Nmdar antagonist for the treatment of inflammatory diseases in patients with depression comorbidity

Abstract

This invention provides a method of treating a subject with inflammatory disease and suffering from depression as a co-morbidity, the method comprising administering an NMDAR antagonist to said subject, and in some aspects, the invention provides a composition comprising an NMDAR antagonist and at least one agent selected from the group consisting of: an antiinflammatory agent, an anxiolytic agent and a mood stabilizing agent, or any combination thereof for use in treating a subject suffering from, or for example, treating a lung disease or disorder and also suffering from depression, as a comorbidity. The NMDAR antagonist is preferably D-cycloserine (DCS).

Description

NMDAR ANTAGONIST FOR THE TREATMENT OF INFLAMMATORY DISEASES IN PATIENTS WITH DEPRESSION COMORBIDITYFIELD OF THE INVENTION

[0001] The present invention relates to the use of N-methyl-D-aspartate type glutamate receptor (NMDAR) antagonists for the treatment of patients with inflammatory diseases, including, in particular, respiratory disease or endometriosis and experiencing depression as a comorbidity. In particular, this invention relates to the treatment of patients suffering from inflammatory disease, who are also suffering from depression, with the use of the partial NMDAR agonist, D-cycloserine at a dosage of at least 150 mg / day. In still further aspects, in particular, this invention relates to the treatment of patients suffering from respiratory disease, such as, for example, COPD, or patients suffering from CO VID- 19 or post-COVID-19, or endometriosis who are also suffering from depression, or suffering from acute stress disorder or suffering from post-traumatic stress disorder, with the use of the partial NMDAR agonist, D-cycloserine at a dosage of at least 150 mg / day.BACKGROUND OF THE INVENTION

[0002] Prolonged lung disease, inflammation and respiratory dysfunction are often accompanied by depression.

[0003] For example, chronic obstructive pulmonary disease (COPD) is a multicomponent slowly developing incurable disorder affecting about 10% of persons over 45 years of age. Depression affects -40% of COPD patients while global estimates of dysthimia and major depressive disorder range between 2 and 6%.

[0004] One in four individuals with COPD-depression comorbidity will experience an unfavorable illness course, depression being associated with increased physical disability and hospital readmission risk, impaired quality of life, etc.

[0005] Some reports suggest that low-grade inflammation may mediate the association of depressive symptoms and pulmonary dysfunction and increased inflammatory markers have been found to be expressed in both late -life depression and COPD.

[0006] Use of SSRIs and SNRIs in treating depression in COPD patients remains controversial and some studies have shown a higher risk of hospitalization, emergency care visits, COPD or pneumonia related mortality and all -cause mortality, in COPD patients receiving SSRIs and SNRIs.

[0007] SSRIs and SNRIs have known effects in inducing sleepiness in patients, which in particular in depressed patients suffering from respiratory disease may further negatively impact upon patients by, among other factors, leading to decreased oxygen and increased carbon dioxide levels and thereby COPD / respiratory disease exacerbation.

[0008] Other lung disease / depression comorbidities have been reported, as well. Dyspnea prevalence ranges from 42-66% at 60-100 day post-acute COVID-19 follow up and clinically predicted depression and anxiety were reported in 30-40% of patients following CO VID- 19. Thus, addressing depression and respiratory disease co-morbidity is of critical need.

[0009] NMD AR are a type of receptor for the excitatory neurotransmitter glutamate. NMD AR contain additional modulatory sites, including the following: glycine binding site, polyamine binding site, redox site, zinc (Zn) site, phosphorylation sites, post-synaptic membrane docking sites and proteinprotein interaction sites.

[0010] The role of the cation channel NMD A glutamatergic receptors (NMD AR) is well characterized in the central nervous system, but their characterization in other tissues is less developed. NMD AR are widely expressed in lung and heart tissue in general and are associated with inflammatory cells. In pathologic instances of NMD AR up-regulation, enzyme and proinflammatory pathway activation and ultimately tissue damage and organ destruction has been described.

[0011] D-cycloserine (DCS), is a bacteriostatic antibiotic used since the 1950’s in tuberculosis. At therapeutic dosages D-cycloserine acts also as a NMDAR-glycine site functional antagonist and has antidepressant effects. DCS has been reported to be potentially effective for the treatment of depression, and studies by the inventor have shown that high doses of DCS are required.

[0012] Although use of DCS in the treatment of various neurological and psychiatric conditions such as Alzheimer’s disease, schizophrenia, depression, and anxiety disorders has been described, most of the data is still preliminary, with very heterogeneous effects reported and therefore, it remains unclear whether DCS can play a definitive role in treating neuropsychiatric diseases in general.

[0013] DCS has been used as an anti-bacterial agent, in the treatment of lung infection has been evaluated, for example in tuberculosis therapy since the late 1950s.

[0014] There remains a need for the development of an appropriate therapeutic regimen for the treatment of patients with inflammatory disease, and in particular, for treating respiratory disease and depression as co-morbidities, which to date has not been addressed.SUMMARY OF THE INVENTION

[0015] This invention provides a method of treating patients with an inflammatory disease and suffering from depression, and in other aspects, this invention provides a method of mitigating the severity of, mitigating the pathogenesis of or lowering the incidence of inflammatory disease and depression in patients with such co-morbidity. The method comprises administering an NMD AR partial agonist / antagonist to the subject in need thereof.

[0016] In some aspects, the invention specifically provides combinations, compositions, kits and methods for treating patients with an inflammatory disease and suffering from depression as a comorbidity, wherein in certain aspects, the combinations, compositions, kits and methods specifically treat, mitigate or abrogate pain in the patients.

[0017] According to this aspect, and in some embodiments, the invention specifically takes into consideration that NMDAR is extensively distributed in various inflamed tissue, in particular, in inflamed mucosal tissue, including, in some aspects, immune cells involved in the inflammatory response, such as monocytes, macrophages, and others, which represent targets for the combinations / compositions / kits / treatments as herein described.

[0018] In some aspects, the co-morbid subject having depression and an inflammatory disease, includes inflammatory diseases of any tissue, including in the respiratory tract, gastrointestinal tract, skin and / or reproductive tissue. In some aspects, the co-morbid subject having depression and an inflammatory disease, includes inflammatory diseases such as cardiovascular disease, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), rheumatoid arthritis, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, irritable bowel syndrome, Crohn’s disease, leaky gut, diabetes type 1 and / or 2, obesity and metabolic syndrome, endometriosis, chronic gingival inflammation and others.

[0019] This invention provides a method of treating patients with respiratory disease and suffering from depression, and in other aspects, this invention provides a method of mitigating the severity of, delaying the onset of, preventing the onset of, mitigating the pathogenesis of or lowering the incidence of respiratory disease and depression in patients with such co-morbidity. The method comprises administering an NMDAR antagonist to the subject in need thereof.

[0020] In some aspects NMDAR over-activation occurs in tissue inflammation, including lung inflammation and injury, which in turn may exacerbate tissue injury and inflammation, in particular, lung injury and inflammation.

[0021] According to this aspect, and in some embodiments, the invention specifically takes into consideration that NMDARs are extensively distributed in inflamed tissue of various sources,including inflamed mucosal tissue, and including but not limited to inflamed lung tissue, for example, alveolar type II cells, alveolar macrophages, and airway epithelial cells, which represent targets for the treatments as herein described.

[0022] This invention is directed to the finding that NMDAR antagonism can be therapeutically applied in chronic inflammatory states, including specifically chronic lung inflammatory states.

[0023] In some aspects, such chronic inflammatory states may include COPD, and CO VID and other related diseases / disorders, including, in some aspects, asthma, pulmonary fibrosis, pulmonary arterial hyper tension, and others, as will be appreciated by the skilled artisan.

[0024] In other aspects, the inflammatory states may include autoimmune disorders characterized by inflammation, such as, for example, Graves’ disease, multiple sclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, diabetes type 1 and others.

[0025] In some aspects, inflammatory disease with depression co-morbidity can be treated with the compositions, kits and methods of this invention, and in some aspects, endometriosis is specifically contemplated in this context.

[0026] In some embodiments, the existence of depression as a co-morbidity in such patients can be surprisingly positively affected in accordance with the methods of this invention and surprisingly, and representing certain embodied aspects of the invention, the combinations / compositions / kits / methods of this invention can optionally improve pain in patients in this group.

[0027] In some aspects the methods of this invention make use of , for example, oral, topical, inhalable, aerosolized or other formulations that specifically deliver or target the NMDAR antagonist to the subject inflamed surfaces, including inter alia, the skin, the gastrointestinal system, the reproductive system or the respiratory system, including, inter alia, oral delivery, topical delivery, aerosol-delivery, intranasal delivery, inhalation delivery or any combination thereof, in addition to intravenous or parenteral routes of administration.

[0028] In some aspects, this invention is specifically directed to the use of D-cycloserine (DCS) as the NMDAR antagonist that can be therapeutically applied in the treatment of chronic lung inflammatory states, such as COPD, and COVID and other related diseases / disorders, which conditions / diseases / disorders are further characterized, in some aspects of the invention, by the patient afflicted thereby as possessing the co-morbidity of depression.

[0029] This invention is directed to the surprising finding that not only is the lung-related inflammatory condition improved by DCS treatment, but the treatment provides added value for its effects on depression as a co-morbidity in the afflicted subjects.

[0030] In accordance with some aspects of this invention, NMD AR antagonist treatment significantly improves quality of life in subjects with respiratory disease and optionally, and in some embodiments, preferably, including depression as a co-morbidity, and such treatment, in some aspects, includes reducing psychopathology symptoms and improving depression, anxiety and suicidality.

[0031] This invention provides a method for treating patients with an inflammatory disease, including respiratory disease and optionally, suffering from depression, the method comprising administering an NMD AR antagonist to the subject.

[0032] This invention also provides a method of mitigating the severity of, mitigating the pathogenesis of or lowering the incidence of inflammatory disease and depression in patients with inflammatory disease and exhibiting depression, the method comprising administering an NMD AR antagonist to the subject.

[0033] This invention also specifically contemplates providing combinations / compositions / kits and methods for mitigating the severity of, mitigating the pathogenesis of or lowering the incidence of inflammatory disease and depression in patients with inflammatory disease and exhibiting depression, the method comprising administering an NMD AR antagonist to the subject.

[0034] This invention also specifically contemplates providing combinations / compositions / kits and methods for mitigating the severity of, mitigating the pathogenesis of or lowering the incidence of inflammatory disease and optionally depression in patients with inflammatory disease and in some aspects, the patients may also exhibit depression, the method comprising administering an NMD AR antagonist to the subject,.

[0035] This invention also specifically contemplates providing combinations / compositions / kits and methods for mitigating the severity of, mitigating the pathogenesis of or lowering the incidence of respiratory inflammatory disease or endometriosis and optionally, depression in patients with respiratory inflammatory disease or endometriosis and in some embodiments, further exhibiting depression, the method comprising administering an NMD AR antagonist to the subject.

[0036] According to these aspects and in some embodiments, the NMDAR antagonist is D- cycloserine (DCS), which D-cycloserine is administered at a dosage of 150-1500 mg / day, or in some embodiments from 200 - 1500 mg / day, or in some embodiments from 250 - 1500 mg / day, or insome embodiments from 300 - 1500 mg / day, or in some embodiments from 350 - 1500 mg / day, or in some embodiments from 400 - 1500 mg / day, or in some embodiments from 450 - 1500 mg / day, or in some embodiments from 500 - 1500 mg / day, or in some embodiments from 550 - 1500 mg / day.

[0037] According to this aspect, and in some embodiments, additional NMDAR antagonists envisioned for use with the methods / compositions of this invention include 7 -Chlorokynurenic acid, ifenprodil, Ketamine, Methandone, Memantine, Amantadine, Dextromethorphan, Auvelty (dextromethorphan + bupropion) and others, as will be appreciated by the skilled artisan.

[0038] According to these aspects and in some embodiments, the NMDAR antagonist is provided as part of a combination therapy with additional anti-inflammatory agents.

[0039] In some embodiments, such anti-inflammatory agents may include Vitamin B6, corticosteroids, phosphodiesterase-4 inhibitors such as roflumilast and others, as will be appreciated by the skilled artisan. In some non-limiting embodiments, the dosage of Vitamin B6 envisioned for administration is from 25-100 mg for every 250 mg DCS provided to the patient. In other nonlimiting embodiments, the dosage of Vitamin B6 envisioned for administration is from 200-300 mg for every 1000 mg DCS provided to the patient. The skilled artisan will appreciate that the dosage of Vitamin B6 can be adjusted to provide a clinical benefit, and will be scaled appropriately, based, in some aspects, on the guidance provided herein with respect to the dosage of DCS being administered to the patient.

[0040] In some embodiments, the Vitamin B6, corticosteroids, phosphodiesterase-4 inhibitors such as roflumilast and others, one or more beta blockers such as bisoprolol, and others, as will be known to the skilled artisan, will be administered as part of a combined composition with the DCS, and in some embodiments, it will be concurrent administration.

[0041] In some embodiments, beta blockers, such as bisoprolol, and others, as will be known to the skilled artisan, may be administered as part of a combined composition with the DCS, and in some embodiments, it will be concurrent administration.

[0042] It should be understood that the invention contemplates combination therapies including a pharmaceutical composition containing the indicated combination in a single composition and / or in a single capsule or tablet formulation and / or including joint administration of two or more pharmaceutical compositions containing the actives described herein.

[0043] In some embodiments, the combination therapy may include compounds which also diminish / decrease an inflammatory response, but are not necessarily classified as anti-inflammatory agents, for example, erythromycin or azithromycin, or other antibiotics , as will be appreciated bythe skilled artisan. It will also be apparent to the skilled artisan what the clinically recommended dosages for the various therapeutics mentioned herein will be and same will serve as a guidance in providing the indicated compounds to patients in need, in accordance with the methods and compositions of this invention.

[0044] According to these aspects and in some embodiments, the treatment reduces pulmonary fibrosis, reduces pulmonary edema, reduces emphysema, reduces lung inflammation, enhances lung function, increases blood oxygenation levels or a combination thereof in said subject.

[0045] In some embodiments, the methods of this invention reduce inflammation in the subject and in some embodiments, the methods modify an immune response in the subject.

[0046] According to this aspect and in some embodiments, the combinations / compositions / kits / methods of this invention specifically reduce mucosal inflammation in the subject, which in some aspects is specifically in the lung, or in other embodiments the female reproductive tract, or in some embodiments, in the peritoneal cavity or in some embodiments, in the oral cavity.

[0047] In some embodiments, the methods of this invention concomitantly reduce signs of depression in the subject.

[0048] In some embodiments, the methods / compositions / kits / uses of the invention are contemplated for use in the context of methods for optimizing a therapeutic regimen in a subject, including mitigating the severity of, mitigating the pathogenesis of, or lowering the incidence of disease in a subject suffering from a mucosal inflammatory disease, with the method comprising determining whether the afflicted subject also exhibits signs of depression, and administering an NMDAR antagonist to the subject optionally with adjunct therapy, thereby optimizing the therapeutic regimen for the subject.

[0049] In still other embodiments of the invention, the methods / compositions / kits / uses of the invention are contemplated for use in the context of methods for optimizing a therapeutic regimen in a subject, including mitigating the severity of, mitigating the pathogenesis of, or lowering the incidence of disease in a subject suffering from a mucosal inflammatory disease, with the method comprising identifying a subject afflicted with a mucosal inflammatory disease and receiving a treatment for such disease, determining whether the afflicted subject also exhibits signs of depression, and administering an NMDAR antagonist to the subject while concurrently reducing the dosage or frequency of administration of the treatment of the mucosal inflammatory disease, thereby optimizing the therapeutic regimen for the subject.

[0050] It will be understood that the methods for optimizing a therapeutic regimen in a subject as described hereinabove may include any embodiment as herein described regarding the compounds for use, dosages, regimens, and related uses as herein described, as being contemplated embodied aspects of the invention.

[0051] All publications, patents, and patent applications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of a conflict between the specification and an incorporated reference, the specification shall control. Where number ranges are given in this document, endpoints are included within the range. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub -range within the stated ranges, optionally including or excluding either or both endpoints, in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. Where a percentage is recited in reference to a value that intrinsically has units that are whole numbers, any resulting fraction may be rounded to the nearest whole number.BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 plots the results of the FST described herein at day 26 of the study.

[0053] Figure 2 plots the results of the FST described herein at day 35 of the study.

[0054] Figure 3 plots the animal body weights assessed over the duration of the study.

[0055] Table 1 describes mean lesion scores of pulmonary inflammation in treated versus control animals.

[0056] Figure 4 plots the pulmonary inflammation score derived for the indicated groups.

[0057] Table 2 describes mean linear intercept values in the lungs of treated versus control animals.

[0058] Figure 5 plots the mean liner intercept score derived for the indicated groups.

[0059] Figure 6-1 - 6-10 presents micrographs representative of each group given the indicated treatments.DETAILED DESCRIPTION OF THE INVENTION

[0060] While the invention will now be described in connection with certain preferred embodiments in the following examples so that aspects thereof may be more fully understood and appreciated, it is not intended to limit the invention to these particular embodiments. On the contrary, it is intended to cover all alternatives, modifications and equivalents as may be included within the scope of the invention as defined by the appended claims.

[0061] This invention provides a method of treating patients with an inflammatory disease and suffering from depression, and in other aspects, this invention provides a method of mitigating the severity of, mitigating the pathogenesis of or lowering the incidence of inflammatory disease and depression in patients with such co-morbidity. The method comprises administering an NMD AR antagonist to the subject in need thereof.

[0062] In some aspects, the invention specifically provides combinations, compositions, kits and methods for treating patients with an inflammatory disease and suffering from depression as a comorbidity, wherein in certain aspects, the combinations, compositions, kits and methods specifically treat, mitigate or abrogate pain in the patients.

[0063] In some aspects, the invention specifically provides combinations, compositions, kits and methods for treating patients with an inflammatory disease, where the inflammatory disease is mucosal inflammatory disease and in some embodiments, the inflammatory disease is a respiratory disease and in still other embodiments, the inflammatory disease is a disease of the female reproductive tract or peritoneal cavity.

[0064] According to this aspect, and in some embodiments, the disease is endometriosis.

[0065] In some aspects, the invention specifically provides combinations, compositions, kits and methods for treating patients with an inflammatory disease, where the inflammatory disease is chronic dental inflammation, including gingivitis.

[0066] According to this aspect, and in some embodiments, the invention specifically takes into consideration that NMD AR, is extensively distributed in various inflamed tissue, including, in some aspects, immune cells involved in the inflammatory response, such as monocytes, macrophages, and others, which represent targets for the combinations / compositions / kits / treatments as herein described.

[0067] In some aspects, the co-morbid subject having depression and an inflammatory disease, includes inflammatory diseases of any tissue, including in the respiratory tract, gastrointestinal tract, skin and / or reproductive tissue. In some aspects, the co-morbid subject having depression and an inflammatory disease, includes inflammatory diseases such as cardiovascular disease, chronicfatigue syndrome, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, irritable bowel syndrome, Crohn’s disease, leaky gut, diabetes type 1 and / or 2, obesity and metabolic syndrome, endometriosis, chronic gingival inflammation and others.

[0068] This invention provides a method for treating patients with respiratory disease and suffering from depression, the method comprising administering an NMD AR antagonist to the subject.

[0069] This invention also provides a method of mitigating the severity of, mitigating the pathogenesis of or lowering the incidence of respiratory disease and depression in patients with respiratory disease and exhibiting depression, said method comprising administering an NMD AR antagonist to said subject.

[0070] In some aspects NMDAR over-activation occurs in tissue inflammation, including lung inflammation and injury, which in turn may exacerbate tissue injury and inflammation, in particular, lung injury and inflammation.

[0071] According to this aspect, and in some embodiments, the invention specifically takes into consideration that NMDARs are extensively distributed in inflamed tissue, including but not limited to inflamed lung tissue, for example, alveolar type II cells, alveolar macrophages, and airway epithelial cells, which represent targets for the treatments as herein described.

[0072] This invention is directed to the finding that NMDAR antagonism can be therapeutically applied in inflammatory states, in particular in inflamed mucosal tissue, including specifically chronic lung inflammatory states.

[0073] According to any of these aspects, and in some embodiments, theNMDAR antagonist is D-cycloserine (DCS), which in some embodiments, is administered at a dosage of at least 150-1500mg / d.

[0074] According to any of these aspects, and in some embodiments, the NMDAR antagonist is D- cycloserine (DCS), which in some embodiments, is administered at a dosage which is altered as a function of time during the treatment period.

[0075] In some embodiments of this aspect, the subject is administered D-cycloserine at a first dosage of from about 150 - 500 mg / day for up to 7 days during a first treatment period. In further embodiments, the subject is administered D-cycloserine at a second dosage of from about 500 - 850 mg / day for up to 14 days during a second treatment period, following the first treatment period. In still other embodiments, the subject is administered D-cycloserine at a third dosage of from about 750 - 1500 mg / day for up to 21 days during a third treatment period, following said second treatment period.

[0076] It will be appreciated that the staggered dosaging can be specifically adjusted to maximize effect in a subject on a personalized basis, and a number of influences may impact the adjustment of the duration, dosage, time course for first, second, third dosages, for example, weight, age, severity of symptomatology, to name but a few considerations. The practicing physician will know how to modify these dosage regimens to optimize the treatment effect in a particular patient and the invention is not to be limited to these specific ranges alone, but same is to serve as a guideline for modification in accordance with good medical practices.

[0077] In some embodiments, the NMDAR antagonist surprisingly positively impacts treatment of patients with depression and respiratory disease as a co-morbidity, in particular COPD or CO VID.

[0078] According to this aspect, and in some embodiments, additional NMDAR antagonists envisioned for use with the methods / compositions of this invention include 7 -Chlorokynurenic acid, memantine, ifenprodil and others, as will be appreciated by the skilled artisan.

[0079] According to this aspect, and in some embodiments, additional NMDAR antagonists envisioned for use with the methods / compositions of this invention include Ketamine, Methandone, Amantadine, Dextromethorphan, Auvelty (Dextromethorphan + Bupropion) and others, as will be appreciated by the skilled artisan.

[0080] In some embodiments, additional compounds targeting the glycine site of the NMDAR showing antagonist activity may be used in accordance with the methods / compositions of this invention.

[0081] In some aspects, D-cycloserine (DCS) may be referred to as “cycloserine” and same can still be considered a further name for the contemplated agent for use in accordance with the methods and compositions of this invention.

[0082] In some embodiments, the DCS is administered as a consistent dosage throughout a treatment cycle and in other embodiments, the DCS is administered at a staggered dosage, throughout a treatment cycle, as described hereinabove.

[0083] In some embodiments, the DCS staggered dosage may comprise use of a dosage of from 150 - 500 mg / day, or in some embodiments, from 450 - 750 mg / day, or in some embodiments, the DCS dosage is incrementally increased over time, over a course of a few days, in any initial dosage as will be deemed appropriate by the treating physician, ultimately resulting in a dosage of from at least 500 mg / day or from 500 mg / day - 1500 mg / day.

[0084] In some embodiments, the DCS is administered at a dosage of 100 mg / day, or in some embodiments, the DCS is administered at a dosage of 150 mg / day, or in some embodiments, theDCS is administered at a dosage of 200 mg / day, the DCS is administered at a dosage of 250 mg / day, or in some embodiments, the DCS is administered at a dosage of 300 mg / day, or in some embodiments, the DCS is administered at a dosage of 350 mg / day, or in some embodiments, the DCS is administered at a dosage of 400 mg / day, or in some embodiments, the DCS is administered at a dosage of 450 mg / day, or in some embodiments, the DCS is administered at a dosage of 500 mg / day, or in some embodiments, the DCS is administered at a dosage of 550 mg / day, or in some embodiments, the DCS is administered at a dosage of 575 mg / day, or in some embodiments, the DCS is administered at a dosage of 600 mg / day.

[0085] According to these aspects and in some embodiments, dosages lower than 500 mg / day are provided at the onset, or in some embodiments, at different times post initiation of the treatment, and in some embodiment, such staggered alteration of dosages reflects a particular patient’s responsiveness to the treatment. It will be appreciated that any dosage of DCS that provokes NMD AR antagonism in the subject, is to be considered as part of this invention.

[0086] In some embodiments, the DCS is administered at a dosage range of from 150-350 mg / day, or in some embodiments, the DCS is administered at a dosage range of from 350-550 mg / day, or in some embodiments, the DCS is administered at a dosage range of from 450- 550 mg / day, or in some embodiments, the DCS is administered at a dosage range of from 450-575 mg / day, or in some embodiments, the DCS is administered at a dosage range of from 400-525 mg / day, or in some embodiments, the DCS is administered at a dosage range of from 510-595 mg / day. In some embodiments, the dosage may be administered from 250-595 mg / day whereby same is incrementally increased over a time course of from 1 - 5 days.

[0087] In some embodiments, the DCS is administered according to a staggered regimen, for example, and in some embodiments, a first, second, third and fourth dosage chosen from a dosage range as described herein may be used. It will be appreciated that any dosage regimen as described herein may be an absolute dosage used throughout a treatment period, or in some embodiments, different dosage ranges may be used over time to treat a subject in accordance with the methods as described herein.

[0088] In some embodiments, the dosage regimen contemplated may comprise a first dosage comprises at least 150 mg / day of D-cycloserine for 3 days, in some embodiments, the second dosage comprises at least 500 mg / day of D-cycloserine for 18 days, in some embodiments, the third dosage comprises at least 750 mg / day of D-cycloserine for 7 days, in some embodiments, the fourth dosage comprises at least 1000 mg / day of D-cycloserine, or in some embodiments, the fourthdosage comprises at least 1500 mg / day of D-cycloserine for 18 days and in some embodiments, the invention provides for the administration of the combined dosage regimen according to this aspect. In some embodiments, the fourth dosage comprises between at least 775 - 2000 mg / day of D- cycloserine

[0089] In some embodiments, the first dosage comprises from at least 150 - 500 mg / day and in some embodiments, from at least 250-500 mg / day of D-cycloserine from day 1-7, or in some embodiments, from days 1-4. In some embodiments, a second dosage is then administered, which second dosage comprises from at least 500 - 800 mg / day of D-cycloserine from day 4-14, or in some embodiments, from days 4-20, or in some embodiments, from days 8-18 or in some embodiments, from days 8-20, or in some embodiments, from days 5-15, or any similar time frame. In some embodiments, a third dosage of DCS is administered to the subject of from at least 750 - 1500 mg / day, following the second dosage administration, for the duration of treatment, which in some embodiments, will span at least 10-20 days.

[0090] In some embodiments, the first dosage comprises from 150 - 500 mg / day or any dosage in such range, such as, for example, 250 mg / day of D-cycloserine from day 0-7, or any number of days from within such range, such as, for example, days 1-3, 1-4, 1-5, etc.

[0091] In some embodiments, the second dosage comprises from 500 - 850 mg / day of D-cycloserine from day 4-20, or any number of days from within such range, such as for example, at a minimum of 10 days within such timeframe, for example, days 4-14, or 7-17 or 5-15, etc.

[0092] In some embodiments, the third dosage comprises 750 - 1500 mg / day of D-cycloserine, following the second dosage, whereby administration is from at least 10-21 days, and optionally the therapeutic period may be extended from 20 - 35 days, or any number of days from within such ranges.

[0093] In some embodiments, the invention provides for the administration of combinations of any dosage regimen as herein described.

[0094] Surprisingly, previously the Inventor has found that higher dosages of D-cycloserine can be significantly well tolerated, especially when the dosage treatment schedule is increased over time in a relatively slow and fixed manner, treating treatment-resistant major depressive disorder, as an adjunct therapy to SSRIs and SNRIs, without any signs of developing psychosis or dissociative phenomenon in the subject.

[0095] In accordance with the provisions of this invention, the inventor has now found that DCS administration also positively and independently treats inflammatory diseases, and in some aspects,wherein depression is a co-morbidity in the subject, an additional benefit is seen, including, in particular, when the inflammation is part of a respiratory disease. In some embodiments, this provides for reducing the dosage of DCS or reducing the dosage of other medications being administered for the inflammatory disease, for example the respiratory disease, over time.

[0096] According to this aspect and in some embodiments, the DCS positive impact on inflammation / respiratory disease may comprise a reduced inflammatory response, or a biasing of the immune response, for example, in a chronic pulmonary disease as a result of infectious origin from a non- protective immune response to a protective immune response, e.g. biasing toward a Thl or Th2 response, depending on the inciting agent.

[0097] In some embodiments, the DCS positive impact on inflammation / respiratory disease may comprise reducing inflammation, emphysema, edema and fibrosis, including pulmonary edema, or pulmonary fibrosis or granulomatous responses in the affected tissue, including lung tissue. In other embodied aspects, the DCS positively impacts tissue function, for example, promoting greater lung capacity, blood oxygenation or lung elasticity, or any combination of positive effects as herein described.

[0098] Furthermore, in some embodiments, it provides for the combination of D-cycloserine with an anxiolytic agent or mood stabilizing agent, however, such combinations are not absolutely necessary to provide the two-hit phenomenon of treating respiratory disease and depression in the subjects as herein described.

[0099] In some embodiments, the dosage regimens herein described provide for a therapeutically effective amount of D-cycloserine, in accordance with the regimens as herein described, providing an effective therapy for both the respiratory disease and concomitant depression and / or neuropsychiatric sequelae.

[0100] In some embodiments, reference to an "effective" amount or a "therapeutically effective amount" of D-cycloserine or other therapeutic agents referenced herein, it is meant a nontoxic but sufficient amount of the same to provide the desired effect.

[0101] In a combination therapy of the present invention, an "effective amount" of one component of the combination is the amount of that compound that is effective to provide the desired effect when used in combination with the other components of the combination. The amount that is "effective" will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the like. Thus, it is not always possible to specify an exact"effective amount." However, an appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation

[0102] The terms "treating" and "treatment" as used herein refer to reduction in severity and / or frequency of symptoms, elimination of symptoms and / or underlying cause, prevention of the occurrence of symptoms and / or their underlying cause, and improvement or remediation of damage. Thus, for example, "treating" a patient involves prevention of a particular disorder or adverse physiological event in a susceptible individual as well as treatment of a clinically symptomatic individual.

[0103] D-cycloserine, or DCS, refers to the chemical D-cycloserine (CA Index Name: 3- Isoxazolidinone, 4-amino-, (4R)- (9CI); CAS Registry No. 68-41-7), or pharmaceutically acceptable salts thereof. DCS is an FDA (United States Food and Drug Administration)- approved drug for treatment of tuberculosis, which has been available commercially, for quite some time. DCS is a structural analog of D-alanine, and is a broad-spectrum antibiotic produced by some strains of Streptomyces orchidaceus and S. garphalus.

[0104] In some embodiments, the methods of this invention in general contemplate combined use of an NMDAR antagonist, which in some aspects is DCS as part of a combination therapy with additional anti-inflammatory agents.

[0105] According to these aspects and in some embodiments, the NMDAR antagonist is provided as part of a combination therapy with additional anti-inflammatory agents.

[0106] In some embodiments, such anti-inflammatory agents may include Vitamin B6, corticosteroids, phosphodiesterase-4 inhibitors such as roflumilast and others, one or more beta blockers such as bisoprolol, or any combination thereof, as will be appreciated by the skilled artisan.

[0107] In some non-limiting embodiments, the dosage of Vitamin B6 envisioned for administration is from 25-100 mg for every 250 mg DCS provided to the patient. In other non-limiting embodiments, the dosage of Vitamin B6 envisioned for administration is from 200-300 mg for every 1000 mg DCS provided to the patient. The skilled artisan will appreciate that the dosage of Vitamin B6 can be adjusted to provide a clinical benefit, and will be scaled appropriately, based, in some aspects, on the guidance provided herein with respect to the dosage of DCS being administered to the patient.

[0108] It will be appreciated that as described herein, it is contemplated to provide staggered dosing of the DCS / NMDAR antagonists as described herein, or in some embodiments, to alter over time the administered dosage of same and in some embodiments, the dosage of B6 is modified to beconsistent with providing from 25-100 mg for every 250 mg DCS provided to the patient accordingly, adjusted per the adjustments provided to the dosage of DCS administered.

[0109] In some embodiments, the Vitamin B6, corticosteroids, bisoprolol, phosphodiesterase-4 inhibitors such as roflumilast and others, will be administered as part of a combined composition with the DCS, and in some embodiments, it will be concurrent administration.

[0110] It should be understood that the invention contemplates combination therapies including a pharmaceutical composition containing the indicated combination in a single composition and / or in a single capsule or tablet formulation and / or including joint administration of two or more pharmaceutical compositions containing the actives described herein.

[0111] In some embodiments, the combination therapy may include compounds which also diminish / decrease an inflammatory response, but are not necessarily classified as anti-inflammatory agents, for example, erythromycin or azithromycin, or other antibiotics, as will be appreciated by the skilled artisan.

[0112] It will also be apparent to the skilled artisan what the clinically recommended dosages for the various therapeutics mentioned herein will be and same will serve as a guidance in providing the indicated compounds to patients in need, in accordance with the methods and compositions of this invention.

[0113] In some embodiments, the combination therapy may include agents for use in treating COPD, such as, for example, vasodilators / alpha-adrenergic blocking agents, such as the imidazoline compounds, as described in U.S. Patent Number 5,096,916, with or without, e.g. inhaled corticosteroids, or in other embodiments, long-acting [32-agonists (LABAs) and / or long-acting antimuscarinic agents (LAMAs), or combinations thereof.

[0114] According to this aspect, and in some embodiments, the combination therapy may include compounds which also target the Beta 2 Adrenergic Rectpor, Phosphodiesterase 4, Muscarinic Acetylcholine Receptor M3, the Glucocorticoid Receptor, Interleukin 33, Cholinergic Receptor Muscarinic Nuclear Factor Erythroid 2 Related Factor 2, Thymic Stromal Lymphopoietin, Alpha 1 Antitrypsin and Arachidonate 5 Lipoxygenase. Further according to this aspect, and in other embodiments, such additional agents constituting a part of the proposed combination therapy may be a small molecule, monoclonal antibody, biologic, cell therapy, recombinant protein, antisense oligonucleotide, synthetic peptide, blood derivative and / or gene-modified cell therapy.

[0115] It should be understood that the invention contemplates combination therapies including a pharmaceutical composition containing the indicated combination in a single composition and / orin a single capsule or tablet formulation and / or including joint administration of two or more pharmaceutical compositions containing the actives described hereinabove, as well.

[0116] It will also be apparent to the skilled artisan what the clinically recommended dosages for the various therapeutics mentioned hereinabove, as well, will be and same will serve as a guidance in providing the indicated compounds to patients in need, in accordance with the methods and compositions of this invention.

[0117] In some embodiments, the invention may also contemplate administering any combination of anti-inflammatory agent, anxiolytic agent or mood stabilizing agent, although it is noted that such agents are not specifically necessary to provide improvement in the treatment of inflammatory disease / respiratory disease and associated depression.

[0118] According to this aspect, and in some embodiments, the dosage of the anxiolytic or mood stabilizing agent is in accordance with standard prescribing guidelines.

[0119] It should be understood that the invention contemplates combination therapies including a pharmaceutical composition containing the indicated combination in a single composition and / or in a single capsule or tablet formulation and / or including joint administration of two or more pharmaceutical compositions containing the actives described hereinabove, as well.

[0120] In some embodiments, the anxiolytic includes, inter alia, Atarax, Benadryl, azaspirones, benzodiazepines, such as Ativan, Centrax, Dalmane, Klonopin, Librium, Paxipam, Restoril, Serax, Tranxene, Valium, Xanax, beta blockers, such as Inderal, Tenormin and others as will be appreciated by the skilled artisan.

[0121] In some embodiments, the regimen comprises administering a second therapeutic agent at a dosage which is considered to be suboptimal in said subject when treating said subject with said second therapeutic agent alone.

[0122] In some embodiments, such administration of the second therapeutic agent may be titrated downward, for example, as the dosage of D-cycloserine is increased in a subject, the dosage of the second therapeutic agent can be diminished gradually, over time. In another embodiment, the invention contemplates reaching maximal treatment levels of both D-cycloserine initially followed by gradual reduction of the second therapeutic agent.

[0123] In some aspects, importantly, the invention specifically contemplates use of an NMDAR antagonist as part of the therapeutic regimen, which inclusion is specific for patients suffering from an inflammatory disease / respiratory disease or having a background inflammatory disease / respiratory disease with depression as co-morbidity and the NMDAR antagonist functions as a two-hit therapeutic agent, positively influencing the patient outcome / recovery / well-being in terms of both the inflammatory disease / respiratory disease and depression symptoms, course of disease, etc.

[0124] In some embodiments, the combinations / compositions / kits / methods of this invention provide for treatment of the inflammatory disease / respiratory disease and depression, wherein the treatment reduces tissue inflammation in the subject, including lung inflammation. In other embodiments, according to this aspect, the treatment modifies an immune response in said subject to positively impact both the inflammatory origin disease or condition and depression.

[0125] In some embodiments, the combinations / compositions / kits / methods of this invention provide for treatment of the inflammatory disease / respiratory disease and depression, where the disease / condition and / or depression symptomatology is reduced or abrogated or eliminated in the subject.

[0126] In some embodiments, the combinations / compositions / kits / methods of this invention provide for treatment of the inflammatory disease / respiratory disease and depression, wherein the treatment includes treating the subject with an adjunct cognitive treatment regimen.

[0127] In some embodiments, the combinations / compositions / kits / methods of this invention provide for treatment of the inflammatory disease / respiratory disease and depression, wherein the method treats a subject suffering from or someone who has suffered from COPD, or Covid- 19 and further suffers from depression as a co-morbidity.

[0128] Surprisingly, the Applicant herein has found that in animal models of respiratory inflammatory disease with depression as a co-morbidity, not only does the NMDAR antagonist DCS treat the developed depression as evidenced by the forced swim test described herein in Example 1, but in histopathology analysis conducted on mice with COPD, lung inflammation per se was positively affected by the treatment, as is evident from Figures 6-1 through 6-10, as described.

[0129] Not only did DCS treatment show improved lung tissue integrity as opposed to Sham controls, but pre-treatment with DCS before the onset of COPD not only positively impacted inflammation, but same also positively impacted depression as can be seen in the pre-treatment group that underwent FST at day 35, as well. Thus the DCS functions, in this aspect, in a highly effective two-hit phenomenon, positively impacting depression pathogenesis and inflammatory disease, as well.

[0130] According to this aspect, therefore, Applicant would submit that DCS can treat inflammatory disorders regardless of the existence of depression.

[0131] In still other aspects, arising from these findings, the Applicant submits that Acute Stress Disorder (ASD), a short-term mental health condition that can occur within the first month after experiencing a traumatic event is a prevalent disorder, where if untreated, the potential for further difficulties increases and PTSD, panic disorders and substance abuse may develop. ASD may be accompanied by depression that can become severe with time. Presently there is an unmet need for the treatment of ASD and the prevention of ASD complications, such as PTSD, which, as can be gleaned from the results presented herein can uniquely be addressed by the methods and compositions of the invention, which were shown to prevent full blown development of depression in treated animals.

[0132] Without being bound by theory, but representing certain embodied aspects of the invention, while NMDAR play a role in learning and memory consolidation, surprisingly herein, we show early signs of the ability to target the molecular basis of memory consolidation, applicable, for example, in the ASD phase in order to prevent the intrusive aspects of traumatic memories from forming and becoming consolidated. According to this aspect and as proposed herein, provided herein is the use of compositions comprising a candidate to pharmacologically manipulate memory consolidation during ASD, the NMDAR antagonist DCS. According to this aspect, and representing certain embodied aspects, blocking the NMDAR at the glycine modulatory site with DCS may result in less intrusive memories when administered in proximity to the traumatic event and may thus have a preventive role versus the development of PTSD and / or other mental morbidity.

[0133] Still further without being bound by theory, but representing certain embodied aspects of the invention, stress may be thought to regulate disease by affecting the immune system. At present most studies focus on the effects of chronic stress on disease and immune cells. However, acute stress is the basis of PTSD and may determine the direction of chronic stress-induced response. How acute stress affects the immune system remains poorly understood. Peripheral pro- inflammatory mediators may contribute to the pathophysiology of PTSD by way of passage to the CNS, where they interact with microglia and immune cells in the brain that in turn release neuroinflammatory mediators. Neuroinflammatory states can modulate neurotransmitter systems, augment symptoms of stress and depression, modulate fear learning and induce neurotoxicity and perhaps elevated levels of systemic inflammation in the aftermath over traumatic exposure and in this manner, lead to the development of PTSD. Surprisingly, the results presented herein may provide a rationale for using DCS therefore in early intervention.

[0134] In some embodiments, the combinations / compositions / kits / methods of this invention provide for treatment of the inflammatory disease / respiratory disease and depression, wherein the method treats a subject suffering from asthma, pulmonary fibrosis or pulmonary arterial hypertension and further suffers from depression as a co-morbidity.

[0135] In some embodiments, the methods / compositions / kits / uses of the invention are contemplated for use in the context of methods for optimizing a therapeutic regimen in a subject, including mitigating the severity of, mitigating the pathogenesis of, or lowering the incidence of disease in a subject suffering from a mucosal inflammatory disease, with the method comprising determining whether the afflicted subject also exhibits signs of depression, and administering an NMD AR antagonist to the subject optionally with adjunct therapy, thereby optimizing the therapeutic regimen for the subject.

[0136] In still other embodiments of the invention, the methods / compositions / kits / uses of the invention are contemplated for use in the context of methods for optimizing a therapeutic regimen in a subject, including mitigating the severity of, mitigating the pathogenesis of, or lowering the incidence of disease in a subject suffering from an inflammatory disease, with the method comprising identifying a subject afflicted with an inflammatory disease and receiving a treatment for such disease, determining whether the afflicted subject also exhibits signs of depression, and administering an NMDAR antagonist to the subject while concurrently reducing the dosage or frequency of administration of the treatment of the mucosal inflammatory disease, thereby optimizing the therapeutic regimen for the subject.

[0137] Furthermore, consistent with the combinations / kits / methods as herein described, the invention also provides a composition comprising an NMDAR antagonist and at least one agent selected from the group consisting of: an anti-inflammatory agent, an anxiolytic agent and a mood stabilizing agent, or any combination thereof.

[0138] In some aspects, the NMDAR antagonist is D-cycloserine (DCS), or any described NMDAR antagonist herein, in any embodiment presented.

[0139] In other embodiments, the composition may further comprise an anti-inflammatory agent including Vitamin B6, one or more corticosteroids, one or more phosphodiesterase-4 inhibitors, one or more beta blockers such as bisoprolol or a combination thereof, or in some embodiments, the anti-inflammatory agent is a non-classical anti-inflammatory agent, and in some embodiments, the anti-inflammatory agent comprises erythromycin or azithromycin or other antibiotic. In some embodiments, the composition comprises a subclinical dosage of any of the anti-inflammatoryagent, anxiolytic agent or mood stabilizing agent or other combination of active ingredients as herein described.

[0140] The pharmaceutical compositions can be administered to the patient by any, or a combination, of several routes, such as oral, intravenous, trans-mucosal (e.g., nasal, vaginal, etc.), pulmonary, intra-nasal, aerosol, inhalation, transdermal, ocular, buccal, sublingual, intraperitoneal, intrathecal, intramuscular, or long term depot preparation. Solid compositions for oral administration can contain suitable carriers or excipients, such as corn starch, gelatin, lactose, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodium chloride, lipids, alginic acid, or ingredients for controlled slow release. Disintegrators that can be used include, without limitation, micro-crystalline cellulose, corn starch, sodium starch glycolate and alginic acid.

[0141] Tablet binders that may be used include, without limitation, acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch, and ethylcellulose.

[0142] Liquid compositions for oral administration prepared in water or other aqueous vehicles can include solutions, emulsions, syrups, and elixirs containing, together with the active compound(s), wetting agents, sweeteners, coloring agents, and flavoring agents. Various liquid and powder compositions can be prepared by conventional methods for inhalation into the lungs of the patient to be treated.

[0143] Injectable compositions may contain various carriers such as vegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, polyols (glycerol, propylene glycol, liquid polyethylene glycol, and the like). For intravenous injections, the compounds may be administered by the drip method, whereby a pharmaceutical composition containing the active compound(s) and a physiologically acceptable excipient is infused. Physiologically acceptable excipients may include, for example, 5% dextrose, 0.9% saline, Ringer's solution or other suitable excipients.

[0144] For intramuscular preparations, a sterile composition of a suitable soluble salt form of the compound can be dissolved and administered in a pharmaceutical excipient such as Water-for-Inj ection, 0.9% saline, or 5% glucose solution, or depot forms of the compounds (e.g., decanoate, palmitate, undecylenic, enanthate) can be dissolved in sesame oil. Alternatively, the pharmaceutical composition can be formulated as a chewing gum, lollipop, or the like.

[0145] It will be apparent to those skilled in the art that various modifications and variations can be made in the solid substrates, kits, process and methods of the present invention without departing from the spirit or scope of the invention.

[0146] In some embodiments, the term "comprise" or grammatical forms thereof, refers to the inclusion of the indicated components of this invention, as well as inclusion of other active agents, and pharmaceutically acceptable carriers, excipients, emollients, stabilizers, etc., as are known in the pharmaceutical industry.

[0147] In one embodiment, the term "about" refers to a variance of from 1- 10%, or in another embodiment, 5 - 15%, or in another embodiment, up to 10%, or in another embodiment, up to 25% variance from the indicated values, except where context indicates that the variance should not result in a value exceeding 100%.

[0148] In one embodiment, the present invention provides combined preparations. In one embodiment, the term "a combined preparation" defines especially a "kit of parts" in the sense that the combination partners as defined above can be used independently or in different combinations i.e., simultaneously, concurrently, separately, or sequentially.

[0149] Thus, the following examples which include preferred embodiments will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purposes of illustrative discussion of preferred embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of formulation procedures as well as of the principles and conceptual aspects of the invention.EXAMPLESEXAMPLE 1In Vivo Efficacy of Add-On NMD AR Functional Antagonists in Treating COPD-Depression ComorbidityD-Cycloserine

[0150] D-Cycloserine was purchased from Sigma Aldrich.

[0151] The formulations are summarized as follows:( Z<a> This is based upon visual observation soluble; SS: slight soluble I: insoluble (suspension or precipitation) formula is kept in tube or vial with brown color or covered with aluminum foil, no protection from light(c)RT : prepared fresh and stored between 20-252C.4°C: prepared fresh and stored in the refrigerator or kept on ice.Animals

[0152] Male BALB / c mice, 7-8 week-old were provided by BioLASCO Taiwan (under Charles River Laboratory Licensee). Space allocation for individual animal was 30 x 19 x 13 cm3. All animals were maintained in an environment under well-controlled temperature (20 - 24°C) and humidity (30% - 70%) with 12 hours light / dark cycles. Free access to standard lab diet [MFG (Oriental Yeast Co., Ltd., Japan)] and autoclaved tap water were granted. All aspects of this work including housing, experimentation, and animal disposal were performed in general accordance with the "Guide for the Care and Use of Laboratory Animals: Eighth Edition" (National Academies Press, Washington, D.C., 2011) in our AAALAC-accredited laboratory animal facility. In addition, the animal care and use protocol was reviewed and approved by the IACUC at Pharmacology Discovery Services Taiwan, Ltd.Chemicals

[0153] Elastase, Porcine Pancreas (PPE)(324682) (Sigma, USA), Isoflurane (Panion & BE biotech, Taiwan), Lipopolysaccharide (LPS, 055:B5)(Sigma, USA), 0.9% NaCl (Sintong Chemical Industry Co., Ltd. Taiwan), Pentobarbital sodium (Health-Tech Pharmaceutical Co., Ltd., Taiwan), and Water for injection (WFI) (Tai- Yu, Taiwan).Equipment

[0154] Animal cage (Allentown Caging, USA), Beaker (1000 mL, Kinmax, USA), Disposable syringe with needle 1 mL (TERUMO, Philipines), Electronic balance (Precisa 600C, 0.01 g - 600.00 g, Switzerland), Electronic scale (1 g ~ 1000 g, TANITA, Japan), Inhalation anesthesia machine (AN- 10-T; DRI, Taiwan), Pipetman (Gilson, France), Stainless forceps (Klappenecker, Germany), Stainless scissors (Klappenecker, Germany), Stopwatch (Casio, China) and Vortex mixer (Thermolyne, USA).Methods

[0155] Male BALB / c mice at 7-8 weeks old were used. Porcine pancreatic elastase (PPE) was administered intratracheally (IT) at a dose of 1.2 U / 20 pL / mouse on Days 0, 7, 14, and 21 and E. Coli lipopolysaccharide (LPS) was administered intratracheally (IT) at a dose of 7 pg / 20 pL / mouse on Days 4, 11, 18 and 25. Sham control mice received same volume of saline intratracheally in the same way and same schedule as PPE and LPS, i.e. on Days 0, 4, 7, 11, 14, 18, 21 and 25.

[0156] Vehicle (saline) or test article, D-Cycloserine at 100 or 200 mg / kg was administered by intraperitoneal injection (IP) once daily (QD) from Day 28 to Day 34 (Groups 1-4, la-4a) or once weekly (Days 7, 14 and 21) and once daily (QD) from Day 28 to Day 34 (Groups 5, 5a).

[0157] For Groups 1-5: on Day 35, for forced swim test (FST), animals were placed in a 1 -liter volume glass beaker (height: 14.5 cm, diameter: 11 cm) containing 10 cm height water at room temperature (22 to 24oC) for 6 minutes. The first 2 minutes were considered a time for the animals to explore and acclimate to the environment. The duration of animal immobility within the last 4 of the 6 minutes was then recorded. As a second readout the fourth and fifth minutes (time 180-300 seconds) was evaluated. A mouse was considered immobile when it ceased struggling and remained floating in the water making only those movements necessary to keep its head above water. Beside immobility, also the parameter swimming and struggling was evaluated. For Groups la-5 a: forced swim test (FST) was performed on Day 26.

[0158] For Group 1-5: on Day 35, a total of four lobes of lung (Rl: Right cranial lobe, R2: Right middle lobe, R3: Right caudal lobe, and A4: Accessory lobe) were filled in with 10% formalin through a tracheal cannula and processed for histopathological analysis (H&E staining). The mean linear intercept (MLI) was calculated and the remaining lobes of lung (L5: Left lobe) were collected and kept in RNAlater for TNF-alpha, IL-1 beta, and IL- 10 mRNA levels by QPCR analysis (optional). For Groups la-5a: on Day 35, the entire lung was harvested for histopathological analysis (H&E staining) only.

[0159] The overall study design was as follows:

[0160]

[0161] Male BALB / c mice at 7-8 weeks old were used. All animals, except those in Groups 1 and la the sham control, are anesthetized with isoflurane and receive intratracheal instillation (IT) of porcine pancreatic elastase (PPE, 1.2 U / 20 pL / mouse) on Days 0, 7, 14, and 21 and E. Coli lipopolysaccharide (LPS, 7 pg / 20 pL / mouse) on Days 4, 11, 18 and 25. Sham control received the same volume of saline intratracheally in the same way and same schedule as PPE and LPS, i.e. on Days 0, 4, 7, 11, 14, 18, 21 and 25.

[0162] Vehicle or test article was administered by intraperitoneal injection (IP) once daily (QD) from Day 28 to Day 34 (Groups 1-4, la-4a) or once weekly (Days 7, 14 and 21) and once daily (QD) from Day 28 to Day 34 (Groups 5, 5a). Vehicle for D -cycloserine: saline (0.9% NaCl).

[0163] Body weight was recorded 3 times per week during the study period.

[0164] On Day 35, animals were anesthetized by pentobarbital (80 mg / kg, i.p.), a total of four lobes of lung (Rl: Right cranial lobe, R2: Right middle lobe, R3: Right caudal lobe, and A4: Accessory lobe) are filled in with 10% formalin through a tracheal cannula and processed for histopathological analysis (H&E staining). The mean linear intercept (MLI) was calculated.

[0165] For Groups la-5a: forced swim test (FST) was performed on Day 26. On Day 35, animals were anesthetized by pentobarbital (80 mg / kg, i.p.), the entire lung was harvested for histopathological analysis (H&E staining) only.Histopathology:

[0166] After necropsy, the lung samples were harvested and then preserved in 10% neutral buffered formalin (NBF). The lung tissues (four lobes from Groups 1-5 or five lobes from Groups la-5a) were prepared for histopathology. They were sectioned at 4-6 pm and stained with hematoxylin and eosin (H&E). Finally, samples were examined through an optical microscope (Leica DM2700M, USA).Quantitative recording of histopathological lesions of the lung (inflammation):

[0167] The severity grading system for all microscopic lesions (H&E stain) was as follows based on the reference published in Toxicologic Pathology (Shackelfold et al., 2002):

[0168] Grade Severity0 Not present1 Minimal (< 1%)2 Slight (1-25%)3 Moderate (26-50%)4 Moderately S evere / high (51-75%)5 Severe / high (76-100%)Mean linear intercept (MLI):

[0169] To assess air space enlargement, the mean linear intercept (MLI) was quantified by one observer in a blinded fashion by superimposing a line grid with a line on the images of lung enlargement sections at a magnification of 100X as described previously. To calculate the MLI, the number of intersections between the lines of the grid and the alveolar walls was quantified for each mouse in 5 non-overlapping fields. Airspace enlargement was quantified by the mean linear intercept (MLI) calculations in randomly selected fields of the lung tissue sections. MLI was obtained by dividing the total length of a line drawn across the lung section by the total number of intercepts encountered. The point-counting technique determined the mean linear intercept (xlOO magnification) in the pulmonary tissue across 5 random, non-overlapping microscopic fields.Statistical analysis:

[0170] All values were expressed in the form of Mean ± SD. The unpaired Student's t-test compared Vehicle control (Group 2) vs. Sham (Group 1) and Vehicle control (Group 2a) vs. Sham (Group la). One-way ANOVA followed by Dunnett's test was used to determine possible significantdifferences (p<0.05) among the Vehicle control (Group 2) vs. treated groups (Groups 3-5) and Vehicle control (Group 2a) vs. treated groups (Groups 3a-5a).RESULTS:

[0171] Animal models to simulate chronic obstructive pulmonary disease (COPD) in mice have been developed, for example, as reported by Pelgrim CE, et.al. (2022) Effects of a nutritional intervention on impaired behavior and cognitive function in an emphysematous murine model of COPD with endotoxin-induced lung inflammation. Front. Nutr. 9: 1010989. doi:10.3389 / fnut.2022.1010989, Sohn, S-H., et al. The effects of Gamijinhae-tang on elastase / lipopolysaccharide-induced lung inflammation in an animal model of acute lung injury. BMC Complement Altern Med. 2013 Jul 16;13:176. doi: 10.1186 / 1472-6882-13-176; and Limjunyawong N., et al. Experimental progressive emphysema in BALB / cJ mice as a model for chronic alveolar destruction in humans. Am J Physiol Lung Cell Mol Physiol. 2015 Oct l;309(7):L662-76. doi: 10.1152 / ajplung.00214.2015) relying on elastase an LPS administration to induce chronic obstructive pulmonary disease (COPD) in mice.

[0172] As noted herein, the invention relates to NMD AR antagonist being a useful treatment for patients with inflammatory diseases, including, in particular, respiratory disease and experiencing depression as a comorbidity. Mouse models of depression are also known in the art, wherein the Forced Swim Test serves as a gold standard for measuremen t / detection of same.

[0173] Toward this end, D-Cycloserine, was evaluated for its potential effects on elastase-induced chronic obstructive pulmonary disease (COPD) in mice with further assessment of depression.

[0174] Porcine pancreatic elastase (PPE) was administered intratracheally (IT) at a dose of 1.2 U / 20 pL / mouse on Days 0, 7, 14, and 21 and E. Coli lipopolysaccharide (LPS) was administered intratracheally (IT) at a dose of 7 pg / 20 pL / mouse on Days 4, 11, 18 and 25. Sham control mice received same volume of saline intratracheally in the same way and same schedule as PPE and LPS, i.e. on Days 0, 4, 7, 11, 14, 18, 21 and 25, serving as a negative control, in that the carrier does not result in COPD or depression development in these test animals, whereas vehicle control animals (saline) or test article, D-Cycloserine (DCS) at 100 or 200 mg / kg was administered by intraperitoneal injection (IP) once daily (QD) from Day 28 to Day 34 (Groups 1-4, la-4a) or once weekly (Days 7, 14 and 21) in combination with once daily (QD) from Day 28 to Day 34 (Group 5, 5a), to assess COPD and depression development in these animals, and DCS impact on such development, if applicable.

[0175] For Groups 1-5: on Day 35, for forced swim test (FST), animals were placed in a 1 -liter volume glass beaker (height: 14.5 cm, diameter: 11 cm) containing 10 cm height water at room temperature (22 to 24oC) for 6 minutes. The first 2 minutes were considered a time for the animals to explore and acclimate to the environment. The duration of animal immobility within the last 4 of the 6 minutes was then recorded. As a second readout the fourth and fifth minutes (time 180- 300 seconds) was evaluated. A mouse was considered immobile when it ceased struggling and remained floating in the water making only those movements necessary to keep its head above water. Beside immobility, the parameter swimming and struggling was also evaluated. For Groups la-5 a: forced swim test (FST) was performed on Day 26.

[0176] For Groups 1-5 on Day 35, the negative control (sham) processed an average immobility time of 124.4 ± 16.4 seconds during the last 4-minute recording period (120-360 seconds), accompanying with the duration of immobility, struggling (climbing) and swimming at 63.0 ± 8.3, 2.9 ± 1.2 and 54.1 ± 8.1 seconds, respectively, in the intervals of 3-5 minutes. Moreover, the vehicle control processed an average immobility time of 180.5 ± 8.3 seconds during the last 4- minute recording period (120-360 seconds), accompanied with the duration of immobility, struggling (climbing) and swimming at 84.8 ± 6.8, 1.4 ± 0.8 and 33.9 ± 6.9 seconds, respectively, in the intervals of 3-5 minutes.

[0177] The PPE / LPS-induced COPD exacerbation in vehicle group significantly increased the total immobility time or significantly reduced the total mobility time compared to the sham group on Day 35 (p<0.05, unpaired Student's t-test; Figure 1 and Figure 2).

[0178] D-Cycloserine given at 100 or 200 mg / kg by intraperitoneal injection (IP) once daily (QD) from Day 28 to Day 34 or once weekly (Days 7, 14 and 21) in combination with once daily (QD) from Day 28 to Day 34 moderately reduced the total duration of immobility, in a dose-dependent manner, compared to the vehicle control, which was associated with the increased swimming time (one-way ANOVA followed by Dunnett’s test; Figure 2). Moreover, D-Cycloserine given at 100 mg / kg, QD x7 (Days 28-34) by IP injection and D-Cycloserine given at 100 mg / kg, xlO (Days 7, 14, 21, 28-34) by IP injection also showed significant reduction on the total duration of immobility or improvement on the total duration of mobility compared to the vehicle group on Day 35 (p<0.05, unpaired Student's t-test; Figure 2).

[0179] In contrast, however, for Groups la-5a on Day 26, no significant differences in the total duration of immobility or the total duration of mobility were observed between negative control (sham) and vehicle control in the PPE / LPS-induced COPD mice (unpaired Student's t-test; andFigure 1), which potentially is due either to the small sample size, or the necessity for additional time for onset of depression in these animals, for example. Moreover, on Day 26, D-Cycloserine given at 100 mg / kg x3 (Days 7, 14 and 21) by IP injection also did not affect the immobility time or mobility time relative to the vehicle control in the study (one-way ANOVA followed by Dunnett’s test or unpaired Student's t-test; and Figure 1).

[0180] At the end of study (Day 35), for Groups 1-5, a total of four lobes of lung (Rl: Right cranial lobe, R2: Right middle lobe, R3: Right caudal lobe, and A4: Accessory lobe) were filled in with 10% formalin through a tracheal cannula and processed for histopathological analysis (H&E staining). The mean linear intercept (MLI) was calculated, while for Groups la-5a: on Day 35, the entire lung was harvested for histopathological analysis (H&E staining) only.

[0181] The severity of lung inflammation in the vehicle control group (Group 2 and Group 2a) was significantly increased compared to the sham group (Group 1 and Group la) (p<0.05; unpaired Student’s t-test). D-Cycloserine (100 mg / kg, xlO, IP) (Group 5) and D-Cycloserine (200 mg / kg, QD x7, IP) (Group 4a) significantly reduced the inflammatory scores when compared to the vehicle group (Group 2 and Group 2a) (p<0.05; One-way ANOVA followed by Dunnett’s test) Figure 4 and Table 1.

[0182] The mean linear intercept (MLI) values as an alternative parameter of emphysema were also shown in Figure 5 and Table 2. The mean linear intercept (MLI) in the vehicle control group (Group 2 and Group 2a) was significantly augmented as compared to the sham group (Group 1 and Group la) (p<0.05; unpaired Student’s t-test). D-Cycloserine (100 mg / kg, QD x7, IP) (Group 3), D- Cycloserine (200 mg / kg, QD x7, IP) (Group 4), D-Cycloserine (100 mg / kg, xlO, IP) (Group 5), D- Cycloserine (100 mg / kg, QD x7, IP) (Group 3a), D-Cycloserine (200 mg / kg, QD x7, IP) (Group 4a), and D-Cycloserine (100 mg / kg, xlO, IP) (Group 5a) significantly reduced alveolar enlargement when compared to the vehicle control group (Group 2 and Group 2a) (p<0.05; Oneway ANOVA followed by Dunnett’s test) (see Figure 5 and Table 2).

[0183] The results revealed that focal to multifocal inflammatory cell infiltration and focal emphysema lesions were found in lung tissues in the vehicle group. The significances were observed compared to the sham group (p<0.05; unpaired Student’s t-test). D-Cycloserine (100 mg / kg, xlO, IP) (Group 5) and D-Cycloserine (200 mg / kg, QD x7, IP) (Group 4a) in pulmonary inflammation lesion and all treated groups (Groups 3-5 and Groups 3a-5a) in lung emphysema lesion were significantly improved when compared to the vehicle control group (Group 2 and Group 2a) (p<0.05; One-way ANOVA followed by Dunnett’s test) (see Figures 6-1 through 6-10).

[0184] The body weights were recorded three times per week during the study period. Test article, D-Cycloserine was well-tolerated at all tested dose levels and no overt toxicities were observed in the study. The body weight in sham control increased gradually during the whole study. Only the body weight was moderately to significantly reduced in COPD induction groups on Day 2 (p<0.05; two-way ANOVA followed by Bonferroni test and Figure 3).

[0185] The Histopathology analysis revealed that focal to multifocal inflammatory cell infiltration and focal emphysema lesions were found in lung tissues in the vehicle group. The significances were observed compared to the sham group (p<0.05; unpaired Student’s t-test). D-Cycloserine (100 mg / kg, xlO, IP) (Group 5) and D-Cycloserine (200 mg / kg, QD x7, IP) (Group 4a) in pulmonary inflammation lesion and all treated groups (Groups 3-5 and Groups 3a-5a) in lung emphysema lesion were significantly improved when compared to the vehicle control group (Group 2 and Group 2a) (p<0.05; One-way ANOVA followed by Dunnett’s test).

[0186] Thus, pulmonary inflammatory cell infiltration, focal emphysema and FST immobility duration, a rodent proxy for depression, were increased (p<0.05) in the vehicle group, whereas the total immobility duration was reduced (p<0.05) in DCS treated groups. The severity grading of lung inflammation and magnitude of mean linear intercept, that measures air space enlargement, were reduced in all DCS-treated groups, as compared to controls.

[0187] These results clearly support the role of DCS as an innovative treatment option in COPD and depression.EXAMPLE 2In Vivo Efficacy of Add-On NMD AR Functional Antagonists in Treating COPD-Depression Comorbidity

[0188] COPD patients suffering also from comorbid depression will be identified and studied in an Open Label, clinical trial setting.

[0189] Stable COPD out or in patients of any gender, race or ethnicity will be assessed in terms of their medical history, clinical examination, symptoms, function and quality of life, pulmonary function tests, lung scan and serum inflammation parameters. Oxygen saturation rate and dyspnea (Modified Medical Research Council (mMRC) Dyspnea scale) will be evaluated, as well.Experimental Treatment

[0190] DCS (seromycin) will be provided as 250 mg capsules (e.g. Elly Lilly Me Leod Pharmaceutics).

[0191] After a 2-week baseline assessment period, subjects will receive DCS for 6 weeks, in addition to their regular medications, the dose of which will remain fixed throughout the study.

[0192] A fixed, slow titration -high dose treatment schedule for COPD pharmacotherapy with DCS will be employed: 250 mg (one capsule ) / d for 3 days; 500 mg (two capsules) / d for 18 days, 750 mg / day for 1 week and 1000 - 1500 mg (four to six capsules) / d for the last 2 weeks.

[0193] This dosing schedule will be pursued in order to: (1) ensure the assessment of NMDAR- antagonist DCS doses; (2) minimize safety risk; (3) allow for patient withdrawal at relatively low doses in case of emergent side-effects.

[0194] Starting from day 4 onward, daily experimental medication will be administered in two divided doses, if necessary. The final dose will be adjusted in the range of 500-1500 mg / day based on the patient's tolerability.

[0195] The necessity of treatment with pyridoxine 50 mg for each 250 mg DCS, for DCS -induced side effects will be clinically determined.

[0196] Patient symptoms, pulmonary function, and side effects, if any, will be assessed, , using, optionally the Hamilton Depression Rating Scale (HDRS), the Hamilton Rating Scale for Anxiety (HAMA), the Beck Depression Inventory and the Positive and Negative Symptom Scale (PANSS) , lung CT, standard pulmonary function tests, a 6-minutes walk test and quality of life scales.

[0197] Lung dysfunction as measured by 6 MWD and FEV1 and depression severity as measured by HDRS are the primary outcome parameters in this study.

[0198] Measurement of inflammation e.g. systemic inflammation ratio (SIR) are an additional outcome parameter in the study.

[0199] The study will show surprisingly that the administration of the treatments / protocols of this invention will result in alleviation of depression and improved lung function and inflammation indices.

[0200] Furthermore, unexpected results in terms of a lack of significant side effects will be observed.EXAMPLE 3In Vivo Efficacy of Add-On NMD AR Functional Antagonists in Preventing PTSD-depression Comorbidity

[0201] Acute Stress Disorder (ASD) patients suffering also from comorbid depression will be identified and studied in an Open Label, clinical trial setting.

[0202] ASD out or in patients, at a maximum of 1 week following the traumatic event, of any gender, race or ethnicity will be assessed in terms of their medical history, clinical examination, symptoms, function and quality of life, and serum inflammation parameters.Experimental Treatment

[0203] DCS (seromycin) will be provided as 250 mg capsules (e.g. Elly Lilly Me Leod Pharmaceutics).

[0204] Subjects will receive DCS for 4 weeks, in addition to their regular medications, the dose of which will remain fixed throughout the study.

[0205] A fixed dose treatment schedule for ASD pharmacotherapy with DCS will be employed: 250 mg (one capsule) / d for 4 days; 500 mg (two capsules) / d for 10 days and 1000-1500 mg (four to six capsules) / d for the last 2 weeks.

[0206] This dosing schedule will be pursued in order to: (1) ensure the assessment of NMDAR- antagonist DCS doses; (2) minimize safety risk; (3) allow for patient withdrawal at relatively low doses in case of emergent side-effects.

[0207] Starting from day 4 onward, daily experimental medication will be administered in two divided doses, if necessary. The final dose will be adjusted in the range of 500-1500 mg / day based on the patient's tolerability.

[0208] The necessity of treatment with pyridoxine 50 mg for each 250 mg DCS, for DCS-induced side effects will be clinically determined.

[0209] Patient symptoms and side effects, if any, will be assessed using: The Acute Stress Disorder Scale (ASDS), The Clinician Administered PTSD Scale (CAPS) and the Hamilton Depression Rating Scale (HDRS). Primary outcome parameters in this study may comprise lung dysfunction measurements by acute stress and / or PTSD and depression severity measured by ASDS, CAPS and HDRS.

[0210] Measurements of inflammation, e.g. systemic inflammation ratio (SIR) are an additional outcome parameter in the study.

[0211] The study will show surprisingly that the administration of the treatments / protocols of this invention will result in alleviation of stress, depression and inflammation indices and in some aspects, reduction in the incidence of, or a reduction in the severity of post -traumatic stress disorder in these subjects.

[0212] Furthermore, unexpected results in terms of a lack of significant side effects will be observed.EXAMPLE 4In Vivo Efficacy of Add-On NMD AR Functional Antagonists in Treating Post-Covid-19 Depression Comorbidity

[0213] Post-Covid- 19 patients suffering also from respiratory dysfunction and comorbid depression will be identified and studied in a clinical trial setting.

[0214] Patients with a past positive test for SARS-CoV-2 infection, but negative for active infection (at least 3 months negative following a PCR test) who are being treated for respiratory dysfunction and depressive symptoms, complaining of their continued symptoms despite the treatment will be evaluated.

[0215] Patients will be interviewed and screened using a Covid-19 Database Form and Post-Co vid. Neuropsychiatric Deficit Checklist followed by the administration to the Modified Medical Research Council (mMRC) Dyspnea Scale, Nijmegen Questionnaire (NQ) and HDRS.

[0216] Patients with dysfunctional breathing as reflected in mMRC Dyspnea Scale and NQ scores and at least moderate depressive symptoms as reflected in HDRS scores (assessed by the above) will be enrolled.

[0217] In addition, the pre-study doses of ongoing medications received by patients will have to be stable for at least 3 weeks prior to study entry.Treatment

[0218] DCS (seromycin) will be provided as 250 mg capsules (e.g. Elly Lilly Me Leod Pharmaceutics). After a 2-week baseline assessment period, subjects will receive DCS for 6 weeks in addition to their regular medications, the dose of which will remain fixed throughout the study.

[0219] Subjects receiving inhaled corticosteroids and B2 agonists will continue to receive same during the study.

[0220] A fixed, slow titration-high dose treatment schedule with DCS will be employed: 250 mg (one capsule) / d for 4 days; 500 mg (two capsules) / d for 18 days, 750 mg / day for one week and 1000- 1500 mg (four to six capsules) / d for the last 2 weeks to subjects.

[0221] This dosing schedule will be pursued in order to: (1) ensure the assessment of NMDAR- antagonist DCS doses; (2) minimize safety risk; (3) allow for patient withdrawal at relatively low doses in case of emergent side-effects.

[0222] Starting from day 4 onward, daily experimental medication will be administered in two divided necessary doses. The final dose will be adjusted in the range of 500-1500 mg / day based on the patient's tolerability.

[0223] The necessity of treatment with 50 mg pyridoxine for each 250 mg DCS, against DCS- induced side effects will be clinically determined.

[0224] Patient symptoms, pulmonary function, and side effects, if any, will be assessed, using, optionally the Hamilton Depression Rating Scale (HDRS), the Hamilton Rating Scale for Anxiety (HAMA), the Beck Depression Inventory and the Positive and Negative Symptom Scale (PANSS) , lung CT, standard pulmonary function tests, a 6-minute walk test and quality of life scales.

[0225] Lung dysfunction as measured by 6 MWD and FEV1 and depression severity as measured by HDRS are the primary outcome parameters in this study.

[0226] Measurements of inflammation, e.g. systemic inflammation ratio (SIR) are an additional outcome parameter in the study.

[0227] The study will surprisingly show significant improvements in subjects administered the treatments / protocols of this invention.

[0228] Furthermore, unexpected results in terms of a lack of significant side effects will be observed.EXAMPLE 5In Vivo Efficacy of Add-On NMD AR Functional Antagonists in Treating Endometriosis- Depression Comorbidity

[0229] Rat models of endometriosis will be utilized for example, as described in Torres-Reveron A. et. al. (Reproductive Sciences (2016) 23(9): 1158-1167.

[0230] Rat models of depression, for example, following some of the protocols as described in Peng, Z. et. al., Int. J. Mol. Sei. 2020, 21(5), 1769; hi^p / / doi:prg / 0;339()dimp2jZhou Y, et.al. Neurosci Lett. 2021 Aug 10;759: 136050. doi: 10.1016 / j.neulet.202L 136050. Epub 2021 Jun 12. PMID: 34126179. or Tang, M. et.al. Transl Psychiatry. 2019; 9: 260; published online 2019 Oct 17. doi: 10.1038 / s41398-019-0605-4 will be used.

[0231] Age- and weight- and otherwise matched wild type rats will also be used to ultimately create groups of mice, for example endometriosis-induced rats; depression-induced rats, endometriosis- and depression-induced rats; and wild type rats.

[0232] DCS will be administered to each group of rats in a dosage that elicits antagonism of the NMD AR receptor, and as adjusted based on the described dosages herein for human treatment.

[0233] Positive effects of the treatment on endometriosis- and depressive phenotype will be evaluated and comparatively assessed amongst the groups.EXAMPLE 6In Vivo Efficacy of Add-On NMD AR Functional Antagonists in Treating Endometriosis- Depression Comorbidity

[0234] Endometriosis patients suffering also from comorbid depression will be identified and studied in an Open Label, clinical trial setting.

[0235] Endometriosis patients will be assessed in terms of their medical history, clinical examination, symptoms, function and quality of life including vaginal and abdominal ultrasound scans. Pain and interference with daily life will be evaluated, as well.Experimental Treatment

[0236] DCS (seromycin) will be provided as 250 mg capsules (e.g. Elly Lilly Me Leod Pharmaceutics).

[0237] After a 2-week baseline assessment period, subjects will receive DCS for 6 weeks, in addition to their regular medications, the dose of which will remain fixed throughout the study.

[0238] A fixed, slow titration-high dose treatment schedule with DCS will be employed: 250 mg (one capsule) / d for 3 days; 500 mg (two capsules) / d for 18 days, 750 mg / day for 1 week and 1000- 1500 mg (four to six capsules) / d for the last 2 weeks.

[0239] This dosing schedule will be pursued in order to: (1) ensure the assessment of NMDAR- antagonist DCS doses; (2) minimize safety risk; (3) allow for patient withdrawal at relatively low doses in case of emergent side-effects.

[0240] Starting from day 4 onward, daily experimental medication will be administered in two divided doses, if necessary. The final dose will be adjusted in the range of 500-1000 mg / day based on the patient's tolerability.

[0241] The necessity of treatment with pyridoxine 50 mg for each 250 mg DCS, for DCS -induced side effects will be clinically determined.

[0242] Patient symptoms, and any changes evident on ultrasound, and side effects, if any, will be assessed, , using, optionally the Hamilton Depression Rating Scale (HDRS), the Hamilton Rating Scalefor Anxiety (HAMA), the Beck Depression Inventory and the Positive and Negative Symptom Scale (PANSS), and quality of life scales.

[0243] Measurements of inflammation, e.g. systemic inflammation ratio (SIR) are an additional outcome parameter in the study.

[0244] Depression severity as measured by HDRS (on a 0 to 100 mm visual analogue scale [VAS]) may be used, as the primary outcome parameters in this study.

[0245] The study will show surprisingly that the administration of the treatments / protocols of this invention will result in alleviation of depression and inflammation secondary to a diagnosis of endometriosis.

[0246] Furthermore, unexpected results in terms of a lack of significant side effects will be observed.

[0247] It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

[0248] It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as set forth in the appended claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed in the scope of the claims.

[0249] In one embodiment of this invention, "about" refers to a quality wherein the means to satisfy a specific need is met, e.g., the size may be largely but not wholly that which is specified but it meets the specific need of cartilage repair at a site of cartilage repair. In one embodiment, "about" refers to being closely or approximate to, but not exactly. A small margin of error is present. This margin of error would not exceed plus or minus the same integer value. For instance, about 0.1 micrometers would mean no lower than 0 but no higher than 0.2. In some embodiments, the term "about" with regard to a reference value encompasses a deviation from the amount by no more than 5%, no more than 10% or no more than 20% either above or below the indicated value.

[0250] In the claims articles such as "a", "an" and "the" mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include "or" or "and / or" between members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention also includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. Furthermore, it is to be understood that the invention provides, in various embodiments, all variations, combinations, and permutations in which one or more limitations, elements, clauses, descriptive terms, etc., from one or more of the listed claims is introduced into another claim dependent on the same base claim unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise. Where elements are presented as lists, e.g. in Markush group format or the like, it is to be understood that each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should be understood that, in general, where the invention, or aspects of the invention, is / are referred to as comprising particular elements, features, etc., certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements, features, etc. For purposes of simplicity those embodiments have not in every case been specifically set forth in haec verba herein. Certain claims are presented in dependent form for the sake of convenience, but Applicant reserves the right to rewrite any dependent claim in independent format to include the elements or limitations of the independent claim and any other claim / s) on which such claim depends, and such rewritten claim is to be considered equivalent in all respects to the dependent claim in whatever form it is in (either amended or unamended) prior to being rewritten in independent format.

Claims

[00251] What is Claimed is:

1. A method of treating a subject with inflammatory disease and suffering from depression as a comorbidity, said method comprising administering an NMD AR antagonist to said subject, preferably wherein said subject suffers from chronic obstructive pulmonary disease.

2. A method of mitigating the severity of, mitigating the pathogenesis of or lowering the incidence of inflammatory disease and depression in patients with respiratory disease and exhibiting depression as a co-morbidity, said method comprising administering an NMD AR antagonist to said subject.

3. A method of mitigating the severity of, mitigating the pathogenesis of, or lowering the incidence of inflammatory disease and suicidality in patients with respiratory disease and exhibiting depression as a co-morbidity, said method comprising administering an NMD AR antagonist to said subject.

4. The method of any one of claims 1-3, wherein said inflammatory disease is mucosal inflammatory disease.

5. The method of any one of claims 1-4, wherein said inflammatory disease is a respiratory disease.

6. The method of any one of claims 1 -4, wherein said inflammatory disease is a disease of the female reproductive tract or peritoneal cavity.

7. The method of claim 6, wherein said disease is endometriosis.

8. The method of any one of claims 1-4, wherein said inflammatory disease is a disease of the gastrointestinal tract.

9. The method of any one of claims 1-4, wherein said inflammatory disease is chronic dental inflammation, including gingivitis.

10. The method of any one of claims 1-8, wherein said NMD AR antagonist is D-cycloserine (DCS).

11. The method of claim 9, wherein said D-cycloserine is administered at a dosage of 150-1500 mg / day.

12. The method of claim 9, wherein the dosage of said D-cycloserine is altered as a function of time during the treatment period.

13. The method of claim 11, wherein said subject is administered D-cycloserine at a first dosage of from about 150 - 500 mg / day for up to 7 days during a first treatment period.

14. The method of claim 11, wherein said subject is administered D-cycloserine at a second dosage of from about 500 - 850 mg / day for up to 14 days during a second treatment period, following said first treatment period.

15. The method of claim 11, wherein said subject is administered D-cycloserine at a third dosage of from about 750 - 1500 mg / day for up to 21 days during a third treatment period, following said second treatment period.

16. The method of any one of claims 1-14, further comprising administering an anti-inflammatory agent comprising Vitamin B6, or one or more corticosteroids, or one or more phosphodiesterase-4 inhibitors, one or more beta blockers such as bisoprolol or any combination thereof.

17. The method of any one of claims 1-14, further comprising administering a non-classical antiinflammatory agent.

18. The method of claim 16, wherein said anti-inflammatory agent comprises erythromycin or azithromycin or other antibiotics.

19. The method of any one of claims 1-14, further comprising administering an anxiolytic agent or mood stabilizing agent.

20. The method of any one of claims 15-18, further comprising administering any combination of said anti-inflammatory agent, anxiolytic agent or mood stabilizing agent.

21. The method of claim 19, wherein said method comprises administering a subclinical dosage of any of said anti-inflammatory agent, anxiolytic agent or mood stabilizing agent.

22. The method of any one of claims 16-21, wherein said anti-inflammatory agent is provided as part of a single composition along with said D-cycloserine.

23. The method of any one of claims 1-22, wherein said treatment reduces pulmonary fibrosis, reduces emphysema, pulmonary inflammation, pulmonary edema, enhances lung function, increases blood oxygenation levels or a combination thereof in said subject.

24. The method of any one of claims 1-22, wherein said method reduces lung inflammation in said subject.

25. The method of any one of claims 1-22, wherein said method modifies an immune response in said subject.

26. The method of any one of claims 1 -22, wherein said method reduces depression symptomatology in said subject.

27. The method of any one of claims 1-22, wherein said method further comprises treating said subject with an adjunct cognitive treatment regimen.

28. The method of any one of claims 1-22, wherein said method treats a subject suffering from or someone who has suffered from COPD, or Covid- 19 and further suffers from depression as a comorbidity.

29. The method of any one of claims 1-22, wherein said method treats a subject suffering from asthma, pulmonary fibrosis or pulmonary arterial hypertension and further suffers from depression as a comorbidity.

30. A composition comprising an NMD AR antagonist and at least one agent selected from the group consisting of: an anti-inflammatory agent, an anxiolytic agent and a mood stabilizing agent, or any combination thereof.

31. The composition of claim 30, wherein said NMD AR antagonist is D-cycloserine (DCS).

32. The composition of claim 31, wherein said D-cycloserine is provided at a dosage of 150-1500 mg / d.

33. The composition of claim 30, wherein said anti-inflammatory agent comprises Vitamin B6, or one or more corticosteroids, or one or more phosphodiesterase-4 inhibitors, one or more beta-blockers or any combination thereof.

34. The composition of claim 30, wherein said anti-inflammatory agent is a non-classical antiinflammatory agent.

35. The composition of claim 34, wherein said anti-inflammatory agent comprises erythromycin or azithromycin or other antibiotics.

36. The composition of claim 30, wherein said composition comprises a subclinical dosage of any of said anti-inflammatory agent, anxiolytic agent or mood stabilizing agent.

37. The composition of any one of claims 30-36, wherein said composition is for use in a subject suffering from a lung disease or disorder and also suffering from depression, as a comorbidity.

38. The composition of claim 37, wherein said composition is for use in treating or reducing pulmonary fibrosis, reducing pulmonary edema, reducing pulmonary emphysema, reducing pulmonary inflammation, enhancing lung function, increasing blood oxygenation levels or a combination thereof in a subject.

39. The composition of claim 37, wherein said composition is for use in reducing lung inflammation in a subject.

40. The composition of claim 37, wherein said composition is for use in modifying an immune response in a subject.

41. The composition of claim 37, wherein said composition is for use in mitigating the severity of, mitigating the pathogenesis of or lowering the incidence of respiratory disease and depression in patients with respiratory disease and exhibiting depression.

42. The composition of claim 37, wherein said composition is for use in mitigating the severity of, mitigating the pathogenesis of or lowering the incidence of Covid-19 or COPD and depression in patients with either Covid- 19 or COPD and exhibiting depression.

43. The composition of claim 37, wherein said composition is for use in mitigating the severity of, mitigating the pathogenesis of or lowering the incidence of respiratory disease and depression in patients with respiratory disease and exhibiting depression.

44. The composition of claim 37, wherein said composition is for use in mitigating the pathogenesis of or lowering the incidence of respiratory disease and suicidality in patients with respiratory disease and exhibiting depression.

45. The composition of any one of claims 37-44, wherein a dosage of D-cycloserine is varied over time during a treatment period constituting said use.

46. The composition of any one of claims 37-45, wherein said D-cycloserine is provided at a first dosage of from about 150 - 500 mg / day for up to at least 7 days during a first period of said treatment period.

47. The composition of any one of claims 37-45, wherein said D-cycloserine is provided at a second dosage of from about 500 - 850 mg / day for up to at least 14 days during a second period of said treatment period.

48. The composition of any one of claims 37-45, wherein said D-cycloserine is provided at a third dosage of from about 750 - 1500 mg / day for up to at least 21 days during a third period of said treatment period.

49. The composition of claim 30, for use in treating a subject suffering from endometriosis.

50. A method for optimizing a therapeutic regimen in a subject, including mitigating the severity of, mitigating the pathogenesis of, or lowering the incidence of disease in a subject suffering from an inflammatory disease, said method comprising determining whether the afflicted subject also exhibits signs of depression, and administering an NMD AR antagonist to said subject optionally with adjunct therapy, thereby optimizing the therapeutic regimen for the subject.

51. A method for optimizing a therapeutic regimen in a subject, including mitigating the severity of, mitigating the pathogenesis of, or lowering the incidence of disease in a subject suffering from a mucosal inflammatory disease, said method comprising administering an NMD AR antagonist to said subject optionally with adjunct therapy, thereby optimizing the therapeutic regimen for the subject.

52. A method for optimizing a therapeutic regimen in a subject, including mitigating the severity of, mitigating the pathogenesis of, or lowering the incidence of disease in a subject suffering from amucosal inflammatory disease, said method comprising identifying a subject afflicted with a mucosal inflammatory disease and receiving a treatment for said disease, determining whether the afflicted subject also exhibits signs of depression, and administering an NMDAR antagonist to said subject while concurrently reducing the dosage or frequency of administration of said treatment of said mucosal inflammatory disease, thereby optimizing the therapeutic regimen for the subject.

53. A method for optimizing a therapeutic regimen in a subject, including mitigating the severity of, mitigating the pathogenesis of, or lowering the incidence of disease in a subject suffering from a mucosal inflammatory disease, said method comprising administering an NMDAR antagonist to said subject while concurrently reducing the dosage or frequency of administration of said treatment of said mucosal inflammatory disease, thereby optimizing the therapeutic regimen for the subject.

54. The method of any one of claims 51 - 54, wherein said inflammatory disease is a respiratory disease.

55. The method of any one of claims 51 - 54, wherein said inflammatory disease is a disease of the female reproductive tract or peritoneal cavity.

56. The method of claim 54, wherein said disease is endometriosis.

57. The method of any one of claims 51-54, wherein said inflammatory disease is a disease of the gastrointestinal tract.

58. The method of any one of claims 51-54, wherein said inflammatory disease is chronic dental inflammation, including gingivitis.

59. The method of any one of claims 51-58, wherein said NMDAR antagonist is D-cycloserine (DCS).

60. The method of claim 59, wherein said D-cycloserine is administered at a dosage of 150- 1500mg / day.

61. The method of claim 59, wherein the dosage of said D-cycloserine is altered as a function of time during the treatment period.

62. The method of claim 61, wherein said subject is administered D-cycloserine at a first dosage of from about 150 - 500 mg / day for up to 7 days during a first treatment period.

63. The method of claim 61, wherein said subject is administered D-cycloserine at a second dosage of from about 500 - 850 mg / day for up to 14 days during a second treatment period, following said first treatment period.

64. The method of claim 61, wherein said subject is administered D-cycloserine at a third dosage of from about 750 - 1500 mg / day for up to 21 days during a third treatment period, following said second treatment period.

65. The method of any one of claims 51-64, further comprising administering an anti-inflammatory agent comprising Vitamin B6, or one or more corticosteroids, or one or more phosphodiesterase-4 inhibitors, one or more beta-blockers or any combination thereof.

66. The method of any one of claims 51 -64, further comprising administering a non-classical antiinflammatory agent.

67. The method of claim 66, wherein said anti-inflammatory agent comprises erythromycin or azithromycin or other antibiotics.

68. The method of any one of claims 51-64, further comprising administering an anxiolytic agent or mood stabilizing agent.

69. The method of any one of claims 63-68, further comprising administering any combination of said anti-inflammatory agent, anxiolytic agent or mood stabilizing agent.

70. The method of claim 69, wherein said method comprises administering a subclinical dosage of any of said anti-inflammatory agent, anxiolytic agent or mood stabilizing agent.

71. The method of any one of claims 63-70, wherein said anti-inflammatory agent is provided as part of a single composition along with said D-cycloserine.

72. The method of any one of claims 51-71, wherein said treatment reduces pulmonary fibrosis, reduces pulmonary edema, reduces emphysema, reduces inflammation, enhances lung function, increases blood oxygenation levels or a combination thereof in said subject.

73. The method of any one of claims 51-71, wherein said method reduces lung inflammation in said subject.

74. The method of any one of claims 51-71, wherein said method modifies an immune response in said subject.

75. The method of any one of claims 51-71, wherein said method reduces depression symptomatology in said subject.

76. The method of any one of claims 51-71, wherein said method further comprises treating said subject with an adjunct cognitive treatment regimen.

77. The method of any one of claims 51-71, wherein said method treats a subject suffering from or someone who has suffered from COPD, or Covid- 19 and further suffers from depression as a comorbidity.

78. The method of any one of claims 51-71, wherein said method treats a subject suffering from asthma, pulmonary fibrosis or pulmonary arterial hypertension and further suffers from depression as a co-morbidity.

79. A method of mitigating, reducing the incidence of, reducing the severity of, reducing the pathogenesis of or treating acute stress disorder, or treating post-traumatic stress disorder or mitigating, or reducing the incidence of, or reducing the severity of, reducing the pathogenesis of post -traumatic stress disorder in a subject, the method comprising administering an NMDAR antagonist to said subject while concurrently reducing the dosage or frequency of administration of said treatment of said mucosal inflammatory disease, thereby optimizing the therapeutic regimen for the subject.

80. The method of claim 79, wherein said NMDAR antagonist is D-cycloserine (DCS).

81. The method of claim 80, wherein said D-cycloserine is administered at a dosage of 150-1500mg / day.

82. The method of claim 80, wherein the dosage of said D-cycloserine is altered as a function of time during the treatment period.

83. The method of claim 80, wherein said subject is administered D-cycloserine at a first dosage of from about 150 - 500 mg / day for up to 7 days during a first treatment period.

84. The method of claim 80, wherein said subject is administered D-cycloserine at a second dosage of from about 500 - 850 mg / day for up to 14 days during a second treatment period, following said first treatment period.

85. The method of claim 80, wherein said subject is administered D-cycloserine at a third dosage of from about 750 - 1500 mg / day for up to 21 days during a third treatment period, following said second treatment period.

86. The method of any one of claims 79-85, further comprising administering an anti-inflammatory agent comprising Vitamin B6, or one or more corticosteroids, or one or more phosphodiesterase-4 inhibitors, one or more beta-blockers or any combination thereof.

87. The method of any one of claims 79-86, further comprising administering a non-classical antiinflammatory agent.

88. The method of claim 87, wherein said anti-inflammatory agent comprises erythromycin or azithromycin or other antibiotics.

89. The method of any one of claims 79-86, further comprising administering an anxiolytic agent or mood stabilizing agent.

90. The method of any one of claims 79-89, further comprising administering any combination of said anti-inflammatory agent, anxiolytic agent or mood stabilizing agent.

91. The method of claim 90, wherein said method comprises administering a subclinical dosage of any of said anti-inflammatory agent, anti-anxiolytic agent or mood stabilizing agent.

92. The method of any one of claims 79-92, wherein said anti-inflammatory agent is provided as part of a single composition along with said D -cycloserine.

93. The method of any one of claims 79-92, wherein said treatment reduces inflammation in said subject.

94. The method of any one of claims 79-93, wherein said method modifies an immune response in said subject.

95. The method of any one of claims 79-94, wherein said method reduces depression symptomatology in said subject.

96. The method of any one of claims 79-94, wherein said method further comprises treating said subject with an adjunct cognitive treatment regimen.

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