Nutritional compositions, supplements, and nutritional fortifiers

Abstract

The present invention relates to a nutritional composition, supplement, or nutritional fortifier comprising L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture. The present invention also relates to a method for enhancing the immune response, a method for treating an infection, a method for preventing an infection, and / or a method for reducing the incidence of an infection, and a method for reducing the occurrence or recurrence of one or more symptoms of an infection, particularly in subjects having tuberculosis.

Description

Technical Field

[0001] The present invention relates to nutritional compositions, supplements, and nutritional fortifiers for dietary management of subjects having an infectious disease and / or having immunodeficiency, particularly subjects having tuberculosis. The present invention also relates to a method of enhancing an immune response, a method of treating an infectious disease, a method of preventing an infectious disease, and / or a method of reducing the occurrence of an infectious disease, or a method of reducing the occurrence or recurrence of one or more symptoms of an infectious disease, particularly in a subject having tuberculosis.

Background Art

[0002] Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis and is one of the major causes of death worldwide. TB has shown a high morbidity rate in socio-economically lower strata and marginalized communities within a population. In India, a national goal of eradicating TB by 2025 has been set by the National Strategic Plan (2017 - 2025) (see, for example, Natarajan, A., et al., 2020. Indian Journal of Tuberculosis, 67(3), pp. 295 - 311).

[0003] Nitric oxide (NO) plays an important role in bacteriostatic and bactericidal processes as part of the host defense mechanism against lung infections. In particular, NO is an important molecule exhibiting antimycobacterial functions and acts regulatoryly on airway function and Mycobacterium tuberculosis growth, and thus is a promising target for anti-TB therapy (see, for example, Jamaati, H., et al., 2017. Frontiers in microbiology, 8, p. 2008).

[0004] L-arginine is a precursor for the endogenous synthesis of NO via NO synthase activity, and L-citrulline is released as a byproduct. L-arginine has been shown to improve clinical outcomes in active TB when used as a chemotherapy adjuvant (see Schon, T., et al., 2003. European Respiratory Journal, 21(3), pp.483-488). L-arginine has also been shown to be useful as an adjuvant therapy in patients with active TB, and its effect is likely mediated by increased NO production (see Farazi, A., et al., 2015. Tuberculosis research and treatment, p.2050-16).

[0005] However, a randomized, double-blind, placebo-controlled trial found that L-arginine supplementation was ineffective in TB patients with pulmonary TB. In pulmonary TB, an immune response that favors arginase production, such as the macrophage type 2 (M2) response, is dominant, and L-arginine can be broken down by arginase into ornithine (and therefore cannot be used for conversion to NO). Increased arginase production has been observed in TB, and it has been hypothesized that arginase overproduction is one of the immune evasion strategies induced by Mycobacterium tuberculosis (see Ralph, AP, et al., 2013. PloS one, 8(8), p.e70032).

[0006] Mycobacterium tuberculosis (Mtb) has developed mechanisms to evade host defense responses and survive for extended periods within host cells, such as macrophages. Mtb is also becoming increasingly resistant to existing anti-TB drugs. Therefore, the development of new therapeutic agents for TB is an urgent task, and host-directed therapeutics (HDTs) have potential as effective treatments for TB.

[0007] Therefore, improved formulations (agents), combinations, or compositions for the dietary management of TB are needed. Improved methods for treating, preventing, and / or reducing the risk of TB occurrence or recurrence are also needed. [Overview of the project]

[0008] The inventors have developed improved nutritional compositions, supplements, and nutritional fortifiers comprising L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture for dietary management of subjects with infectious diseases and / or immunodeficiency, particularly subjects with TB.

[0009] The inventors have also developed a method for treating, preventing, and / or reducing the risk of TB in subjects by administering L-citrulline. The inventors have also developed a method for enhancing the immune response, treating, preventing, and / or reducing the occurrence of infections, or reducing the occurrence or recurrence of one or more symptoms of an infection, particularly in subjects having TB, by administering a combination of L-arginine and L-citrulline.

[0010] In one embodiment, the present invention provides L-citrulline or L-arginine for reducing the intracellular load of Mtb in macrophages.

[0011] L-citrulline supplementation may increase plasma NO levels and decrease arginase activity. Furthermore, supplemental L-citrulline may be more efficient than L-arginine in improving systemic L-arginine utilization. The combination of L-citrulline and L-arginine may act synergistically to enhance the target immune response. Vitamins and minerals may further enhance the target immune response.

[0012] In one embodiment, the present invention provides a nutritional composition, supplement, or nutritional fortifier comprising L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture.

[0013] Nutritional compositions, supplements, or nutritional fortifiers may contain L-arginine and L-citrulline in any amount suitable for enhancing the immune response of the target. Preferably, L-arginine is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides an L-arginine dose of about 0.5 g / day or more. Preferably, L-citrulline is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides an L-citrulline dose of about 0.5 g / day or more. Preferably, L-arginine and L-citrulline are present in weight ratios of about 0.1:1 to about 10:1, about 0.2:1 to about 5:1, about 0.25:1 to about 4:1, about 0.3:1 to about 3:1, about 0.5:1 to about 2:1, or about 1:1.

[0014] Nutritional compositions, supplements, or nutritional fortifiers may contain any vitamin mixture suitable for enhancing the immune response of a target. Preferably, the vitamin mixture contains one or more of the following: vitamin A, vitamin D2, vitamin E, vitamin C, vitamin B1, vitamin B2, niacin, vitamin B6, folic acid, and vitamin B12. In some embodiments, the vitamin mixture contains vitamin A, vitamin D2, vitamin E, vitamin C, vitamin B1, vitamin B2, niacin, vitamin B6, folic acid, and vitamin B12. In some embodiments, each of vitamin A, vitamin D2, vitamin E, vitamin C, vitamin B1, vitamin B2, niacin, vitamin B6, folic acid, and vitamin B12 is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides each vitamin at a dose of approximately 50% RDA / day or more.

[0015] Nutritional compositions, supplements, or nutritional fortifiers may contain any mineral mixture suitable for enhancing the immune response of the target. Preferably, the mineral mixture contains one or more of potassium, magnesium, iron, zinc, and selenium. In some embodiments, the mineral mixture contains potassium, magnesium, iron, zinc, and selenium. In some embodiments, each of potassium, magnesium, iron, zinc, and selenium is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides each mineral at a dose of approximately 15% RDA / day or more. In some embodiments, each of iron, zinc, and selenium is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides each mineral at a dose of approximately 30% RDA / day or more.

[0016] The nutritional composition, supplement, or fortifier may further comprise any mixture suitable for enhancing the target immune response, including antioxidants. Suitable antioxidants include one or more of glutathione, coenzyme Q10, lipoic acid, flavonoids, phenols, polyphenols, and phytoestrogens. In some embodiments, the antioxidant is present in an amount that provides the nutritional composition, supplement, or fortifier with at least approximately 15% RDA / day. In some embodiments, the antioxidant is present in an amount that provides the nutritional composition, supplement, or fortifier with at least approximately 30% RDA / day. The recommended daily dose corresponds to 8 to 11,000 antioxidant units per day.

[0017] Nutritional compositions, supplements, or nutritional fortifiers may further comprise any mixture containing fiber that is suitable for promoting the gastrointestinal health of the subject. Suitable fibers include one or more of soluble fiber, insoluble fiber, inulin, or plant gum.

[0018] Soluble or insoluble fiber may be beneficial in alleviating symptoms of diarrhea or constipation and gastrointestinal discomfort.

[0019] Inulin and oligosaccharides may contribute to anti-inflammatory effects on the intestines. They may also increase the absorption of calcium, magnesium, and iron.

[0020] Plant-based gum fibers such as guar gum and gum arabic may further contribute to alleviating symptoms of gastrointestinal discomfort.

[0021] In some embodiments, fiber is present in an amount that provides a nutritional composition, supplement, or nutritional fortifier with a dose of approximately 15% RDA / day or more. In some embodiments, fiber is present in an amount that provides a nutritional composition, supplement, or nutritional fortifier with a dose of approximately 30% RDA / day or more. The recommended daily dose corresponds to 20g to 30g of dietary fiber per day.

[0022] Nutritional compositions, supplements, or nutritional fortifiers may further contain any other suitable ingredients and may be provided in any suitable form. Preferably, nutritional compositions, supplements, or nutritional fortifiers further contain carbohydrates and / or proteins. Preferably, nutritional compositions, supplements, or nutritional fortifiers are in powder form.

[0023] In one embodiment, the nutritional composition, supplement, or nutritional fortifier is a food for special dietary uses. Foods for special dietary uses may be provided in powder form for reconstitution with water or milk. Foods for special dietary uses may be nutritionally complete.

[0024] In another embodiment, the nutritional composition, supplement, or nutritional fortifier is a food for special dietary uses. Foods for special dietary uses may be provided in the form of a liquid, gel, or spoonable food. Foods for special dietary uses may be nutritionally complete.

[0025] Foods for special dietary uses may contain L-arginine, L-citrulline, vitamins, minerals, antioxidants, and fiber, as well as other ingredients, in any amount suitable for enhancing the target immune response.

[0026] Preferably, the special-purpose food contains L-arginine in an amount of about 1 g / serving or more. Preferably, the special-purpose food contains L-citrulline in an amount of 1 g / serving or more. Preferably, the special-purpose food contains (a) L-arginine in an amount of about 1 g / serving or more and (b) L-citrulline in an amount of about 1 g / serving or more.

[0027] Preferably, the special-purpose food contains (a) vitamin A in an amount of about 300 μg RE / serving or more, (b) vitamin D2 in an amount of about 5 μg / serving or more, (c) vitamin E in an amount of about 3 mg TE / serving or more, (d) vitamin C in an amount of about 25 mg / serving or more, (e) vitamin B1 in an amount of about 0.5 mg / serving or more, (f) vitamin B2 in an amount of about 0.7 mg / serving or more, (g) niacin in an amount of about 5 mg / serving or more, (h) vitamin B6 in an amount of about 0.6 mg / serving or more, (i) folic acid in an amount of about 60 μg / serving or more, and (j) vitamin B12 in an amount of about 0.7 μg / serving or more.

[0028] Preferably, the special-purpose food contains (a) potassium in an amount of about 250 mg / serving or more, (b) magnesium in an amount of about 30 mg / serving or more, (c) iron in an amount of about 4 mg / serving or more, (d) zinc in an amount of about 2 mg / serving or more, and (e) selenium in an amount of about 6 μg / serving or more.

[0029] Preferably, the special-purpose food contains (a) protein in an amount of about 8 g / serving to about 14 g / serving, about 10 g / serving to about 12 g / serving, or about 11 g / serving, (b) fat in an amount of about 5 g / serving to about 10 g / serving, about 6 g / serving to about 9 g / serving, or about 7.5 g / serving, and (c) carbohydrates in an amount of about 20 g / serving to about 35 g / serving, about 25 g / serving to about 30 g / serving, or about 27 g / serving.

[0030] Preferably, the special-purpose food contains about 100 to about 300 kcal / serving, about 150 to about 250 kcal / serving, or about 200 kcal / serving.

[0031] In one embodiment, the nutritional composition, supplement, or fortifier is a nutritional supplement. The nutritional supplement may be a powder supplement for sprinkling on food or beverages.

[0032] In another embodiment, the nutritional composition, supplement or fortifier is a nutritional supplement in the form of a liquid, gel, or spoonable food.

[0033] The nutritional supplement may contain L-arginine, L-citrulline, vitamins, minerals, and other ingredients in any amount suitable for enhancing the immune response of the subject.

[0034] Preferably, the nutritional supplement contains L-arginine in an amount of about 0.5 g / serving or more. Preferably, the nutritional supplement contains L-citrulline in an amount of about 0.5 g / serving or more. Preferably, the nutritional supplement contains (a) L-arginine in an amount of about 0.5 g / serving or more and (b) L-citrulline in an amount of about 0.5 g / serving or more.

[0035] Preferably, the nutritional supplement contains (a) vitamin A in an amount of about 200 μg RE / serving or more, (b) vitamin D2 in an amount of about 3 μg / serving or more, (c) vitamin E in an amount of about 2 mg TE / serving or more, (d) vitamin C in an amount of about 16 mg / serving or more, (e) vitamin B1 in an amount of about 0.3 mg / serving or more, (f) vitamin B2 in an amount of about 0.4 mg / serving or more, (g) niacin in an amount of about 3 mg / serving or more, (h) vitamin B6 in an amount of about 0.4 mg / serving or more, (i) folic acid in an amount of about 36 μg / serving or more, and (j) vitamin B12 in an amount of about 0.4 μg / serving or more.

[0036] Preferably, the nutritional supplement contains (a) at least 250 mg of potassium per serving, (b) at least 33 mg of magnesium per serving, (c) at least 5 mg of iron per serving, (d) at least 3 mg of zinc per serving, and (e) at least 5 μg of selenium per serving.

[0037] Nutritional compositions, supplements, or nutritional fortifiers may be used for the dietary management of subjects with infectious diseases and / or immunodeficiency, particularly for the dietary management of subjects with tuberculosis (TB).

[0038] In another aspect, the present invention provides a method for enhancing the immune response of a subject, comprising administering a nutritional composition, supplement, or nutritional fortifier according to the present invention to the subject.

[0039] In another aspect, the present invention provides a method for treating, preventing, and / or reducing the risk of an infectious disease in a subject, comprising administering a nutritional composition, supplement, or nutritional fortifier according to the present invention to the subject.

[0040] In another aspect, the present invention provides a method for preventing tuberculosis by keeping it under control in a latent state, the method comprising administering a nutritional composition, supplement, or nutritional fortifier according to the present invention to a subject.

[0041] In a preferred embodiment, the infection is tuberculosis (TB). In a more preferred embodiment, the infection is pulmonary TB.

[0042] In another aspect, the present invention provides a method for treating, preventing, and / or reducing the risk of developing one or more symptoms of an infectious disease in a subject, comprising administering a nutritional composition, supplement, or nutritional fortifier according to the present invention to the subject. The symptoms of the infectious disease may be selected from (i) a positive sputum culture, (ii) cough, (iii) chest pain, (iv) fever, (v) nocturnal sweating, (vi) hemoptysis, (vii) dyspnea, and (viii) GI symptoms of diarrhea or constipation.

[0043] In another aspect, the present invention provides a method for promoting wound healing in a subject, comprising administering a nutritional composition, supplement, or nutritional fortifier according to the present invention to the subject.

[0044] In another aspect, the present invention provides a method for treating or preventing chronic obstructive pulmonary disease (COPD) in a subject, comprising administering a nutritional composition, supplement, or nutritional fortifier according to the present invention to the subject.

[0045] In another aspect, the present invention provides L-citrulline for use in the treatment, prevention, and / or reduction of the risk of tuberculosis (TB) in a subject.

[0046] In another aspect, the present invention provides a method for treating tuberculosis (TB) in a subject or reducing the risk thereof, comprising administering a therapeutically effective amount of L-citrulline to the subject.

[0047] In another aspect, the present invention provides a method for reducing the occurrence of one or more symptoms of an infection in a subject having tuberculosis (TB), comprising administering a therapeutically effective amount of L-citrulline to the subject, wherein the symptoms of the infection are selected from (i) a positive sputum culture, (ii) cough, (iii) chest pain, (iv) fever, (v) nocturnal sweating, (vi) hemoptysis, (vii) dyspnea, and (viii) GI symptoms of diarrhea or constipation.

[0048] L-citrulline can be administered to a subject by any preferred route and in any preferred dose. Preferably, L-citrulline is administered orally to the subject. Preferably, L-citrulline is administered to the subject in an amount of about 0.5 g / day or more. Preferably, L-citrulline is administered to the subject in the form of a nutritional composition, supplement, or nutritional fortifier, for example, the above-mentioned nutritional composition, supplement, or nutritional fortifier.

[0049] L-citrulline can be administered in combination with L-arginine. L-citrulline and L-arginine can be administered simultaneously. Preferably, L-arginine is administered in an amount of about 0.5 g / day or more.

[0050] L-citrulline may be administered to a patient as an adjunct therapy, for example, when the primary treatment is an antimicrobial agent. One or more symptoms of an infection may be reduced or prevented in the patient, for example, the symptoms of the infection are selected from (i) a positive sputum culture, (ii) cough, (iii) chest pain, (iv) fever, (v) nocturnal sweating, (vi) hemoptysis, (vii) dyspnea, and (viii) GI symptoms of diarrhea or constipation.

[0051] In another aspect, the present invention provides a combination of L-arginine and L-citrulline for use in enhancing the immune response of a target.

[0052] In another aspect, the present invention provides a combination of L-arginine and L-citrulline for use in treating, preventing, and / or reducing the risk of infection in a subject.

[0053] In another embodiment, the present invention provides a combination of L-arginine and L-citrulline for use in promoting wound healing in a subject.

[0054] In another aspect, the present invention provides a combination of L-arginine and L-citrulline for use in the treatment and / or prevention of chronic obstructive pulmonary disease (COPD) in a subject.

[0055] In another aspect, the present invention provides a method for enhancing the immune response of a subject, comprising administering an effective amount of a combination of L-arginine and L-citrulline to the subject.

[0056] In another aspect, the present invention provides a method for treating an infection in a subject or reducing the risk thereof, comprising administering an effective amount of a combination of L-arginine and L-citrulline to the subject.

[0057] In another aspect, the present invention provides a method for reducing the occurrence of one or more symptoms of an infectious disease in a subject, comprising administering an effective amount of a combination of L-arginine and L-citrulline to the subject, for example, the symptoms of the infectious disease being selected from (i) a positive sputum culture, (ii) cough, (iii) chest pain, (iv) fever, (v) nocturnal sweating, (vi) hemoptysis, (vii) dyspnea, and (viii) GI symptoms of diarrhea or constipation.

[0058] In another aspect, the present invention provides a method for promoting wound healing in a subject, comprising administering an effective amount of a combination of L-arginine and L-citrulline to the subject.

[0059] In another aspect, the present invention provides a method for treating and / or preventing chronic obstructive pulmonary disease (COPD) in a subject, comprising administering an effective amount of a combination of L-arginine and L-citrulline to the subject.

[0060] This combination can be administered to a subject by any preferred route and in any preferred dosage. L-citrulline may be administered to a subject in an amount of approximately 0.5 g / day or more, and / or L-arginine may be administered to a subject in an amount of approximately 0.5 g / day or more. The combination of L-citrulline and L-arginine may be administered to the subject simultaneously. This combination may be administered orally to the subject. This combination may be administered to the subject in the form of a nutritional composition, supplement, or nutritional fortifier, for example, the above-mentioned nutritional composition, supplement, or nutritional fortifier.

[0061] The subject can be any subject that requires it. Preferably, the subject is an adult human. In some embodiments, the subject has immunodeficiency or is at risk of immunodeficiency. [Brief explanation of the drawing]

[0062] [Figure 1] The synthesis and metabolic pathways of arginine are shown. L-arginine is metabolized to NO and L-citrulline by nitric oxide synthase (NOS), or hydrolyzed to L-ornithine and urea by arginase. [Figure 2A] Arginine and citrulline reduce intracellular Mtb load in macrophages. Both L-arginine and L-citrulline have been shown to reduce intracellular Mtb load in macrophages over 120 hours post-infection compared to untreated patients. [Figure 2B] Arginine and citrulline reduce intracellular Mtb load in macrophages. Both L-arginine and L-citrulline have been shown to reduce intracellular Mtb load in macrophages over 120 hours post-infection compared to untreated patients. [Modes for carrying out the invention]

[0063] Herein, various preferred features and embodiments of the present invention are described by non-limiting examples.

[0064] When used in this specification and the appended claims, it should be noted that the singular forms "a," "an," and "the" refer to multiple subjects unless otherwise indicated.

[0065] As used herein, the terms “comprising,” “comprises,” and “comprised of” are synonymous with “including,” “includes,” “containing,” or “contains,” and are all-encompassing, i.e., open-ended, and do not exclude additional, unlisted components, elements, or processes. The terms “comprising,” “comprises,” and “comprised of” also include the term “consisting of.”

[0066] A numerical range includes the number that defines that range. As used herein, the term “about” means approximately, nearly, roughly, or near. When the term “about” is used with a number or range, the value or range is modified by extending the upper and lower boundaries of the stated number(s). Generally, the terms “about” and “near” are used herein to adjust numbers(s) that are more or less than 10% above and below a given value(s).

[0067] The publications discussed herein are provided simply because they were disclosed prior to the filing date of this application. No document cited herein should be construed as constituting prior art with respect to the claims attached herein.

[0068] This disclosure is not limited to the exemplary methods and materials disclosed herein, and any methods and materials similar or equivalent to those described herein may be used in carrying out or testing the embodiments of this disclosure. Those skilled in the art will understand that all features of the invention disclosed herein can be combined without departing from the scope of the disclosed invention.

[0069] All publications referenced herein are incorporated herein by reference.

[0070] Nutritional compositions, supplements, and nutritional fortifiers In one embodiment, the present invention provides a nutritional composition, supplement, or nutritional fortifier comprising L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture.

[0071] L-arginine L-arginine (also known as 2-amino-5-guanidinopentanoic acid) is classified as a conditionally essential or semi-essential amino acid. Animal sources of L-arginine include meat, dairy products, and eggs, while plant sources include all types of seeds, such as grains, beans, and nuts. L-arginine has the following formula:

[0072] [ka]

[0073] L-arginine is a precursor for the endogenous synthesis of nitric oxide (NO) via NO synthase (NOS) activity, and NOS releases L-citrulline as a byproduct (see Figure 1). L-arginine has been shown to be useful as an adjunctive therapy in patients with active tuberculosis, and its effect is likely mediated by increased NO production (see Farazi, A., et al., 2015. Tuberculosis research and treatment, p. 2050-16).

[0074] Nutritional compositions, supplements, or nutritional fortifiers can be formulated so that L-arginine is administered in a therapeutically effective dose. Those skilled in the art can adjust the amount of L-arginine in the nutritional composition, supplement, or nutritional fortifier to achieve a desired dose, for example, as described in the section titled “Route of Administration and Dosage” below.

[0075] Preferably, L-arginine is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides an L-arginine dose of approximately 0.5 g / day or more, approximately 1.0 g / day or more, approximately 1.5 g / day or more, approximately 2.0 g / day or more, or approximately 2.5 g / day or more. Preferably, L-arginine is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides an L-arginine dose of approximately 10.0 g / day or less.

[0076] In some embodiments, L-arginine is present in such an amount that the nutritional composition, supplement, or nutritional fortifier provides an L-arginine dose of approximately 0.5 g / day or more.

[0077] In some embodiments, L-arginine is present in such an amount that the nutritional composition, supplement, or nutritional fortifier provides an L-arginine dose of approximately 1.0 g / day or more.

[0078] Nutritional compositions, supplements, or nutritional fortifiers may be formulated to administer L-arginine in a suitable amount per serving. As used herein, “serving” may refer to the recommended or typical amount of product to be administered at one time. As used herein, “per serving” on food packaging may refer to the nutritional information provided on the label and how it relates to a single serving of product.

[0079] Preferably, the nutritional composition, supplement, or nutritional fortifier contains L-arginine in an amount of approximately 0.1 g / serving or more, approximately 0.2 g / serving or more, approximately 0.3 g / serving or more, approximately 0.4 g / serving or more, approximately 0.5 g / serving or more, approximately 1.0 g / serving or more, approximately 1.5 g / serving or more, approximately 2.0 g / serving or more, or approximately 2.5 g / serving or more. Preferably, the nutritional composition, supplement, or nutritional fortifier contains L-arginine in an amount of approximately 10.0 g / serving or less.

[0080] In some embodiments, the nutritional composition, supplement, or fortifier contains L-arginine in an amount of about 0.5 g / serving or more. In some embodiments, the nutritional composition, supplement, or fortifier contains L-arginine in an amount of about 1.0 g / serving or more.

[0081] In some embodiments, the nutritional composition, supplement, or fortifier contains L-arginine in an amount of about 0.5 g / serving. In some embodiments, the nutritional composition, supplement, or fortifier contains L-arginine in an amount of about 1.0 g / serving.

[0082] Preferably, the nutritional composition, supplement, or nutritional fortifier contains L-arginine in an amount of about 0.1% or more by dry weight, about 0.2% or more by dry weight, about 0.3% or more by dry weight, about 0.4% or more by dry weight, about 0.5% or more by dry weight, about 1.0% or more by dry weight, about 1.5% or more by dry weight, about 2.0% or more by dry weight, or about 2.5% or more by dry weight. Preferably, the nutritional composition, supplement, or nutritional fortifier contains L-arginine in an amount of about 10.0% or less by dry weight.

[0083] Preferably, the nutritional composition, supplement, or nutritional fortifier contains L-arginine in an amount of approximately 0.1g / 100kcal or more, approximately 0.2g / 100kcal or more, approximately 0.3g / 100kcal or more, approximately 0.4g / 100kcal or more, approximately 0.5g / 100kcal or more, approximately 1.0g / 100kcal or more, approximately 1.5g / 100kcal or more, approximately 2.0g / 100kcal or more, or approximately 2.5g / 100kcal or more. Preferably, the nutritional composition, supplement, or nutritional fortifier contains L-arginine in an amount of approximately 10.0g / 100kcal or less.

[0084] L-citrulline L-citrulline (also known as 2-amino-5-(carbamoylamino)pentanoic acid) is a non-protein-building amino acid and is most abundant in melons. L-citrulline has the following formula:

[0085] [ka]

[0086] L-citrulline supplementation has been shown to increase plasma NO levels and decrease arginase activity in patients with type 2 diabetes (see Shatanawi, A., et al., 2020. Frontiers in pharmacology, 11, pp. 584669). Furthermore, supplemental L-citrulline may be more efficient than L-arginine in improving systemic L-arginine utilization (see Agarwal, U., et al., 2017. The Journal of Nutrition, 147(4), pp. 596-602).

[0087] L-citrulline supplementation may also contribute to reversing resistance in mycobacteria to antibiotics. For example, exogenous citrulline has been shown to contribute to reversing resistance in Salmonella to apramycin (see Yong, Y., et al., 2021. Frontiers in Microbiology, 12, pp. 759-170).

[0088] Nutritional compositions, supplements, or fortifiers can be formulated so that L-citrulline is administered in a therapeutically effective dose. Those skilled in the art can adjust the amount of L-citrulline in the nutritional composition, supplement, or fortifier to achieve a desired dose, for example, as described in the section titled “Route of Administration and Dosage” below.

[0089] Preferably, L-citrulline is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides an L-citrulline dose of approximately 0.5 g / day or more, approximately 1.0 g / day or more, approximately 1.5 g / day or more, approximately 2.0 g / day or more, or approximately 2.5 g / day or more. Preferably, L-citrulline is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides an L-citrulline dose of approximately 10.0 g / day or less.

[0090] In some embodiments, L-citrulline is present in such an amount that the nutritional composition, supplement, or nutritional fortifier provides a dose of approximately 0.5 g / day or more of L-citrulline.

[0091] In some embodiments, L-citrulline is present in such an amount that the nutritional composition, supplement, or nutritional fortifier provides a dose of L-citrulline of approximately 1.0 g / day or more.

[0092] Nutritional compositions, supplements, or nutritional fortifiers can be formulated so that L-citrulline is administered in a suitable amount per serving.

[0093] Preferably, the nutritional composition, supplement, or nutritional fortifier contains L-citrulline in an amount of approximately 0.1 g / serving or more, approximately 0.2 g / serving or more, approximately 0.3 g / serving or more, approximately 0.4 g / serving or more, approximately 0.5 g / serving or more, approximately 1.0 g / serving or more, approximately 1.5 g / serving or more, approximately 2.0 g / serving or more, or approximately 2.5 g / serving or more. Preferably, the nutritional composition, supplement, or nutritional fortifier contains L-citrulline in an amount of approximately 10.0 g / serving or less.

[0094] In some embodiments, the nutritional composition, supplement, or fortifier contains L-citrulline in an amount of about 0.5 g / serving or more. In some embodiments, the nutritional composition, supplement, or fortifier contains L-citrulline in an amount of about 1.0 g / serving or more.

[0095] In some embodiments, the nutritional composition, supplement, or fortifier contains L-citrulline in an amount of about 0.5 g / serving. In some embodiments, the nutritional composition, supplement, or fortifier contains L-citrulline in an amount of about 1.0 g / serving.

[0096] Preferably, the nutritional composition, supplement, or nutritional fortifier contains L-citrulline in an amount of about 0.1% or more by dry weight, about 0.2% or more by dry weight, about 0.3% or more by dry weight, about 0.4% or more by dry weight, about 0.5% or more by dry weight, about 1.0% or more by dry weight, about 1.5% or more by dry weight, about 2.0% or more by dry weight, or about 2.5% or more by dry weight. Preferably, the nutritional composition, supplement, or nutritional fortifier contains L-citrulline in an amount of about 10.0% or less by dry weight.

[0097] Preferably, the nutritional composition, supplement, or nutritional fortifier contains L-citrulline in an amount of approximately 0.1 g / 100 kcal or more, approximately 0.2 g / 100 kcal or more, approximately 0.3 g / 100 kcal or more, approximately 0.4 g / 100 kcal or more, approximately 0.5 g / 100 kcal or more, approximately 1.0 g / 100 kcal or more, approximately 1.5 g / 100 kcal or more, approximately 2.0 g / 100 kcal or more, or approximately 2.5 g / 100 kcal or more. Preferably, the nutritional composition, supplement, or nutritional fortifier contains L-citrulline in an amount of approximately 10.0 g / 100 kcal or less.

[0098] A combination of L-arginine and L-citrulline Nutritional compositions, supplements, or nutritional fortifiers can be formulated such that L-arginine and L-citrulline are present in a therapeutically effective ratio. Preferably, L-arginine and L-citrulline are present in weight ratios of about 0.1:1 to about 10:1, about 0.2:1 to about 5:1, about 0.25:1 to about 4:1, about 0.3:1 to about 3:1, about 0.5:1 to about 2:1, or about 1:1.

[0099] In some embodiments, L-arginine and L-citrulline are present in a weight ratio of approximately 1:1.

[0100] Preferably, (a) L-arginine is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides an L-arginine dose of about 0.5 g / day or more and / or about 10.0 g / day or less, and (b) L-citrulline is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides an L-citrulline dose of about 0.5 g / day or more and / or about 10.0 g / day or less.

[0101] In some embodiments, (a) L-arginine is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides an L-arginine dose of about 0.5 g / day or more, and (b) L-citrulline is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides an L-citrulline dose of about 0.5 g / day or more.

[0102] In some embodiments, (a) L-arginine is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides an L-arginine dose of approximately 1.0 g / day or more, and (b) L-citrulline is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides an L-citrulline dose of approximately 1.0 g / day or more.

[0103] In some embodiments, (a) L-arginine is present in such an amount that the nutritional composition, supplement, or nutritional fortifier provides a dose of approximately 0.5 g / day of L-arginine, and (b) L-citrulline is present in such an amount that the nutritional composition, supplement, or nutritional fortifier provides a dose of approximately 0.5 g / day of L-citrulline.

[0104] In some embodiments, (a) L-arginine is present in such an amount that the nutritional composition, supplement, or nutritional fortifier provides a dose of approximately 1.0 g / day of L-arginine, and (b) L-citrulline is present in such an amount that the nutritional composition, supplement, or nutritional fortifier provides a dose of approximately 1.0 g / day of L-citrulline.

[0105] Preferably, the nutritional composition, supplement, or nutritional fortifier comprises (a) L-arginine in an amount of about 0.1 g / serving or more and / or about 10.0 g / serving or less, and (b) L-citrulline in an amount of about 0.1 g / serving or more and / or about 10.0 g / serving or less.

[0106] In some embodiments, the nutritional composition, supplement, or nutritional fortifier comprises (a) L-arginine in an amount of about 0.5 g / serving or more, and (b) L-citrulline in an amount of about 0.5 g / serving or more.

[0107] In some embodiments, the nutritional composition, supplement, or nutritional fortifier comprises (a) L-arginine in an amount of about 1.0 g / serving or more, and (b) L-citrulline in an amount of about 1.0 g / serving or more.

[0108] In some embodiments, the nutritional composition, supplement, or nutritional fortifier comprises (a) L-arginine in an amount of about 0.5 g / serving and (b) L-citrulline in an amount of about 0.5 g / serving.

[0109] In some embodiments, the nutritional composition, supplement, or nutritional fortifier comprises (a) L-arginine in an amount of about 1.0 g / serving, and (b) L-citrulline in an amount of about 1.0 g / serving.

[0110] Preferably, the nutritional composition, supplement, or nutritional fortifier comprises (a) L-arginine in an amount of about 0.1% by weight or more and / or about 10.0% by weight or less, on a dry weight basis, and (b) L-citrulline in an amount of about 0.1% by weight or more and / or about 10.0% by weight or less, on a dry weight basis.

[0111] Preferably, the nutritional composition, supplement, or nutritional fortifier comprises (a) L-arginine in an amount of about 0.1 g / 100 kcal or more and / or about 10.0 g / 100 kcal or less, and (b) L-citrulline in an amount of about 0.1 g / 100 kcal or more and / or about 10.0 g / 100 kcal or less.

[0112] Vitamin mixture As used herein, “vitamin mixture” may mean a mixture of one or more vitamins. Vitamins are organic micronutrients that the body requires to perform a set of normal functions, and examples of vitamins include vitamin A, vitamin D2, vitamin E, vitamin K1, vitamin C, vitamin B1, vitamin B2, niacin (or vitamin B3), pantothenic acid (or vitamin B5), vitamin B6, folic acid (or vitamin B9), vitamin B12, and biotin (or vitamin B7).

[0113] Preferably, the vitamin mixture contains one or more vitamins that enhance the target immune response. Several major vitamins, such as vitamins A, B, C, D, and E, have been reported to boost the immune system by enhancing the activity of immune cells during any pathogen attack (see, for example, Aslam, F., et al., 2017. Vitamins & Minerals, 6(1), p.1000153).

[0114] Preferably, the vitamin mixture may contain one or more vitamins selected from vitamin A, vitamin D2, vitamin E, vitamin C, vitamin B1, vitamin B2, niacin, vitamin B6, folic acid, and vitamin B12.

[0115] In some embodiments, the vitamin mixture contains two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, or nine or more vitamins selected from vitamin A, vitamin D2, vitamin E, vitamin C, vitamin B1, vitamin B2, niacin, vitamin B6, folic acid, and vitamin B12.

[0116] In some embodiments, the vitamin mixture comprises or consists of vitamin A, vitamin D2, vitamin E, vitamin C, vitamin B1, vitamin B2, niacin, vitamin B6, folic acid, and vitamin B12.

[0117] In some embodiments, the vitamin mixture comprises or consists of vitamin A, vitamin D2, vitamin E, vitamin K1, vitamin C, vitamin B1, vitamin B2, niacin, pantothenic acid, vitamin B6, folic acid, vitamin B12, and biotin.

[0118] Nutritional compositions, supplements, or fortifiers can be formulated so that vitamins are administered in therapeutically effective doses. Those skilled in the art can adjust the amount of vitamins in the nutritional composition, supplement, or fortifier to achieve a desired dose. Suitable doses are known in the art and may be expressed as "Recommended Dietary Allowances" or "RDAs."

[0119] The RDA can refer to the average daily intake level sufficient to meet the nutritional requirements of nearly all healthy individuals (e.g., 97-98% of individuals) and is typically used to plan nutritionally appropriate meals for individuals (see, for example, Recommended Dietary Allowance: 10th Edition. Washington (DC): National Academies Press (US); 1989).

[0120] Preferably, each vitamin is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides each vitamin at a dose of approximately 10% RDA / day or more, approximately 20% RDA / day or more, approximately 30% RDA / day or more, approximately 40% RDA / day or more, approximately 50% RDA / day or more, approximately 60% RDA / day or more, approximately 70% RDA / day or more, or approximately 80% RDA / day or more. Preferably, each vitamin is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides each vitamin at a dose of approximately 100% RDA / day or less.

[0121] In some embodiments, each vitamin is present in such an amount that the nutritional composition, supplement, or nutritional fortifier provides each vitamin at a dose of approximately 50% RDA / day or more.

[0122] Preferably, the nutritional composition, supplement, or fortifier contains each vitamin in an amount of approximately 10% RDA / serving or more, approximately 20% RDA / serving or more, approximately 30% RDA / serving or more, approximately 40% RDA / serving or more, approximately 50% RDA / serving or more, approximately 60% RDA / serving or more, approximately 70% RDA / serving or more, or approximately 80% RDA / serving or more. Preferably, the nutritional composition, supplement, or fortifier contains each vitamin in an amount of approximately 100% RDA / serving or less.

[0123] In some embodiments, the nutritional composition, supplement, or nutritional fortifier contains each vitamin in an amount of approximately 40% RDA / serving or more.

[0124] Vitamin A In some embodiments, the vitamin mixture includes vitamin A.

[0125] Vitamin A can refer to the lipid-soluble compound all-trans-retinol, and is also commonly used to refer to retinol and its active metabolites, including retinal, retinyl esters, and retinoic acid. Vitamin A is known as an anti-inflammatory vitamin due to its important role in enhancing immune function, participating in the development of the immune system and playing a regulatory role in cellular and humoral immune responses. Vitamin A has shown therapeutic effects in the treatment of various infectious diseases (see, for example, Huang, Z., et al., 2018. Role of vitamin A in the immune system. Journal of clinical medicine, 7(9), p.258).

[0126] The appropriate dosage of vitamin A is known to those skilled in the art. For example, the RDA of vitamin A may be about 500 μgRE to about 1500 μgRE. For example, the RDA of vitamin A may be about 1000 μgRE. "RE" may refer to retinol equivalents, where 1 μg of retinol = 6 μg of β-carotene = 12 μg of other active carotenoids.

[0127] Vitamin D In some embodiments, the vitamin mixture contains vitamin D. In some embodiments, the vitamin mixture contains vitamin D2.

[0128] Several forms of vitamin D exist. The two main forms are vitamin D2 and vitamin D3. Vitamin D2 is commonly known as ergocalciferol, and vitamin D3 is commonly known as cholecalciferol. Vitamin D plays an important role in regulating the human immune response, and its activity in the expression of genes that produce proteins toxic to numerous foreign microorganisms is well known (see, for example, Mora, JR, et al., 2008. Nature reviews immunology, 8(9), pp.685-698).

[0129] Suitable dosages of vitamin D (e.g., vitamin D2) are known to those skilled in the art. For example, the RDA of vitamin D2 may be about 10 μg to about 20 μg. For example, the RDA of vitamin D2 may be about 15 μg.

[0130] Vitamin E In some embodiments, the vitamin mixture includes vitamin E.

[0131] Vitamin E can refer to a group of eight lipid-soluble compounds, including four tocopherols and four tocotrienols (alpha, beta, gamma, and delta). Vitamin E deficiency has been shown to impair the normal function of the immune system in animals and humans, and this can be corrected by vitamin E supplementation (see, for example, Lewis, ED, et al., 2019. IUBMB life, 71(4), pp. 487-494).

[0132] Suitable dosages of vitamin E are known to those skilled in the art. For example, the RDA of vitamin E may be about 5 μg TE to about 15 μg TE. For example, the RDA of vitamin E may be about 10 μg TE. The nutritional value of vitamin E can be defined based on its equivalence with α-tocopherol activity.

[0133] Vitamin C In some embodiments, the vitamin mixture includes vitamin C.

[0134] Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus fruits and other fruits and vegetables. Vitamin C contributes to immune defense by supporting various cellular functions in both the innate and adaptive immune systems (see, for example, Carr, AC and Maggini, S., 2017. Nutrients, 9(11), p. 1211).

[0135] The appropriate dosage of vitamin C is known to those skilled in the art. For example, the RDA of vitamin C may be about 60 mg to about 100 mg. For example, the RDA of vitamin C may be about 80 mg.

[0136] Vitamin B1 In some embodiments, the vitamin mixture contains vitamin B1.

[0137] Vitamin B1 (also known as thiamine) is necessary for the body's efficient breakdown of carbohydrates. Vitamin B1 is found in a range of foods, including grains, nuts, beans, yeast, and meat. Vitamin B1 is known to have a protective effect against oxidative retinal damage induced by anti-tuberculosis drugs and may help limit the growth of Mycobacterium tuberculosis by modulating innate immunity (Hu, S., et al., 2018. Frontiers in immunology, 9, p.1778).

[0138] The appropriate dosage of vitamin B1 is known to those skilled in the art. For example, the RDA of vitamin B1 may be about 1.0 mg to about 2.0 mg. For example, the RDA of vitamin B1 may be about 1.4 mg.

[0139] Vitamin B2 In some embodiments, the vitamin mixture includes vitamin B2.

[0140] Vitamin B2 (also known as riboflavin) is essential for the formation of two major coenzymes, flavin mononucleotide and flavin adenine dinucleotide. These coenzymes are involved in energy metabolism, cellular respiration, antibody production, and normal growth and development. Vitamin B2 plays a role in oxidative metabolism and has anti-inflammatory properties (see, for example, Mikkelsen, K. and Apostolopoulos, V., 2019. Nutrition and Immunity, pp. 115-125).

[0141] The appropriate dosage of vitamin B2 is known to those skilled in the art. For example, the RDA of vitamin B2 may be about 1.0 mg to about 2.5 mg. For example, the RDA of vitamin B2 may be about 2.0 mg.

[0142] Vitamin B3 In some embodiments, the vitamin mixture contains vitamin B3. In some embodiments, the vitamin mixture contains niacin.

[0143] Vitamin B3 can refer to a vitamin family that includes three forms, namely vitamers: niacin (nicotinic acid), nicotinamide (niacinamide), and nicotinamide riboside. All three forms are converted to nicotinamide adenine dinucleotide (NAD) in the body. Nicotinamide adenine dinucleotide is a central coenzyme in metabolism. Niacin has important regulatory effects on the production of inflammatory mediators and the migration of immune cells (see, for example, Spinas, E., et al., 2015. J Biol Regul Homeost Agents, 29(2), pp.283-8).

[0144] The suitable dosage of vitamin B3 (e.g., niacin) is known to those skilled in the art. For example, the RDA of vitamin B3 (e.g., niacin) may be about 10 mg to about 20 mg. For example, the RDA of vitamin B3 (e.g., niacin) may be about 14 mg.

[0145] Vitamin B6 In some embodiments, the vitamin mixture includes vitamin B6.

[0146] Vitamin B6 can refer to pyridoxine, pyridoxal, pyridoxamine, and their respective phosphorylated derivatives. Pyridoxal 5'-phosphate is the active form of vitamin B6 involved in metabolism and acts as a cofactor in many cellular responses. Experimental models in humans and animals have shown that vitamin B6 deficiency affects both innate and adaptive immunity, with reported decreases in the number, function, and proliferation of immune cells, including T lymphocytes (see, for example, Spinas, E., et al., 2015. J Biol Regul Homeost Agents, 29(2), pp.283-8).

[0147] The suitable dosage of vitamin B6 is known to those skilled in the art. For example, the RDA of vitamin B6 may be about 1.0 mg to about 2.5 mg. For example, the RDA of vitamin B6 may be about 1.9 mg.

[0148] Folic acid In some embodiments, the vitamin mixture includes folic acid.

[0149] Folic acid (also known as vitamin B9 and folacin) is essential for the body's ability to synthesize DNA and RNA, as well as for amino acid metabolism necessary for cell division. Folic acid supplementation has been shown to improve immune responses in both animal and human models (see, for example, Mikkelsen, K. and Apostolopoulos, V., 2019. Nutrition and Immunity, pp. 103–114).

[0150] The appropriate dosage of folic acid is known to those skilled in the art. For example, the RDA of folic acid may be about 100 μg to about 400 μg. For example, the RDA of folic acid may be about 180 μg.

[0151] Vitamin B12 In some embodiments, the vitamin mixture includes vitamin B12.

[0152] Vitamin B12 (also known as cobalamin) is a water-soluble vitamin involved in metabolism. Vitamin B12 supplementation has been shown to improve immune responses in both animal and human models (see, for example, Mikkelsen, K. and Apostolopoulos, V., 2019. Nutrition and Immunity, pp. 103-114).

[0153] The appropriate dosage of vitamin B12 is known to those skilled in the art. For example, the RDA of vitamin B12 may be about 1.5 mg to about 3 mg. For example, the RDA of vitamin B12 may be about 2.2 mg.

[0154] Mineral mixture As used herein, “mineral mixture” may refer to a mixture of one or more minerals. Minerals are elements that the body needs to perform various normal functions, and examples of minerals include calcium, phosphorus, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, and molybdenum. Minerals are usually added in salt form.

[0155] Preferably, the mineral mixture contains one or more minerals that enhance the target immune response. Several minerals, such as iron, zinc, copper, selenium, and magnesium, have been reported to play important roles in the immune response (see, for example, Gombart, AF, et al. Nutrients, 12(1), p.236).

[0156] Preferably, the mineral mixture may contain one or more minerals selected from potassium, magnesium, iron, zinc, and selenium.

[0157] In some embodiments, the mineral mixture comprises two or more, three or more, or four or more minerals selected from potassium, magnesium, iron, zinc, and selenium.

[0158] In some embodiments, the mineral mixture includes or consists of potassium, magnesium, iron, zinc, and selenium.

[0159] In some embodiments, the mineral mixture includes or consists of potassium, magnesium, iron, zinc, selenium, sodium, calcium, phosphorus, copper, manganese, iodine, chromium, and molybdenum.

[0160] Nutritional compositions, supplements, or fortifiers can be formulated so that minerals are administered in therapeutically effective doses. Those skilled in the art can adjust the amount of minerals in the nutritional composition, supplement, or fortifier to achieve a desired dose.

[0161] Preferably, each mineral is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides each mineral at a dose of approximately 10% RDA / day or more, approximately 15% RDA / day or more, approximately 20% RDA / day or more, approximately 25% RDA / day or more, approximately 30% RDA / day or more, approximately 40% RDA / day or more, approximately 50% RDA / day or more, approximately 60% RDA / day or more, approximately 70% RDA / day or more, or approximately 80% RDA / day or more. Preferably, each mineral is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides each mineral at a dose of approximately 100% RDA / day or less.

[0162] In some embodiments, each mineral is present in such an amount that the nutritional composition, supplement, or nutritional fortifier provides each mineral at a dose of approximately 15% RDA / day or more.

[0163] In some embodiments, potassium and magnesium are present in amounts such that the nutritional composition, supplement, or nutritional fortifier provides potassium and magnesium, respectively, at a dose of approximately 15% RDA / day or more.

[0164] In some embodiments, iron, zinc, and selenium are present in amounts such that the nutritional composition, supplement, or nutritional fortifier provides each of iron, zinc, and selenium at a dose of approximately 30% RDA / day or more.

[0165] Preferably, the nutritional composition, supplement, or fortifier contains each mineral in an amount of approximately 10% RDA / serving or more, approximately 15% RDA / serving or more, approximately 20% RDA / serving or more, approximately 25% RDA / serving or more, approximately 30% RDA / serving or more, approximately 35% RDA / serving or more, or approximately 40% RDA / serving or more. Preferably, the nutritional composition, supplement, or fortifier contains each mineral in an amount of approximately 100% RDA / serving or less.

[0166] In some embodiments, the nutritional composition, supplement, or nutritional fortifier contains each mineral in an amount of approximately 15% RDA / serving or more.

[0167] In some embodiments, the nutritional composition, supplement, or nutritional fortifier contains potassium and magnesium in amounts of about 15% RDA / serving or more.

[0168] In some embodiments, the nutritional composition, supplement, or nutritional fortifier contains iron, zinc, and selenium in amounts of approximately 30% RDA / serving or more.

[0169] potassium In some embodiments, the mineral mixture includes potassium.

[0170] The appropriate dosage of potassium is known to those skilled in the art. For example, the RDA of potassium may be approximately 2500 mg to 4000 mg. For example, the RDA of potassium may be approximately 3500 mg.

[0171] magnesium In some embodiments, the mineral mixture includes magnesium.

[0172] Magnesium plays a role in both innate and adaptive immune responses, participating in the synthesis of immunoglobulins as cofactors, immune cell adhesion, antibody-dependent cytosis, and T helper B cell adhesion. Epidemiological data show that higher magnesium intake is associated with a lower incidence of respiratory disorders (see, for example, Agrawal, Y., et al., 2017. Journal of Clinical and Diagnostic Research: JCDR, 11(6), p.BC01).

[0173] Suitable dosages of magnesium are known to those skilled in the art. For example, the RDA of magnesium may be approximately 350 mg to 500 mg. For example, the RDA of magnesium may be approximately 440 mg.

[0174] iron In some embodiments, the mineral mixture contains iron.

[0175] Both iron deficiency and excess exist in TB patients and may contribute to disease progression and poor clinical outcomes. Strategies to maintain normal iron levels in TB patients may be useful in reducing TB morbidity and mortality (see, for example, Isanaka, S., et al., 2012. PloS one, 7(5), p.e37350).

[0176] Suitable dosages of iron are known to those skilled in the art. For example, the RDA of iron may be about 10 mg to about 40 mg. For example, the RDA of iron may be about 29 mg.

[0177] zinc In some embodiments, the mineral mixture includes zinc.

[0178] Zinc is an essential micronutrient for proper immune system function and plays a crucial role in combating TB. Zinc supplementation has been shown to lead to earlier sputum smear improvements in micronutrient groups within six weeks of starting treatment (see, for example, Zolfaghari, B., et al., 2021. Reports of biochemistry & molecular biology, 10(2), p.173).

[0179] The appropriate dosage of zinc is known to those skilled in the art. For example, the RDA of zinc may be about 10 mg to about 20 mg. For example, the RDA of zinc may be about 17 mg.

[0180] selenium In some embodiments, the mineral mixture includes selenium.

[0181] Selenium status can affect the function of cells in both adaptive and innate immunity. Four studies have reported significantly lower serum selenium levels in patients with TB compared to healthy controls (see, for example, Steinbrenner, H., et al., 2015. Advances in nutrition, 6(1), pp.73-82).

[0182] Suitable dosages of selenium are known to those skilled in the art. For example, the RDA of selenium may be about 30 μg to about 60 μg. For example, the RDA of selenium may be about 40 μg.

[0183] Antioxidant In some embodiments, the nutritional composition, supplement, or nutritional fortifier of the present invention may contain any antioxidant.

[0184] Antioxidants are molecules that can slow down or stop the oxidation or electron transfer of other molecules. Antioxidants can be found in food. Antioxidants are molecules that reduce oxidative stress by preventing the formation and oxidation of free radicals.

[0185] Suitable antioxidants include one or more of glutathione, coenzyme Q10, lipoic acid, flavonoids, phenols, polyphenols, and phytoestrogens. In some embodiments, the antioxidant is present in an amount that provides the nutritional composition, supplement, or nutritional fortifier with a dose of approximately 15% RDA / day or more. In some embodiments, the antioxidant is present in an amount that provides the nutritional composition, supplement, or nutritional fortifier with a dose of approximately 30% RDA / day or more. The recommended daily dose corresponds to 8 to 11,000 antioxidant units per day.

[0186] fiber In some embodiments, the nutritional composition, supplement, or nutritional fortifier of the present invention may contain any fiber.

[0187] Dietary fiber is edible plant matter or similar carbohydrates that are resistant to digestion and absorption in the human small intestine and fully or partially fermented in the large intestine. Dietary fiber includes polysaccharides, oligosaccharides, lignin, and related plant substances. Dietary fiber promotes beneficial physiological effects in the gastrointestinal tract, including the relief of diarrhea and constipation, as well as the suppression of blood cholesterol and / or blood glucose attenuation.

[0188] Nutritional compositions, supplements, or nutritional fortifiers may further comprise any mixture containing fiber that is suitable for promoting the gastrointestinal health of the subject. Suitable fibers include one or more of soluble fiber, insoluble fiber, inulin, or plant gum.

[0189] Soluble or insoluble fiber may be beneficial in alleviating symptoms of diarrhea or constipation and gastrointestinal discomfort.

[0190] Inulin and oligosaccharides may contribute to anti-inflammatory effects on the intestines. Inulin and oligosaccharides may increase the absorption of calcium, magnesium, and iron.

[0191] Plant gum fibers, such as guar gum and gum arabic, may further contribute to alleviating symptoms of gastrointestinal discomfort.

[0192] In some embodiments, fiber is present in an amount that provides a nutritional composition, supplement, or nutritional fortifier with a dose of approximately 15% RDA / day or more. In some embodiments, fiber is present in an amount that provides a nutritional composition, supplement, or nutritional fortifier with a dose of approximately 30% RDA / day or more. The recommended daily dose corresponds to 20g to 30g of dietary fiber per day.

[0193] Other ingredients The nutritional composition, supplement, or nutritional fortifier of the present invention may contain any other suitable components, particularly components that contribute to the normal nutrition of the subject or components that enhance the immune response of the subject.

[0194] Preferably, the nutritional composition, supplement, or fortifier further comprises one or more major nutrients, such as protein, carbohydrates, or lipids. In some embodiments, the nutritional composition, supplement, or fortifier contains protein. In some embodiments, the nutritional composition, supplement, or fortifier contains carbohydrates. In some embodiments, the nutritional composition, supplement, or fortifier contains lipids. In some embodiments, the nutritional composition, supplement, or fortifier contains protein and carbohydrates. In some embodiments, the nutritional composition, supplement, or fortifier contains protein, carbohydrates, and lipids.

[0195] The nutritional composition, supplement, or nutritional fortifier of the present invention may also contain other substances that may have beneficial effects, such as lactoferrin, osteopontin, TGFβ, slgA, glutamine, nucleotides, nucleosides, etc.

[0196] Nutritional composition In one embodiment, the present invention provides a nutritional composition comprising L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture.

[0197] "Nutritional composition" may refer to a composition that provides nutrition to a subject. Nutritional compositions can be prepared in any preferred form. Nutritional compositions are not particularly limited as long as they are suitable for administration (e.g., oral, enteral, or intravenous). Examples of suitable nutritional compositions include powder formulations, food products, beverages, enteral nutrition products, and drug bases.

[0198] The nutritional composition according to the present invention may be a food for dietary management of subjects with disease-related malnutrition. In particular, this disease is an infectious disease, such as TB.

[0199] The nutritional composition according to the present invention may be a food for dietary management of subjects having infectious diseases and / or immunodeficiency. In particular, the nutritional composition according to the present invention may be a food for dietary management of subjects having TB.

[0200] The nutritional composition according to the present invention may be provided in powder form. The powder formulation can be reconstituted with a liquid such as water or milk before ingestion. In some embodiments, the powder is intended to be reconstituted with water. In some embodiments, the powder is intended to be reconstituted with milk. Reconstitution with milk may allow for less vitamin addition, a better taste for the product, and cost savings.

[0201] The nutritional composition according to the present invention may be provided in the form of a liquid, gel, or food that can be scooped with a spoon.

[0202] The nutritional composition according to the present invention may be nutritionally complete. A "nutritionally complete" food may provide all the carbohydrates, fats, proteins, vitamins, and minerals necessary to nourish a subject.

[0203] Preferably, in the context of a nutritional composition (e.g., a nutritional composition in powder form), "one serving" may be about 20 g to about 100 g. In some embodiments, "one serving" in the context of a nutritional composition (e.g., a nutritional composition in powder form) is about 50 g.

[0204] L-arginine The nutritional composition may contain L-arginine in any therapeutically effective amount.

[0205] Preferably, the nutritional composition contains L-arginine in an amount of about 0.5 g / serving or more and / or about 10.0 g / serving or less. In some embodiments, the nutritional composition contains L-arginine in an amount of about 1.0 g / serving or more. In some embodiments, the nutritional composition contains L-arginine in an amount of about 1.0 g / serving.

[0206] Preferably, the nutritional composition contains L-arginine in an amount of about 1.0% by weight or less and / or about 20.0% by weight or less. In some embodiments, the nutritional composition contains L-arginine in an amount of about 2.0% by weight or more. In some embodiments, the nutritional composition contains L-arginine in an amount of about 2.0% by weight. This may be on a dry weight basis.

[0207] Preferably, the nutritional composition contains L-arginine in an amount of about 0.25 g / 100 kcal or more and / or about 5.0 g / 100 kcal or less. In some embodiments, the nutritional composition contains L-arginine in an amount of about 0.5 g / 100 kcal or more. In some embodiments, the nutritional composition contains L-arginine in an amount of about 0.5 g / 100 kcal.

[0208] L-citrulline The nutritional composition may contain L-citrulline in any therapeutically effective amount.

[0209] Preferably, the nutritional composition contains L-citrulline in an amount of about 0.5 g / serving or more and / or about 10.0 g / serving or less. In some embodiments, the nutritional composition contains L-citrulline in an amount of about 1.0 g / serving or more. In some embodiments, the nutritional composition contains L-citrulline in an amount of about 1.0 g / serving. In some embodiments, the nutritional composition contains L-citrulline in an amount of about 1.25 g / serving or more. In some embodiments, the nutritional composition contains L-citrulline in an amount of about 1.25 g / serving.

[0210] Preferably, the nutritional composition contains L-citrulline in an amount of about 1.0% by weight or more and / or about 20.0% by weight or less. In some embodiments, the nutritional composition contains L-citrulline in an amount of about 2.5% by weight or more. In some embodiments, the nutritional composition contains L-citrulline in an amount of about 2.5% by weight. This may be on a dry weight basis.

[0211] Preferably, the nutritional composition contains L-citrulline in an amount of about 0.25 g / 100 kcal or more and / or about 5.0 g / 100 kcal or less. In some embodiments, the nutritional composition contains L-citrulline in an amount of about 0.6 g / 100 kcal or more. In some embodiments, the nutritional composition contains L-citrulline in an amount of about 0.6 g / 100 kcal.

[0212] A combination of L-arginine and L-citrulline In some embodiments, the nutritional composition comprises (a) L-arginine in an amount of about 1.0 g / serving or more, and (b) L-citrulline in an amount of about 1.0 g / serving or more.

[0213] In some embodiments, the nutritional composition comprises (a) L-arginine in an amount of about 1.0 g / serving or more, and (b) L-citrulline in an amount of about 1.25 g / serving or more.

[0214] In some embodiments, the nutritional composition comprises (a) L-arginine in an amount of about 1.0 g / serving and (b) L-citrulline in an amount of about 1.0 g / serving.

[0215] In some embodiments, the nutritional composition comprises (a) L-arginine in an amount of about 1.0 g / serving and (b) L-citrulline in an amount of about 1.25 g / serving.

[0216] In some embodiments, the nutritional composition comprises, for example, on a dry weight basis, (a) about 2.0% by weight or more of L-arginine and (b) about 2.5% by weight or more of L-citrulline.

[0217] In some embodiments, the nutritional composition comprises, for example, on a dry weight basis, (a) about 2.0% by weight of L-arginine and (b) about 2.5% by weight of L-citrulline.

[0218] In some embodiments, the nutritional composition comprises (a) L-arginine in an amount of about 0.5 g / 100 kcal or more, and (b) L-citrulline in an amount of about 0.6 g / 100 kcal or more.

[0219] In some embodiments, the nutritional composition comprises (a) L-arginine in an amount of about 0.5 g / 100 kcal and (b) L-citrulline in an amount of about 0.6 g / 100 kcal.

[0220] Vitamin mixture The nutritional composition may contain vitamins in any therapeutically effective amount. Preferably, the nutritional composition is (a) Vitamin A in amounts of approximately 300 μg RE / serving or more, approximately 400 μg RE / serving or more, approximately 500 μg RE / serving or more, or approximately 600 μg RE / serving or more. (b) Vitamin D2 in amounts of approximately 5 μg / serving or more, approximately 6 μg / serving or more, approximately 7 μg / serving or more, approximately 8 μg / serving or more, approximately 9 μg / serving or more, or approximately 10 μg / serving or more. (c) Vitamin E in amounts of approximately 3.0 mg TE / serving or more, approximately 3.5 mg TE / serving or more, approximately 4.0 mg TE / serving or more, approximately 4.5 mg TE / serving or more, approximately 5.0 mg TE / serving or more, approximately 5.5 mg TE / serving or more, approximately 6.0 mg TE / serving or more, or approximately 6.5 mg TE / serving or more. (d) Vitamin C in amounts of approximately 25 mg / serving or more, approximately 30 mg / serving or more, approximately 35 mg / serving or more, approximately 40 mg / serving or more, approximately 45 mg / serving or more, or approximately 50 mg / serving or more. (e) Vitamin B1 in amounts of approximately 0.5 mg / serving or more, approximately 0.6 mg / serving or more, approximately 0.7 mg / serving or more, approximately 0.8 mg / serving or more, approximately 0.9 mg / serving or more, or approximately 1.0 mg / serving or more. (f) Vitamin B2 in amounts of approximately 0.7 mg / serving or more, approximately 0.8 mg / serving or more, approximately 0.9 mg / serving or more, approximately 1.0 mg / serving or more, approximately 1.1 mg / serving or more, approximately 1.2 mg / serving or more, approximately 1.3 mg / serving or more, or approximately 1.4 mg / serving or more. (g) Niacin in amounts of approximately 5 mg / serving or more, approximately 6 mg / serving or more, approximately 7 mg / serving or more, approximately 8 mg / serving or more, approximately 9 mg / serving or more, or approximately 10 mg / serving or more. (h) Vitamin B6 in amounts of approximately 0.6 mg / serving or more, approximately 0.7 mg / serving or more, approximately 0.8 mg / serving or more, approximately 0.9 mg / serving or more, approximately 1.0 mg / serving or more, approximately 1.1 mg / serving or more, or approximately 1.2 mg / serving or more. (i) Folic acid in an amount of approximately 60 μg / serving or more, approximately 70 μg / serving or more, approximately 80 μg / serving or more, approximately 90 μg / serving or more, approximately 100 μg / serving or more, approximately 110 μg / serving or more, or approximately 120 μg / serving or more, and / or (j) Contains vitamin B12 in an amount of approximately 0.7 μg / serving or more, approximately 0.8 μg / serving or more, approximately 0.9 μg / serving or more, approximately 1.0 μg / serving or more, approximately 1.1 μg / serving or more, approximately 1.2 μg / serving or more, approximately 1.3 μg / serving or more, or approximately 1.4 μg / serving or more.

[0221] In some embodiments, nutritional composition, (k) Vitamin K1 in amounts of approximately 6 μg / serving or more, approximately 7 μg / serving or more, approximately 8 μg / serving or more, approximately 9 μg / serving or more, approximately 10 μg / serving or more, approximately 11 μg / serving or more, or approximately 12 μg / serving or more. (l) Pantothenic acid in an amount of approximately 0.35 mg / serving or more, approximately 0.40 mg / serving or more, approximately 0.45 mg / serving or more, approximately 0.50 mg / serving or more, approximately 0.55 mg / serving or more, approximately 0.60 mg / serving or more, approximately 0.65 mg / serving or more, approximately 0.70 mg / serving or more, or approximately 0.75 mg / serving or more, and / or (m) Further contains biotin in amounts of approximately 2.0 μg / serving or more, approximately 2.5 μg / serving or more, approximately 3.0 μg / serving or more, approximately 3.5 μg / serving or more, approximately 4.0 μg / serving or more, or approximately 4.5 μg / serving or more.

[0222] In some embodiments, the nutritional composition includes (a) vitamin A in an amount of about 250 μg RE / 100 kcal or more, (b) vitamin D2 in an amount of about 4 μg / 100 kcal or more, (c) vitamin E in an amount of about 3.0 mg TE / 100 kcal or more, (d) vitamin C in an amount of about 20 mg / 100 kcal or more, (e) vitamin B1 in an amount of about 0.4 mg / 100 kcal or more, (f) vitamin B2 in an amount of about 0.6 mg / 100 kcal or more, (g) niacin in an amount of about 4 mg / 100 kcal or more, (h) vitamin B6 in an amount of about 0.5 mg / 100 kcal or more, (i) folic acid in an amount of about 50 μg / 100 kcal or more, and / or (j) vitamin B12 in an amount of about 0.6 μg / 100 kcal or more.

[0223] In some embodiments, the nutritional composition comprises (k) vitamin K1 in an amount of about 5 μg / 100 kcal or more, (l) pantothenic acid in an amount of about 0.3 mg / 100 kcal or more, and / or (m) biotin in an amount of about 2 μg / 100 kcal or more.

[0224] Mineral mixture The nutritional composition may contain minerals in any therapeutically effective amount. Preferably, the nutritional composition is (a) Potassium in amounts of approximately 250 mg / serving or more, approximately 300 mg / serving or more, approximately 350 mg / serving or more, approximately 400 mg / serving or more, approximately 450 mg / serving or more, or approximately 500 mg / serving or more. (b) Magnesium in amounts of approximately 30 mg / serving or more, approximately 35 mg / serving or more, approximately 40 mg / serving or more, approximately 45 mg / serving or more, approximately 50 mg / serving or more, approximately 55 mg / serving or more, approximately 60 mg / serving or more, or approximately 65 mg / serving or more. (c) an amount of iron of approximately 4 mg / serving or more, approximately 5 mg / serving or more, approximately 6 mg / serving or more, approximately 7 mg / serving or more, or approximately 8 mg / serving or more. (d) Zinc in an amount of approximately 2 mg / serving or more, approximately 3 mg / serving or more, approximately 4 mg / serving or more, or approximately 5 mg / serving or more, and / or (e) Contains selenium in an amount of approximately 6 μg / serving or more, approximately 7 μg / serving or more, approximately 8 μg / serving or more, approximately 9 μg / serving or more, approximately 10 μg / serving or more, approximately 11 μg / serving or more, or approximately 12 μg / serving or more.

[0225] In some embodiments, nutritional composition, (f) Sodium in amounts of approximately 50 mg / serving or more, approximately 60 mg / serving or more, approximately 70 mg / serving or more, approximately 80 mg / serving or more, approximately 90 mg / serving or more, or approximately 100 mg / serving or more. (g) Phosphorus in amounts of approximately 70 mg / serving or more, approximately 80 mg / serving or more, approximately 90 mg / serving or more, approximately 100 mg / serving or more, approximately 110 mg / serving or more, approximately 120 mg / serving or more, approximately 130 mg / serving or more, approximately 140 mg / serving or more, approximately 150 mg / serving or more. (h) Copper in amounts of approximately 0.05 mg / serving or more, approximately 0.10 mg / serving or more, approximately 0.15 mg / serving or more, approximately 0.20 mg / serving or more, approximately 0.25 mg / serving or more, or approximately 0.30 mg / serving or more. (i) Manganese in amounts of approximately 300 μg / serving or more, approximately 400 μg / serving or more, approximately 500 μg / serving or more, approximately 600 μg / serving or more. (j) an amount of iodine of approximately 10 μg / serving or more, approximately 12 μg / serving or more, approximately 14 μg / serving or more, approximately 16 μg / serving or more, approximately 18 μg / serving or more, approximately 20 μg / serving or more, or approximately 22 μg / serving or more. (k) Chromium in amounts of approximately 3 μg / serving or more, approximately 4 μg / serving or more, approximately 5 μg / serving or more, approximately 6 μg / serving or more, or approximately 7 μg / serving or more, and / or (l) Further comprising molybdenum in an amount of approximately 3 μg / serving or more, approximately 4 μg / serving or more, approximately 5 μg / serving or more, approximately 6 μg / serving or more, or approximately 7 μg / serving or more.

[0226] In some embodiments, the nutritional composition comprises (a) potassium in an amount of about 200 mg / 100 kcal or more, (b) magnesium in an amount of about 30 mg / 100 kcal or more, (c) iron in an amount of about 4 mg / 100 kcal or more, (d) zinc in an amount of about 2 mg / 100 kcal or more, and / or (e) selenium in an amount of about 5 μg / 100 kcal or more.

[0227] In some embodiments, the nutritional composition further comprises (f) sodium in an amount of about 50 mg / 100 kcal or more, (g) phosphorus in an amount of about 70 mg / 100 kcal or more, (h) copper in an amount of about 0.10 mg / 100 kcal or more, (i) manganese in an amount of about 250 μg / 100 kcal or more, (j) iodine in an amount of about 10 μg / 100 kcal or more, (k) chromium in an amount of about 3 μg / 100 kcal or more, and / or (l) molybdenum in an amount of about 3 μg / 100 kcal or more.

[0228] In some embodiments, the nutritional composition further comprises an antioxidant.

[0229] In some embodiments, the nutritional composition further comprises fiber.

[0230] Proteins, carbohydrates, and lipids The nutritional composition may contain all the nutrients necessary for maintaining health. The nutritional composition of the present invention may contain a protein source, a carbohydrate source, and / or a lipid source.

[0231] Protein may be present in any suitable amount in the nutritional composition. For example, the protein content of the nutritional composition may be about 30 g / L to about 200 g / L, about 40 g / L to about 150 g / L, or about 50 g / L to about 100 g / L after reconstitution with water or milk, for example.

[0232] In some embodiments, the nutritional composition contains protein in amounts of about 8 g / serving to about 14 g / serving, about 10 g / serving to about 12 g / serving, or about 11 g / serving.

[0233] In some embodiments, the nutritional composition contains protein in amounts of approximately 3 g / 100 kcal to approximately 7 g / 100 kcal, approximately 4 g / 100 kcal to approximately 6 g / 100 kcal, or approximately 5.1 g / 100 kcal.

[0234] The protein source can be any protein source suitable for use in the nutritional composition. For example, in addition to soy-based protein sources, protein sources based on milk protein, whey, casein, and mixtures thereof may be used. As far as whey protein is concerned, the protein source may be based on acidic whey, sweet whey, or mixtures thereof.

[0235] The protein may be in its undenatured state, hydrolyzed state, or a mixture of undenatured and hydrolyzed states. The term "intact" means that the main part of the protein is undenatured, i.e., its molecular structure remains unchanged, for example, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 100% of the protein remains unchanged.

[0236] In the context of this invention, the term "hydrolyzed" means that a protein has been hydrolyzed, or broken down into its constituent amino acids. The protein may be completely hydrolyzed or partially hydrolyzed. The degree of hydrolysis (DH) of the protein may be 2 to 20, or 8 to 40, or 20 to 60, or 20 to 80, or greater than 10, greater than 20, greater than 40, greater than 60, greater than 80, or greater than 90. Preferably, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 100% of the protein may be hydrolyzed. If a hydrolyzed protein is required, the hydrolysis process may be carried out as desired, as is known in the art. For example, a hydrolyzed whey protein can be prepared by enzymatically hydrolyzing the whey fraction in one or more steps.

[0237] Lipids (fats) may be present in the nutritional composition in any suitable amount. For example, the fat content of the nutritional composition may be about 10 g / L to about 200 g / L, about 15 g / L to about 150 g / L, or about 20 g / L to about 100 g / L after reconstitution with water or milk, for example.

[0238] In some embodiments, the nutritional composition contains fat in amounts of approximately 5 g / serving to approximately 10 g / serving, approximately 6 g / serving to approximately 9 g / serving, approximately 7 g / serving to approximately 8 g / serving, or approximately 7.5 g / serving.

[0239] In some embodiments, the nutritional composition contains fat in amounts of approximately 2.0 g / 100 kcal to approximately 5.0 g / 100 kcal, approximately 2.5 g / 100 kcal to approximately 4.5 g / 100 kcal, approximately 3.0 g / 100 kcal to approximately 4.0 g / 100 kcal, or approximately 3.5 g / 100 kcal.

[0240] Examples of lipids for use in the nutritional compositions of the present invention include sunflower oil, low erucic acid rapeseed oil, safflower oil, canola oil, olive oil, coconut oil, palm kernel oil, soybean oil, fish oil, palm oleic oil, high oleic acid sunflower oil and high oleic acid safflower oil, and microbial fermentation oils containing long-chain polyunsaturated fatty acids. Lipids may also be in the form of fractions derived from oils, such as palm oleic acid, medium-chain triglycerides (MCTs), and fatty acid esters, such as esters of arachidonic acid, linoleic acid, palmitic acid, stearic acid, docosahexaenoic acid, linolenic acid, oleic acid, lauric acid, capric acid, caprylic acid, and caproic acid. Further examples of lipids include structured lipids (i.e., lipids that have undergone chemical or enzymatic modification to alter their structure).

[0241] Long-chain polyunsaturated fatty acids, such as dihomo-γ-linolenic acid, arachidonic acid (ARA), eicosapentaenoic acid, and docosahexaenoic acid (DHA), may be added. Essential fatty acids such as linoleic acid and α-linolenic acid may also be added, as may small amounts of oil, such as fish oil or microbial oil, that are rich in preform arachidonic acid and docosahexaenoic acid.

[0242] Carbohydrates may be present in any suitable amount in the nutritional composition. For example, the carbohydrate content of the nutritional composition may be about 30 g / L to about 300 g / L, about 40 g / L to about 250 g / L, or about 50 g / L to about 200 g / L after reconstitution with water or milk, for example.

[0243] In some embodiments, the nutritional composition contains carbohydrates in amounts of approximately 20 g / serving to approximately 35 g / serving, approximately 25 g / serving to approximately 30 g / serving, or approximately 27 g / serving.

[0244] In some embodiments, the nutritional composition contains carbohydrates in amounts of approximately 8g / 100kcal to approximately 16g / 100kcal, approximately 9g / 100kcal to approximately 15g / 100kcal, approximately 10g / 100kcal to approximately 14g / 100kcal, approximately 11g / 100kcal to approximately 13g / 100kcal, approximately 12g / 100kcal to approximately 13g / 100kcal, or approximately 12.7g / 100kcal.

[0245] The carbohydrate source may be any carbohydrate source suitable for use in the nutritional composition. Some suitable carbohydrate sources include lactose, sucrose, maltodextrin, starch, and mixtures thereof.

[0246] Other ingredients The nutritional composition of the present invention may contain emulsifiers and stabilizers, such as soybeans, lecithin, and citrate esters of mono and diglycerides.

[0247] The nutritional composition of the present invention may also contain one or more carotenoids.

[0248] The nutritional composition of the present invention may also contain other substances that may have beneficial effects, such as lactoferrin, osteopontin, TGFβ, slgA, glutamine, nucleotides, nucleosides, etc.

[0249] The nutritional composition of the present invention may further contain at least one indigestible oligosaccharide (e.g., a prebiotic). Examples of prebiotics may be fructooligosaccharides and galactooligosaccharides.

[0250] The nutritional composition of the present invention may further contain at least one probiotic. The term “probiotic” may refer to a preparation or component of microbial cells that has beneficial effects on the health or well-being of the host. Specifically, probiotics can improve intestinal barrier function. Examples of probiotic microorganisms for use in the nutritional composition of the present invention include yeasts, e.g., Saccharomyces, Debaromyces, Candida, Pichia, and Torulopsis, and bacteria, e.g., Bifidobacterium, Bacteroides, Clostridium, Fusobacterium, Melissococcus, Propionibacterium, Strep Examples include the genera Streptococcus, Enterococcus, Lactococcus, Staphylococcus, Peptostrepoccus, Bacillus, Pediococcus, Micrococcus, Leuconostoc, Weissella, Aerococcus, Oenococcus, and Lactobacillus. Specific examples of suitable probiotic microorganisms include Saccharomyces cereviseae, Bacillus coagulans, Bacillus licheniformis, Bacillus subtilis, Bifidobacterium bifidum, and Bifidobacterium infantis.Lactobacillus infantis), Bifidobacterium longum, Enterococcus faecium, Enterococcus faecalis, Lactobacillus acidophilus, Lactobacillus alimentarius, Lactobacillus casei subsp. casei, Lactobacillus casei Shirota, Lactobacillus curvatus, Lactobacillus delbruckii subsp. lactis, Lactobacillus falsiminas Lactobacillus farciminus), Lactobacillus gasseri, Lactobacillus helveticus, Lactobacillus johnsonii, Lactobacillus rhamnosus (Lactobacillus GG), Lactobacillus sake, Lactobacillus lactis, Micrococcus varians, Pediococcus acidilactici, Pediococcus pentosaceus, Pediococcus acidilactici, Pediococcus halophilus halophilus), Streptococcus faecalis, Streptococcus thermophilusThese include Staphylococcus thermophilus, Staphylococcus carnosus, and Staphylococcus xylosus.

[0251] Energy The nutritional composition may provide an appropriate amount of energy for maintaining good health.

[0252] Preferably, the nutritional composition may contain approximately 500 kcal / L to 3000 kcal / L, approximately 750 kcal / L to 2500 kcal / L, or approximately 1000 kcal / L to 2000 kcal / L after reconstitution with water or milk, for example.

[0253] In some embodiments, the nutritional composition includes approximately 100 kcal / serving to approximately 500 kcal / serving, approximately 150 kcal / serving to approximately 400 kcal / serving, approximately 200 kcal / serving to approximately 300 kcal / serving, or approximately 200 kcal / serving to approximately 250 kcal / serving. In some embodiments, the nutritional composition includes approximately 214 kcal / serving.

[0254] In some embodiments, the nutritional composition contains approximately 200 kcal / 100g to approximately 600 kcal / 100g, approximately 300 kcal / 100g to approximately 500 kcal / 100g, or approximately 350 kcal / 100g to approximately 450 kcal / 100g. In some embodiments, the nutritional composition contains approximately 429 kcal / 100g.

[0255] Supplements and nutritional fortifiers In one embodiment, the present invention provides a supplement or nutritional fortifier comprising L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture.

[0256] "Supplements" or "dietary supplements" may be used to complement an individual's nutrition (typically so, but supplements or dietary supplements may also be added to nutritional compositions). The term "nutritional fortifier" may refer to a liquid or solid composition that is suitable for mixing with a nutritional composition.

[0257] The supplement or nutritional fortifier according to the present invention may be a supplement or nutritional fortifier for dietary management of a person having disease-related malnutrition. In particular, this disease is an infectious disease, such as TB.

[0258] Supplements or nutritional fortifiers may be in the form of, for example, sprinkles, sticks, tablets, capsules, lozenges, liquids, gels, or spoonable foods. In a preferred embodiment, the supplement or nutritional fortifier is in the form of a powder supplement for sprinkling onto food or beverages. The powder supplement may be provided in sachets.

[0259] Supplements or nutritional fortifiers may contain vitamins, minerals, trace elements, and other micronutrients in accordance with the recommendations of government agencies such as the USRDA, in addition to organic or inorganic carrier materials (e.g., maltodextrin) suitable for oral or enteral administration. Supplements or nutritional fortifiers may be provided in unit dose form.

[0260] Preferably, in the context of supplements or nutritional fortifiers, "one serving" may be about 1 g to about 10 g. In some embodiments, "one serving" in the context of supplements or nutritional fortifiers is about 5 g.

[0261] L-arginine Supplements or nutritional fortifiers may contain L-arginine in any therapeutically effective amount.

[0262] Preferably, the supplement or nutritional fortifier contains L-arginine in an amount of about 0.5 g / serving or more and / or about 10.0 g / serving or less. In some embodiments, the supplement or nutritional fortifier contains L-arginine in an amount of about 0.5 g / serving or more. In some embodiments, the supplement or nutritional fortifier contains L-arginine in an amount of about 0.5 g / serving.

[0263] Preferably, the supplement or nutritional fortifier contains L-arginine in an amount of about 1.0% by weight or more and / or about 20.0% by weight or less. In some embodiments, the supplement or nutritional fortifier contains L-arginine in an amount of about 10.0% by weight or more. In some embodiments, the supplement or nutritional fortifier contains L-arginine in an amount of about 10.0% by weight. This may be on a dry weight basis.

[0264] Preferably, the supplement or nutritional fortifier contains L-arginine in an amount of about 0.5 g / 100 kcal or more and / or about 10.0 g / 100 kcal or less. In some embodiments, the supplement or nutritional fortifier contains L-arginine in an amount of about 3.6 g / 100 kcal or more. In some embodiments, the supplement or nutritional fortifier contains L-arginine in an amount of about 3.6 g / 100 kcal.

[0265] L-citrulline Supplements or nutritional fortifiers may contain L-citrulline in any therapeutically effective amount.

[0266] Preferably, the supplement or nutritional fortifier contains L-citrulline in an amount of about 0.5 g / serving or more and / or about 10.0 g / serving or less. In some embodiments, the supplement or nutritional fortifier contains L-citrulline in an amount of about 0.5 g / serving or more. In some embodiments, the supplement or nutritional fortifier contains L-citrulline in an amount of about 0.5 g / serving.

[0267] Preferably, the supplement or nutritional enhancer contains L-citrulline in an amount of about 1.0% by weight or more and / or about 20.0% by weight or less. In some embodiments, the supplement or nutritional enhancer contains L-citrulline in an amount of about 10.0% by weight or more. In some embodiments, the supplement or nutritional enhancer contains L-citrulline in an amount of about 10.0% by weight. This may be on a dry weight basis.

[0268] Preferably, the supplement or nutritional enhancer contains L-citrulline in an amount of about 0.5 g / 100 kcal or more and / or about 10.0 g / 100 kcal or less. In some embodiments, the supplement or nutritional enhancer contains L-citrulline in an amount of about 3.6 g / 100 kcal or more. In some embodiments, the supplement or nutritional enhancer contains L-citrulline in an amount of about 3.6 g / 100 kcal.

[0269] Combination of L-arginine and L-citrulline In some embodiments, the supplement or nutritional enhancer contains (a) L-arginine in an amount of about 0.5 g / serving or more and (b) L-citrulline in an amount of about 0.5 g / serving or more.

[0270] In some embodiments, the supplement or nutritional enhancer contains (a) L-arginine in an amount of about 0.5 g / serving and (b) L-citrulline in an amount of about 0.5 g / serving.

[0271] In some embodiments, the supplement or nutritional enhancer contains, for example on a dry weight basis, (a) L-arginine in an amount of about 10.0% by weight or more and (b) L-citrulline in an amount of about 10.0% by weight or more.

[0272] In some embodiments, the supplement or nutritional enhancer contains, for example on a dry weight basis, (a) L-arginine in an amount of about 10.0% by weight and (b) L-citrulline in an amount of about 10.0% by weight.

[0273] In some embodiments, the supplement or fortifier comprises (a) L-arginine in an amount of about 3 g / 100 kcal or more and (b) L-citrulline in an amount of about 3 g / 100 kcal or more.

[0274] In some embodiments, the supplement or fortifier comprises (a) L-arginine in an amount of about 3.6 g / 100 kcal and (b) L-citrulline in an amount of about 3.6 g / 100 kcal.

[0275] Vitamin mixture The supplement or fortifier may contain vitamins in any therapeutically effective amount. Preferably, the supplement or fortifier (a) vitamin A in an amount of about 200 μg RE / serving or more, about 250 μg RE / serving or more, about 300 μg RE / serving or more, about 350 μg RE / serving or more, or about 400 μg RE / serving or more, (b) vitamin D2 in an amount of about 3 μg / serving or more, about 4 μg / serving or more, about 5 μg / serving or more, or about 6 μg / serving or more, (c) vitamin E in an amount of about 2.0 mg TE / serving or more, about 2.5 mg TE / serving or more, about 3.0 mg TE / serving or more, about 3.5 mg TE / serving or more, or about 4.0 mg TE / serving or more, (d) vitamin C in an amount of about 16 mg / serving or more, about 20 mg / serving or more, about 24 mg / serving or more, about 28 mg / serving or more, or about 32 mg / serving or more, (e) vitamin B1 in an amount of about 0.30 mg / serving or more, about 0.35 mg / serving or more, about 0.40 mg / serving or more, about 0.45 mg / serving or more, about 0.50 mg / serving or more, or about 0.55 mg / serving or more, (f) Vitamin B2 in amounts of approximately 0.40 mg / serving or more, approximately 0.45 mg / serving or more, approximately 0.50 mg / serving or more, approximately 0.55 mg / serving or more, approximately 0.60 mg / serving or more, approximately 0.65 mg / serving or more, approximately 0.70 mg / serving or more, approximately 0.75 mg / serving or more, or approximately 0.80 mg / serving or more. (g) Niacin in amounts of approximately 3.0 mg / serving or more, approximately 3.5 mg / serving or more, approximately 4.0 mg / serving or more, approximately 4.5 mg / serving or more, approximately 5.0 mg / serving or more, or approximately 5.5 mg / serving or more. (h) Vitamin B6 in amounts of approximately 0.40 mg / serving or more, approximately 0.45 mg / serving or more, approximately 0.50 mg / serving or more, approximately 0.55 mg / serving or more, approximately 0.60 mg / serving or more, approximately 0.65 mg / serving or more, approximately 0.70 mg / serving or more, or approximately 0.75 mg / serving or more. (i) Folic acid in an amount of approximately 36 μg / serving or more, approximately 40 μg / serving or more, approximately 45 μg / serving or more, approximately 50 μg / serving or more, approximately 55 μg / serving or more, approximately 60 μg / serving or more, approximately 65 μg / serving or more, or approximately 70 μg / serving or more, and / or (j) Contains vitamin B12 in an amount of approximately 0.4 μg / serving or more, approximately 0.5 μg / serving or more, approximately 0.6 μg / serving or more, approximately 0.7 μg / serving or more, approximately 0.8 μg / serving or more, or approximately 0.9 μg / serving or more.

[0276] In some embodiments, the supplement or nutritional fortifier contains (a) vitamin A in an amount of about 2500 μg RE / 100 kcal or more, (b) vitamin D2 in an amount of about 40 μg / 100 kcal or more, (c) vitamin E in an amount of about 25 mg TE / 100 kcal or more, (d) vitamin C in an amount of about 200 mg / 100 kcal or more, (e) vitamin B1 in an amount of about 4 mg / 100 kcal or more, (f) vitamin B2 in an amount of about 5 mg / 100 kcal or more, (g) niacin in an amount of about 40 mg / 100 kcal or more, (h) vitamin B6 in an amount of about 5 mg / 100 kcal or more, (i) folic acid in an amount of about 500 μg / 100 kcal or more, and / or (j) vitamin B12 in an amount of about 6 μg / 100 kcal or more.

[0277] In some embodiments, the supplement or nutritional fortifier contains no other vitamins other than those mentioned above.

[0278] Mineral mixture Supplements or nutritional fortifiers may contain minerals in any therapeutically effective amount. Preferably, supplements or nutritional fortifiers (a) Potassium in amounts of approximately 250 mg / serving or more, approximately 300 mg / serving or more, approximately 350 mg / serving or more, approximately 400 mg / serving or more, approximately 450 mg / serving or more, or approximately 500 mg / serving or more. (b) Magnesium in amounts of approximately 33 mg / serving or more, approximately 35 mg / serving or more, approximately 40 mg / serving or more, approximately 45 mg / serving or more, approximately 50 mg / serving or more, approximately 55 mg / serving or more, approximately 60 mg / serving or more, or approximately 65 mg / serving or more. (c) an amount of iron of approximately 5 mg / serving or more, approximately 6 mg / serving or more, approximately 7 mg / serving or more, approximately 8 mg / serving or more, approximately 9 mg / serving or more, approximately 10 mg / serving or more, or approximately 11 mg / serving or more. (d) zinc in amounts of approximately 3 mg / serving or more, approximately 4 mg / serving or more, approximately 5 mg / serving or more, approximately 6 mg / serving or more, or approximately 7 mg / serving or more, and / or (e) Contains selenium in an amount of approximately 5 μg / serving or more, approximately 6 μg / serving or more, approximately 8 μg / serving or more, approximately 10 μg / serving or more, approximately 12 μg / serving or more, approximately 14 μg / serving or more, or approximately 16 μg / serving or more.

[0279] In some embodiments, the supplement or nutritional fortifier contains (a) potassium in an amount of about 3000 mg / 100 kcal or more, (b) magnesium in an amount of about 400 mg / 100 kcal or more, (c) iron in an amount of about 80 mg / 100 kcal or more, (d) zinc in an amount of about 40 mg / 100 kcal or more, and / or (e) selenium in an amount of about 100 μg / 100 kcal or more.

[0280] In some embodiments, the supplement or nutritional fortifier contains no other minerals other than those mentioned above.

[0281] Other ingredients The supplement or nutritional fortifier of the present invention may contain any other suitable ingredients such as proteins and / or carbohydrates.

[0282] In some embodiments, the supplement or nutritional fortifier contains protein in amounts of approximately 0.5 g / serving or more, approximately 0.6 g / serving or more, approximately 0.7 g / serving or more, approximately 0.8 g / serving or more, or approximately 0.9 g / serving or more.

[0283] In some embodiments, the supplement or nutritional fortifier contains carbohydrates in amounts of approximately 1.0 g / serving or more, approximately 1.5 g / serving or more, approximately 2.0 g / serving or more, or approximately 2.5 g / serving or more.

[0284] In some embodiments, the supplement or nutritional fortifier is fat-free.

[0285] In some embodiments, the supplement or fortifier comprises from about 5 kcal / serving to about 20 kcal / serving, from about 10 kcal / serving to about 15 kcal / serving, or about 13.8 kcal / serving.

[0286] Use as a medicament In one aspect, the present invention provides a combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture for use as a medicament.

[0287] In another aspect, the present invention provides the use of a combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture for the manufacture of a medicament.

[0288] In another aspect, the present invention provides a nutritional composition, supplement, or fortifier according to the present invention for use as a medicament.

[0289] In another aspect, the present invention provides the use of a nutritional composition, supplement, or fortifier according to the present invention for the manufacture of a medicament.

[0290] The medicament can be a food for dietary management of a subject, such as a subject having or at risk of having an infectious disease and / or immunodeficiency, particularly a subject having or at risk of having TB. Preferably, the medicament can be administered in the form of a nutritional composition, supplement, or fortifier according to the present invention.

[0291] The medicament can be an adjunctive therapy, such as a therapeutic or prophylactic agent for an infectious disease. As used herein, "adjunctive therapy" (also referred to as "adjunct therapy") can refer to a therapeutic agent that is administered in addition to a primary therapeutic agent or "primary therapy" to maximize its effectiveness. For example, the primary therapeutic agent can be an antibacterial therapeutic agent. In some embodiments, the medicament is an adjunctive therapy for the treatment of tuberculosis (TB), and optionally, the primary therapeutic agent is a TB drug regimen.

[0292] subject A combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture (e.g., in the form of a nutritional composition, supplement, or nutritional fortifier) ​​may be administered to any subject in need. The subject may be a human subject.

[0293] The target group may be of any age. For example, the target group may be children or adults. The term "child" may refer to a target group under 18 years of age. The term "adult" may refer to a target group 18 years of age or older. In some embodiments, the target group is adults.

[0294] The subjects are individuals who have an infectious disease and / or immunodeficiency, or who are at risk of developing one.

[0295] In some embodiments, the subject has or is at risk of having an infection. The infection may be a bacterial infection. The infection may be a respiratory tract infection. The infection may be a lung infection. In some embodiments, the infection may be tuberculosis (TB), for example, pulmonary TB.

[0296] In some embodiments, the subject has latent tuberculosis, and the infection is in a latent state.

[0297] In some embodiments, the subjects have immunodeficiency or are at risk of immunodeficiency. Immunodeficiency is a partial or complete impairment of the immune system, which prevents patients from effectively coping with infections or diseases. Immunodeficiency can be secondary immunodeficiency resulting from, for example, immunosuppressants, malnutrition, aging, medication, environmental toxins, or disease, such as cancer or HIV infection (see, for example, Tuano, KS, et al., 2021. Annals of Allergy, Asthma & Immunology, 127(6), pp. 617-626).

[0298] Route of administration and dosage A combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture (for example, in the form of a nutritional composition, supplement, or nutritional fortifier) ​​may be administered by any suitable route, for example, orally, parenterally, or enterally.

[0299] In some embodiments, a combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture (e.g., in the form of a nutritional composition, supplement, or nutritional fortifier) ​​is administered orally.

[0300] The combination of L-arginine, L-citrulline, the vitamin mixture, and the mineral mixture can be administered simultaneously, sequentially, or separately. In a preferred embodiment, the combination is administered simultaneously.

[0301] A combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture (e.g., in the form of a nutritional composition, supplement, or nutritional fortifier) ​​can be administered in any suitable dose.

[0302] Preferably, L-arginine is administered to the subject in an amount of about 0.5 g / day or more, for example, about 0.5 g / day, about 0.6 g / day, about 0.7 g / day, about 0.8 g / day, about 0.9 g / day, about 1.0 g / day, about 1.1 g / day, about 1.2 g / day, about 1.3 g / day, about 1.4 g / day, or about 1.5 g / day. In some embodiments, L-arginine is administered to the subject in an amount of about 0.5 g / day or more. In some embodiments, L-arginine is administered to the subject in an amount of about 1.0 g / day or more. Preferably, L-arginine is administered to the subject in an amount of about 10.0 g / day or less. In some embodiments, L-arginine is administered to the subject in an amount of about 0.5 g / day. In other embodiments, L-arginine is administered to the subject in an amount of about 1.0 g / day.

[0303] Preferably, L-citrulline is administered to the subject in amounts of about 0.5 g / day or more, for example, about 0.5 g / day, about 0.6 g / day, about 0.7 g / day, about 0.8 g / day, about 0.9 g / day, about 1.0 g / day, about 1.1 g / day, about 1.2 g / day, about 1.3 g / day, about 1.4 g / day, or about 1.5 g / day. In some embodiments, L-citrulline is administered to the subject in amounts of about 0.5 g / day or more. In some embodiments, L-citrulline is administered to the subject in amounts of about 1.0 g / day or more. Preferably, L-citrulline is administered to the subject in amounts of about 10.0 g / day or less. In some embodiments, L-citrulline is administered to the subject in amounts of about 0.5 g / day. In other embodiments, L-citrulline is administered to the subject in amounts of about 1.0 g / day.

[0304] Preferably, L-arginine and L-citrulline are administered to the subject in a weight ratio of approximately 0.1:1 to 10:1, approximately 0.2:1 to 5:1, approximately 0.25:1 to 4:1, approximately 0.3:1 to 3:1, approximately 0.5:1 to 2:1, or approximately 1:1. In some embodiments, L-arginine and L-citrulline are administered to the subject in a weight ratio of approximately 1:1.

[0305] In some embodiments, L-arginine is administered to the subject at a dose of approximately 0.5 g / day, and L-citrulline is administered to the subject at a dose of approximately 0.5 g / day.

[0306] In some embodiments, L-arginine is administered to the subject at a dose of approximately 1.0 g / day, and L-citrulline is administered to the subject at a dose of approximately 1.0 g / day.

[0307] Preferably, each vitamin in the vitamin mixture is administered to the subject in amounts of approximately 10% RDA / day or more, approximately 20% RDA / day or more, approximately 30% RDA / day or more, approximately 40% RDA / day or more, approximately 50% RDA / day or more, approximately 60% RDA / day or more, approximately 70% RDA / day or more, or approximately 80% RDA / day or more. Preferably, each vitamin in the vitamin mixture is administered to the subject in amounts of approximately 100% RDA / day or less.

[0308] In some embodiments, each vitamin in the vitamin mixture is administered to the subject at a dose of approximately 50% RDA / day or more.

[0309] Preferably, each mineral in the mineral mixture is administered to the subject in amounts of approximately 10% RDA / day or more, approximately 20% RDA / day or more, approximately 30% RDA / day or more, approximately 40% RDA / day or more, approximately 50% RDA / day or more, approximately 60% RDA / day or more, approximately 70% RDA / day or more, or approximately 80% RDA / day or more. Preferably, each mineral in the mineral mixture is administered to the subject in amounts of approximately 100% RDA / day or less.

[0310] In some embodiments, each mineral in the mineral mixture is administered to the subject in an amount of approximately 15% RDA / day or more.

[0311] Methods to enhance the target immune response The formulations, combinations, and compositions of the present invention may be used to enhance the immune response of a target.

[0312] In one embodiment, the present invention provides a combination of L-arginine and L-citrulline for use in enhancing the immune response of a target.

[0313] In another aspect, the present invention provides the use of a combination of L-arginine and L-citrulline for the manufacture of a pharmacopoeia for enhancing the immune response of a target.

[0314] In another aspect, the present invention provides a method for enhancing the immune response of a subject, comprising administering a combination of L-arginine and L-citrulline to the subject.

[0315] In one embodiment, the present invention provides a combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture for use in enhancing the immune response of a target.

[0316] In another aspect, the present invention provides the use of a combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture for the manufacture of a pharmacopoeia for enhancing the immune response of a target.

[0317] In another aspect, the present invention provides a method for enhancing the immune response of a subject, comprising administering a combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture to the subject.

[0318] In another aspect, the present invention provides a method for enhancing the immune response of a subject, comprising administering a combination of L-arginine, L-citrulline, a vitamin mixture, a mineral mixture, and an antioxidant mixture to the subject.

[0319] In another aspect, the present invention provides nutritional compositions, supplements, or nutritional fortifiers according to the present invention for use in enhancing the immune response of a target.

[0320] In another aspect, the present invention provides the use of a nutritional composition, supplement, or nutritional fortifier according to the present invention for the manufacture of a pharmaceutical product for enhancing the immune response of a target.

[0321] In another aspect, the present invention provides a method for enhancing the immune response of a subject, comprising administering a nutritional composition, supplement, or nutritional fortifier according to the present invention to the subject.

[0322] The primary role of the immune system is to protect individuals from pathogenic organisms such as bacteria, viruses, fungi, and parasites. To provide effective defense against a diverse range of threatening organisms, the human immune system has evolved to include many different cell types, numerous signaling molecules, and multiple functional responses. Nutrition is one of several factors that govern the immune response, and good nutrition is crucial for maintaining it (see, for example, Calder, PC, 2021. Nutrition & Diabetes, 11(1), p.19).

[0323] The target immune response can be enhanced by increasing the activity of macrophages against pathogens, such as bacteria (e.g., Mycobacterium tuberculosis). NO plays a crucial role in host defense against intracellular pathogens. Many invading organisms impair the function of host macrophages by inhibiting host NOS activity and reducing NO production. Therefore, a decrease in host NO production creates a more sustainable niche for host infections. Thus, it is hypothesized that administering NO donors to TB patients can compensate for the deficiency of endogenous NO caused by impaired macrophages (see, for example, Jamaati, H., et al., 2017. Frontiers in microbiology, 8, p. 2008).

[0324] Methods for treating, preventing, and / or reducing the incidence of infectious diseases The formulations, combinations, and compositions of the present invention may be used for the treatment, prevention, and / or reduction of the incidence of infections in a subject. The formulations, combinations, and compositions of the present invention may reduce the amount of pharmaceuticals (e.g., antimicrobial agents) required to treat infections.

[0325] As used herein, “to treat” an infection means that the subject has an infection, and the formulation, combination, or composition reduces, lessens, or improves at least one symptom associated with the infection, and / or delays, reduces, or eliminates the infection.

[0326] As used herein, “preventing” an infection means that the subject is not yet infected with an infection and / or does not exhibit any symptoms of an infection, and that the formulation, combination, or composition prevents an infection and / or prevents at least one symptom associated with an infection.

[0327] As used herein, “reducing the occurrence” of an infection means that the formulation, combination, and composition reduces the likelihood of an infection and / or at least one symptom associated with an infection.

[0328] As used herein, “prevent” an infection and “reduce the occurrence” an infection may also mean that the subject has a latent form of tuberculosis and that the prevention and / or reduction of at least one symptom of tuberculosis infection.

[0329] In one embodiment, the present invention provides L-citrulline for use in the treatment, prevention, and / or reduction of the incidence of infectious diseases in a subject.

[0330] In one embodiment, the present invention provides L-citrulline for reducing the intracellular load of Mtb in macrophages.

[0331] In one embodiment, the present invention provides L-arginine for reducing the intracellular load of Mtb in macrophages.

[0332] In another aspect, the present invention provides the use of L-citrulline for the manufacture of a medicament for treating, preventing, and / or reducing the incidence of an infectious disease in a subject.

[0333] In another aspect, the present invention provides a method for treating, preventing, and / or reducing the incidence of an infection in a subject, comprising administering L-citrulline to the subject.

[0334] In another aspect, the present invention provides a combination of L-arginine and L-citrulline for use in treating, preventing, and / or reducing the incidence of infectious diseases in a subject.

[0335] In another aspect, the present invention provides the use of a combination of L-arginine and L-citrulline for the manufacture of a pharmacopoeia for treating, preventing, and / or reducing the incidence of an infectious disease in a subject.

[0336] In another aspect, the present invention provides a method for treating, preventing, and / or reducing the incidence of an infection in a subject, comprising administering a combination of L-arginine and L-citrulline to the subject.

[0337] In another aspect, the present invention provides a combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture for use in treating, preventing, and / or reducing the incidence of infectious diseases in a subject.

[0338] In another aspect, the present invention provides the use of a combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture for the manufacture of a pharmacopoeia for treating, preventing, and / or reducing the incidence of infectious diseases in a subject.

[0339] In another aspect, the present invention provides a method for treating, preventing, and / or reducing the occurrence of an infectious disease in a subject, comprising administering a combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture to the subject.

[0340] In another aspect, the present invention provides nutritional compositions, supplements, or nutritional fortifiers according to the present invention for use in treating, preventing, and / or reducing the incidence of infectious diseases in a subject.

[0341] In another aspect, the present invention provides the use of a nutritional composition, supplement, or nutritional fortifier according to the present invention for the manufacture of a pharmaceutical product for treating, preventing, and / or reducing the incidence of an infectious disease in a subject.

[0342] In another aspect, the present invention provides a method for treating, preventing, and / or reducing the incidence of an infectious disease in a subject, comprising administering a nutritional composition, supplement, or nutritional fortifier according to the present invention to the subject.

[0343] As used herein, “infection” refers to the invasion of the body tissue in question by any pathogen, including viruses, bacteria, fungi, parasites, and arthropods. Preferably, the infection is a bacterial infection or a viral infection.

[0344] Infections can be respiratory infections. "Respiratory tract infections" can refer to infections of parts of the body involved in respiration, such as the sinuses, throat, airways, or lungs. Respiratory infections can be upper respiratory tract infections (URTIs) and / or lower respiratory tract infections (LRTIs). URTIs may be characterized by the following clinical symptoms: nasal symptoms (runny nose, nasal congestion, snorrhea, yellow discharge, bloody discharge, sneezing); and / or pharyngeal symptoms (itchy throat, sore throat, hoarseness); accompanied by fever (greater than 38°C) and / or otitis media. LRTIs may be characterized by the following clinical symptoms: pneumonia (an episode of pneumonia may be defined as an illness reported as cough or dyspnea); and / or bronchial symptoms (cough and / or discharge and / or yellow discharge).

[0345] In a preferred embodiment, the infection is tuberculosis (TB). In another preferred embodiment, the infection is pulmonary TB.

[0346] The formulations, combinations, and compositions of the present invention may reduce or prevent one or more symptoms and / or signs of an infection in a subject. The signs and symptoms of an infection may vary depending on the type of infection. Some signs of an infection affect the entire body broadly, such as fatigue, loss of appetite, weight loss, fever, nocturnal sweating, chills, pain, and aches. Other signs are specific to individual body parts, such as skin rash, cough, or runny nose. For example, symptoms of an infection may include (i) a positive sputum culture, (ii) cough, (iii) chest pain, (iv) fever, (v) nocturnal sweating, (vi) hemoptysis, (vii) dyspnea, and (viii) GI symptoms of diarrhea or constipation.

[0347] The formulations, combinations, and compositions of the present invention can reduce or prevent one or more symptoms and / or signs of TB in a subject. For example, the formulations, combinations, and compositions of the present invention can reduce the TB score in a subject. The TB score may consist of five symptoms (cough, hemoptysis, dyspnea, chest pain, and nocturnal sweating) and six signs (pallor of the lower conjunctiva, pulse rate greater than 90 beats / min, positive findings on lung auscultation, body temperature greater than 37°C [axillary], body mass index [BMI] less than 18 / less than 16, and middle upper arm circumference [MUAC] less than 220 mm / <200 mm) (see Rudolf, F., 2014. Health Action, 7(1), p. 24303).

[0348] The formulations, combinations, and compositions of the present invention can alleviate or prevent one, two, three, four, five, six, or seven or more symptoms of an infection (e.g., TB) in a subject. In some embodiments, the symptoms of the infection (e.g., TB) include (i) a positive sputum culture, (ii) cough, (iii) chest pain, (iv) fever, (v) nocturnal sweating, (vi) hemoptysis, (vii) dyspnea, and (viii) GI symptoms of diarrhea or constipation.

[0349] In some embodiments, the formulations, combinations, and compositions of the present invention can reduce sputum culture positivity in subjects. Methods for processing sputum cultures are known in the art (see, for example, Steingart, KR, et al., 2006. The Lancet Infectious Diseases, 6(10), pp. 664-674).

[0350] In some embodiments, the formulations, combinations, and compositions of the present invention can reduce coughing in subjects.

[0351] In some embodiments, the formulations, combinations, and compositions of the present invention can reduce chest pain in subjects.

[0352] In some embodiments, the formulations, combinations, and compositions of the present invention can reduce fever in the subject.

[0353] In some embodiments, the formulations, combinations, and compositions of the present invention can reduce nocturnal sweating in subjects.

[0354] In some embodiments, the formulations, combinations, and compositions of the present invention can reduce hemoptysis in subjects. Hemoptysis is the coughing up of blood originating from the airways below the larynx.

[0355] In some embodiments, the formulations, combinations, and compositions of the present invention can reduce respiratory distress in subjects. Respiratory distress is commonly referred to as shortness of breath.

[0356] In some embodiments, the formulations, combinations, and compositions of the present invention can reduce GI symptoms of diarrhea or constipation in subjects.

[0357] Methods to promote wound healing The formulations, combinations, and compositions of the present invention may be used to promote wound healing.

[0358] Wound healing is a normal biological process in the human body, achieved through four strictly controlled stages: hemostasis, inflammation, proliferation, and remodeling (see, for example, Guo, SA and DiPhytro, LA, 2010. Journal of Dental Research, 89(3), pp. 219-229). Methods for evaluating the rate of wound healing are publicly known in the art (see, for example, Barber, S., 2008. Ostomy Wound and Management, 54(3), p. 42).

[0359] The role of dietary intervention in the form of arginine supplementation has been proposed to normalize or promote wound healing in humans (see, for example, Stechmiller, JK, et al., 2005. Nutrition in Clinical Practice, 20(1), pp. 52-61).

[0360] In one embodiment, the present invention provides a combination of L-arginine and L-citrulline for use in promoting wound healing.

[0361] In another aspect, the present invention provides the use of a combination of L-arginine and L-citrulline for the manufacture of a pharmacopoeia for promoting wound healing.

[0362] In another aspect, the present invention provides a method for promoting wound healing, comprising administering a combination of L-arginine and L-citrulline to a subject in need thereof.

[0363] In one embodiment, the present invention provides a combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture for use in promoting wound healing.

[0364] In another aspect, the present invention provides the use of a combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture for the manufacture of a pharmacopoeia for promoting wound healing.

[0365] In another aspect, the present invention provides a method for promoting wound healing, comprising administering a combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture to a subject in need thereof.

[0366] In one embodiment, the present invention provides a nutritional composition, supplement, or nutritional fortifier for use in promoting wound healing.

[0367] In another aspect, the present invention provides the use of a nutritional composition, supplement, or nutritional fortifier according to the present invention for the manufacture of a medicine for promoting wound healing.

[0368] In one embodiment, the present invention provides a method for promoting wound healing, comprising administering a nutritional composition, supplement, or nutritional fortifier according to the present invention to a subject in need thereof.

[0369] Methods for treating and / or preventing chronic obstructive pulmonary disease (COPD) The formulations, combinations, and compositions of the present invention may be used for the treatment and / or prevention of chronic obstructive pulmonary disease (COPD).

[0370] Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. Methods for diagnosing and monitoring COPD are well known in the art (see, for example, Johns, DP, et al., 2014. Journal of thoracic disease, 6(11), p. 1557).

[0371] NO production in the lungs and airways can play diverse roles in lung development, regulating airway and vascular smooth muscle tone, and participating in inflammatory processes and host defense (see, for example, Scott, JA, et al., 2021. Frontiers in Pharmacology, 12, p. 627503).

[0372] In one embodiment, the present invention provides a combination of L-arginine and L-citrulline for use in the treatment and / or prevention of COPD.

[0373] In another aspect, the present invention provides the use of a combination of L-arginine and L-citrulline for the manufacture of a medicament for the treatment and / or prevention of COPD.

[0374] In another aspect, the present invention provides a method for treating or preventing COPD, comprising administering a combination of L-arginine and L-citrulline to a subject in need thereof.

[0375] In one embodiment, the present invention provides a combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture for use in the treatment and / or prevention of COPD.

[0376] In another aspect, the present invention provides the use of a combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture for the manufacture of a pharmacopoeia for the treatment and / or prevention of COPD.

[0377] In another aspect, the present invention provides a method for treating and / or preventing COPD, comprising administering a combination of L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture to a subject in need thereof.

[0378] In one embodiment, the present invention provides a nutritional composition, supplement, or nutritional fortifier for use in the treatment and / or prevention of COPD.

[0379] In another aspect, the present invention provides the use of a nutritional composition, supplement, or nutritional fortifier according to the present invention for the manufacture of a medicament for the treatment and / or prevention of COPD.

[0380] In one embodiment, the present invention provides a method for treating and / or preventing COPD, comprising administering a nutritional composition, supplement, or nutritional fortifier according to the present invention to a person in need thereof.

[0381] Manufacturing method In one embodiment, the present invention provides a method for producing a nutritional composition, supplement, or nutritional fortifier according to the present invention.

[0382] The method of the present invention may include (i) preparing a base nutritional composition, supplement, or nutritional fortifier, and (ii) adding L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture to the base nutritional composition, supplement, or nutritional fortifier to provide a nutritional composition, supplement, or nutritional fortifier according to the present invention.

[0383] The nutritional composition, supplement, or nutritional fortifier of the present invention can be prepared by any suitable method known in the art.

[0384] For example, nutritional compositions, supplements, or nutritional fortifiers can be prepared by blending a protein source, a carbohydrate source, and optionally a fat source in appropriate proportions. Emulsifiers, if used, can be included at this stage. Vitamins and minerals may be added at this stage, but can also be added later to avoid thermal decomposition. Any lipophilic vitamins and emulsifiers, etc., can be dissolved in the fat source before blending. Water, preferably reverse-osmotic water, can then be mixed to form a liquid mixture. A commercially available liquefaction device can also be used to form the liquid mixture.

[0385] In particular, if the final product is in liquid form, L-arginine and L-citrulline may be added at this stage. If the final product is in powder form, they may also be added at this stage if desired. Alternatively, L-arginine and L-citrulline may be added later to avoid thermal decomposition.

[0386] The liquid mixture may then be homogenized, for example, in two steps.

[0387] The liquid mixture can then be subjected to a heat treatment to reduce bacterial load, for example, by rapidly heating the liquid mixture to a temperature in the range of approximately 80°C to 150°C for approximately 5 seconds to approximately 5 minutes. This heating can be carried out by steam injection, by autoclave, or by heat exchanger, such as a plate heat exchanger.

[0388] Next, the liquid mixture can be cooled to approximately 60°C to 85°C, for example, by flash cooling. Then, the liquid mixture may be homogenized again, for example, in two stages: in the first stage to approximately 10 MPa to 30 MPa, and in the second stage to approximately 2 MPa to 10 MPa. The homogenized mixture may then be further cooled, and any heat-sensitive components, such as vitamins and minerals, may be added. The pH and solids content of the homogenized mixture are usually adjusted at this point.

[0389] If a liquid composition is preferred, the homogenized mixture may be sterilized and then aseptically filled into a suitable container, or it may be filled into a container first and then retort sterilized.

[0390] When the final product is to be in powder form, the homogenized mixture may be transferred to a suitable drying apparatus, such as a spray dryer or freeze dryer, to convert it into a powder. The moisture content of the powder may be less than approximately 5% by weight. At this stage, L-arginine, L-citrulline, vitamins, and minerals may be added or substituted by dry mixing or blending. [Examples]

[0391] The present invention will now be further illustrated by examples. These examples are provided to assist those skilled in the art in carrying out the present invention and are not intended in any way to limit the scope of the invention.

[0392] Example 1 - Exemplary nutritional composition An example of a powdered nutritional composition according to the present invention is shown below. The exemplary powdered nutritional composition can be reconstituted with water for dietary management of TB.

[0393] [Table 1]

[0394] Example 2 - Exemplary Nutritional Supplement An example of a powdered nutritional supplement according to the present invention is shown below. This exemplary powdered nutritional supplement can be sprinkled on food for dietary management of TB.

[0395] [Table 2]

[0396] Example 3 - Effects of L-arginine and L-citrulline on intracellular Mtb loading in macrophages One of the key stages in tuberculosis (TB) infection is the uptake of foreign MtB by macrophages, particularly those in lung tissue. This uptake occurs because macrophages recognize the bacteria through their surface proteins and glycolipids, and the uptaken MtB can survive for extended periods.

[0397] Mycobacterium tuberculosis (Mtb) has developed mechanisms to evade host defense responses and survive for extended periods within host cells, such as macrophages.

[0398] Therefore, the inventors investigated the effects of L-arginine and L-citrulline treatment on intracellular Mtb proliferation in THP-1 macrophages in vitro and compared it with the untreated area to confirm whether there may be a direct effect on macrophages.

[0399] THP-1 cells were differentiated into macrophages, and 200,000 cells per well were seeded into a 24-well plate in arginine-free DMEM medium supplemented with 10% FBS.

[0400] L-arginine or L-citrulline was added to macrophages at one of the following points: 24 hours before Mtb infection, simultaneously with infection, or 24 hours after infection. The MOI (multiplicity of infection) was set to 1.0. Uninfected and untreated cells were included as a control group.

[0401] Infection was allowed for up to 96 hours. Samples were taken every 24 hours from T=0 to 96 hours. Samples included cell-free supernatant, whole cells, and cell lysates.

[0402] The inventors administered L-arginine at doses of 100 μM and 1000 μM and tracked its effects up to 120 hours after infection with Mtb. The inventors observed a significant reduction in Mtb load in macrophages in the arginine-treated group compared to the untreated group.

[0403] The inventors administered L-citrulline at doses of 100 μM and 1000 μM and tracked its effects up to 120 hours after infection by Mtb. The inventors observed a significant reduction in Mtb load in macrophages in the citrulline-treated group compared to the untreated group.

[0404] As shown in Figures 2A and 2B, the inventors were able to demonstrate that the compounds of the present invention help reduce MTb load in macrophages. This represents an important step in the management of tuberculosis by preventing infection and / or reducing the incidence of infection and by reducing the occurrence or recurrence of one or more symptoms of TB infection.

[0405] Embodiment Various preferred features and embodiments of the present invention are described below with reference to the numbered paragraphs.

[0406] Paragraph 1. A nutritional composition, supplement, or nutritional fortifier comprising L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture.

[0407] Paragraph 2. The nutritional composition, supplement, or fortifier according to Paragraph 1, wherein the L-arginine is present in such an amount that the nutritional composition, supplement, or fortifier provides an L-arginine dose of approximately 0.5 g / day or more.

[0408] Paragraph 3. The nutritional composition, supplement, or fortifier according to Paragraph 1 or 2, wherein the L-citrulline is present in an amount such that the nutritional composition, supplement, or fortifier provides an L-citrulline dose of approximately 0.5 g / day or more.

[0409] Paragraph 4. A nutritional composition, supplement, or nutritional fortifier according to any of Paragraphs 1 to 3, wherein the L-arginine and L-citrulline are present in a weight ratio of approximately 0.1:1 to approximately 10:1, approximately 0.2:1 to approximately 5:1, approximately 0.25:1 to approximately 4:1, approximately 0.3:1 to approximately 3:1, approximately 0.5:1 to approximately 2:1, or approximately 1:1.

[0410] Paragraph 5. A nutritional composition, supplement, or nutritional fortifier according to any one of Paragraphs 1 to 4, wherein the vitamin mixture contains one or more of the following: vitamin A, vitamin D2, vitamin E, vitamin C, vitamin B1, vitamin B2, niacin, vitamin B6, folic acid, and vitamin B12.

[0411] Paragraph 6. A nutritional composition, supplement, or nutritional fortifier according to any one of Paragraphs 1 to 5, wherein the vitamin mixture comprises vitamin A, vitamin D2, vitamin E, vitamin C, vitamin B1, vitamin B2, niacin, vitamin B6, folic acid, and vitamin B12.

[0412] Paragraph 7. A nutritional composition, supplement, or fortifier according to any one of Paragraphs 1 to 6, wherein each of vitamins A, D2, E, C, B1, B2, niacin, B6, folic acid, and B12 is present in an amount such that the nutritional composition, supplement, or fortifier provides each of the vitamins at a dose of approximately 50% RDA / day or more.

[0413] Paragraph 8. A nutritional composition, supplement, or nutritional fortifier according to any one of Paragraphs 1 to 7, wherein the mineral mixture comprises one or more of potassium, magnesium, iron, zinc, and selenium.

[0414] Paragraph 9. A nutritional composition, supplement, or fortifier according to any of Paragraphs 1 to 8, wherein the mineral mixture comprises potassium, magnesium, iron, zinc, and selenium.

[0415] Paragraph 10. The nutritional composition, supplement, or fortifier according to Paragraph 9, wherein each of potassium, magnesium, iron, zinc, and selenium is present in such an amount that the nutritional composition, supplement, or fortifier provides each of the minerals at a dose of approximately 15% RDA / day or more.

[0416] Paragraph 11. The nutritional composition, supplement, or fortifier according to Paragraph 9 or 10, wherein each of iron, zinc, and selenium is present in such an amount that the nutritional composition, supplement, or fortifier provides each of the minerals at a dose of approximately 30% RDA / day or more.

[0417] Paragraph 12. The nutritional composition, supplement, or nutritional fortifier according to any one of paragraphs 1 to 11, wherein the nutritional composition, supplement, or nutritional fortifier further comprises carbohydrates and / or proteins.

[0418] Paragraph 13. The nutritional composition, supplement, or nutritional fortifier according to any one of paragraphs 1 to 12, wherein the nutritional composition, supplement, or nutritional fortifier is in the form of a powder.

[0419] Paragraph 14. The nutritional composition, supplement, or nutritional fortifier described in any of Paragraphs 1 to 13, wherein the nutritional composition, supplement, or nutritional fortifier is a food for special dietary uses.

[0420] Paragraph 15. The nutritional composition, supplement, or nutritional fortifier described in Paragraph 14, wherein the special-use food is provided in powder form for reconstitution with water or milk.

[0421] Paragraph 16. The nutritional composition, supplement, or nutritional fortifier described in Paragraph 14 or 15, wherein the food for special dietary uses is nutritionally complete.

[0422] Paragraph 17. A nutritional composition, supplement, or nutritional fortifier according to any of paragraphs 14-16, wherein the special-use food contains L-arginine in an amount of approximately 1 g / serving or more.

[0423] Paragraph 18. The nutritional composition, supplement, or nutritional fortifier described in any of Paragraphs 14 to 17, wherein the special-use food contains L-citrulline in an amount of 1 g / serving or more.

[0424] Paragraph 19. The nutritional composition, supplement, or nutritional fortifier according to any of paragraphs 14 to 18, wherein the special dietary food comprises (a) L-arginine in an amount of about 1 g / serving or more, and (b) L-citrulline in an amount of about 1 g / serving or more.

[0425] Paragraph 20. A nutritional composition, supplement, or nutritional fortifier according to any of paragraphs 14 to 19, wherein the special dietary food comprises (a) vitamin A in an amount of about 300 μg RE / serving or more, (b) vitamin D2 in an amount of about 5 μg / serving or more, (c) vitamin E in an amount of about 3 mg TE / serving or more, (d) vitamin C in an amount of about 25 mg / serving or more, (e) vitamin B1 in an amount of about 0.5 mg / serving or more, (f) vitamin B2 in an amount of about 0.7 mg / serving or more, (g) niacin in an amount of about 5 mg / serving or more, (h) vitamin B6 in an amount of about 0.6 mg / serving or more, (i) folic acid in an amount of about 60 μg / serving or more, and (j) vitamin B12 in an amount of about 0.7 μg / serving or more.

[0426] Paragraph 21. A nutritional composition, supplement, or nutritional fortifier according to any one of paragraphs 14 to 20, wherein the special dietary food comprises (a) potassium in an amount of about 250 mg / serving or more, (b) magnesium in an amount of about 30 mg / serving or more, (c) iron in an amount of about 4 mg / serving or more, (d) zinc in an amount of about 2 mg / serving or more, and (e) selenium in an amount of about 6 μg / serving or more.

[0427] Paragraph 22. A nutritional composition, supplement, or fortifier according to any of paragraphs 14 to 21, wherein the special dietary food comprises (a) protein in an amount of about 8 g / serving to about 14 g / serving, about 10 g / serving to about 12 g / serving, or about 11 g / serving; (b) fat in an amount of about 5 g / serving to about 10 g / serving, about 6 g / serving to about 9 g / serving, or about 7.5 g / serving; and (c) carbohydrate in an amount of about 20 g / serving to about 35 g / serving, about 25 g / serving to about 30 g / serving, or about 27 g / serving.

[0428] Paragraph 23. A nutritional composition, supplement, or nutritional fortifier according to any of paragraphs 14-22, wherein the special-use food contains approximately 100-300 kcal / serving, approximately 150-250 kcal / serving, or approximately 200 kcal / serving.

[0429] Paragraph 24. The nutritional composition, supplement, or nutritional fortifier according to any one of paragraphs 1 to 13, wherein the nutritional composition, supplement, or nutritional fortifier is a nutritional supplement.

[0430] Paragraph 25. The nutritional composition or supplement according to Paragraph 24, wherein the nutritional supplement is a powder supplement for sprinkling on food or beverages.

[0431] Paragraph 26. The nutritional composition, supplement, or nutritional fortifier according to Paragraph 24 or 25, wherein the nutritional supplement contains an amount of L-arginine of approximately 0.5 g / serving or more.

[0432] Paragraph 27. A nutritional composition, supplement, or nutritional fortifier according to any of paragraphs 24-26, wherein the nutritional supplement contains an amount of L-citrulline of approximately 0.5 g / serving or more.

[0433] Paragraph 28. A nutritional composition, supplement, or nutritional fortifier according to any of paragraphs 24 to 27, wherein the nutritional supplement comprises (a) an amount of L-arginine of about 0.5 g / serving or more, and (b) an amount of L-citrulline of about 0.5 g / serving or more.

[0434] Paragraph 29. A nutritional composition, supplement, or nutritional fortifier according to any of paragraphs 24 to 28, wherein the nutritional supplement comprises (a) vitamin A in an amount of about 200 μg RE / serving or more, (b) vitamin D2 in an amount of about 3 μg / serving or more, (c) vitamin E in an amount of about 2 mg TE / serving or more, (d) vitamin C in an amount of about 16 mg / serving or more, (e) vitamin B1 in an amount of about 0.3 mg / serving or more, (f) vitamin B2 in an amount of about 0.4 mg / serving or more, (g) niacin in an amount of about 3 mg / serving or more, (h) vitamin B6 in an amount of about 0.4 mg / serving or more, (i) folic acid in an amount of about 36 μg / serving or more, and (j) vitamin B12 in an amount of about 0.4 μg / serving or more.

[0435] Paragraph 30. A nutritional composition, supplement, or nutritional fortifier according to any of Paragraphs 23-29, wherein the nutritional supplement comprises (a) potassium in an amount of approximately 250 mg / serving or more, (b) magnesium in an amount of approximately 33 mg / serving or more, (c) iron in an amount of approximately 5 mg / serving or more, (d) zinc in an amount of approximately 3 mg / serving or more, and (e) selenium in an amount of approximately 5 μg / serving or more.

[0436] Paragraph 31. The nutritional composition, supplement, or fortifier according to any one of paragraphs 1 to 30, wherein the nutritional composition, supplement, or fortifier is for the dietary management of a person having an infectious disease and / or immunodeficiency, and preferably, the nutritional composition, supplement, or fortifier is for the dietary management of a person having tuberculosis (TB).

[0437] Paragraph 32. A nutritional composition, supplement, or fortifier described in any of Paragraphs 1-30, for use in enhancing the immune response.

[0438] Paragraph 33. A nutritional composition, supplement, or fortifier according to any of Paragraphs 1 to 30, for use in the treatment, prevention, and / or reduction of the risk of an infectious disease, preferably the infectious disease being tuberculosis (TB), and more preferably the infectious disease being pulmonary TB.

[0439] Paragraph 34. A nutritional composition, supplement, or fortifier described in any of Paragraphs 1-30, for use as an adjunct therapy in combination with an antimicrobial agent.

[0440] Paragraph 35. A nutritional composition, supplement, or fortifier described in any of Paragraphs 1 to 30, for use in treating, preventing, and / or reducing the risk of developing one or more symptoms of an infectious disease, wherein the symptoms of the infectious disease are selected from (i) a positive sputum culture, (ii) cough, (iii) chest pain, (iv) fever, (v) nocturnal sweating, (vi) hemoptysis, and (vii) dyspnea, and (viii) GI symptoms of diarrhea or constipation.

[0441] Paragraph 36. A nutritional composition, supplement, or fortifier described in any of Paragraphs 1-30, for use in promoting wound healing.

[0442] Paragraph 37. A nutritional composition, supplement, or fortifier described in any of paragraphs 1-30, for use in the treatment or prevention of chronic obstructive pulmonary disease (COPD).

[0443] Paragraph 38. A method for enhancing the immune response of a subject, comprising administering to the subject a nutritional composition, supplement, or nutritional fortifier described in any of Paragraphs 1 to 30.

[0444] Paragraph 39. A method for treating, preventing, and / or reducing the risk of an infection in a subject, comprising administering to the subject a nutritional composition, supplement, or nutritional fortifier described in any of Paragraphs 1 to 30, preferably wherein the infection is tuberculosis (TB).

[0445] Paragraph 40. A method for treating, preventing, and / or reducing the risk of the occurrence or recurrence of one or more symptoms of an infection in a subject, comprising administering to the subject a nutritional composition, supplement, or nutritional fortifier described in any of Paragraphs 1 to 30, wherein the symptoms of the infection are selected from (i) a positive sputum culture, (ii) cough, (iii) chest pain, (iv) fever, (v) nocturnal sweating, (vi) hemoptysis, (vii) dyspnea, and (viii) GI symptoms of diarrhea or constipation.

[0446] Paragraph 41. A method for promoting wound healing in a subject, comprising administering to the subject a nutritional composition, supplement, or nutritional fortifier described in any of Paragraphs 1 to 30.

[0447] Paragraph 42. A method for treating or preventing chronic obstructive pulmonary disease (COPD) in a subject, comprising administering to the subject a nutritional composition, supplement, or nutritional fortifier described in any of Paragraphs 1 to 30.

[0448] Paragraph 43. L-citrulline for use in the treatment, prevention, and / or reduction of the risk thereof of tuberculosis (TB) in subjects.

[0449] Paragraph 44. L-citrulline for use as described in Paragraph 43, wherein the L-citrulline is administered orally to the subject.

[0450] Paragraph 45. L-citrulline for use as described in Paragraph 43 or 44, wherein the L-citrulline is administered to the subject in an amount of approximately 0.5 g / day or more.

[0451] Paragraph 46. The L-citrulline is administered to the subject in the form of a nutritional composition, supplement, or nutritional fortifier, wherein the nutritional composition, supplement, or nutritional fortifier is optionally defined according to any of paragraphs 1 to 30, and the L-citrulline is for use according to any of paragraphs 43 to 45.

[0452] Paragraph 47. L-citrulline for use as described in any of paragraphs 43-46, wherein the L-citrulline is administered in combination with L-arginine.

[0453] Paragraph 48. L-citrulline for use as described in Paragraph 47, wherein L-citrulline and L-arginine are administered simultaneously.

[0454] Paragraph 49. L-citrulline for use as described in Paragraph 47 or 48, wherein the L-arginine is administered in an amount of approximately 0.5 g / day or more.

[0455] Paragraph 50. L-citrulline for use as described in any of paragraphs 43-49, wherein the subject is an adult human.

[0456] Paragraph 51. L-citrulline for use as described in any of paragraphs 43 to 50, wherein the L-citrulline is administered to the subject as an adjunct therapeutic agent, and the primary therapeutic agent is an antimicrobial agent.

[0457] Paragraph 52. L-citrulline for use as described in any of paragraphs 43 to 51, wherein one or more symptoms of an infectious disease are reduced or prevented in the subject, and the symptoms of the infectious disease are selected from (i) positive sputum culture, (ii) cough, (iii) chest pain, (iv) fever, (v) nocturnal sweating, (vi) hemoptysis, (vii) dyspnea, and (viii) GI symptoms of diarrhea or constipation.

[0458] Paragraph 53. A method for treating tuberculosis (TB) in a subject or reducing the risk thereof, comprising administering a therapeutically effective dose of L-citrulline to the subject.

[0459] Paragraph 54. A method for reducing the occurrence of one or more symptoms of an infection in a subject having tuberculosis (TB), comprising administering a therapeutically effective amount of L-citrulline to the subject, wherein the symptoms of the infection are selected from (i) a positive sputum culture, (ii) cough, (iii) chest pain, (iv) fever, (v) nocturnal sweating, (vi) hemoptysis, (vii) dyspnea, and GI symptoms of diarrhea or constipation.

[0460] Paragraph 55. A combination of L-arginine and L-citrulline for use in enhancing the immune response of the target.

[0461] Paragraph 56. A combination of L-arginine and L-citrulline for use in the treatment, prevention, and / or reduction of the risk of infection in the subject.

[0462] Paragraph 57. The combination for use described in Paragraph 56, wherein the infectious disease is tuberculosis (TB).

[0463] Paragraph 58. A combination of uses as described in any of paragraphs 55-57, wherein the symptoms of one or more infections are reduced or prevented in the subject, and the symptoms of the infections are selected from (i) positive sputum culture, (ii) cough, (iii) chest pain, (iv) fever, (v) nocturnal sweating, (vi) hemoptysis, (vii) dyspnea, and (viii) GI symptoms of diarrhea or constipation.

[0464] Paragraph 59. A combination of L-arginine and L-citrulline for use in promoting wound healing in the subject.

[0465] Paragraph 60. A combination of L-arginine and L-citrulline for use in the treatment and / or prevention of chronic obstructive pulmonary disease (COPD) in the subject.

[0466] Paragraph 61. The combination for use described in any of paragraphs 55-60, wherein the L-citrulline is administered to the subject in an amount of approximately 0.5 g / day or more, and / or the L-arginine is administered to the subject in an amount of approximately 0.5 g / day or more.

[0467] Paragraph 62. The combination for use described in any of paragraphs 55 to 61, wherein the L-citrulline and L-arginine are administered simultaneously to the subject.

[0468] Paragraph 63. The combination for use described in any of paragraphs 55-62, wherein the combination is administered orally.

[0469] Paragraph 64. The combination described above is administered to the subject in the form of a nutritional composition, supplement, or nutritional fortifier, and optionally, the combination for use described above is defined according to any of paragraphs 55 to 63, wherein the nutritional composition, supplement, or nutritional fortifier is defined according to any of paragraphs 1 to 30.

[0470] Paragraph 65. A combination of uses described in any of paragraphs 55-64, wherein the subject is an adult human.

[0471] Paragraph 66. The combination of uses described in any of paragraphs 55-65, wherein the subject has immunodeficiency or is at risk of immunodeficiency.

[0472] Paragraph 67. The combination for use described in any of paragraphs 55 to 77, wherein the combination is administered to the subject as an adjunct therapy, and the primary therapy is an antimicrobial agent.

[0473] Paragraph 68. A method for enhancing the immune response of a subject, comprising administering to the subject an effective amount of a combination of L-arginine and L-citrulline.

[0474] Paragraph 69. A method for treating an infection in a subject or reducing the risk thereof, comprising administering to the subject an effective amount of a combination of L-arginine and L-citrulline.

[0475] Paragraph 70. The method according to Paragraph 69, wherein the infectious disease is tuberculosis (TB).

[0476] Paragraph 71. A method for reducing the occurrence of one or more symptoms of an infection in a subject, comprising administering to the subject an effective amount of a combination of L-arginine and L-citrulline, wherein the symptoms of the infection are selected from (i) a positive sputum culture, (ii) cough, (iii) chest pain, (iv) fever, (v) nocturnal sweating, (vi) hemoptysis, and (vii) dyspnea, and (viii) GI symptoms of diarrhea or constipation.

[0477] Paragraph 72. A method for promoting wound healing in a subject, comprising administering to the subject an effective amount of a combination of L-arginine and L-citrulline.

[0478] Paragraph 73. A method for treating and / or preventing chronic obstructive pulmonary disease (COPD) in a subject, comprising administering an effective amount of a combination of L-arginine and L-citrulline to the subject.

Claims

1. A nutritional composition, supplement, or nutritional fortifier comprising L-arginine, L-citrulline, a vitamin mixture, and a mineral mixture.

2. The nutritional composition, supplement, or nutritional fortifier according to claim 1, wherein the L-arginine is present in an amount such that the nutritional composition, supplement, or nutritional fortifier provides an amount of L-arginine of about 0.5 g / day or more and an amount of L-citrulline of about 0.5 g / day or more.

3. The nutritional composition, supplement, or nutritional fortifier according to claim 1 or 2, wherein the L-arginine and L-citrulline are present in a weight ratio of approximately 0.1:1 to approximately 10:1, approximately 0.2:1 to approximately 5:1, approximately 0.25:1 to approximately 4:1, approximately 0.3:1 to approximately 3:1, approximately 0.5:1 to approximately 2:1, or approximately 1:

1.

4. The nutritional composition, supplement, or fortifier according to any one of claims 1 to 3, wherein the vitamin mixture comprises vitamin A, vitamin D2, vitamin E, vitamin C, vitamin B1, vitamin B2, niacin, vitamin B6, folic acid, and vitamin B12, and optionally each of vitamin A, vitamin D2, vitamin E, vitamin C, vitamin B1, vitamin B2, niacin, vitamin B6, folic acid, and vitamin B12 is present in an amount such that the nutritional composition, supplement, or fortifier provides each of the vitamins at a dose of approximately 50% RDA / day or more.

5. The nutritional composition, supplement, or fortifier according to any one of claims 1 to 4, wherein the mineral mixture comprises potassium, magnesium, iron, zinc, and selenium, and optionally each of potassium, magnesium, iron, zinc, and selenium is present in such an amount that the nutritional composition, supplement, or fortifier provides each of the minerals at a dose of approximately 15% RDA / day or more.

6. The nutritional composition, supplement, or fortifier according to any one of claims 1 to 6, wherein the nutritional composition, supplement, or fortifier is a food for special dietary uses, and optionally, the food for special dietary uses is provided in the form of a powder for reconstitution with water or milk, and / or the food for special dietary uses is nutritionally complete.

7. The nutritional composition, supplement, or nutritional fortifier according to any one of claims 1 to 6, wherein the nutritional composition, supplement, or nutritional fortifier is a nutritional supplement, and optionally, the nutritional supplement is a powder supplement for sprinkling on food or beverages.

8. The nutritional composition, supplement, or fortifier according to any one of claims 1 to 7, wherein the nutritional composition, supplement, or fortifier is for the dietary management of a person having an infectious disease and / or immunodeficiency, and preferably, the nutritional composition, supplement, or fortifier is for the dietary management of a person having tuberculosis (TB).

9. A nutritional composition, supplement, or fortifier according to any one of paragraphs 1 to 8, for use in enhancing the immune response.

10. A nutritional composition, supplement, or nutritional fortifier according to any one of claims 1 to 8, for use in the treatment, prevention, and / or reduction of the risk of occurrence or recurrence of an infectious disease, preferably the infectious disease being tuberculosis (TB).

11. A nutritional composition, supplement, or nutritional fortifier according to any one of claims 1 to 8, for use as an adjunct therapy in combination with an antimicrobial agent.

12. For use in treating, preventing, and / or reducing the risk of developing one or more symptoms of an infectious disease, wherein the symptoms of the infectious disease are (i) a positive sputum culture, (ii) cough, (iii) chest pain, (iv) fever, (v) nocturnal sweating, (vi) hemoptysis, (vii) dyspnea, and (viiii) diarrhea or constipation (GI symptoms). A nutritional composition, supplement, or nutritional fortifier according to any one of claims 1 to 8, selected from the above.

13. L-citrulline for use in the treatment, prevention, and / or reduction of the risk of tuberculosis (TB) development or recurrence in the target population.

14. A combination of L-arginine and L-citrulline for use in enhancing the target immune response.

15. A combination of L-arginine and L-citrulline for use in the treatment, prevention, and / or reduction of the risk of occurrence or recurrence of an infection in a subject, wherein the infection is optionally tuberculosis (TB).

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