Treatment of hyperinflammatory syndrome

Abstract

Disclosed is an antagonist of a mammalian P2X7R for use in treating hyperinflammatory syndrome in a mammalian patient by primary lymph node targeted administration of the P2X7R antagonist in the mammalian patient until the concentration of the antagonist of the mammalian P2X7R in the primary target lymph node of the mammal exceeds the maximum tolerated plasma level.

Description

[Technical Field]

[0001] The present invention relates to an antagonist of a mammalian P2X7 receptor (P2X7R) for use in the treatment of hyperinflammatory syndrome in a mammalian patient by primary lymph node targeted administration of the P2X7R antagonist in the mammalian patient until the concentration of the antagonist of the mammalian P2X7R in the primary target lymph node exceeds the maximum tolerated plasma level of the mammal. DETAILED DESCRIPTION OF THE INVENTION

[0002] (Background technology) Hyperinflammatory syndrome or hyperinflammation is a known phenomenon in medicine and is a symptom of numerous diseases that have dramatic, if not fatal, consequences for the patient. The term "hyperinflammation" is defined by the following six criteria (Webb et al., Lancet Rheumatol 2020, 2, (12) 754-763): (1) fever, defined as a temperature above 38.0°C; (2) macrophage activation, defined as ferritin levels ≥700 μg / l; (3) Neutrophil-to-lymphocyte ratio of 10 or more, or hemoglobin concentration of 9.2 g / dL or less and platelet count of 110 × 10 9 impaired hematologic function defined as cells / L or less; (4) coagulation disorder defined as D-dimer concentration ≥ 1.5 μg / ml; (5) liver dysfunction defined as lactate dehydrogenase levels ≥ 400 U / L or aspartate aminotransferase levels ≥ 100 U / L; (6) cytokineemia, defined as an interleukin-6 concentration of 15 pg / ml or more, or a triglyceride concentration of 150 mg / dl or more, or a CRP concentration of 15 mg / dl or more.

[0003] Dyspnea and pneumonia are common and numerous symptoms consistent with hyperinflammation, particularly as a result of respiratory tract infection. A key event in the development of hyperinflammation is the release of intracellular ATP. Intercellular signaling via nucleotides (ATP, ADP, UTP, and UDP) and nucleosides (adenosine) is known in the art as purinergic signaling.

[0004] Under normal resting conditions, extracellular levels of ATP are extremely low at nanomolar concentrations (2-3 nM), but certain conditions can increase ATP release by more than 1000-fold; such conditions can occur in diseases described in the corresponding section below, "Diseases Associated with Hyperinflammation," including inflammatory responses, mechanical stress, surfactant release, membrane depolarization, and hypoxia.

[0005] In purinergic signaling, multiple receptors are known for the ligand adenosine, also known as P1 receptors, and for nucleotide ligands, known as P2 receptors. For adenosine, the effect midway between the baseline and maximum effect (half the maximally effective dose, EC 50 The extracellular concentrations of ligands required to reach the EC (EC ) are in the nanomolar range, whereas for ATP, UTP, or ADP, these concentrations range from 0.01 to 10 μM. All these receptors are known to undergo desensitization. Receptor desensitization is defined as the loss of transmembrane anion current in response to ligand activation and zero transmembrane anion current. However, one P2 receptor, P2X7R, is not prone to desensitization and has an EC of 100,000, at which ATP activates this receptor. 50 is much higher, i.e., above 1 mM. At such ATP levels, all other P1 and P2 purinergic receptors are completely desensitized.

[0006] During severe infections and other diseases, infected cells release large amounts of extracellular ATP, which can become trapped in the airway mucosa and lungs or spread to multiple organs. Extracellular ATP has been observed to accumulate to 1.4 mM (NO) (Zhao et al., Front Immunol 2019, 10, 2524), resulting in vigorous activation of P2X7R, triggering a massive proinflammatory immune response, the release of large amounts of proinflammatory and anti-inflammatory cytokines, and hyperinflammation accompanied by tissue cell destruction and the formation of large pores (Savio et al., Front Pharmacol 2018, 9, 52).

[0007] As a result of desensitization of P1 and P2 receptors, the physiological inflammatory response is inactivated (known as immunoparalysis) and patients become more susceptible to secondary infections.

[0008] Regulatory T cells (Tregs) are key components in controlling hyperinflammation and accelerate adenosine production from extracellular ATP. Activation of P2X7R inhibits the suppressive capacity and stability of Tregs.

[0009] P2X7R plays an important role in many chronic and acute diseases, which can be confined to one organ (Alzheimer's disease, multiple sclerosis, colitis) or can spread diffusely, such as in bacterial sepsis or severe microbial infections, such as COVID-19 (see also the section below on "Diseases associated with hyperinflammation").

[0010] Current treatments for hyperinflammation are actually anti-inflammatory. These drugs literally block the activation of the immune response by inhibiting one or more pro-inflammatory pathways. These treatments attenuate the physiological function of the pro-inflammatory immune response, i.e., recognizing an "attack" by an invading microorganism (the "alarm phase") and subsequently activating the first line of defense (the innate immune system) when activation of the adaptive immune system is required to specifically neutralize the invader. Examples of such drugs that interfere with a patient's inflammatory response are dexamethasone, baricitinib, and anakinra.

[0011] Thus, treating hyperinflammation has heretofore been troublesome. The present invention now provides a method of treating a patient suffering from hyperinflammation without interfering with the patient's inflammatory response, or at least to a much lesser extent.

[0012] The art suggests that P2X7R may be a good target for treating hyperinflammation and the associated respiratory distress and pneumonia. P2X7R antagonists block active activation of P2X7R. Because most ATP release into the extracellular space is mediated by P2X7R, its antagonism reduces extracellular ATP levels. This may suppress hyperinflammation and the associated immune paralysis. It has also been reported that inhibition of P2X7R promotes the cell-autonomous conversion of CD4+ T cells into Tregs after T cell receptor stimulation (Schenk et al., Sci Signal 2011, 4 (162) ra12). The improvement of hyperinflammation by P2X7R inhibition is thought to be due to increased activation and clonal expansion of anti-inflammatory Treg populations.

[0013] Many P2X7R antagonists have been identified to date (North and Jarvis, Mol Phar, 2013 (83) 759-769; Sluyter, Adv Exp Med Biol Prot Rev 2017 (19) 17 - 53). To achieve efficacy, these antagonists have been administered systemically to be transported by the blood to the intended site of action.

[0014] For example, CE-224,535 500 (Pfizer), AZD9056 (Astra-Zeneca), and JNJ54175446 (Johnson & Johnson) have been administered orally, but without significant success. The anesthetic lidocaine has been reported to be a P2X7R antagonist (Okura et al., Anesth Analg 2015, 120 (3), 597-605). Additional P2X7R antagonists are described in the "P2X7R Antagonists" section below.

[0015] P2X7R antagonists can reduce hyperinflammation and restore the immune system's ability to fight secondary infections, improving the clinical condition of critically ill patients suffering from severe respiratory tract infections, but the problem with these compounds is that, to be effective, the antagonist must bind to P2X7R to such an extent that hyperinflammation and preferably its associated effects, such as shortness of breath, are effectively counteracted. Such an effect is observed at the concentration at which the receptor antagonist inhibits the receptor by 10% (the so-called IC 10 The preferred inhibition is 50% receptor inhibition, or IC 50 However, for P2X7R antagonists, such concentrations exceed the maximum allowable plasma level of the antagonist, which means that it will cause undesirable side effects such as anxiety, dizziness or reduced or worsened spinal reflexes.For example, the maximum allowable plasma level of lidocaine in humans is about 4.7 μg / ml, see Table 1: [Table 1]

[0016] For each P2X7R antagonist, the skilled artisan knows how to determine the maximum tolerable plasma level.

[0017] However, P2X7R antagonists have not been used effectively to treat hyperinflammation because, to be effective, the systemic dose required far exceeds the maximum tolerated plasma level.

[0018] The present invention provides herein a P2X7R antagonist for use in treating hyperinflammatory syndrome in a mammalian patient by administering the P2X7R antagonist to a primary lymph node targeted administration in the mammalian patient until the concentration of the P2X7R antagonist in the primary target lymph node exceeds the maximum tolerated plasma level of the mammal. By targeting the primary lymph node, the expected IC x The inventors have investigated the IC values ​​estimated in lymph nodes. x Establishing this value has been found to provide effective treatment of hyperinflammation, significantly alleviating respiratory distress and other symptoms of hyperinflammation in patients with severe respiratory tract infections. Targeting lymph nodes was envisioned because the lymphatic system was thought to be exclusively populated by immune cells, namely naive T cells, activated T cells, B cells, dendritic cells, monocytes, macrophages, neutrophils, mast cells, eosinophils, basophils, and other immune-related cells. Selective inhibition of P2X7R on immune cells in the lymphatic system with P2X7R antagonists was found to induce clonal expansion of Tregs. These Tregs then migrate throughout the body, exerting anti-inflammatory activity that reduces systemic and (distal) local hyperinflammation.

[0019] The term "targeting the primary lymph node" refers to an administration or delivery route in which the majority of the receptor antagonist is delivered directly from the administration site to the lymph node, and the effective amount of the receptor antagonist in the plasma is at least 5-fold, preferably at least 10-fold or at least 15-fold less than in the lymph node. In particular, administration is preferential to the lymph node.

[0020] The concentration of the antagonist in the target lymph node is equal to or exceeds the IC x The IC x is above the maximum tolerable plasma level of the antagonist in the mammal, and x is 10 or greater, preferably 20 or greater, more preferably 30 or greater, even more preferably 40 or greater, and most preferably about 50. 1010% receptor inhibition was observed at IC 20 For example, 20% receptor inhibition is observed at x = 0.01, and so on. The higher x, the greater the receptor inhibition and the more effectively hyperinflammation is treated. Those skilled in the art will understand that a receptor antagonist that binds more strongly to a receptor will have a lower IC value than a receptor antagonist that binds less strongly to a receptor. The stronger the binding of an antagonist, the lower the amount of the antagonist required to achieve the same effect compared to a weaker binding antagonist. The IC value is preferably determined as described in Okura, supra.

[0021] Those skilled in the art are aware of the delivery and administration routes suitable for lymph node targeting administration.Local and invasive administration are preferred.Invasive administration may not be appropriate outside of hospital environment.Therefore, administering receptor antagonist by local administration is very attractive.As local route, transmucosal and transdermal administration are preferred.In this case, antagonist is preferably administered in lipophilic form, because hydrophilic form tends to be preferentially absorbed into blood, which causes undesirable increase in the plasma level of receptor antagonist in blood, and reduces delivery in lymph nodes.For this purpose, receptor antagonist is preferably in its free base form.

[0022] In a highly attractive embodiment, lymph node-targeted administration includes transmucosal administration to a body cavity covered with a mucosa, preferably close to one or more lymph nodes to allow for rapid and direct delivery. The oral cavity is particularly suitable for such administration. However, intranasal and intranasal administration are also possible. For intranasal delivery, care must be taken to avoid or minimize inhalation of the receptor antagonist, since inhalation of the receptor antagonist may cause an undesirable increase in the plasma level of the receptor antagonist. When administered to the oral cavity, administration is preferably buccal, sublingual, pharyngeal, or a combination thereof. The mucosa preferably has low systemic permeability and is close to lymph nodes. The permeability of various mucosal tissues is described, for example, in Goyal et al., Nanomed Biotechnol 2018, 46 (sup2), 539-551 and Lesch, et al., J Dent Res 1989, 68(9), 1345-1349.

[0023] Oral administration has long been considered an inefficient drug delivery route (Di Vergilio et al., Br J Pharmacol 2020). However, sublingual and buccal administration of receptor antagonists, particularly lidocaine, has now been shown to be highly effective without significantly increasing plasma antagonist levels. It has been reported that the permeability of skin and mucous membranes to water and drugs depends on the administration site. For example, the permeability constants for tritium-labeled water in the floor of the mouth (sublingual mucosa), the lateral edge of the tongue, and the buccal mucosa are 22, 17, and 13 times higher than those in human skin, respectively. Furthermore, the ability of submucosal capillaries to absorb molecules is much greater than that of subcutaneous capillaries. Lidocaine hydrochloride is highly soluble in water (solubility of 680 mg / ml in water) and is primarily absorbed through submucosal capillaries. In contrast, the highly lipophilic lidocaine base (solubility 4 mg / ml in water, 760 mg / ml in 95% ethanol, and 790 mg / ml in chloroform) is preferably absorbed by the local lymphatic capillaries (initial lymphatics) in the submucosal tissue (Groningsson, et al., In Analytical Profiles of Drug Substances, Florey, K., Ed. Academic Press: 1985; Vol. 14, pp. 207-243). Furthermore, lymphatic drainage of the floor of the mouth is extensive, involving numerous lymph nodes.

[0024] Sublingual and buccal administration of lipophilic lidocaine base or any other P2X7R antagonist is preferred. The use of high concentrations at relatively low total doses allows for the IC20 of P2X7R in regional lymph nodes. 50 This can be achieved to control systemic hyperinflammation and avoid the toxic plasma levels of lidocaine or any other P2X7R antagonists. It should be noted that sublingual and buccal administration of lipophilic lidocaine differs from oral administration of lidocaine. Oral administration of lidocaine aims for drug reabsorption in the digestive tract, i.e., systemic administration.

[0025] In another embodiment, administration is transdermal, and is in the form of cream, ointment or lotion, patch or plaster, and / or comprises microneedle or their combination.In this type of administration, receptor antagonist is preferably lipophilic for the same reasons as above.Transdermal administration of P2X7R antagonist, particularly in lipophilic form, can provide convenient application, optionally combined with skin penetration enhancer such as α-terpineol, ethanol, lipid-based nano-preparation.

[0026] In another embodiment, administration is invasive, particularly intradermal, subdermal, or subcutaneous administration. Dermal capillaries can transport substances from the blood to tissues, but reabsorption of substances from tissues back into the blood is minimal, if at all. Specialized lymphatic capillaries, apparently containing one-way valve leaflets that can absorb fluids and molecules from the interstitium, are located in the dermis. The absorbed lymph is then propelled forward through the lymphatic network by collecting lymphatic vessels containing rhythmically contracting muscle layers. This system delivers fluids and particles to lymph nodes, where many immune processes occur. Absorption into lymph nodes after intradermal application is thought to be 10 times slower than after deep subcutaneous application, resulting in higher concentrations in lymph nodes associated with these lymphatic vessels. Small particles move faster toward lymphatic vessels and lymph nodes than larger particles. The route and rate of clearance after intradermal and subcutaneous administration to the back of the human hand was 1% / min of the clearance of the administered compound after subcutaneous injection and 8-10% / min after intradermal injection.

[0027] An additional advantage is that the plasma concentration of subcutaneously administered lidocaine is much lower than that of intravenously administered lidocaine. Intravenous administration of 2 mg / kg lidocaine in cats resulted in a peak plasma concentration of 3.6 μg / mL almost immediately (Thomasy et al., Am J Vet Res 2005, 66 (7), 1162-1166). In contrast, the mean peak plasma concentrations achieved after subcutaneous administration of 30 mg / kg, 20 mg / kg, and 10 mg / kg lidocaine were much lower: 1.69, 1.07, and 0.77 μg / mL, respectively (Hatef et al., Aesthet Surg J 209 (2), 122-128). The applied subcutaneous doses were 15, 10, and 5 times the intravenous dose, respectively. The difference in plasma concentrations after intravenous and subcutaneous administration of lidocaine is caused by the fact that, in contrast to intravenous administration, most of the subcutaneously administered lidocaine is drained into the lymphatic system, which slows the release of lidocaine into the venous blood.

[0028] Lymphatic absorption after intradermal administration is much higher than after deep subcutaneous administration. Because intradermal injection of lidocaine is not a recognized route of administration for lidocaine, subdermal administration of lidocaine using a catheter inserted just below the dermis has been proposed, which results in higher concentrations of lidocaine in the draining local lymph nodes than deep subcutaneous or intravenous injection.

[0029] For invasive administration according to the present invention, the receptor antagonist is preferably hydrophilic, particularly in the form of a water-soluble pharmaceutically acceptable salt thereof, such as the chloride salt.

[0030] In another embodiment, administration is intravenous, and the antagonist is lipophilic and is enclosed in a drug delivery system, for example, by using nano-sized drug delivery systems, liposomes or polymeric micelles, to avoid direct release into the blood.Oral administration of P2X7R antagonists is also possible using a delivery system for intestinal lymphatic drug transport, such as chylomicrons, which avoids delivery to plasma.Intravenous administration at low doses that do not exceed the maximum tolerated plasma level does not produce significant effects, if any.For lidocaine, intravenous administration of 0.6mg / kg / hour can be applied.

[0031] In particular, P2X7R activation is activated by extracellular ATP. However, P2X7R can also be activated by membrane stretching, apoptotic cell proteins, LL-37, cathelicidin, and antimicrobial peptides. It should be noted that all such forms of receptor activation can be antagonized by P2X7R antagonists.

[0032] In an attractive embodiment, administration is in immediate release or sustained release form.

[0033] Preferably, administration comprises one or more bolus administrations, or continuous administration or their combinations.Bolus administration should be understood as administration of a single tablet, pouch, injection, aerosol, etc., or any combination of multiple administrations when administered without significant time intervals thereafter.Continuous administration is also attractive, for example as infusion, or as the combination between one or more bolus administrations and continuous administration.

[0034] In certain embodiments, the bolus dose is at least 1,000 times, preferably at least 5,000 times, more preferably at least 10,000 times the amount of receptor antagonist contained in 1 ml of plasma at the maximum acceptable plasma level of receptor antagonist.According to this embodiment, the bolus dose is defined by the amount of receptor antagonist present in 1 ml of plasma at the maximum acceptable plasma level.For example, the maximum acceptable plasma level of lidocaine in humans is 4.7 μ g / ml.This means that the bolus dose is at least 1,000 times 4.7 μ g, that is, 4.7 mg.

[0035] The bolus is preferably administered 2 to 10 times daily.

[0036] The antagonist is preferably administered in a liquid medium containing at least 1 wt / v%, preferably at least 5 wt / v%, and most preferably at least 10 wt / v% of the receptor antagonist. Such high concentrations of receptor antagonists, particularly lidocaine, have not been used in the art. Such concentrations, when used according to the art, i.e., for systemic delivery via the blood, would cause unacceptably high plasma levels of the antagonist, exceeding the maximum tolerable plasma level. For example, to treat hyperinflammation and associated respiratory distress in patients suffering from severe respiratory tract infections, such as those caused by SARS-CoV-2 infection.

[0037] With regard to invasive administration, lymph node-targeted administration is preferably by continuous intradermal, subdermal, or subcutaneous infusion, particularly in patients who are intubated for ventilation and / or in a coma, which may require such a route of administration.

[0038] For administration by continuous infusion, the dose is preferably 1 / 1000 IC per kg of body weight per hour. 10 at least 10 times the value, more preferably IC per kg of body weight per hour 20 at least 10 times the value, and even more preferably IC per kg of body weight per hour30 At least 10 times the value, and even more preferably, IC per kg of body weight per hour 40 at least 10 times the value, most preferably IC per kg body weight per hour 50 At least 10 times the value, IC per kg of body weight per hour 10 At least 10 times the value, IC per kg of body weight per hour 10 More preferably, the dose corresponds to at least 10 times the IC per kg of body weight per hour. 50 The IC value is at least 15 times higher. For lidocaine, the latter value corresponds to approximately 1 mg / kg / hour. 50 The value is 66 μg / ml (0.066 x 15 = 0.99).

[0039] According to a very attractive embodiment, the disease comprises the hyperinflammatory syndrome of disease selected from the group consisting of autoimmune disease and immune-related disease, such as asthma, allergy and chronic lung disease; treatment-induced immune-related disease, such as chemotherapy; infectious disease, such as viral and bacterial infection; cardiovascular disease and neurovascular disease; neuroinflammatory and neurodegenerative disease; epilepsy disorder; affective disorder and psychiatric syndrome; fibrosis; cancer-related disorder; tumor pseudoprogression; cancer and neoplasm; trauma and traumatic syndrome; post-organ transplant syndrome, including transplanted organ rejection.However, treatment can comprise any disease in which P2X7R activation plays a role and which can be treated by P2X7R antagonist.These diseases are listed in the following section "diseases associated with hyperinflammation".

[0040] The hyperinflammatory syndrome preferably includes dyspnea, particularly dyspnea associated with viral infection, bacterial infection, cancer, chronic obstructive pulmonary disease (COPD), asthma, allergy, or chemotherapy. The viral infection is caused by a virus selected from the group consisting of coronavirus, particularly SARS-CoV-2; influenza; Ebola; respiratory syncytial virus; and HIV.

[0041] P2X7R antagonists are preferably aminoamide derivatives, in particular lidocaine, bupivacaine, ropivacaine and mepivacaine; antibodies against P2X7R, in particular monoclonal antibodies; aminoester derivatives, in particular benzocaine and procaine; adamantanamide derivatives; triazole derivatives; diarylimidazolidine derivatives; pyroglutamic acid amide derivatives; pyrazoleacetamide derivatives; dihydrodibenzo[a,g]quinolizinium derivatives; tetrazole derivatives; tyrosine-based derivatives; pyrazolodiazepine derivatives; imidazole derivatives; benzyl benzoate derivatives; The P2X7R antagonist is selected from the group consisting of: benzoxamide derivatives, KN62 analogs and derivatives; adamantanecarboxamides; arylcarbohydrazides; cyanoguanidines; aryltetrazoles and aryltriazoles; PPADS tetrasodium salt; brilliant blue G (BBG); oxidized ATP (o-ATP); massadin; styrisadin A and B; P2X7R inhibitors C23, C40 and C60; [3H]A-804598 ([3H]2-cyano-1-[(1S)-1-phenylethyl]-3-quinolin-5-ylguanidine); bicycloheteroaryl compounds. However, further suitable P2X7R antagonists are listed in the section "P2X7R Antagonists" below.

[0042] In a very attractive embodiment, the P2X7R antagonist comprises lidocaine. Lidocaine has been shown to be very effective in treating hyperinflammation. Lidocaine is preferably administered topically, and is preferably in free base form. Administration is preferably oral. Lidocaine base is preferably administered in a liquid medium that contains at least 2.5 w / v%, preferably at least 5 w / v%, more preferably at least 10 w / v% receptor antagonist. Such a liquid medium can be, for example, ethanol-based.

[0043] In another attractive embodiment, the treatment involves invasive administration of a water-soluble salt form of lidocaine, particularly lidocaine-HCl. The lidocaine salt is preferably administered intradermally, subdermally, or subcutaneously. The lidocaine salt is preferably administered by continuous intradermal, subdermal, or subcutaneous infusion.

[0044] The mammalian patient is preferably a human patient, but may be any mammal suffering from a disease mediated by P2X7R activation.

[0045] The present invention includes the following aspects and embodiments. [Item 1] An antagonist of a mammalian P2X7 receptor (P2X7R) for use in treating a hyperinflammatory syndrome in a mammalian patient by administering the P2X7R antagonist to a primary lymph node in the mammalian patient until the concentration of the antagonist of the mammalian P2X7R in the primary target lymph node exceeds the maximum tolerable plasma level of the mammal. [Item 2] The antagonist has a concentration in the target lymph node that is equal to or exceeds the IC x The IC x is greater than the maximum tolerated plasma level of said antagonist in said mammal, and x is 10 or more, preferably 20 or more, more preferably 30 or more, even more preferably 40 or more and most preferably about 50. [Item 3] The mammalian P2X7R antagonist for use according to Item 1 or 2, wherein the lymph node-targeted administration is selected from local and invasive administration. [Item 4] The mammalian P2X7R antagonist for use according to Item 3, wherein the administration is local, selected from transmucosal and transdermal administration. [Item 5] The mammalian P2X7R antagonist for use according to Item 4, wherein the antagonist is lipophilic. [Item 6] The antagonist of mammalian P2X7R for use according to Item 5, wherein the lipophilic antagonist is a free base. [Item 7] The mammalian P2X7R antagonist for use according to Item 5 or 6, wherein the lymph node-targeted administration comprises transmucosal administration in the oral cavity. [Item 8] The mammalian P2X7R antagonist for use according to Item 7, wherein administration is buccal, sublingual, pharyngeal or a combination thereof. [Item 9] The mammalian P2X7R antagonist for use according to any one of items 4 to 6, wherein the administration is transdermal and in the form of a cream, ointment or lotion, patch or plaster, and / or comprises microneedles or a combination thereof. [Item 10] The mammalian P2X7R antagonist for use according to Item 3, wherein the administration is invasively selected from intradermal, subdermal, and subcutaneous administration. [Item 11] The mammalian P2X7R antagonist for use according to Item 10, wherein the antagonist is hydrophilic, particularly in the form of a water-soluble pharmaceutically acceptable salt thereof. [Item 12] An antagonist of mammalian P2X7R for use according to Item 3, wherein the administration is intravenous and the antagonist is lipophilic and is entrapped in a drug delivery system that avoids direct release into the blood. [Item 13] The antagonist of mammalian P2X7R for use according to any one of Items 1 to 12, wherein P2X7R activation is activated by extracellular ATP. [Item 14] The mammalian P2X7R antagonist for use according to any one of Items 1 to 13, wherein the administration is in an immediate-release dosage form or a sustained-release dosage form. [Item 15] The mammalian P2X7R antagonist for use according to any one of Items 1 to 14, wherein the administration comprises one or more bolus administrations, or comprises continuous administration, or a combination thereof. [Item 16] The mammalian P2X7R antagonist for use according to Item 15, wherein the bolus dose is at least 1,000 times, preferably at least 5,000 times, more preferably at least 10,000 times the amount of the receptor antagonist contained in 1 ml of plasma at the maximum tolerable plasma level of the receptor antagonist. [Item 17] The mammalian P2X7R antagonist for use according to Item 15 or 16, wherein the bolus is administered 2 to 10 times a day. [Item 18] The mammalian P2X7R antagonist for use according to any one of items 1 to 17, wherein the antagonist is administered in a liquid medium comprising at least 1 w / v%, preferably at least 5 w / v%, and most preferably at least 10 w / v% of the receptor antagonist. [Item 19] The mammalian P2X7R antagonist for use according to Items 10 and 15, wherein the lymph node-targeted administration is by continuous intradermal, subdermal or subcutaneous injection. [Item 20] The dose is IC per kg of body weight per hour. 10 20. The antagonist of mammalian P2X7R for use according to paragraph 19, which corresponds to at least 10 times the value. [Item 21] An antagonist of mammalian P2X7R for use according to any of items 1 to 20, wherein the treatment comprises hyperinflammatory syndromes of diseases selected from the group consisting of autoimmune diseases and immune-related diseases, such as asthma, allergies and chronic lung diseases; treatment-induced immune-related diseases, such as chemotherapy; infectious diseases, such as viral and bacterial infections; cardiovascular and neurovascular diseases; neuroinflammatory and neurodegenerative diseases; epilepsy disorders; affective and psychiatric syndromes; fibrosis; cancer-related disorders; tumor pseudoprogression; cancers and neoplasms; trauma and post-traumatic syndromes; and post-organ transplant syndromes, including transplant organ rejection. [Item 22] The mammalian P2X7R antagonist for use according to any one of Items 1 to 21, wherein the hyperinflammatory syndrome includes dyspnea. [Item 23] The mammalian P2X7R antagonist for use according to Item 22, wherein the shortness of breath is associated with a viral infection, a bacterial infection, carcinoma, chronic obstructive pulmonary disease (COPD), asthma, allergy, or chemotherapy. [Item 24] An antagonist of mammalian P2X7R for use according to any one of items 21 to 23, wherein the viral infection is caused by a virus selected from the group consisting of coronavirus, particularly SARS-CoV-2; influenza; Ebola; respiratory syncytial virus; and HIV. [Item 25] P2X7R antagonists include aminoamide derivatives, particularly lidocaine, bupivacaine, ropivacaine and mepivacaine; antibodies against P2X7R, particularly monoclonal antibodies; aminoester derivatives, particularly benzocaine and procaine; adamantanamide derivatives; triazole derivatives; diarylimidazolidine derivatives; pyroglutamic acid amide derivatives; pyrazoleacetamide derivatives; dihydrodibenzo[a,g]quinolizinium derivatives; tetrazole derivatives; tyrosine-based derivatives; pyrazolodiazepine derivatives; imidazole derivatives; benzamide derivatives, KN62 analogues and derivatives. 25. The antagonist of mammalian P2X7R for use according to any one of items 1 to 24, selected from the group consisting of: aryl tetrazoles and aryl triazoles; PPADS tetrasodium salt; brilliant blue G (BBG); oxidized ATP (o-ATP); massadin; styrisadins A and B; P2X7R inhibitors C23, C40 and C60; [3H]A-804598 ([3H]2-cyano-1-[(1S)-1-phenylethyl]-3-quinolin-5-ylguanidine); and bicycloheteroaryl compounds. [Item 26] The mammalian P2X7R antagonist for use according to any one of Items 1 to 25, wherein the P2X7R antagonist comprises lidocaine. [Item 27] ​​The mammalian P2X7R antagonist for use according to Item 26, wherein the treatment comprises topical administration of lidocaine in its free base form. [Item 28] The mammalian P2X7R antagonist for use according to Item 27, wherein the treatment comprises administering lidocaine base into the oral cavity. [Item 29] The mammalian P2X7R antagonist for use according to Item 28, wherein lidocaine base is administered in a liquid medium containing at least 2.5 w / v%, preferably at least 5 w / v%, more preferably at least 10 w / v% of the receptor antagonist. [Item 30] An antagonist of mammalian P2X7R for use according to Item 26, wherein the treatment comprises invasive administration of a water-soluble salt form of lidocaine, particularly lidocaine-HCl. [Item 31] The mammalian P2X7R antagonist for use according to Item 30, wherein the lidocaine salt is administered intradermally, subdermally or subcutaneously. [Item 32] The mammalian P2X7R antagonist for use according to Item 31, wherein the lidocaine salt is administered by continuous intradermal, subdermal or subcutaneous infusion. The invention will now be further illustrated by the following figures and examples. [Brief explanation of the drawings]

[0046] Figures 1a-f show six cases of severe COVID-19 treated with subdermal lidocaine. All patients were COVID-19 cases with positive COVID-19 tests. Two patients were treated with mechanical ventilation and extracorporeal membrane oxygenation (ECMO), and four patients were treated with mechanical ventilation alone. The maximum dose of intravenous lidocaine was 0.6 mg / kg / h, and the maximum dose of subdermal lidocaine was 1 mg / kg / h. All patients fully recovered from the disease. [Figure 1a] A 63-year-old man (Example 1) was admitted to the hospital with COVID-19-induced ARDS. CT scan showed bilateral ground-glass opacities. Comorbidities included COPD and a history of smoking 60 cigarettes per day for over 40 years. Approximately 40 years prior to admission, the patient had suffered a pneumothorax. After admission, his clinical condition deteriorated, and on day 4, he required intensive care unit (ICU) admission and mechanical ventilation. On day 11, continuous intravenous lidocaine at 0.6 mg / kg / h was initiated, but the patient's condition continued to deteriorate due to high pulmonary artery pressure and decreased pulmonary aeration. On day 19, continuous intravenous lidocaine at 0.6 mg / kg / h was changed to continuous subcutaneous lidocaine at 1 mg / kg / h. This was followed by clinical improvement, and on day 20, pulmonary aeration improved, although pulmonary artery pressure remained elevated. Despite this, the P / F ratio gradually improved, and on day 50, the patient was weaned off ECMO. No new cardiac ECG changes were observed during lidocaine treatment. Serum metHb levels were within the normal range (0.3-0.8%). [Figure 1b]A 68-year-old man with COVID-19-induced ARDS (Example 2) was admitted to the ICU and required mechanical ventilation. CT scan showed bilateral ground-glass opacities. Comorbidity: asthma. After admission, the patient's condition worsened. On day 5, continuous intravenous lidocaine at 0.6 mg / kg / hour was initiated, but his clinical condition and P / F ratio continued to deteriorate. On day 11, the intravenous lidocaine at 0.6 mg / kg / hour was changed to continuous subcutaneous lidocaine at 1 mg / kg / hour. After several days, his clinical condition and P / F ratio improved. No new cardiac ECG changes were observed during lidocaine treatment. Blood metHb was within the normal range (0.1-0.6%). [Figure 1c] A 59-year-old man (Example 3) presented with dyspnea and bilateral ground-glass opacities on CT scan. Comorbidities: diabetes mellitus and gout. No new cardiac ECG changes were observed during lidocaine treatment. Blood MetHb was within the normal range (0.1-0.4%). [Figure 1d] A 51-year-old man (Example 4) presented with fever, shortness of breath, and cough due to COVID-19. CT scan showed bilateral ground-glass opacities. There were no comorbidities. No new cardiac ECG changes were observed during lidocaine treatment. Blood metHb was within the normal range (0.1-0.3%). [Figure 1e] A 58-year-old man (Example 5) presented with fever, shortness of breath, and cough due to COVID-19. CT scan showed bilateral ground-glass opacities. Comorbidities: fatty liver. No new cardiac ECG changes were observed during lidocaine treatment. Blood metHb was within the normal range (0.1-0.3%). [Figure 1f] A 59-year-old man (Example 6) presented with fever, shortness of breath, and cough due to COVID-19. CT scan revealed bilateral ground-glass opacities. Comorbidities: medication-induced hypertension. No new cardiac ECG changes were observed during lidocaine treatment. MetHb was within the normal range (0.1-0.3%). [Example]

[0047] Examples 1 to 6 From April 2020 to the end of July 2020, six critically ill patients with COVID-19 were hospitalized and received intravenous and subdermal continuous infusions of lidocaine. This treatment was initiated based on compassionate use. The concentration of the lidocaine infusion solution was 20 mg / mL (2%). The first two patients were treated with lidocaine intravenously, a route commonly used for continuous lidocaine administration in routine clinical practice. The intravenous dose was 0.6 mg / kg / h. Due to the limited efficacy of intravenous lidocaine and the hypothesis that it selectively targets the inhibition of P2X7R on immune cells, the infusion in both patients was changed to a 1.0 mg / kg / h subdermal infusion after 7 and 6 days, respectively. The other four patients were treated with subdermal infusions alone. The time course of clinical parameters for these six patients is shown in Figures 1a–f.

[0048] Patient 1: Example 1 The first patient, a 63-year-old man (75 kg, 168 cm), developed fever and nausea on March 27, 2020. Three days later, he developed a cough and difficulty breathing. Five days later, a PCR COVID-19 test was positive and he was hospitalized with COVID-19-induced ARDS. Comorbidities included COPD and a history of smoking 60 cigarettes per day for over 40 years. Approximately 40 years prior, the patient had suffered a pneumothorax. On day 3, the patient deteriorated and was intubated and placed on a ventilator due to low blood gas levels. No hemodynamic instability was observed. A CT scan showed bilateral ground-glass opacities consistent with ARDS. On day 5, the patient was transferred to the intensive care unit at a university hospital due to further respiratory deterioration. Due to the extremely low PaO2 / FiO2 ratio of 63.3 mmHg and the progression of respiratory disease, prone position mechanical ventilation was initiated (severe ARDS according to the Berlin definition. The Berlin definition of ARDS includes severe PaO2 / FiO2 ratio ≦100 mmHg, moderate PaO2 / FiO2 100-≦200 mmHg, mild PaO2 / FiO2 200-≦300 mmHg, and non-ARDS PaO2 / FiO2 >300 mmHg

[0361] ). Initial settings of the ventilator: APRV, P high 27cmH2O, T high 7.0s, P low 0cmH2O, TlowThe PaCO2 was normal. The echocardiographically estimated pulmonary artery systolic pressure (PASP) was 80 mmHg. The plasma level of Krebs von Lungen 6 (KL-6, a marker of pulmonary fibrosis

[0362] ) was extremely high (1299 U / mL; normal value, <425 U / mL), and the CRP level was also high (40.4 mg / L; normal value, <10 mg / L). The albumin level was 2.2 g / dL. The white blood cell count, platelet count, and urine output were normal. On day 4, the chest x-ray showed no improvement. On day 6, the PaO2 / FiO2 ratio increased slightly but remained low at 103 mmHg, and the chest x-ray showed progression of ARDS. ECMO was initiated due to exhaustion of ventilation strategies. On day 9, the PaO2 / FiO2 ratio improved but remained low at approximately 153 mmHg, while the CRP level decreased to approximately 21.8 mg / L. The patient was administered a muscle relaxant. The patient's ARDS condition improved from severe to moderate ARDS. From days 10 to 30, the ferritin level was >1000 ng / ml (>100 μg / dL). From days 11 to 62, the D-dimer level was extremely high, reaching 121.9 nM / L on day 14. On day 11, no improvement in blood gases was observed, and it was decided to treat the patient with continuous intravenous lidocaine at 0.6 mg / kg / h. On day 16, the CRP level showed a gradual decline from 19 (day 12) to 12.8 (day 16) and 7.4 (day 19), but the PaO2 / FiO2 ratio remained low at approximately 90 mmHg (severe ARDS according to the Berlin criteria), and chest radiographs on day 15, 3 days after the initiation of intravenous lidocaine infusion, showed a dramatic deterioration. The lidocaine plasma concentration was 3.4 μg / ml on day 13 and 5.4 μg / ml on day 14. On day 19, the continuous intravenous lidocaine infusion was replaced with a continuous subdermal lidocaine infusion at 1 mg / kg / hour. The PaO2 / FiO2 ratio remained unchanged on day 20 (1 day after the switch to continuous subdermal lidocaine), but the chest radiographs clearly improved. On day 21, the lidocaine plasma concentration was 2.6 μg / ml, and the albumin level was 2.5 g / dL. From day 22, the PaO2 / FiO2 ratio gradually improved, reaching 151 mmHg (moderate ARDS) on day 34. KL-6 on day 22 decreased to 458 U / L (which is only slightly above the normal value of <450 U / L).On day 31, the CRP level was low at 1 mg / L, and the lidocaine plasma concentration was 1.2 μg / mL. The muscle relaxant was discontinued. The albumin level was 2.3 g / dL. On day 33, the chest X-ray further improved, and the CRP level remained low at 5.5 mg / L. The patient was awake and able to communicate with the nurses. On day 38, the lidocaine plasma level was 2.3. On day 43, the PaO2 / FiO2 ratio increased to 214 mmHg. According to the Berlin Definition of ARDS

[0361] , the patient's ARDS status changed from moderate to mild. The albumin level was 2.8 g / dL. On day 50, the patient was removed from ECMO. On day 51, the patient underwent tracheotomy. The patient's clinical condition stabilized with a low CRP level of 6.3 mg / L on day 55, and continuous subcutaneous lidocaine was discontinued on day 57. On day 69, he developed a pneumothorax requiring pleural drainage. On day 99, he was weaned from the ventilator and discharged from the ICU on day 121. The patient received favipiravir for 14 days. No new cardiac ECG changes were observed during lidocaine treatment. Blood metHb levels were within the normal range (0.3-0.8%). The patient was discharged home on day 187 and was able to walk, but required supplemental oxygen at 2 L / min. Nine months after admission, the patient is doing well and has returned to work.

[0049] Patient 2: Example 2 The second patient, a 68-year-old man, had COVID-19-induced ARDS and was hospitalized with a positive PCR test. Comorbidities included asthma. CT scans showed bilateral ground-glass opacities. The patient's hemodynamic status was stable. On day 2, his respiratory status worsened, with a PaO2 / FiO2 ratio of 118 mmHg (moderate ARDS according to the Berlin ARDS definition

[0361] ). The patient was intubated and required mechanical ventilation. Initial ventilator settings were pressure control, peak inspiratory pressure 28 cmH2O, PEEP 13 cmH2O, and respiratory rate 30 / min. CRP was 10.6 mg / L, and KL-6 was 486 U / mL. White blood cell count, platelet count, and urine output were normal. Ferritin levels remained >1000 ng / mL (100 μg / dL) throughout his ICU stay. Albumin was 2.9 g / dL. Over the next 3 days, the PaO2 / FiO2 ratio improved to approximately 150 mmHg. The PaO2 / FiO2 ratio decreased from 152 mmHg on day 5 to 84 mmHg on day 6. CRP increased to 22.9, and KL-6 increased to 762 U / mL. The patient was placed in the prone position and given a muscle relaxant. Continuous intravenous lidocaine was initiated at 6 mL / kg / hour. Albumin was 1.8 g / dL. On day 7, the PaO2 / FiO2 ratio increased to 128 mmHg, CRP decreased to 10.3 mg / mL, and the lidocaine plasma concentration was 2.2 μg / mL. From day 3 until ICU discharge, the D-dimer level increased, reaching 75 nM / L on day 14. On day 8, the PaO2 / FiO2 ratio improved from 84 to 125 mmHg, but the patient exhausted the mechanical ventilation strategy and was placed on ECMO. KL-6 increased to 845 U / L, and the lidocaine plasma level was 2.9 μg / ml. On day 9, the PaO2 / FiO2 ratio improved to 238 mmHg. On day 10, a rapid decline in the PaO2 / FiO2 ratio to 60 mmHg was observed, and the CRP level was 2.0 mg / ml. The patient's ARDS status changed from moderate to severe according to the Berlin ARDS criteria (Ranieri et al., Jama 2020, 307 (23), 252-2533). Lidocaine treatment was switched from continuous intravenous administration to continuous subcutaneous administration (dose: 1 mg / kg / h). On day 14, the lidocaine plasma level was 2.7 μg / ml. KL-6 decreased to 549 U / l.On day 17, the patient's clinical condition improved, with a PaO2 / FiO2 ratio of 158 mmHg. The patient was removed from ECMO. The PaO2 / FiO2 ratio further improved, reaching 291 mmHg on day 21, and the patient's ARDS status changed from moderate to mild ARDS (Ranieri, supra). On day 22, the ventilator was discontinued, and the patient was extubated. The patient remained oriented, and no signs of confusion were detected. Lidocaine treatment was continued until discharge from the ICU on day 30. The patient received tocilizumab on day 8 and favipiravir for 14 days. No new cardiac ECG changes were observed during lidocaine treatment. Blood metHb levels were within the normal range (0.1-0.6%). Three months after admission, the patient is doing well.

[0050] Patient 3: Example 3 The third patient was a 59-year-old man admitted with dyspnea and bilateral ground-glass opacities on a CT scan. Dependencies: diabetes mellitus and gout. The patient required immediate intubation and mechanical ventilation. Initial ventilator settings: pressure control, peak inspiratory pressure 30 cmH2O, PEEP 15 cmH2O, respiratory rate 25 / min. On admission, the PaO2 / FiO2 ratio was 160 mmHg (moderate ARDS according to the Berlin definition

[0361] ), CRP was 39.3 mg / L, and KL-6 was 294 U / ml. The white blood cell count was 13.10 -9The blood pressure increased by 1 / L, while the platelet count and urine production were normal. The albumin level was 2.1 g / dL. Hemodynamic parameters were stable. Continuous subcutaneous lidocaine was initiated at 1 mg / kg / h on the day of admission. On day 2, the PaO2 / FiO2 ratio improved to 283 mmHg, and the patient's ARDS status changed from moderate to mild ARDS. The CRP level was 41 mg / L, the KL-6 level was 268 U / L, and the lidocaine plasma level was 3.7 μg / mL. The albumin level was 1.7 g / dL. On day 4, the PaO2 / FiO2 ratio was 302 mmHg, and the patient's ARDS status changed from mild ARDS to non-ARDS according to the Berlin ARDS criteria. On day 5, the PaO2 / FiO2 ratio further improved to 328 mmHg, the CRP level decreased to 16.4, and the patient was extubated. The patient remained oriented and showed no signs of confusion. The patient was discharged from the ICU on day 8, with a CRP level of 2.3 mg / ml and albumin level of 2.5 g / dl. The patient received tocilizumab on day 3 and favipiravir for 15 days. No new cardiac ECG changes were observed during lidocaine treatment. Blood MetHb levels were within the normal range (0.1-0.4%). The patient was discharged on day 20. Three months later, the patient is doing well.

[0051] Patient 4: Example 4 The fourth patient was a 51-year-old man. He developed fever 10 days before admission and dyspnea and cough 2 days before admission. On the day of admission, a PCR COVID-19 test was positive. A CT scan showed bilateral ground-glass opacities. There were no comorbidities. The patient was intubated and placed on a ventilator upon admission. On day 3, his pulmonary condition worsened, and he was transferred to a university hospital. Initial ventilator settings were pressure control, peak inspiratory pressure 24 cmH2O, PEEP 12 cmH2O, and respiratory rate 15 / min. His hemodynamic status was stable. His white blood cell and platelet counts were normal. His albumin level was 2.6 g / dL. Continuous subcutaneous lidocaine was immediately initiated. On day 3, his PaO2 / FiO2 ratio was 214 (moderate ARDS according to the Berlin definition

[0361] ). His KL-6 level was 177 U / L, and his CRP level was 17.4 mg / L. On day 5, the PaO2 / FiO2 ratio increased to 382 (the patient's ARDS status changed from mild ARDS to non-ARDS), and the lidocaine plasma concentration was 5.2 μg / mL. CRP was 27.3 mg / L. Lidocaine plasma levels were 3.4 and 4.2 μg / mL on days 3 and 4, respectively. KL-6 was 163 U / L. The patient was extubated. The patient remained oriented, and no signs of confusion were detected. The patient was discharged from the ICU on day 8, with a CRP of 9.3 mg / L. The patient received favipiravir for 14 days. No new cardiac ECG changes were observed during lidocaine treatment. Blood metHb was within the normal range (0.1-0.3%). The patient was discharged on day 28. Three months later, the patient was doing well and had returned to work.

[0052] Patient 5: Example 5 The fifth patient was a 58-year-old man. Nine days before admission, he developed a sore throat. The next day, he developed a fever. Two days before admission, he developed a cough and difficulty breathing. On the day of admission, a PCR COVID-19 test was positive. A CT scan showed bilateral ground-glass opacities. Comorbidities included fatty liver. The patient was initially admitted to a general ward. On the third day, the patient deteriorated and had to be intubated and placed on a ventilator. On the fourth day, due to worsening pulmonary conditions, the patient was transferred to a university hospital. Initial ventilator settings were pressure control, maximum inspiratory pressure 27 cmH2O, PEEP 12 cmH2O, respiratory rate 25 / min. The PaO2 / FiO2 ratio was 188 (moderate ARDS according to the Berlin definition). Hemodynamic parameters were stable, with a CRP of 12.9 mg / ml. Although the white blood cell count was elevated (14.4.10), 9 The blood pressure was 184 / L, and the platelet count was normal. The KL-6 level was 330 U / L. Continuous subcutaneous lidocaine was initiated at 1 mg / kg / hour. The albumin level was 2.8 g / dL. On day 5, the PaO2 / FiO2 ratio remained unchanged, the CRP level was 10.4 mg / L, and the lidocaine plasma level was 4 μg / mL. On day 6, the lidocaine plasma level was 3.2 μg / mL. The KL-6 level remained at 400 U / L. The albumin level was 2.3 g / dL. On day 10, the respiratory failure resolved, but the PaO2 / FiO2 ratio remained at 184, the CRP level decreased to 2.4 mg / L, and the KL-6 level was 322 U / L. The patient was extubated, remained oriented, and no signs of confusion were detected. The patient was discharged from the ICU on day 14. The patient received tocilizumab on day 7 and favipiravir for 10 days. No new cardiac ECG changes were observed during lidocaine treatment. Blood metHb levels were within the normal range (0.1-0.3%). The patient was discharged on day 20 and is doing well 3 months after admission.

[0053] Patient 6: Example 16 The sixth patient was a 59-year-old man with fever, dyspnea, and cough due to COVID-19. CT scan showed bilateral ground-glass opacities. Comorbidities included medication-induced hypertension. The patient was admitted to a general ward. KL-6 was 233 U / L, and the white blood cell and platelet counts were normal. Albumin was 3.6 g / dL. On day 3, respiratory function deteriorated, requiring transfer to the ICU and mechanical ventilation. Initial ventilator settings were pressure control, peak inspiratory pressure 22 cmH2O, PEEP 10 cmH2O, and respiratory rate 20 / min. After admission to the ICU, continuous subcutaneous lidocaine was initiated at 1 mg / kg / h. Hemodynamic parameters remained stable. CRP was 6.3 mg / L, and KL-6 was 263 U / L. On day 4, progressive respiratory failure occurred, requiring intubation and mechanical ventilation. The PaO2 / FiO2 ratio was 218 mmHg, and hemodynamic parameters remained stable. CRP was 6.3 mg / L, and the white blood cell and platelet counts were normal. The lidocaine plasma level was 4.6 μg / mL. On day 5, the PaO2 / FiO2 ratio further decreased to 164 mmHg. The lidocaine plasma level was 3.4 μg / mL. Albumin was 3.2 g / dL. On day 9, the patient's clinical condition improved. The ventilator settings could be reduced, and the PaO2 / FiO2 ratio remained at 207 mmHg during the weaning period, with the CRP level at 0.7 mg / L. On day 10, the patient was extubated, remained oriented, and no signs of confusion were detected. On day 13, the patient was discharged from the ICU. On day 4, tocilizumab was administered. The patient received favipiravir for 11 days. No new cardiac ECG changes were observed during lidocaine treatment. Blood metHb levels were within the normal range (0.1-0.3%). The patient was discharged on the 20th day and, 3 months after admission, is doing well, playing golf, and has returned to work.

[0054] Example 7: COVID-19 On March 24, 2020, a 49-year-old woman developed cough, dyspnea, muscle pain, buttock and groin pain, and shivering, but no fever. COVID-19 testing was not performed. This occurred 1 week after working closely with a colleague who had developed severe COVID-19 requiring hospitalization. Lidocaine treatment was initiated 4 hours after symptom onset. After initiation of a continuous subdermal (subsurface) infusion of 0.5 mg / kg / hour lidocaine, symptoms gradually subsided, and after several hours, symptoms were virtually resolved. After 12 hours, lidocaine was discontinued. A few hours later, symptoms recurred and subsided again after resuming the continuous subcutaneous infusion of lidocaine. Lidocaine treatment was continued for 3 days.

[0055] On April 1, 2020, symptoms recurred, and subdermal lidocaine injections were restarted. After several days, the patient's clinical condition improved, and lidocaine treatment was discontinued. The patient was able to work from home but experienced fatigue. Four weeks later, she had fully recovered from all symptoms.

[0056] On July 12, 2020 (day 1), the patient developed new symptoms, including tremors, joint pain (knees, hips, and shoulders), and conjunctivitis of the left eye. He reported illness at work. Transmission likely occurred on July 1, 2020. That day, he met many people while working in the office and went to a bar with several colleagues for drinks in the evening. Transmission occurred despite social distancing and hand hygiene. No one was wearing a face mask at the time. He was treated with a subdermal infusion of lidocaine (0.63 mg / kg / hour). Symptoms improved within a few hours. On July 15, 2020 (day 4), the lidocaine infusion was discontinued for several hours, and he visited his GP for COVID-19 testing. On July 21, 2020 (day 10), the COVID-19 IgA antibody test result was positive. One week later, daytime lidocaine infusion was discontinued because the infusion system and syringe pump significantly interfered with daily activities.

[0057] On the 11th day, symptoms increased: tingling in the lungs, chest pain, tremors, difficulty breathing, frequent yawning, and dizziness. Lidocaine infusions were administered 24 hours a day. Symptoms gradually improved.

[0058] On day 12, chest pain, shivering, and increasing proximal muscle and joint pain developed. Temperature was 35.9°C, SpO2 (oxygen saturation) 86%, HR (heart rate) 70 beats per minute, and BP (blood pressure) 110 / 70 mmHg. Bronchial breath sounds were heard in the left lower lobe of the lung and, to a much lesser extent, in the right lower lobe. Subdermal lidocaine infusions (0.63 mg / kg / hour) were still being administered, and the patient was further treated with amoxicillin 3 × 500 mg / day for suspected secondary bacterial pneumonia. The patient fell asleep, and the next day all symptoms were significantly improved, and the infusions were continued uninterrupted.

[0059] On day 18, the subdermal lidocaine infusion was discontinued because the infusion system and syringe pump significantly interfered with the patient's daily activities. Several hours later, clinical deterioration occurred, with extreme fatigue, chest pain, and pain in the right upper arm. Treatment was changed to transdermal lidocaine cream. The formulation was 2.5% alpha-terpineol, 20% lidocaine, 10% castor oil, 1% polysorbate 20, 0.5% carbopol, and 56% water (lidocaine cream 200 mg / ml). A 400 mg dose of the cream was applied to the skin and covered with a Tegaderm transparent wound dressing. However, after 1 hour, the patient's symptoms had not improved, so a subdermal infusion of 40 mg / hour of lidocaine was initiated. Clinical improvement was evident after 1 hour. However, after 6 hours, symptoms persisted, so the infusion rate was increased to 63 mg / hour (1 mg / kg / hour). Subsequently, symptoms, except for pain in the upper arm, resolved.

[0060] On the 19th day, I had pain in my right arm that lasted for several weeks. The pain was mainly felt in the muscles of my upper arm, and sometimes in my shoulder, elbow, and lower arm. This led to a severe frozen shoulder syndrome.

[0061] Day 22, period of excessive yawning and temperature (measured orally) of 34°C.

[0062] On day 23, the patient developed a wavelike tremor along with cough, dyspnea, tingling in the lungs, chest pain, sore throat, headache, yawning, conjunctivitis of the left eye, and joint pain. Lidocaine infusions reduced the symptoms tolerably.

[0063] On day 24, the patient was adequately infused and the lidocaine infusion was changed to transdermal lidocaine cream 20% 400 mg, 2 × 50 cm 2 The cream was applied to the surface of the skin and covered with Tegaderm. The cream was almost completely absorbed after 6 hours and was replaced with a new dose each time.

[0064] On day 25, the Tegaderm wound dressing broke overnight, causing loss of a portion of the cream dose. The patient woke up with pain in the right vastus dorsi area, accompanied by sternal pain and discomfort. SpO2 98%, HR 74 / min, BP 114 / 71, and temperature 35.3°C. A new cream dose was applied, and an additional 100 mg cream was massaged into the skin as a bolus dose. One hour later, the patient's clinical condition improved. Lidocaine 400 mg cream was scheduled to be administered every 6 hours.

[0065] On day 26, the cream applied to the abdominal wall did not appear to be adequately absorbed by the skin overnight. Symptoms recurred, and a new dose of lidocaine cream was applied to the upper extremities, which relieved symptoms within an hour. By 16:00, the cream was completely absorbed, and symptoms recurred. A new dose of lidocaine cream was again effective.

[0066] On day 27, absorption of lidocaine cream applied to the arms and abdominal wall was much less than that on the medial side of the upper extremities.

[0067] At 07:30 on day 32, less than 80% of the lidocaine cream had been absorbed. The patient's clinical condition worsened, with SpO2 periodically dropping to 90%. Two doses of 200 μg beclomethasone nasal spray were administered. Periodic sighing and coughing were required to maintain SpO2 above 92%. An additional 100 mg of cream was applied as a bolus dose to the skin, which improved the patient's condition within 30 minutes. At 12:00, the left knee became extremely painful and was treated again with a new dose of cream. Another 100 mg of cream was again applied as a bolus dose to the skin, which improved the patient's condition. The total daily dose of lidocaine cream was 2000 mg.

[0068] The night of Days 32-33, I had no symptoms other than pain in my right upper arm. This was my first symptom-free night since Day 1 (July 12, 2020).

[0069] At 11:10 on day 33, the patient experienced sudden, intense pain between the shoulder blades. He had difficulty breathing, hyperventilated, and turned pale. SpO2 was 97%, HR 66 / min, BP 112 / 60 mmHg, and temperature 35.3°C. Hospital analysis showed a normal lung x-ray, normal metHb, and normal d-dimer. Further routine laboratory tests were normal.

[0070] On day 35, the patient had no other symptoms except for fatigue and pain in the right upper arm. Lidocaine cream was tapered to 4 x 100 mg / day without a Tegaderm covering.

[0071] On day 46, at 03:30, SpO2 alarmed at 86%, HR 55 / min, BP 115 / 70 mmHg, pulmonary tingling, and left conjunctivitis. Lidocaine cream was removed, and a continuous subdermal infusion of 0.63 mg / kg / hour lidocaine was initiated. Symptoms improved within 30 minutes. Pain in the right upper arm remained unchanged.

[0072] After 1 week, the lidocaine infusion was discontinued.

[0073] At 04:20 on Day 61, a new episode occurred with tingling in the lungs, left conjunctivitis, and increasing pain in the right upper arm. A continuous subdermal infusion of lidocaine 0.63 mg / kg / hour was initiated, and symptoms subsided. Eight hours later, the lidocaine infusion was discontinued. At 19:40 after dinner, the patient became shivering, felt unwell, and had to go to bed. Temperature 34.1, BP 96 / 60 mmHg, SpO2 100%, and HR 86 beats per minute. A continuous subdermal infusion of lidocaine 0.63 mg / kg / hour was resumed along with 400 μg beclomethasone nasal spray and oral hydrocortisone. Symptoms subsided immediately.

[0074] On day 66, the patient felt well, except for pain in the right upper arm, which fluctuated in intensity and sometimes migrated to the shoulder or elbow. The general practitioner was not convinced that this was related to COVID-19. The lidocaine infusion was discontinued.

[0075] On the 67th day, I was a passenger in a car trip to visit a friend 200km from my home.

[0076] On day 85, approximately 3 weeks later, the patient was free of symptoms except for fluctuating upper arm pain, but the tingling in the lungs returned. SpO2 96%, HR 90 / min, BP 95 / 68 mmHg, and temperature 33.5°C. Sublingual lidocaine 3 x 100 mg / day was initiated. The lidocaine was held in the mouth for 15 minutes and then swallowed. Inhalation of the lidocaine solution was avoided. Lidocaine formulation: xylocaine 5 g in 50 ml (10% solution, 100 mg / ml), ethanol 96%, polyethylene glycol 400, banana extract, and purified water.

[0077] Beginning on day 85, after initiating sublingual lidocaine treatment, the patient experienced tingling and chest tightness before taking the morning dose and before taking the sublingual lidocaine at the end of the day. These symptoms disappeared 20 minutes after administration of the sublingual lidocaine. This occurred repeatedly almost daily.

[0078] Example 8: COVID-19 On December 20, 2020, a 46-year-old man developed a runny nose, mild headache, stiffness and severe pain in his neck and right shoulder, loss of smell, and a significantly decreased sense of taste. He felt tired and lethargic. The patient had been in contact with a COVID-19 patient 5 days prior. Two days after the onset of symptoms, a PCR swab test for COVID-19 was positive. The following day, his symptoms progressed.

[0079] On day 5, the patient received 5 x 60 mg lidocaine using a fixed dose. The drug was administered sublingually and held in the mouth for 15 minutes. The lidocaine solution was then swallowed. Inhalation of lidocaine was avoided. The lidocaine formulation was: xylocaine 5 g (10% solution, 100 mg / ml) in 50 ml, ethanol 96%, polyethylene glycol 400, banana extract, and purified water. On day 6 (24 hours after the start of treatment), the runny nose, headache, neck pain, and neck stiffness disappeared. On day 6, the patient received 4 x 60 mg lidocaine / day, and from day 7, the patient was treated with 3 x 60 mg lidocaine / day. On day 9, the patient felt significantly less fatigued, more energetic, and began thoroughly cleaning the house. For the first time, she reported dry mouth. On day 8, all symptoms completely disappeared except for dry mouth and mild fatigue. On day 11, the patient took a 1-hour walk and felt well.

[0080] Example 9: ARDS due to Staphylococcus aureus sepsis An example of the off-label use of lidocaine as a last resort drug to treat a patient suffering from severe ARDS: a 43-year-old woman was admitted to an ICU in the Hague area at the end of 2019. A patient developed severe ARDS from staphylococcal sepsis. The sepsis developed after intravenous administration of contrast material for MRI imaging. The patient was placed on a ventilator. Despite appropriate antibiotic treatment, the ARDS and sepsis worsened, resulting in inadequate oxygenation on the ventilator and unstable hemodynamics, necessitating extremely high doses of norepinephrine and vasopressin. The patient was placed on extracorporeal membrane oxygenation (ECMO) and transferred to University Hospital Rotterdam. While the patient remained on ECMO, surgical removal of the lungs and treatment with antibiotics for two months were planned to remove the microorganisms from the pleural cavity. This procedure would be followed by a lung transplant. Due to hemodynamic instability and low oxygenation, the intensivist continued to treat the patient with low-dose lidocaine, intended to inhibit P2X7R, even while on ECMO. The patient's condition stabilized within 1.5 hours after the initiation of a 1 mg / kg / h continuous lidocaine infusion. Over the next few days, the dosage of norepinephrine and vasopressin could be gradually reduced, and several days later, oxygenation with regular ventilation was restored, and the ECMO was discontinued. Needless to say, the planned lung transplant was canceled. After 1.5 months, the patient was removed from the ventilator and transferred to a general ward. The patient was administered lidocaine for two weeks.

[0081] Example 10: Polymyalgia rheumatica In January 2012, a 59-year-old man presented with progressive muscle pain, initially described as statin-related. He was barely able to turn in bed. His loss of strength fluctuated, but his weight remained stable at 54 kg. He had no fever. He also complained of fatigue and general malaise. He had no familial skin or muscle disorders, but he had asthma and CVD. 18 months earlier, he had been bitten by a tick and developed a rash with erythema chronicum migrans (ECM). Suspected infection with Borrelia burgdorferi led to the patient being treated with amoxicillin for 4 weeks. Laboratory tests showed an increase in his erythrocyte sedimentation rate (ESR) of 47 mm / hour (November 1, 2012) and 85 mm / hour (February 2013). A chest x-ray and CT scan of his chest and abdomen were unremarkable. The diagnosis was polymyalgia rheumatica. The patient was initially treated with high-dose corticosteroids. This medication was tapered and discontinued after 6 months.

[0082] Symptoms recurred in September 2019. The patient was initially treated with continuous subdermal lidocaine infusions of 0.5 mg / kg / hour at night for 8 hours twice weekly. After the initial treatment, symptoms resolved. After several months, the subdermal lidocaine infusions were replaced with transdermal 5% lidocaine ointment 300 mg twice daily. This treatment was ineffective. On September 10, 2020, the patient began using sublingual lidocaine 2 × 60 mg / day. The lidocaine was held in the mouth for 15 minutes and then swallowed. Inhalation of lidocaine was avoided. The lidocaine formulation was: xylocaine 5 g (10% solution, 100 mg / ml) in 50 ml, ethanol 96%, polyethylene glycol 400, banana extract, and purified water. Symptoms resolved within an hour and did not recur (while undergoing treatment) until the end of follow-up on January 2, 2021.

[0083] Example 11: Psoriatic Arthritis A 60-year-old woman presented with a cutaneous herpes zoster infection on her back that extended down to her abdominal wall. She had developed psoriasis 4 years prior. Last year, she developed progressive rheumatoid arthritis and lichen planus. Her symptoms progressed, and for the past few weeks, she had been unable to prepare meals. She could barely dress or undress. She had been treated with corticosteroids and methotrexate. In early July 2020, the herpes zoster infection on her trunk became extremely painful, and the patient was treated with morphine. Morphine did not relieve the pain but caused constipation. This was her condition at the time of her referral. On August 8, 2020, our team began treatment with 10% lidocaine cream. The formulation was: 2.5% alpha-terpineol, 10% lidocaine, 10% castor oil, 1% polysorbate 20; 0.5% carbopol, and 66% water (lidocaine cream 100 mg / ml). Lidocaine cream was administered at a dose of 200 mg / day and applied to the skin of the forearm and covered with a transparent Tegaderm wound dressing. The cream was applied alternately to the left and right forearms each day. Morphine treatment was tapered. Because the Tegaderm dressing was damaging to the skin, it was replaced by a plastic wrap dressing with an elastic dressing.

[0084] Constipation disappeared within two days, the shingles infection rapidly subsided, and after 14 days her happiness rating increased from 3 to 7.5 on a 10-point scale. She was able to perform her daily activities normally at home. After four weeks, she was able to easily garden and her ability to perform daily activities was back to normal.

[0085] Example 12: Spondyloarthropathies A 62-year-old patient from Italy presented with an intractable, progressive, and debilitating degenerative disease of the vertebrae (L2-L3, L3-L4, and L4-L5). He suffered from severe pain, could barely walk, and was unable to perform his job as a crane operator or his hobby (repairing racing bikes). The condition had been progressing for 20 years. Painkillers were ineffective.

[0086] In December 2019, the patient was administered 2 x 1400 mg / day lidocaine patches. The patches were applied to different areas of the skin to prevent skin irritation. The patient reported that 70% and 90% of her symptoms had resolved after 4 days and 2 weeks, respectively. She was largely pain-free and was able to return to work and take up her hobbies again.

[0087] Example 13: Chronic interstitial cystitis (chronic inflammatory bladder condition) An 88-year-old woman with comorbidities including hypertension, glaucoma, type 2 diabetes mellitus with renal dysfunction, and chronic inflammation of the uterus and bladder had complained of intractable, progressive, and extreme bladder pain for the past two years, especially during urination. Treatment with oxycodone (a morphine analog), paracetamol, and antibiotics had no effect on her symptoms. Treatment with continuous subcutaneous lidocaine at 1 mg / kg / hour gradually reduced her symptoms, and after two days she was virtually symptom-free. One week later, treatment was discontinued due to problems with drug delivery, and her symptoms recurred. After resuming lidocaine infusion, her symptoms again resolved.

[0088] Example 14: Knee osteoarthritis A 43-year-old woman suffered from osteoarthritis of the right knee. Her right knee was edema-prone and extremely painful. Her maximum walking distance was 100 meters, and pain forced her to stop walking and sit down. She could barely climb the stairs at home and was unable to ride a bicycle. MRI showed edema in her right knee joint. Knee resection was refused due to a defect in the ventral portion of the femoro-tibial cartilage tissue, which was revealed on MRI. On January 25, 2020, she underwent treatment with 2 × 1400 mg / day lidocaine patches. Within 6 weeks, her right knee edema and pain improved, her walking range exceeded 500 meters, and she was able to climb stairs. After 8 weeks, she was able to ride a bicycle.

[0089] Example 15: Multiple Sclerosis A 46-year-old patient was diagnosed with relapsing-remitting multiple sclerosis (RRMS) in 2005. He was treated with Avonex from 2005 to 2006. In January 2020, he complained of fatigue. He had to rest from 10:00 AM to 2:00 PM due to fatigue. Neurological symptoms included paresthesia in the right arm. He was treated with 1 x 700 mg / 48-hour lidocaine patch. After 4 weeks, his fatigue improved, he was able to eliminate daytime rest periods, and he felt more energetic in his daily activities.

[0090] Example 16: Advanced cervical cancer and renal insufficiency A 65-year-old woman was diagnosed with advanced cervical cancer in July 2018. The tumor mass blocked both ureters, causing bilateral hydronephrosis. Drainage of the hydronephrosis was successful, and the patient was treated with paclitaxel and bevacizumab. Renal dysfunction developed in October 2018. In August 2019, a CT scan of the chest and abdomen revealed a large tumor mass in the pelvic cavity, multiple parailiac lymph node metastases, and a peripancreatic mass. Cancer-related ascites developed. The conclusion was that the tumor growth was progressive. However, due to progressive impairment of renal function, the intended treatment with carboplatin and gemcitabine was postponed.

[0091] On September 15, 2019, the patient began receiving a continuous subdermal lidocaine infusion at 1 mg / kg / hour. Renal function improved. Six weeks later, due to improved renal function, the patient was able to receive treatment with carboplatin and gemcitabine. Five months later, in February 2020, tumor growth stabilized, allowing chemotherapy treatment to be discontinued. At that time, the patient was still receiving lidocaine infusions.

[0092] Example 17: Various cancers Ten patients had prostate cancer (two patients), exocrine pancreatic cancer (four patients), colon cancer (two patients), cervical cancer (one patient), and breast cancer (one patient). All patients had no further cancer treatment options remaining, and all patients were being treated with palliative opiates. The patients were prescribed continuous subcutaneous lidocaine 1 mg / kg / hour instead of morphine.

[0093] Seven patients experienced relief of pain, nausea, and / or extreme fatigue within 2 hours, and the remaining patients experienced relief within 48 hours, which improved further over the following week and remained stable for several weeks.

[0094] For example, an 81-year-old patient with end-stage metastatic colon cancer went from a lot of pain, discomfort, and malignant ascites to being able to perform with a rock band in a wheelchair after three weeks.

[0095] The disability illness impact profile (SIP68) was applied to the inventory data. Before treatment: SIP68: 48 (range 18-68). After 3 days: SIP68: 33 (range 12-58), all patients improved. After 7 days: SIP68: 28 (range 12-56), all patients improved.

[0096] Example 18: Amyotrophic lateral sclerosis (ALS) A 63-year-old man was referred to the outpatient clinic for evaluation of bilateral calf muscle spasms, left foot drop, and weakness in both arms, shoulders, and legs. The spasms occurred almost exclusively after voluntary movement. There was no memory impairment and no family history of the disease.

[0097] Physical examination revealed atrophy of the bilateral supraspinatus, infraspinatus, thenar and hypothenar eminences, and left calf muscles. There were hyperreflexia in the lower extremities and bilateral hallux extensor responses (positive Babinski sign). Muscle fibrosis was present in the calves and shoulders. The MRC strength physical examination scores (Medical Research Council, UK, mrc.ukri.org) were: upper arm abduction (left 4, right 4); upper arm adduction (left 5, right 5); elbow flexion (left 4, right 4); elbow extension (left 5, right 5); knee flexion (left 4, right 4); knee extension (left 5, right 5); foot extension (left 1, right 1); foot flexion (left 2, right 2). The remaining muscles were unaffected.

[0098] Spine imaging (CT and MRI scans) ruled out structural impingement of the motor tracts. EMG showed denervation of the limb muscles. The diagnosis was ALS.

[0099] The patient was treated with sublingual lipophilic lidocaine base 4 x 100 mg / day (5 g xylocaine spray in a 50 ml metered dose spray bottle). The patient held the lidocaine solution in their mouth for 15 minutes, after which they swallowed the solution as intended.

[0100] After one week, the patient noted that the muscle spasms gradually disappeared. After three weeks, muscle strength began to gradually improve. Six months after the initiation of lidocaine therapy, repeated muscle strength testing (using the MRC scale) showed the following: upper arm abduction left 5, right 5 (improved); elbow flexion left 4, right 4 (no change); knee flexion left 5, right 5 (improved); foot extension left 2, right 2 (improved); foot flexion left 3, right 3 (improved); the remaining muscles were unaffected. This treatment resulted in a clinically significant improvement in disease symptoms.

[0101] Example 19: Alzheimer's dementia A 72-year-old man had been experiencing increasing memory loss. Symptoms began 6 years ago and included a gradual loss of episodic memory, followed by an inability to recall new information. In contrast, older memories appeared to remain intact. Symptoms progressed to the point where they severely affected daily activities such as social functioning, cooking, gardening, and shopping. There was no family history of cardiovascular, psychiatric, or neurological disease.

[0102] Physical examination revealed no abnormalities. The Mini-Mental State Examination (MMSE) test total score was 15 (severe cognitive impairment). Routine blood chemistry and hematology were normal. Thyroid function analysis, blood rheumatologic screening, vitamin B12, and homocysteine ​​showed no abnormalities. Urine (24-hour sample) analysis showed no evidence of heavy metal intoxication. Routine chest x-ray was normal. Brain MRI was unremarkable. The diagnosis was Alzheimer's disease.

[0103] Lumbar puncture showed decreased β-amyloid (Aβ42) levels.

[0104] The patient was transferred to a dementia care home. The patient was administered sublingual lipophilic lidocaine base 4 × 100 mg / day (5 g xylocaine spray in a 50 ml metered-dose spray bottle). The patient held the lidocaine solution in their mouth for a maximum of 15 minutes and then swallowed the solution as intended. Compliance was ensured by specialized nurses.

[0105] Gradually, memory imprinting ability increased, and after 3 months the total score on the MMSE test was 23 (mild cognitive impairment). This treatment resulted in a clinically significant improvement in the symptoms of the disease.

[0106] Example 20: Idiopathic Parkinson's disease A 76-year-old man presented with a progressive tendency to fall (postural instability). Symptoms began 8 years before the patient was referred to the clinic. Three years later, he developed a progressive tremor in his right arm, especially when the arm was not moving (resting tremor). Two years after the onset of the right arm tremor, he developed a resting tremor in his left arm.

[0107] The patient was treated with levodopa, which initially resulted in a clear improvement in symptoms. Six years later, symptoms recurred, and after increasing the levodopa dose, the patient developed levodopa-induced chorea. The patient was not treated with neuroleptics.

[0108] There was no history of repeated strokes, repeated head trauma, encephalitis, gaze seizures, supranuclear gaze palsy, amnesic autonomic symptoms, or MPTP ((1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) abuse). Brain MRI was unremarkable. The diagnosis was idiopathic Parkinson's disease.

[0109] Patients were treated with sublingual lipophilic lidocaine base 4 × 100 mg / day (5 g xylocaine spray in a 50 ml metered-dose spray bottle). Patients held the lidocaine solution in their mouths for up to 15 minutes, after which they swallowed the solution as intended.

[0110] After one month, the patient reported a gradual improvement in his tendency to fall. His tremor had almost disappeared. This treatment resulted in a clinically significant improvement in his disease symptoms.

[0111] Example 21: Epileptic seizures A 30-year-old woman was rushed to the emergency room after a car accident. She was sitting next to the driver and complained of a headache. Her medical history was clean.

[0112] On physical examination, the patient's Glasgow Coma Score (GCS) was 15 out of 15 on admission. A subcutaneous hematoma was noted on the forehead. No other abnormalities were noted.

[0113] A CT scan of the head and cervical spine was unremarkable. One hour after arrival, the patient's level of consciousness began to decrease and he developed generalized epileptic seizures.

[0114] Treatment with repeated intravenous diazepam 10 mg was ineffective, and the patient was intubated and deeply sedated with a continuous midazolam infusion. A repeat CT scan 4 hours after arrival at the emergency room revealed a hemorrhagic contusion lesion in the left parietal lobe. The patient was admitted to the ICU, placed on a ventilator, and placed in a pentobarbital coma under EEG monitoring. Five days later, the patient was weaned from pentobarbital and began experiencing generalized epileptic seizures with increasing intensity. The diagnosis was post-traumatic epileptic seizures.

[0115] Treatment with 1 mg / kg / hour subdermal (subcutaneous) lidocaine HCl (20 mg / ml solution) was initiated, and within 30 minutes the seizures resolved. Eight hours later, the patient regained consciousness, and four hours later, he was removed from the ventilator and extubated.

[0116] The next day, the GCS was 15 out of 15, and physical examination revealed no neurological deficits. The patient received continuous subdermal lidocaine treatment for 2 weeks, which resulted in clinically significant improvement of the post-traumatic seizures.

[0117] Example 22: Multiple Sclerosis A 56-year-old woman was diagnosed with primary progressive multiple sclerosis (PPMS) 10 years ago. The diagnosis was confirmed by cerebrospinal magnetic resonance imaging (MRI) and CSF findings.

[0118] Treatment with ocrelizumab and dexamethasone did not improve symptoms.

[0119] On presentation to us, the patient's Kurtzke Expanded Disability Status Scale (EDSS) score was 7.5 (Kurtzke (1983) Neurology. 33 (11): 1444-52). The patient was confined to a wheelchair and was unable to walk more than a few steps.

[0120] Patients were treated with sublingual lipophilic lidocaine base 4 × 100 mg / day (5 g xylocaine spray in a 50 ml metered-dose spray bottle). Patients held the lidocaine solution in their mouths for up to 15 minutes, after which they swallowed the solution as intended.

[0121] Over the next few weeks, the patient's clinical condition improved. After 3 months, her EDSS score improved from 7.5 to 5.5, and she was able to walk approximately 120 meters unassisted, but still required assistance for full activities of daily living. This treatment resulted in a clinically significant improvement in EDSS scores after treatment with sublingual lidocaine.

[0122] Example 23: Diabetic Polyneuropathy A 72-year-old woman with diabetes mellitus was diagnosed with diabetic polyneuropathy. She suffered from symmetric tingling in the hands and feet and loss of muscle strength in the hands. Medications: intermediate-acting insulin 2 × 12 U / day and metformin 3 × 500 mg / day.

[0123] Physical examination revealed paresthesias and loss of sensation in the hands and feet, and loss of strength in both the finger flexors and hand extensors (MRC 4 / 5). The patient was treated with sublingual lipophilic lidocaine base 4 × 100 mg / day (5 g xylocaine spray in a 50 ml metered-dose spray bottle). The patient held the lidocaine solution in their mouth for up to 15 minutes, after which they swallowed the solution as intended.

[0124] After a few days, the tingling sensation in the hands and feet completely disappeared, and after three months, the muscle strength in the hands improved significantly. This treatment resulted in a clinically significant improvement in diabetic polyneuropathy.

[0125] Example 24: Myasthenia gravis A 36-year-old man was diagnosed with myasthenia gravis. He suffered from arm and hand weakness after physical activity. The diagnosis was confirmed by EMG and a positive test for antibodies to the acetylcholine receptor (AChR). He was treated with an oral anticholinesterase drug (mestinon) at 4 × 60 mg / day. During an influenza A virus infection, the patient developed severe weakness in his arms and hands, and anticholinesterase treatment was no longer effective. The patient was treated with sublingual lipophilic lidocaine base at 4 × 100 mg / day (5 g xylocaine spray in a 50 ml metered-dose spray bottle). The patient held the lidocaine solution in his mouth for up to 15 minutes and then swallowed the solution as intended. Within 4 hours, his arm and hand weakness significantly improved. Furthermore, the symptoms of influenza A virus infection almost completely resolved. Treatment was continued for 2 weeks. This treatment resulted in a clinically significant improvement in muscle weakness during the exacerbation of myasthenia gravis symptoms.

[0126] Example 25: Chronic Obstructive Pulmonary Disease (COPD) A 67-year-old woman was diagnosed with COPD. The diagnosis was confirmed by a spirometry test that revealed an FEV1 of 72% (moderate COPD). A chest x-ray and routine blood tests were unremarkable. The patient was treated with beclomethasone 2 × 40 μg / day. Over the next 6 years, she experienced progressive shortness of breath during exercise, such as climbing stairs at home and cycling. Daily activities were severely affected by the condition. The FEV1 decreased to 60%. The patient was treated with sublingual lipophilic lidocaine base 4 × 100 mg / day (5 g xylocaine spray in a 50 ml metered-dose spray bottle). The patient held the lidocaine solution in her mouth for up to 15 minutes and then swallowed the solution as intended. Within 1 week, she improved and was able to climb stairs and ride a bicycle without shortness of breath. After 3 months, repeat spirometry showed that FEV1 had improved to 84% (mild COPD). Lidocaine treatment relieved COPD symptoms.

[0127] Example 26: Graves' disease A 50-year-old woman was diagnosed with Graves' disease several years ago. Her hyperthyroidism was treated and under control, but her ocular symptoms remained evident. Until 1 year ago, she had received five steroid injections, but her eyes showed only short-term improvement. The final treatment option was surgical decompression of both orbits. The patient had not yet consented to this procedure due to diplopia as a possible side effect. Before applying lidocaine cream to the eyelids, the ocular condition of both eyes was as follows: conjunctival redness; moderate, non-fluid periorbital swelling; no eyelid erythema; and no signs or symptoms of optic neuropathy or corneal exposure. Application of 5% xylocaine ointment to the eyelids three times daily significantly improved the conjunctival redness and periorbital swelling. This treatment resulted in a clinically significant improvement in disease symptoms.

[0128] Example 27: Ulcerative colitis A 40-year-old woman was diagnosed with ulcerative colitis 5 years ago. Symptoms included episodes of abdominal pain, bloody diarrhea with mucus, anemia, and weight loss. Routine blood tests were unremarkable, except for anemia. CT scan showed approximately 8 mm of wall thickening in several segments of the colon. Colonoscopy showed segmental colonic inflammation with erythema, loss of normal vascular pattern, granularity, erosions, hemorrhage, and ulcers. There was a clear demarcation between the inflamed and normal intestinal mucosa. No signs of dysplasia or malignant transformation were observed. Histopathology showed decreased crypt density, an irregular appearance of the mucosa, and diffuse inflammation. No granulomas were seen. In previous episodes of colitis exacerbations, the patient responded well to treatment with oral mesalamine CR at 3 × 400 mg / day. However, in this exacerbation episode, symptoms did not respond to mesalamine treatment. The patient was treated with sublingual lipophilic lidocaine base 4 x 100 mg / day (5 g xylocaine spray in a 50 ml metered-dose spray bottle). The patient held the lidocaine solution in her mouth for a maximum of 15 minutes, then swallowed the solution as intended. Symptoms gradually decreased over 48 hours and disappeared completely after 3 days. Sublingual lidocaine was continued for 2 weeks, and the patient remained symptom-free for several months thereafter. Lidocaine eradicated the symptoms of the disease.

[0129] Example 28: Inflammatory Bowel Disease A 1.5-year-old dog developed a small perianal fistula, oozing a white, opaque fluid from the opening. The fistula gradually increased in size, and the fistula began to emit a foul odor and develop diarrhea. The dog was in pain, especially during defecation. Physical examination revealed an extremely painful, inflamed perianal fistula. The dog was diagnosed with inflammatory bowel disease with perianal fistula. The veterinarian decided to surgically remove the anal sacs. After surgery, the disease progressed rapidly and the dog's suffering significantly increased. The dog was treated with lipophilic lidocaine base 4 x 100 mg / day (5 g xylocaine spray in a 50 ml metered-dose spray bottle) applied to the largest fistula. After one week, the oozing opaque fluid and foul odor disappeared. Pain during defecation also significantly decreased. The lining of the fistula began to form granulation tissue. Lidocaine relieved the symptoms and infection of the anal fistula.

[0130] Example 29: Allergic reaction to marching caterpillar venom A 33-year-old man accidentally ran over an oak marching caterpillar with his vehicle. He immediately developed an itchy rash on his arms, chest, face, and neck. After several minutes, he became short of breath. The patient was treated with 100 mg of sublingual lidocaine base (5 g xylocaine spray in a 50 ml metered-dose spray bottle). The patient held the lidocaine solution in his mouth for up to 15 minutes and then swallowed the solution as intended. Within 10 minutes, his symptoms began to improve. After 15 minutes, all respiratory symptoms had disappeared, and after 1 hour, the itchy skin rash had dramatically improved. Treatment was discontinued 48 hours later (4 × 100 mg / day), and symptoms did not recur. This treatment resulted in a clinically significant improvement in the allergic reaction to marching caterpillar venom.

[0131] Example 30: Rheumatoid arthritis A 62-year-old woman was diagnosed with rheumatoid arthritis of bilateral wrist and finger joints. She suffered from severe pain, swelling, and joint fever. Her ability to perform daily activities was significantly impaired, and she was almost completely dependent on others. Blood tests for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) were clearly positive. Her Clinical Disease Activity Index score for Rheumatoid Arthritis (Aletaha & Smolen, Clin. Exp. Rheumatol. 2005 Sep-Oct;23(5 Suppl. 39):S100-8) was 52 out of a total of 76, indicating high disease activity. The diagnosis was rheumatoid arthritis.

[0132] Treatment with disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and tocilizumab, did not improve symptoms, and the patient suffered from side effects. The patient was treated with sublingual lipophilic lidocaine base 4 × 100 mg / day (5 g xylocaine spray in a 50 ml metered-dose spray bottle). The patient held the lidocaine solution in their mouth for up to 15 minutes, after which they swallowed the solution as intended.

[0133] After four weeks, inflammation in the wrist and hand joints had almost completely disappeared. The patient still complained of stiffness in these joints. The Rheumatoid Arthritis Clinical Disease Activity Index score improved from 52 out of a total of 76 to 2, indicating remission. This treatment resulted in a clinically significant improvement in clinical disease activity after treatment with sublingual lidocaine in severe rheumatoid arthritis.

[0134] Example 31: Ischemic cardiomyopathy in patients with diabetes mellitus A 61-year-old man with a 15-year history of diabetes mellitus underwent stenting for triple-vessel disease 8 years ago, followed by coronary artery bypass graft (CABG) surgery. For the past 5 years, the patient had experienced recurrent chest pain, gradually increasing dyspnea at night and during exercise, and extreme fatigue. His blood pressure was 140 / 90 mmHg. He was diagnosed with ischemic cardiomyopathy. An estimated transthoracic echocardiogram showed an ejection fraction of 31%. The diagnosis was ischemic cardiomyopathy. The patient was not a candidate for surgery and requested treatment with lidocaine. The patient was treated with sublingual lipophilic lidocaine base 4 × 100 mg / day (5 g xylocaine spray in a 50 ml metered-dose spray bottle). The patient held the lidocaine solution in his mouth for up to 15 minutes, then swallowed the solution as intended. After 3 weeks, the patient reported a significant reduction in episodes of chest pain, a noticeable improvement in dyspnea, and a feeling of increased daytime energy. Three months later, a repeat transthoracic echocardiogram showed that the cardiac ejection fraction had improved from 31% to 42%. This procedure resulted in clinically significant improvement in symptoms and cardiac function in patients with severe ischemic cardiomyopathy.

[0135] Example 32: Acute low back pain in a patient with a history of polymyalgia rheumatica A 67-year-old man with a history of polymyalgia rheumatica was suffering from severe back pain. The previous day, he had cycled 45 km on a road bike with drop handlebars. Strong headwinds made the ride difficult for most of the trip.

[0136] The next morning, the patient woke up with severe back pain. The pain prevented her from straightening her back. She could only walk carefully in a very bent position and could barely climb stairs. The patient was treated with sublingual lipophilic lidocaine base 4 x 100 mg / day (5 g xylocaine spray in a 50 ml metered-dose spray bottle). The patient held the lidocaine solution in her mouth for 15 minutes and then swallowed the solution as intended. After 30 minutes, 95% of her symptoms had disappeared. The patient was able to resume a normal upright position and was able to walk and ascend and descend stairs without difficulty.

[0137] Example 33: Systemic lupus erythematosus (SLE) A 79-year-old man with confirmed SLE was referred to our hospital. He was 42 years old when he was diagnosed with SLE. Over time, he was regularly admitted for recurrent SLE-induced pericarditis, accompanied by pericardial effusion, peritonitis, and pleurisy. A few days before his referral, he began experiencing new episodes of peritonitis. He suffered from abdominal pain, nausea, and obvious abdominal distension due to ascites. The patient felt a lack of energy. Laboratory tests of the peritoneal fluid showed IL-6 11,000 pg / ml (serum IL-6 28 pg / ml) and LDH 102 IU / L. The patient was treated with sublingual lipophilic lidocaine base 4 × 100 mg / day (5 g xylocaine spray in a 50 ml metered-dose spray bottle). The patient held the lidocaine solution in his mouth for 15 minutes and then swallowed the solution as intended. Clinical symptoms resolved within 6 days, and abdominal distension completely resolved after 2 weeks. Treatment with sublingual lidocaine was continued.

[0138] Section A: P2X7R antagonists A. P2X7R-specific monoclonal antibodies B. Chemicals a. Amide derivatives i. Oxoprolinamide derivatives described in KR101398264B1 ii. Aminoamide group: lidocaine, articaine, bupivacaine, cinchocaine (dibucaine), etidocaine, levobupivacaine, lidocaine (lignocaine), mepivacaine, prilocaine, ropivacaine, trimecaine b. Amino ester derivatives i. Procaine, benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine (larocaine), piperocaine, propoxycaine, proparacaine, tetracaine (ametocaine) c. Phenyl-substituted 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine P2X7 antagonists d. Bicycloheteroaryl compounds as p2x7 modulators and their use (WO2007 / 109192) C. P2X7R inhibitors used in clinical trials and tested in humans a. CE-224,535 500 (Pfizer) b. AZD9056 (AstraZeneca) c. JNJ-54175446 (Johnson & Johnson) a. Mehta N, et al. Bioorg Med Chem, 2014 22 (1) 54-88. The existing P2XR inhibitors that are not selective for P2X7R alone are: PPADS tetrasodium salt, Brilliant Blue G (BBG), and oxidized ATP (o-ATP). b. Existing specific 2X7R inhibitors: KN-62, AZ9056, A-740003, A-438079, GSK314181A, A-804598, A-839977, and AZ-116453743 c. Classification based on parent structure, 181 compounds: adamantanamide derivatives, triazole derivatives, diarylimidazolidine derivatives, pyroglutamic acid amide derivatives, pyrazoleacetamide derivatives, dihydrodibenzo[a,g]quinolizinium derivatives, tetrazole derivatives, tyrosine-based derivatives, pyrazolodiazepine derivatives, imidazole derivatives, benzamide derivatives, KN62 analogue derivatives, natural antagonists of P2X7R d. Three P2X7R inhibitors from natural product extracts: massadin, stilisadin A, and stilisadin B a. 75 top-ranked compounds: C1 to C73 after virtual screening of approximately 100,000 structurally diverse compounds against the ATP-binding pocket in hP2X7R, P2X7R inhibitors published by Caseley EA, et al. Biochem Pharmacol 2016 (116) 130-139 b. Three of these compounds appeared to effectively inhibit transmembrane currents due to P2X7R activation and macropore formation (YO-PRO-1 uptake): C23, C40, and C60. AZ11645373, Brilliant Blue G, KN-62, calmidazolium and zinc 58368839, P2X7R inhibitors published by Bin Dayel A, et al. Mol Pharmacol 2019, 96 (3) 355-363 a. Existing P2XR inhibitors that are not selective for P2X7R alone, such as BBG, PPADS, suramin, and o-ATP, are P2X7R inhibitors published by North RA, et al. Physiol Rev 2002, 82, (4), 1013-67. b. Existing specific 2X7R inhibitors: A-438079, A-804598, A-740003.0, KN-62, AZ10606120, AZ11645373, GW791343, and JNJ47965567 d. Sluyter, Adv Exp Med Biol -Prot Rev 2017, (19) 17-53. The existing P2XR inhibitors that are not selective for P2X7R alone are: BBG, o-ATP, PPNDS, PPADS, MRS2159, NF279, and NF449. e. Existing specific 2X7R inhibitors: AACBA, AstraZeneca, A-438079, A-804598, A-740003.0, and KN-62 P2X7R inhibitors published by D. Carroll, et al. Purinergic signal 2009, 5, (1) 63-73 57 compounds: adamantanecarboxamides, arylcarbohydrazides, cyanoguanidines, aryltetrazoles / aryltriazoles P2X7R inhibitors published by E. Donnelly-Roberts DL, et al., Neuropharmacology 2009, 56, (1), 223-9 [3H]A-804598 ([3H]2-cyano-1-[(1S)-1-phenylethyl]-3-quinolin-5-ylguanidine) P2X7R inhibitors published by F. Ruiz-Ruiz q, et al., Front Mol Neurosci 2020, 13, 93 AZ11645373, AZD-9056, A-438079, A740003, CE-224,535, GSK-1482160, JNJ-47965567, A-804598, 2, JNJ-54175446, JNJ-55308942

[0139] Section B: Hyperinflammatory diseases - involving activation of P2X7R in the immune system 1. Autoimmune and immune-related diseases 2. Treatment-induced immune-related diseases 3. Infectious diseases 4. Cardiovascular and neurovascular diseases 5. Neuroinflammatory and neurodegenerative diseases 6. Epileptic disorders 7. Affective and psychiatric disorders 8. Fibrosis 9. Cancer-related disorders 10. Cancer and Neoplasms 11. Trauma and Post-Traumatic Syndrome 12. Post-transplant syndrome, including transplanted organ rejection

[0140] 1. Autoimmune and immune-related diseases Primary immunodeficiency Systemic inflammatory diseases: (1) Systemic Inflammatory Response Syndrome (SIRS) in Advanced Cancer, (2) Sepsis: a. Bacterial Sepsis: Pseudomonas, Staphylococcus, Streptococcus, b. Viral Sepsis and ARDS: Influenza A virus, SARS, MERS, COVID-19, etc., c. Severe Post-Splenectomy Sepsis: Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, d. Babesiosis: Babesia microti (USA), B. divergens (Europe), e. Meningococcemia with Sepsis and Meningitis: N. meningitidis, f. Rocky Mountain Spotted Fever (RMSF): Rickettsia rickettsiae, g. Purpura fulminans: S. pneumoniae, H. influenzae, N. meningitidis, h. Erythroderma, toxic shock syndrome: Group A Streptococcus, Staphylococcus aureus, i. Necrotizing fasciitis: Group A Streptococcus, mixed aerobic / anaerobic flora, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), j. Clostridial myonecrosis: Clostridium perfringens, k. Gas gangrene, (3) hyperinflammation and cytokine storm, (4) anaphylactic reactions including shock, (5) systemic allergic reactions, (6) systemic injury-inducing syndrome (SIRS), (7) acute postoperative (post-transplant) inflammation and SIRS. Endocrine disorders: (1) Type I and II diabetes, (2) Addison's disease, (3) autoimmune polyendocrine syndrome (APS) types 1, 2, and 3, (4) autoimmune pancreatitis (AIP), (5) autoimmune thyroiditis, (6) Ord's thyroiditis, (7) Graves' disease, (8) Hashimoto's thyroiditis, (9) autoimmune oophoritis, (10) endometriosis, (11) autoimmune orchitis, (12) Sjögren's syndrome, (13) osteoporosis, and (14) Paget's disease. Connective tissue diseases: (1) mixed connective tissue disease, (2) undifferentiated connective tissue disease, (3) steatosis dolorosa, (4) systemic lupus erythematosus (SLE), (5) drug-induced lupus, (6) adult-onset Still's disease, (7) CREST syndrome, (8) enterocolitis-associated arthritis, (9) eosinophilic fasciitis, (10) Felty syndrome, (11) IgG4-related disease, (12) Parry-Romberg syndrome, (13) Parsonage-Turner syndrome, (14) sarcoidosis, (15) Schnitzler syndrome, and (16) undifferentiated connective tissue disease (UCTD). Eye diseases: (1) diabetic retinopathy, (2) autoimmune retinopathy, (3) autoimmune uveitis, (4) moderate uveitis, (5) dry and wet age-related macular degeneration (AMD), (6) retinitis pigmentosa (RP), (7) lignified conjunctivitis, (8) Mooren's ulcer, (9) scleritis, and (10) sympathetic ophthalmia. Ear disorders: (1) Autoimmune inner ear disease (AIED). Pulmonary disease: (1) Asthma, (2) Allergic rhinitis, (3) Chronic obstructive pulmonary disease (COPD), and (4) Autoimmune inner ear disease (AIED). Gastrointestinal diseases: (1) drug-induced liver disease, (2) autoimmune hepatitis, (3) inflammatory bowel syndrome, (4) Crohn's disease, (5) ulcerative colitis, (6) irritable bowel syndrome, (7) microscopic colitis, (8) autoimmune enteropathy, (9) celiac disease, (10) gluten intolerance, (11) lactose intolerance, (12) Plummer-Vinson syndrome, (13) achalasia, and (14) idiopathic peritonitis. Muscle, bone and skin disorders: (1) Skin immune response after insect bites, (2) contact dermatitis, (3) polymyositis, (4) myositis, (5) dermatomyositis, (6) dermatitis of various causes, (7) inclusion body myositis, (8) fibromyalgia, (9) systemic sclerosis, (10) psoriasis, (11) alopecia areata, (12) autoimmune angioedema, (13) autoimmune progesterone dermatitis, (14) autoimmune urticaria, (15) Bullous pemphigoid, (16) cicatricial pemphigoid, (17) gestational pemphigoid, (18) dermatitis herpetiformis, (19) discoid lupus erythematosus, (20) epidermolysis bullosa acquisita, (21) erythema nodosum, (22) hidradenitis suppurativa, (23) lichen planus, (24) lichen sclerosus, (25) linear immunoglobulin A disease (LAD), (26) morphea, (27) pemphigus vulgaris, (28) pityriasis rubra: a. Pityriasis alba, b. Pityriasis alba lichenoides, c. Pityriasis rosea, d. Pityriasis areata, e. Pityriasis rubra pilaris, f. Pityriasis versicolor, g. Dandruff, historically called pityriasis capitis, h. Pityriasis amianthacea, i. Acute pityriasis lichenoides varioliformes (PLEVA), j. Mucha-Habermann disease, (29) Vitiligo, (30) Angioedema: a. Acquired angioedema, b. Hereditary angioedema, c. Antineurotic edema (Quincke's edema), (31) eczema, (32) rheumatoid arthritis, (33) chronic inflammation of the knee, hip, and spinal joints, (34) chronic spondyloarthropathy, (35) chronic osteochondritis and osteoarthritis, (36) juvenile arthritis, (37) ankylosing spondylitis, (38) psoriatic arthritis, (39) relapsing rheumatoid arthritis, (40) relapsing polychondritis, (41) polymyalgia rheumatica, and (42) antisynthetase syndrome. Genitourinary diseases: (1) chronic interstitial cystitis, (2) recurrent cystitis, (3) drug-induced nephropathy, (4) diabetic nephropathy, (5) nephrotic syndrome, (6) nephritic syndrome, (7) rapidly progressive glomerulonephritis, (8) acute renal failure, and (9) secondary renal dysfunction.

[0141] 2. Treatment-induced immune-related diseases (1) Radiation-induced encephalopathy, (2) Chemotherapy-related kidney damage: a. Complex renal cysts, b. Interstitial nephritis, c. Papillary necrosis, d. Renal infarction, e. Acute tubular necrosis, (3) Chemotherapy-related bladder damage: a. Chemotherapy-induced cystitis, b. Hemorrhagic cystitis, (4) Chemotherapy-related gastrointestinal damage: a. Stomatitis, b. Pharyngitis, c. Esophagopharyngitis, d. Mucositis, e. Oral and anal inflammation or ulcers, f. Intestinal necrosis, g. Gastrointestinal ulcers, h. Enteritis, i. Pancreatitis, j. Acute hepatitis.

[0142] 3. Infectious diseases Viral diseases: Hepatitis A, B, C, and D (HAV, HBV, HCV, and HDV); human retroviruses; human immunodeficiency virus (HIV); HTLV-1; Abelson murine leukemia virus; Rous sarcoma virus; Zika virus (ZiKV); influenza A and B viruses (IAV and IBV); coronaviruses: MERS, SARS, SARS-CoV-2; rhinovirus; human respiratory syncytial virus; adenovirus; enterovirus; human metapneumovirus; herpes simplex or varicella-zoster encephalitis; herpes simplex or varicella-zoster dermatitis; herpesviruses 6, 7, and 8 types; Dengue virus; West Nile virus; Ebola virus and Marburg virus infections; Hendra virus; Nipah virus; Human papillomavirus (HPV); Epstein-Barr virus (EBV), infectious mononucleosis; Rubeola; Measles virus; Rubella; Mumps; Smallpox; Chickenpox; Yellow fever; Viral myocarditis; Viral hemorrhagic fever; Rabies; Hand, foot and mouth disease; Oral parapox virus; Molluscum contagiosum (scrub typhus); Norovirus; Cytomegalovirus (CMV); Condyloma acuminata; Parvovirus; Arthropod-borne and rodent-borne viral infections. Bacterial infection: Cat scratch disease; Tularemia; Donovanosis; Nocardiosis; Actinomycosis and Whipple's disease; Typhoid fever; Leptospirosis; Q fever; Brucellosis; Melioidosis; Echinococcosis (hydatid disease); Chronic osteomyelitis; Lyme disease (Borrelia burgdorferi); Tick-borne spotted fever; Tuberculosis; Buruli ulcer: Mycobacterium ulcerans; Cutaneous tuberculosis: M. tuberculosis; Leprosy: M. leprae; Helicobacter pylori; Schistosomiasis; Histoplasmosis; Entamoeba histolytica; Giardiasis; Filariasis; Visceral larval migration; Anthrax: Bacillus anthracis; Ulcer Tularemia; Francisella tularensis; Bubonic plague: Yersinia pestis; Chancroid: Haemophilus ducreyi; Primary syphilis: T. pallidum; Gonococcal infection; Syphilis; Treponematosis; Mycoplasma pneumoniae infection; Chlamydia infection; C. trachomatis infection; Meningitis, encephalitis and brain abscess; Bacterial meningitis; Brain abscess, suppurative intracranial infection; Cerebral malaria: Plasmodium falciparum; Spinal epidural abscess; Japanese encephalitis; Erysipelas cellulitis; Folliculitis; Myositis and myonecrosis; Tetanus; Legionella infection; Infectious gastroenteritis; Pneumonia; Acute respiratory distress syndrome (ARDS); Lung abscess; Infective endocarditis. fungal infection: mycosis Coccidioidomycosis; histoplasmosis; blastomycosis; phaeohyphomycosis; penicillinosis; sporotrichosis; paracoccidioidomycosis; candidiasis; aspergillosis; cryptococcosis; mucormycosis (zygomycosis); scedosporiosis; trichosporonosis; fusariosis; pneumocystosis. Protozoan infection: Entamoeba histolytica; malaria: Plasmodium falciparum; babesiosis; leishmaniasis; Chagas disease and African trypanosomiasis; toxoplasmosis; trichomoniasis. Helminth infections.

[0143] 4. Cardiovascular and neurovascular diseases Cerebral: (1) Cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL), (2) Ischemic stroke, (3) Aneurysmal subarachnoid hemorrhage, (4) Cerebral ischemia after subarachnoid hemorrhage, (5) Cerebral vasospasm: atherosclerosis; systemic arterial hypertension; pulmonary hypertension; deep vein thrombosis and pulmonary embolism; Heart: (1) Angina pectoris, (2) Myocardial ischemia, (3) Myocardial infarction, (4) Myocardial stunning, myocardial hibernation, (5) Postischemic myocardial dysfunction, (6) Ischemic cardiomyopathy, (7) Atrial and ventricular arrhythmias including atrial fibrillation, (8) Postmyocardial infarction syndrome, (9) Postpericardiotomy syndrome, (10) Pericarditis, (11) Myocarditis, (12) Rheumatic fever, (13) Cardiac complications after brain injury: a. Stress cardiomyopathy, b. Broken heart syndrome, c. Cardiac dysfunction and arrhythmias after subarachnoid hemorrhage, d. Cardiac dysfunction and arrhythmias after traumatic brain injury.

[0144] 5. Neuroinflammatory and neurodegenerative diseases Alzheimer's disease; Parkinson's disease; Huntington's disease; Extrapyramidal symptoms: (1) acute dystonic reaction, (2) upward eye movement attacks, (3) akathisia, (4) pseudoparkinsonism, (5) tardive dyskinesia, Sydenham chorea; acute disseminated encephalomyelitis (ADEM); Hashimoto's encephalopathy; Bickerstaff's encephalitis; anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis; spinocerebellar ataxia; Susac syndrome; Tolosa-Hunt syndrome; Meniere's disease; multiple sclerosis; idiopathic inflammatory demyelinating diseases; transverse myelitis; neuromyelitis optica (Devic's disease); optic neuritis; Baroconcentric sclerosis; Acquired neurological disorders: a. chronic secondary polyneuropathy, b. chronic inflammatory demyelinating polyneuropathy (CIDP), c. progressive inflammatory neuropathy, d. Guillain-Barré syndrome, e. Critical illness polyneuropathies, f. Acute and chronic motor axonal neuropathy; Hereditary neuropathies: a. Charcot-Marie-Tooth disease types 1, 2 and 3, b. Hereditary neurogic amyotrophy; Myotonic dystrophy types I and II; Amyotrophic lateral sclerosis (ALS); Neurogic amyotrophy (Parsonage-Turner syndrome); Neuromyotonia; Myasthenia gravis; Restless legs syndrome; Stiff person syndrome.

[0145] 6. Epileptic disorders Generalized epileptic seizures (grand mal seizures) including status epilepticus;Focal epileptic seizures: a. Frontal lobe epilepsy, b. Temporal lobe epilepsy, c. Benign rolandic epilepsy, d. Benign occipital epilepsy of childhood;Autosomal dominant nocturnal frontal lobe epilepsy;Childhood absence epilepsy;Dravet syndrome;Epilepsy in mentally retarded women;Juvenile myoclonic epilepsy;Lennox-Gastaut syndrome;Febrile infection-associated epilepsy syndrome;West syndrome;Taihara syndrome;Reflex epilepsy;Progressive myoclonic epilepsy;Rasmussen encephalitis.

[0146] 7. Affective and psychiatric disorders Schizophrenia; depression; bipolar disorder; occupational burnout; pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS); attention deficit hyperactivity disorder; post-traumatic stress disorder; fibromyalgia.

[0147] 8. Fibrosis Primary fibrosis: Interstitial pulmonary fibrosis (ILD); retroperitoneal fibrosis; primary biliary cholangitis (primary biliary cirrhosis or primary liver cirrhosis). Disease-induced fibrosis: Secondary pulmonary fibrosis; secondary inflammation due to cystic fibrosis; primary sclerosing cholangitis; interstitial bladder fibrosis; secondary cirrhosis: a. alcoholic cirrhosis, b. hepatitis C-induced cirrhosis, c. human immunodeficiency virus-induced cirrhosis, d. metastatic carcinomatous cirrhosis. Cancer-induced fibrosis: fibrosis formation induced by cancer. Tumor pseudoprogression: Treatment induces fibrosis that mimics tumor progression, especially in neuroendocrine tumors. Treatment-induced fibrosis: Fibrosis induced by medical, surgical, or radiation treatment, i.e., peritoneal fibrosis after laparotomy with or without ileus; fibrosis after organ transplantation; chemotherapy-induced chronic gastrointestinal fibrosis.

[0148] 9. Paraneoplastic syndromes: Paraneoplastic cerebellar degeneration; Lambert-Eaton myasthenic syndrome; Paraneoplastic cerebellar degeneration; Encephalomyelitis, limbic encephalitis; Brainstem encephalitis; Opsoclonus-myoclonus ataxia syndrome; Anti-NMDA receptor encephalitis; Polymyositis; Acanthosis nigricans; Dermatomyositis; Laser-Troller sign; Necrolytic erythema migrans; Sweet's syndrome; Erythematous skin papillomatosis; Pyoderma gangrenosum; Acquired generalized hypertrichosis.

[0149] 10. Cancer and Neoplasms Immune-related and neoplastic hematological disorders: Aplastic anemia; antiphospholipid syndrome (APS, APLS); thrombotic thrombocytopenic purpura (TTP); idiopathic thrombocytopenic purpura (ITP); autoimmune hemolytic anemia; autoimmune lymphoproliferative syndrome; autoimmune neutropenia; cold agglutinin disease; essential mixed cryoglobulinemia; Evans syndrome; pernicious anemia; pure red cell aplasia; thrombocytopenia; lymphangitis carcinomatosa; myelodysplastic / myeloproliferative neoplasms (MPN / MPD): (1) polycythemia vera, (2) essential thrombocythemia, (3) primary myelofibrosis, (4) fibrous myelofibrosis, (5) lymphoma: a. non-Hodgkin's lymphoma, b. childhood non-Hodgkin's lymphoma (Burkitt lymphoma), c. Hodgkin's disease, d. cutaneous lymphoma, e. Waldenstrom's macroglobulinemia, f. Multiple myeloma (Kohler's disease), g. Primary cerebral lymphoma, (6) Leukemia: a. Acute myeloid leukemia, b. Chronic myeloid leukemia, c. Acute lymphocytic leukemia, d. Chronic lymphocytic leukemia, (6) Unclassifiable MPN / MPD. Solid tumors: A. Neuroendocrine tumors (NETs) (1) Pituitary gland: NETs of the anterior pituitary gland, (2) Thyroid gland: Neuroendocrine thyroid tumors and medullary carcinoma, (3) Parathyroid NETs, ​​(4) Thymic and mediastinal carcinoid tumors, (5) Lung NETs: a. Bronchial NETs, ​​b. Pulmonary carcinoid tumors: Typical and atypical carcinoids, c. Small cell lung cancer (SCLC), d. Large cell neuroendocrine carcinoma of the lung (LCNEC), e. Extrapulmonary small cell carcinoma (ESCC or EPSCC), (6) Gastroenteropancreatic neuroendocrine tumors (GEP-NETs): a. Foregut NETs (stomach, proximal duodenum, thymus, lung, and bronchus), b. Pancreatic NETs, ​​c. Midgut GEP-NETs (distal half of the second part of the duodenum to the proximal two-thirds of the transverse colon), appendix NETs, ​​e. Hindgut NETs, ​​(7) Liver and gallbladder NETs, ​​(8) Adrenal tumors and adrenal medullary tumors, (9), (10) Pheochromocytoma, (11) Peripheral nervous system NETs: a. Schwannoma, b. Paraganglioma, c. Neuroblastoma, (12) Breast NETs, ​​(13) Genitourinary tract NETs: a. Urinary tract carcinoid tumors and neuroendocrine carcinomas, b. Ovarian NETs, ​​c. Cervical NETs, ​​d. Prostate NETs, ​​e. Testicular NETs, ​​(14) Merkel cell carcinoma (trabecular carcinoma) of the skin, (15) Hereditary NETs: a. Multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2), b. von Hippel-Lindau (VHL) disease, c. Neurofibromatosis type 1 and type 2, d. Schwannomatosis, e. Tuberous sclerosis, f. Carney complex (LAMB or NAME syndrome). B. Central nervous system tumors (1) Brain and spinal cord tumors: a. metastatic brain tumor, b. pilocytic astrocytoma, c. glioma, d. glioblastoma multiforme (GBM), e. oligodendroglioma, f. ependymoma, g. medulloblastoma, h. meningeal tumor, i. meningioma, j. metastatic meningeal carcinomatosis. C. Oropharyngeal tumors: Benign tumors: eosinophilic granuloma, fibroma, granular cell tumor, keratoacanthoma, leiomyoma, osteochondroma, lipoma, schwannoma, neurofibroma, papilloma, condyloma acuminata, verrucous xanthomas, pyogenic granuloma, rhabdomyoma, odontogenic tumors, precancerous lesions, leukoplakia, erythroplakia, erythroleukoplakia, malignant tumors, squamous cell carcinoma, verrucous carcinoma, minor salivary gland carcinoma, lymphoma. D. Laryngeal cancer Cancer of the paranasal sinuses and nasal cavity, nasopharyngeal carcinoma, teratoma, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, salivary gland carcinoma, thyroid carcinoma: a. papillary thyroid carcinoma, b. noninvasive follicular thyroid tumor with papillary nuclear features, c. follicular thyroid carcinoma, c. poorly differentiated thyroid carcinoma, d. anaplastic thyroid carcinoma, e. thyroid lymphoma, f. thyroid squamous cell carcinoma, g. sarcoma of the thyroid, h. Hürthle cell carcinoma. E. Skin cancer Basal cell carcinoma, squamous cell carcinoma, malignant melanoma, Kaposi's sarcoma. F. Vascular cancer Hemangiosarcoma, epithelioid hemangioendothelioma, hemangiopericytoma, lymphangiosarcoma, kaposiform hemangioendothelioma (KHE), infantile hemangioma, congenital hemangioma, hemangioblastoma, pyogenic granuloma, tufted hemangioma, glomus tumor. G. Muscle and bone tumors Leiomyoma, leiomyosarcoma, smooth muscle tumor of unknown malignancy (STUMP), metastatic tumor, osteosarcoma, chondrosarcoma, Ewing's sarcoma, fibrosarcoma, undifferentiated pleomorphic sarcoma, teratoma, osteoma, osteoid osteoma, osteochondroma, osteoblastoma, enchondroma, giant cell tumor of bone, aneurysmal bone cyst. H. Breast cancer Metastatic tumors, invasive ductal carcinoma, invasive lobular carcinoma, tubular carcinoma, mucinous (colloid) carcinoma, carcinoma with medullary features, invasive papillary carcinoma, breast lymphoma, breast sarcoma. I. Lung tumors Metastatic tumors, bronchial leiomyoma, primary lung cancer: a. small cell lung cancer (SCLC), b. non-small cell lung cancer (NSLC), c. pleuropulmonary blastoma, d. pulmonary lymphoma, e. pulmonary sarcoma, f. mediastinal tumor, g. pleural tumor, h. malignant mesothelioma, j. pleural sarcoma, k. pleural angiosarcoma, l. pleural desmoplastic small round cell tumor (DSRCT), m. pleural synovial sarcoma, n. solitary fibrous tumor of the pleura (SFT), o. pleural smooth muscle tumor, p. pleural carcinoma, q. pleural mucoepidermoid carcinoma, r. pleural pseudomesothelial adenocarcinoma, s. pleural calcifying fibrous pseudotumor. J. Gastrointestinal tumors (1) Krukenberg tumor (metastatic tumor): (2) Esophageal cancer, a. squamous cell carcinoma (ESCC), b. esophageal adenocarcinoma (EAC), c. Barrett's esophagus, d. gastric cancer, e. gastric adenocarcinoma, f. signet ring cell carcinoma, g. gastric lymphoma, h. extranodal marginal zone B-cell lymphoma (MALT lymphoma), (2) Carcinoid: a. duodenal adenocarcinoma, b. appendix, c. carcinoid, (3) Pseudomyxoma peritonei: a. colorectal tumor, (4) Colorectal polyp: a. adenoma, b. hyperplasia, c. juvenile, d. sessile serrated adenoma, e. traditional serrated adenoma, f. Peutz-Jeghers syndrome, (5) Cronkhite-Canada syndrome, (6) Polyposis syndrome: a. Juvenile MUTYH-associated familial adenomatous and serrated polyposis, (7) adenocarcinoma, (8) familial adenomatous polyposis, (10) hereditary nonpolyposis colorectal cancer, (11) anal tumors: squamous cell carcinoma, (12) liver cancer, (13) metastatic tumors, (14) hepatocellular carcinoma, (15) hepatoblastoma, (16) hepatocellular adenoma, (17) cavernous hemangioma, (18) focal nodular hyperplasia, (19) nodular regenerative hyperplasia, (20) gallbladder carcinoma, (21) cholangiocarcinoma, (22) Klatzkin tumor, (23) gallbladder adenocarcinoma, (24) pancreatic cancer, (25) exocrine tumors: a. adenocarcinoma, b. pancreatic ductal adenocarcinoma, (26) cystic tumors: a. serous microcystic adenoma, b. intraductal papillary mucinous neoplasm, c. Mucinous cystic tumor, d. Solid pseudopapillary tumor, e. Pancreatoblastoma, (27) Endocrine PanNET: a. MALT lymphoma, b. Peritoneal tumor, (28) Metastatic peritonitis carcinomatosis. K. Genitourinary cancer (1) Renal tumor: a. Metastatic tumor, b. Renal cell carcinoma (RCC): b1. Clear cell RCC, b2. Papillary RCC, b. Chromophobe RCC, b4. Collecting tubule RCC, c. Clear cell sarcoma, d. Mesodermal nephroma, e. Wilms tumor (nephroblastoma), f. Renal oncocytoma, g. Cystic nephroma, h. Angiomyolipoma, i. Metanephric adenoma, j. Renal medullary fibroma, (2) Ureteral carcinoma: a. Transitional cell carcinoma, b. Ureteral tumor, (3) Bladder tumor: a. Metastatic tumor, b. Papillary transitional cell carcinoma, c. Non-papillary transitional cell carcinoma, d. Squamous cell carcinoma, e. Adenocarcinoma, f. Sarcoma, g. Small cell carcinoma, (4) Ovarian tumor, a. Malignant ovarian cancer: A1. Epithelial cancer, A2. Germ cell cancer, A3. Stromal carcinoma, b. Benign: b1. Surface epithelial tumor, b2. Stromal tumor, b3. Germ cell tumor, (5) Uterine tumors: a. Uterine fibroids or leiomyoma, (6) Cervical tumors: a. Cervical carcinoma, a1. Squamous cell carcinoma, a2. Adenocarcinoma, a3. Adenosquamous carcinoma, a4. Small cell carcinoma, a5. Neuroendocrine tumor, a6. Ground glass cell carcinoma, a7. Chorioadenocarcinoma, b. Cervical intraepithelial neoplasia, (7) Testicular tumors: a. Germ cell tumors: a1. Intratubular germ cell tumor, a2. Seminoma, a3. Spermatocyte tumor, a4. Embryonal carcinoma, a5. Yolk sac tumor, b. Trophoblastic tumor: b1. Choriocarcinoma, b2. Monophasic choriocarcinoma, b3. Placental site trophoblastic tumor, b4. Cystic trophoblastic tumor, c. Teratoma: c1. Dermoid cyst, c2. Epidermoid cyst, c3. Monodermal teratoma (carcinoid), c4. Primitive neuroectodermal tumor (PNET), c5. Nephroblastoma-like tumor, c6. Teratoma with somatic malignancy, d. Sex cord-gonadal stromal tumor: d1. Leydig cell tumor, d2. Sertoli cell tumor, d3. Lipid-rich variant, d4. Sclerosing variant, d5. Large cell calcifying variant, d6. Intratubular Sertoli cell tumor in Peutz-Jeghers syndrome, d7. Granulosa cell tumor, d8. Adult type, d9. Juvenile type, d10. Tecoma fibroma group, d11. Tecoma, d12. Fibroma, d13. Poorly differentiated tumor, d14. Mixed tumors, e. Mixed germ cell and sex cord / gonadal stromal tumors: e1. Gonadoblastoma, e2. Germ cell-sex cord / gonadal stromal tumor, unclassified, f. Other tumors of the testis: f1. Lymphomas: f1a. Primary testicular diffuse large B-cell lymphoma, f1b. Mantle cell lymphoma of the testis, f1c.Testicular extranodal marginal zone B-cell lymphoma, f1d. Extranodal NK / T-cell lymphoma, nasal type, f1e. Testicular peripheral T-cell lymphoma, f1f. Testicular activin receptor-like kinase-1-negative anaplastic large cell lymphoma, f1g. Testicular pediatric-type follicular lymphoma, f2. Carcinoid, f3. Ovarian epithelial tumors: f3a. Borderline serous tumors, f3b. Serous carcinoma, f3c. Well-differentiated endometrioid tumors, f3d. Mucinous cystadenoma, f3e. Mucinous cystadenocarcinoma, f3f. Brenner tumor, f4. Nephroblastoma, f5. Paraganglioma, g. Hematopoietic tumors, h. Tumors of the collecting duct and retina: h1. Adenoma, h2. Carcinoma, i. Tumors of paratesticular structures: i1. adenomatous tumors, i2. malignant and benign mesothelioma, i3. adenocarcinoma of the epididymis, i4. papillary cystadenoma of the epididymis, i5. melanotic neuroectodermal tumor, i6. desmoplastic small round cell tumor, j. Mesenchymal tumors of the spermatic cord and testicular appendages: j1. lipoma, J2. liposarcoma, j3. rhabdomyosarcoma, j4. advanced angiomyxoma, j5. angiomyofibroblastoid tumor (see myxoma), j6. fibromatosis, j7. fibroma, j8. solitary fibrous tumor, j9. other, k. secondary tumors of the testis, (8) urethral carcinomas: a. transitional cell carcinoma, b. squamous cell carcinoma, c. adenocarcinoma, d. melanoma, e. prostate tumor, f. metastatic prostate tumor, g. Benign prostatic hyperplasia, i. prostate cancer, (9) penile tumors: a. phimosis, b. penile cancer. L. Retroperitoneal tumor (1) Solid tumors: a. metastatic tumor, b. fibroma, fibrosarcoma, malignant fibrous histiocytoma, c. lipoma, liposarcoma, d. leiomyoma, leiomyosarcoma, e. desmoid tumor, e. ganglioneuroma, ganglioneuronoblastoma, f. schwannoma, neurofibroma, g. extragonadal germ cell tumor, h. lymphoma, i. lymphadenopathy, (2) Cystic tumors: a. cystic lymphangioma, b. cystic teratoma, c. cystadenoma, cystadenocarcinoma, d. cystic mesothelioma, e. epidermoid cyst, f. Tarlov cyst (perineural cyst).

[0150] 11. Trauma and Post-Traumatic Syndrome (1) traumatic subarachnoid hemorrhage, (2) head trauma including severe traumatic head injury, (3) cerebral ischemia after traumatic brain injury, (4) polytrauma state, and (5) post-traumatic epileptic seizures.

[0151] 12. Inflammation after organ transplants such as lung, kidney, heart, and liver transplants (1) Acute immune response after organ transplantation, (2) Chronic organ tissue rejection by the host, and (3) fibrosis after organ transplantation.

Claims

1. 1. A medicament comprising lidocaine for the systemic treatment of distal hyperinflammatory syndrome in a mammalian patient by primary lymph node targeted administration of lidocaine in the mammalian patient until the concentration of lidocaine in the primary target lymph node exceeds the maximum tolerated plasma level of the mammal, Lidocaine is delivered directly from the administration site to the lymph nodes, the route of administration is invasive administration selected from intradermal, subcutaneous including subdermal, in which lidocaine is administered in a hydrophilic form; The administration twice-daily administration of bolus doses containing at least 4.7 mg of lidocaine, and Continuous infusion of a dose containing at least 1 mg of lidocaine per kg of body weight per hour Selected from A medicament wherein the lidocaine is administered in a liquid medium containing at least 1% w / v lidocaine.

2. 2. The method of claim 1, wherein the hydrophilic form of lidocaine is in the form of a water-soluble pharmaceutically acceptable salt.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the administration is in an immediate release or sustained release dosage form.

4. 10. The method of claim 1, wherein the bolus dose comprises at least 23.5 mg of lidocaine.

5. The method of claim 4, wherein the bolus is administered 2 to 10 times daily.

6. The method of any one of claims 1 to 5, wherein the lidocaine is administered in a liquid medium containing at least 5% w / v lidocaine.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the hyperinflammatory syndrome is a disease selected from the group consisting of COVID-19, sepsis, polymyalgia rheumatica, psoriatic arthritis, spondyloarthropathy, chronic interstitial cystitis, chronic inflammatory bladder conditions, knee arthropathy, multiple sclerosis, systemic inflammatory response syndrome (SIRS) and renal dysfunction, amyotrophic lateral sclerosis, Alzheimer's disease, idiopathic Parkinson's disease, diabetic polyneuropathy, myasthenia gravis, chronic obstructive pulmonary disease (COPD), Graves' disease, ulcerative colitis, inflammatory bowel disease, allergic reaction to marching caterpillar venom, rheumatoid arthritis, ischemic cardiomyopathy in patients with diabetes mellitus, acute lower back pain, and systemic lupus erythematosus (SLE).

8. The pharmaceutical composition of claim 7, wherein the hyperinflammatory syndrome includes dyspnea associated with viral infection, bacterial infection, cancer, chronic obstructive pulmonary disease (COPD), asthma, allergy, and chemotherapy.

9. The pharmaceutical composition of claim 8, wherein the viral infection is caused by a virus selected from the group consisting of coronavirus; influenza; Ebola; respiratory syncytial virus; and HIV.

10. 2. The method of claim 1, wherein the treatment comprises invasive administration of lidocaine in its water-soluble salt form, the invasive administration being by continuous intradermal or subdermal injection.

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