vibratory mechanical stimulation, harmonic stimulation, magnetic, ultrasound (including thermal, pulsed, high intensity focused, and / or others), laser energy or other light therapy, x-ray energy, plasma energy, microwave energy, temperature change, and any other means of modulation of the nerve via an external modality (non-invasive or invasive), or a combination of one or more of the foregoing forms of stimulation as outlined in block 225.

[0038] As shown in block 215, in the treatment method according to the present invention, neuromodulation may be performed using signals delivered through an implanted device, through a device in contact with the skin, through a device away from the skin, by a probe or other instrument that penetrates the skin, or by other means designed to stimulate the nerve. Neuromodulation may also be achieved by implantable means in contact with or in close proximity to the nerve; through temporary probes and / or needles in contact with or in close proximity to the nerve; through permanent conductive elements; through bioabsorbable conductive elements; or through other forms of modulation with a modulation source internal or external to the patient. Neuromodulation may also be performed in contact with the patient's skin (i.e., transdermally) or away from the skin, but in a manner sufficient to modulate the nerve, or including a combination of stimulation approaches. Delivery of the modulation signal may be by application and / or induction of visible, ultraviolet, or infrared light from one or more electrodes, transducers, harmonic elements, ultrasound elements, catheters, needles, vibrating probes, wires, nanoparticles, LEDs, lasers, or other sources, and / or electromagnetic fields.

[0039] Neuromodulation according to the therapeutic methods of the invention may be delivered via a fixation device over a target area, such as using an attachment device like those used for ECG leads or similar monitoring elements, and placed on, adjacent to, or in contact with a target nerve, such as the splenic nerve, branches of the vagus nerve, trigeminal nerve, tibial nerve, sacral nerve, or other nerve, or combinations thereof, that can affect the nerve and thereby generate a modulated neural response, including but not limited to an anti-inflammatory response, particularly via the release of anti-inflammatory T cells and other anti-inflammatory cells from the patient's spleen. The methods of the invention may also include, as a separate step, administering an anti-inflammatory drug before, during, or after modulating at least one nerve or administering a therapeutic agent.

[0040] If the modulation does not involve an implantable means, the modulation element may be fixed directly to the skin or to a device fixed to the skin via a patch, adhesive material, microneedle fixation, expandable polymer or other fixation device that may be separate or part of the neuromodulation element to ensure consistent and accurate delivery, or the modulation element may be sized to fit within a particular body structure, such as the concha or other aspects of the ear, including the inside of the ear, or other anatomical structure. In some embodiments, the modulation element may fit the ear, or may be implanted in a scarf or other adjustable element, or may be temporarily taped or otherwise fixed to or adjacent to the skin, including a finger cuff, arm cuff, wearable device, probe, band, handheld device, or combinations thereof (including patches). Similarly, other delivery locations may be utilized for target nerve applications, including, for example, on or near the tibial, sacral, or splenic nerves or other peripheral nerves.

[0041] Neuromodulation may also be performed through natural orifices in the body, such as eye drops of a therapeutic agent / chemical to reach branches of the trigeminal nerve or to stimulate one or more additional or other nerves. Alternatively, neuromodulation may be performed by applying a transdermal patch containing a therapeutic agent / chemical to the patient's forehead, around above or behind the ear, as well as areas of the shoulders, neck, and head innervated by cranial nerves, or areas traversed by other target nerves, such as cranial nerves or other peripheral nerves.

[0042] As shown in block 220, neuromodulation may occur around, in contact with, in proximity to, or otherwise delivered to the location where the neuromodulation signal is delivered, through a bioabsorbable material or contact injected, delivered through iontophoresis or other transdermal delivery, or otherwise delivered, or through a contact or agent, which in embodiments may be an electrode. Neuromodulation may also be via a hydrogel or other gel that is conductive, or otherwise responsive to an external signal and stimulates or modulates the nerve, or transmits the signal to the nerve in a manner that improves signal transmission to the nerve, such as by removing air between the neuromodulation element and the skin, nerve, or other point of contact with the patient.

[0043] As shown in block 230, a method of treatment according to the present invention can include chemically delivered neuromodulation. Delivery can be by immediate and / or time release delivery of chemicals to one or more nerves or tissue surrounding the nerves by injection. Alternatively, in some embodiments, chemical delivery can be via injection, oral delivery, topical delivery, or a patch applied to the skin in proximity to one or more nerves that has the ability to elute a chemical entity that modulates the nerve, which in some embodiments can occur via microneedles, electrophoresis, iontophoresis or other transdermal delivery, or other delivery and / or elution means.

[0044] Chemical modulation can be via one or more drugs that can effect modulation of the nerve, including, but not limited to, targeting muscarinic receptors and / or b-adrenergic receptors; vagotomimetics such as acetylcholine, pyridostigmine, galantamine and / or choline, statins, insulin, vitamin B12, saline, potassium, menthol, or other chemical elements that can cause the nerve to release a signal.

[0045] Additionally, neuromodulation may utilize one or more chemical elements to improve the nerve response, such as formulations containing vitamin B12 to improve nerve sheath response, and / or gels to eliminate air spaces between the stimulating form and the skin overlying the nerve, and / or delivery of gels formulated to aid in carrying the stimulating means across the skin to the underlying nerve.

[0046] The dosing of the neural signal may vary depending on the patient's physiology. For example, the degree of obesity of the patient may increase the physical distance between the surface of the skin and the neural target, thus altering the power requirements necessary to activate the intended nerve. Also, nerve fiber projections to the periphery, particularly cranial nerves that innervate the auricle or scalp or forehead, may vary between patients due to genetic variations or previous trauma.

[0047] In some exemplary embodiments, when electrical energy is used to modulate a nerve, the range of delivered energy required may vary depending on the patient's anatomy, and this amount of energy may differ from the energy that actually reaches the nerve. In preferred embodiments, between 0-100 milliamps may be required to reach the nerve for nerve modulation. Delivery of electrical energy or other modulating elements, including magnetic, harmonic, ultrasound, laser or other light therapy, chemical or other elements, may be done in waveforms, including morphologies with pulse shapes (e.g., sinusoidal, square, trapezoidal, etc.). Various frequency ranges, amperages and voltages may be part of preferred embodiments depending on the particular patient, which may include, but are not limited to, combinations of frequency (about 1-50 Hz), amperage (about 0.5-3.5 mA), voltage (about 5-60 V), pulse width (about 1-350 microseconds), pulse shape (e.g., sinusoidal, square, trapezoidal, etc.), charge balance (AC current, or DC current with a neutral electrode), pulse interval (time between positive and negative pulses in the case of AC), pulse train (number of pulses followed by a short "off" interval), duty cycle (amount of "on" time per hour), and intensity of therapy delivery (e.g., the device may operate for 2 minutes twice a day, or may operate more frequently (e.g., 4 minutes a day if operated 2-4 times a day, 25 seconds every 10 minutes if operated), or less frequently in response to monitoring feedback indications, so that it can be turned on less frequently or more frequently depending on the patient's particular needs, ongoing disease state, improvement or worsening of condition, and other factors.

[0048] In some embodiments, therapeutic methods according to the invention include delivering one or more forms of modulation to the nervous system to create the production and release of anti-inflammatory cells, including T cells, monocytes / macrophages, and neutrophils, and anti-inflammatory cytokines, including interleukins, such as, but not limited to, (IL)-1 receptor antagonists, IL-4, IL-10, IL-11, and IL-13, which have the benefit of inhibiting pro-inflammatory processes induced by exogenously delivered immunotherapy or endogenous disease pathology.

[0049] Pain is also frequently caused by cytokines that activate proinflammatory cells and afferent pain pathways, therefore antagonizing the proinflammatory response can inhibit the pain process as well as other effects such as activating the release of naturally occurring endogenous opioids.

[0050] Administration of one or more therapeutic agents

[0051] As shown in block 400 of FIG. 4, a method of treatment according to the present invention includes administering a therapeutic agent to a patient in need thereof as part of the therapeutic dosing. In the method of the present invention, a particular therapeutic agent may be administered under the current treatment regimen or otherwise based on the patient's need. The method of the present invention adds a step of modulating one or more nerves of the patient before, during or after administration of the therapeutic agent to enhance the therapeutic effect of the therapeutic agent being administered. The increase in therapeutic efficacy may include an increase in the desired direct therapeutic effect, a decrease in side effects, or both. Typically, a therapeutic agent is administered using the same dosage, amount, and regimen in its prescribing information, although in an exemplary method of the present invention, a lower dosage may be determined and used. FIG. 4 summarizes certain aspects of the administration of one or more therapeutic agents in a method of treatment according to the present invention as part of the therapeutic dosing of the method.

[0052] The present invention also provides related apparatus comprising a device for administering a therapeutic agent to a patient in need of administration of the therapeutic agent. In some exemplary embodiments, the present invention provides a device for delivering a therapeutic agent to target a cytokine storm, such as a cytokine storm caused by CAR-T. In exemplary embodiments of the present invention, the device used to administer the therapeutic agent comprises at least one of the following group: a microneedle patch, a microparticle depot, a transdermal patch, a transdermal topical applicator, a multiparticulate system, a nanoparticle, an implantable device (including a controlled release implantable device), a polymeric film, a capsule (including a pH-responsive capsule, an injection device, a liquid delivery device, an intranasal delivery device, an infusion device, and a hydrogel). In some exemplary embodiments of the present invention, the device delivers a compound as a secondary therapeutic agent, such as to target a cytokine storm caused by CAR-T, while in some exemplary embodiments, the device delivers both a "primary" therapeutic agent (e.g., CAR-T) and a "secondary therapeutic agent" simultaneously and / or in the same device.

[0053] As an exemplary embodiment of the invention, the method of treatment includes treating the patient's immune system by modulating one or more nerves in the patient before, during, or after administering an immune system modifying agent. In other embodiments, the method of treatment according to the invention includes administering a therapeutic agent known to cause an inflammatory condition, or to treat an autonomic condition such as, for example, rheumatoid arthritis, lupus, irritable bowel syndrome, sepsis / septic shock / acute respiratory distress syndrome (including those caused by novel pathogens such as SARS-CoV-2), diabetic complications, or other autoimmune diseases, infectious diseases (such as HIV and AIDs) or cardiovascular diseases; neuroinflammatory conditions including stroke, traumatic brain injury / concussion, post-traumatic stress disorder, and seizure disorders; and diseases of autonomic dysfunction (fibromyalgia, opioid withdrawal syndrome, insomnia, chronic pain, headaches, incontinence, hypertension, stress / anxiety, autism / attention deficit hyperactivity disorder, bleeding conditions, postural orthostatic tachycardia syndrome, or post-operative ileus). This includes treating a patient by modulating one or more nerves of the patient before, during, or after administering a therapeutic agent used to treat an inflammation-related condition, such as a neurological dysfunction disease. Examples of therapeutic agents that may be administered to a patient in need according to the methods of the present invention include, but are not limited to, immunotherapeutic agents, drugs for treating autoimmune conditions, anti-inflammatory drugs, blood clotting factors (such as factor VIII), steroids, gasdamine-D inhibitors (such as disulfiram), antibodies for treating infectious diseases, antiviral drugs (or combinations of antiviral drugs) or other drugs, chimeric antigen receptor T cell therapy, chimeric antigen receptor macrophage therapy, or other cell-based immuno-oncology therapeutics, or gene-based therapy, as outlined in FIG.

[0054] The therapeutic methods according to the invention may also be used as a separate, stand-alone therapy to reduce cytokine levels and other indicators of inflammation in patients, as well as to treat other conditions such as asthma, rheumatoid arthritis, lupus, irritable bowel syndrome, sepsis / septic shock / acute respiratory distress syndrome (including those caused by novel pathogens such as SARS-CoV-2), diabetic complications, or other autoimmune, infectious or cardiovascular diseases; neuroinflammatory conditions including stroke, traumatic brain injury / concussion, post-traumatic stress disorder, and seizure disorders.

[0055] Therapeutic methods according to the invention include treating a patient's immune system by modulating one or more nerves in the patient prior to or in conjunction with administration of chemotherapy or other immune system modifying agents in order to suppress the patient's immune system prior to administration of CAR-T, CAR-M or other immuno-oncology therapy.

[0056] Physiological Parameter Monitoring

[0057] An exemplary treatment method according to the present invention includes an optional step of monitoring one or more physiological parameters of a patient undergoing treatment, as shown in block 100 of FIG. 1. The need or desirability of monitoring depends on the particular treatment. Monitoring one or more of the patient's physiological parameters, particularly real-time and dynamic monitoring, allows for adaptive statistically-based analysis and learning / adjustment involving measurements of one or more physiological parameters. The monitoring can confirm successful neurostimulation(s) and can confirm both successful neurostimulation and ongoing beneficial physiological outcomes dynamically in real-time. Using moving average statistical calculations and other interrelated statistical calculations based on multiple physiological parameters, the systems and methods according to the present invention can confirm that the neuromodulation technique results in an intended beneficial physiological response for the patient. In one example of a treatment method according to the present invention, the modulation of at least one neuron of the patient and the administration of a therapeutic agent to the patient are confirmed by monitoring one or more physiological parameters of the patient. The neuromodulation and / or therapeutic administration can be adjusted in response to the monitored physical parameters.

[0058] A monitoring step may then be used to confirm the therapeutic dosing aspect of the method, which may include confirming modulation of at least one neuron in the patient and / or confirming administration of a therapeutic agent to the patient. In one example of a therapeutic method according to the present invention, neuromodulation and / or administration of a therapeutic agent is informed by monitoring one or more physiological parameters of the patient on a monitor in real time and dynamically. Real time and dynamic monitoring of one or more physiological parameters of the patient may allow comparison to a baseline of one or more physiological parameters of the patient to establish when to initiate or repeat neuromodulation, when to initiate or repeat administration of a therapeutic agent, or both. For example, as shown in block 500 of FIG. 5 , monitoring physiological parameters to ascertain the effectiveness of the neuromodulation and / or therapeutic agent may include, but is not limited to, monitoring one or more physiological parameters such as heart rate, body temperature, pupil size or response, blood chemistry, blood pressure, cardiac output, oxygen levels (including oxygen saturation, pulse oxygen levels, and other measures of oxygenation), reduction in inflammation, reduction in pain, brain wave activity detected by electroencephalography (EEG), electromyography (EMG), galvanic skin response, impedance neuroscopy, ocular hydration, skin temperature, etc.

[0059] Therapeutic methods that include monitoring at least one physiological parameter of a patient have at least three uses and advantages: 1) monitoring engagement of target nerves by a neuromodulation strategy; 2) monitoring for the emergence of a cytokine response syndrome using a subset of the measured physiological parameters; and 3) monitoring for improvement to the cytokine response syndrome following application of a neuromodulation strategy.

[0060] The therapeutic method according to the present invention may also monitor physiological parameters including immune / inflammatory, cardiopulmonary, gastrointestinal, and central and autonomic nervous system biomarkers. These biomarkers are useful for confirming target engagement of neuromodulatory intervention, monitoring therapeutic efficacy, and evaluating patient response to both immunomodulatory therapy (to detect the onset of cytokine response syndrome) and neuromodulatory therapy (to inhibit cytokine response syndrome). Each of these biomarkers represents a single dimension in which these responses can be evaluated, and each can be monitored across at least two additional dimensions, namely time and magnitude of change from baseline.

[0061] An apparatus implementing the invention by monitoring pupillary response may use a device to cover one or more eyes of a patient in association with the measurement of the pupillary response to prevent external stimuli, such as light or other elements, from adversely affecting the measurement of the pupil of one or more eyes for pupillary response prior to, in association with, and following a neuromodulation attempt. The device may be a patch, glasses, a hood, a funnel-shaped cover, or other means of limiting or eliminating external light and other external stimuli. The pupillary response device includes a measurement element, which may be a camera or other means for capturing the before and after view of one or more pupils in real time or otherwise. The camera may be a smartphone capable of transmitting images to a measurement program; a smartphone, tablet with an app capable of measurement; part of a computer with an internal or external camera or a standalone device capable of capturing and / or measuring changes in the pupil.

[0062] Additionally, monitoring one or more physiological parameters of the patient has the important advantage of allowing for an individualized approach to patient care in terms of delivering neuromodulation and therapeutic agents. Certain patients may not be effective candidates for monitoring in this context without access to more than one parameter and real-time dynamic information and associated activity, including important information that is acquired, analyzed, and compared over a period of time. For example, in some forms of neural stimulation or modulation, such as vagus nerve modulation, a change in heart rate variability can indicate that the vagus nerve has been successfully modulated. However, without a patient-specific baseline, other factors may also cause changes in heart rate variability, so this form of neuromodulation confirmation may not be reliable unless the heart rate can be compared to a patient-specific baseline. Additionally, certain patients may have cardiac conditions, such as cardiac arrhythmias, that do not support reliable measurement of heart rate variability due to this form of cardiac disease. Other patients may have had this form of cardiac disease that was treated with a pacemaker or implantable defibrillator, again preventing reliable measurement of heart rate variability due to the intended effect of the pacemaker or implantable defibrillator.

[0063] Utilizing a single physiological parameter or alternative physiological parameters may introduce other problems unless the physiological parameter is combined with other physiological parameters and / or coupled with additional physiological parameters. For example, while the pupil response may change in association with the success of vagus and / or trigeminal and / or tibial and / or other peripheral nerve modulation, the reliability and usefulness of this parameter also requires a valid baseline and may lose its usefulness as a monitoring parameter in some circumstances. For example, if a patient experiences a concussion or other neurological trauma, the pupil response may be altered such that it loses its usefulness as a monitoring parameter. Furthermore, certain drugs and other substances may affect the pupil response which negatively impacts its usefulness in this situation as an accurate monitoring parameter to indicate the success of neuromodulation. Even if the patient's physical condition allows the use of pupil response as an indicator of the success of neuromodulation, excitation of the pupil to determine whether neuromodulation is successful requires the absence of other stimuli that can excite the pupil or an accurate indicator of a clear pupil response associated with the attempted modulation of the nerve is not obtained. All forms of stray light can cause the pupil to respond even in the absence of actual neuromodulation. Additionally, pupillary responses can also vary from patient to patient depending on health level, age, and any underlying diseases the patient is dealing with, whether the patient has a form of ocular disease (e.g., cataracts, etc.), so developing a pupillary response baseline that is undistorted from external stimuli is important to successfully confirm effective neuromodulation.

[0064] In the treatment method according to the invention, monitoring one or more physiological parameters of a single patient undergoing treatment may be performed across tens of dimensions. These data may also be integrated with physiological parameter data from other patients using artificial intelligence and / or neural network platforms, or other algorithmic means, to analyze the data and present trends to the healthcare provider. Thus, the step of monitoring one or more physiological parameters in the treatment method according to the invention may include, together with or separately from the confirmation step, integrating the physiological parameter data of the patient being treated with physiological parameter data from other patients treated with the treatment method according to the invention. Depending on the physiological data used, the patients may be treated with the same neuromodulation technique, different neuromodulation techniques, may be administered the same therapeutic agent, or may be administered different therapeutic agents. In other words, a patient population may be receiving the same or different therapeutic medications using the treatment method according to the invention. EXAMPLES

[0065] Animal studies were performed to demonstrate that peripheral nerves can be activated by targeted delivery of chemical agents to interact with neural receptors to produce signaling in the cervical vagus nerve. Delivery was performed topically and transdermally.

[0066] Chemical compounds were applied to the vagus nerve in the neck or trigeminal nerve fibers or peripheral nerves in the forehead of some rats while simultaneously recording vagus nerve activity in the neck. The trigeminal nerve is part of a larger vagus nerve network, and compounds were applied to the trigeminal nerve via intradermal injection to mimic transdermal iontophoresis.

[0067] Experiment Summary:

[0068] This study demonstrates that the target compounds activate peripheral nerves via agonists of chemoreceptors or somatosensory receptors, resulting in signal transduction in the cervical vagus nerve. These compounds exhibit chemical neuroactivation that has effects similar to electrical stimulation of the vagus nerve, but through chemical agents that engage neural sensors, but with effects like electrical stimulation of the vagus nerve, which has known therapeutic effects in multiple disease states, including epilepsy, depression, opioid withdrawal syndrome, headache disorders, and stroke rehabilitation (neuroplasticity), inflammation reduction, etc.

[0069] Approach and Methodology:

[0070] Adult male Lewis rats (350-500 g) were anesthetized with isoflurane via a nose cone and then maintained with a continuous infusion of alphaxane. Rats were implanted with femoral venous and arterial catheters for delivery of anesthetics and monitoring of heart rate and blood pressure, respectively. The cervical vagus nerve was isolated from the left carotid artery and suspended on a bipolar platinum electrode connected to BioPac recording hardware. Various concentrations of transient receptor potential cation channel subfamily V (TrpV) or subfamily M (TrpM) agonists were applied to the exposed cervical vagus nerve or injected intradermally on the forehead near the trigeminal nerve fiber endings. Cervical vagus nerve activity was continuously recorded and compound applications were time-stamped with BioPac AcKnowledge software. After the experiment was completed, data acquired with the AcKnowledge software were converted to MatLab file types using Python. MatLab was then used to analyze 60-second segments of recorded vagus nerve activity from -70 seconds to -10 seconds before agonist application (pre-treatment, "PRE") and from +10 seconds to +70 seconds after agonist application (post-treatment, "POST"). Root mean square (RMS) was calculated for each 60-second segment, and nerve activity spikes were defined as voltages >3 x RMS. Spike activity was calculated as spikes / second + / - standard error of the mean (SEM). Comparisons of spike counts were made between POST and PRE conditions using two-tailed paired T-tests. p<0.05 was considered significant.

[0071] Example 1. Effect of capsaicin on the cervical vagus nerve

[0072] Baseline recordings of spontaneous vagus nerve signaling revealed a mean spike count of 3.6+ / -1.3 spikes / sec. Capsaicin is a known agonist of TRPV1, a chemoreceptor with known expression on cranial nerve fibers, including the trigeminal nerve. Direct application of a low concentration (10 nM) of capsaicin to the cervical vagus nerve increased the mean spike count (7.6+ / -0.7 spikes / sec, p=0.03). Direct application of a high concentration (100 nM) of capsaicin to the cervical vagus nerve further increased the mean spike count (14.5+ / -0.7 spikes / sec, p=0.03). Intradermal application of a high concentration (100 nM) of capsaicin increased the mean spike count of the cervical vagus nerve to 13.5+ / -0.5 spikes / sec (p=0.008).

[0073] Representative 10-second cervical vagus nerve recordings were obtained at baseline (green, panels A-C), or after cervical application of low (red, A) or high (red, B) concentrations of capsaicin, or intradermal application of high concentration (red, C), as shown in Figure 6A-C. Figure 6D shows histogram representations of cervical vagus nerve activity at baseline (BL); after application of low (Low) or high (High) concentrations of capsaicin to the cervical vagus nerve; and after intradermal application of capsaicin at the forehead near the trigeminal nerve endings (ID) (data presented as mean + / - SEM; *=p<0.05).

[0074] TRPV1 is a chemoreceptor expressed on multiple tissues, including the lungs, gastrointestinal tract, joints, skin, and trigeminal nerve. Capsaicin, the active ingredient in hot peppers, is an agonist of TRPV1. Direct application of capsaicin to the cervical vagus nerve induced an increase in vagal nerve activity, as detected by spike count analysis of electroneurograms recorded from the cervical vagus nerve. Intradermal application of capsaicin to the trigeminal dermatome on the forehead also activated neural firing of the main cervical vagus nerve, suggesting that chemoreceptor-mediated afferent signaling to the brain can activate efferent activity of the vagus nerve to the visceral organs.

[0075] In addition, other agonists of TRPV1, including but not limited to oxytocin, ketamine, palvanil, olvanil, resiniferatoxin, anandamide, 12-hydroxyeicosatetranoic acid, N-arachidonoyldopamine, piperine and zingerone, have similar activity to capsaicin.Similar to capsaicin, these compounds also activate TRPV1 or open TRPV1 ion pores, thus activating neuronal firing.Other molecules that regulate TRPV1 activity to induce neuronal firing include, for example, calcium calmodulin, bradykinin, serotonin, histamine or prostaglandins.

[0076] Example 2. Effect of GSK1016790A on the cervical vagus nerve

[0077] Baseline recordings of spontaneous vagus nerve signaling revealed a mean spike count of 7.5 + / - 1.6 spikes / sec. GSK1016790A is a known agonist of TRPV4, a chemoreceptor with known expression on cranial nerve fibers, including the trigeminal nerve. Direct application of low (10 nM) or high (100 nM) concentrations of GSK1016790A to the cervical vagus nerve had no effect on spike counts (data not shown). Intradermal application of a low concentration (10 nM) of GSK1016790A did not increase cervical vagus nerve mean spike counts (7.0 + / - 0.5 spikes / sec (p = 0.829). Intradermal application of a high concentration (100 nM) of GSK1016790A increased cervical vagus nerve mean spike counts to 13.8 + / - 1.0 spikes / sec (p = 0.015).

[0078] Representative 10-second cervical vagus nerve recordings were obtained at baseline (green, panels A-B) or after intradermal application of low (red, A) or high (red, B) concentrations of GSK1016790A, as shown in Figures 7A-B. Figure 6C shows histogram representations of cervical vagus nerve activity after intradermal application of baseline (BL); low (Low) or high (High) concentrations of GSK1016790A to the forehead near the trigeminal nerve endings (data presented as mean + / - SEM; *=p<0.05).

[0079] TRPV4 is a chemoreceptor expressed on multiple tissues, including the lungs, gastrointestinal tract, joints, skin, and trigeminal nerve. GSK1016790A is a potent and selective agonist of TRPV4. Direct application of GSK1016790A to the cervical vagus nerve induced an increase in vagal nerve activity, as detected by spike count analysis of electroneurograms recorded from the cervical vagus nerve. Intradermal application of GSK1016790A to the trigeminal dermatome on the forehead also activated neural firing of the main cervical vagus nerve, suggesting that chemoreceptor-mediated afferent signaling to the brain can activate efferent activity of the vagus nerve to the visceral organs.

[0080] In addition, other agonists of TRPV4, including but not limited to 4-phorbol 12,13-didecanoate (4PDD) and its derivatives, epoxyeicosatrienoic acids 5,6-EET and 8,9-EET, bisandrographolide A, RN-1747, and derivatives of GSK1016790A, have similar activity to capsaicin. Like GSK1016790A, these compounds also activate TRPV4 or open the TRPV4 ion pore, thus activating neuronal firing.

[0081] Example 3. Effect of WS-12 on the cervical vagus nerve

[0082] Baseline recordings of spontaneous vagus nerve signaling revealed a mean spike count of 4.3 + / - 0.7 spikes / sec. WS-12 is a known agonist of TRPM8, a chemoreceptor with known expression on autonomic and somatosensory nerve fibers in the lungs, gastrointestinal tract, and skin. Direct application of a low concentration (1.2 μM) of capsaicin to the cervical vagus nerve increased the mean spike count to 11.2 + / - 0.6 spikes / sec (p = 0.02). Direct application of a high concentration (12 μM) of capsaicin to the cervical vagus nerve increased the mean spike count to 17.7 + / - 0.8 spikes / sec (p = 0.007). Intradermal application of a high concentration (12 μM) of capsaicin increased the mean spike count of the cervical vagus nerve to 9.6 + / - 0.5 spikes / sec (p = 0.03).

[0083] Representative 10-second cervical vagus nerve recordings were obtained at baseline (green, panels A-C), or after cervical application of low (red, A) or high (red, B) concentrations of WS-12, or intradermal application of high concentration (red, C), as shown in Figures 8A-C. Figure 8D shows histogram representations of cervical vagus nerve activity at baseline (BL); after application of low (Low) or high (High) concentrations of WS-12 to the cervical vagus nerve; and after intradermal application of WS-12 at the forehead near the trigeminal nerve endings (ID) (data presented as mean + / - SEM; *=p<0.05).

[0084] TRPM8 is a molecular transducer of cold and warm somatosensation expressed on sensory neurons. Certain compounds, including menthol and its derivatives, can also activate TRPM8. Among menthol derivatives, WS-12 is one of the most selective. Direct application of WS-12 to the cervical vagus nerve induced an increase in vagal nerve activity, as detected by spike count analysis of electroneurograms recorded from the cervical vagus nerve. Intradermal application of WS-12 to the trigeminal dermatome of the forehead also activated neural firing of the main cervical vagus nerve. These observations indicate that TRPM8-mediated afferent signaling to the brain can activate efferent activity of the vagus nerve to the viscera.

[0085] In addition, other agonists of TRPM8, including but not limited to menthol, icilin, and dialkyl phosphoryl alkanes such as 1-diisopropyl phosphoryl nonane (cryosin-3), l-menthol, 1-diisopropyl phosphoryl-pentane, 1-diisopropyl phosphoryl-hexane, 1-diisopropyl phosphoryl-heptane, 1-diisopropyl phosphoryl-octane, 1-diisopropyl phosphoryl-nonane, 1-di-sec-butyl phosphoryl-4, 1-di-sec-butyl phosphoryl-pentane, 1-di-sec-butyl phosphoryl-hexane, 1-di-sec-butyl phosphoryl-heptane, 1-di-sec-butyl phosphoryl-octane, 1-diisobutyl phosphoryl-pentane, 1-di-sec-butyl phosphoryl-3-methyl-butane, have similar activity to WS-12. Like WS-12, these compounds activate TRPM8 or open the TRPM8 ion pore, thus activating neuronal firing.

[0086] Additionally, agonists of other neurochemical receptors have similar neuroactivating properties as capsaicin, GSK1016790A and WS-12 when applied intradermally or transdermally. Other chemical receptors include, but are not limited to, other members of the transient receptor potential channel family, including TRPC, TRPV, TRPVL, TRPM, TRPS, TRPN, TRPA, TRPP and TRPML; cannabinoid receptors CB1, CB2, GPR18, GPR55 / CB3, GPR119 and the PPAR family of receptors; and opioid receptors delta, kappa, mu, nociceptive receptors and zeta. Compounds are known to activate peripheral nerves, including cranial and tibial nerves, and therefore intradermal or transdermal application of agonists of these receptors has similar neuromodulatory properties.

[0087] Conclusion:

[0088] The systems, devices, and methods according to the invention use targeted compounds to activate peripheral nerves via agonists of chemoreceptors or somatosensory receptors that result in signaling in the cervical vagus nerve. These compounds exhibit chemical neuroactivation by the vagus nerve, but via chemical agents that engage neural sensors, but with effects similar to electrical stimulation of the vagus nerve, which has known therapeutic effects in multiple disease states including epilepsy, depression, opioid withdrawal syndrome, headache disorders, and stroke rehabilitation (neuroplasticity), inflammation reduction, incontinence, etc. Chemical stimulation of the vagus nerve includes similar therapeutic effects as electrical vagus nerve stimulation in several additional indications including rheumatoid arthritis, inflammatory bowel disease, acute and chronic COVID-19, post-traumatic stress disorder, acute stroke, and traumatic brain injury.

Claims

1. A step of regulating one or more nerves in the patient, The steps include administering therapeutic agents to patients who require them, Optionally, the procedure includes the step of monitoring one or more physiological parameters of the patient. Treatment methods, including those mentioned above.

2. The treatment method according to claim 1, wherein the step of regulating one or more nerves of the patient includes the patient's vagus nerve, trigeminal nerve, splenic nerve, cervical nerve, tibial nerve, or a combination thereof.

3. The therapeutic method according to claim 1 or 2, wherein the step of administering a therapeutic agent to a patient requiring the administration of a therapeutic agent is to administer a therapeutic agent for the treatment of at least one of the following: inflammation, pain, cancer, cardiovascular disease, asthma, rheumatoid arthritis, lupus, irritable bowel syndrome, sepsis / septic shock / acute respiratory distress syndrome (including those caused by novel pathogens such as SARS-CoV-2), diabetic complications, or other autoimmune diseases, infections; hemorrhage, neuroinflammatory conditions including stroke, traumatic brain injury / concussion, post-traumatic stress disorder, seizure disorder, incontinence, and postoperative ileus.

4. The treatment method according to claim 1 or 2, comprising the step of monitoring one or more physiological parameters of a patient.

5. The treatment method according to claim 4, wherein the monitoring step establishes one or more baselines of one or more physiological parameters of the patient.

6. The therapeutic method according to claim 4, further comprising the step of monitoring one or more physiological parameters of a patient to confirm neuromodulation.

7. The therapeutic method according to claim 4, further comprising the step of monitoring one or more physiological parameters of a patient on a monitor in real time and dynamically to indicate nerve modulation, administration of a therapeutic agent, or both.

8. The therapeutic method according to claim 5, comprising the step of dynamically monitoring one or more physiological parameters of a patient in real time against a baseline of one or more of the patient's physiological parameters in order to determine when to initiate or repeat nerve modulation, when to initiate or repeat administration of a therapeutic agent, or both.

9. The treatment method according to claim 1 or 2, wherein the step of regulating one or more nerves in the patient is performed before the step of administering the therapeutic agent to a patient who requires the administration of the therapeutic agent.

10. The treatment method according to claim 1 or 2, wherein the step of regulating one or more nerves in the patient is performed during the step of administering a therapeutic agent to a patient who requires the administration of a therapeutic agent.

11. The treatment method according to claim 1 or 2, wherein the step of regulating one or more nerves in the patient is performed after the step of administering a therapeutic agent to a patient who requires the administration of a therapeutic agent.

12. The therapeutic method according to claim 1 or 2, comprising the step of monitoring one or more physiological parameters of a patient to confirm the modulation of at least one nerve of the patient, the administration of a therapeutic agent to the patient, or both.

13. The treatment method according to claim 1 or 2, wherein the step of monitoring one or more physiological parameters of a patient includes integrating physiological parameter data across a patient population.

14. A therapeutic method according to claim 1 or 2, comprising the steps of regulating one or more nerves in a patient, administering a therapeutic agent to a patient requiring administration of a therapeutic agent, or both steps, being adjusted in response to monitored physical parameters.

15. The therapeutic method according to claim 1 or 2, further comprising the step of administering an anti-inflammatory drug to a patient.

16. An apparatus comprising: a device for regulating one or more nerves in a patient before, during, or after administration of a therapeutic drug to a patient requiring therapeutic drug administration; a device for delivering a therapeutic drug to a patient requiring therapeutic drug delivery; and a device for monitoring one or more physiological parameters of a patient.

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